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WO2025097090A1 - Substituted (piperidin-4-yl)-1,5-naphthyridine and (piperidin-4-yl)quinoline derivatives and uses thereof - Google Patents

Substituted (piperidin-4-yl)-1,5-naphthyridine and (piperidin-4-yl)quinoline derivatives and uses thereof Download PDF

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Publication number
WO2025097090A1
WO2025097090A1 PCT/US2024/054315 US2024054315W WO2025097090A1 WO 2025097090 A1 WO2025097090 A1 WO 2025097090A1 US 2024054315 W US2024054315 W US 2024054315W WO 2025097090 A1 WO2025097090 A1 WO 2025097090A1
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alkyl
haloalkyl
carbocyclyl
independently
heteroatoms selected
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French (fr)
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Jennifer Rae GRIFFIN
Xiaoxi Liu
John E. Tellew
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Neomorph Inc
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Neomorph Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the HIE transcription factors are master regulators of the cellular response to hypoxia.
  • the HIE transcriptional regulator acts as a heterodimeric complex consisting of the constitutively expressed hypoxia inducible factor 1 beta (HIF-lb, also known as ARNT) and either of the two HIF-a isoforms, HIF-la or
  • HIF-2a HIF-lb is a key player in both the hypoxic-response pathway and the aryl hydrocarbon receptor (AHR) pathway.
  • AHR aryl hydrocarbon receptor
  • Oxygen supply to tissues is essential in maintaining mammalian cell function and physiology and a deficiency in oxygen supply to tissues is a characteristic of a number of conditions in which there is insufficient blood flow to provide adequate oxygenation.
  • diseases affected by inadequate oxygen supply include ischemic disorders, cancer, and atherosclerosis.
  • Activation of a signaling cascade occurs in response to this hypoxic environment in tissues which drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo- vascularization), glucose metabolism, and cell survival/death.
  • angiogenesis neo- vascularization
  • glucose metabolism and cell survival/death.
  • a key to this hypoxic transcriptional response lies in the transcription factors, the hypoxia inducible factors (HIF).
  • HIF hypoxia inducible factors
  • HIF-a proteins are then translocated to the nucleus, where they interact with HIF-lb to form a heterodimeric transcription factor (Kallio et al., Embo J, 1998, 17, 6573-65, 86).
  • the dimerization step has been shown in HIF-lb deficient cells to be an absolute requirement for the transcriptional activation of hypoxia response element genes (Wood et al., J. Biol. Chem., 1996, 271, 15117-15123).
  • hypoxia response element genes Wang et al., J. Biol. Chem., 1996, 271, 15117-15123.
  • oxygen transport genes such as erythropoietin (Semenza, et al., J. Biol.
  • HIF-2a/HIF-lb heterodimer protein which contains the core recognition sequence 5’-TACGTG-3’, binds to the hypoxic response element and is found in the cis- regulatory regions of hypoxia-regulated genes (Ema, et al., Proc. Natl. Acad. Sci.
  • a range of other genes regulated by the dioxin response element (DRE) can also be activated by HIF dimers resulting in some of the toxic and carcinogenic effects associated with many of the AHR ligands, such as immunotoxicity, developmental and reproductive toxicity, disruption of endocrine pathways, wasting syndrome, and tumor promotion (Safe Toxicol. Lett., 2001, 120, 1-7). It has been demonstrated that the AHR/HIF-lb heterodimer directly associates with the estrogen receptors ER-a and ER-b and that this association results in the recruitment of unliganded estrogen receptor and coactivator p300 to estrogen-responsive gene promoters. This association has been shown to lead the activation of transcription and estrogenic effects and to give rise to the adverse estrogen-related actions of dioxin-type environmental contaminants (Ohtake et al., Nature, 2003, 423, 545-550).
  • HIF-lb plays an important role in both the hypoxia-induced and AHR signaling pathways, which have been linked to various forms of malignancies (Harris, Nat. Rev. Cancer, 2002, 2, 8- 47; Safe Toxicol. Lett., 2001, 120 1-7)
  • the angiogenic promoting capabilities of HIF-lb also make it a potential therapeutic target for a variety of angiogenic disorders, such as arthritis, cardiovascular diseases, skin conditions, aberrant wound healing and ocular conditions (e.g., macular degeneration, diabetic retinopathy, diabetic macular edema and retinopathy of prematurity).
  • HIF-lb levels with small molecule modulators therefore has the potential to be a treatment for a range of diseases, including cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-related diseases.
  • VHL von Hippel-Lindau
  • PAH pulmonary arterial hypertension
  • autoimmune and inflammatory-related diseases and conditions neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-related diseases.
  • the compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary disorders (e.g., pulmonary arterial hypertension (PAH)), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other HIF-lb-related diseases.
  • VHL von Hippel-Lindau
  • PAH pulmonary arterial hypertension
  • the compounds of the disclosure have HIF-lb degrader activity.
  • the HIF-lb degrader activity is at or below the 50 pM level, and more preferably at or below the 10 pM level, when administered to a cell or subject.
  • VHL von Hippel-Lindau
  • PHA pulmonary arterial hypertension
  • autoimmune and inflammatory-related diseases and conditions neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other diseases for which such degrader activity would be beneficial.
  • X3 is N or CR4 a ;
  • X4 is N or CR4bi X5 is N or CR4b-;
  • Xe is N or CR5;
  • X? is N or N(O); wherein no more than three of X 2 , X 2 , X4, X5, Xe and X? is simultaneously N;
  • Ri is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -
  • R 2a , R 2 b, R 2 c, and R 2 d are each independently H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, halogen, or -OH, wherein two of R 2a , R 2 b, R 2c , and R 2 d may be taken together with the carbon atom to which they are attached form a (Cs-Cvlcarbocyclyl or (C 3 -C 7 )
  • R?b, R?c, and R?d are each independently H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, or (Ci-C 2 )haloalkyl; or two of R 2a , R?b, R?c, and R?d are taken together with the carbon atoms to which they are attached form a (C 3 -C 7 )carbocyclyl, (C 3 -C 7 )spirocarbocyclyl, or a 4- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (
  • compositions comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an HIF-lb-dependent disease or disorder by reducing HIF-lb protein levels wherein reduction of HIF-lb protein levels treats the HIF-lb-dependent disease or disorder.
  • the pharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • compositions comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is useful in the treatment of diseases or disorders affected by the reduction of HIF-lb protein levels.
  • the pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
  • the present disclosure relates to a method of degrading HIF-lb, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
  • RCC renal cell carcinoma
  • VHL von Hippel-Lindau disease
  • PAH pulmonary arterial hypertension
  • glioblastoma colitis
  • Crohn’s disease ulcerative colitis
  • the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the cancer is VHL-deficient cancer.
  • the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or nonHodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.
  • RCC renal cell carcinoma
  • glioblastoma T cell leukemia or T cell lymphoma
  • Hodgkin’s lymphoma or nonHodgkin’s lymphoma non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC
  • Another aspect of the present disclosure relates to a method for reducing HIF-lb levels, comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • VHL von Hippel-Lindau
  • Another aspect of the present disclosure relates to a method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present disclosure relates to a method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
  • the present disclosure provides degraders of HIF-lb that are therapeutic agents in the treatment of diseases such as cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF-lb protein levels, and in the treatment HIF- Ib-dependent diseases or disorders.
  • diseases such as cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF-lb protein levels, and in the treatment HIF- Ib-dependent diseases or disorders.
  • diseases such as cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH),
  • the disease or disorder that can be treated by the compounds of the present disclosure is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, including but not limited to, renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (G
  • the present disclosure provides agents with novel mechanisms of action toward HIE- lb proteins in the treatment of various types of diseases including cancer von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF- 1b protein levels, and in the treatment HIF-lb-dependent diseases or disorders.
  • VHL cancer von Hippel-Lindau
  • PAH pulmonary arterial hypertension
  • the present disclosure relates to compounds and compositions that are capable of modulating HIF- lb protein levels.
  • the disclosure features methods of treating, preventing, or ameliorating a disease or disorder in which HIF-lb plays a role by administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the methods of the present disclosure can be used in the treatment of a variety of HIF-lb-dependent diseases and disorders by modulating HIF-lb protein levels. Modulation of HIF-lb protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, and other HIF- lb-dependent diseases or disorders.
  • the compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-lb-related diseases.
  • VHL von Hippel-Lindau
  • PAH pulmonary arterial hypertension
  • autoimmune and inflammatory-related diseases and conditions neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-lb-related diseases.
  • the compounds of the disclosure have HIF-lb degradation activity, preferably having such activity at or below the 50 pM level, and more preferably having such activity at or below the 10 pM level.
  • the compounds of the disclosure have usefulness in treating cancer and other diseases for which such degradation activity would be beneficial for the patient.
  • the present disclosure provides novel HIF-lb degraders useful for the treatment of cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other disease related to the modulation of HIF-lb-related diseases.
  • VHL von Hippel-Lindau
  • PAH pulmonary arterial hypertension
  • autoimmune and inflammatory-related diseases and conditions neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other disease related to the modulation of HIF-lb-related diseases.
  • the compounds of Formula (I) are described: pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein Ri, R2a, R 2b , R2c, R2d, Re, R?a, R?b, R?c, R7d, R7e, Rs, Xi, X2, X3, X4, X5, X6, X 7 , o, p, r and subvariables thereof are as defined herein.
  • (C 1 -C 10 )alkyl means an alkyl group or radical having 1 to 10 carbon atoms.
  • the last named group is the radical attachment point, for example, "alkylaryl” means a monovalent radical of the formula alkyl-aryl-, while “arylalkyl” means a monovalent radical of the formula aryl-alkyl-.
  • alkylaryl means a monovalent radical of the formula alkyl-aryl-
  • arylalkyl means a monovalent radical of the formula aryl-alkyl-.
  • designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, -O-(C 2 -C6)alkenyl, -O-(C2-C 6 )alkynyl, (C 2 -C6)alkenyl, (C2-Cg)alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 )alkyl, -OC(O)O(C 1 -C 6 )alkyl, -NH
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • aryl means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl.
  • aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, -H, -halogen, -CN, -O-(C 1 -C 6 )alkyl, (Cl-CS)alkyl, -O-(C 2 -C5)alkenyl, -O-(C 2 - C 6 )alkynyl, (C 2 -C 5 )alkenyl, (C 2 -C 6 )alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(Ci-C 5 )alkyl, -C(O)(C 1 -C 6 )alkyl, - OC(O)O(C1-C 6 ) alkyl, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , -S(O) 2 -(C 1 -C 6 )alkyl, -S(O
  • the substituents are themselves optionally substituted.
  • the aryl groups when containing two fused rings, optionally have an unsaturated or partially saturated ring fused with a fully saturated ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, 0, or S.
  • the aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3 ,2-b] thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c
  • the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring.
  • exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.
  • Alkyl means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms.
  • Examples of a (C 1 -C 6 )alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • Alkoxy means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "0" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkenyl means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the "alkenyl” group contains at least one double bond in the chain.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted and may be straight or branched.
  • Alkynyl means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the "alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • Alkylene or "alkylenyl” means a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a (C 1 -C 6 )alkylene. An alkylene may further be a (Ci -Chalky lene.
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH 2 C(CH 3 ) 2 -, -CH2CH2CH2-, -CH2CH2CH2CH-, and the like.
  • Amino means a substituent containing at least one nitrogen atom (e.g., NH2).
  • Cycloalkyl or “carbocyclyl” means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbon ring containing 3-18 carbon atoms.
  • Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof.
  • a (C3-Cs)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • a cycloalkyl group can be fused (e.g. , decalin) or bridged (e.g., norbornane).
  • Deuteroalkyl means an alkyl group substituted with one or more deuterium (“D”). Examples of deuteroalkyl groups include -CDH2, -CD3, -CHD2, -CD2CH3, -CD2CD3, CH2CD3, -CHDCH3, - CD2CH2CD3, etc.
  • Halogen or "halo” mean fluorine, chlorine, bromine, or iodine.
  • Haloalkyl means an alkyl group substituted with one or more halogens.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • Haloalkoxy means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • Halohydroxyalkyl means an alkyl group substituted with at least one halogen and at least one - OH group.
  • halohydroxyalkyl groups include, but are not limited to, HO-C(H)F-, HO-CH(F)- CH 2 -, CF 3 -CH(OH)-CH 2 -, and CH 3 -CH(OH)-, etc.
  • Heterocyclyl or “heterocycloalkyl” means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (0, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted.
  • heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1 ,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazo
  • Hydroalkyl means an alkyl group substituted with one or more -OH groups.
  • hydroxyalkyl groups include H0-CH 2 -, HO-CH 2 CH 2 -, and CH 3 -CH(0H)-.
  • Spirocarbocyclyl or "spirocycloalkyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • a (C 3 -Ci 2 )spirocarbocyclyl is a spirocycle containing between 3 and 12 carbon atoms.
  • Spiroheterocyclyl or “spiroheterocycloalkyl” means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g. , one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings).
  • One or both of the rings in a spiroheterocyclyl can be fused to another ring, e.g., carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • Prodrug or “prodrug derivative” means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
  • prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound for example by hydrolysis in blood and generally include esters and amide analogs of the parent compounds.
  • the prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and/or decreased side effects (e.g., toxicity).
  • prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
  • Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp.
  • “Pharmaceutically acceptable prodrug” as used herein means a prodrug of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
  • Salt means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound.
  • Salts of the compounds of the present disclosure can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • “Pharmaceutically acceptable salt” means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
  • the term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sei., 1977, 66, pp.
  • “Pharmaceutically-acceptable acid addition salt” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid
  • “Pharmaceutically-acceptable base addition salt” means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium
  • solute means a complex of variable stoichiometry formed by a solute, for example, a Compound of Formula (I)) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute.
  • Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • Hydrophilate means a solvate wherein the solvent molecule(s) is/are water.
  • the compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.
  • “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.
  • the term includes stereoisomers and geometric isomers.
  • Steps or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof.
  • the compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
  • stereoisomers can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.
  • Enantiomers means a pair of stereoisomers that are non-superimposable mirror images of each other.
  • Diastereoisomers or “diastereomers” mean optical isomers, which are not mirror images of each other.
  • Racemic mixture or “racemate” mean a mixture containing equal parts of individual enantiomers.
  • Non-racemic mixture means a mixture containing unequal parts of individual enantiomers.
  • Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.
  • enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like.
  • one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer.
  • one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.
  • racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent.
  • ibuprofen had been previously administered as a racemate, it has been shown that only the S -isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer).
  • enantiomers may have distinct biological activity.
  • S -penicillamine is a therapeutic agent for chronic arthritis, while inactive, R-penicillamine is toxic.
  • R-penicillamine is toxic.
  • some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.
  • one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.
  • Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus.
  • the subject is a primate.
  • the subject is a human.
  • an “effective amount” or “therapeutically effective amount” when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • pharmaceutically effective amount or “therapeutically effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician.
  • the amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
  • composition refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • Carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • a subject is "in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).
  • the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treat refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term “prevent”, “preventing”, or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • Disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administering means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • “Compounds of the present disclosure”, “compounds of the disclosure”, and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formulae (I), (la), (lb), (le), (Id), (le), (If), (1g), (Ih), (li), (Ij), (Ik), (II), (Im), (Io), (Ip) (Iq), (Ir), (lu), (Iv), (Iw), (lx), (ly), (Iz), (laa), (Ibb), (Icc), (Idd), (lee), (Iff), (Igg), (Ihh), (lii), (Ijj), (Ikk), (Imm), (loo), (Ipp), (Iqq), (Irr), (Iss), (Itt), (luu), (Ivv), (Iww
  • solvates and hydrates are generally considered compositions.
  • the compounds of the disclosure and the formula designating the compounds of the disclosure are understood to only include stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits.
  • particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative, and it is not intended to exclude other instances when the context so permits.
  • “Stable compound” or “stable structure” means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent.
  • a compound, which would have a "dangling valency" or is a carbanion is not a compound contemplated by the disclosure.
  • the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
  • the yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • “Simultaneously n” or “simultaneous” when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time.
  • “Separately” or “separate” when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.
  • therapeutic administration means, when referring to a method of treating or a therapeutic use with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times.
  • the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins.
  • a one of the active ingredients i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)
  • a one of the active ingredients i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)
  • Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and the one or more second agents the therapeutic administration over a period of time could be such that a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered once a day and the one or more second agent(s) is administered once every four weeks).
  • a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered once
  • the compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • HIF-lb-dependent disease or disorder means any disease or disorder which is directly or indirectly affected by the modulation of HIF-lb protein levels.
  • VHL gene mutations associated with this condition either prevent the production of any VHL protein or lead to the production of an abnormal version of the protein, with more than 370 inherited mutations in the VHL gene having been identified in people with von Hippel-Lindau disease (http://www.umd.be/VHL/).
  • VHL disease is characterized by the formation of multiple benign and malignant tumors and fluid-filled sacs (cysts) in many different parts of the body, including: retinal hemangioblastoma, CNS hemangioblastoma, clear cell renal cell carcinoma (CCRCC), pheochromocytoma, pancreatic islet tumor, endolymphatic sac tumors and cysts in testes and broad ligament.
  • Colitis is an inflammation of the colon.
  • the colitis may be acute or chronic.
  • colitis includes ulcerative colitis, microscopic colitis, lymphocytic colitis, collagenous colitis, diversion colitis, chemical colitis, ischemic colitis, infections colitis, pancolitis, left-sided colitis, extensive colitis, segmental colitis, microscopic colitis, radiation-induced colitis, medication-induced colitis and proctitis.
  • the present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of modulating HIF-lb protein levels, which are useful for the treatment of diseases and disorders associated with modulation of HIF-lb protein levels.
  • the disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for reducing or decreasing HIF-lb protein levels.
  • the present disclosure features compounds of Formula (I): pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X] is N or ClRsh: X2 is N, N(O), or CR5; X3 is N or CR4 a ; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or N(O); wherein no more than three of X2, X3, X4, X5, Xe and X?
  • Ri is H, D, -C(O)Rn, -CH20C(0)Rn, - CH 2 OC(O)NHRi2, -CH 2 OC(O)ORi2, -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(ORi2)2, -CH 2 OP(O)(OH)ORi2, -
  • R 2a , R 2 b, R 2c , and R 2 d are each independently H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, halogen, or -OH, wherein two of R 2a , R 2 b, R 2c , and R 2 ⁇ I may be taken together with the carbon atom to which they are attached form a (C 3 -C 7 )carbocyclyl or (C 3 -C 7 )spirocarb
  • R?b, R?c, and R?ci are each independently H, D, (Ci- Cs)alkyl, (C 1 -C 6 )deuteroalkyl, or(Ci-C 2 )haloalkyl; or two of R?a, R?b, R?c, and Rg.i are taken together with the carbon atoms to which they are attached form a (C 3 -C 7 )carbocyclyl, (C 3 -C 7 )spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (
  • Ris- when on the same carbon atom form C (0);
  • Rie is H, (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, - OH, -NH2, -SF5, -SR18, or -CN;
  • Ris is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )haloalkyl; each Rn is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ',
  • the compound of Formula (I) is a compound of Formula (La): pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR3; X2 is N or CR4a-; X3 is N or CR4 a ; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or CRv; wherein no more than three of X2, X3, X4, X5, Xe and X?
  • Ri is H, D, -C(0)Rn, -CH20C(0)Rn, - CH 2 OC(O)NHRi2, -CH 2 OC(O)ORi2, -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(ORI 2 )2, -CH 2 OP(O)(OH)ORi2, - CH 2 OP(O)(RI 2 )2, -CH 2 OC(O)CH 2 NHC(O)CH 2 NH 2 , -CH 2 OC(O)CH(RI 2 -)NHRI 2 ⁇ , -CH 2 OC(O)(CH 2 )q- C(O)ORI 2 ', or -CH 2 OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -C(0)0RB’, -C(0)Ri3, and -C(O)NRi3’Ri3’;
  • Rs is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, ICi-Gjhaloalkyl, (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S,
  • the compound of Formula (I) is a compound of Formula (I-b): or a pharmaceutically accept-able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR 3 ; X 2 is N or CR 5 ’ ; Ri is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 ,
  • R 2a , R 2 b, Ric. and R2d are each independently H or D;
  • R3 is H, D, (Ci-C3)alkyl, or (Ci-
  • the compounds of Formula (I) have the structure of Formula (I-c): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-c): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-c): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-c): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-c): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers,
  • the compounds of Formula (I-d) have the structure of Formula (I-e): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-f): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-g) pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-h): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-i): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula ( pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-k): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-i): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-m): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-o): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-o): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-o): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-o): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-q): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (I-r): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (lu): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iw): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the ssttrruuccttuurree of Formula (ly): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iz): (Iz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (laa) (laa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ibb): or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iz): (Iz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iz): (Iz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereois
  • Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Idd): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (lee): (lee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iff): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (Iff) have the structure of Formula (Iff): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ihh): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (lii): (lii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ijj): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Imm): (Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Imm): (Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Imm): (Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Imm): (Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (loo) (loo), or pharmaceutically acceptable salts hydrates solvates prodrugs stereoisomers and tautomers thereof
  • the compounds of Formula (I) have the structure of Formula (Ipp): (Ipp), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ipp): (Ipp), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (In): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Itt): pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (luu) (luu), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ivv): (Ivv), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ivv): (Ivv), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ivv): (Ivv), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula ( pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ixx): (Ixx), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ixx): (Ixx), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula ( pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Izz): (Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Izz): (Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Izz): (Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Izz): (Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (laaa) (laaa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ibbb): (Ibbb), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ibbb): (Ibbb), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (Iccc) (Iccc), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iddd): (Iddd), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iddd): (Iddd), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Iddd): (Iddd), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (leee) (leee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ifff): (Ifff), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ifff): (Ifff), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (Iggg): (Iggg), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ihhh): (Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ihhh): (Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ihhh): (Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ihhh): (Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (liii) (liii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ijjj): (Ijjj), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • the compounds of Formula (I) have the structure of Formula (Ijjj): (Ijjj), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • Formula (I) have the structure of Formula (Ikkk): (Ikkk), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
  • X 2 is N or CR 5 -;
  • Ri is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHR 12 , -CH 2 OC(O)OR 12 , -P(O)(ORI 2 ) 2 ,
  • R 2a , R 2 t>, R2C, and R 2 d are each independently H or D;
  • Ra is H, D, (Ci-Ca)alkyl, or (C 1 -C 6 )deuteroalkyl; each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, ((C 1 -CJ 6 )alkoxy.
  • Rs- is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10;
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 , -CH 2 OC(O)OR 12 , -P(O)(OR )2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -CH 2 OP(O)(RI 2 ) 2 ;
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to four R19, the aryl and heteroaryl are
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 ) alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris 1 ;
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, -NH 2 , -N(H)(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl) 2 , (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH 2 , and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH
  • RI 2 is independently at each occurrence H, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (Ci- C 6 )haloalkyl, halogen, -OH, -NH 2 , and -CN, or (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (Ci- C 6 )haloalkyl, halogen, -OH, -NH2, and -CN;
  • R12- is independently at each occurrence H or (C 1 -C 6 )alkyl
  • R13 is independently at each occurrence (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • Ro- is independently at each occurrence H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R14 and R M are each independently at each occurrence H or (C 1 -C 6 )alkyl
  • Ri4a is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R15 and Rn- are each independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered hetero
  • Rie is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF 5 , -SRis, or -CN;
  • Ris is H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )haloalkyl; each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24; R 20 and R 20 ' are each independently at each occurrence H or (C 1 -C 6 )alkyl;
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (G-Gjalkoxy, (C 1 -C 6 )haloalkoxy, (G-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Czjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (
  • R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
  • R30 and R31 are each independently at each occurrence H, (C 1 -C 6 )alkyl, or -CiOjRxi;
  • R32, R33, and R34 are each independently at each occurrence H or (C 1 -C 6 )alkyl
  • R35 and R36 are each independently at each occurrence H, (C 1 -C 6 )alkyl, or -GOjRsj;
  • R37, R38, and R39 are each independently at each occurrence H or (C 1 -C 6 )alkyl; o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.
  • Xi is N. In another embodiment, Xi is CR3. In yet another embodiment, Xi is CD. In another embodiment, Xi is CH.
  • X 2 is N. In another embodiment, X 2 is CR 5 1 .
  • R is H, D, -C(0)Rn, -CH 2 0C(0)Ru,
  • Ri is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -
  • Ri is H, D, -CH 2 OC(O)CH 2 NHC(O)CH2NH2, - CH2OC(O)CH(Ri2-)NHRi2', -CH2OC(O)(CH2) q C(O)ORi2-, or -CH 2 OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S).
  • Ri is -C(O)Rn, -CH 2 OC(O)Ru, -CH 2 OC(O)NHRI 2 , -CH 2 OC(O)OR12, -P(O)(OR] 2 ) 2 , -CH 2 OP(O)(OR1 2 ) 2 , -CH 2 OP(O)(OH)OR12, -CH 2 OP(O)(R, 2 ) 2 , - CH 2 OC(O)CH2NHC(O)CH 2 NH2, -CH 2 OC(O)CH(R12')NHR12', -CH 2 OC(O)(CH 2 ) q C(O)ORi2', or
  • Ri is -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRi2, -CH 2 OC(O)ORi2, - P(O)(OR
  • R is -CH 2 OC(O)CH 2 NHC(O)CH2NH2, -CH 2 OC(O)CH(Ri 2 )NHRi2-, -CH 2 OC(O)(CH 2 ) q C(O)ORi2-, or - CH 2 OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S).
  • Ri is -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)N
  • R 2a is H or D. In another embodiment, R 2a is D. In yet another embodiment, R 2a is H.
  • R 2 b is H or D. In another embodiment, R 2 b is D. In yet another embodiment, R 2 b is H.
  • R 2c is H or D. In another embodiment, R 2c is D. In yet another embodiment, R 2c is H.
  • R 2 d is H or D. In another embodiment, R 2 d is D. In yet another embodiment, R 2 d is H. In some embodiments of the formulae above, R3 is H, D, (C 3 -C 7 )alkyl, or (C 3 -C 7 )deuteroalkyl. In another embodiment, R3 is D, (C 1 -C 6 )alkyl, or (C 3 -C 7 )deuteroalkyl. In yet another embodiment, R3 is H, (C 3 -C 7 )alkyl, or (C 3 -C 7 )deuteroalkyl.
  • R3 is H, D, or (C 3 -C 7 )alkyl. In yet another embodiment, R3 is H, D, or (C 3 -C 7 )deuteroalkyl. In another embodiment, R3 is (C 3 -C 7 )alkyl or (Ci- C3)deuteroalkyl. In another embodiment, R3 is D or (C 3 -C 7 )deuteroalkyl. In another embodiment, R3 is H or (C 3 -C 7 )deuteroalkyl. In another embodiment, R3 is D or (C 3 -C 7 )alkyl. In another embodiment, R3 is H or (C 3 -C 7 )alkyl. In another embodiment, R3 is H or (C 3 -C 7 )alkyl. In another embodiment, R3 is H or D. In yet another embodiment, R3 is D. In another embodiment, R3 is H.
  • each R4 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci-Gjhaloalkoxy. halogen, -OH, or - NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 lalkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, or -OH.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci-Crjdcutcroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, -OH, or - NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 lalkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- Cs)deuteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (Ci- C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, - OH, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )alkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, iCi-C,)alkoxy, halogen, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C 3 -C 7 )alkyl, (C 3 -C 7 )alkoxy, halogen, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (Ci- C3)alkyl, (C 3 -C 7 )alkoxy, halogen, or -NR9R10.
  • each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 lhaloalkoxy, halogen, -OH, or - NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, or -OH.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, -OH, or - NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 lalkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (Ci- C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, - OH, or -NR9R10.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )alkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )alkoxy, halogen, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 3 -C 7 )alkyl, (C 1 -C 6 )deuteroalkyl, (C1-C3) alkoxy, halogen, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci-Qjalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10. In another embodiment, each R$ is independently at each occurrence D, (C 3 -C 7 )alkyl, (C 3 -C 7 )alkoxy, halogen, or -NR9R10.
  • each R$ is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- Cs)haloalkyl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, or -NR9R10.
  • each Rs is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (Ci- C3)alkyl, (C 3 -C 7 )alkoxy, halogen, or -NR9R10.
  • Rs- is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • Rs’ is H, D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, or -OH.
  • Rs- is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, or -NR9R10.
  • Rs- is H, D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, -OH, or -NR9R10.
  • Rs- is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, halogen, -OH, or -NR9R10.
  • Rs- is H, D, (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • Rs 1 is H, D, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • Rs- is H, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • Rs- is D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, or -NR9R10.
  • R5' is H, D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, halogen, or -NR9R10.
  • Rs- is H, D, (C 3 -C 7 )alkyl, (C 1 -C 6 )deuteroalkyl, halogen, or -NR9R10.
  • Rs- is H, D, (Ci-Cft)alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, D, (C 3 -C 7 )alkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, (C 3 -C 7 )alkyl, halogen, or -NR9R10.
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, - CH 2 OC(O)NHR1 2 , -CH 2 OC(O)OR ]2 , -P(O)(OR1 2 ) 2 , -CH 2 OP(O)(OH)OR1 2 , or -CH 2 OP(O)(RI 2 ) 2 .
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHR, 2 , -CH 2 OC(O)OR, 2 , -P(O)(OR, 2 ) 2 , or -CH 2 OP(O)(OH)ORI 2 .
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, - CH 2 OC(O)NHR, 2 , -CH 2 OC(O)ORI 2 , -P(O)(ORI 2 ) 2 , or -CH 2 OP(O)(R, 2 ) 2 .
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHR, 2 , -CH 2 OC(O)ORI 2 , -CH 2 OP(O)(OH)ORI 2 , or - CH 2 OP(O)(RI 2 ) 2 .
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHR] 2 , - P(O)(ORI 2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -CH 2 OP(O)(RI 2 ) 2 .
  • Re is H, D, -C(O)Rn, - CH 2 OC(O)Rn, -CH 2 OC(O)ORI 2 , -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -CH 2 OP(O)(R 12 ) 2 .
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)NHR, 2 , -CH 2 OC(O)ORI 2 , -P(O)(OR, 2 ) 2 , -
  • Re is H, D, -CH 2 OC(O)Rn, -
  • Re is H, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 , -CH 2 OC(O)ORI 2 , -
  • Re is D, -C(O)Rn, -
  • Re is H, D, -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 , or -CH 2 OC(O)ORI 2 .
  • Re is H, D, -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -
  • Re is -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 , - CH 2 OC(O)ORI 2 , -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -CH 2 OP(O)(RI 2 ) 2 .
  • Re is -C(O)Rn, -CH 2 OC(O)Rn, -CH 2 OC(O)NHRI 2 , - CH 2 OC(O)ORI 2 , -P(O)(ORI 2 ) 2 , -CH 2 OP(O)(OH)ORI 2 , or -CH 2 OP(O)(RI 2 ) 2 .
  • Re is
  • Re is D. In another embodiment, Re is H.
  • R? a is H, D, (Ci-C 2 )alkyl, (Ci-C 2 )deuteroalkyl, or (Cr C 2 )haloalkyl.
  • R 2a is H, D, (Ci-C 2 )alkyl, or (Ci-C 2 )deuteroalkyl.
  • R 2a is H, D, (Ci-C 2 )alkyl, or (Ci-C 2 )haloalkyl.
  • R 2a is H, D, (Ci- C 2 )deuteroalkyl, or (Ci-C 2 )haloalkyl.
  • R 2a is H, (Ci-C 2 )alkyl, (Ci- C 2 )deuteroalkyl, or (Ci-C 2 )haloalkyl.
  • R 2a is D, (Ci-C 2 )alkyl, (Ci-C 2 )deuteroalkyl, or (Ci-C 2 )haloalkyl.
  • R? a is H D or (Ci-C 2 )alkyl
  • R 2a is H, D, or (Ci-C2)deuteroalkyl.
  • R? a is H, D, or (Ci-C2)haloalkyl.
  • R? a is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R? a is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R? a is (Ci-C2)alkyl or (Ci-C2)haloalkyl.
  • R? a is H or D.
  • R? a is D.
  • R? a is H.
  • R?b is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl.
  • R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • Rvb is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?b is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?b is D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?b is H, D, or (Ci-C2)alkyl.
  • R?b is H, D, or (Ci-C2)deuteroalkyl.
  • R?b is H, D, or (Ci-C2)haloalkyl.
  • R?b is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?b is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?b is (Ci-C2)alkyl or (Ci-C2)haloalkyl.
  • R?b is H or D.
  • R?b is D.
  • R?b is H.
  • R? c is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Cr C2)haloalkyl.
  • R? L is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl.
  • R? L is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R? c is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R? c is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • Rv c is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • Rv c is D, (Ci-C2)alkyl, (Cj-Cdidcutcroalkyl, or (Ci-C2)haloalkyl.
  • R? c is H, D, or (Ci-C2)alkyl.
  • R? c is H, D, or (Ci-C2)deuteroalkyl.
  • Rv c is H, D, or (Ci-C2)haloalkyl.
  • R?c is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?c is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?c is (Ci-C2)alkyl or (Ci-C2)haloalkyl.
  • R?c is H or D.
  • R? c is D.
  • R? c is H.
  • Rva is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl.
  • R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • Rvd is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?d is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R?d is D, (Ci-Cdlalkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl.
  • R? ⁇ i is H, D, or (Ci-C2)alkyl.
  • R?d is H, D, or (Ci-C2)deuteroalkyl.
  • R?d is H, D, or (Ci-C2)haloalkyl.
  • R? ⁇ i is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?d is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl.
  • R?d is (Ci-C2)alkyl or (Ci-C2)haloalkyl.
  • Rv ⁇ i is H or D.
  • R?d is D.
  • R?d is H.
  • each R??d is H.
  • e is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (Ci- C6)hydroxyalkyl, -CN, -OH, -0-(C 1 -C 6 )hydroxy alkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and hetero
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C3- C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl is optionally substituted with one to four R22.
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxy alkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one to
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -0-(C 1 -C 6 )hydroxy alkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the heterocyclyl is optionally substituted with one
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -0-(C 1 -C 6 )hydroxy alkyl, (C 6 -C 10 ) aryl, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl is optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxy alkyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the heteroaryl is optionally substituted with one to six R21, and the carbocyclyl and heterocycly
  • each R?e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substitute
  • each R? e is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (Ci- C 6 )hydroxyalkyl, -CN, -O-(C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 ,
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, -0-(C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -CN, - OH, -O-(C 1 -C 6 )hydroxy alkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and
  • each R?e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -0- (C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxy alkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocycly
  • each R? e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally
  • each Rv e is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, - CN, -OH, -0-(C 1 -C 6 )hydroxyalkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • alkyl is optionally substituted with one six R19
  • aryl and heteroaryl are optionally substituted with one to six R21
  • carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
  • e is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted
  • each R? e is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
  • each R? e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 ,
  • each R?e is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH, -O-(C 1 -C 6 )hydroxyalkyl, wherein the alkyl is optionally substituted with one to six R19.
  • each R? is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -CN, -OH
  • e is independently at each occurrence (C 6 -C 10 ) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
  • each Rv e is independently at each occurrence D, (C 1 -C 6 ialkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22.
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C6)haloalkyl, (Cj-CoJalkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci- C6)haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRI3'RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci-Gjhaloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB’.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C 6 )hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.
  • two R?e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 4- or 5-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB'.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- or 5 -membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB’.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.
  • two R?e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB RB'.
  • two R? e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB'RB-.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four halogen.
  • two R7 6 when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci- C6)haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRB’RB’-
  • spiroheterocyclyl when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(O)NRi3'Ri3’.
  • two R7 e when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R7e when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four halogen.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (Ci-Gjalkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four RD-.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C6)halohydroxyalkyl, or (C 1 -C 6 )alkyl substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Riy.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, or (Cr C6)halohydroxy alkyl. In another embodiment, Rg is (C 1 -C 6 )haloalkyl or (C 1 -C 6 )hydroxy alkyl. In yet another embodiment, Rg is (C 1 -C 6 )haloalkyl or (C 1 -C 6 )halohydroxyalkyl. In another embodiment, Rg is (Ci- C6)hydroxy alkyl or (C 1 -C 6 )halohydroxy alkyl.
  • Rg is (C 1 -C 6 )haloalkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRi4 a , - NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’.
  • Rg is iC 1 -C(,) hydroxy alky I or (C 1 -C 6 ) alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
  • Rg is (C 1 -C 6 )haloalkyl, (Ci-Gjhydroxyalkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ri v.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRu a , phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRua, -NRuRu-, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris'.
  • Rg is (Ci-Cjhaloalkyl, (C 1 -C 6 )hydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, -SRi4a, -NR14R14', phenyl, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (Ci-G,)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the heterocyclyl is optionally substituted with one to four Ris-.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from D, (C 1 -C 6 )alkoxy, -SF5, - SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, and (C 3 -C 7 )carbocyclyl, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl is optionally substituted with one to four R15'.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )halohydroxyalkyl, or (C 1 -C 6 )alkyl substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
  • Rg is (C 1 -C 6 )haloalkyl, (C 1 -C 6 )halohydroxyalkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R 15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-.
  • Rg is (Ci-C 6 )haloalkyl, (C 1 -C 6 )halohydroxyalkyl, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from phen
  • Rg is (C 1 -C 6 lhaloalkyl or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-.
  • Rg is (C 1 -C 6 )hydroxy alkyl or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, and 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-.
  • Rg is (C 1 -C 6 )halohydroxy alkyl or (Ci- Coialkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris 1 .
  • Rg is independently at each occurrence H, D, (Ci- C 6 )alkyl, or (C 1 -C 6 ldeuteroalkyl. In another embodiment, Rg is independently at each occurrence D, (Ci- C 6 )alkyl, or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence H, D, or (C 1 -C 6 )deuteroalkyl. In another embodiment, Rg is independently at each occurrence H, D, or (Ci- C6)alkyl. In yet another embodiment, Rg is independently at each occurrence H or D.
  • Rg is independently at each occurrence D or (C 1 -C 6 )alkyl. In yet another embodiment, Rg is independently at each occurrence H or (C 3 -C 7 )alkyl. In another embodiment, Rg is independently at each occurrence H or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C 1 -C 6 )deuteroalkyl. In another embodiment, Rg is independently at each occurrence (C1-C3) alkyl or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C 3 -C 7 )alkyl.
  • Rg is independently at each occurrence (C 1 -C 6 )deuteroalkyl. In yet another embodiment, R9 is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Rg is independently at each occurrence D. In yet another embodiment, Rg is independently at each occurrence H.
  • Rio is independently at each occurrence H, D, (Ci- C 6 )alkyl, or (C 1 -C 6 )deuteroalkyl. In another embodiment, Rio is independently at each occurrence D, (Ci- C 6 )alkyl, or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence H, D, or (C 1 -C 6 )deuteroalkyl. In another embodiment, Rio is independently at each occurrence H, D, or (Ci- C 6 )alkyl. In yet another embodiment, Rio is independently at each occurrence H or D.
  • Rio is independently at each occurrence D or (C 1 -C 6 )alkyl. In yet another embodiment, Rio is independently at each occurrence H or (C 3 -C 7 )alkyl. In another embodiment, Rio is independently at each occurrence H or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C 1 -C 6 )deuteroalkyl. In another embodiment, Rio is independently at each occurrence (C 3 -C 7 )alkyl or (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C 3 -C 7 )alkyl.
  • Rio is independently at each occurrence (C 1 -C 6 )deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Rio is independently at each occurrence D. In yet another embodiment, Rio is independently at each occurrence H.
  • Rn is independently at each occurrence H, (Ci- C6)alkoxy, -NH2, -N(H)(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl)2, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (Ci-
  • C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (Ci- C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, -NH2, -N(H)(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl)2, or (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (Ci- C6)hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, -NH2, -N(H)(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl)2, (Ci- C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Ri 1 is independently at each occurrence H, (C 1 -C 6 )alkoxy, -NH2, -N(H)(Ci- C 6 )alkyl, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (Ce- Ciolaryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, -NH2, -N((C 1 -C 6 )alkyl)2, (Ci- C 6 )alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, -N(H)(Ci- C 6 )alkyl, -N((C 1 -C 6 )alkyl)2, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and
  • Rn is independently at each occurrence H, -NH2, -N(H)(C 1 -C 6 )alkyl, -N((Ci- C 6 )alkyl)2, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci- C6)alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkoxy, -NH2, -N(H)(Ci- C6)alkyl, -N((C 1 -C 6 )alkyl)2, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN
  • Rn is independently at each occurrence H, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (Ci- C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci-Gjalkoxy. (Ci- C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • R12 is independently at each occurrence H, (Ci- C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • substituents independently selected from (C 6 -C 10 )aryl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6
  • R12 is independently at each occurrence H, (C 1 -C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )hydroxy alkyl, (Ci- C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • R12 is independently at each occurrence H, (C 1 -C 6 )alkyl substituted with one to four substituents independently selected from (Ce- Ciolaryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • substituents independently selected from (Ce- Ciolaryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (C 1 -C 6 )haloalkyl, hal
  • RB is independently at each occurrence H, or (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (Ci- C6)hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • RB is independently at each occurrence H.
  • RB is independently at each occurrence (Ci- C 6 )alkyl optionally substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • RB is independently at each occurrence (C 6 -C 10 )aryl optionally substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH 2 , and -CN.
  • R12 is independently at each occurrence (C 1 -C 6 )alkyl substituted with one to four substituents independently selected from (C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN.
  • RB is independently at each occurrence (C6-Cio)aryl substituted with one to four substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, and -CN.
  • RB' is independently at each occurrence H or (Ci- C6)alkyl.
  • RB’ is independently at each occurrence H or (C 3 -C 7 )alkyl.
  • RB’ is independently at each occurrence (C 1 -C 6 )alkyl.
  • RB’ is independently at each occurrence H.
  • R B is independently at each occurrence (C 1 -C 6 ) alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R B is independently at each occurrence (C 3 -C 7 )alkyl or (Ci- C3)haloalkyl. In another embodiment, RB is independently at each occurrence (C 1 -C 6 )haloalkyl. In another embodiment, RB is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, RB is independently at each occurrence (C 3 -C 7 )haloalkyl. In another embodiment, RB is independently at each occurrence (C 3 -C 7 )alkyl.
  • R B- is independently at each occurrence H, (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • RB- is independently at each occurrence H, (Ci- C3)alkyl or (C 3 -C 7 )haloalkyl.
  • RB- is independently at each occurrence H or (Ci- C 6 )alkyl.
  • RB- is independently at each occurrence H or (C 1 -C 6 )haloalkyl.
  • RB' is independently at each occurrence (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • RB- is independently at each occurrence (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl.
  • RBV is independently at each occurrence (C 1 -C 6 )alkyl.
  • RB- is independently at each occurrence (C 3 -C 7 )alkyl.
  • Ruv is independently at each occurrence (C 1 -C 6 )haloalkyl.
  • Ru is independently at each occurrence (Ci- C3)haloalkyl.
  • R u is independently at each occurrence H.
  • Ru is independently at each occurrence H or (Ci- C 6 )alkyl. In another embodiment, Ru is independently at each occurrence H or (C 3 -C 7 )alkyl. In yet another embodiment, Ru is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Ru is independently at each occurrence (C 3 -C 7 )alkyl. In another embodiment, Ru is independently at each occurrence H.
  • Ru- is independently at each occurrence H or (Ci- C 6 )alkyl. In another embodiment, Ru- is independently at each occurrence H or (C 3 -C 7 )alkyl. In yet another embodiment, Ru- is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Ru- is independently at each occurrence (C 3 -C 7 )alkyl. In another embodiment, Ru- is independently at each occurrence H.
  • Rua is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, Ru a is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, Ru a is H or (Cr C 6 )alkyl. In another embodiment, Ru a is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, Ru a is (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • Ru a is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, Ru a is (C 1 -C 6 )alkyl. In another embodiment, Ru a is (C 3 -C 7 )alkyl. In another embodiment, Ru a is (C 1 -C 6 )haloalkyl. In another embodiment, Ru a is (C 3 -C 7 )haloalkyl. In another embodiment, Ru a is H.
  • R 15 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -O(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms
  • R15 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -0(C3- C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 hetero
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 hetero
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - 0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 lalkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, -OH, - NR30R31, -SFs, -SR16, -CN, -C(O)NRS2R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -0(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -0(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH,
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR3ZR33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S
  • R15 is independently at each occurrence D, (Ci-Co.idcutcroalkyl. (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, - C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S
  • R15 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -0(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising
  • R15 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, or -C(O)OR32-
  • R15 is independently at each ooccccuurrrreennccee (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C 6 )hydroxyalkyl, halogen, -OH, -NR30
  • R15 is independently at each occurrence (C 3 -C 7 )carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C 1 -C 6 )alkyl, (C 1
  • R15 is independently at each occurrence (C 3 -C 7 )carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6
  • R 15 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms
  • Ris- is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to
  • Riv is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR 32 R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N
  • R15’ is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- Cs)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SFs, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - ⁇ -(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N,
  • R15' is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N,
  • R15’ is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (Ci-Gjalkoxy.
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, -OH, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatom
  • Riv is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH,
  • R15' is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N,
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N,
  • R45’ is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR32R33, -C(O)OR 32 , (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S
  • Ris- is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, - C(O)NR32R33, -C(O)OR32, (C 3 -C 7 )carbocyclyl, -O(C 3 -C 7 )carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH,
  • Ris- is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, or -C(O)OR32-
  • Riv is independently at each ooccccuurrrreennccee (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31
  • R15- is independently at each occurrence (C 3 -C 7 )carbocyclyl, -O(Cs- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C 1 -C 6 )alkyl, (C
  • Ris- is independently at each occurrence (C 3 -C 7 )carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C 1 -C 6 )alkyl, (C 1
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four R17.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C -Cv.icarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (Cs-Cvjcarbocyclyl, wherein the phenyl, heteroaryl, and carbocyclyl are optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, and heterocyclyl are optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, (C 3 -C 7 jcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn-
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Ca-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
  • Rn when on adjacent atoms, together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from
  • Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl or (C 3 -C 7 )carbocyclyl, wherein the phenyl and carbocyclyl are optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R n.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four Rn.
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn-
  • two Rn when on adjacent atoms, together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.
  • two Rn- when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn-
  • two R15’ when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are substituted with one to four Rn-
  • two Rn- when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl is optionally substituted
  • a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl is substituted with one to four Rn and the heteroaryl is optionally substituted with one to four Rn.
  • two Rn- when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn.
  • two Rn- when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R17.
  • two Rn- when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is substituted with one to four Rn.
  • two R15' together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn.
  • two Riv together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn.
  • two Rm together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn.
  • two Rm together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
  • two Ris- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- to 6-membered heterocyclyl
  • two R15’ together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17.
  • two R15’ together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17.
  • two R15- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 6- or 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn.
  • two Rm together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.
  • two Rm together with the atoms to which they are attached form a (Cs-Cvjcarbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Riv.
  • two Rn- together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.
  • two R 15 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
  • two R15' together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17.
  • two Ris- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn.
  • two R15’ together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17.
  • two Riv together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a (C3-C5)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn-
  • two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are
  • two Rn- together with the atoms to which they are attached form a (C4-C7)carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn-
  • two R iv together with the atoms to which they are attached form a (C5-C 6 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.
  • two Rn together with the atoms to which they are attached form a (C3- C 6 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
  • two R15' together with the atoms to which they are attached form a (Ca-Cslcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
  • two Ris- together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 hetero
  • two Ris- together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (Ce-Cvlcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C5-C 6 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
  • two R 15 together with the atoms to which they are attached form a (C3- C 6 )carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (Cs-C ⁇ carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C4-Cv)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
  • two R15' together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17.
  • two Ris- together with the atoms to which they are attached form a (C6-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
  • two R15’ together with the atoms to which they are attached form a (G-Gjcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
  • two Riv together with the atoms to which they are attached form a (C3- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
  • two Rn together with the atoms to which they are attached form a (C3- C5)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn.
  • two Ris- together with the atoms to which they are attached form a (C3-Cs)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn-
  • two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four R 17.
  • two Rn- together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
  • two R 15 together with the atoms to which they are attached form a (C4- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a (C4-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four R17.
  • two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
  • two Rn together with the atoms to which they are attached form a (Ce- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a (C6-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn-
  • two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn-
  • two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn-
  • two R 15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four R
  • two Ris- together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.
  • two Rm together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn-
  • two R i v together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.
  • two Ris- together with the atoms to which they are attached form a 6- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn-
  • two Rn- together with the atoms to which they are attached form a 6- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn-
  • two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.
  • two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.
  • two Rn- together with the atoms to which they are attached form a 4- to 5- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.
  • two Ri together with the atoms to which they are attached form a 4- to 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn-
  • two Ri v together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn-
  • two Ris- together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.
  • Ris is independently at each occurrence H, (Ci- Cs)alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, Ris is independently at each occurrence H, (Ci- C3)alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, Ris is independently at each occurrence H or (Ci- Cs)alkyl. In another embodiment, Ris is independently at each occurrence H or (C 1 -C 6 )haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • Ris is independently at each occurrence (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Ris is independently at each occurrence (C 3 -C 7 )alkyl. In another embodiment, Ris is independently at each occurrence (C 1 -C 6 )haloalkyl. In another embodiment, Ris is independently at each occurrence (Ci- C3)haloalkyl. In another embodiment, Ris is independently at each occurrence H.
  • Rn is independently at each occurrence D, (Ci- Cs)alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -SRis.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NHj, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 ialkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN.
  • R17 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, or halogen.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, or -CN.
  • Rn is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )hydroxyalkyl, halogen, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, or halogen.
  • Rn is independently at each occurrence halogen, -OH, -NH2, -SF5, -SRn, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, - NH2, -SF5, -SRis, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, -OH, -NH2, -SF5, -SRn, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, or -CN.
  • Rn is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )hydroxyalkyl, halogen, or -CN.
  • Rn is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, or -CN.
  • Rn is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • Rn is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl.
  • Rn is H or (Ci- C6)alkyl.
  • Ris is H or (C 1 -C 6 )haloalkyl.
  • Ris is (Ci- C6)alkyl or (C 1 -C 6 )haloalkyl.
  • Ris is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl.
  • Ris is (C 1 -C 6 )alkyl.
  • Rn is (C 3 -C 7 )alkyl.
  • Rn is (C 1 -C 6 )haloalkyl.
  • Rn is (C 3 -C 7 )haloalkyl.
  • Rn is H.
  • each Rig is independently at each occurrence (Ci- Cs)alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ’, -CN, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 ) alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ’, -CN, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C 6 -C 10 ) aryl, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, - NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ’, -CN, (C 3 -C 7 )carbocyclyl, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein carbocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C6)haloalkoxy, -NR 20 R 20 ', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each Rig is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ’, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each Rig is independently at each occurrence (C 1 -C 6 )haloalkoxy, - NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ', or -CN. In yet another embodiment, each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, or -NR 20 R 20 '.
  • each R19 is independently at each occurrence (C 3 -C 7 )carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ), wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23.
  • each R19 is independently at each occurrence ((C 1 -CJ 6 )alkoxy, (Ci- C6)haloalkoxy, -NR 20 R 20 ’, -CN, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ’, -CN, (C 3 -C 7 )carbocyclyl, or (C 6 -C 10 ) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
  • each Rig is independently at each occurrence (C 1 -C 6 )alkoxy, -NR 20 R 20 ', - CN, (C 3 -C 7 )carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, -NR 20 R 20 ', -CN, (C 3 -C 7 )carbocyclyl, or (C 6 -C 10 ) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, -NR 20 R 20 ’, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, -NR 20 R 20 ', (C 3 -C 7 )carbocyclyl, or (C 6 -C 10 ) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, - NR 20 R 20 ', 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 )alkoxy, -NR 20 R 20 ', (C 3 -C 7 )carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 6 -C 10 ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
  • each R19 is independently at each occurrence (C 1 -C 6 ialkoxy, -NR 20 R 20 ’, (C 3 -C 7 )carbocyclyl, or (C 6 -C 10 ) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
  • R 20 is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, R 20 is independently at each occurrence H or (C 3 -C 7 )alkyl. In yet another embodiment, R 20 is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, R 20 is independently at each occurrence (C 3 -C 7 )alkyl. In yet another embodiment, R 20 is independently at each occurrence H.
  • R 20 ' is independently at each occurrence H or (Ci- C 6 alkyl. In another embodiment, R2o- is independently at each occurrence H or (C 3 -C 7 )alkyl. In yet another embodiment, R 20 ' is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, R 20 ' is independently at each occurrence (C 3 -C 7 )alkyl. In yet another embodiment, R 20 ' is independently at each occurrence H.
  • each R21 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C 3 -C 7 )carbocyclyl.
  • each R21 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci-Cojhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 lalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C6)haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, or -CN.
  • each R21 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, (C3- Cvjcarbocyclyl. or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R21 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R21 when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R21 when on adjacent atoms, together with the atoms to which they are attached form a phenyl.
  • two R21, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R21 when on adjacent atoms, together with the atoms to which they are attached form a 5 -membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R21 when on adjacent atoms, together with the atoms to which they are attached form a 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R22 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 (carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C 3 -C 7 jcarbocyclyl.
  • each R22 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, - CN, phenyl, (C 3 -C 7 jcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C?)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 lalkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -SF5, -SR26, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci-Cjhaloalkoxy, (C 1 -C 6 )hydroxyalkyl, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, or -CN.
  • each R22 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R22 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl.
  • two R22 together with the atoms to which they are attached form a (C3-C6)carbocyclyl.
  • two R22 together with the atoms to which they are attached form a (Cs-CsKarbocyclyl.
  • two R22 together with the atoms to which they are attached form a (C3-C4)carbocyclyl.
  • two R22 together with the atoms to which they are attached form a (C4-C7)carbocyclyl.
  • two R22 together with the atoms to which they are attached form a (C5-C7)carbocyclyl.
  • two R22 together with the atoms to which they are attached form a (C6-C7)carbocyclyl.
  • two R22 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a 4- or 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R22 together with the atoms to which they are attached form a 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (Ci- C6)alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 lalkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 lhydroxyalkyl, halogen, -OH, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 ialkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci-Cjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci- C6)haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, or -CN.
  • each R23 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR27, -CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R23 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R23 together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N. NH, and S.
  • two R23 together with the atoms to which they are attached form a (C 3 -C 7 )carbocyclyl.
  • two R23 together with the atoms to which they are attached form a (C3-C6)carbocyclyl.
  • two R23 together with the atoms to which they are attached form a (Cs-Cs ⁇ arbocyclyl.
  • two R23 together with the atoms to which they are attached form a (C3-C4)carbocyclyl.
  • two R23 together with the atoms to which they are attached form a (C4-C7)carbocyclyl.
  • two R23 together with the atoms to which they are attached form a (C5-C7)carbocyclyl.
  • two R23 together with the atoms to which they are attached form a (C6-C7)carbocyclyl.
  • two R23 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R23 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • two R23 together with the atoms to which they are attached form a 4- or 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R23 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • two R23 together with the atoms to which they are attached form a 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (Ci- C6)alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C 3 -C 7 )carbocyclyl.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci-Crjalkoxy, (C 1 -C 6 lhaloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 ialkyl, (Ci- C6)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, phenyl, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
  • each R24 is independently at each occurrence D, (Ci- C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C6)haloalkyl, (Ci-Gjalkoxy, (C 1 -C 6 )haloalkoxy, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (Ci- C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 ialkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, or -CN.
  • each R24 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (Ci-G>)haloalkoxy.
  • each R24 is independently at each occurrence D, (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- Cs)haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • each R24 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C 3 -C 7 )carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
  • R25 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R25 is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R25 is H or (Ci- C 6 )alkyl. In another embodiment, R25 is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, R25 is (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • R25 is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R25 is (C 1 -C 6 )alkyl. In another embodiment, R25 is (C 3 -C 7 )alkyl. In another embodiment, R25 is (C 1 -C 6 )haloalkyl. In another embodiment, R25 is (C 3 -C 7 )haloalkyl. In another embodiment, R25 is H.
  • R26 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R26 is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R26 is H or (Ci- C 6 )alkyl. In another embodiment, R26 is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, R26 is (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • R26 is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R26 is (C 1 -C 6 )alkyl. In another embodiment, R26 is (C 3 -C 7 )alkyl. In another embodiment, R26 is (C 1 -C 6 )haloalkyl. In another embodiment, R26 is (C 3 -C 7 )haloalkyl. In another embodiment, R26 is H.
  • R27 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R27 is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R27 is H or (Ci- C 6 )alkyl. In another embodiment, R27 is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, R27 is (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • R27 is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R27 is (C 1 -C 6 )alkyl. In another embodiment, R27 is (C 3 -C 7 )alkyl. In another embodiment, R27 is (C 1 -C 6 )haloalkyl. In another embodiment, R27 is (C 3 -C 7 )haloalkyl. In another embodiment, R27 is H.
  • R28 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R28 is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R28 is H or (Ci- C6)alkyl. In another embodiment, R28 is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, R28 is (Ci- C6)alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R28 is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl.
  • R28 is (C 1 -C 6 )alkyl. In another embodiment, R28 is (C 3 -C 7 )alkyl. In another embodiment, R28 is (C 1 -C 6 )haloalkyl. In another embodiment, R28 is (C 3 -C 7 )haloalkyl. In another embodiment, R28 is H.
  • R29 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl. In another embodiment, R29 is H, (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R29 is H or (Ci- C 6 )alkyl. In another embodiment, R29 is H or (C 1 -C 6 )haloalkyl. In yet another embodiment, R29 is (Ci- C 6 )alkyl or (C 1 -C 6 )haloalkyl.
  • R29 is (C 3 -C 7 )alkyl or (C 3 -C 7 )haloalkyl. In yet another embodiment, R29 is (C 1 -C 6 )alkyl. In another embodiment, R29 is (C 3 -C 7 )alkyl. In another embodiment, R29 is (C 1 -C 6 )haloalkyl. In another embodiment, R29 is (C 3 -C 7 )haloalkyl. In another embodiment, R29 is H.
  • R30 is H, (C 1 -C 6 )alkyl, or -C(O)R34- In another embodiment, R30 is H, (C 3 -C 7 )alkyl, or -C(O)R34- In yet another embodiment, R30 is H or (C 1 -C 6 )alkyl. In another embodiment, R30 is H or -C(O)R34- In yet another embodiment, R30 is (C 1 -C 6 lalkyl or -C(O)R34- In another embodiment, R30 is (C 1 -C 6 Oalkyl. In yet another embodiment, R30 is -C(O)R34- In another embodiment, R30 is H.
  • R31 is H, (C 1 -C 6 )alkyl, or -C(O)R34. In another embodiment, R31 is H, (C 3 -C 7 )alkyl, or -C(O)R34. In yet another embodiment, R31 is H or (C 1 -C 6 )alkyl. In another embodiment, R31 is H or -C(O)R34 In yet another embodiment R31 is (C 1 -C 6 )alkyl or -C(O)R34 In another embodiment, R31 is (C 3 -C 7 )alkyl. In yet another embodiment, R31 is -C(O)R34- In another embodiment, R31 is H.
  • R32 is H or (C 1 -C 6 )alkyl. In another embodiment, R32 is H or (C 3 -C 7 )alkyl. In yet another embodiment, R32 is (C 1 -C 6 )alkyl. In another embodiment, R32 is (Ci- C3)alkyl. In yet another embodiment, R32 is H.
  • R34 is H or (C 1 -C 6 )alkyl. In another embodiment, R34 is H or (C 3 -C 7 )alkyl. In yet another embodiment, R34 is (C 1 -C 6 )alkyl. In another embodiment, R34 is (Ci- C3)alkyl. In yet another embodiment, R34 is H.
  • R36 is H, (C 1 -C 6 )alkyl, or -C(O)R39. In another embodiment, R36 is H, (C 3 -C 7 )alkyl, or -C(O)R39. In yet another embodiment, R36 is H or (C 1 -C 6 )alkyl. In another embodiment, R36 is H or -C(O)R39. In yet another embodiment, R36 is (C 3 -C 7 )alkyl or -C(O)R39. In another embodiment, R36 is (C 3 -C 7 )alkyl. In yet another embodiment, R36 is -C(O)R39. In another embodiment, R36 is H.
  • R37 is H or (C 1 -C 6 )alkyl. In another embodiment, R37 is H or (C 3 -C 7 )alkyl. In yet another embodiment, R37 is (C 1 -C 6 )alkyl. In another embodiment, R37 is (Ci- C3)alkyl. In yet another embodiment, R37 is H.
  • R38 is H or (C 1 -C 6 )alkyl. In another embodiment, R38 is H or (C 3 -C 7 )alkyl. In yet another embodiment, R38 is (C 1 -C 6 )alkyl. In another embodiment, R38 is (Ci- C3)alkyl. In yet another embodiment, R38 is H.
  • R39 is H or (C 1 -C 6 )alkyl. In another embodiment, R39 is H or (C 3 -C 7 )alkyl. In yet another embodiment, R39 is independently at each occurrence (C 1 -C 6 )alkyl. In another embodiment, Rvi is (C 3 -C 7 )alkyl. In yet another embodiment, R39 is H.
  • 0 is 1 or 2. In another embodiment, o is 1. In another embodiment, o is 2. In some embodiments of the formulae above, m is 0, 1 or 2. In another embodiment, m is 0 or 2. In yet another embodiment, m is 0 or 1. In another embodiment, m is 1 or 2. In yet another embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2.
  • n is 0, 1 or 2. In another embodiment, n is 0 or 2. In yet another embodiment, n is 0 or 1. In another embodiment, n is 1 or 2. In yet another embodiment, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2.
  • p is 0, 1, 2, 3, or 4. In another embodiment, p is 0, 1,
  • p is 0, 1, 2, or 4. In another embodiment, p is 0, 1, 3 or 4. In yet another embodiment, p is 0, 2, 3, or 4. In another embodiment, p is 1, 2, 3 or 4. In yet another embodiment, p is 0, 1, or 2. In another embodiment, p is 2, 3, or 4. In yet another embodiment, p is 1, 2, or 3. In another embodiment, p is 0 or 1. In yet another embodiment, p is 1 or 2. In another embodiment, p is 2 or 3. In yet another embodiment, p is 3 or 4. In another embodiment, p is 0 or 2. In yet another embodiment, p is 0 or
  • q is 1, 2, or 3. In another embodiment, q is 1 or 3. In yet another embodiment, q is 2 or 3. In another embodiment, q is 1 or 2. In yet another embodiment, q is 1. In another embodiment, q is 2. In yet another embodiment, q is 3.
  • Xj is N or CR3. In another embodiment, Xi is N or
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • Xi is N or CR3
  • X2 is N or
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R 2c is H
  • R2d is H.
  • Xi is N or CR3
  • X2 is N or
  • Ri is H, R2a is H, Rdb is H, R 2c is H, R 2d is H, and R3 is H.
  • Xi is N or CR3, X2 is N or CR 5 - , Ri is H, R2 a is H, R 2b is H, R 2c is H, R2d is H, R3 is H, and Re is H.
  • Xi is N or CR3, X2 is N or CR 5 -, Ri is H, R2 a is H, R 2b is H, R 2c is H, R2d is H, R3 is H, Re is H, and R? a is
  • Xi is N or CR3
  • X2 is N or CRe-
  • Ri is H
  • Rd a is H
  • R 2b is H
  • R2c is H
  • R 2d is H
  • R3 is H, R 6 is H, R 7a is H, and R 7b is H.
  • Xi is N or CR3
  • X2 is N or CR 5 -
  • Ri is
  • R 2a is H
  • R 2b is H
  • R 2c is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H.
  • Xi is N or CR3
  • X2 is N or CR 5 -
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • R 2d is
  • R3 is H, Re is H, and R 7a is H, R?b is H, R? c is H, and R?d is H.
  • X is N or CR3,
  • X2 is N or CR 5 - Ri is H, R2a is H, R 2b is H, R 2c is H, R 2d is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, and n is 0 or 1.
  • Xi is N or CR3
  • Xi is N or CR 5 -
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ric is H
  • Rid is H
  • R? a is H
  • R?b is H, R?
  • c is H, R?d is H, and n is O.
  • Xi is N or CR3
  • Xi is N or CR5'
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Re is
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0, and m is 0, 1 , or 2.
  • Xi is N or CR3
  • X2 is N or CR 5 -
  • Ri is H
  • Ria is H
  • Rib is H
  • Ri c is H
  • Rid is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • Xi is N or CR3
  • X2 is N or CRs
  • Ri is H
  • R2 a is H
  • Rdb is H
  • R2 C H
  • R2d is H
  • R3 H
  • Re is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is N or CR3
  • Xi is N or CR5
  • ' Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • Rid H
  • R3 is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • Xi is N or CR3
  • Xi is N or CR 5 -
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • RM is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10
  • R5’ is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10
  • p is 0, 1, 2, or 3
  • each R7 e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with
  • Xi is N or CR3, X2 is N or CR 5 -, Ri is H, Rda is H, R 2b is H, R2 C is H, R 2d is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (Ci- C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxy alkyl, -OH, (C 6 -C 10 ) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Rn, and the carbocyclyl is optionally substituted with one to four Rn; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deutero
  • Xi is N or CR3
  • X2 is N or CR 5 -
  • Ri is H
  • Rda is H
  • R 2b is H
  • Rdd is R 2c
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Re- is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C-C-Jcaihocyclyl.
  • alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C,-C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C,-C 6 )haloalkyl, (C,-C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C,- C6)hydroxyalkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRi3’Ri3’, and Rg is (C 1
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or - NR9R10, Rv is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (Cd-Cvlcarbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21
  • X] is N or CR3. In another embodiment, Xi is N or
  • Xi is N or CR3
  • Xi is N
  • Ri is H
  • Ri a is H
  • RM is H
  • RM is H
  • R3 is H.
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is H, RM is H, RM is H, R3 is H, and Re is H.
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is H, RM is H, RM is H, R3 is H, Re is H, and R? a is H.
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is
  • R 2c is H
  • RM is H
  • R3 is H
  • Re is H
  • R? a is H
  • Rib is H.
  • X is N or CR3
  • X2 is N
  • Ri is H
  • R 2a is H
  • Rib is H
  • RM is H
  • Rid is H
  • R3 is H
  • Re is H
  • R? a is H
  • Rib is H
  • Ri c is H.
  • Xj is N or CR3
  • Xi is N
  • Ri is H
  • Ri a is H
  • RM is H
  • RM is H
  • Rid is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H.
  • Xi is N or CRg
  • Xi is N or CRg
  • Ri is H, Ria is H, Rib is H, RM is H, Rid is H, R3 is H, Re is H, and R? a is H, RM is H, R? c is H, Rid is H, and n is 0 or 1.
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is H, RM is H, RM is H, R3 is H, Rs is H, and R? a is H, R?b is H, R? c is H, Rva is H, and n is 0.
  • Xi is N or CR3
  • X2 is N
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Rs is H
  • R? a is H
  • R?b is H
  • R? c is
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is H, RM is H, RM is H, R3 is H, Re is H, and R? a is H, R?b is H, Rv c is H, RM is H, n is 0, m is 0, 1 , or 2, and each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • Xi is N or CR3
  • Xi is N
  • Ri is H
  • R 2a is H
  • RM is H
  • RM is H
  • Rid is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R?c is H
  • R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, RM is H, RM is H, RM is H, R3 is H, Rs is H, and Rv a is H, RM is H, R? c is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • X] is N or CR3, Xi is N, Ri is H, Ri a is H, Rib is H, Ri c is H, RM is H, R3 is H, Rs is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rv is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, and each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R?
  • spirocarbocyclyl when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C 6 )hydroxyalkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB’RB’.
  • substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )deuteroalkyl, (C 1 -C 6 )haloalky
  • Xi is N or CR3, Xi is N, Ri is H, Ri a is H, Rib is H, Ri c is H, RM is H, R3 is H, Re is H, and R? a is H, R?b is H, R?c is H, Ria is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R7 e , when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 )de
  • X] is N or CR3. In another embodiment, Xi is N or
  • CR3 and Xi is CR 5 -.
  • Xi is N or CR3, Xi is CR 5 -, and Ri is H.
  • Xi is N or CR3, Xi is CR 5 -, Ri is H, and Ri a is H.
  • Xi is N or CR3, Xi is CR 5 -, Ri is H, Ri a is H and Rib is H.
  • X, is N or CR3, Xi is CR 5 -, Ri is H, Ri a is H, R 2b is H, and Ric is H.
  • Xi is N or CR3, Xi is CR 5 -, Ri is H, Ri a is H, Rib is
  • Ric is H
  • RM is H
  • Xi is N or CR3
  • Xi is CR 5 -
  • Ri is H
  • Ri a is H
  • Rib is H
  • RM is H, RM is H, and R3 is H.
  • X] is N or CR3, Xi is CR 5 -, Ri is H, Ri a is H, Rib is H, Ric is H, RM is H, R3 is H, and Re is H.
  • Xi is N or CR3, Xi is CR 5 -, Ri is H, R2a is H, R 2b is H, R2 C is H, Rdd is H, R3 is H, Re is H, and R? a is H.
  • Xi is N or
  • CR3, X2 is CR5', Ri is H, Rda is H, R 2b is H, R2 C is H, Rdd is H, R3 is H, Re is H, R? a is H, and R?b is H.
  • Xi is N or CR3, X2 is CR 5 -, Ri is H, R2a is H, R 2b is H, is H, R2d is H,R R 2c 3 is H, Re is H, R? a is H, R?b is H, and R? c is H.
  • Xi is N or CR3
  • X2 is CR 5 -
  • Ri is H
  • R2a is H
  • Rdb is H
  • R2 C is H
  • R2d is H
  • R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, and R?d is H.
  • Xi is N or CR3
  • X2 is CR 5 -
  • Ri is H
  • R 2a is H
  • R 2b is H
  • RR2 2 d c is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0 or 1.
  • X is N or CR3
  • X2 is CR5'
  • Ri is H
  • Rda is H
  • R 2b is H
  • R2 C is H
  • Rdd is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0.
  • Xi is N or CR3, X2 is CR 5 -, Ri is H, R2a is H, Rdb is H, R2 C is H, R2d is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, and m is 0, 1, or 2.
  • Xi is N or CR3
  • X2 is CR 5 -
  • Ri is H
  • Rda is H
  • R 2b is H
  • R2 C is H
  • Rdd is
  • R 3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • Xi is N or CR3
  • X2 is CR 5 -
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • R2d H
  • R3 is H
  • Re is H
  • R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (Ci- C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and R5' is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is N or CR3
  • X2 is CR5'
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R c is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H, R?b is H, R?
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, R5’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • Xi is N or CR3
  • X2 is CR 5 -
  • Ri is H
  • R2 a is H
  • Rdb is H
  • R2 C is H
  • R2d is H
  • R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs’ is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, and each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rv e , when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 )spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6
  • Xi is N or CR3, X2 is CR 5 -, Ri is H, Rda is H, R 2b is H, R2 C is H, Rdd is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rv is H, (C 1 -C 6 )alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- Cs)alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R?
  • Xi is N. In another embodiment, Xi is N and Xi is
  • Xi is N, Xi is N, and Ri is H.
  • Xj is N, X2 is N, Ri is H, and Ri a is H.
  • Xi is N, Xi is N, Ri is H, Ri a is H and Rib is H.
  • Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, and Ri c is H.
  • Xj is N, X2 is N, Ri is H, Ri a is H, Rib is H, Ri c is H, and Rid is H.
  • Xi is N, Xi is N, Ri is N, Ri is
  • Ri a is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Xi is N
  • Xi is N
  • Ri is H
  • Ria is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Rs is H
  • Xi is N
  • Xi is N
  • Ri is H
  • Ria is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Rs is H
  • R? a is H.
  • Xi is N,
  • X2 is N, Ri is H, Ria is H, Rib is H, Ri c is H, Rid is H, R3 is H, Re is H, R? a is H, and R?b is H.
  • Xi is N
  • X2 is N
  • Ri is H
  • Ria is H
  • Rib is H
  • Ric is H
  • Rid is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b H
  • R? c is H.
  • Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ri c is H, Rid is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, and R? ⁇ i is H.
  • Xi is N, X2 is N, Ri is H, Ri a is
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • Rv ⁇ i is H
  • n is 0 or 1.
  • Xi is N
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • Rid is H
  • R3 is H
  • Re H
  • R?a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0.
  • Xi is N
  • Xi is N
  • Ri is H
  • Ri a is H
  • Rib is H
  • Ri c is H
  • RM is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • Rv c is H
  • Rv ⁇ is H
  • n is 0, and m is
  • Xi is N
  • X2 is N
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?e is H
  • R? c is H
  • R?d is H
  • n is 0, m is 0, 1 , or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • X is N
  • X2 is N
  • Ri is H
  • R 2a is H
  • R 2b is H
  • R2C is H
  • Rdd is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R?c is H
  • R?d is H
  • n is 0, m is 0, 1, or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or - NR9R10
  • Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is N
  • X2 is N
  • Ri is H
  • R 2a is H
  • R 2b is H
  • R2C is H
  • Rdd is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0, m is 0, 1, or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or - NR9R10
  • Re- is H
  • p is 0, 1, 2, or 3.
  • Xi is N
  • X2 is N
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H, R?
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optional
  • Xi is N
  • X2 is N
  • Ri is H
  • R2 a is H
  • R2t> is H
  • R2 C is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0, m is 0, 1, or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10
  • Rs- is H
  • p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R70 when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (Ci- C6)deuteroalky
  • Xi is CR3. In another embodiment, Xi is CR3 and X2 is CR 5 -. In yet another embodiment, Xi is CR3, X2 is CR5’, and R, is H. In another embodiment, Xi is CR3, X2 is CR 5 -, Ri is H, and Rd a is H. In yet another embodiment, Xi is CR3, X2 is CR 5 -, Ri is H, Rd a is H and Rdb is H. In another embodiment, Xi is CR3, X2 is CR 5 -, Ri is H, R2 a is H, Rye is H, and Ry c is H.
  • Xi is CR3, X2 is CR 5 -, Ri is H, Rd a is H, Rye is H, Ry c is H, and Rye is H.
  • Xi is CR3, X2 is CR 5 -, Ri is H, R2 a is H, Rye is H, R2 C is H, Rdd is H, and R3 is H.
  • Xi is CR3, X2 is CR 5 -, Ri is H, Ry a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, and Re is H.
  • Xi is CR3, X2 is CR 5 -, Ri is H, Ry a is H, Rye is H, Ry c is H, Ryd is H, R3 is H, Re is
  • Xi is CR3
  • Xy is CR 5 -
  • Ri is H
  • Ry a is H
  • Rye is H
  • Ry c is H
  • Ryd is
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • Xi is CR3
  • X2 is CR 5
  • Ri is H
  • Ry a is
  • R 2b is H
  • Ry c is H
  • Rye is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H.
  • Xi is CR3
  • X2 is CR 5 -
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • R2d is H
  • R3 is
  • Xi is CR3, X2 is CR5', Ri is H, R 2a is H, R 2b is H, R2C is H, Ryd is H, R3 is H, Rd is H, and R? a is H, R?b is H, R7 C is H, R?d is H, and n is 0 or 1.
  • Xi is CR3, X2 is CR5', Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, Re is H, and R?
  • a is H, R?b is H, R? c is H, R?a is H, and n is 0.
  • Xi is CR3, X2 is CR5’, Ri is H, Ry a is H, Ryb is H, Ry c is H, Ryd is H, R3 is H, Re is H, and R? a is H, Rye is H, R? c is H, R?d is H, n is 0, and m is 0, 1, or 2.
  • Xi is CR3, X2 is CR 5 ’
  • Ri is H
  • R2 a is H
  • R 2b is H
  • R2 C is H
  • Ry ⁇ i is H
  • R3 is H
  • R 6 is H
  • R? a is H
  • R?b is H
  • Rv c is H
  • R? ⁇ 1 is H
  • n is 0, m is 0, 1 , or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 ) alkoxy, halogen, or -NR9R10.
  • Xi is CR3, X2 is CR 5 -, Ri is H, Rd a is H, Rdb is H, Ry c is H, Rdd is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H,
  • R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and Ry is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is CR3, X2 is CR 5 -, Ri is H, R 2a is H, R 2b is H, Rd C is H, R2d is H, R3 is H, Re is H, and Ry a is H, Rvi- is H, R? c is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • X] is CR3, X2 is CR 5 -, Ri is H, R2 a is H, R 2b is H, Rye is H, R2d is H, R3 is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is
  • Xi is CR3, X2 is CR5’
  • Ri is H
  • Rda is H
  • R 2b is H
  • R2 C is H
  • Rdd is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0, m is 0, 1, or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10
  • Rs- is H
  • p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C 3 -C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R7 e , when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6
  • Xi is N. In another embodiment, Xi is N and X2 is
  • Xi is N
  • X2 is CRv
  • Ri is H
  • Xi is N
  • X2 is N
  • CR 5 -, Ri is H, and R2a is H.
  • Xi is N, X2 is CR 5 -, Ri is H, R2a is H and R 2b is H.
  • Xi is N, X2 is CR 5 -, Ri is H, Rda is H, R 2b is H, and R2 C is H.
  • Xi is N, X2 is CR 5 -, Ri is H, R2 a is H, R 2b is H, R2 C is H, and R2d is H.
  • Xi is N, X2 is CR 5 -, Ri is H, R2 a is H, R 2b is H, R2 C is H, and R2d is H.
  • Xi is N, X2 is CR5', Ri is H, R2a is H, R 2b is H, R2 C is H, R2d is H, and R3 is H.
  • Xi is N, X2 is CR 5 -, Ri is H, R2a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, and Re is H.
  • Xi is N, X2 is CR 5 -, Ri is H, Rda is H, Rdb is H, Rdc is H, Rdd is H, R3 is H, Re is H, and R? a is
  • Xi is N, X2 is CR 5 -, Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, Re is H, R 7a is H, and R 7 b is H.
  • Xi is N, X2 is CRy, Ri is H, R 7a is H, R 7 b is H, R 7c is
  • R 2d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H.
  • Xi is N
  • X2 is CRe-
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R?e is H
  • R 7c is H
  • Rva is H
  • Xi is N
  • X2 is CR5’
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R?b is H
  • R 7c is H
  • R?d is H
  • n is 0 or
  • Xi is N, X2 is CR 5 -, Ri is H, R 7a is H, R 7 b is H, R 7c is H, R 7 d is H, R3 is H, Re is H, and R 7a is H, R 7 b is H, R 7c is H, R 7 d is H, and n is 0.
  • Xi is N, X2 is CR 5 -, Ri is
  • R 7a is H
  • R 2b is H
  • R 7c is H
  • R2d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R 7b is H
  • R 7c is H
  • R 7 d is H
  • n is 0, and m is 0, 1, or 2.
  • Xi is N
  • X2 is CR 5 -
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R?b is H
  • R 7c is H
  • R 7 d is H
  • n is 0, m is 0, 1, or 2
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • Xi is N
  • X2 is
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is N
  • X2 is CRr
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • n is
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or - NR9R10, R5’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • Xi is N
  • X2 is CR5’
  • Ri is H
  • R2 a is H
  • R 7 b is H
  • R2 C is H
  • R2d is H
  • R3 is H
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rv is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R 7e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C3-C 7 )carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally
  • Xi is N
  • X2 is CRe-
  • Ri is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • R3 is H
  • Re is H
  • R 7a is H
  • R 7 b is H
  • R 7c is H
  • R 7 d is H
  • n is 0, m is 0, 1
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10
  • Rs- is H
  • p is 0, 1, 2, or 3
  • each R 7e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C
  • Xi is CR3. In another embodiment, Xi is CR3 and X2 is N. In yet another embodiment, Xi is CR3, X2 is N, and Ri is H. In another embodiment, X] is CR3, X2 is N, Ri is H, and R2 a is H. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2 a is H and R 2b is H. In another embodiment, Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, and R2 C is H.
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, and R2d is H.
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, and R3 is H.
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, Re is H, and Rv a is H.
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, Rdd is H, R3 is H, Re is H, R? a is H, and R?b is H.
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, Re is H, R? a is H, Rve is H, and Rv c is H.
  • X] is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, R2 C is H, R2d is H, R3 is H,
  • Re is H, and Rv, is H, R?b is H, R? c is H, and R?d is H.
  • X is CR3, X2 is N, Ri is H,
  • R 2a is H
  • R 2b is H
  • R2 C is H
  • R2d is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0 or
  • Xi is CR3, X2 is N, Ri is H, R2 a is H, R 2b is H, Rdc is H, R2d is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, and n is 0.
  • Xi is CR3, X2 is N, Ri is
  • R 2a is H
  • Rdb is H
  • Rd C is H
  • Rdd is H
  • R3 is H
  • Re is H
  • R? a is H
  • R?b is H
  • R? c is H
  • R?d is H
  • n is 0, and m is 0, 1 , or 2.
  • Xi is CR3, X2 is N, Ri is H, R23 is H, R 2b is H, is H, R2d is H,R R 2c 3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10.
  • X is CR3, X2 is N, Ri is H, R 2a is H, R 2b is H, R2 C is H, R2d is H, R3 is H, Re is H, and R? a is H, R?b is H, R? c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, and R5’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10.
  • Xi is CR3, Xi is N, Ri is H, Ri a is H, Rib is H, Ri c is H, Rid is H, R3 is H, Re is H, and Ria is H, Rib is H, Ri c is H, Rid is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
  • X] is CR3, X2 is N, Ri is H, Ri a is H, Rib is H, Ric is H, Rid is H, R3 is H,
  • each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, Rs- is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each Ri e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (Ci- C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally
  • spirocarbocyclyl when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (C 1 -C 6 ldeuteroalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (Ci- C 6 )hydroxyalkyl, halogen, -C(O)ORi3’, -C(O)Ri3, and -C(O)NRi3’Ri3’-
  • Xi is CR3, Xi is N, Ri is H, Ria is H, Rib is H, Ri c is H, Rid is H, R3 is H, Re is H, and Ri a is H, Rib is H, Ri c is H, Rid is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, or -NR9R10, R5’ is H, (C 1 -C 6 )alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?
  • e is independently at each occurrence (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )hydroxyalkyl, -OH, (C 6 -C 10 ) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two Ri e , when on the same carbon atom, together with the carbon atom to which they are attached form a (C 3 -C 7 ) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C 1 -C 6 )alkyl, (Ci- C 6 )deuteroal
  • Non-limiting illustrative compounds of the disclosure include the compounds in Table 1: Cmpd

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Abstract

The present disclosure provides a Compound of Formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R1, R2a, R2b, R2c, R2d, R6, R7a, R7b, R7c, R7d, R7e, R8, X1, X2, X3, X4, X5, X6, X7, o, p, r and subvariables thereof are as defined herein.

Description

SUBSTITUTED (PIPERIDIN-4-YL)-l,5-NAPHTHYRIDINE AND (PIPERIDIN-4-
YDQUINOLINE DERIVATIVES AND USES THEREOF
CLAIM OF PRIORITY
The present application claims priority to U.S. Application No. 63/547,059, filed November 2, 2023, and U.S. Application No. 63/547,060, filed November 2, 2023. The entire contents of each of the foregoing applications are incorporated by reference in their entirety.
FIELD OF THE DISCLOSURE
The present disclosure relates to substituted (piperidin-4-yl)-l,5-naphthyridine and (piperidin-4- yl)quinoline compounds and compositions for modulation of hypoxia inducible factor 1 beta (HIF-lb) and their use for the treatment of HIF-lb-dependent diseases or disorders or where reduction of HIF-lb protein levels can ameliorate a disease or disorder.
BACKGROUND OF THE DISCLOSURE
The HIE transcription factors are master regulators of the cellular response to hypoxia. The HIE transcriptional regulator acts as a heterodimeric complex consisting of the constitutively expressed hypoxia inducible factor 1 beta (HIF-lb, also known as ARNT) and either of the two HIF-a isoforms, HIF-la or
HIF-2a. HIF-lb is a key player in both the hypoxic-response pathway and the aryl hydrocarbon receptor (AHR) pathway. The first evidence provided that the HIF heterodimer not only activates the erythropoietin gene but is also part of a widespread oxygen-sensing and signal transduction mechanism was demonstrated when HIF activity was detected in various non-erythropoietin-producing cell lines cultured under hypoxic conditions (Wang and Semenza, Proc. Natl. Acad. Set. USA, 1993, 90, 4304-4308; Maxwell et al., Proc. Natl. Acad. Set. USA, 1993, 90, 2423-2427).
Oxygen supply to tissues is essential in maintaining mammalian cell function and physiology and a deficiency in oxygen supply to tissues is a characteristic of a number of conditions in which there is insufficient blood flow to provide adequate oxygenation. Examples of diseases affected by inadequate oxygen supply include ischemic disorders, cancer, and atherosclerosis. Activation of a signaling cascade occurs in response to this hypoxic environment in tissues which drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo- vascularization), glucose metabolism, and cell survival/death. A key to this hypoxic transcriptional response lies in the transcription factors, the hypoxia inducible factors (HIF).
It has been shown that both HIF-a isoforms are rapidly degraded under normoxic conditions due to the oxygen-dependent hydroxylation of specific proline residues that mark the proteins for proteasomal degradation (Jewell, et al., Faseb. J., 2001, 15, 1312-1314; Gorlach, et al., Biochim. BioPhase. Acta, 2000, 1493, 125-134) and that under hypoxic conditions this hydroxylation is reversed, and the protein is further stabilized by phosphorylation (Wang et al., Biochip. Biophys. Res. Comrnun, 1995, 216, 669-675). Consequently, the HIF-a proteins are then translocated to the nucleus, where they interact with HIF-lb to form a heterodimeric transcription factor (Kallio et al., Embo J, 1998, 17, 6573-65, 86). The dimerization step has been shown in HIF-lb deficient cells to be an absolute requirement for the transcriptional activation of hypoxia response element genes (Wood et al., J. Biol. Chem., 1996, 271, 15117-15123). As a result, there are categories of genes that are activated by the HIF dimer which include oxygen transport genes, such as erythropoietin (Semenza, et al., J. Biol. Chem., 1994, 269, 23757- 23763) and transferrin (Rolfs et al., J. Biol. Chem., 1997, 272, 20055-20062); as well as genes involved in angiogenesis, such as VEGF (Levy et al., J. Biol. Chem., 1995, 270, 13333-13340); and genes involved in anaerobic metabolism, such as glucose transporter 1 (Ebert et al., J. Biol. Chem., 1995, 270, 29083-29089). It is thought that hypoxia- induced genes such as VEGF play a role in promoting angiogenesis and subsequent tumor growth (Harris, Nat. Rev. Cancer, 2002, 2, 38-47).
Cellular oxygen concentration precisely regulates HIF transcriptional activity. While changes in oxygen levels do not affect HIF-lb protein levels, the abundance of the HIF-a subunits is markedly increased upon exposure of cells to hypoxia, primarily due to stabilization of the alpha subunits (Safran and Kaelin, J. Clin. Invest., 2003, 111, 779-783). The HIF-2a/HIF-lb heterodimer protein, which contains the core recognition sequence 5’-TACGTG-3’, binds to the hypoxic response element and is found in the cis- regulatory regions of hypoxia-regulated genes (Ema, et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94, 4273- 4278; Hogenesch, et al., J. Biol. Chem., 1997, 272, 8581-8593). It has been shown that binding of the heterodimer to the hypoxia-responsive element (HRE) induces gene expression (Wiesener, et al., Blood, 1998, 92, 2260-2268).
A range of other genes regulated by the dioxin response element (DRE) can also be activated by HIF dimers resulting in some of the toxic and carcinogenic effects associated with many of the AHR ligands, such as immunotoxicity, developmental and reproductive toxicity, disruption of endocrine pathways, wasting syndrome, and tumor promotion (Safe Toxicol. Lett., 2001, 120, 1-7). It has been demonstrated that the AHR/HIF-lb heterodimer directly associates with the estrogen receptors ER-a and ER-b and that this association results in the recruitment of unliganded estrogen receptor and coactivator p300 to estrogen-responsive gene promoters. This association has been shown to lead the activation of transcription and estrogenic effects and to give rise to the adverse estrogen-related actions of dioxin-type environmental contaminants (Ohtake et al., Nature, 2003, 423, 545-550).
In summary, HIF-lb plays an important role in both the hypoxia-induced and AHR signaling pathways, which have been linked to various forms of malignancies (Harris, Nat. Rev. Cancer, 2002, 2, 8- 47; Safe Toxicol. Lett., 2001, 120 1-7) The angiogenic promoting capabilities of HIF-lb also make it a potential therapeutic target for a variety of angiogenic disorders, such as arthritis, cardiovascular diseases, skin conditions, aberrant wound healing and ocular conditions (e.g., macular degeneration, diabetic retinopathy, diabetic macular edema and retinopathy of prematurity). Reduction of HIF-lb levels with small molecule modulators therefore has the potential to be a treatment for a range of diseases, including cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-related diseases. For this reason, there remains a considerable need for novel and potent small molecule modulators of HIF-lb.
SUMMARY OF THE DISCLOSURE
The compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary disorders (e.g., pulmonary arterial hypertension (PAH)), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other HIF-lb-related diseases. In one aspect, the compounds of the disclosure have HIF-lb degrader activity. In some embodiments, the HIF-lb degrader activity is at or below the 50 pM level, and more preferably at or below the 10 pM level, when administered to a cell or subject. The compounds of the disclosure have usefulness in treating cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases, and other diseases for which such degrader activity would be beneficial.
A first aspect of the present disclosure relates to compounds of Formula (I):
Figure imgf000004_0001
pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CRp X2 is N, N(O), or CR5;
X3 is N or CR4a; X4 is N or CR4bi X5 is N or CR4b-; Xe is N or CR5; X? is N or N(O); wherein no more than three of X2, X2, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -
CH2OC(O)NHRI2, -CH2OC(O)OR]2, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)ORI2,
CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(RI2-)NHRI2-, -CH2OC(O)(CH2)q- C(0)0Ri2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, R2c, and R2d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, R2b, R2c, and R2d may be taken together with the carbon atom to which they are attached form a (Cs-Cvlcarbocyclyl or (C3-C7)spirocarbocyclyl; R3 is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, halogen, or -OH, wherein R3 may be taken together with one of R2a, R2b, R2c, and R2d with the carbon atom to which they are attached to form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; Rda, R4b, and R4b' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, O(C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or - NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R4oR4a- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R5 and Rs- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3- C7)carbocyclyl, O(C3-C7)carbocyclyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R4oR4a' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R() is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6) aminoalkyl, (C1-C6)alkyl-0-(Ci- C6)hydroxyalkyl, -C(0)Rn, -CH20C(0)Rn, -CH2OC(O)NHR,2, -CH2OC(O)OR,2, -P(O)(OR,2)2, - CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R?a, R?b, R?c, and R?d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci-C2)haloalkyl; or two of R2a, R?b, R?c, and R?d are taken together with the carbon atoms to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)Ri3, and -C(O)NRi3'Ri3'; each R2e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(Ci-Cb)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R21, and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R2e together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3- C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3 , -C(0)RB, and -C(O)NRi3'Ri3-; one Rve is taken together with any one of Rva, R?b, R?c, and R?d and the atoms to which they are attached form a (Cs-Cvlcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; Rs is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C3-C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, - SF5, -SRua, -NR14R14', -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R 15 ; R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci- C6)haloalkyl; Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Cs-Cio)aryl, (C1-C6)alkoxy, ((C1-Cj6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (Ci-Gjalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12’ is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl; R13’ is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; Ru and Ru- are each independently at each occurrence H or (C1-C6)alkyl; Rua is H, (Ci- C6)alkyl or (C1-C6)haloalkyl; R15 and Riv are each independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, alkoxy,”" phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)Rs7, - C(O)OR37, -SF5, -SR29, SO2NR30R31, -CN, and R19; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two R 15 , when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together with the atoms to which they are attached form a (Cs-C-icarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two R 15 when on the same carbon atom form C=(0); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN; Rn is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci-Cjhaloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20 and R20’ are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6lhaloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more Rp; R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)Rs9; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, - 0(C3-C7)carbocyclyl, phenyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.
In one aspect of the disclosure, the hydrogens in the Compound of Formula (I) are present in the normal isotopic abundances. In a preferred aspect of the disclosure, the hydrogens are isotopically enriched in deuterium (D), as discussed in more detail concerning isotopes and isotopic enrichment below.
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient for use in the treatment of an HIF-lb-dependent disease or disorder by reducing HIF-lb protein levels wherein reduction of HIF-lb protein levels treats the HIF-lb-dependent disease or disorder. The pharmaceutical composition is useful in the treatment of HIF-lb-dependent diseases or disorders. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is useful in the treatment of diseases or disorders affected by the reduction of HIF-lb protein levels. The pharmaceutical composition may further comprise at least one additional pharmaceutical agent.
In another aspect, the present disclosure relates to a method of degrading HIF-lb, comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the present disclosure relates to a method of modulating HIF-lb levels comprising administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
In another aspect, the present disclosure relates to an in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the present disclosure relates to a method of treating a disease or disorder that is affected by the modulation of HIF-lb levels, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
In another aspect, the present disclosure relates to a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the cancer is VHL-deficient cancer. In another embodiment, the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or nonHodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.
Another aspect of the present disclosure relates to a method for reducing HIF-lb levels, comprising administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
In another aspect, the present disclosure relates to a method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the present disclosure relates to a method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
In another aspect, the present disclosure relates to a method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
The present disclosure provides degraders of HIF-lb that are therapeutic agents in the treatment of diseases such as cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF-lb protein levels, and in the treatment HIF- Ib-dependent diseases or disorders.
In one embodiment, the disease or disorder that can be treated by the compounds of the present disclosure is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, including but not limited to, renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
The present disclosure provides agents with novel mechanisms of action toward HIE- lb proteins in the treatment of various types of diseases including cancer von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases, in the treatment of diseases affected by the modulation of HIF- 1b protein levels, and in the treatment HIF-lb-dependent diseases or disorders. Ultimately the present disclosure provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with HIF-lb proteins.
DETAILED DESCRIPTION OF THE DISCLOSURE
The present disclosure relates to compounds and compositions that are capable of modulating HIF- lb protein levels. The disclosure features methods of treating, preventing, or ameliorating a disease or disorder in which HIF-lb plays a role by administering to a patient in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present disclosure can be used in the treatment of a variety of HIF-lb-dependent diseases and disorders by modulating HIF-lb protein levels. Modulation of HIF-lb protein levels through degradation provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, and other HIF- lb-dependent diseases or disorders.
In one aspect, the compounds of the disclosure have use as therapeutic agents, particularly for cancers, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other HIF-lb-related diseases. In one aspect, the compounds of the disclosure have HIF-lb degradation activity, preferably having such activity at or below the 50 pM level, and more preferably having such activity at or below the 10 pM level. The compounds of the disclosure have usefulness in treating cancer and other diseases for which such degradation activity would be beneficial for the patient. In summary, the present disclosure provides novel HIF-lb degraders useful for the treatment of cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, metabolic diseases, allergic and genetic diseases and other disease related to the modulation of HIF-lb-related diseases.
In a first aspect of the disclosure, the compounds of Formula (I) are described:
Figure imgf000012_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein Ri, R2a, R2b, R2c, R2d, Re, R?a, R?b, R?c, R7d, R7e, Rs, Xi, X2, X3, X4, X5, X6, X7, o, p, r and subvariables thereof are as defined herein.
The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.
Definition of Terms and Conventions Used
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification and appended claims, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
A. Chemical Nomenclature, Terms, and Conventions
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, (C1-C10)alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups comprising two or more subgroups, the last named group is the radical attachment point, for example, "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, while "arylalkyl" means a monovalent radical of the formula aryl-alkyl-. Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
The term "and/or" means either "and" or "or" unless indicated otherwise.
The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g. , heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-Cg)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted whose meaning is described below.
The term "substituted" means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
The term "unsubstituted" means that the specified group bears no substituents.
Unless otherwise specifically defined, "aryl" means a cyclic, aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group are optionally joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group is optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -CN, -O-(C1-C6)alkyl, (Cl-CS)alkyl, -O-(C2-C5)alkenyl, -O-(C2- C6)alkynyl, (C2-C5)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C5)alkyl, -C(O)(C1-C6)alkyl, - OC(O)O(C1-C6) alkyl, NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents are themselves optionally substituted. Furthermore, when containing two fused rings, the aryl groups optionally have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, 0, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno [3 ,2-b] thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1 ,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b ][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3- ajpyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l ,2-a]pyrimidinyl, tetrahydropyrrolo[l ,2-a]pyrimidinyl, 3,4-dihydro-2H- lA2-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3- c]pyridinyl, lH-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[l,2,3]triazolyl, imidazo[l,2a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c] [l,2,5]thiadiazolyl, benzo[c] [1,2,5] oxadiazole, l,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo [1,5-b] [l,2]oxazinyl,4,5,6, 7-tetrahydropyrazolo [l,5-a]pyridinyl, thiazolo[5,4d]thiazolyl, imidazo[2,l-b] [ 1 ,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.
"Alkyl" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6)alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. "Alkoxy" means a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "0" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
"Alkenyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted and may be straight or branched.
"Alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.
"Alkylene" or "alkylenyl" means a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a (C1-C6)alkylene. An alkylene may further be a (Ci -Chalky lene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH-, and the like.
"Amino" means a substituent containing at least one nitrogen atom (e.g., NH2).
"Cyano" means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C=N
"Cycloalkyl" or "carbocyclyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbon ring containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A (C3-Cs)cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g. , decalin) or bridged (e.g., norbornane).
"Deuteroalkyl" means an alkyl group substituted with one or more deuterium (“D”). Examples of deuteroalkyl groups include -CDH2, -CD3, -CHD2, -CD2CH3, -CD2CD3, CH2CD3, -CHDCH3, - CD2CH2CD3, etc.
“Halogen” or "halo" mean fluorine, chlorine, bromine, or iodine.
"Haloalkyl" means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. "Haloalkoxy" means an alkoxy group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
“Halohydroxyalkyl” means an alkyl group substituted with at least one halogen and at least one - OH group. Examples of halohydroxyalkyl groups include, but are not limited to, HO-C(H)F-, HO-CH(F)- CH2-, CF3-CH(OH)-CH2-, and CH3-CH(OH)-, etc.
"Heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, or sulfur (0, N, or S) and wherein there is not delocalized n electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1 ,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolanyl, and homotropanyl.
"Hydroxyalkyl" means an alkyl group substituted with one or more -OH groups. Examples of hydroxyalkyl groups include H0-CH2-, HO-CH2CH2-, and CH3-CH(0H)-.
"Spirocarbocyclyl " or "spirocycloalkyl" means carbogenic bicyclic ring systems with both rings connected through a single atom. The rings can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. A (C3-Ci2)spirocarbocyclyl is a spirocycle containing between 3 and 12 carbon atoms.
"Spiroheterocyclyl" or "spiroheterocycloalkyl" means a spirocycle wherein at least one of the rings is a heterocycle one or more of the carbon atoms can be substituted with a heteroatom (e.g. , one or more of the carbon atoms can be substituted with a heteroatom in at least one of the rings). One or both of the rings in a spiroheterocyclyl can be fused to another ring, e.g., carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions
"Prodrug" or "prodrug derivative" means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound for example by hydrolysis in blood and generally include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased aqueous solubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger’s Medicinal Chemistry and Drug Discovery, Sth Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.
"Pharmaceutically acceptable prodrug" as used herein means a prodrug of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
"Salt" means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound. Salts of the compounds of the present disclosure can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
"Pharmaceutically acceptable salt" means a salt of a compound of the disclosure which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. As the compounds of the present disclosure are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sei., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety. "Pharmaceutically-acceptable acid addition salt" means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2- naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3 -phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.
"Pharmaceutically-acceptable base addition salt" means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, N,N’ -dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
"Solvate" means a complex of variable stoichiometry formed by a solute, for example, a Compound of Formula (I)) and solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, such solvents selected for the purpose of the disclosure do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
"Hydrate" means a solvate wherein the solvent molecule(s) is/are water.
The compounds of the present disclosure as discussed below include the free base or acid thereof, their salts, solvates, and prodrugs and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structure, although not explicitly stated or shown, particularly the pharmaceutically acceptable forms thereof Such forms, particularly the pharmaceutically acceptable forms, are intended to be embraced by the appended claims.
C. Isomer Terms and Conventions
"Isomers" means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.
"Stereoisomer" or "optical isomer" mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.
“Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" or "diastereomers" mean optical isomers, which are not mirror images of each other.
"Racemic mixture" or "racemate" mean a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" means a mixture containing unequal parts of individual enantiomers.
"Geometrical isomer" means a stable isomer, which results from restricted freedom of rotation about double bonds (e.g., cis-2-butene and trans-2-butene) or in a cyclic structure (e.g., cis- 1,3- dichlorocyclobutane and trans-l,3-dichlorocyclobutane). Because carbon-carbon double (olefinic) bonds, C=N double bonds, cyclic structures, and the like may be present in the compounds of the disclosure, the disclosure contemplates each of the various stable geometric isomers and mixtures thereof resulting from the arrangement of substituents around these double bonds and in these cyclic structures. The substituents and the isomers are designated using the cis/trans convention or using the E or Z system, wherein the term "E" means higher order substituents on opposite sides of the double bond, and the term "Z" means higher order substituents on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, 1992, which is hereby incorporated by reference in its entirety. Several of the following examples represent single E isomers, single Z isomers, and mixtures of E/Z isomers. Determination of the E and Z isomers can be done by analytical methods such as x-ray crystallography, *H NMR, and 13C NMR.
Some of the compounds of the disclosure can exist in more than one tautomeric form. As mentioned above, the compounds of the disclosure include all such tautomers.
It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the ait will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.
Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S -isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S -penicillamine is a therapeutic agent for chronic arthritis, while inactive, R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.
Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.
Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.
In general, all tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.
D. Pharmaceutical Administration and Treatment Terms and Conventions
A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
An "effective amount" or "therapeutically effective amount" when used in connection with a compound means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
The terms "pharmaceutically effective amount" or "therapeutically effective amount" means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound of according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.
As used herein, the term "pharmaceutical composition" refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
"Carrier" encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. A subject is "in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).
As used herein, the term "inhibit", "inhibition", or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treat", "treating", or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
As used herein, the term "prevent", "preventing", or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder. "Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
"Disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
"Administer", "administering", or "administration" means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. "Compounds of the present disclosure", "compounds of the disclosure", and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formulae (I), (la), (lb), (le), (Id), (le), (If), (1g), (Ih), (li), (Ij), (Ik), (II), (Im), (Io), (Ip) (Iq), (Ir), (lu), (Iv), (Iw), (lx), (ly), (Iz), (laa), (Ibb), (Icc), (Idd), (lee), (Iff), (Igg), (Ihh), (lii), (Ijj), (Ikk), (Imm), (loo), (Ipp), (Iqq), (Irr), (Iss), (Itt), (luu), (Ivv), (Iww), (Ixx), (Iyy), (Izz), (laaa), (Ibbb), (Iccc), (Iddd), (leee), (Ifff), (Iggg), (Ihhh), (liii), (Ijjj), and (Ikkk), as herein described including the tautomers, the prodrugs, salts particularly the pharmaceutically acceptable salts, and the solvates and hydrates thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and/or hydrates). For the purposes of this disclosure, solvates and hydrates are generally considered compositions. In general and preferably, the compounds of the disclosure and the formula designating the compounds of the disclosure are understood to only include stable compounds thereof and exclude unstable compounds, even if an unstable compound might be considered to be literally embraced by the compound formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative, and it is not intended to exclude other instances when the context so permits.
"Stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic or diagnostic agent. For example, a compound, which would have a "dangling valency" or is a carbanion is not a compound contemplated by the disclosure.
In a specific embodiment, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
"Simultaneously n" or "simultaneous" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by the same route and at the same time.
"Separately" or "separate" when referring to a method of treating or a therapeutic use means with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s) means administration of the compound and the one or more second agent(s) by different routes and at approximately the same time.
By therapeutic administration "over a period of time" means, when referring to a method of treating or a therapeutic use with a combination of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more second agent(s), administration of the compound and the one or more second agent(s) by the same or different routes and at different times. In some embodiments, the administration of the compound or the one or more second agent(s) occurs before the administration of the other begins. In this way, it is possible to administer a one of the active ingredients (i.e., a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or one or more second agent(s)) for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. Another therapeutic administration over a period of time consists of the administration over time of the two or more active ingredients of the combination using different frequencies of administration for each of the active ingredients, whereby at certain time points in time simultaneous administration of all of the active ingredients takes place whereas at other time points in time only a part of the active ingredients of the combination may be administered (e.g., for example, a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and the one or more second agents the therapeutic administration over a period of time could be such that a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered once a day and the one or more second agent(s) is administered once every four weeks).
The compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
"HIF-lb-dependent disease or disorder" means any disease or disorder which is directly or indirectly affected by the modulation of HIF-lb protein levels. The term “von Hippel-Lindau disease” or “VHL disease” or “VHL syndrome” or “von Hippel- Lindau syndrome”, as used herein, refers to a rare disease caused by a mutation in the von Hippel-Lindau (VHL) tumor suppressor leading to an aberrant non-functional VHL protein and to an absence of VHL protein. VHL gene mutations associated with this condition either prevent the production of any VHL protein or lead to the production of an abnormal version of the protein, with more than 370 inherited mutations in the VHL gene having been identified in people with von Hippel-Lindau disease (http://www.umd.be/VHL/). VHL disease is characterized by the formation of multiple benign and malignant tumors and fluid-filled sacs (cysts) in many different parts of the body, including: retinal hemangioblastoma, CNS hemangioblastoma, clear cell renal cell carcinoma (CCRCC), pheochromocytoma, pancreatic islet tumor, endolymphatic sac tumors and cysts in testes and broad ligament.
"Colitis" is an inflammation of the colon. The colitis may be acute or chronic. As used herein, colitis includes ulcerative colitis, microscopic colitis, lymphocytic colitis, collagenous colitis, diversion colitis, chemical colitis, ischemic colitis, infections colitis, pancolitis, left-sided colitis, extensive colitis, segmental colitis, microscopic colitis, radiation-induced colitis, medication-induced colitis and proctitis.
E. Compounds
The present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of modulating HIF-lb protein levels, which are useful for the treatment of diseases and disorders associated with modulation of HIF-lb protein levels. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for reducing or decreasing HIF-lb protein levels.
The present disclosure features compounds of Formula (I):
Figure imgf000025_0001
pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein X] is N or ClRsh: X2 is N, N(O), or CR5; X3 is N or CR4a; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or N(O); wherein no more than three of X2, X3, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(O)Rn, -CH20C(0)Rn, - CH2OC(O)NHRi2, -CH2OC(O)ORi2, -P(O)(ORI2)2, -CH2OP(O)(ORi2)2, -CH2OP(O)(OH)ORi2, -
CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12-)NHR12 , -CH2OC(O)(CH2)q- C(0)0Ri2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, R2c, and R2d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, R2b, R2c, and R2<I may be taken together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; R3 is H, D, (Ci-Cb)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein Runay be taken together with one of R2a, R2b, R2c, and R2<I with the carbon atom to which they are attached to form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl; Rda, Rdb, and R*' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Cb)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, O(C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or - NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more R^Rto- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R5 and Rs- are each independently H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3- C7)carbocyclyl, O(C3-C7)carbocyclyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10;, wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, and carbocyclyl is optionally substituted with one or more RdoRra' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; Rg is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)aminoalkyl, , (C1-C6)alkyl-0- (C1-C6)hydroxyalkyl, -C(0)Rn, -CH20C(0)RH, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(ORI2)2, - CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R?a, R?b, R?c, and R?ci are each independently H, D, (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, or(Ci-C2)haloalkyl; or two of R?a, R?b, R?c, and Rg.i are taken together with the carbon atoms to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)RB, and -C(O)NRi3'Ri3’; each R7e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(Ci-Cb)hydroxyalkyl, (Ce- C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one or more R21, and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R?e together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRi3'Ri3’; one R?e is taken together with any one of R7a, R?b, R?c, and Rva and the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to
7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; Rs is (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C3-C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRir, -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R15’ ; R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (Ci-G,)dcutcroalkyl, or (C1-C6)haloalkyl; Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl,-N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one or more substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; Rm is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (Ci- C6)alkyl or (C1-C6)haloalkyl; Rm is independently at each occurrence H, (C1-C6)alkyl or (C1-C6) haloalkyl; Ru and Rm are each independently at each occurrence H or (C1-C6)alkyl; Rma is H, (Ci- C6)alkyl or (C1-C6)haloalkyl; R15 and Rm are each independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, alkoxy,”" phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cgjhydroxyalkyl, halogen, -OH, -NR35R36, - C(O)NR37R38, -C(O)R37, -C(O)OR37, -SFS, -SR29, SO2NR30R31, -CN, and R19; or two Ris, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (O-C-Jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ri5', when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Ris- together with the atoms to which they are attached form a (C s-C- Jcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Ri? ; or two Ris- when on the same carbon atom form C=(0); Rie is H, (Ci- C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NH2, -SF5, -SR18, or -CN; Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each Rn is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (Cs-Cvjcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (Cs-Cvjcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20 and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SFs, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Ris; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R2e, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more RJ7; R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)Rs9; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, - 0(C3-C7)carbocyclyl, phenyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.
In some embodiments, the compound of Formula (I) is a compound of Formula (La):
Figure imgf000029_0001
pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR3; X2 is N or CR4a-; X3 is N or CR4a; X4 is N or CR4t>; X5 is N or CR4b-; Xe is N or CR5; X? is N or CRv; wherein no more than three of X2, X3, X4, X5, Xe and X? is simultaneously N; Ri is H, D, -C(0)Rn, -CH20C(0)Rn, - CH2OC(O)NHRi2, -CH2OC(O)ORi2, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)ORi2, - CH2OP(O)(RI2)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(RI2-)NHRI2 ■, -CH2OC(O)(CH2)q- C(O)ORI2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
N, NH, and S); R2a, RM, R2c, and RM are each independently H or D; Rs is H, D, (C1-C6)alkyl, or (Ci- Cs)deuteroalkyl; Rga and R» are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; R4a' are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, or halogen; R4t>’ is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Rs is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NRgRio; Re is H, D, -C(0)R„, -CH20C(0)Rn, -CH2OC(O)NHR,2, - CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2; R7a, R7b, Rvc, and R7d are each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl; each R7e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from
O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)Ri3, and -C(O)NRi3’Ri3’; Rs is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, - NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R 15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R15S Rg and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl; Rn is independently at each occurrence H, (C1-C6) alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6) alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R 12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Ce- Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Cio)aryl optionally substituted with one or more substituents independently selected from (Ci-Cgjalkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12' is independently at each occurrence H or (C1-C6)alkyl; RB is independently at each occurrence (C1-C6)alkyl or (Ci- C6)haloalkyl; RB' is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; R14 and Ru- are each independently at each occurrence H or (Ci-Cgjalkyl; Rua is H, (C1-C6)alkyl or (Ci-Cft)haloalkyl; RB and RB- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl,
(C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -OtGs-Cvjcarbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (Ci -C6)alkyl, (C1-C6)haloalkyl, (Ci-Crjalkoxy, (Ci-Qjhaloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)Rs7, -C(O)OR3?, -SF5, -SR29, and -CN; or two RB, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Ri?; two RB’, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two RB1 together with the atoms to which they are attached form a (Cs-C-lcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two RB- when on the same carbon atom form C=(O); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (Ci-G>)haloalkyl, (C1-C6)alkoxy, (G-G>)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN; Rn is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (G-Cdcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; R20 and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from
O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, ICi-Gjhaloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R34; R32, R33, and R34 are each independently at each occurrence H or (Ci -C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R,u; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.
In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):
Figure imgf000033_0001
or a pharmaceutically accept-able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein Xi is N or CR3; X2 is N or CR5’ ; Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2,
-CH2OC(O)OR12, -P(O)(OR12)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(RI2)2, -
CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12’)NHR12’, -CH2OC(O)(CH2)qC(O)ORi2’, or
-CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S); R2a, R2b, Ric. and R2d are each independently H or D; R3 is H, D, (Ci-C3)alkyl, or (Ci-
C3)deuteroalkyl; each R4 is independently at each occurrence D, (Ci-Celalkyl, (Ci- C6)deuteroalkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkoxy, halogen, -OH, or -NR9R10; each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10; Rs- is H, D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10; Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, - CH2OC(O)OR,2, -P(O)(OR,2)2, -CH2OP(O)(OH)OR,2, or -CH2OP(O)(R,2)2; R7a, R7b, R7c, and R7d are each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl; each R7e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-Gjhaloalkyl, ((C1-Cj6)alkoxy, (C1-C6lhaloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more R 19, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci-Cb)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3', -C(0)RB, and -C(O)NRi3'Ri3’; Rs is (C1-C6)haloalkyl, (Ci-Cjhydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SFs, -SRua, -NRuRu', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more Rir; Rg and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl; Rn is independently at each occurrence H, (C1-C6) alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6) alkoxy, (Ci- Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- Gjhydroxyalkyl. (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (Ce- Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one or more substituents independently selected from (Ci-Cgjalkyl, (Ci- C6)alkoxy, (G-Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN; R, 2 is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C1-C6)alkyl or (Ci- Gjhaloalkyl; Ri v is independently at each occurrence H, (C1-C6)alkyl or (Ci-Cgjhaloalkyl; R14 and Ru- are each independently at each occurrence H or (C1-C6)alkyl; Ri4a is H, (C1-C6)alkyl or (Ci-Cgjhaloalkyl; R15 and Ri5' are each independently at each occurrence D, (C1-C6)alkyl, (G-G>)deuteroalkyl, (C1-C6)haloalkyl, (‘G-Gjalkoxy, (G-Gjhaloalkoxy, (G-Gjhydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -OIGnGjcaiFocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (G-Gjalkoxy, (C1-C6)haloalkoxy, (Ci- Gjhydroxyalkyl, halogen, -OH, -NR35R36, -GOiNRnRsx, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ri5', when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and SO, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Ris- when on the same carbon atom form C=(0); Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl; Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR18, or -CN; Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6) alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; R20 and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- Cv)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, ((C1-CJ6)alkoxy, (Cj-Gjhaloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl; R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -QOjRu: R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl; R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(0)R3p; R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.
In one embodiment, the compounds of Formula (I) have the structure of Formula (I-c):
Figure imgf000036_0001
or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000036_0002
(I-d), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-e):
Figure imgf000036_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (I-f):
Figure imgf000037_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (I-g)
Figure imgf000037_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (I-h):
Figure imgf000037_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (I-i):
Figure imgf000037_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of Formula (I) have the structure of Formula (
Figure imgf000038_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-k):
Figure imgf000038_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula
Figure imgf000038_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (I-m):
Figure imgf000038_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000039_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (I-o):
Figure imgf000039_0002
or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of
Formula (I) have the structure of Formula
Figure imgf000039_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-q):
Figure imgf000039_0004
or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (I-r):
Figure imgf000040_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000040_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (lu):
Figure imgf000040_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000040_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Iw):
Figure imgf000041_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000041_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the ssttrruuccttuurree of Formula (ly):
Figure imgf000041_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Iz):
Figure imgf000041_0004
(Iz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (laa)
Figure imgf000042_0001
(laa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ibb):
Figure imgf000042_0002
or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In yet another embodiment, the compounds of
Formula (I) have the structure of Formula
Figure imgf000042_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Idd):
Figure imgf000042_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (lee):
Figure imgf000043_0001
(lee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Iff):
Figure imgf000043_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula
Figure imgf000043_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Ihh):
Figure imgf000043_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (lii):
Figure imgf000044_0001
(lii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Ijj):
Figure imgf000044_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000044_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Imm):
Figure imgf000044_0004
(Imm), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (loo)
Figure imgf000044_0005
(loo), or pharmaceutically acceptable salts hydrates solvates prodrugs stereoisomers and tautomers thereof In another embodiment, the compounds of Formula (I) have the structure of Formula (Ipp):
Figure imgf000045_0001
(Ipp), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula
Figure imgf000045_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (In):
Figure imgf000045_0003
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula
Figure imgf000045_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Itt):
Figure imgf000046_0001
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (luu)
Figure imgf000046_0002
(luu), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Ivv):
Figure imgf000046_0003
(Ivv), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (
Figure imgf000046_0004
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ixx):
Figure imgf000047_0001
(Ixx), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (
Figure imgf000047_0002
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Izz):
Figure imgf000047_0003
(Izz), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (laaa)
Figure imgf000047_0004
(laaa), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ibbb):
Figure imgf000048_0001
(Ibbb), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (Iccc)
Figure imgf000048_0002
(Iccc), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In another embodiment, the compounds of Formula (I) have the structure of Formula (Iddd):
Figure imgf000048_0003
(Iddd), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (leee)
Figure imgf000048_0004
(leee), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ifff):
Figure imgf000049_0001
(Ifff), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (Iggg):
Figure imgf000049_0002
(Iggg), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In yet another embodiment, the compounds of Formula (I) have the structure of Formula (Ihhh):
Figure imgf000049_0003
(Ihhh), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (liii)
Figure imgf000049_0004
(liii), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of Formula (I) have the structure of Formula (Ijjj):
Figure imgf000050_0001
(Ijjj), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof. In another embodiment, the compounds of
Formula (I) have the structure of Formula (Ikkk):
Figure imgf000050_0002
(Ikkk), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
In some embodiments of the formulae above (e.g. , Formula (I), Formula (la), Formula (lb) Formula (le), or Formula (Id) Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (lii), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (hr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula
(Ifff), Formula (Iggg), Formula (Ihhh), Formula (liii), Formula (Ijjj), and/or Formula (Ikkk)), wherein: Xi is N or CR2;
X2 is N or CR5-;
Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2,
-CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2,
-CH2OC(O)CH(RI2')NHRI2', -CH2OC(O)(CH2)qC(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);
R2a, R2t>, R2C, and R2d are each independently H or D;
Ra is H, D, (Ci-Ca)alkyl, or (C1-C6)deuteroalkyl; each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, ((C1-CJ6)alkoxy. (Ci-Gjhaloalkoxy, halogen, -OH, or -NR9R10; each R5 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10;
Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10;
Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(OR)2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2;
R?a, R?b, R?c, and R?d are each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-
C2)haloalkyl; each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to four R19, the aryl and heteroaryl are optionally substituted with one to four R2I, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (Cj-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3', -C(0)RB, and -C(O)NRi3'Ri3’;
Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6) alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris1 ;
R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl;
Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;
RI2 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN;
R12- is independently at each occurrence H or (C1-C6)alkyl;
R13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl;
Ro- is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R14 and R M are each independently at each occurrence H or (C1-C6)alkyl;
Ri4a is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R15 and Rn- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- Cvjcarbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn; two Ris’, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and SO, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn; or two Ris- together with the atoms to which they are attached form a (Cs-C-Jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn; or two Ris- when on the same carbon atom form C=(0);
Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;
Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24; R20 and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Gjalkoxy, (C1-C6)haloalkoxy, (Ci-Gjhydroxyalkyl. halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Czjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (G-Gjalkoxy, (C1-C6)haloalkoxy, (G-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Cjalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S;
R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -CiOjRxi;
R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl;
R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -GOjRsj;
R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.
In some embodiments of the formulae above, Xi is N. In another embodiment, Xi is CR3. In yet another embodiment, Xi is CD. In another embodiment, Xi is CH.
In some embodiments of the formulae above, X2 is N. In another embodiment, X2 is CR5 1.
In some embodiments of the formulae above, R, is H, D, -C(0)Rn, -CH20C(0)Ru,
CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)OR12,
CH2OP(O)(RI2)2, -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(Ri2-)NHRi2-,
CH2OC(O)(CH2)qC(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S). In another embodiment, Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -
CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(ORI2)2, -CH2OP(O)(OH)OR12, or -
CH2OP(O)(RI2)2. In yet another embodiment, Ri is H, D, -CH2OC(O)CH2NHC(O)CH2NH2, - CH2OC(O)CH(Ri2-)NHRi2', -CH2OC(O)(CH2)qC(O)ORi2-, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S).
In some embodiments of the formulae above, Ri is -C(O)Rn, -CH2OC(O)Ru, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(OR]2)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R,2)2, - CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(R12')NHR12', -CH2OC(O)(CH2)qC(O)ORi2', or
CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S). In yet another embodiment, Ri is -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRi2, -CH2OC(O)ORi2, - P(O)(OR|2)2, -CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(R|2)2, In another embodiment, R, is -CH2OC(O)CH2NHC(O)CH2NH2, -CH2OC(O)CH(Ri2 )NHRi2-, -CH2OC(O)(CH2)qC(O)ORi2-, or - CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S). In another embodiment, Ri is H or D. In yet another embodiment, Ri is D. In another embodiment, Ri is H.
In some embodiments of the formulae above, R2a is H or D. In another embodiment, R2a is D. In yet another embodiment, R2a is H.
In some embodiments of the formulae above, R2b is H or D. In another embodiment, R2b is D. In yet another embodiment, R2b is H.
In some embodiments of the formulae above, R2c is H or D. In another embodiment, R2c is D. In yet another embodiment, R2c is H.
In some embodiments of the formulae above, R2d is H or D. In another embodiment, R2d is D. In yet another embodiment, R2d is H. In some embodiments of the formulae above, R3 is H, D, (C3-C7)alkyl, or (C3-C7)deuteroalkyl. In another embodiment, R3 is D, (C1-C6)alkyl, or (C3-C7)deuteroalkyl. In yet another embodiment, R3 is H, (C3-C7)alkyl, or (C3-C7)deuteroalkyl. In another embodiment, R3 is H, D, or (C3-C7)alkyl. In yet another embodiment, R3 is H, D, or (C3-C7)deuteroalkyl. In another embodiment, R3 is (C3-C7)alkyl or (Ci- C3)deuteroalkyl. In another embodiment, R3 is D or (C3-C7)deuteroalkyl. In another embodiment, R3 is H or (C3-C7)deuteroalkyl. In another embodiment, R3 is D or (C3-C7)alkyl. In another embodiment, R3 is H or (C3-C7)alkyl. In another embodiment, R3 is H or D. In yet another embodiment, R3 is D. In another embodiment, R3 is H.
In some embodiments of the formulae above, each R4 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-Gjhaloalkoxy. halogen, -OH, or - NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci-Crjdcutcroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, -OH, or - NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.
In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- Cs)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.
In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, - OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, iCi-C,)alkoxy, halogen, or -NR9R10.
In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence D, (C3-C7)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.
In another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each R4 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R4 is independently at each occurrence (Ci- C3)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.
In some embodiments of the formulae above, each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6lhaloalkoxy, halogen, -OH, or - NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -OH. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, -OH, or - NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.
In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10.
In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, - OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)alkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C3-C7)alkyl, (C1-C6)deuteroalkyl, (C1-C3) alkoxy, halogen, or -NR9R10.
In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence D, (C1-C6)alkyl, (Ci-Qjalkoxy, halogen, -OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, each R$ is independently at each occurrence D, (C3-C7)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.
In another embodiment, each R$ is independently at each occurrence (C1-C6)alkyl, (Ci- Cs)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, - OH, or -NR9R10. In yet another embodiment, each Rs is independently at each occurrence (C1-C6)alkyl, (Ci- C6)alkoxy, halogen, or -NR9R10. In another embodiment, each Rs is independently at each occurrence (Ci- C3)alkyl, (C3-C7)alkoxy, halogen, or -NR9R10.
In some embodiments of the formulae above, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs’ is H, D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, or -OH. In yet another embodiment, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, -OH, or -NR9R10. In yet another embodiment, Rs- is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs- is H, D, (Ci- C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In yet another embodiment, Rs1 is H, D, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, Rs- is H, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In yet another embodiment, Rs- is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10. In another embodiment, R5' is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, D, (C3-C7)alkyl, (C1-C6)deuteroalkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, D, (Ci-Cft)alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, D, (C3-C7)alkyl, halogen, or -NR9R10. In another embodiment, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Rs- is H, (C3-C7)alkyl, halogen, or -NR9R10.
In some embodiments of the formulae above, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, - CH2OC(O)NHR12, -CH2OC(O)OR]2, -P(O)(OR12)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)OR,2, -P(O)(OR,2)2, or -CH2OP(O)(OH)ORI2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, - CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(ORI2)2, or -CH2OP(O)(R,2)2. In another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -CH2OP(O)(OH)ORI2, or - CH2OP(O)(RI2)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR]2, - P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -C(O)Rn, - CH2OC(O)Rn, -CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(R12)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)ORI2, -P(O)(OR,2)2, -
CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is H, D, -CH2OC(O)Rn, -
CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2. In yet another embodiment, Re is H, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, -CH2OC(O)ORI2, -
P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is D, -C(O)Rn, -
CH2OC(O)R11, -CH2OC(O)NHRI2, -CH2OC(O)ORI2, -P(O)(OR12)2, -CH2OP(O)(OH)OR12, or
CH2OP(O)(R,2)2. In yet another embodiment, Re is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, or -CH2OC(O)ORI2. In another embodiment, Re is H, D, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -
CH2OP(O)(RI2)2. In yet another embodiment, Re is -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHRI2, - CH2OC(O)ORI2, -P(O)(ORI2)2, -CH2OP(O)(OH)ORI2, or -CH2OP(O)(RI2)2. In another embodiment, Re is
H or D. In yet another embodiment, Re is D. In another embodiment, Re is H.
In some embodiments of the formulae above, R?a is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Cr C2)haloalkyl. In another embodiment, R2a is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R2a is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, R2a is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R2a is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R2a is D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment R?a is H D or (Ci-C2)alkyl In another embodiment R2a is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?a is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?a is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?a is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?a is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?a is H or D. In yet another embodiment, R?a is D. In another embodiment, R?a is H.
In some embodiments of the formulae above, R?b is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?b is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvb is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?b is D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is H, D, or (Ci-C2)alkyl. In another embodiment, R?b is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?b is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?b is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?b is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?b is H or D. In yet another embodiment, R?b is D. In another embodiment, R?b is H.
In some embodiments of the formulae above, R?c is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Cr C2)haloalkyl. In another embodiment, R?L is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?L is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, R?c is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvc is D, (Ci-C2)alkyl, (Cj-Cdidcutcroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is H, D, or (Ci-C2)alkyl. In another embodiment, R?c is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, Rvc is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?c is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?c is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, R?c is H or D. In yet another embodiment, R?c is D. In another embodiment, R?c is H.
In some embodiments of the formulae above, Rva is H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?d is H, D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In another embodiment, Rvd is H, D, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is H, (Ci-C2)alkyl, (Ci- C2)deuteroalkyl, or (Ci-C2)haloalkyl. In another embodiment, R?d is D, (Ci-Cdlalkyl, (Ci-C2)deuteroalkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?<i is H, D, or (Ci-C2)alkyl. In another embodiment, R?d is H, D, or (Ci-C2)deuteroalkyl. In yet another embodiment, R?d is H, D, or (Ci-C2)haloalkyl. In another embodiment, R?<i is H, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is D, (Ci-C2)alkyl, or (Ci-C2)haloalkyl. In yet another embodiment, R?d is (Ci-C2)alkyl or (Ci-C2)haloalkyl. In another embodiment, Rv<i is H or D. In yet another embodiment, R?d is D. In another embodiment, R?d is H. In some embodiments of the formulae above, each R?e is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (Ci- C6)hydroxyalkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C3- C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl is optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the aryl and heteroaryl are optionally substituted with one to six R21, and the heterocyclyl is optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -0-(C1-C6)hydroxy alkyl, (C6-C10) aryl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more Rig, the aryl is optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one to six Rig, the heteroaryl is optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (Ci- C6)hydroxyalkyl, -CN, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, -0-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -CN, - OH, -O-(C1-C6)hydroxy alkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -CN, -OH, -0- (C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(C1-C6)hydroxy alkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each Rve is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)alkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, - CN, -OH, -0-(C1-C6)hydroxyalkyl, (Cg-Cio) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. wherein the alkyl is optionally substituted with one six R19, the aryl and heteroaryl are optionally substituted with one to six R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the alkyl is optionally substituted with one six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R21, and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one to six R19, the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each R?e is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxy alkyl, -CN, -OH, -O-(C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one to six R19. In another embodiment, each R?e is independently at each occurrence (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to six R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one to four R22.
In another embodiment, each Rve is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22. In yet another embodiment, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (Cj-CoJalkoxy, halogen, (C1-C6)hydroxy alkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to six R21 , and the carbocyclyl is optionally substituted with one to four R22.
In some embodiments of the formulae above, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'. In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRI3'RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-Gjhaloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB’. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 4- to 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.
In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- or 5-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 4- or 5 -membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.
In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?) spirocarbocyclyl or a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB’.
In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 5- or 6-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.
In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB', -C(0)RB, and -C(0)NRB'RB'. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7) spirocarbocyclyl or a 6- or 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB’.
In another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB RB'. In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB'RB-. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C?)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one to four halogen.
In another embodiment, two R76, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRB’RB’- In yet another embodiment, two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(O)NRi3'Ri3’. In another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a 5- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spiroheterocyclyl is optionally substituted with one to four halogen.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (Ci-Gjalkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'. In another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four RD-.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxyalkyl, or (C1-C6)alkyl substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Riy. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, or (Cr C6)halohydroxy alkyl. In another embodiment, Rg is (C1-C6)haloalkyl or (C1-C6)hydroxy alkyl. In yet another embodiment, Rg is (C1-C6)haloalkyl or (C1-C6)halohydroxyalkyl. In another embodiment, Rg is (Ci- C6)hydroxy alkyl or (C1-C6)halohydroxy alkyl.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, - NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’. In yet another embodiment, Rg is iC 1 -C(,) hydroxy alky I or (C1-C6) alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15'. In another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 . In yet another embodiment, Rg is (C1-C6)haloalkyl, (Ci-Gjhydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ri v.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15-. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRu-, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris'. In yet another embodiment, Rg is (Ci-Cjhaloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14', phenyl, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (Ci-G,)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the heterocyclyl is optionally substituted with one to four Ris-. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkoxy, -SF5, - SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, and (C3-C7)carbocyclyl, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl is optionally substituted with one to four R15'.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R15’. In yet another embodiment, Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ru-.
In some embodiments of the formulae above, Rg is (C1-C6)haloalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R 15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-. In yet another embodiment, Rg is (Ci-
C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7Karbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-.
In some embodiments of the formulae above, Rg is (C1-C6lhaloalkyl or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvKarbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-. In yet another embodiment, Rg is (C1-C6)hydroxy alkyl or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris-. In another embodiment, Rg is (C1-C6)halohydroxy alkyl or (Ci- Coialkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris1.
In some embodiments of the formulae above, Rg is independently at each occurrence H, D, (Ci- C6)alkyl, or (C1-C6ldeuteroalkyl. In another embodiment, Rg is independently at each occurrence D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence H, D, or (C1-C6)deuteroalkyl. In another embodiment, Rg is independently at each occurrence H, D, or (Ci- C6)alkyl. In yet another embodiment, Rg is independently at each occurrence H or D. In another embodiment, Rg is independently at each occurrence D or (C1-C6)alkyl. In yet another embodiment, Rg is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, Rg is independently at each occurrence H or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C1-C6)deuteroalkyl. In another embodiment, Rg is independently at each occurrence (C1-C3) alkyl or (C1-C6)deuteroalkyl. In yet another embodiment, Rg is independently at each occurrence D or (C3-C7)alkyl. In another embodiment, Rg is independently at each occurrence (C1-C6)deuteroalkyl. In yet another embodiment, R9 is independently at each occurrence (C1-C6)alkyl. In another embodiment, Rg is independently at each occurrence D. In yet another embodiment, Rg is independently at each occurrence H.
In some embodiments of the formulae above, Rio is independently at each occurrence H, D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence D, (Ci- C6)alkyl, or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence H, D, or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence H, D, or (Ci- C6)alkyl. In yet another embodiment, Rio is independently at each occurrence H or D. In another embodiment, Rio is independently at each occurrence D or (C1-C6)alkyl. In yet another embodiment, Rio is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, Rio is independently at each occurrence H or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C1-C6)deuteroalkyl. In another embodiment, Rio is independently at each occurrence (C3-C7)alkyl or (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence D or (C3-C7)alkyl. In another embodiment, Rio is independently at each occurrence (C1-C6)deuteroalkyl. In yet another embodiment, Rio is independently at each occurrence (C1-C6)alkyl. In another embodiment, Rio is independently at each occurrence D. In yet another embodiment, Rio is independently at each occurrence H.
In some embodiments of the formulae above, Rn is independently at each occurrence H, (Ci- C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci-
C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, or (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In another embodiment, Ri 1 is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(Ci- C6)alkyl, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (Ce- Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N((C1-C6)alkyl)2, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, -N(H)(Ci- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, Rn is independently at each occurrence H, -NH2, -N(H)(C1-C6)alkyl, -N((Ci- C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In another embodiment, Rn is independently at each occurrence (C1-C6)alkoxy, -NH2, -N(H)(Ci- C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-Cio)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, Rn is independently at each occurrence H, (C1-C6)alkoxy, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci-Gjalkoxy. (Ci- C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In some embodiments of the formulae above, R12 is independently at each occurrence H, (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Cg-Cio)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, or (C1-C6)hydroxy alkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, R12 is independently at each occurrence H, (C1-C6)alkyl substituted with one to four substituents independently selected from (Ce- Ciolaryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Ce- Ciolaryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In another embodiment, RB is independently at each occurrence H, or (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, RB is independently at each occurrence H. In another embodiment, RB is independently at each occurrence (Ci- C6)alkyl optionally substituted with one to four substituents independently selected from (C6-C10)aryl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN. In another embodiment, RB is independently at each occurrence (C6-C10)aryl optionally substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In another embodiment, R12 is independently at each occurrence (C1-C6)alkyl substituted with one to four substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN. In yet another embodiment, RB is independently at each occurrence (C6-Cio)aryl substituted with one to four substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN.
In some embodiments of the formulae above, RB' is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, RB’ is independently at each occurrence H or (C3-C7)alkyl. In another embodiment, RB’ is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB’ is independently at each occurrence H.
In some embodiments of the formulae above, R B is independently at each occurrence (C1-C6) alkyl or (C1-C6)haloalkyl. In another embodiment, R B is independently at each occurrence (C3-C7)alkyl or (Ci- C3)haloalkyl. In another embodiment, RB is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, RB is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB is independently at each occurrence (C3-C7)haloalkyl. In another embodiment, RB is independently at each occurrence (C3-C7)alkyl.
In some embodiments of the formulae above, R B- is independently at each occurrence H, (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, RB- is independently at each occurrence H, (Ci- C3)alkyl or (C3-C7)haloalkyl. In yet another embodiment, RB- is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, RB- is independently at each occurrence H or (C1-C6)haloalkyl. In yet another embodiment, RB' is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, RB- is independently at each occurrence (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, RBV is independently at each occurrence (C1-C6)alkyl. In another embodiment, RB- is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ruv is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, Ru is independently at each occurrence (Ci- C3)haloalkyl. In another embodiment, R u is independently at each occurrence H.
In some embodiments of the formulae above, Ru is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, Ru is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, Ru is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ru is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ru is independently at each occurrence H.
In some embodiments of the formulae above, Ru- is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, Ru- is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, Ru- is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ru- is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ru- is independently at each occurrence H.
In some embodiments of the formulae above, Rua is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Rua is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Rua is H or (Cr C6)alkyl. In another embodiment, Rua is H or (C1-C6)haloalkyl. In yet another embodiment, Rua is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Rua is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Rua is (C1-C6)alkyl. In another embodiment, Rua is (C3-C7)alkyl. In another embodiment, Rua is (C1-C6)haloalkyl. In another embodiment, Rua is (C3-C7)haloalkyl. In another embodiment, Rua is H.
In some embodiments of the formulae above, R 15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, R15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, - SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or -0-(4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- Cs)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - 0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from
O, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6lalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, - NR30R31, -SFs, -SR16, -CN, -C(O)NRS2R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR3ZR33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (Ci-Co.idcutcroalkyl. (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15 is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, or -C(O)OR32- In yet another embodiment, R15 is independently at each ooccccuurrrreennccee (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, or -C(O)OR32.
In another embodiment, R15 is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN.
In yet another embodiment, R15 is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, - SF5, -SR29, and -CN.
In some embodiments of the formulae above, R 15 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Cjhaloalkoxy. (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, Ris- is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R3s, -C(O)R37, -C(O)OR37, - SF5, -SR29, and -CN.
In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (C3- C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), or -0-(4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15’ is independently at each occurrence D, (C1-C6)alkyl, (Ci- Cs)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SFs, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, - □-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Cr C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Cj-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-G,)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from
O, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(O)OR37, -SF5, -SR29, and -CN. In another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -0- phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15’ is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci-Gjalkoxy. (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, - NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(0)R3?, -C(0)0R3?, -SF5, -SR29, and -CN.
In another embodiment, Riv is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -ClOjNRuRx -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, R15' is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN.
In another embodiment, R45’ is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-G,)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(0)0R3?, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, - C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0- (monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Cjalkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R3s, -C(O)Rs7, -C(O)OR37, -SF5, -SR29, and -CN.
In another embodiment, Ris- is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN. In yet another embodiment, Ris- is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, or -C(O)OR32- In yet another embodiment, Riv is independently at each ooccccuurrrreennccee (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, -SR16, -CN, -C(O)NR32R33, or -C(O)OR32-
In another embodiment, R15- is independently at each occurrence (C3-C7)carbocyclyl, -O(Cs- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -C(O)NR3?R38, -C(O)R37, - C(O)OR37, -SF5, -SR29, and -CN.
In yet another embodiment, Ris- is independently at each occurrence (C3-C7)carbocyclyl, -0(C3- C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S), 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR35R36, -ClOjNRnR^, -C(0)Rs7, -C(O)OR37, - SF5, -SR29, and -CN.
In some embodiments of the formulae above, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four R17. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C -Cv.icarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (Cs-Cvjcarbocyclyl, wherein the phenyl, heteroaryl, and carbocyclyl are optionally substituted with one to four Rn.
In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, and heterocyclyl are optionally substituted with one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, (C3-C7jcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn- In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Ca-Cvjcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one to four Rn.
In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0,
N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn- In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from
O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or (C3-C7)carbocyclyl, wherein the phenyl and carbocyclyl are optionally substituted with one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl and heterocyclyl are optionally substituted with one to four R n.
In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four Rn. In another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a (C3-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn, when on adjacent atoms, together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn.
In some embodiments of the formulae above, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four Rn- In another embodiment, two R15’ , when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are substituted with one to four Rn- In yet another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl is optionally substituted with one to four Rn and the heteroaryl is substituted with one to four Rn- In another embodiment, two R iv. when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl is substituted with one to four Rn and the heteroaryl is optionally substituted with one to four Rn.
In another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is optionally substituted with one to four R17. In another embodiment, two Rn-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, wherein the phenyl is substituted with one to four Rn. In yet another embodiment, two Ris- , when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heteroaryl is substituted with one to four Rn.
In some embodiments of the formulae above, two R15' together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In yet another embodiment, two Riv together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn. In yet another embodiment, two Rm together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is to optionally substituted with one to four Rn- In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn- In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn.
In another embodiment, two R15’ together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17. In yet another embodiment, two R15’ together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R17. In another embodiment, two R15- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In another embodiment, two Rm together with the atoms to which they are attached form a (Cs-Cvjcarbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Riv. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.
In another embodiment, two R 15 together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
In another embodiment, two R15' together with the atoms to which they are attached form a (C3- C7)carbocyclyl or 4- or 5-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17. In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In another embodiment, two R15’ together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17.
In another embodiment, two Riv together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C5)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In another embodiment, two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C4-C7)carbocyclyl or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn-
In another embodiment, two Rn- together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C6-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn. In another embodiment, two R iv together with the atoms to which they are attached form a (C5-C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four Rn.
In another embodiment, two Rn together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R15' together with the atoms to which they are attached form a (Ca-Cslcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In another embodiment, two Ris- together with the atoms to which they are attached form a (C3-C4)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R n together with the atoms to which they are attached form a (C4-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn.
In another embodiment, two Ris- together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (Ce-Cvlcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is substituted with one to four Rn and the heterocyclyl is optionally substituted with one to four Rn-
In another embodiment, two R 15 together with the atoms to which they are attached form a (C3- C6)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (Cs-Cslcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In another embodiment, two Rn- together with the atoms to which they are attached form a (Cs-C^carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C4-Cv)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
In another embodiment, two R15' together with the atoms to which they are attached form a (C5- C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four R17. In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C6-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn- In another embodiment, two R15’ together with the atoms to which they are attached form a (G-Gjcarbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl is optionally substituted with one to four Rn and the heterocyclyl is substituted with one to four Rn-
In another embodiment, two Riv together with the atoms to which they are attached form a (C3- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
In another embodiment, two Rn together with the atoms to which they are attached form a (C3- C5)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Ris- together with the atoms to which they are attached form a (C3-Cs)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R iv together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four R 17. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C3-C4)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
In another embodiment, two R 15 together with the atoms to which they are attached form a (C4- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C4-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four R17. In another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C5-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn.
In another embodiment, two Rn together with the atoms to which they are attached form a (Ce- C7)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rn- together with the atoms to which they are attached form a (C6-C7)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two R15' together with the atoms to which they are attached form a (C3-C6)carbocyclyl, wherein the carbocyclyl is substituted with one to four Rn- In another embodiment, two R 15' together with the atoms to which they are attached form a (C4-C6)carbocyclyl, wherein the carbocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two R15’ together with the atoms to which they are attached form a ('Cn-Cjcarbocyclyl. wherein the carbocyclyl is substituted with one to four Rn-
In another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Rm together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two R i v together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn. In another embodiment, two Ris- together with the atoms to which they are attached form a 6- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Rn- together with the atoms to which they are attached form a 6- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Ris- together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.
In another embodiment, two Rn- together with the atoms to which they are attached form a 4- to 5- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn. In yet another embodiment, two Ri, together with the atoms to which they are attached form a 4- to 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn- In another embodiment, two Ri v together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four Rn- In yet another embodiment, two Ris- together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is substituted with one to four Rn.
In some embodiments of the formulae above, two Ris’ when on the same carbon atom form C=(0);
In some embodiments of the formulae above, Ris is independently at each occurrence H, (Ci- Cs)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence H, (Ci- C3)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is independently at each occurrence H or (Ci- Cs)alkyl. In another embodiment, Ris is independently at each occurrence H or (C1-C6)haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is independently at each occurrence (C1-C6)alkyl. In another embodiment, Ris is independently at each occurrence (C3-C7)alkyl. In another embodiment, Ris is independently at each occurrence (C1-C6)haloalkyl. In another embodiment, Ris is independently at each occurrence (Ci- C3)haloalkyl. In another embodiment, Ris is independently at each occurrence H.
In some embodiments of the formulae above, Rn is independently at each occurrence D, (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -SRis. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SRis, or -CN.
In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NHj, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN. In another embodiment, R17 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6) alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SRis, or -CN.
In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, or halogen. In yet another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, or -CN. In another embodiment, Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)hydroxyalkyl, halogen, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, or -CN.
In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, or halogen. In yet another embodiment, Rn is independently at each occurrence halogen, -OH, -NH2, -SF5, -SRn, or -CN. In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, - NH2, -SF5, -SRis, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, -SF5, -SRn, or -CN. In another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, or -CN. In yet another embodiment, Rn is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)hydroxyalkyl, halogen, or -CN. In another embodiment, Rn is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, halogen, or -CN.
In some embodiments of the formulae above, Rn is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Rn is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Rn is H or (Ci- C6)alkyl. In another embodiment, Ris is H or (C1-C6)haloalkyl. In yet another embodiment, Ris is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, Ris is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, Ris is (C1-C6)alkyl. In another embodiment, Rn is (C3-C7)alkyl. In another embodiment, Rn is (C1-C6)haloalkyl. In another embodiment, Rn is (C3-C7)haloalkyl. In another embodiment, Rn is H.
In some embodiments of the formulae above, each Rig is independently at each occurrence (Ci- Cs)alkoxy, (C1-C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6) alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are substituted with one to four R24.
In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C6-C10) aryl, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, - NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein carbocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In another embodiment, each Rig is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24.
In another embodiment, each Rig is independently at each occurrence (C1-C6)haloalkoxy, - NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', or -CN. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -NR20R20'.
In another embodiment, each R19 is independently at each occurrence (C3-C7)carbocyclyl, 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10), wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23.
In another embodiment, each R19 is independently at each occurrence ((C1-CJ6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, -CN, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20’, -CN, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20', -CN, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
In another embodiment, each Rig is independently at each occurrence (C1-C6)alkoxy, -NR20R20', - CN, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (Ci- C6)haloalkoxy, -NR20R20’, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is optionally substituted with one to four R23 and the aryl is optionally substituted with one to four R24. In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, - NR20R20', 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the heterocyclyl is optionally substituted with one to four R23 and the heteroaryl is optionally substituted with one to four R24.
In another embodiment, each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one to four R23 and the aryl and heteroaryl are optionally substituted with one to four R24. In yet another embodiment, each R19 is independently at each occurrence (C1-C6ialkoxy, -NR20R20’, (C3-C7)carbocyclyl, or (C6-C10) aryl, wherein the carbocyclyl is substituted with one to four R23 and the aryl is optionally substituted with one to four R24.
In some embodiments of the formulae above, R20 is independently at each occurrence H or (Ci- C6)alkyl. In another embodiment, R20 is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, R20 is independently at each occurrence (C1-C6)alkyl. In another embodiment, R20 is independently at each occurrence (C3-C7)alkyl. In yet another embodiment, R20 is independently at each occurrence H.
In some embodiments of the formulae above, R20' is independently at each occurrence H or (Ci- C6 alkyl. In another embodiment, R2o- is independently at each occurrence H or (C3-C7)alkyl. In yet another embodiment, R20' is independently at each occurrence (C1-C6)alkyl. In another embodiment, R20' is independently at each occurrence (C3-C7)alkyl. In yet another embodiment, R20' is independently at each occurrence H.
In some embodiments of the formulae above, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C3-C7)carbocyclyl. In yet another embodiment, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cojhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6lalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, or -CN. In yet another embodiment, each R21 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, (C3- Cvjcarbocyclyl. or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Cvjcarbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl. In yet another embodiment, two R21, when on adjacent atoms, together with the atoms to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, two R21, when on adjacent atoms, together with the atoms to which they are attached form a 5 -membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R21, when on adjacent atoms, together with the atoms to which they are attached form a 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
In some embodiments of the formulae above, each R22 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7(carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or (C3-C7jcarbocyclyl. In yet another embodiment, each R22 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, - CN, phenyl, (C3-C7jcarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C?)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (C1-C6lalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -SF5, -SR26, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (Ci-Cjhaloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S.
In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, or -CN. In yet another embodiment, each R22 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl. In another embodiment, two R22 together with the atoms to which they are attached form a (C3-C6)carbocyclyl. In yet another embodiment, two R22 together with the atoms to which they are attached form a (Cs-CsKarbocyclyl. In another embodiment, two R22 together with the atoms to which they are attached form a (C3-C4)carbocyclyl. In yet another embodiment, two R22 together with the atoms to which they are attached form a (C4-C7)carbocyclyl. In another embodiment, two R22 together with the atoms to which they are attached form a (C5-C7)carbocyclyl. In yet another embodiment, two R22 together with the atoms to which they are attached form a (C6-C7)carbocyclyl.
In another embodiment, two R22 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R22 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In another embodiment, two R22 together with the atoms to which they are attached form a 4- or 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R22 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, two R22 together with the atoms to which they are attached form a 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, each R23 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C3-C7)carbocyclyl. In yet another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, phenyl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6lalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxyalkyl, halogen, -OH, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-CvXarbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, or -CN. In yet another embodiment, each R23 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR27, -CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R23 is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R23 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R23 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N. NH, and S. In another embodiment, two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl. In another embodiment, two R23 together with the atoms to which they are attached form a (C3-C6)carbocyclyl. In yet another embodiment, two R23 together with the atoms to which they are attached form a (Cs-Cs^arbocyclyl. In another embodiment, two R23 together with the atoms to which they are attached form a (C3-C4)carbocyclyl. In yet another embodiment, two R23 together with the atoms to which they are attached form a (C4-C7)carbocyclyl. In another embodiment, two R23 together with the atoms to which they are attached form a (C5-C7)carbocyclyl. In yet another embodiment, two R23 together with the atoms to which they are attached form a (C6-C7)carbocyclyl.
In another embodiment, two R23 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R23 together with the atoms to which they are attached form a 4- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In another embodiment, two R23 together with the atoms to which they are attached form a 4- or 5 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, two R23 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, two R23 together with the atoms to which they are attached form a 6- or 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, each R24 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, or (C3-C7)carbocyclyl. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Crjalkoxy, (C1-C6lhaloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, phenyl, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (Ci- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Gjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C?)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0 N NH and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6lhydroxy alkyl, halogen, -OH, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, ( (C1-C6)hydroxyalkyl.-OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C?)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (Ci-Gjalkoxy, (C1-C6)haloalkoxy, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence D, (C1-C6ialkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, or -CN. In yet another embodiment, each R24 is independently at each occurrence halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-G>)haloalkoxy. (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, - SR28, -CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence D, (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In another embodiment, each R24 is independently at each occurrence (C1-C6)alkyl, (Ci- Cs)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, - CN, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In yet another embodiment, each R24 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. In another embodiment, each R24 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -CN, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S.
In some embodiments of the formulae above, R25 is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R25 is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R25 is H or (Ci- C6)alkyl. In another embodiment, R25 is H or (C1-C6)haloalkyl. In yet another embodiment, R25 is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R25 is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R25 is (C1-C6)alkyl. In another embodiment, R25 is (C3-C7)alkyl. In another embodiment, R25 is (C1-C6)haloalkyl. In another embodiment, R25 is (C3-C7)haloalkyl. In another embodiment, R25 is H.
In some embodiments of the formulae above, R26 is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R26 is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R26 is H or (Ci- C6)alkyl. In another embodiment, R26 is H or (C1-C6)haloalkyl. In yet another embodiment, R26 is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R26 is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R26 is (C1-C6)alkyl. In another embodiment, R26 is (C3-C7)alkyl. In another embodiment, R26 is (C1-C6)haloalkyl. In another embodiment, R26 is (C3-C7)haloalkyl. In another embodiment, R26 is H.
In some embodiments of the formulae above, R27 is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R27 is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R27 is H or (Ci- C6)alkyl. In another embodiment, R27 is H or (C1-C6)haloalkyl. In yet another embodiment, R27 is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R27 is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R27 is (C1-C6)alkyl. In another embodiment, R27 is (C3-C7)alkyl. In another embodiment, R27 is (C1-C6)haloalkyl. In another embodiment, R27 is (C3-C7)haloalkyl. In another embodiment, R27 is H.
In some embodiments of the formulae above, R28 is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R28 is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R28 is H or (Ci- C6)alkyl. In another embodiment, R28 is H or (C1-C6)haloalkyl. In yet another embodiment, R28 is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R28 is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R28 is (C1-C6)alkyl. In another embodiment, R28 is (C3-C7)alkyl. In another embodiment, R28 is (C1-C6)haloalkyl. In another embodiment, R28 is (C3-C7)haloalkyl. In another embodiment, R28 is H.
In some embodiments of the formulae above, R29 is H, (C1-C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R29 is H, (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R29 is H or (Ci- C6)alkyl. In another embodiment, R29 is H or (C1-C6)haloalkyl. In yet another embodiment, R29 is (Ci- C6)alkyl or (C1-C6)haloalkyl. In another embodiment, R29 is (C3-C7)alkyl or (C3-C7)haloalkyl. In yet another embodiment, R29 is (C1-C6)alkyl. In another embodiment, R29 is (C3-C7)alkyl. In another embodiment, R29 is (C1-C6)haloalkyl. In another embodiment, R29 is (C3-C7)haloalkyl. In another embodiment, R29 is H.
In some embodiments of the formulae above, R30 is H, (C1-C6)alkyl, or -C(O)R34- In another embodiment, R30 is H, (C3-C7)alkyl, or -C(O)R34- In yet another embodiment, R30 is H or (C1-C6)alkyl. In another embodiment, R30 is H or -C(O)R34- In yet another embodiment, R30 is (C1-C6lalkyl or -C(O)R34- In another embodiment, R30 is (C1-C6Oalkyl. In yet another embodiment, R30 is -C(O)R34- In another embodiment, R30 is H.
In some embodiments of the formulae above, R31 is H, (C1-C6)alkyl, or -C(O)R34. In another embodiment, R31 is H, (C3-C7)alkyl, or -C(O)R34. In yet another embodiment, R31 is H or (C1-C6)alkyl. In another embodiment, R31 is H or -C(O)R34 In yet another embodiment R31 is (C1-C6)alkyl or -C(O)R34 In another embodiment, R31 is (C3-C7)alkyl. In yet another embodiment, R31 is -C(O)R34- In another embodiment, R31 is H.
In some embodiments of the formulae above, R32 is H or (C1-C6)alkyl. In another embodiment, R32 is H or (C3-C7)alkyl. In yet another embodiment, R32 is (C1-C6)alkyl. In another embodiment, R32 is (Ci- C3)alkyl. In yet another embodiment, R32 is H.
In some embodiments of the formulae above, R33 is H or (C1-C6)alkyl. In another embodiment, R33 is H or (C3-C7)alkyl. In yet another embodiment, R33 is (C1-C6)alkyl. In another embodiment, R33 is (Ci- C3)alkyl. In yet another embodiment, R33 is H.
In some embodiments of the formulae above, R34 is H or (C1-C6)alkyl. In another embodiment, R34 is H or (C3-C7)alkyl. In yet another embodiment, R34 is (C1-C6)alkyl. In another embodiment, R34 is (Ci- C3)alkyl. In yet another embodiment, R34 is H.
In some embodiments of the formulae above, R35 is H, (C1-C6)alkyl, or -C(O)R39. In another embodiment, R35 is H, (C3-C7)alkyl, or -C(O)R39. In yet another embodiment, R35 is H or (C1-C6)alkyl. In another embodiment, R35 is H or -C(O)R39. In yet another embodiment, R35 is (C1-C6lalkyl or -C(O)R39. In another embodiment, R35 is (C3-C7)alkyl. In yet another embodiment, R35 is -C(O)R39. In another embodiment, R35 is H.
In some embodiments of the formulae above, R36 is H, (C1-C6)alkyl, or -C(O)R39. In another embodiment, R36 is H, (C3-C7)alkyl, or -C(O)R39. In yet another embodiment, R36 is H or (C1-C6)alkyl. In another embodiment, R36 is H or -C(O)R39. In yet another embodiment, R36 is (C3-C7)alkyl or -C(O)R39. In another embodiment, R36 is (C3-C7)alkyl. In yet another embodiment, R36 is -C(O)R39. In another embodiment, R36 is H.
In some embodiments of the formulae above, R37 is H or (C1-C6)alkyl. In another embodiment, R37 is H or (C3-C7)alkyl. In yet another embodiment, R37 is (C1-C6)alkyl. In another embodiment, R37 is (Ci- C3)alkyl. In yet another embodiment, R37 is H.
In some embodiments of the formulae above, R38 is H or (C1-C6)alkyl. In another embodiment, R38 is H or (C3-C7)alkyl. In yet another embodiment, R38 is (C1-C6)alkyl. In another embodiment, R38 is (Ci- C3)alkyl. In yet another embodiment, R38 is H.
In some embodiments of the formulae above, R39 is H or (C1-C6)alkyl. In another embodiment, R39 is H or (C3-C7)alkyl. In yet another embodiment, R39 is independently at each occurrence (C1-C6)alkyl. In another embodiment, Rvi is (C3-C7)alkyl. In yet another embodiment, R39 is H.
In some embodiments of the formulae above, 0 is 1 or 2. In another embodiment, o is 1. In another embodiment, o is 2. In some embodiments of the formulae above, m is 0, 1 or 2. In another embodiment, m is 0 or 2. In yet another embodiment, m is 0 or 1. In another embodiment, m is 1 or 2. In yet another embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2.
In some embodiments of the formulae above, n is 0, 1 or 2. In another embodiment, n is 0 or 2. In yet another embodiment, n is 0 or 1. In another embodiment, n is 1 or 2. In yet another embodiment, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2.
In some embodiments of the formulae above, p is 0, 1, 2, 3, or 4. In another embodiment, p is 0, 1,
2, or 3. In yet another embodiment, p is 0, 1, 2, or 4. In another embodiment, p is 0, 1, 3 or 4. In yet another embodiment, p is 0, 2, 3, or 4. In another embodiment, p is 1, 2, 3 or 4. In yet another embodiment, p is 0, 1, or 2. In another embodiment, p is 2, 3, or 4. In yet another embodiment, p is 1, 2, or 3. In another embodiment, p is 0 or 1. In yet another embodiment, p is 1 or 2. In another embodiment, p is 2 or 3. In yet another embodiment, p is 3 or 4. In another embodiment, p is 0 or 2. In yet another embodiment, p is 0 or
3. In another embodiment, p is 0 or 4. In yet another embodiment, p is 1 or 2. In another embodiment, p is 1 or 3. In yet another embodiment, p is 1 or 4. In another embodiment, p is 0 or 2. In yet another embodiment, p is 2 or 4. In another embodiment, p is 0. In yet another embodiment, p is 1. In another embodiment, p is 2. In yet another embodiment, p is 4.
In some embodiments of the formulae above, q is 1, 2, or 3. In another embodiment, q is 1 or 3. In yet another embodiment, q is 2 or 3. In another embodiment, q is 1 or 2. In yet another embodiment, q is 1. In another embodiment, q is 2. In yet another embodiment, q is 3.
In some embodiments of the formulae above, Xj is N or CR3. In another embodiment, Xi is N or
CR3 and X2 is N or CRv. In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, and Ri is H. In another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, and R2a is H. In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, R2a is H and Rdb is H. In another embodiment, Xi is N or CR3, X2 is
N or CR5’, Ri is H, R2a is H, R2b is H, and R2C is H. In yet another embodiment, Xi is N or CR3, X2 is N or
CR5-, Ri is H, R2a is H, R2b is H, R2c is H, and R2d is H. In another embodiment, Xi is N or CR3, X2 is N or
CR5-, Ri is H, R2a is H, Rdb is H, R2c is H, R2d is H, and R3 is H. In yet another embodiment, Xi is N or CR3, X2 is N or CR5- , Ri is H, R2a is H, R2b is H, R2c is H, R2d is H, R3 is H, and Re is H. In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, R2a is H, R2b is H, R2c is H, R2d is H, R3 is H, Re is H, and R?a is
H. In another embodiment, Xi is N or CR3, X2 is N or CRe-, Ri is H, Rda is H, R2b is H, R2c is H, R2d is H,
R3 is H, R6 is H, R7a is H, and R7b is H. In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is
H, R2a is H, R2b is H, R2c is H, R2d is H, R3 is H, Re is H, R?a is H, R?b is H, and R?c is H.
In another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, R2a is H, R2b is H, R2C is H, R2d is
H, R3 is H, Re is H, and R7a is H, R?b is H, R?c is H, and R?d is H. In another embodiment, X, is N or CR3,
X2 is N or CR5- Ri is H, R2a is H, R2b is H, R2c is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0 or 1. In yet another embodiment, Xi is N or CR3, Xi is N or CR5-, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is O.In another embodiment, Xi is N or CR3, Xi is N or CR5', Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is
H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, and m is 0, 1 , or 2.
In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, Ria is H, Rib is H, Ric is H,
Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, Xi is N or CR3, X2 is N or CRs, Ri is H, R2a is H, Rdb is H, R2C is H, R2d is H, R3 is H, Re is
H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is N or CR3, Xi is N or CR5,' Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is
H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, Xi is N or CR3, Xi is N or CR5-, Ri is H, Ria is H, Rib is H, Ric is H, RM is
H, R3 is H, R6 is H, and R7a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, R5’ is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, and each R7e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORi3’, -C(O)Ri3, and -C(O)NRi3’Ri3’.
In yet another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, Rda is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxy alkyl, -OH, (C6-C10) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Rn, and the carbocyclyl is optionally substituted with one to four Rn; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- Cs)hydroxyalkyl, halogen, -C(O)ORB', -C(0)RB, and -C(0)NRB’RB’, and Rg is (C1-C6)haloalkyl or (Ci- Cs)alkyl optionally substituted with one to four substituents independently selected from phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four RB and the carbocyclyl and heterocyclyl are optionally substituted with one to four RB-.
In another embodiment, Xi is N or CR3, X2 is N or CR5-, Ri is H, Rda is H, R2b is H, is H, Rdd is R2c
H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Re- is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C-C-Jcaihocyclyl. wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C,-C6)alkyl, (C1-C6)deuteroalkyl, (C,-C6)haloalkyl, (C,-C6)alkoxy, (C1-C6)haloalkoxy, (C,- C6)hydroxyalkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRi3’Ri3’, and Rg is (C1-C6)haloalkyl or (Ci- Cb)alkyl substituted with one to four substituents independently selected from phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four RB and the carbocyclyl and heterocyclyl are optionally substituted with one to four Ris .In yet another embodiment, Xi is N or CR3, X2 is N or CRv, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Rs is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or - NR9R10, Rv is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (Cd-Cvlcarbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Cb)haloalkoxy, (Ci-Cb)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB-RB', and Rg is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, - NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-Ci)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
In some embodiments of the formulae above, X] is N or CR3. In another embodiment, Xi is N or
CR3 and Xi is N. In yet another embodiment, Xi is N or CR3, Xi is N, and Ri is H. In another embodiment, Xi is N or CR3, Xi is N, Ri is H, and Ria is H. In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H and RM is H. In another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, and RM is H. In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, Ric is H, and RM is H.
In another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, and R3 is H.
In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, R3 is H, and Re is H. In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, R3 is H, Re is H, and R?a is H. In another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is
H, R2c is H, RM is H, R3 is H, Re is H, R?a is H, and Rib is H. In yet another embodiment, X, is N or CR3, X2 is N, Ri is H, R2a is H, Rib is H, RM is H, Rid is H, R3 is H, Re is H, R?a is H, Rib is H, and Ric is H.
In another embodiment, Xj is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, and R?d is H. In another embodiment, Xi is N or CRg, Xi is
N, Ri is H, Ria is H, Rib is H, RM is H, Rid is H, R3 is H, Re is H, and R?a is H, RM is H, R?c is H, Rid is H, and n is 0 or 1. In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, R3 is H, Rs is H, and R?a is H, R?b is H, R?c is H, Rva is H, and n is 0. In another embodiment, Xi is N or CR3, X2 is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Rs is H, and R?a is H, R?b is H, R?c is
H, R?d is H, n is 0, and m is 0, 1 , or 2.
In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, R3 is H, Re is H, and R?a is H, R?b is H, Rvc is H, RM is H, n is 0, m is 0, 1 , or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, Xi is N or CR3, Xi is N, Ri is H, R2a is H, RM is H, RM is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H,
R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, RM is H, RM is H, RM is H, R3 is H, Rs is H, and Rva is H, RM is H, R?c is
H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, X] is N or CR3, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, RM is H, R3 is H, Rs is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rv is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB’RB’.
In yet another embodiment, Xi is N or CR3, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, RM is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, Ria is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB’, -C(O)RB, and -C(O)NRB’R13’, and Rg is (C1-C6)haloalkyl, (Ci- Cs)hydroxyalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NRuRu', phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four RB and the carbocyclyl and heterocyclyl are optionally substituted with one to four RB-.
In some embodiments of the formulae above, X] is N or CR3. In another embodiment, Xi is N or
CR3 and Xi is CR5-. In yet another embodiment, Xi is N or CR3, Xi is CR5-, and Ri is H. In another embodiment, Xi is N or CR3, Xi is CR5-, Ri is H, and Ria is H. In yet another embodiment, Xi is N or CR3, Xi is CR5-, Ri is H, Ria is H and Rib is H. In another embodiment, X, is N or CR3, Xi is CR5-, Ri is H, Ria is H, R2b is H, and Ric is H. In yet another embodiment, Xi is N or CR3, Xi is CR5-, Ri is H, Ria is H, Rib is
H, Ric is H, and RM is H. In another embodiment, Xi is N or CR3, Xi is CR5-, Ri is H, Ria is H, Rib is H,
RM is H, RM is H, and R3 is H. In yet another embodiment, X] is N or CR3, Xi is CR5-, Ri is H, Ria is H, Rib is H, Ric is H, RM is H, R3 is H, and Re is H. In yet another embodiment, Xi is N or CR3, Xi is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H. In another embodiment, Xi is N or
CR3, X2 is CR5', Ri is H, Rda is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, R?a is H, and R?b is H. In yet another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, is H, R2d is H,R R2c3 is H, Re is H, R?a is H, R?b is H, and R?c is H.
In another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, Rdb is H, R2C is H, R2d is H,
R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, and R?d is H. In another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, is H, RR22dc is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0 or 1. In yet another embodiment, X, is N or CR3, X2 is CR5', Ri is H, Rda is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0. In another embodiment,
Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, Rdb is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, and m is 0, 1, or 2.
In yet another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, Rda is H, R2b is H, R2C is H, Rdd is
H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and
R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (Ci- C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and R5' is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is N or CR3, X2 is CR5', Ri is H, R2a is H, R2b is H, R;c is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, R5’ is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, R2a is H, Rdb is H, R2C is H, R2d is H,
R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs’ is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRB'RBJ.
In yet another embodiment, Xi is N or CR3, X2 is CR5-, Ri is H, Rda is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rv is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- Cs)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- Cs)hydroxyalkyl, halogen, -C(O)ORB-, -C(O)RB, and -C(O)NRBVRB-, and Rs is (C1-C6)haloalkyl, (Ci- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRw, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four RB and the carbocyclyl and heterocyclyl are optionally substituted with one to four RB-.
In some embodiments of the formulae above, Xi is N. In another embodiment, Xi is N and Xi is
N. In yet another embodiment, Xi is N, Xi is N, and Ri is H. In another embodiment, Xj is N, X2 is N, Ri is H, and Ria is H. In yet another embodiment, Xi is N, Xi is N, Ri is H, Ria is H and Rib is H. In another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, and Ric is H. In yet another embodiment, Xj is N, X2 is N, Ri is H, Ria is H, Rib is H, Ric is H, and Rid is H. In another embodiment, Xi is N, Xi is N, Ri is
H, Ria is H, Rib is H, Ric is H, Rid is H, and R3 is H. In yet another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, and Rs is H. In yet another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Rs is H, and R?a is H. In another embodiment, Xi is N,
X2 is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, R?a is H, and R?b is H. In yet another embodiment, Xi is N, X2 is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, R?a is H, R?b is H, and R?c is H.
In another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, and R?<i is H. In another embodiment, Xi is N, X2 is N, Ri is H, Ria is
H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, Rv<i is H, and n is 0 or 1. In yet another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0. In another embodiment, Xi is N, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, RM is H, R3 is H, Re is H, and R?a is H, R?b is H, Rvc is H, Rv< is H, n is 0, and m is
0, 1, or 2. In yet another embodiment, Xi is N, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?e is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, X, is N, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or - NR9R10, and Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is N, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or - NR9R10, Re- is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, Xi is N, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs’ is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB'.
In yet another embodiment, Xi is N, X2 is N, Ri is H, R2a is H, R2t> is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R70 when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6lalkoxy, (Ci-Cb)haloalkoxy, (Ci-Cb)hydroxyalkyl, halogen, - C(O)ORB', -C(O)RB, and -C(0)NRB'RB', and Rs is (Ci-Cbjhaloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O N NH and S (C3-C7)carbocyclyl and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
In some embodiments of the formulae above, Xi is CR3. In another embodiment, Xi is CR3 and X2 is CR5-. In yet another embodiment, Xi is CR3, X2 is CR5’, and R, is H. In another embodiment, Xi is CR3, X2 is CR5-, Ri is H, and Rda is H. In yet another embodiment, Xi is CR3, X2 is CR5-, Ri is H, Rda is H and Rdb is H. In another embodiment, Xi is CR3, X2 is CR5-, Ri is H, R2a is H, Rye is H, and Ryc is H. In yet another embodiment, Xi is CR3, X2 is CR5-, Ri is H, Rda is H, Rye is H, Ryc is H, and Rye is H. In another embodiment, Xi is CR3, X2 is CR5-, Ri is H, R2a is H, Rye is H, R2C is H, Rdd is H, and R3 is H. In yet another embodiment, Xi is CR3, X2 is CR5-, Ri is H, Rya is H, R2b is H, R2C is H, R2d is H, R3 is H, and Re is H. In yet another embodiment, Xi is CR3, X2 is CR5-, Ri is H, Rya is H, Rye is H, Ryc is H, Ryd is H, R3 is H, Re is
H, and R?a is H. In another embodiment, Xi is CR3, Xy is CR5-, Ri is H, Rya is H, Rye is H, Ryc is H, Ryd is
H, R3 is H, Re is H, R?a is H, and R?b is H. In yet another embodiment, Xi is CR3, X2 is CR5 , Ri is H, Rya is
H, R2b is H, Ryc is H, Rye is H, R3 is H, Re is H, R?a is H, R?b is H, and R?c is H.
In another embodiment, Xi is CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is
H, Re is H, and R?a is H, R?b is H, R?c is H, and R?d is H. In another embodiment, Xi is CR3, X2 is CR5', Ri is H, R2a is H, R2b is H, R2C is H, Ryd is H, R3 is H, Rd is H, and R?a is H, R?b is H, R7C is H, R?d is H, and n is 0 or 1. In yet another embodiment, Xi is CR3, X2 is CR5', Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?a is H, and n is 0. In another embodiment, Xi is CR3, X2 is CR5’, Ri is H, Rya is H, Ryb is H, Ryc is H, Ryd is H, R3 is H, Re is H, and R?a is H, Rye is H, R?c is H, R?d is H, n is 0, and m is 0, 1, or 2.
In yet another embodiment, Xi is CR3, X2 is CR5’, Ri is H, R2a is H, R2b is H, R2C is H, Ry<i is H, R3 is H, R6 is H, and R?a is H, R?b is H, Rvc is H, R?< 1 is H, n is 0, m is 0, 1 , or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6) alkoxy, halogen, or -NR9R10. In another embodiment, Xi is CR3, X2 is CR5-, Ri is H, Rda is H, Rdb is H, Ryc is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H,
R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and Ry is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, RdC is H, R2d is H, R3 is H, Re is H, and Rya is H, Rvi- is H, R?c is
H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, X] is CR3, X2 is CR5-, Ri is H, R2a is H, R2b is H, Rye is H, R2d is H, R3 is
H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'RB'.
In yet another embodiment, Xi is CR3, X2 is CR5’, Ri is H, Rda is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or - NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C,- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB'R13', and Rg is (C1-C6)haloalkyl, (Ci- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NRuRw, phenyl, 5- or 6- membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four RB and the carbocyclyl and heterocyclyl are optionally substituted with one to four RB1.
In some embodiments of the formulae above, Xi is N. In another embodiment, Xi is N and X2 is
CR5-. In yet another embodiment, Xi is N, X2 is CRv, and Ri is H. In another embodiment, Xi is N, X2 is
CR5-, Ri is H, and R2a is H. In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, R2a is H and R2b is H. In another embodiment, Xi is N, X2 is CR5-, Ri is H, Rda is H, R2b is H, and R2C is H. In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, and R2d is H. In another embodiment,
Xi is N, X2 is CR5', Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, and R3 is H. In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, and Re is H. In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, Rda is H, Rdb is H, Rdc is H, Rdd is H, R3 is H, Re is H, and R?a is
H. In another embodiment, Xi is N, X2 is CR5-, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, R7a is H, and R7b is H. In yet another embodiment, Xi is N, X2 is CRy, Ri is H, R7a is H, R7b is H, R7c is
H, R2d is H, R3 is H, Re is H, R7a is H, R7b is H, and R7c is H.
In another embodiment, Xi is N, X2 is CRe-, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H,
Re is H, and R7a is H, R?e is H, R7c is H, and Rva is H. In another embodiment, Xi is N, X2 is CR5’, Ri is H,
R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R?b is H, R7c is H, R?d is H, and n is 0 or
1. In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R7b is H, R7c is H, R7d is H, and n is 0. In another embodiment, Xi is N, X2 is CR5-, Ri is
H, R7a is H, R2b is H, R7c is H, R2d is H, R3 is H, Re is H, and R7a is H, R7b is H, R7c is H, R7d is H, n is 0, and m is 0, 1, or 2.
In yet another embodiment, Xi is N, X2 is CR5-, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R?b is H, R7c is H, R7d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, Xi is N, X2 is
CR5-, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R7b is H, R7c is H, R7d is
H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is N, X2 is CRr, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R7b is H, R7c is H, R7d is H, n is
0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or - NR9R10, R5’ is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, Xi is N, X2 is CR5’, Ri is H, R2a is H, R7b is H, R2C is H, R2d is H, R3 is H,
Re is H, and R7a is H, R7b is H, R7c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rv is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each R7e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two R7e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORi3-, -C(O)Ri3, and -C(O)NRi3'Ri3'.
In yet another embodiment, Xi is N, X2 is CRe-, Ri is H, R7a is H, R7b is H, R7c is H, R7d is H, R3 is H, Re is H, and R7a is H, R7b is H, R7c is H, R7d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R7e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six Rig, the aryl is optionally substituted with one to four R21, and the carbocyclyl is optionally substituted with one to four R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - C(O)ORB', -C(O)Ri3, and -C(O)NRB'RI3', and Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRua, -NRuRu-, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four RB-.
In some embodiments of the formulae above, Xi is CR3. In another embodiment, Xi is CR3 and X2 is N. In yet another embodiment, Xi is CR3, X2 is N, and Ri is H. In another embodiment, X] is CR3, X2 is N, Ri is H, and R2a is H. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H and R2b is H. In another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, and R2C is H. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, and R2d is H. In another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, and R3 is H. In yet another embodiment, X, is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2c is H, R2d is H, R3 is H, and Re is H. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and Rva is H. In another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, Rdd is H, R3 is H, Re is H, R?a is H, and R?b is H. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, R?a is H, Rve is H, and Rvc is H.
In another embodiment, X] is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H,
Re is H, and Rv, is H, R?b is H, R?c is H, and R?d is H. In another embodiment, X, is CR3, X2 is N, Ri is H,
R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0 or
1. In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R2a is H, R2b is H, Rdc is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, and n is 0. In another embodiment, Xi is CR3, X2 is N, Ri is
H, R2a is H, Rdb is H, RdC is H, Rdd is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, and m is 0, 1 , or 2.
In yet another embodiment, Xi is CR3, X2 is N, Ri is H, R23 is H, R2b is H, is H, R2d is H,R R2c3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, and each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10. In another embodiment, X, is CR3, X2 is N, Ri is H, R2a is H, R2b is H, R2C is H, R2d is H, R3 is H, Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, and R5’ is H, (C1-C6)alkyl, halogen, or -NR9R10. In yet another embodiment, Xi is CR3, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and Ria is H, Rib is H, Ric is H, Rid is H, n is 0, m is 0, 1, or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs’ is H, (C1-C6)alkyl, halogen, or -NR9R10, and p is 0, 1, 2, or 3.
In another embodiment, X] is CR3, X2 is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H,
Re is H, and R?a is H, R?b is H, R?c is H, R?d is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, Rs- is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, and each Rie is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORi3’, -C(O)Ri3, and -C(O)NRi3’Ri3’-
In yet another embodiment, Xi is CR3, Xi is N, Ri is H, Ria is H, Rib is H, Ric is H, Rid is H, R3 is H, Re is H, and Ria is H, Rib is H, Ric is H, Rid is H, n is 0, m is 0, 1 , or 2, each R4 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, halogen, or -NR9R10, R5’ is H, (C1-C6)alkyl, halogen, or -NR9R10, p is 0, 1, 2, or 3, each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, halogen, (C1-C6)hydroxyalkyl, -OH, (C6-C10) aryl, or (C3-Ci)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19, the aryl is optionally substituted with one to four Ru, and the carbocyclyl is optionally substituted with one to four Ru; or two Rie, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7) spirocarbocyclyl, wherein the spirocarbocyclyl is optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (Ci- C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci-Cjhaloalkoxy, (C1-C6)hydroxyalkyl, halogen, - C(O)ORi3', -C(O)Ri3, and -C(O)NRi3-Ri3', and Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (Ci- C6)halohydroxyalkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-Ci)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to four R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to four R 15 .
Non-limiting illustrative compounds of the disclosure include the compounds in Table 1:
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Cmpd
C No.
Figure imgf000134_0001
Figure imgf000135_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
F P'N
1-116 F ■°x, 4 Jk
1 N
F 1-123 .Y HA A Y? F Y o^i HAx
F
■CL P'N
1-117 F YY a 4 Jk
1-124 N
A F O^N^O
H A Y^ F Y QANA0
H .
F N
.CL P'N
1-118 F 4 OH[|
[I Jk
1-125 N
N F
O N 0 H
F. •CL
1-119 A P'N
F1 y Y Y F 0i<JXNxA0 4 Jk
1-126 N H
F^ N
1-120 P'N
F1 y A F oA 4 Jk
1-127 N
HA N
O' N O
H
F.
1-121 •O'T P'N
F7 4 Jk
1-128 N
P'N
4 N Jk
1-122
A (3^ F (Mrx FY
1-129
H
"O' F cAA H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
F P-N
F.
1-130 F 1-137
N
O' '0 o' N •o H
N
F P-N FOl OHII
1-131 F^" 1-138
F N
O' O N O' N rO H H
N
P-N P~N (\ H x ji
1-132 rfP F 0n 1-139
N OH p V 0 0 N 0 H H
N N
P-N P~N
OH[| o
1-133 1-140
N F N OH p
O' N •o O' N o H H
,N
P-N P-N
U- Il
1-134 1-141
N I OH p
F O^NA O' N to H
H
N
P-N O'
1-135 1-142
N OH p
F O N o oAA O H
H
N
P-N O'
1-136 1-143
N OH p
F oAA o o N o H H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
O'
R F
1-144 1-1 HN— . l 51 F'
N t)H p
O' N C> H Y i5<? F0 on^i HA
F.
1-145
F (A 1-152
HAo N
N
N
HN- OH[|
1-146 ci , Z1 1-153 'r 'N
Y A FF nAA ■o CIXf N
H O' N O H
N
1-147 Cl HN~,
=U Y N 1-154
A (4-c F o O<nVo
H 0
N N
Ohf| OH[|
1-148 Cl HN-.
1-155 F^ /N
=U N F I
O N N F
// ' H O N O H
N
F, FJ OH[| 149 F" 1- F^ /N-
1- 156
N F
0 N 0 H
N
A N QHII
1-157 F^
1-150 ,N F
O' N 0 H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N N
OH||
1-158 N'N 1-164 ^"
N F N
N OH p
0 N o 0 N O H H
N N
OH[|
1-159 ZN'N
1-165 N-N
N F
O N 0 N OH F H 0 N O H
N
QH[| N
1-160
N F
O' N 0 1-166 N-N H N OH p
0 N o H
N N
1-161 N OH[|
1-167
N
O^N^O H
N
FJ
1-162 OH
. ’ 1
F^ 0.
1-168
F o^rA N
H O^-NAD
H
F •N X. N Fs/I OH
1-163 F^ 1-169
,N F
0 N O N H ‘O' o^iAo H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N N
4
1-170
N OH p 1-176
O' N 0 ’OH H N
0 N 0 H
N
FJ E F
1-171 F Mx
N OH p
0 N 0 1-177 I H F^
‘OH
N o N O H
N
FJ
1-172 F rtD F. N
N H F
O' N 0 H
1-178
N
0 N 0
N H
1-173
N OH p
O' N 0 4 H 1-179 F^"
N
H
N
1-174
F
OH 1-180
N p
0 N 0 H cA ClA Hx
N
HI 4
1-1 F^
1-175 81
N I OH p N oAAo
0 N 0 H H Cmpd
Compound Struct No.
FJ-
1-182 F3^ rf
F^
1-184 F
N
FJ
1-185 r M
F FJI
1-186 F-^
FJ FV?O
1-187 F"^
N
F^ E
M
1-188
N
Figure imgf000145_0001
Cmpd
Compound No.
Figure imgf000146_0001
Cmpd
Compo nd Structure No.
F^
1-208 F^
A a Fa oAaA
1-209 F^
1-210
Figure imgf000147_0001
Cmpd
Compound Structure ure No.
Figure imgf000148_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
F
N F. I
1-233 1-239 F
N N OH p
0 0 N o
H H
N N
OH |
1-24 F^" -234 N. 0
1 N I OH
HN O' N '0
F H
O' N '0 H
N
N,
1-241
N OH p
O' N o
1-235 N-N H
N
N 1-242
OHI|
1-236 N-N
N F
O' N ‘0 H
1-243
1-237 N-N
0
N
OH[|
1-244 F /N Nx I N F
F^ I O' N 0 H
1-238 F-^
N OH F
0 N o H
F^
1-245 F^ /N I Cmpd Cmpd
Compound Structure Compound Structure No. No.
FJ F
1-246 F ,M QHO Fx/I
1-253 F^ r F N o
H
N F^
/N rW 1-254 F^
1-247 I F a ■N'-/ F O^hAo
N O H H
F-
N CF N
N
1-248 OH||
Y ?Y X 1-255
F o^rAo H N F
0 N 0 H
N
/N F
1-249 I N (XT> ? F° 0AnNA0 1-256 F
H
F O^N^O
H p4
1-250 F^-
F 0ANA0 1-257
H I
O' NX F 0ANA0 H H
1-251 F F4 M °n FJ
1-258 F
H U 0XNX
H 0
1-252 F F^^
F cA HA Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
N
1-259 1-265
N OHp
N 0 N O o H
N
N
N
F^ OH| 1-266
N OHp
1-260 F^ O N o H
N o' N H
N
N II
1-267
F. N I OH p
O'
1-261 F N 0 H
N
1-268 F^ /N I N OHp
O' N 0
1-262 F H
O' x H^ xn H N
1-269 F /N
N I N OH p
OH[| O' N ■o
H
1-263 F NH [
F
O' O' N ’0 H N
F FJI N
1-270 F^
N I'OH p o N o H
1-264 K NH o' F o^rA
H N
1-271
N OH p
0 N O H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
Fj
1-272 O' 1-279 /N I
OH p N
N
O' N 0 H
N
Fx
1-273 F- 1-280
N OH p o' N O N H
N
N
/N FJ
1-274 I N OH p 1-281 r
O' N 0 N H O' N '0 H
N
N
1-275 /N I N OH F 1-282 F^ /N
O' N 0 I N H O' N O H
N
N 1 N
1-276 /N 1
OH | I N FOH p
O' N O 1-283 H N F
O' N O H
1-277 N
N 1-284
N
0' N 0 H
N
1-278
N o^iA H Cmpd
Compound Structure No.
N /N
1-287 I M
F-
F-
1-289 F^
N
Figure imgf000153_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
Fx OH|| N.
1-297 F- 1-304 F
N F o' N ■0 F O F cr ’N'^o H '
H
Nx
N OH[| F
F. OH I
1-298 1-305 F
F
N o N NH2 H o' N "0 H
N M
OH|| OH I
1-299 NH 1-306
N F
0 N O N
O^N^O H H
N N
OH|| F
F. OH
1-300 ^~NH r 1-307 F
F N
0 N O O^N' X) H H
N
QH[|
1-308
1-301 NH F-^
N F <AA
O' N 0 H H
N
F
F.
N 1-309 F
1-302 N
F o' N "0 O^N^( o H
H
1-303 1-310
F oAAo N
N H Cmpd Cm
Compound Structure No. N
Figure imgf000155_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N~N \ o 3k
1-324
N 1-331
F. N
1-325 F^
/NHO^NAO H
1-332
N
F^ 0 N 0 H
1-326 F^
".J /' 0^NA0
H
1-333
F
F.
1-327 N
F
N o
N
HO
N
1-334
1-328 N
0 N 0
N OH p H
O N 0 H
1-335
1-329
N
N Nx
FJ OH
OH|| 1-336 ' I
F
1-330 N o N O
N o H
N 0 H Cmpd
Compound Structure No.
Figure imgf000157_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N— . N
OH[|
1-351 1-358
F N F o^A O' N 0 H H
N-i
1-352 1-359
V Vi z, N-M N F o^A F o^A H H
/N N
N I OH[|
1-360
1-353 N F
V i O N o hk..
// N A F oAA H H
N«N
/=N 1-361
1-354 V
F <AA>
H
<%
/=N 1-362
VN
1-355
N,
/=N 1-363
VN
1-356 F o^A H
F o^A H
N
/N^ OHJJ
N-, 1-364 V-NXz
1-357 V 1 N F
V o N o H
F o^A H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N. AN
S, J
1-365
A A F° 1-372 onA^o
H A n H
N AN
OH[| s
1-366 Cl . A
1-373
N F o N o NX/^ F CT 'N'A) H H
0 /=N s, A
1-367 N' 1-374
A n
A F O^N4 F oMo
H H / o
C Nx
1-368 VCl 1-375
A F O^NA ^ F° Or^Nx^O H H
N o-i
Oh[|
1-376
1-369
N F
O' N 0 A F 0M>
H H / N.
1-377
1-370 A r^A F fX
H
H
P~N
1-378 N
1-371 N
N A A A F° onA^o X> F° 0nANA0
H H Cmpd Cmpd
Compound Structure Compound Structure No. No.
/=N /=N °s 0. A
1-379 N 1-386 p p p A pp F 0pANA0 A F (AA: H H
/=N ^9
1-380 N 1-387 N pp p pp p
A F 0ANA0 NX^ F (ANA) H H
N=N -TO s. A N A
1-381 ppp 1-388 hr pp p
A F <A^0 Nx/ F cr 'N' X)
H H
N=N po
S, J N A
1-382 1-389 pPp ppp
A F A F <AA>
H H
N=N /TO sv A N A
1-383 1-390 Yr pP n
A F O^N\ A pp F 0pANA0
H H
/=N ox A N>
1-384 91 N A
1-3
A pp F OlANl\ A pp F ApNA0
H H
N
/=N
0. J N A
1-385 1-392 pP n. ,N
A F oM o o' N 0 H
H Cmpd Cmpd
Compound Structure Compound Structure No. No.
F ro F
\
N J N 'F
1-393 Yr
1-399 N.x
X Fo o^aA H
N
/( S ^ :x ,N-
1-394 N — N
Nx> FF nX 1-400
NA ■o H F cr 'N'^o
H
S
OH [| N.
1-395 N — N
N F 1-401
O' N H F O^A H
N
N; N
O — N QHII
1-396 1-402
N A-x> FF n X 0 N F
H o' N ■0 H
F F
\
N^. 'F N N A
OH|
1-397 N3 1-403 aX F 0Aa
F NA
N Q
O' H
H
F r-s
F N A
\ N-. 'F 1-404
1-398 rX F O^aN' X) H
F o^rA
H
N J
1-405 X F on^rAo H Cmpd
Compound Structure ture No.
P'N
N -N
1-406 ^ F° CArNxA)
H .Tr°x H.
P'N
<\ N Jk N
1-407 f
F (M H
P'N
<\ A
1-408 N /N-
1-409
H
N
Figure imgf000162_0002
N
Figure imgf000162_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
.0.
N
F
F.
1-420 ZN'M' 1
TT F V O^Ai 1-426 F
N 1'OH F H o N o H
.0. N
F
1-421 F. rA 1-427 F
F O^aN^O
H N OH p o' N ■o H
N
.0.
Nx
P~N
1-422 N~0 <x 1
1-428 N
N F N OH p
0 N o o' N o H H
N .0.
P~N Nx
4 Jk ■ I
1-423 /=N 1-429 Nr S. J N F N OH p
O' N ■0
0 N 0 H H
.0.
.0. N
N P'N
FJ 4 >
1-430 N 1
1-424 N r'OH F
N OH p O' N 0
O' N P H H
N
.0.
Mx OH|| ' I
1-425 1-431
F^
N OH p N F o' N 0 0 N o H H Cmpd
Compound Structure No.
H H
Figure imgf000164_0001
Cmpd
Compound Structure No.
Figure imgf000165_0001
Cmpd
Compound Structure tructure No.
Figure imgf000166_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
P'N
4 JI N
1-473 N 1-480 f
P'N
— N „
4 Ji
1-474 N 1-481
F
,N ,F
P'N \
'F
4 Ji Nxjj
1-475 N 1-482
,N
O N O H
F
N. A \ ,F
'F N
1-476 N OH[|
1-483 \jj
N F
O^N^O H
/=N
S. J F F
1-477 \
N"< 'F
F
O^N^O 1-484 H
N
N— <
Ohf|
1-478 V
N F
1-485
N— N o «
S N
1-479
N
O^N^O H 1-486
O' N ■o H Cmpd
Compound Structure No.
,N
1-487 o' N H
Figure imgf000168_0001
Cmpd
Compound Structure No.
Figure imgf000169_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
A
1-513 / CK
F^ N I 1-520
N
O' N 0 F O^N^O H H
FJ ,N Ck
1-514 F^ 1-521
N A — A rK Nx 1 A F A o^iA.
O' N H H
N
F OH A Cl
/N 1 1 D
1-515 F^ -522 I A FA N F o^Ax o N O
H H
1-523
1-516 F o^A
A F cA H HA
Cl
1-524
1-517
0
1-525
A F A o^Ai
/ H
1-518 F^ N I
F o^A H N
P'N
<\ Jk OH[|
1-526 N
N N F
A o' N
Q ■o
X H| N H
1-519 F
N F
O' N H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N ,0.
P~N N
4 jk OH[|
1-527 N 1-534 F^
N F o' N 0 N I 'OH F H
H
N
P~N N
QH P'N
4 Jk I|
1-528 N 4 Jk
1-5 N
N F 35
O' N "0 N OH p H O' N ■o H
N .Cl
P-N N
OH[| P'N
<\ JI
1-529 4 Jk
1-536 N
N F
O^N^O N OH F H O' N •o H
N .Cl
P-N N
O P~N
4 Jk H[|
1-530 N 4 Jk
1-537 N
N F
O^N^O N OH F H O' N O H
N .Cl
P~N N
4 Jk QH[| OH[|
1-531 N
1-538 HN-^
N F
O^N^O =V N F H Y O' N 0 H
.0.
N N
FJ OH||
1-532 r 1-539
N OH p HN~1 N F oAAo H Y O' N 0 H
.0. N
N
F R/l OH[|
1-533 F^ 1-540 HN"1
N OH p N F
O^N^O O' N 0 H Y H Cmpd
Compound Structure No.
P~N
4 Jk OH[
1-541 N
N
P~N
4 Jk OH
1-542 N
N
P~N
4 Jk QH[|
1-543 N
N
Figure imgf000172_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
.OH
1-555 1-561
A F oAAo
H
.OH P'N
4 Jk
1-556 1-562 N
A F 0ANA
H 0 F O^NA)
D H
N
P-N OH[| 57 // NH
1-5 A FF nAN N
O' NA 1-563 H N F o'- N ■o
Hl H N D
N
NH r 1-564
1-558 .N A A FM A o'QA
H
III N
N
P~N <X Jk
OH[| 1-565 N
1/ NH
1-559 F A A F n o
H
N ■o D H
Hl N
CK
N 1-566
FJ
1-560 F^
N OH p o' N O H
CK
1-567 1 Cmpd
Comp No.
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
1-620 1-627
O' N O H
Figure imgf000178_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N P'N
QH|| 4 JI.
1-64 N
1-634 N-N 1 rA l
N F F F oAAo
O' N 0 H H
N ,°'N
OH[| 4 Ji
1-642 N
1-635 N'N'
F F 0^NX0
N F H
0 N C H
P'N
N 4 JI
OH|| 1-643 N"^
1-636 N~M' F
N F o' N O ry?°n H H
N
P'N
N 4 JL OH[|
QH[| 1-644 N
1-637 ^'N N F
F
N F o N 0
0 N 0 H H
P'N
N
4 Ji.
.0 OHII 1-645 N
1-638 F
N F
O^N^O H
P'N
N
I 4 JI .0 1-646 N
1-639 F
N
O^N^O H
P'N
I 4 1 .0 1-647 N
1-640 F
Figure imgf000180_0001
Figure imgf000181_0001
Cmpd
Com No.
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
Fx N
F- P'N <x JL OH[|
1-714 1-721 N
F o^iA N F
H F O^N^ X)
H
Fx N
F- P'N rW Ja 4 J OH||
1-715 I
1-722 N
F 0^4 N F H F
H
Fx
F- P'N
1-716 4 Jt
1-723 N
F
N.
1-717 HO.
/°x^0- 1-724
N ^ F° onAA)
H
1-718 N HO.
F oAAo H 1-725
F o^iA
H
1-719 N HO.
1-726
N
OH[| N
1-720 N .OH OH||
N F oAAo 1-727 H
N F
F 0 N O H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N N
■OH OH[|
O,
1-728 Ai 1-735
N F
F O' N 0 N
H o N 0 H
N N
.OH OH]
1-729 0,
1-736
N F
F O' N O N
H O^NA)
H
.0.
N N
0 ’ I OHI| o.
1-730 1-737
N OH p N F oAA O^N^O H H
N
N
UN
— N QH[| 1-738
1-731 ►U f 0*
N F NA
H 0
N
N, QHI| 1-739
1-732 F
F 0M 0
N F
F' H
‘O' O
H
UN
1-740
1-733 s->
N0 F <A\>
H
N
.OH OH||
HN N 1-741
N F
F O' N 0
1-734 H
O^lAo
H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
.OH OH[|
1-742 1-749 ZN-N
F A F O^A N F H 0 N 0 H
N
.OH
OH||
1-743
1-750 N~N'
F NX/ F O^N'X
H N F
O' N ■0 H
N
1-744 T QHI|
A F oAA 1-751 N-N
H N F
O' N 0 H
N
OH[| N
1-745 OH||
N F
O' N 0 1-752 N; H — N N F
O' N •o H
1-746
"O
1-753 N, — N A F H
Cl
1-747
O, XJ
OH 1-754 N;
— N ^ °n
H
N
1-748 ,N
O'
F O' O N o H N
1-755
N o' N ■o H
Figure imgf000188_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N N
Cl OH[|
1-770 I ,N ,N 1-777
"O' o' N 0 — N H N' N F
0 N 0 H
N
F FVl QH[| N
1-771 F"^ P
0
N F x 'yH N.
"O' O^N^O 1-778 H N.
O' N 0 H
N
N
N
1-772
N
F oAAo H 1-779
N OH p
0 N O
N H
N
1-773
N
F O' N 0 H
1-780
N
N
OH[|
1-774
N F
F oAA) H
Figure imgf000189_0001
Cmpd No.
1-784
Figure imgf000190_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
OH||
F4
1-797 N-N 1-803 F^
N F y ° (AnA) H
F^
1-798 F
1-804 F
N
OH |
1-799 N~N
N F FJ
0 N O 1-805 F H
H
N o
1-800 N I H 0. N
N N
O' N 0 OH|| H 1-806 F
N o N 0
I H 0. N
OH[|
1-801 F
N
0 N o FJ H 1-807 F"^
1-802 F^
O. N
QH[|
1-808 F^
N
O' N O H
Figure imgf000192_0001
Figure imgf000193_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
N
1- /N
1-835 N'N 841 I
N F
0 N O H
N
OH| , _ _ N~,
1-842 /T ^N
1-836
N F
0 III
H N
N
O F F
F, H[|
1-843 F N:
1-837 F- -X N
N F
N
QHI|
N: , _ , N.
1-838 1-844 N ^X-N
N F oAA H
F Cl
F^
1- F^
1-839 845
— N N W F n H
M
F
F. OH ’ 1
1-846
1-840 0 F
N
F o' N 0 H
Figure imgf000195_0001
Figure imgf000196_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N F F F-X
,CI M
1-871 N.
1 OH 1 — N -878
N
O' N 0 N H o^rAo
H
N
N
OH | /=N
OH[|
1-872 1-879 °s N A
N F N F
0 N o H nX HX
N
OH |
1-880
1-873 HN
0
N F 0
N
F^.
I 1-881
1-874 N N
O' N o H
N
FJ
1-875 1-882 F^"
N o N o H
N
F Nx
1-876 N Fxj OH
1-883 I F^
N
O' N 0 H
N
F F N
1-877 F"X
1-884 N~NH
N OH p o' N o
H C
1
Figure imgf000198_0001
Cm No
1-89
Figure imgf000199_0001
Ċ
Figure imgf000200_0001
Figure imgf000201_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
Cl N N;
•N
1-935 1-942
N
O' N o NX/^ F O^N"SD H H
N. N
— N •N OH[|
1-936 N' 1-943
F O^A N F
O' N ■o
H H
N N^,
— N •N
1-937 N' 1-944
N F QANA0 o N o H H
N \
— N OH[| VN
N' 1-945
1-938
N F o' N "0 H '5a'5n H
.0. \ -
I VMNJ
N
1-939 k'N/ 1-946
F O^N" X) F o^A
H H
1-940 N"J A 1-947
F o^aA A F° On^A H H
.0.
1-941 N F v 1-948
N A F oAAo
H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N~.
F — N
1-949 1-956
A F oA Cl H
N P'N
F -A\ Jk
1-950 1-957 F
N A A F° A n F n 0AA
On n' K NA H H
N P'N n jk
■OH OH[| 1-958 F N^
1-951 A F
F °n H
0
H
P'N
N Jk
1-959 F
•OH OH[| N A 2 A. F° on^A
1-95 H
N F
O' N 0 H
V N /
1-960 F
N
.OH QHI| A A F°n H
1-953
N F
O' N H
Fx VM ,
1-961 F
N. A F oAo — N H
1-954 ci A F onNn
H o
F. Ns, ■N /
1-962 F
N~- A a F a onNn.
H o — N
1-955
Cl A A FF On' N H N.
— N
1-963
F A n F n onNA H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N; N N
O ,N=N
— N H|| — N A
1-964 1-971
N F N
F o' N 0 o N 0 H H
N. N N
,N=N
— N — N A
1-965
N F 1-972
F o' N 0 N H O N ■c H
N
N=N
— N J I .0
1-966
F 1-973
'0 rxsCOn
H NA F CANA)
H
,N=N
— N J I .0
1-967
NA F 1-974 O^NA)
H
N=N N — N A I .0
1-968
N F 1-975
O' N ■o H
,N=N .0 — N A
1-969 N
F 0<AA) 1-976
H 1 NA F 0ANA0
H
N
,N=N — N A OH[| .0
1-970 N
.N F OH[|
O' N o 1-97 N
H 7 1 N F
O' N o H
Figure imgf000205_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
XN
1-998 V
1-991 FJ
H ?dA oAAo H-„ H
N
OH
N CI¬
/^N 1-999 CI °. a N
1-992 N o' N O H
N
O' N ■0 H
N Cl-A
/^N 1-1000 Cl
1-993 N A H
N o' N ■o H
N
/=N x CI^Z^
1-1001 Cl
OH ’ I
1-994 N o
H
M
N x
OH ' I
N 1-1002
/=N
N a N O N o
1-995 H
N
F O' N 0 H
F P'N
F-7 JI
N 1-1003 F
/=N
0. 996 X N x-^ O^N^O
H
1- N
N.
Cl O N 0 H
F. P'N
F-)
1-1004 F N A n H
1-997
N
Figure imgf000207_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N-N
\ o JI.
1-1019
1-1026
N-N
\ JL
1-1020 CJ
1-1027 N~N
N
N-N
'< Jk
1-1021 0^
1-1028 N-N
OH
1-1022 0 T N F
O' N ■o H
N-N 1-1029
1-1023 '< cr A
Nx
OH I
1-1030 N-N
1-1024
N F
N O N O H x N
N x
OH
OH I I
1-1031 N~N
1-1025
N F
N F O' N O
O N o H
H Cmpd Cmpd
Compound Structure Compound Structure No. No.
N P~N
OH (\ '1
1-1032 J 1-1039
N-N ".
N F
0 N o H
O-N N 0
1-1040
N o' N ■o
H
1-1033 N~N ^ Xi f n <A HA> P-N
1-1041
N ■o
N-N H er ‘s A
1-1034 0
F O^NA) H
1-1042
F-7
P~N F F
U H
1-1035
0 F oAA)
H
1-1043
P~N
0
1-1036
N0 F cr 'N' X) H
P~N 1-1044
F-/ ■ F I
F k
1-1037 N0 (ArAo H o
O-, 0
P-N Nx 1-1045
OH 0 I
1-1038 N0 F o^A H
N F
O' N '0 H
Figure imgf000210_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
F
A Nx
OH
1-1062 ’ I
F a 1-1069 w (bA H N F
O N O H ft F
1-1063 — N J,
1-1 'hlft
Cl A F o^A 070 H ft Fft O^-Nl,
H\
Nx ft OH I ,F
1-1064
II N F 1-1071 N' or O' N o H ft°n H
N
N
1-1065 M 1-1072 V
Ff N
Cl Ft X N Hx A ■,o N'-/J F cr 'N'b H
,F N ,N
,N^ — N OH /ft OH
1-1066 1-1073 VN
F N F
N '0 o' N
H ■o H
F
N~- N — N _
1-1067 1-1074 VN-v
N F
0 N 0 F o^A
H H
N
NJ ,F OH L I — N 1-1075
1-1068 N. F
O' N 0
N A ° C OVn H ' N
H Cmpd
Compou d Structure No.
Figure imgf000212_0001
C
Figure imgf000213_0001
Figure imgf000214_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
,N-N — N A
1-1121 F Fy-O N 1-1129
A F 0M JI H or
1-1122 V F A N~N Nx N — N A OH I
1-1130
■o N F
Cl 0 N O H
OH I N
,^'N
1-1123 J
N F
0 N 0 1-1131 H N ci O' N ■o H
N
1-1124 ,N=N
F N — N A
N
O' N o 1-1132 H II or N '0 H
N
F,
1-1125 F N
N
0 N O 1-1133 v N H
Cl A F oAA) H
,N=N
— N A
1-1126 fX"N . cA 1-11 v N or F 34
HA or
H
,N=N — N A
1-1127 A °n r v>-N. . ci A F o^A 1-1135 N H 1
N — F O^N' X) H
,N=N
— N A
1-1128
Cl Cmpd Cmpd
Compound Structure Compound Structure No. No.
M.
I OH v>-N. 1 — N
1-1136 1-114 N'
J 3
N. F CK O' N 0 II H cr F O^NA) H
N.
N
O-N. . OH 137 — N OH
1-1 V N
1-1144 N'
,N F cr O' N o ,N F H Cl O' N ■o H
N
N
F
1-1138 v>-N. N .
— N
J N 1 w cr 0 N 0 -1145
H N
Cl O' N '0 H
N
>-N .
1-1139 v N — N
N 1-11 N'
Cl O' N ■o 46 H J cr
— N J F.
1-1140
N I cr F cAA, 1-1147 F N
H
Cl F oA HA
N
— Ns OH F.
1-1141 'N'
II N F 1-1148 F N cr O' N o Jl H cr rfA F oAaA) H
— N
1-1142 N' F)-N^
1-1149 F N II
Cl o cr Cmpd
Compound Structu No.
1-1150 cr
Fy-A H
1-1151 F N J, or ,N F D o' N •o H
F. N
0 N 0 H H F o^A
H
Figure imgf000217_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
-Cl Nx Nx
/=N
— N OH — N A OH
1-1165 'N 1-1172 'IT
N F N F
O' N ■o O' N 0 H H
.01 N /=N
— N OH — N A \ 1166 1-11 r
1- N' 73
F
N o A F oM H H
,CI M
N /=N x — N J OH
— N I
1-1 Yr
1-1167 N' 174
N F N F o' N ■o O' N 0 H H
_N.
,01 N /=N
— N A OHI
— N OH N 1-1175
1-1168 N F
N F 0' 'N o
O N o H H
N
/=N
.01 — N J
— N 1-1176
1-1169 N' N
O' N 0 H
N o H
/=N Nx
.01 NX — N OH I
Yr
— N OH 1-1177
1-1170 N' N F
O' N o
F H
,N
0 N O
H
/*N 1-1178 \'N
— N J 71 Y F oAA
1-11 r H
A FF nA NA O H
1-1179 V
F o^A
H Cmpd
Compo nd Structure No. N 180 XX Jk
1-1 N'N
F (ZN' X)
H
Figure imgf000219_0001
Cmpd
Compound St No.
Cl¬
1-1196 ef o' N 0 H
P'N
1-1198
P'N JL
1-1199 N
Figure imgf000220_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
F N
F F
1-1209 — N 1-1216 N N o N O
A F ZA 0 H H
,N
/^N
F F
1-1 CN
AF 217
N o N O
1-1210 — N
M Xn H
N’ A F 0^NA0
H
F. /=N
CN
1-1218 F
/*N F
F- V,N H
1-1211
A X FX <ZaA
H
F /=N
1-1219 F
/^N A F O^N\
F H
"^N
1-1212
A F <AA H F. /=sN
CN
1-1220 F
F O^N\
/=N H
F VN
1-1213
A F 0^NA( H F, /^N ^/N
1-1221 F
/*N
F- CN
1-1214 ro
R /*N
CN
1-1222 F
/^N
F- V,N
1-1215 o F
VN
1-1223 F Cmpd
Comp ure No.
E /^ ^
1-1224 F
A ^ F 3T H\
Figure imgf000222_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
F F^F
N: Z^F
1-1239 v N 1-1253 — N a a
A F O^N HA
,F N,
F F
1-1240 v N N~. 'F N
N
O' N ■o 1-1254 H
N o N 0 H
,F
V>-N .
1-1241 v N F^F / ~F ,N
OH
1-1255 — N _
N F
0 N O H
1-1249
1-1256
A F oA-A
H
1-1250 \ N»
1-1257
A A F° QnANA0
H
N. < F\Z"FF N
1-1251 — N OH 1-1258
F A o a Fa oAA H
H
F F
N. 'F /N~s, 1-1259
1-1252 — N OH ' I F 0M H 0
N F
O' N o H
Figure imgf000224_0001
Figure imgf000225_0001
Cmpd Cmpd
Compound Structure Compound Structure No. No.
N
N
1-1288 1-1295 w
N
F N F oAA F O N 0
H H
N N
N
1-1289 1-1296
N N
O' N N H F O' N ■o H
N.
,N N
QH[|
1-1290
N F 1-1297 N
O' N ■o N H F O N 0 H r N
1-1291 x^Cxa 0
N 1-1298
F F O^N^O
H F oAA)
H
N
1-1292 N 0
1-1299
F F O^N^O
H " ■> F
H
N
1-1293 N O
F 1-1300
A °n
H
N
N
1-1294 OH[|
N 0
1-1301
F F
H N F
O' N ■o H Cmpd Cmpd
Compound Structure Compound Structure No. No.
,N
N
QH[|
0
1-1302
N F 1-1309 o' N O H
N
N
OH||
O .N. N.
1-1303 j' ' N
N F
O' N 0 1-1310 H ,N
O' N 0 H
N
N o
1-1304 N
N
O N O 1-1311 H N o' N 0 H ft
1-1305 A F° On' 1-1312
H u A F
H
<%
1-1306 ft F° on N. AA N I H 1-1313
N
O N 0 H
'QHfl
1-1307
F
O' N'
H 1-1314 N"j ftft F 0^aNA0
H ft
1-1308
F o^A N I
■o
H 1-1315 'NX F o^A
H
Figure imgf000228_0001
Figure imgf000229_0001
* Absolute and relative stereochemistry was not assigned.
Embodiment 1: A Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
Xi is N or CR3;
X2 is N or CR5-;
Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2,
-CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2,
-CH2OC(O)CH(RI2 )NHRIT, -CH2OC(O)(CH2)qC(O)ORi2’, or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);
R2a, Ra, R2C, and RM are each independently H or D;
Ra is H, D, (Ci-Ca)alkyl, or (Ci-Ca)deuteroalkyl; each R4 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10; each R5 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -OH, or -NR9R10;
Rs1 is H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, halogen, -OH, or -NR9R10;
R6 is H, D, -C(0)RH, -CH2OC(O)Rn, -CH2OC(O)NHR,2, -CH2OC(O)OR]2, -P(O)(OR,2)2, -CH2OP(O)(OH)OR12, or -CH2OP(O)(Ri2)2;
R?a, R -?7bb,, R7C, and R7d are each independently H, D, (Ci-C2)alkyl, (Ci-C2)deuteroalkyl, or (Ci-
C2)haloalkyl; each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -0-(C1-C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R21, and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two Rve, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3-, -C(0)Ri3, and -C(O)NRi3’Ri3’;
Rs is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R 15 ;
R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, or (C1-C6)deuteroalkyl;
Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (Cs-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;
R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN;
Rn- is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl;
Rn- is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R14 and Rn- are each independently at each occurrence H or (C1-C6)alkyl;
Ri4a is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R15 and Ris- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR30R31, -SF5, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (Cs-Crjcarbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NR35R36, -C(O)NR37R3s, -C(O)R37, -C(O)OR37, -SF5, -SR29, and -CN; or two RL5, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- Cvjcarbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ris’, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and SO, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Ri?; or two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Ris- when on the same carbon atom form C=(0);
Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;
Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (Ci-Gjalkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (Cs-Cvjcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; R20 and R20' are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (Ci-Cgjalkyl, (C1-C6)haloalkyl, (Ci-Cgjalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Czjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (Cs-Cyjcarbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (Ci-Gjalkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S;
R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R30 and R31 are each independently at each occurrence H, (C1-C6)alkyl, or -GOjRxi;
R32, R33, and R34 are each independently at each occurrence H or (C1-C6)alkyl;
R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R39i
R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl; o is 1 or 2; m and n are each independently 0, 1 or 2; p is 0, 1, 2, 3 or 4; and q is 1, 2, or 3.
Embodiment 2: The compound according to embodiment 1, having a Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), or Formula (Ih), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 3: The compound according to any one of embodiment 1 or 2, wherein R2a is H.
Embodiment 4: The compound according to any one of embodiments 1-3, wherein R.2b is H.
Embodiment 5: The compound according to any one of embodiments 1-4, wherein R2C is H.
Embodiment 6: The compound according to any one of embodiments 1-5, wherein R2d is H.
Embodiment 7: The compound according to any one of embodiments 1-6, wherein Xi is CR3.
Embodiment 8: The compound according to any one of embodiments 1-6, wherein Xi is N.
Embodiment 9: The compound according to any one of embodiments 1-8, wherein X2 is N.
Embodiment 10: The compound according to any one of embodiments 1-8, wherein Xi is CRv.
Embodiment 11 : The compound according to any one of embodiments 1-10, wherein R?a is H.
Embodiment 12: The compound according to any one of embodiments 1-11, wherein R?b is H.
Embodiment 13: The compound according to any one of embodiments 1-12, wherein R?c is H.
Embodiment 14: The compound according to any one of embodiments 1-13, wherein R?d is H.
Embodiment 15: The compound according to any one of embodiments 1-14, wherein o is 0.
Embodiment 16: The compound according to any one of embodiments 1-14, wherein o is 1.
Embodiment 17: The compound according to any one of embodiment 1 or 2, having a Formula (li), Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), or Formula (Ip), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 18: The compound according to any one of embodiments 1-17, wherein Ri is H.
Embodiment 19: The compound according to any one of embodiments 1-18, wherein R3 is H.
Embodiment 20: The compound according to any one of embodiments 1-19, wherein Rs is H.
Embodiment 21: The compound according to any one of embodiments 1-20, wherein n is 0.
Embodiment 22: The compound according to any one of embodiments 1-21 wherein m is 0 Embodiment 23: The compound according to any one of embodiments 1-21, wherein m is 1.
Embodiment 24: The compound according to any one of embodiments 1-21, wherein m is 2.
Embodiment 25: The compound according to any one of embodiments 1-24, wherein each R4 is independently at each occurrence (C1-C6)alkyl, halogen, or -NR9R10.
Embodiment 26: The compound according to any one of embodiments 1-25, wherein Rs- is H, (Ci- C6)alkyl, or halogen.
Embodiment 27: The compound according to any one of embodiments 1-26, wherein each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, or (C3-C7)carbocyclyl, wherein the alkyl is optionally substituted with one to six R19 and the carbocyclyl is optionally substituted with one to three R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(O)ORB', -C(O)RB, and -C(O)NRB’RB’.
Embodiment 28: The compound according to any one of embodiments 1-27, wherein Rg is (Ci- C6)haloalkyl, (C1-C6lhydroxy alkyl, (C1-C6)alkyl optionally substituted with one to three substituents independently selected from D, (C1-C6)alkoxy, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl optionally substituted with one to three RB and the carbocyclyl and heterocyclyl are optionally substituted with one to three RB-.
Embodiment 29: The compound according to any one of embodiments 1-28, wherein Rg is (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)alkyl substituted with one to three substituents independently selected from D, (C1-C6)alkoxy, -SRua, -NR14R14’, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one to three RB and the carbocyclyl and heterocyclyl are optionally substituted with one to three RB-.
Embodiment 30: The compound according to any one of embodiments 1-29, wherein each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20’, or (Cr-Cvjcarbocyclyl wherein carbocyclyl is optionally substituted with two to four R23.
Embodiment 31 : A compound selected from the group consisting of: 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-2-methyl-6-(l, 3, 3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l,3-diethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-fluoro-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3,3-dipropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(3-(2,2-difluoroethyl)-3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-(trifluoromethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(6-(3-benzyl-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3-isobutylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl- 1 ,5-naphthyridin-3-yl)piperidine- 2, 6-dione;
3-(6-(3-(cyclopropylmethyl)-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine -2, 6-dione; l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
1 -(6-(4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione;
3-(6-(4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
1 -(6-(4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)- 1 ,5-naphthyridin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione; l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione;
3-(6-(3-benzyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-(2,2-difluoroethyl)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2,6- dione; l-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoroquinolin-3-yl)dihydropyrimidine-
2,4(lH,3H)-dione; l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-
2,4(lH,3H)-dione; l-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-
2,4(lH,3H)-dione; l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione;
3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-(methoxymethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(9-hydroxy-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[3.5]nonan-9-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methyl-l,5-naphthyridin- 3 -yl)piperidine-2, 6-dione ;
3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3,3-dipropylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione; l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione;
3-(6-(8-hydroxy-5-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.5]octan-8-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(l-ethyl-4-hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3,3-bis(ethyl-d5)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(6-(4-hydroxy-3,3-dimethyl- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl- 1 ,5-naphthyridin-3- yl)piperidine-2, 6-dione;
3-(6-(3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione; 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione; l-(5-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione;
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(3-ethyl-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-
2,6-dione;
3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(l, 3, 3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-(cyclopropylmethyl)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2,6-dione;
3-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2,4-dimethylquinolin-3-yl)piperidine-2,6- dione; l-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione;
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(2-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-
2,6-dione;
3-(6-(l-(4-cyclopropylbenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione; 3-(6-(l-(4-(difluoromethoxy)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-cyclopropoxybenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione;
3-(6-( 1 -(4-( IH-pyrazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-(difluoromethyl)-3-methoxybenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-
3 -yl)piperidine-2, 6-dione ;
3-(6-(l-(4-(2,2-difluoroethoxy)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(3-methoxy-4-(trifluoromethyl)benzyl)-3,3-dimethylpiperidin-4-yl)quinolin-
3 -yl)piperidine-2, 6-dione ;
3-(5-fluoro-6-(4-hydroxy-l-(4-(isoxazol-3-yl)benzyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(3.3-diethyl-4-hydroxy-l-(4-(isoxazol-3-yl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione;
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(oxetan-3-yl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((7-methyl-lH-indol-3-yl)methyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-((7-chloro-lH-indol-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((7-(trifluoromethyl)-lH-indol-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fhioro-6-(4-hydroxy-3-(trifluoromethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methyl-l,5-naphthyridin-3- yl)piperidine-2, 6-dione;
3-((4-(7-(2,6-dioxopiperidin-3-yl)-6-methyl-l,5-naphthyridin-2-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl) - 1 H-indole-7 -carbonitrile ; 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((1 -methyl- lH-pyrazol-5-yl)methyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fhioro-2-methylquinolin-6-yl)-4-hydroxypiperidin-l-yl)methyl)-lH- indole-7 -carbonitrile ;
3-(6-(3-(bicyclo[ 1.1.1 ]pentan-2-ylmethyl)-4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-(bicyclo[ 1.1.1 ]pentan-2-yl)-4-hydroxy-l -(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3,3-diethyl-4-hydroxy- 1 -(( 1 -methyl- lH-pyrazol-5-yl)methyl)piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4-hydroxypiperidin-l- yl)methyl)benzonitrile; l-(6-(4-hydroxy-l-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-
2,4(lH,3H)-dione;
1 -(6-(4-hydroxy- 1 -(3-methoxy-4-(trifluoromethoxy)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-
3 -yl)piperidine-2, 6-dione ;
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2,6- dione;
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(9,9-difluoro-5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-ethyl-4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(5-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3,3-dimethyl- 1 -(4-(trifhioromethyl)benzyl)piperidin-4-yl)- 1 ,5-naphthyridin-3- yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)- 1 ,5-naphthyridin-3-yl)piperidine-2, 6-dione;
3-(4-amino-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione; 3-(6-(4-hydroxy-3,3-bis(methoxymethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(3-fluoro-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(3,3,3-trifluoropropyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(5-fluoro-6-(4-hydroxy-l, 3, 3-trimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(cyclopropylmethyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-l-isopropyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(oxetan-3-ylmethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)quinolin-3- yl)piperidine-2,6-dione;
3-(6-(3-cyclopropyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(3-((dimethylamino)methyl)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine -2, 6-dione;
3-(2-amino-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-(2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-((lH-pynol-2-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-((l-hydroxycyclopropyl)methyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(2-hydroxy-2-methylpropyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione; 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(pyridin-2-ylmethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(pyridin-3-ylmethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(pyridin-4-ylmethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione;
4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)benzonitrile;
3-(6-(l-((lH-pyrazol-4-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((1 -methyl- lH-pyrazol-5-yl)methyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(9-hydroxy-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[3.5]nonan-9-yl)quinolin-3- yl)piperidine-2, 6-dione;
4-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-9-hydroxy-6-azaspiro[3.5]nonan-6- yl)methyl)benzonitrile;
6-amino-5-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)picolinonitrile;
3-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l-yl)methyl)- 1 H-indole-7 -carbonitrile ;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
5-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)picolinonitrile;
3-(6-(3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione;
3-(6-(l-ethyl-4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(4-(difluoromethyl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((6-oxo- 1 ,6-dihydropyridin-2-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione; 3-(6-(4-hydroxy-3-isopropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(l-ethyl-4-hydroxy-3-isopropylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-3-isobutyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(l-((4-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((6-oxo-5-(trifluoromethyl)- 1 ,6-dihydropyridin-2- yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((4-oxo-5-(trifluoromethyl)- 1 ,4-dihydropyridin-2- yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((4-oxo- 1 ,4-dihydropyridin-2-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxypiperidin-l- yl)methyl)benzonitrile;
3-(6-(3,3-diethyl-4-hydroxy-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-5-fluoroquinolin-
3 -yl)piperidine-2, 6-dione ;
3-(6-(3,3-diethyl-4-hydroxy-l-isobutylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3,3-diethyl-4-hydroxy-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-((4,4-difluorocyclohexyl)methyl)-3,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
5-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxypiperidin-l- yl)methyl)picolinonitrile;
3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2,6- dione;
4-((4-(7-(2,6-dioxopiperidin-3-yl)-6-methyl-l,5-naphthyridin-2-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)benzonitrile;
3-(6-(4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-2-methyl-l,5- naphthyridin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy- 1 -isobutyl-3,3-dimethylpiperidin-4-yl)-2-methyl- 1 ,5-naphthyridin-3-yl) piperidine-2,6- dione;
3-(6-(3-cyclopropyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione; 3-(6-(3-cyclopropyl-4-hydroxy-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-cyclopropyl-4-hydroxy-l-isobutylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
4-((3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidin-l- yl)methyl)benzonitrile;
3-(6-(3-ethyl-4-hydroxy-l-isobutylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-ethyl-4-hydroxy-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
5-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4-hydroxypiperidin-l- yl)methyl)picolinonitrile;
3-(6-(l-ethyl-4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine- 2,6-dione;
3-(5-fluoro-6-(4-hydroxy-3-(trifluoromethyl)-l-(4-(trifluorornethyl)benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-isobutyl-3-(trifluoromethyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine- 2,6-dione;
3-(5-fluoro-6-(4-hydroxy-l-isobutyl-3-(trifluoromethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(9-hydroxy-6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-6-azaspiro[3.5]nonan-9- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-((4,4-difluorocyclohexyl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione;
4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)benzonitrile;
3-(6-(l-((lH-pynol-2-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione;
4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l-yl)methyl)-
2-methylbenzonitrile ;
3-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)benzonitrile; 2-(difluoromethoxy)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidin- 1 -yl)methyl)benzonitrile;
3-(5-amino-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione; l-(6-(l-benzyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione;
3-(6-(3-ethoxy-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(2-ethyl-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fhioro-6-(4-hydroxy-3,3-dimethyl-l-propylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-((4,4-difluorocyclohexyl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l, 3, 3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3-(2,2,2-trifluoroethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-ethyl-3,4-dihydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(2-methylbenzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -((4-oxo-6-(trifluoromethyl)- 1 ,4-dihydropyridin-3- yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(4-(2H-l,2,3-triazol-2-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(5-methyl-l,3,4-oxadiazol-2-yl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-4-(methylamino)quinolin-3-yl)piperidine- 2,6-dione;
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-4-methoxyquinolin-3-yl)piperidine-2,6- dione;
3-(6-(3-(2,2-difluoroethyl)-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(6-ethyl-9-hydroxy-6-azaspiro[3.5]nonan-9-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-cyclopropyl-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione; 3-(6-(3-cyclopropyl-l-ethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(3-(2,2-difluoroethyl)-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-ethyl-4-hydroxy-3-(hydroxymethyl)-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(2-methoxybenzyl)-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione;
3-(6-(4-hydroxy-3-phenyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
1 -(6-( 1 -(4-( 1 ,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methyl-l,5- naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione;
3-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methyl-l,5- naphthyridin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-(l,3-dimethyl-lH-pyrazol-4-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(3-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-( 1 -(3-( IH-pyrazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(6-( 1 -(4-( 1H- 1 ,2,4-triazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(4-methylthiazol-5-yl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(pyridazin-3-yl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-(l-(4-(lH-imidazol-l-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(oxazol-2-yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione;
3-(6-(l-(3-(lH-imidazol-l-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-4-yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione; 3-(5-fluoro-6-(4-hydroxy-l-(4-(isoxazol-4-yl)benzyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(3-methyl-4-(l,2,4-oxadiazol-3-yl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(4-(l,2,3-thiadiazol-4-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(oxazol-4-yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-
2,6-dione;
3-(6-(l-(4-(l,3,4-oxadiazol-2-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-2-yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-
2,6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-4- yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-5-yl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-
2,6-dione;
3-(6-(l-((6-(l,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-( 1 -(4-( IH-indazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-2-yloxy)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-2-ylamino)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(6-( 1 -((3-cyclopropyl- 1 -methyl- lH-pyrazol-5-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((l-methyl-3-phenyl-lH-pyrazol-5-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-((l,2,4-oxadiazol-5-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(thiazol-4-ylmethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione; 3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-9-oxa-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-9-oxa-2-azaspiro[5.5]undecan-5-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(2-(4-(l,2,4-oxadiazol-3-yl)benzyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((l-methyl-lH-l,2,4-triazol-5-yl)methyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-((lH-pyrazol-5-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-l-(isoxazol-5-ylmethyl)-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(5-hydroxy-2-((l-methyl-lH-pyrazol-5-yl)methyl)-9-oxa-2-azaspiro[5.5]undecan-5- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(2-(4-(l,2,4-oxadiazol-3-yl)benzyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(5-hydroxy-2-((l-methyl-lH-pyrazol-5-yl)methyl)-9-oxa-2-azaspiro[5.5]undecan-5-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione;
3-(6-( 1 -(4-(4-acetylpiperazin- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
5-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidin-l- yl)methyl)picolinamide;
3-(6-(l-(4-(l,2,4-oxadiazol-5-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(3-methyl-l,2,4-oxadiazol-5-yl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-(l-(4-(lH-benzo[d]imidazol-l-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione; l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-9-oxa-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ; l-(5-fluoro-6-(9-hydroxy-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[3.5]nonan-9-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(6-(2-(4-(l,2,4-oxadiazol-3-yl)benzyl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(6-(l-(4-(lH-benzo[d]imidazol-l-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ; l-(6-(l-(4-(l,3,4-oxadiazol-2-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(5-fluoro-6-(4-hydroxy-l-(4-(isoxazol-3-yl)benzyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(oxazol-2-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(oxazol-4-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(5-fluoro-6-(4-hydroxy-l-(4-(isoxazol-4-yl)benzyl)-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(6-(l-(4-(3,5-dimethylisoxazol-4-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(6-(l-((6-(l,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(3-methyl-4-( 1 ,2,4-oxadiazol-3-yl)benzyl)piperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(thiazol-5-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(thiazol-4-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(4-methylthiazol-5-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(6-(l-(4-(l,3-dimethyl-lH-pyrazol-4-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(l -methyl-5-(trifluoromethyl)- lH-pyrazol-4- yl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(pyridazin-3-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ; l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-2-ylamino)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ; l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(thiazol-2-yloxy)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione;
1 -(6-( 1 -(3-( IH-pyrazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(thiazol-2-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione; l-(6-(l-(4-cyclopropylbenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ; l-(6-(l-(3-(lH-imidazol-l-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H )-dione ; l-(6-(l-(3-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
1 -(6-( 1 -(4-( 1H- 1 ,2,4-triazol- 1 -yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
1 -(5-fluoro-6-(4-hydroxy-3,3-dimethyl- 1 -(4-(l -methyl- lH-pyrazol-4-yl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
(R)-l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4( 1 H, 3H)-dione ;
(S)-l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione;
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione-3-d;
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)-3- methylpiperidine-2, 6-dione ;
(R)-3-(6-((R)-8-hydroxy-5-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.5]octan-8-yl)quinolin-3- yl)piperidine-2, 6-dione;
(S)-3-(6-((S)-8-hydroxy-5-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.5]octan-8-yl)quinolin-3- yl)piperidine-2, 6-dione;
(S)-3-(6-((R)-8-hydroxy-5-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.5]octan-8-yl)quinolin-3- yl)piperidine-2, 6-dione;
(R)-3-(6-((S)-8-hydroxy-5-(4-(trifluoromethyl)benzyl)-5-azaspiro[2.5]octan-8-yl)quinolin-3- yl)piperidine-2, 6-dione; l-(6-(l-((6-(l,3,4-oxadiazol-2-yl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione;
(R)-3-(6-((R)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione;
(R)-3-(6-((S)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione;
(S)-3-(6-((R)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione;
(S)-3-(6-((S)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
(S)-3-(6-((S)-4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
(S)-3-(6-((R)-4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
(R)-3-(6-((S)-4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione;
(R)-3-(6-((R)-4-hydroxy-l-isobutyl-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine -2, 6-dione;
(S)-3-(5-fluoro-6-((R)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
(S)-3-(5-fluoro-6-((S)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
(R)-3-(5-fluoro-6-((R)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
(R)-3-(5-fluoro-6-((S)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(6-((S)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(6-((R)-l-benzyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-((S)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
3-(5-fluoro-6-((R)-4-hydroxy-3,3-dimethyl-l-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione;
(R)-3-(6-((R)-l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione-3-d;
(R)-3-(6-((S)-l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione-3-d;
(S)-3-(6-((R)-l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione-3-d; 3-(6-((R)-l-(4-cyclopropylbenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione-3-d;
(S)-3-(6-((S)-l-(4-chlorobenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-
2,6-dione-3-d; and
3-(6-((S)-l-(4-cyclopropylbenzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione-3-d; or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 32: A pharmaceutical composition comprising a compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
Embodiment 33: The pharmaceutical composition according to embodiment 32, further comprising at least one additional pharmaceutical agent.
Embodiment 34: The pharmaceutical composition according to embodiment 32 or 33 for use in the treatment of a disease or disorder that is affected by the reduction of HIF-lb levels.
Embodiment 35: A method of degrading HIF-lb, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 36: A method of modulating HIF-lb levels comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 37: An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 38: A method of treating a disease or disorder that is affected by the modulation of HIF-lb levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 39: The method according to embodiment 38, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases metabolic diseases and allergic and genetic diseases Embodiment 40: The method according to embodiments 38 or 39, wherein the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
Embodiment 41 : A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 42: The method according to embodiment 39, wherein the cancer is VHL-deficient cancer.
Embodiment 43: The method according to embodiment 39, wherein the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.
Embodiment 44: A method for reducing HIE- lb levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof.
Embodiment 45: A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 46: A method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1- 31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Embodiment 47 : A method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Embodiment 48: The method of embodiment 47, wherein the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
Embodiment 49: The method according to any one of embodiments 35-48, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.
Embodiment 50: A compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of HIF-lb levels.
Embodiment 51: A compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of HIE- lb levels.
Embodiment 52: Use of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of HIE- lb levels.
Embodiment 53: Use of a compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of HIF-lb levels.
Embodiment 54: The compound for use according to embodiment 50 or 51 or the use according to embodiment 52 or 53, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases.
In another embodiment of the disclosure, the compounds of the present disclosure are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of the present disclosure may be (+) or (-) enantiomers.
It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included. Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.
The compounds of the disclosure may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Masher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers or via chiral chromatography. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column.
It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure and chemical structures and names. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.
All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, esters, and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a Compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or is admixed, for example, as racemates or with all other, or other selected, stereoisomers.
The chiral centers of the compounds of the disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.
The use of the terms "salt", "solvate", "ester," "prodrug", and the like, is intended to equally apply to the salt, solvate, ester, and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the inventive compounds.
The compounds of the disclosure may form salts which are also within the scope of this disclosure. Reference to a compound of the Formula herein is generally understood to include reference to salts thereof, unless otherwise indicated.
The compounds and intermediates may be isolated and used as the compound per se. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and, such as 2H, 3H, ”C, 13C, 14C, 15N, 18F, 31P, 32P, respectively.
The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H, 13C, and 14C, are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F, lie or labeled compound may be particularly desirable for PET or SPECT studies.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent) or an improvement in therapeutic index. For example, substitution with deuterium may modulate undesirable side effects of the undeuterated compound, such as competitive CYP450 inhibition, time dependent CYP450 inactivation, etc. It is understood that deuterium in this context is regarded as a substituent in compounds of the present disclosure. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation, at 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out the procedures disclosed in the schemes or in the examples and preparations described below using an appropriate isotopically-labeled reagent in place of the non-isotopically labeled reagent.
Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO.
The present disclosure relates to compounds which are modulators of HIF-lb protein levels. In one embodiment, the compounds of the present disclosure decrease HIF-lb protein levels. In yet one embodiment, the compounds of the present disclosure reduce HIF-lb protein levels. In another embodiment, the compounds of the present disclosure are degraders of HIF-lb.
As used herein, the term “IC50” refers to half maximal inhibitory concentration. As used herein, the term “DC50” refers to half maximal degradation concentration. As used herein, the term “EC50” refers to half maximal effective concentration. As used herein, the term “AC50” refers to half maximal activation.
As used herein, Dmax is the maximum level of degradation achievable.
In some embodiments, the degradation of HIF-lb is measured by DC50.
Potency of a compound of the present disclosure towards degradation of HIF-lb can be measured by its DC50 value. A compound with a lower DC50 value, as determined under substantially similar degradation conditions, is a more potent degrader relative to a compound with a higher DC50 value. In some embodiments, the substantially similar conditions comprise determining degradation of protein levels in cells expressing the specific protein, or a fragment of any thereof. As used herein, Dmax is the maximum level of degradation achievable.
In some embodiments, a compound of the present disclosure exhibits selectivity for HIF-lb over another target, such as IKZF1, IKZF2, IKZF3, CKla. SALL4, or GSPT1. Selectivity for modulating the degradation of one target protein (e.g., HIF-lb) over another protein may be measured using any number of methods known in the art. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof exhibits selectivity for degradation of HIF-lb over another protein (e.g., IKZF1, IKZF2, IKZF3, CKla. SALL4, or GSPT1) at a ratio of greater than 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, or 100.
In some embodiments, a compound of the present disclosure exhibits improved cell membrane permeability upon administration to a cell or subject compared to another compound, e.g., in a standard assay for measuring cell permeability. In some embodiments, a compound of the present disclosure exhibits improved cell viability upon administration to a cell or subject compared with another compound, e.g., in a standard assay for measuring cell viability. In some embodiments, a compound of the present disclosure exhibits improved metabolic stability upon administration to a cell or subject compared with another compound, e.g., in a standard assay for measuring metabolic stability. In some embodiments, a compound of the present disclosure exhibits reduced hERG inhibition upon administration to a cell or subject compared with another compound, e.g., in a standard assay for measuring hERG inhibition.
The disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.
F. Methods of Synthesizing Compounds of Formula (I)
The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
The compounds of the present disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of Compounds of Formula (I).
Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure. Accordingly, the present disclosure includes all possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereo specific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
Preparation of Compounds
Compounds of the present disclosure can be synthesized by following the steps outlined in General Schemes I, II, III, IV, V, and VI which comprise different sequences of assembling intermediates La, Lb, Lc, Ld, Le, ILa, ILb, ILc, ILd, ILe, IILa, IILb, IV-a, V-a, and VLa. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated in the Examples section herein below.
General Scheme I:
Figure imgf000258_0001
wherein R4, Rs, Rs-, Re, R?a, R?t>, R?c, R?d, R?e, m, n, o and p are as defined in Formula (I).
The general way of preparing Compounds of Formula (I), wherein R§ is (C1-C6)haloalkyl, (Ci- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl by using intermediates La, Lb, Lc, Ld, and I- e is outlined in General Scheme I Alkylation of La with Lb via an intermediate organometallic species (e.g., via the corresponding aryl lithium species through treatment with /i-Butyl lithium, etc.) in a solvent (e.g., tetrahydrofuran (THF), diethyl ether, etc.) provides I-c. Hydrogenation of I-c (when P is e.g., a benzyl group) in the presence of a suitable catalyst (e.g., dihydroxypalladium (Pd(0H)2), palladium on carbon (Pd/C), platinum dioxide (PtCF), etc.) in a solvent (e.g., N,N-dimethylformamide (DMF), dichloromethane (DCM), ethanol (EtOH), etc. or a combination thereof) and under an atmosphere of hydrogen gas provides I-d. Deprotection of I-d using an acid such as methanesulfonic acid, trifluoroacetic acid (TFA) or hydrochloric acid (HC1) in a solvent (e.g., THF, 1,2, -dichloroethane, dioxane, DCM, acetonitrile (ACN), etc. or a combination thereof) optionally at elevated temperature provides I-e. Reductive animation of I-e with an aldehyde or a ketone in the presence of a reducing agent (e.g., sodium borohydride (NaBH-O, sodium triacetoxyborohydride (STAB), sodium cyanoborohydride (NaBHsCN). MP-cyanoborohydride, etc.), optionally a base (e.g., DIPEA, sodium acetate, etc.) or an acid (e.g., acetic acid, etc.), and in a solvent (e.g., DMF, methanol (MeOH), dichloroethane, (DCE), DCM, etc.) optionally at elevated temperature provides a compound of Formula (I) where Rs is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl. Alternatively, treatment of I-e and aldehyde or ketone with decaborane in a solvent (e.g., DMF, etc.) optionally at elevated temperatures provides a compound of Formula (I) where Rs is (Ci- C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl.
General Scheme II:
Figure imgf000259_0001
wherein Xi, X2, Ri, R2a, RM, RM, RM, Rr, Rs, R?a, R?b, R?c, R?d, R?e, m, n, o and p are as defined in Formula (I).
Intermediate Il-e can be prepared by using intermediates Il-a, Il-b, II-c, and Il-d is outlined in General Scheme II. Borylation of bromide Il-a using a borylation reagent (e.g., tetramethyl-2,2’-bi(l,3,2- dioxaborinane), bis(pinacolato)diboron (B2Pin2), or bis(catecholato)diboron (B2Cat2), etc.) in the presence of aa suitable metal catalyst (e.g., Pd(dppf)Cl2*DCM, Pd(tBu2P)2, Pd(0Ac)2 and tert- butyldiphenylphosphane, etc.) and a base (e.g., potassium carbonate (K2CO2), cesium carbonate (Cs2CO3), potassium acetate (KOAc), K3PO4, etc.) in a solvent (e.g. DMF, dioxane, water, etc.) and optionally at elevated temperature (e.g., heat, microwave) provides Il-b. Coupling of boronic ester Il-b with II-c using a suitable metal catalyst (e.g., Pd(dppf)Cl2 eDCM, Pd(tBu3P)2, etc.) and a base (e.g., N,N- diisopropylethylamine (DIPEA), triethylamine (Et?N), KOAc, K2C(>3, Cs2CC>3, K3PO4, etc.), in a solvent (e.g. , DMF, 1,4-dioxane, water, etc. or a combination thereof) optionally at elevated temperature (e.g. , heat, microwave) provides Il-d. Hydration of Il-d using oxygen, a suitable metal catalyst (e.g., Mn(dpm)3, Co(acac)2, etc.) and an alkyl or aryl silane (e.g., phenylsilane, triethylsilane, etc.) or a borohydride reagent (e.g., NaBH4, etc.) in a solvent (e.g. , DCM, isopropanol (IP A), DMF, etc. or a combination thereof) provides Intermediate Il-e. Intermediate Il-e can be deprotected and alkylated via reductive amination with an aldehyde or ketone as described in General Scheme I to provide a Compound of Formula (I) wherein Rs is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl.
General Scheme III:
Figure imgf000260_0001
wherein Xi, X2, Ri, R2a, R2b, R2c, R2d, Rr, Rs, R?a, R?b, R?c, R?d, R?e, m, n, o and p are as defined in Formula (I).
Intermediate Il-d can also be prepared by using intermediates Ill-a and Ill-b as outlined in General Scheme III. Coupling of boronic ester Ill-a with Ill-b using a suitable metal catalyst (e.g., XPhos Pd G3 and Xphos, bis(tn’-t-butylphosphine)palladium(0), cataCXium A Pd G< PdfdppfjCh'DCM. PdftBu^Ph. etc.) and a base (e.g., DIPEA, triethylamine (EtsN), KO Ac, K2CO3, CS2CO3, K3PO4, K2HPO4, etc.), in a solvent (e.g., DMF, 1,4-dioxane, water, etc. or a combination thereof) optionally at elevated temperature (e.g., heat, microwave) provides Il-d.
General Scheme IV:
Figure imgf000261_0001
Re is H or a protecting group
P-i is an amine protecting group (e.g.,
Boc, Fmoc, etc.)
Figure imgf000261_0002
wherein X2, R4, Rs-, R?a, R?b, R?c, R?d, R?e, m, n, o, and p are as defined in Formula (I).
Intermediate IV-a, wherein Ri, R2a, R2b, R2c, and R2d are H, Xi is CR3, and R3 is methyl, can be prepared according to the procedures and examples as reported in PCT Application Publication No. WO2017/197046 by using Intermediate Il-e as outlined in General Scheme IV. Deprotonation of Il-e with a suitable base such as lithium bis(trimethylsilylamide) in a suitable solvent such as tetrahydrofuran, at a suitable temperature, for example, about -78 °C, followed by treatment with iodomethane provides IV-a. Intermediate IV-a can be deprotected and alkylated via reductive amination with an aldehyde or ketone as described in General Scheme I to provide a Compound of Formula (I) wherein Rs is (Ci-Cb)haloalkyl, (Ci- C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl.
General Scheme V:
Figure imgf000262_0002
•7b Il-e
R6 is H or a protecting group
P-i is an amine protecting group (e.g.,
Boc, Fmoc, etc.)
Figure imgf000262_0001
wherein X2, Rr, R5', R?a, R?b, R?c, R?d, R?e, m, n, o, and p are as defined in Formula (I).
Intermediate V-a wherein Ri, Ria, Rib, R20 and Rid are H, Xi is CR3, and R3 is deuterium, can be prepared according to the procedures and examples as reported in PCT Application Publication No. WO2017/197046 by using Intermediate Il-e as outlined in General Scheme V. Deprotonation of Il-e with a suitable a base such as lithium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran, at a suitable temperature, for example, about -78 °C, followed by treatment with acetic acid-c/ provides Intermediate V-a. Intermediate V-a can be deprotected and alkylated via reductive amination with an aldehyde or ketone as described in General Scheme I to provide a Compound of Formula (I) wherein Rg is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxyalkyl, (C1-C6)alkyl or (C1-C6)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl.
General Scheme VI:
Figure imgf000263_0001
R6 is H or a protecting group
P1 is an amine protecting group (e.g., Boc, Fmoc, etc.)
Figure imgf000263_0002
wherein X2, Rr, Rs-, R?a, R?b, R?c, R?d, R?e, m, n, o, and p are as defined in Formula (I).
Intermediate Vl-a wherein Ri, R2C, and R2d are H, Xi is CR3, R3 is deuterium, and R2a and R2b are deuterium, can be prepared according to the procedures and examples as reported in PCT Application Publication No. WO2022/012622 by using Intermediate Il-e as outlined in General Scheme VI. Treatment of Il-e with chlorotrimethylsilane and triethylamine in a suitable solvent, such as acetonitrile, at a suitable temperature, for example, between 23 °C and 80 °C, followed by treatment with D2O at low temperature, for example at 0 °C, provides Vl-a. Intermediate Vl-a can be deprotected and alkylated via reductive amination with an aldehyde or ketone as described in General Scheme I to provide a Compound of Formula (I) wherein Rs is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)halohydroxy alkyl, (C1-C6)alkyl or (Ci- Cb)alkyl substituted with optionally substituted phenyl, heteroaryl, carbocyclyl, or heterocyclyl.
A mixture of enantiomers, diastereomers, and cis/trans isomers resulting from the process described above can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.
Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0’-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor- 10-sulfonic acid. Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Any resulting mixtures of stereoisomers ccaann bbee sseeppaarraatteedd oonn the basis of the physicochemical differences of the constituents, into the pure oorr ssuubbssttaannttiiaallllyy ppuurree ggeeoommeettrriicc or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
It should be understood that in the description and formula shown above, the various groups Xi, X2, R1, R2a, R2b, R2C, R2d, Rr, Rs, Rs , Re, R?a, R?a, R?b, R?c, R?d, R?e, m, n, o and p, and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of General Schemes I, II, III, IV, V, and VI are merely representative with elected radicals to illustrate the general synthetic methodology of the Compounds of Formula (I) as defined herein.
G. Methods of Using Compounds of Formula (I)
In one aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with or affected by modulation of HIF-lb protein levels. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of HIF-lb protein levels an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Examples of diseases or conditions associated with or affected by modulation of HIF-lb protein levels include, but not limited to, cell proliferative diseases and disorders (e.g., cancer or benign neoplasms), von Hippel-Lindau (VHL) disease, iron overload disorders, immune-related disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, viral diseases, bacterial infections, fungal infections, parasitic infections, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or nonHodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’ s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC) In yet another embodiment the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
In another aspect, the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder that is affected by the reduction of or decrease in HIF-lb protein levels. The method comprises administering to a patient in need of a treatment for diseases or disorders affected by the reduction of HIF-lb protein levels an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is associated with or affected by the modulation of HIF-lb protein levels. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von
Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is and coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH). In another aspect, the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is affected by the reduction of or a decrease in HIF-lb protein levels. In one embodiment, the disease or disorder is selected from cancer, von Hippel- Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
Another aspect of the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is associated with or affected by the modulation of HIF-lb protein levels. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
Another aspect of the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder that is associated with or affected by the reduction of, or a decrease in HIF-lb protein levels. In one embodiment, the disease or disorder is selected from cancer, von Hippel- Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
In another aspect, the present disclosure is directed to a method of modulating, reducing, or decreasing HIF-lb protein levels. The method involves administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, HIF-lb protein levels are modulated, reduced, or decreased through degradation of the HIF- lb protein. In other embodiments, HIF-lb protein levels are modulated, reduced, or decreased through degradation of the HIF-lb protein mediated by an E3 ligase.
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a disease or disorder that is associated with or affected by the modulation, reduction, decrease of HIF-lb protein levels. In some embodiments, HIF-lb protein levels are modulated, reduced, or decreased through degradation of the HIF-lb protein. In other embodiments, HIF- lb protein levels are modulated, reduced, or decreased through degradation of the HIF-lb protein mediated by an E3 ligase. In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating an HIF-lb-dependent disease or disorder in a patient in need thereof by modulating HIF-lb protein levels through the degradation of HIF-lb. In some embodiments, HIF-lb protein degradation is mediated by an E3 ligase.
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for treating, preventing, inhibiting, or eliminating an HIF-lb-dependent disease or disorder in a patient in need thereof by modulating HIF-lb protein levels through the degradation of HIF-lb. In some embodiments, I HIF-lb protein degradation is mediated by an E3 ligase.
In another aspect, the present disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition or elimination of an HIF-lb-dependent disease or disorder in a patient in need thereof by modulating HIF-lb protein levels through the degradation of HIF-lb. In some embodiments, I HIF-lb protein degradation is mediated by an E3 ligase.
Another aspect of the disclosure relates to a method of reducing the proliferation of a cell, the method comprising contacting the cell with a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, that reduces HIF-lb protein levels. In some embodiments, HIF-lb protein levels are reduced through degradation of the HIF-lb protein. In some embodiments, HIF-lb protein levels are reduced through degradation of the HIF-lb protein is mediated by an E3 ligase.
Another aspect of the disclosure relates to a method of degrading HIF-lb. The method comprises administering to a patient in need thereof an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, HIF-lb protein degradation is mediated by an E3 ligase.
In another aspect, the present disclosure relates to a method for treating a HIF-lb-dependent disease or disorder. The method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or nonHodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’ s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
Another aspect of the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a HIF-lb-dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment, the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, the disease or disorder is coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
In another aspect, the present disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a HIF-lb-dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, compounds of the present invention may be used to treat coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
Another aspect of the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a HIF-lb-dependent disease or disorder. In one embodiment, the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases. In another embodiment, the disease or disorder is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease. In one embodiment, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis. In another embodiment, compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma. In yet another embodiment, the disease or disorder is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. In another embodiment, the disease or disorder is non-small cell lung cancer (NSCLC). In yet another embodiment, the disease or disorder is renal cell carcinoma (RCC). In one embodiment, renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In another embodiment, the disease or disorder is melanoma. In yet another embodiment the disease or disorder is triple-negative breast cancer (TNBC). In another embodiment, the disease or disorder is nasopharyngeal cancer (NPC). In yet another embodiment, the disease or disorder is microsatellite stable colorectal cancer (mssCRC). In another embodiment, the disease or disorder is thymoma. In yet another embodiment, the disease or disorder is carcinoid. In another embodiment, the disease or disorder is gastrointestinal stromal tumor (GIST). In yet another embodiment, the disease or disorder is myeloid leukemia. In another embodiment, compounds of the present invention may be used to treat coronary heart disease. In yet another embodiment, the disease or disorder is pulmonary arterial hypertension (PAH).
In another aspect, the present disclosure relates to a method of reducing HIF-lb protein levels. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
In another aspect, the present disclosure relates to a method of reducing HIF-lb protein levels, wherein reduction of HIF-lb protein levels treats or ameliorates the disease or disorder. The method comprises administering to the patient in need thereof a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
In another aspect, the disclosure relates to a method of treating, preventing, inhibiting, or eliminating von Hippel-Lindau (VHL) disease. The method comprises administering to a patient in need of a treatment for VHL disease an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of von Hippel-Lindau (VHL) disease.
In another aspect, the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating von Hippel-Lindau (VHL) disease.
In one embodiment, the patient suffering from VHL disease also suffers from hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor or renal cell carcinoma. In another embodiment, the patient suffering from VHL disease also suffers from renal cell carcinoma.
In another aspect, the disclosure relates to a method of treating, preventing, inhibiting, or eliminating renal cell carcinoma (RCC). The method comprises administering to a patient in need of a treatment for renal cell carcinoma an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of renal cell carcinoma.
In another aspect, the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating renal cell carcinoma. In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
In another aspect, the disclosure relates to a method of reducing inflammation of the digestive system in a patient in need thereof. The method comprises administering to a patient in need of reduction in inflammation an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
Another aspect of the disclosure relates to the use of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for reducing inflammation of the digestive system in a patient in need thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
In another aspect, the disclosure relates to a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for reducing inflammation of the digestive system in a patient in need thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
Another aspect of the disclosure relates to a method of reducing inflammation of the digestive system. The method comprises administering to a patient in need of a treatment in need of reduction in inflammation of the digestive system an effective amount of a HIF-lb modulator Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
Another aspect of the disclosure relates to the use of a HIF-lb modulator Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for reducing inflammation of the digestive system in a patient in need thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
In another aspect, the disclosure relates to a HIF-lb modulator Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for reducing inflammation of the digestive system in a patient in need thereof. In one embodiment, the patient suffers from inflammatory bowel disease. In another embodiment, the patient suffers from Crohn’s disease or colitis. In another embodiment, the patient suffers from ulcerative colitis. In one embodiment, the administration of a compound of the present disclosure induces remission of the inflammation. In another embodiment, the administration of a compound of the present disclosure reduces intestinal inflammation. In yet another embodiment, the administration of a compound of the present disclosure inhibits recruitment of inflammatory cells.
Examples of cell proliferative diseases and disorders (e.g., cancers) that can be treated with compounds of the present disclosure include, but are not limited to, acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, agnogenic myeloid metaplasia, AIDS-related cancers, AIDS-related lymphoma, ALK+ anaplastic large cell lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, B-cell non-Hodgkin’s lymphoma, bellini duct carcinoma, benign monoclonal gammopathy, biliary cancer, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain cancer, brain tumor, breast cancer, brenner tumor, bronchial tumor, bronchial adenomas/carcinoids, bronchioloalveolar carcinoma, brown tumor, Burkitt’s lymphoma/leukemia, carcinoid tumor, carcinoma, carcinosarcoma, Castleman’s disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear-cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B cell lymphoma (DLBCL) (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, essential thrombocythemia, esthesioneuroblastoma, Ewing’s sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extrahepatic cholangiocarcinoma extramammary Paget’s disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular lymphoma (FL), follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal/stomach (GIST) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, gestational trophoblastic tumor glioma, giant cell tumor of bone, glioblastoma, glioblastoma multiforme (GBM), glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemangioblastoma, hemangioendothelioma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intrahepatic bile duct cancer, intraocular (eye) melanoma, intrahepatic cholangiocarcinoma, islet cell tumors (endocrine, pancreas), islet cell carcinoma, islet cell pancreatic cancer, myxosarcoma, myxosarcoma enile, myelomonocytic leukemia, Kaposi’s sarcoma, kidney cancer, klatskin tumor, krukenberg tumor, laryngeal cancer, leiomyosarcoma, lentigo maligna melanoma, leukemia, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoid neoplasm, lymphoma, lymphomatoid papulosis, lymphoplasmacytic lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantle cell lymphoma (MCL), mast cell leukemia, mast cell neoplasms, mediastinal germ cell tumor, mediastinal tumor, mediastinal (thymic) large B-cell lymphoma, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, merkel cell carcinoma, mesenchymous or mixed mesodermal tumor, mesothelioma, mesothelial sarcoma, metastatic pancreatic adenocarcinoma, metastatic squamous neck cancer with occult primary, metastatic urothelial carcinoma, mixed mullerian tumor, monocytic leukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasia (MEN), multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplasia, myelodysplastic disease/syndromes, myeloid leukemia, myeloid neoplasms, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin’s lymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancoast tumor, pancreatic cancer, pancreatic neuroendocrine tumor, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polycythemia vera, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer (e.g. , metastatic castration resistant prostate cancer), pseudomyxoma peritonei, rectal cancer, refractory B-cell non-Hodgkin’s lymphoma, relapsed B-cell non-Hodgkin’s lymphoma, renal cancer, renal cell carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter’ s transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome, signet ring cell carcinoma, skin cancer (non-melanoma), small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, small lymphocytic leukemia, small lymphocytic lymphoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicular cancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer (medullary and papillary thyroid carcinoma), tongue cancer, transitional cell cancer of renal pelvis and ureter, transitional cell carcinoma, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urachal cancer, urethral cancer, urinary bladder cancer, urogenital neoplasm, uterine cancer, uterine sarcoma, uveal melanoma, vaginal cancer, verner morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, cervix cancer, uterine corpus carcinoma, uterine corpus cancer, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, brain tumors such as glioblastoma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, basalioma, choroidea melanoma, craniopharyngeoma, myosarcoma, fibrosarcoma, colon carcinoma, familiary adenomatous polyposis carcinoma, and hereditary non-polyposis colorectal cancer, melanoma, plasmocytoma, Waldenstrom’s macroglobulinemia, Warthin’s tumor, visual pathway and hypothalamic glioma, and Wilms’ tumor, or any combination thereof.
Examples of other diseases or disorders that can be treated with compounds of the present disclosure include, but are not limited to, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, autoimmune and inflammatory-related diseases and conditions, pulmonary arterial hypertension (PAH), neurodegenerative diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, allergic and genetic diseases, etc.) that can be treated with compounds of the present disclosure include, but are not limited to, pulmonary arterial hypertension (e.g., primary or secondary iron overload disorders including, but not limited to, hemochromatosis (e.g., iron hemochromatosis, HEE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis), polycythemia (e.g., polycythemia vera), Pacak-Zhuang Syndrome, erythrocytosis, porphyria cutanea tarda, hereditary spherocytosis, hyprochromic anemia, hysererythropoietic anemia (CDAI), faciogenital dysplasia (FGDY), Aarskog syndrome, atransferrinemia, sideroblastic anemia (SA), aplastic anemia, pure red cell anemia, pyridoxine -responsive sidero-blastic anemia, and hemoglobinopathies such as thalassemia and sickle cell disease, cardiac ischemia, and pulmonary arterial hypertension; idiopathic PAH, heritable PAH (e.g., BMPR2, ALK 1, endoglin), drug-induced PAH, toxin-induced PAH, and PAH associated with another condition (e.g., connective tissue diseases, HIV infection, HIV-1, HIV-2, human T-cell leukemia virus-I (HTLV-I), HTLV-II, HTLV-III, simian immunodeficiency virus (SIV), lymphadenopathy associated virus (LAV-2), simian T-lymphotrophic virus-I (STLV-I), STLV-II, STLV-III, simian B-lymphotrophic (SBL) virus, Gibbon ape leukemia virus (GALV), bovine leukemia virus (BEV), equine infectious anemia virus (EIAV), feline leukemia virus (FELV), murine leukemia virus (MuLV), avian leukosis virus (ALV), other virus infections such as hepadnaviridae (Hepatitis B), herpesviridae (Herpes simplex I, Herpes simplex II, Varicella-Zoster, Herpes Zoster, Epstein-Ban virus and cytomegalovirus), parvoviridae (human parvovirus B-19), papovaviridae (human papilloma virus types I to 60, JC and BK viruses), pox viruses (variola major, variola minor, vaccinia, monkey pox, cowpox, paravaccinia or milker’s node virus, parapox or ORF virus, molluscum contagiosum, AIDS, influenza virus cytomegalovirus, portal hypertension, congenital heart diseases, schistosomiasis, or chronic hemolytic anemia), arthritis (e.g., rheumatoid arthritis), kidney failure, lupus, asthma, psoriasis, pancreatitis, hyaline membrane disease, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, fibromyalgia, Alzheimer’s disease, chronic heart failure, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, acute coronary syndrome, osteoporosis, Parkinson’s disease, infections, inflammatory bowel disease (e.g., Crohn’s disease and colitis such as ulcerative colitis), chronic obstructive pulmonary disease (COPD), atherosclerosis, glomerular disease, allergic contact dermatitis and other eczemas, atopic dermatitis, dermatitis herpetiformis, erythema multiforma, systemic sclerosis, transplantation multiple sclerosis, type II diabetes, multiple sclerosis, chronic gastritis, irritable bowel syndrome, cachexia, Graves’ disease, Bechterefs disease, myasthenia gravis, autoimmune hepatitis, autoimmune multiglandular endocrine insufficiency Disease (APECED), endocrine opthalmopathy, Churg-Strauss syndrome, glomerulonephritis (with and without nephrotic syndrome, e g. including idiopathic nephrotic syndrome or minal change nephropathy), nephritis, celiac disease, periodontitis, eosinophilic enteropathy, appendicitis, Guillain-Barre syndrome, Hashimoto’s disease, sclerosis of lichen, systemic lupus erythematosus, pediatric autoimmune streptococcal-related neuropsychiatric disorder (PANDAS), Rheumatic fever, sarcoidosis, Sjogren’s syndrome, systemic stiffness syndrome, scleroderma, Wegener’s granulomatosis, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, autoimmune enteropathy, Goodpasture syndrome, autoimmune allergic disease, allergic rhinitis, ocular allergy, allergic conjunctivitis, chronic granulomatous disease, asthma and organ transplantation, systemic lupus erythematosus, alopecia areata, anklosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome (alps), autoimmune thrombocytopenic purpura (ATP), Behcet’s disease, vasculitis, diverticulitis, interstitial cystitis, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome immune deficiency, syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Dego’s disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, guillain-barre, hashimoto’s thyroiditis, idiopathic sprue, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, juvenile arthritis, systemic juvenile idiopathic arthritis, Meniere’s disease, mixed connective tissue disease, pernicious anemia, polyarteritis nodosa, polychondritis, polyglancular syndromes, acute lung injury, acute respiratory distress syndrome, polymyalgia rheumatica, cryopyrin- associated periodic syndrome, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, cirrhosis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, sarcoidosis, alveolitis, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, uveitis (anterior and posterior), vasculitis, Hashimoto’s thyroiditis, autoimmune hemolytic anemia, glaucoma, retinal disease, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, sepsis, septic shock, dacryoadenitis, cryopyrin associated periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, CD14 mediated sepsis, Steven-Johnson syndrome, non-CD14 mediated sepsis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, vernal conjunctivitis, toxic shock syndrome, asthma, adult respiratory distress syndrome, pulmonary disease, chronic pulmonary inflammation, chronic graft rejection, hidradenitis suppurativa, Goodpasture’s disease, autoimmune thrombocytopenia, sympathetic ophthalmia, juvenile-onset diabetes, Addison’s disease, lichen planus, bullous pemphigus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, immunoglobulin A nephropathy, Wegener granulomatosis, granulomatous orchitis, autoimmune oophoritis, psoriatic arthritis, acute and chronic renal disease, leptospiriosis renal disease, pancreatic fibrosis, hepatic fibrosis, sarcoidosis, rheumatic carditis, pyresis, restenosis, cervicitis, stroke and ischemic injury, neural trauma, acute and chronic pain, chronic aggressive and active hepatitis, membranous glomerulopathy, malaria, leprosy, leishmaniasis, Lyme disease, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptured, or prolapsed intervertebral disk syndrome, osteopetrosis, rhinosinusitis, thrombosis, silicosis, pulmonary sarcosis, 22ql 1.2 deletion syndrome, Angelman syndrome, Canavan disease, Charcot- Marie-Tooth disease, color blindness, Cri du chat, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, haemophilia, Klinefleter’s syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, Tay-Sachs disease, Turner syndrome, urea cycle disorders, otitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, chronic hypersensitivity pneumonitis, interstitial lung fibrosis, amyotrophic lateral sclerosis, asociality, varicosis, vaginitis, depression, Sudden Infant Death Syndrome, gout, asbestosis, alcoholic liver disease, nonalcoholic steatohepatitis, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, macular degeneration, proliferative retinopathy, macular edema, retinopathy of prematurity, ascites, pleural effusion, cerebral oedema, pulmonary oedema, ischemic heart disease, cerebrovascular disorders, endometriosis, insulin resistance, and obesity, or any combination thereof.
In one embodiment of the methods herein above, the disease or condition is selected from renal cell carcinoma, von Hippel-Lindau disease, pulmonary arterial hypertension, glioblastoma, and colitis.
In some embodiments, the compounds of the present invention may be used to treat T cell leukemia or T cell lymphoma.
In some embodiments, the compounds of the present invention may be used to treat Hodgkin’s lymphoma or non-Hodgkin’ s lymphoma.
In some embodiments, the compounds of the present invention may be used to treat on-small cell lung cancer (NSCLC).
In some embodiments, the compounds of the present invention may be used to renal cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In some embodiments, the compounds of the present invention may be used to treat melanoma.
In some embodiments, the compounds of the present invention may be used to treat triple-negative breast cancer (TNBC).
In some embodiments, the compounds of the present invention may be used to treat nasopharyngeal cancer (NPC).
In some embodiments, the compounds of the present invention may be used to treat microsatellite stable colorectal cancer (mssCRC).
In some embodiments, the compounds of the present invention may be used to treat thymoma.
In some embodiments, the compounds of the present invention may be used to treat carcinoid.
In some embodiments, the compounds of the present invention may be used to treat gastrointestinal stromal tumor (GIST).
In some embodiments, the compounds of the present invention may be used to treat myeloid leukemia.
In some embodiments, the compounds of the present invention may be used to treat coronary heart disease.
In some embodiments, the compounds of the present invention may be used to pulmonary arterial hypertension (PAH).
In one embodiment, the present disclosure provides a method of treating, preventing, inhibiting, or eliminating a proliferative disorder in a patient in need thereof. The method comprises administering to a patient in need of a treatment for said proliferative disorder an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof or a composition comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the proliferative disorder is a HIF-1 > -dependent or HIF-1 > -associated proliferative disorder. In one embodiment, the proliferative disorder is a cancer. Representative cancers that compounds of Formula (I), are useful for treating, preventing, inhibiting, or eliminating include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood-borne tumors.
In some embodiments, the cancer is a cancer selected from the group consisting of lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, renal cell carcinoma, prostate cancer, neuroendocrine cancer, gastric cancer, bladder cancer, uterus cancer, testes cancer, kidney cancer, skin cancer, gastrointestinal tract cancer (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), cervix cancer, and colon cancer. In some further embodiments, said cancer condition is a cancer selected from the group consisting of lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, renal cell carcinoma, prostate cancer, neuroendocrine cancer, gastric cancer, bladder cancer and colon cancer. In some further embodiments, the cancer condition is selected from the group consisting of non-small-cell lung carcinoma, melanoma, renal cell carcinoma, colorectal cancer, castration-resistant prostate cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, and a hematologic malignancy. In another embodiment, the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma. In another embodiment, the cancer condition is renal cell carcinoma (RCC).
In a further embodiment, the present disclosure provides a method of treating a cancer condition, wherein the HIF-2a inhibitor is effective in one or more of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, killing cancer cells and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some other embodiments, said method comprises administering to the cancer cells a therapeutically effective amount of a HIF-2a inhibitor. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo.
In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is relapsed. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory. In yet still another embodiment, the cancer is VHL-deficient RCC.
In another embodiment, the cancer is bladder cancer. In yet another embodiment, the cancer is breast cancer. In another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is
CRC. In another embodiment, the cancer is RCC. In yet another embodiment, the cancer is HCC. In another embodiment, the cancer is melanoma.
In one embodiment, the cancer is advanced RCC. In another embodiment, the RCC is advanced
RCC with clear cell component (ccRCC). In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is relapsed RCC. In another embodiment, the cancer is refractory RCC. In yet still another embodiment, the cancer is relapsed and refractory RCC. In another embodiment, the cancer is VHL-deficient RCC.
The disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
H. Administration, Pharmaceutical Compositions, and Dosing of Compounds of the Disclosure Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
Another aspect of the disclosure is directed to pharmaceutical compositions comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.
Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-30 molar and 10-90 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
I. Combination Therapy
The compounds of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities e.g., non-drug therapies. For example, synergistic effects can occur with other cancer agents. Where the compounds of the application are administered in conjunction with other therapies, dosages of the coadministered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
The compounds can be administered simultaneously (as a single preparation or separate preparation), sequentially, separately, or over a period of time to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.
In another aspect, the disclosure includes a Compound of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (lii), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (Irr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula (Ifff), Formula (Iggg), Formula (Ihhh), Formula (liii), Formula (Ijjj), and/or Formula (Ikkk), a compound according to any one of embodiment No. 1 to No. 54, or any embodiment of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (lii), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (Irr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula (Ifff), Formula (Iggg), Formula (Ihhh), Formula (liii), Formula (Ijjj), and/or Formula (Ikkk), described herein, or a pharmaceutically acceptable salt thereof, for use in a combination therapy. A compound, composition, medicament and compounds for use of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li) Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (Ill), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (Irr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula (Ifff), Formula (Iggg), Formula (Ihhh), Formula (Illi), Formula (Ijjj), and/or Formula (Ikkk), a compound according to any one of embodiment No. 1 to No. 54, or any embodiment of Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li) Formula (Ij), Formula (Ik), Formula (II), Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), Formula (Icc), Formula (Idd), Formula (lee), Formula (Iff), Formula (Igg), Formula (Ihh), Formula (lii), Formula (Ijj), Formula (Ikk), Formula (Imm), Formula (loo), Formula (Ipp), Formula (Iqq), Formula (Irr), Formula (Iss), Formula (Itt), Formula (luu), Formula (Ivv), Formula (Iww), Formula (Ixx), Formula (Iyy), Formula (Izz), Formula (laaa), Formula (Ibbb), Formula (Iccc), Formula (Iddd), Formula (leee), Formula (Ifff), Formula (Iggg), Formula (Ihhh), Formula (liii), Formula (Ijjj), and/or Formula (Ikkk), described herein, or a pharmaceutically acceptable salt thereof, may also be used to advantage in combination with one or more other therapeutic agents.
Another aspect of the disclosure is directed to pharmaceutical compositions comprising a Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, a pharmaceutically acceptable carrier, and one or more therapeutic agents. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second agent such as, but not limited to, a second agent that targets HIF-lb (e.g., a second HIF-lb inhibitor or degrader), a second agent that targets one or more of the HIF transcription factors, non-drug therapies (such as, but not limited to, surgery or radiation treatment), anti-cancer agents, immune-modulators, therapeutic antibodies, anti-Von Hippel- Lindau disease agents, antibiotics, anti-inflammatory, immunosuppressive, vasoactive antiseptic agents (e.g., anti-bacterial agents, anti-fungicides, anti-viral agents, anti-parasitic agents, etc.), immunomodulatory agents, immuno-oncology agents, RNA interference-based therapies to silence gene expression, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, cardiovascular agents, hypertension agents, and combinations thereof.
“Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in alternation and in any order, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.
In accordance with the foregoing, the present disclosure also provides a therapeutic combination, e.g., a kit, kit of parts, e.g., for use in any method as defined herein, comprising a Compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be used concomitantly or in sequence with at least one pharmaceutical composition comprising at least one or more other therapeutic agents, or a pharmaceutically acceptable salt thereof. The kit may comprise instructions for its administration. The combination can be a fixed combination (e.g., in the same pharmaceutical composition) or a free combination (e.g., in separate pharmaceutical compositions).
Similarly, the present disclosure provides a kit of parts comprising: (i) a pharmaceutical composition of the disclosure; and (ii) a pharmaceutical composition comprising one or more other therapeutic agents, or a pharmaceutically acceptable salt thereof, in the form of two separate units of the components (i) to (ii).
Likewise, the present disclosure provides a method as defined above comprising co- administration, e.g., concomitantly or in sequence, of a therapeutically effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
ENUMERATED EMBODIMENTS
1. A compound of Formula (I’):
Figure imgf000289_0001
pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
Xi is N or CR5; X2 is N, N(O), or CR5;
X7 is N and N(O);
Ri is H, D, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(ORI2)2, -
CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, -
CH2OC(O)CH(RI2')NHRI2', -CH2OC(O)(CH2)q-C(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);
R2a, RM, R2C, and RM are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, RM, R2c, and RM may be taken together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl optionally substituted with one or more R40;
R3 is H, D, (C1-C6)alkyl, (Ci-Gjdcutcroalkyl. or halogen, wherein Pi may be taken together with one of RM, RM, RM, and RM with the carbon atom to which they are attached to form a (C3-C7)carbocyclyl or (C3-C7)spirocarbocyclyl optionally substituted with one or more R40;
R4IS D (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- Cs)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;
Rs is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- Cs)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, O(C3-C7)carbocyclyl, (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10, wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;
Rs is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, (C1-C6)aminoalkyl, (C1-C6)alkyl-O- (C1-C6)hydroxyalkyl, -C(0)Rn, -CH20C(0)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(OR12)2, - CH2OP(O)(OH)OR12, or -CH2OP(O)(RI2)2;
R?a, R?b, R7C, and R7d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or
(Ci-C2)haloalkyl; or two of R7a, R7b, R70 and R?d are taken together with the carbon atoms to which they are attached form (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- Cs)hydroxyalkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB'RB-; each R?e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R21 , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R?e together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3- C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB , -C(0)RB, and -C(0)NRB’RI3’; one R?e is taken together with any one of R?a, RTI>, R70 and R7d and the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22;
Rg is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C3- C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, -SF5, -SRi4a, -NR14R14’, -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more RB and the carbocyclyl and heterocyclyl are optionally substituted with one or more RB-;
R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (C1-C6)haloalkyl;
Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((C1-C6)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-Cio)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;
R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN;
R12- is independently at each occurrence H or (C1-C6)alkyl; R 13 is independently at each occurrence (C1-C6)alkyl or (C1-C6)haloalkyl;
Ro- is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R14 and Rn- are each independently at each occurrence H or (C1-C6)alkyl;
Ri4a is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R15 and Rn- are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -O-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -0-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroalkyl, phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37RS8, -C(0)RS7, -C(O)OR37, -SF5, -SR29, SO2NR30R31, -CN, and R^; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two Ris-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Ris- together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Rn- when on the same carbon atom form C=(0);
Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci-Cgjhydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;
Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (C3-C7)carbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C6-C10) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or two R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20 and R20’ are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Czjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cs-Crjcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (Ci- C6)haloalkyl; R30 and Rsi are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C7)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more R 17 ;
R32, R33, and R34 are each independently at each occurrence H or (C1-C6) alkyl;
R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -ClOjR^;
R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl;
R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl; m and n are each independently 0, 1 or 2; o is 0, 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.
2. The compound according to embodiment 1, wherein Ri is H.
3. The compound according to any one of embodiment 1 or 2, wherein R2a is H.
4. The compound according to any one of embodiments 1-3, wherein R2b is H.
5. The compound according to any one of embodiments 1-4, wherein R2C is H.
6. The compound according to any one of embodiments 1-5, wherein R2d is H.
7. The compound according to any of embodiments 1-6, wherein one to four members of R2a, R2t>, R2C, and R2d is CH3.
8. The compound according to any one of embodiments 1-7, wherein Xi is CR3.
9. The compound according to any one of embodiments 1-7, wherein Xi is N.
10. The compound according to any one of embodiments 1-9, wherein X2 is N.
11. The compound according to any one of embodiments 1-9, wherein X2 is CR5.
12. The compound according to any of embodiments 1-11, wherein R3 is H.
13. The compound according to any of embodiments 1-11, wherein R3 is D. 14. The compound according to any of embodiments 1-11, wherein R3 is CH3.
15. The compound according to any one of embodiments 1-14, wherein R4 is independently in each instance (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.
16. The compound according to any one of embodiments 1-15, wherein R4 is independently in each instance -CH3, -C2H5, -CF3, -OH, -OCH3, -NH2, -NHCH3, or -Cl.
17. The compound according to any one of embodiments 1-16, wherein Rs is independently in each instance (C1-C6)alkyl or halogen.
18. The compound according to any one of embodiments 1-17, wherein Rs is independently in each instance -CH3, -F.
19. The compound according to any one of embodiments 1-18, wherein Rs is independently in each instance (C1-C6)alkyl, (Cs-Cvjcarbocyclyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.
20. The compound according to any one of embodiments 1-19, wherein Rs is independently in each instance -CH3, cyclopropyl, -OH, -OCH3, -NH2, -F, -Cl.
21. The compound according to any one of embodiments 1-20, wherein Rs is -F and m is 1
22. The compound according to any one of embodiments 1-21, wherein n is 0.
23. The compound according to any one of embodiments 1-21, wherein n is 1.
24. The compound according to any one of embodiments 1-23, wherein m is 0.
25. The compound according to any one of embodiments 1-23, wherein m is 1.
26. The compound according to any one of embodiments 1-23, wherein m is 2.
27. The compound according to any one of embodiments 1-26, wherein is H.
28. The compound according to any one of embodiments 1-27, wherein R-;i is H, or (C1-C6)alkyl.
29. The compound according to any one of above embodiments, wherein R?a is -H, -CH3, or - CH(CH3)2.
30. The compound according to any one of the above embodiments, wherein R?b is H.
31. The compound according to any one of the above embodiments, wherein R2c is H.
32. The compound according to any one of the above embodiments, wherein R?d is H. 33. The compound according to any one of the above embodiments, wherein each R?e is independently at each occurrence (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, -O-(C1-C6)alkyl, (Cs-CvXarbocyclyl, or phenyl wherein the alkyl is optionally substituted with one to six R19 and the carbocyclyl is optionally substituted with one to five R22 and the phenyl is optionally substituted with one to five R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3- C7)spirocarbocyclyl or 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (Ci- C6)alkoxy, (Ci-Gjhaloalkoxy. (C1-C6)hydroxy alkyl, halogen, -C(0)0RB-, -C(0)RB, and -C(0)NRB’RB’.
34. The compound according to any one of the above embodiments, wherein each R?e is independently
Figure imgf000296_0002
two R?e, when on the same carbon atom, together with the carbon atom to which they are attached,
F form
Figure imgf000296_0001
, wherein
R in each instance is independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB , -C(0)RB, and -C(0)NRB’RI3S and
R21, R22, and R24 are defined as in embodiment 1.
35. The compound according to any one of the above embodiments, wherein each R?e is independently
Figure imgf000296_0003
two Rve, when on the same carbon atom, together with the carbon atom to which they are attached,
Figure imgf000297_0001
36. The compound according to any one of embodiments 1-35, wherein o is 2.
37. The compound according to any one of embodiments 1-35, wherein o is 1.
38. The compound according to any of the above embodiments, wherein p is 0.
39. The compound according to any of the above embodiments, wherein p is 1.
40. The compound according to any of the above embodiments, wherein p is 2.
41. The compound according to any of the above embodiments, wherein p is 4.
42. The compound according to any of the above embodiments, having a Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), or Formula (II):
Figure imgf000297_0002
Figure imgf000298_0001
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
43. The compound according to any one of the above embodiments, having a Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), or Formula (Icc):
Figure imgf000298_0002
Figure imgf000299_0001
44. The compound according to any one of the above embodiments, wherein Rs is (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkyl optionally substituted with one to three substituents independently selected from D, (C1-C6)alkoxy, -SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S. (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0 N NH and S wherein the phenyl and heteroaryl optionally substituted with one to three Ris and the carbocyclyl and heterocyclyl are optionally substituted with one to three Ris-.
45. The compound according to any of the above embodiments, wherein Rg is selected from:
Figure imgf000300_0001
each of X^, and X3b is independently selected from 0, S, NH, and NR15;
X4 is 0, S, NH, and NRLV;
R is selected from (C1-C6)alkyl and (C3-C7)cycloalkyl, and is optionally substituted with one or more of D, hydroxy, halogen, alkoxy, imidazol-2-yl, and -CfOjNlXlX; and
Ris, Ris-, R32, and R33 are as defined in embodiment 1.
46. The compound according to any of the above embodiments, wherein Rg is selected from:
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
—
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
47. The compound according to any one of the above embodiments, wherein each R19 is independently at each occurrence (C1-C6)alkoxy, -NR20R20', or (C3-C7)carbocyclyl wherein carbocyclyl is optionally substituted with two to four R23.
48. The compound according to any one of the above embodiments, wherein the compound is selected from any compound provided in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
49. A pharmaceutical composition comprising a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
50. The pharmaceutical composition according to embodiment 48, further comprising at least one additional pharmaceutical agent.
51. The pharmaceutical composition according to claims 49 or 50 for use in the treatment of a disease or disorder that is affected by the reduction of HIF-1 [3 levels.
52. A method of degrading HIF-1 [3, comprising administering to a patient in need thereof an effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
53. A method of modulating HIF-1 [3 levels comprising administering to a patient in need thereof an effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. 54. An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
55. A method of treating a disease or disorder that is affected by the modulation of HIF-1J3 levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
56. The method according to embodiment 55, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary diseases, autoimmune and inflammatory -related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, neovascular diseases, retinal vascular diseases, fibrosis, endometriosis, preeclampsia, and allergic and genetic diseases.
57. The method according to embodiment 55 or 56, wherein the disease or disorder is selected from renal cell carcinoma (RCC), vvoonn Hippel-Lindau disease (VHL), advanced pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
58. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
59. The method according to embodiment 58, wherein the cancer is VHL-deficient cancer.
60. The method according to embodiment 58, wherein the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia. 61. A method for reducing HIF-1 [3 levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt thereof.
62. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
63. A method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
64. A method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
65. The method of embodiment 64, wherein the renal cell carcinoma is clear cell renal cell carcinoma
(ccRCC).
66. The method according to any one of embodiments 55-65, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.
67. A compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of HIF-113 levels.
68. A compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of HIF-1 [3 levels.
69. Use of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of H I H- 1 [3 levels.
70. Use of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of HIF-1 [3 levels. 71. The compound for use according to embodiments 69 or 70 or the use according to embodiments 53 or 54, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases.
EXAMPLES
The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.
Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, lohn Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
Analytical Methods, Materials, and Instrumentation
Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either 500 MHz Bruker Avance II, AV-500 spectrometer, 400 MHz B inker spectrometer, or Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used where indicated as an internal standard. Chemical shifts are reported in ppm using dimethyl sulfoxide (d 2.50), methanol (d 3.31), chloroform (d 7.26) or other solvent residual protons as an internal reference, as indicated in NMR spectral data. A small amount of the dry sample (2- 5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemBioDraw Ultra v21 from CambridgeSoft.
Mass spectra (HESLMS) were collected using a Thermo Scientific UHPLC-MS Vanquish with a LTQ quadrupole or mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent- 1260 Infinity (6120 Quadrupole); all masses reported are the m/z of the protonated parent ions unless recorded otherwise. The sample was dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and was injected directly into the column using an automated sample handler. The analysis is performed on one of the following:
Waters Acquity UPLC system. Column: Waters Acquity UPLC BEH CIS 1.7pm, 2.1 x 30mm;
Flow rate: 1 mL/min; Column temperature: 55°C; Solvent A: 0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH; gradient 95% Solvent A from 0 to 0.10 min; 95% Solvent A to 20% Solvent A from 0.10 to 0.50 min; 20% Solvent A to 5% Solvent A from 0.50 to 0.60 min; hold 25 at 5% Solvent
A from 0.6 min to 0.8 min; 5% Solvent A to 95% Solvent A from 0.80 to 0.90 min; and hold 95% Solvent
A from 0.90 to 1.15 min.
Thermo Vanquish UHPLC-MS system. Column: Waters Acquity UPLC BEH CIS 1.7pm, 2.1 x 50mm; Flow rate: 0.3 mL/min; Column temperature: 25°C; Solvent A: 0.1% formic acid in water, Solvent B: 0.1% formic acid in acetonitrile; gradient: 95% Solvent A from 0 to 0.50 min; 95% Solvent A to 0% Solvent A from 0.5 to 2.5 min; hold 0% Solvent A from 2.50 to 3.50 min; Flow rate increased to
0.6 mL/min and Solvent A to 95% 3.5 mins to 3.7 mins; hold 95% Solvent A at 0.6 mL/min 3.7 mins to
4.4 mins; drop flow rate to 0.3 mL/min and hold at 95% Solvent A from 4.4 min to 4.5 min.
Agilent 1290 Infinity II UHPLC-MS system. Column: Waters Acquity UPLC BEH CIS 1.7pm,
2.1 x 30mm; Flow rate: 1.6 mL/min; Column temperature: 60°C; Solvent A: 0.1% formic acid in water, Solvent B: 0.5% formic acid in acetonitrile. Gradient: 99% Solvent A from 0 to 0.15 min; 99% Solvent A to 1% Solvent A from 0.15 to 1.65 min; hold 1% Solvent A from 1.65 to 1.90 min; 1% Solvent A to 99%
Solvent A from 1.90 to 1.91 min; hold 99% Solvent A from 1.91 to 2.0 min.
Purification of final compounds, salt forms, and stereochemistry
Final compounds of the invention were in many cases purified by reverse-phase chromatography in the presence of additives such as formic acid, hydrochloric acid, acetic acid or ammonium acetate, followed by lyophilization. In some cases, the salt form of a final compound was changed by relyophilization in the presence of the desired salt, for example, by taking up a formic acid salt in a mixture of acetonitrile and dilute hydrochloric acid and lyophilizing to provide the hydrochloric acid salt. Depending on the characteristics of the final compound and the lyophilization conditions, the free base form can be generated following lyophilization, even when the chromatography mobile phase contained salt-forming additives. The stated salt forms of final compounds of the invention are based on NMR evidence and consideration of the purification conditions and the characteristics of the compound. Further, in cases where stereoisomers were purified from a mixture of stereoisomers, the stereochemistry assigned is relative and arbitrary.
Abbreviations used in the following examples and elsewhere herein are:
ACN Acetonitrile AcOH acetic acid
AIBN azobisisobutyronitrile
APCI atmospheric pressure chemical ionization aq. aqueous
Bipini bis(pinacolato)diboron
B0C2O or Boc anhydride di-tert-butyl dicarbonate
Bn benzyl
Bu butyl br broad cataCXium A Pd G3 Mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-
1,1'- biphenyl)]palladium(II)
CO carbon monoxide
CS2CO3 cesium carbonate d doublet dd doublet of doublets ddd doublet of doublet of doublets ddq doublet of doublet of quartets ddt doublet of doublet of triplets dq doublet of quartets dt doublet of triplets dtd doublet of triplet of doublets
DAST N,N-diethylaminosulfur trifluoride
DC50 half maximal degradation concentration
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIEA or DIPEA diisopropylethylamine or N,N-diisopropylethylamine
Dioxane 1 ,4-dioxane
DMAP 4-dimethylaminopyridine
Dmax maximum level of degradation
DME 1.2-dimethoxyethane
DME N,N-dimethylformamide
DMP Dess-Martin Periodinane, l,l,l-Tris(acetyloxy)-l,l-dihydro-
1.2-benziodoxol-3-( lH)-one
DPPA diphenylphosphoryl azide DMSO dimethylsulfoxide
ECso half maximal effective concentration
EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride eq. equivalent
ES electrospray
EtOH ethanol
EtiO diethyl ether
Et3N triethylamine
EtOAc ethyl acetate
FA formic acid
Grubbs® 2nd gen. catalyst (l,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-
(phenylmethylene)(tricyclohexylphosphine)ruthenium
HC1 hydrogen chloride hept heptet
HPLC high performance liquid chromatography h or hr hour
HRMS high resolution mass spectrometry g gram
IC50 half maximal inhibitory concentration
IP A or iPrOH isopropyl alcohol
Ir(ppy)2(dtbbpy)PF6 [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine-Nl,Nl']bis[2-(2- pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate
K2CO3 potassium carbonate
KI potassium iodide
KOAc potassium acetate
KOtBu potassium tert-butoxide
K3PO4 tripotassium phosphate
LAH lithium aluminum hydride
LCMS liquid chromatography mass spectrometry
EDA lithium diisopropylamide
LiHMDS Lithium bis(trimethylsilyl)amide m multiplet
M molar
Mel methyl iodide MTBE methyl tertiary-butyl ether
MeCN acetonitrile
MeOH methanol mg milligram
MHz megahertz min minute(s) mL milliliter mmol millimole
Mn(dpm)3 tris(2,2,6,6-tetramethyl-3,5-heptanedionato)-manganese(III)
MP-cyanoborohydride macroporous polymer supported cyanoborohydride
MS mass spectrometer
MW microwave
NaHCO3 sodium bicarbonate
NaBH(OAc)3 sodium triacetoxyborohydride
NaCNBH3 sodium cyanoborohydride
NaHMDS sodium bis(trimethylsilyl)amide
NaoSOi sodium sulfate
NBS A-bromosuccinimide n-BuLi n-butyllithium
NMR nuclear magnetic resonance
PdCl2(dppf)e DCM 1 , 1’ -B is(diphenylphosphino)ferrocene] -dichloropalladium(II) , complex with dichloromethane, PdCl2(dppf)e CH2C12
Pd(OAc)2 palladium(II) acetate
PhSO3H benzene sulfonic acid
PTSA p-toluenesulfonic acid q quartet qd quartet of doublets quint quintet quintd quintet of doublets rt room temperature
Rt retention time s singlet sat. saturated
Selectfluor ( 1 -chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
SEC supercritical fluid chromatography
STAB sodium triacetoxyborohydride t triplet td triplet of doublets tdd triplet of doublet of doublets
TEA (NEt3) triethylamine tBuOH tert-butyl alcohol
TEA trifluoroacetic acid
TfOH triflic Acid
Tf2NPh N-phenyl-bis(trifluoromethanesulfonimide) or N-phenylbis(trifluoromethanesulfonyl)amine
THE tetrahydrofuran
TEC thin-layer chromatography
TMP 2,2,6,6-tetramethylpiperidine
TMSOTf trimethylsilyl triflate
Ts tosyl or p-tolucnesu Ifonyl tt triplet of triplets ttd triplet of triplet of doublets
TTFA thallium(III) trifluoroacetate
UPLC ultra-Performance Liquid Chromatography wt. weight
GENERAL PROCEDURES FOR SYNTHESIS OF COMPOUNDS OF FORMULA (I) General Procedure 1: Synthesis of I-GP1
Figure imgf000317_0001
General Procedure 1, Step A: Synthesis of Bromoquinoline GP-lc
To an oven-dried reaction vial equipped with a stir bar and vacuum purged with argon was added GP-la (1 eq.) and THF (0.16 M) and the resulting mixture cooled to -78 °C using a dry ice-acetone bath. n-Butyllithium (1.6 M in hexanes, 1.5 eq.) was then added and the reaction mixture was stirred at -78 °C for 1 h. Piperidinone GP-lb (1.4 eq.) dissolved in THF (1.3 M) was added and stirring was continued at - 78 °C for 1 h. The reaction mixture was warmed to ambient temperature and then stirred for an additional 1-3 h at ambient temperature. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was quenched with water or saturated ammonium chloride solution and extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel column chromatography eluting with EtOAc and heptane. The desired fractions were collected, combined, and concentrated in vacuo to provide the desired product, boc-protected piperidine quinoline GP-lc.
General Procedure 1, Step B: Synthesis of Boc-protected piperidine quinoline GP-ld
Boc-protected piperidine quinoline GP-lc (1.0 eq.) and solvent (4:1 DMF:EtOH or DMF, 0.04 M) were added into a reaction vial equipped with a stir bar and under an atmosphere of argon. Dihydroxypalladium (20% wt, 0.2 eq.) or 10% Pd/C (10% wt) was then added and the resulting mixture was sparged continuously for 2-10 h using a balloon of hydrogen gas. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was worked up and purified via Workup/Method (a) or Workup/Purification Method (b) below.
Workup/Purification Procedure (a): the reaction mixture was filtered through a pad of celite®, the filter cake was washed with EtOAc, and the fdtrate was concentrated in vacuo. The crude product was loaded onto a Cl 8 column for purification eluting with MeCN and H2O. The desired fractions were collected, combined and concentrated in vacuo to provide the desired glutarimide product GP-ld.
Workup/Purification Procedure (b): The reaction mixture was filtered through a pad of celite®, the filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude product was purified via flash column chromatography using silica gel flash chromatography eluting with ethyl acetate in heptane or hexanes, or on neutral alumina eluting with a linear gradient of 0- 20% IPA in EtOAc. The desired fractions were collected, combined and concentrated in vacuo to provide the desired glutarimide product GP-ld.
General Procedure 1, Step C: Synthesis of piperidine product GP-le
To a stirred solution of glutarimide product GP-ld (1.0 eq.) and a 1:1 mixture of DCM and MeCN (0.05 M) in a reaction vial was added methanesulfonic acid (4 eq.), or to a stirred solution of glutarimide product GP-ld (1.0 eq.) and DCM was added 4M HC1 in 1,4-dioxane (20 eq.) or TFA (to obtain 20% V/V). The resulting mixture was allowed to stir for 30 min. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was worked up via Workup Procedure (a) or Workup Procedure (b) below, or in the case of DCM/TFA, by concentration under reduced pressure.
Workup Procedure (a): the reaction mixture was cooled to 0 °C using an ice-water bath and triethylamine (10 eq.) was added. The resulting mixture was then concentrated under reduced pressure and the crude piperidine product GP-le was then earned forward to the next step without further purification (quantitative yield was assumed).
Workup Procedure (b): The reaction mixture was cooled to 0 °C using an ice-water bath and triethylamine (10 eq.) was added. The resulting mixture was triturated using MTBE and pentane and the resulting solid was filtered and dried to afford the desired material, piperidine product GP-le, which was used in the next step without further purification.
General Procedure 1, Step D: Synthesis of I-GP1
Method A: To a stirred solution of piperidine product GP-le (1.0 eq.) and an aldehyde (1.1 eq.) in DMF (1 mL) in a reaction vial equipped with a stir bar was added decaborane (0.4 eq.). The resulting mixture was stirred at either room temperature overnight or heated to 70 °C for 30 min. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Purification Method (a) or Purification Method (b) below.
Method B: To a stirred solution of piperidine product GP-le (1.0 eq.) and an aldehyde (1.1 eq.) in DMF (1 mL) in a reaction vial equipped with a stir bar was added sodium triacetoxyborohydride (3 eq.). The resulting mixture was stirred at either room temperature overnight. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Purification Method (a) or Purification Method (b) below.
Purification Method (a): Waters Prep-HPLC [Method info: Phenomenex Luna C18 column 50 x 21.2mm; 5 pm; eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 50 mL/min for 15 min]. The desired fractions were collected, combined and concentrated via lyophilization to yield the desired final product I-GP1.
Purification Method (b): Shimadzu Prep-HPLC [Method info: Phenomenex Kinetex EVO Cl 8 column 150 x 21.2mm; 5 pm; eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 30 mL/min for 15 min]. The desired fractions were collected, combined and concentrated via lyophilization to yield the desired final product I-GP1.
The following compounds were made according to General procedure 1.
The following compounds in Table 2 were prepared from the appropriate amine and aldehyde starting material for each compound described in Table 2 below according to the reductive amination procedure described in General Procedure 1, Step D.
Table 2:
Figure imgf000320_0001
Figure imgf000321_0001
Rg is alkyl substituted with one or more optionally substituted phenyl General Procedure 2, Step A: Synthesis of piperidine quinoline GP-2a
To an oven-dried reaction vial equipped with a stir bar and vacuum purged with argon was added a 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline GP-2b (1 eq.) and THF (0.16 M). and the resulting mixture cooled to -78 °C using a dry ice-acetone bath. /z-Butyl lithium (1.6 M in hexanes, 1.5 eq.) was then added and the reaction mixture was stirred at -78 °C for 1 h. Piperidinone GP-2a (1.4 eq.) in THF (1.3 M). was added and stirring was continued at -78 °C for 1 h. The reaction mixture was warmed to ambient temperature and then stirred for an additional 1-3 h at ambient temperature. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was quenched with water or saturated ammonium chloride solution and extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na^SCfi. filtered, and concentrated in vacuo. The material was then loaded onto a silica column for purification with EtOAc and heptanes. The desired fractions were collected, combined, and concentrated in vacuo to provide the desired product, piperidine quinoline GP-2a.
General procedure 2, Step B: Synthesis of I-GP2
Piperidine quinoline GP-lc (1.0 eq.) and solvent (e.g., 4:1 DMF:EtOH or DMF) were added into a reaction vial equipped with a stir bar and under an atmosphere of argon. Dihydroxypalladium (20% wt, 0.2 eq.) or 10%-50% Pd/C (2 eq.) was then added and the resulting mixture was sparged continuously for 2-10 h using a balloon of hydrogen gas. Upon complete consumption of starting material, as confirmed by LCMS, the reaction was filtered through a pad of celite®, the filter cake was washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified via Purification Method (a) or Purification Method (b) below.
Purification Method (a): Waters Prep-HPLC [Method info: Phenomenex Luna C18 column 50 x 21.2mm; 5 pm; eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 50 mL/min for 15 min]. The desired fractions were collected, combined and concentrated via lyophilization to yield the desired final product I-GP2.
Purifi cation Method (b): Shimadzu Prep-HPLC [Method info: Regis Evoke Cl 8 column 15 cm x 21 mm; 5 pm; eluting with 0.05% ammonium acetate in H2O: MeCN, Flow rate: 30 mL/min for 15 min]. The desired fractions were collected, combined and concentrated via lyophilization to yield the desired final product I-GP2.
General Procedure 3: Synthesis of I-GP3 (R )
Figure imgf000323_0001
General Procedure 3, Step A: Synthesis of boronic ester GP-3b
The solution of aromatic bromide GP-3a (1 eq.), bis(pinacolato)diboron (1.5 eq.) or 5,5,5',5'- tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (2 eq.) and potassium acetate (3 eq.) in 1, 4-dioxane (0.2M) was sparged with N2 or argon at 25 °C for 10 min. To this resulting solution was added Pd(dppf)C12 eDCM (10 mol%) or Pd(OAc)2 (10 mol%)/tert butyldiphenylphosphine (20 mol%) in one portion, and the resulting reaction mixture was subje iation at 100 °C for 1 h, or conventional heating overnight. The reaction mixt nder reduced pressure. This crude material was purified by silica gel flash colum ting with 0-100% EtOAc in hexanes or heptane to afford desired product, boronic and ester GP-3b.
General Procedure 3, Step B ( Suzuki coupling I): Synthesis of dihydropiperidine GP-3d
To the solution of boronic ester GP-3b (1 eq.) and enol triflate GP-3c (1.2 eq.) in 1, 4-dioxane (0.2 M) in a microwave vial under an atmosphere of nitrogen was added a base (e.g., CS2CO3 (1.5 to 2 eq.), K3PO4 (1.5 to 2 eq.) or K2CO3 (1 to 2 eq.)) dissolved in water (10% v/v) at room temperature. This resulting mixture was sparged with nitrogen for 10 min and Pd(dppf)C12*DCM (10 mol%) was then added in one portion. The reaction mixture was subjected to microwave irradiation at 80 °C for 40 min to 1 h, or conventional heating overnight. The reaction mixture was filtered through a pad of celite® and the filtrate was concentrated under reduced pressure. This crude material was purified via flash column chromatography on silica gel eluting with a linear gradient of 0-100% EtOAc in hexanes or heptane, or C18 column eluting with 0% to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid) to afford desired product, dihydropiperidine GP-3d.
General Procedure 3, Step C (Mukaiyama hydration): Synthesis of I-GP3
To a stirred solution of dihydropiperidine GP-3d (1 eq.) in DCM and 2-propanol (-1:1 to —3:1, v/v, 0.025M), or 0.2M DCM with 0.2M 2-propanol with 0.7M DMF were added Mn(dpm)s (0.5 to 1 eq.) and either phenylsilane (~2.5 eq.) or NaBH4 (~2 eq.) at 0 °C under oxygen atmosphere and the reaction mixture was stirred at 25 °C for 2 to 48h. The reaction mixture was worked up and purified via Workup/purification Procedure (a), Workup/purification Procedure (b) or Workup/purification
Procedure (c).
Workup/purif ication Procedure (a): The reaction mixture was concentrated under reduced pressure and then purified by normal-phase or reverse phase chromatography or preparative HPLC to afford the desired product I-GP3.
Workup/purification Procedure (b): Saturated sodium hypochlorite solution was added and the resulting mixture was stirred for 1 h at room temperature. The crude material was silica gel chromatography or preparative HPLC to afford the desired product I-GP3.
Workup/purification Procedure (c): Saturated sodium thiosulphate was added and the resulting mixture was extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera® or preparative HPLC to afford the desired product I-GP3.
General Procedure 4: Synthesis of I-GP4
Figure imgf000324_0001
To a stirred solution of substituted or unsubstituted bromoquinolinyl GP-4a (1 eq.), and dihydropiperidine boronic ester GP-4b (1.5 eq.) in solvent (1,4-dioxane/water (4:1, v/v, -0.05M) or 100% 1,4-dioxane (0.13M)) under an atmosphere of nitrogen was added a base (DIPEA (2.4 eq.), or K3PO4 (2 eq. in 2.5% water v/v), or K2HPO4 (1-2 eq.), or K2CO3 (1-2 eq.)) followed by palladium catalyst (bis(tri-terLbutylphosphine)palladium(O) (10 mol%) or Pd(dppf)C12 *DCM (10 mol%) at room temperature. The reaction mixture was subjected to microwave irradiation at 80 to 100 °C for 1 h and was then filtered through a pad of celite®. The filtrate was concentrated under reduced pressure and the crude compound was purified by column chromatography to provide the desired product I-GP4.
General Procedure 5: Synthesis of I- GPS
Figure imgf000325_0002
To a stirred solution of chloroquinolinyl GP-5a (1 eq.) and dehydropiperidine boronic ester GP- 4b (1.2 eq.) in 1,4-dioxane or DMF and water (0.1M, v/v=9:l) was added base (K2CO3, DIPEA or CS2CO3, 1-3 eq.) at room temperature. This resulting mixture was sparged with N2gas for 10 minutes. To this resulting mixture was added XPhos Pd G3 (5 mol%) followed by Xphos (10 mol%), or bis(tri-t- butylphosphine)palladium(O) (10 to 20 mol%) or cataCXium A Pd G3 (10 to 20 mol%) or Pd(dppf)C12*DCM (10 mol%) at room temperature, and the reaction mixture was sparged with N2gas for another 10 minutes, and the reaction mixture was stirred at 120 °C with conventional heating overnight or subjected to microwave irradiation at 80 °C or 120 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the erode compound was purified by column chromatography to provide the desired product I-GP4.
General Procedure 6: Synthesis of I-GP6
Figure imgf000325_0001
General Procedure 6, Step A: Synthesis of piperidine quinoline GP-6b
To a stirred solution of boc-protected piperidine quinoline GP-6a (1.0 eq.) in a 1:1 mixture of DCM and MeCN (0.05 M) in a reaction vial was added methanesulfonic acid (4 eq.), or DCM with 4M HC1 in 1,4-dioxane (20 eq.). The resulting mixture was allowed to stir for 30 min before monitoring through LCMS. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was worked up via Workup Procedure (a) or Workup Procedure (b) below.
Workup Procedure (a): the reaction mixture was cooled to 0 °C using an ice -water bath and triethylamine (10 eq.) was added. The resulting mixture was then concentrated under reduced pressure and the crude piperidine product GP-6b was then carried forward to the next step without further purification (quantitative yield was assumed). Workup Procedure (b): The reaction mixture was cooled to 0 °C using an ice-water bath and triethylamine (10 eq.) was added. The resulting mixture was triturated using MTBE and pentane and the resulting solid was filtered and dried to afford the desired material, piperidine quinoline GP-6b, which was used in the next step without further purification.
General Procedure 6, Step B: Synthesis of I-GP6
Method A; To a stirred solution of piperidine quinoline GP-6b (1.0 eq.) and aldehyde or ketone (1.1 eq.) in DMF (1 mL) in a reaction vial equipped with a stir bar was added decaborane (0.4 eq.). The resulting mixture was stirred at either room temperature overnight or heated to 70 °C for 30 min. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Purification Method (a), Purification Method (b), or Purification Method (c) below.
Method B: To a stirred solution of piperidine quinoline GP-6b (1.0 eq.) and aldehyde or ketone (1.1 eq.) in DMF (1 mL) in a reaction vial equipped with a stir bar was added sodium triacetoxyborohydride (3 eq.). The resulting mixture was stirred at room temperature overnight. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Purification Method (a), Purification Method (b), or Purification Method (c) below.
Purification Method (a): Waters Prep-HPLC [Method info: Phenomenex Luna C18 column 50 x 21.2mm; 5 pm; eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 50 mL/min for 15 min]. The desired fractions were collected, combined, and concentrated via lyophilization to yield the desired final product I-GP6.
Purification Method (b): Shimadzu Prep-HPLC [Method info: Phenomenex Kinetex EVO Cl 8 column 150 x 21.2mm; 5 pm; eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 30 mL/min for 15 min]. The desired fractions were collected, combined, and concentrated via lyophilization to yield the desired final product I-GP6.
Purification Method (c): Preparative-HPLC [Method info: (Column: X SELECTCI 8 (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The desired fractions were collected, combined, and concentrated via lyophilization to yield the desired final product I-GP6.
Example 1: Synthesis of 5-l-(6-bromoquinolin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione (INT-1)
Figure imgf000326_0001
Step 1: Synthesis of l-(6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine- 2,4(lH,3H)-dione (1c) l-(6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (1c) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2021/188948.
To a stirred solution of 6-bromo-3 -iodoquinoline (la, 4.6 g, 13.77 mmol, 1 eq.) and 3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 3.75 g, 14.19 mmol, 1.03 eq.) in DMSO (92 mL, 20 vol.) was added potassium phosphate tribasic (4.12 g, 17.91 mmol, 1.3 eq.), Cui (0.079 g, 0.413 mmol, 0.03 eq.) and (R,R)-(-)-N,N’ -dimethyl- 1,2-diaminocyclohexane (0.059 g, 0.413 mmol, 0.03 eq.) under continuous nitrogen bubbling for 15 min. The resulting mixture was stirred at 100 °C for 16 h. After complete consumption of starting materials, as confirmed by LCMS, the reaction mixture was cooled to room temperature and poured into ice-cold water (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine solution (150 mL), dried under anhydrous Na2SC>4 filtered, and concentrated under reduced pressure to provide the crude compound. The crude compound was purified by silica gel flash column chromatography, eluting with 80-85% EtOAc in hexane to afford l-(6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione (1c, 2.83 g, 4.75 mmol, 36% yield). LCMS: m/z: MM-ES+APCI, positive [M+2]+ 472.3; >H NMR (400 MHz, DMS(M, 298 K) 8 (ppm): 8.99 (d, J= 2.4 Hz, 1H), 8.36- 8.21 (m, 2H), 7.97 (d, J= 8.9 Hz. 1H), 7.86 (dd, J = 2.3, 9.0 Hz, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.46 (dd, 7= 2.4, 8.4 Hz, 1H), 4.82 (s, 2H), 4.08-4.02 (m, 2H), 3.80 (s, 3H), 3.74 (s. 3H), 3.03 (t, 7= 6.6 Hz, 2H).
Step 2: Synthesis of 5-l-(6-bromoquinolin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione (INT-1)
To a stirred solution of l-(6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)-dihydropyrimidine- 2,4(1 H,3H)-dione (1c, 8 g, 17.01 mmol, 1 eq.) in DCM (80 mL, 10 vol.) were added trifluoroacetic acid (20 mL, 2.5 vol.) followed by triflic acid (3.02 mL, 34.0 mmol. 2 eq.) at 0 °C under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC/LCMS. The reaction mixture was then concentrated under reduced pressure to yield the crude compound. The crude compound was basified with saturated sodium bicarbonate solution (100 mL). The resulting precipitated solid was filtered and washed with water (200 mL) and DCM (2 x 50 mL) and dried under reduced pressure to provide l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (INT-1, 4.3 g, 13.12 mmol, 77% yield). LCMS: m/z: MM-ES+APCI, positive [M+2]+ 322.2; *H NMR (400 MHz, DMSO-ds, 298 K) 8 (ppm): 10.89-10.44 (m, 1H), 8.99 (d, J= 2.4 Hz, 1H), 8.25 (dd, J = 2.1, 18.2 Hz, 2H), 7.96 (d, J = 9.0 Hz, 1H), 7.85 (dd, 7= 2.2, 8.9 Hz, 1H), 3.97 (t, J= 6.6 Hz, 2H), 2.80 (t, 7= 6.6 Hz, 2H). Example 2: Synthesis of 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-2) 0
O ,OH
H2SO4, EtOH
Br-
H Br- .OH
2b o 85 °C, 12 h,
NH2 NaOH, MeOH,
N 65 °C, 16 h Step 2
2a 2c 2d
Step 1
0 H
0. N ■0
NH2
2e Br-
NaH, THF, r j rt, 3 h
Step 3 INT-2
Step 1: Synthesis of 2-(6-bromo-2-methylquinolin-3-yl)acetic acid (2c)
2-(6-bromo-2-methylquinolin-3-yl)acetic acid (2c) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2022/253713.
4-oxopentanoic acid (2b, 3.77 g, 32.5 mmol, 1 eq.) and NaOH (19.50 mL, 2M solution, 39.0 mmol, 1.2 eq.) were added to a stirred solution of 2-amino-5-bromobenzaldehyde (2a, 6.5 g, 32.5 mmol, 1 eq.) in MeOH (50 mL, 7.69 vol.) at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred at 65 °C for 16 h. The progress of the reaction was monitored by LCMS. After complete consumption of starting materials, as confirmed by LCMS/TLC, the reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure and the resulting crude residue was diluted with water (20 mL). The pH was adjusted pH to ~2-3 with acetic acid. A solid precipitated which was filtered, washed with water, and dried under reduced pressure to afford 2-(6- bromo-2-methylquinolin-3-yl)acetic acid (2c, 7.3 g, 26 mmol, 80% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 280.0; *H NMR (400 MHz, DMSO-t/e, 298 K) 5 (ppm): 13.17-12.26 (m, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.88-7.84 (m, 1H), TS'l-im (m, 1H), 3.85 (s, 2H), 2.60 (s, 3H).
Step 2: Synthesis of ethyl 2-(6-bromo-2-methylquinolin-3-yl)acetate (2d)
Ethyl 2-(6-bromo-2-methylquinolin-3-yl)acetate (2d) was prepared according to the procedures and examples as reported in EP Application No. EP3848367 AL
To a stirred solution of 2-(6-bromo-2-methylquinolin-3-yl)acetic acid (2c, 13 g, 46.4 mmol, 1 eq.) in ethanol (130 mL, 10 vol.) was added sulfuric acid (3.73 mL, 69.6 mmol, 1.5 eq.) at 25 °C under an atmosphere of nitrogen. The resulting mixture was then stirred at 85 °C for 12 h. After complete consumption of the starting materials, as confirmed by LCMS/TLC, the reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The resulting crude residue was dissolved in EtOAc (200 mL), washed with saturated sodium bicarbonate solution (2 x 50 mL), dried over anhydrous Na2SC>4 and filtered. The solvent was removed in vacuo to afford ethyl 2-(6-bromo-2- methylquinolin-3-yl)acetate (2d, 12 g, 34.7 mmol, 75% yield), LCMS: m/z: MM-ES+APCI, positive [M+2]+ 309.9; *H NMR (400 MHz, DMSO-de) 5 ppm: 8.27 (br s, 2H), 7.90 (br s, 2H), 4.14 (q, 7 = 7.0 Hz, 2H), 3.99 (s, 2H), 2.65 (s, 3H), 1.21 (t. 7 = 7.1 Hz, 3H).
Step 3: Synthesis of 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-2)
3-(6-Bromo-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-2) was prepared according to the procedures and examples as reported in EP Patent Application No. EP3848367 Al.
To a stirred solution of ethyl 2-(6-bromo-2-methylquinolin-3-yl)acetate (2d, 4 g, 12.98 mmol, 1 eq.) in THF (40 mL, 10 vol.) was added 60% wt NaH (0.623 g, 15.58 mmol, 1.2 eq.) at -20 °C under an atmosphere of nitrogen. The resulting mixture was stirred at the same temperature for 1 h. Acrylamide (2e, 1.015 g, 14.28 mmol, 1.1 eq.) in THF (1 mL) was then added drop-wise at -20 °C, and the reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 2 h. The reaction mixture was quenched with 1.5N HC1 in dioxane upon complete consumption of starting materials, as confirmed by LCMS and concentrated under reduced pressure. To the resulting crude residue was added saturated NaHCCL solution (20 mL) and the resulting mixture was stirred for 30 min. The resulting solid precipitate was filtered, washed the solid with water (2 x 25 mL) and dried under reduced pressure to afford the crude product. The crude product was then triturated in ACN (20 mL), stirred for 30 min, and filtered. The resulting solid was washed with hexane and dried under reduced pressure to afford 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-2, 2 g, 5.22 mmol, 40% yield). LCMS: m/z MM+ES+APCI, positive [M+H]+ 333.1; *H NMR (400 MHz, DMSO-rfc) 5 ppm: 11.14-10.70 (m, 1H), 8.30-7.99 (m, 2H), 7.91-7.76 (m, 2H), 4.36-4.22 (m, 1H), 2.95-2.71 (m, 1H), 2.66 (s, 4H), 2.43-2.31 (m, 1H), 2.15 (d, 7= 3.1 Hz, 1H).
Example 3: Synthesis of 3-(6-bromoquinolin-3-yl)piperidine-2, 6-dione (INT-3)
Figure imgf000329_0001
Step 1: Synthesis of ((l-(tert-butoxy)vinyl)oxy)(te/7-butyl)dimethylsilane (3b)
((l-(Tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (3b) was prepared according to the procedures and examples as reported in US Patent Application No. US2005272665 AL To a stirred solution of tert-butyl acetate (3a, 50 g, 430 mmol, 1 eq.) in THF (500 mL, 50 vol.) was added 2 M lithium diisopropylamide in THF (237 mL, 473 mmol, 1.1 eq.) drop-wise at -70 °C under an atmosphere of nitrogen and the resulting mixture was stirred at the same temperature for 30 min. Hexamethylphosphoramide (59.9 mL, 344 mmol, 0.8 eq.) and tert-butyldimethylsilyl chloride (68.1 g, 452 mmol, 1.05 eq.) dissolved in THF (100 mL) were then added to the pre-stirred reaction mixture at -70 °C. The reaction mixture was warmed to room temperature for 1 h. The progress of the reaction was monitored by TLC. After complete consumption of starting materials, the reaction mixture was concentrated under reduced pressure (below 40 °C, >10 mbar). The resulting crude compound (oily liquid) was dissolved in hexane (1000 mL) and the organic phase was washed with water (1000 mL) and brine solution (500 mL), dried over anhydrous Na?SO4 filtered, and concentrated under reduced pressure (below 40 °C, >10 mbar) to afford the crude compound. The crude compound was then further purified via distillation (bp 75 °C-80 °C at 2 mbar) to afford ((l-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (3b, 65 g, 282 mmol, 66% yield). *H NMR (400 MHz, DMSO-Js) 5 ppm: 3.48 (dd, J= 1.3, 9.4 Hz, 2H), 1.37 (s, 9H), 0.96 (s, 9H), 0.23-0.17 (m, 6H).
Step 2: Synthesis of tert-butyl 2-(6-bromoquinolin-3-yl)acetate (3c)
Tert-butyl 2-(6-bromoquinolin-3-yl)acetate (3c) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2022/253713.
To a stirred solution of 6-bromo-3 -iodoquinoline (la, 5 g, 14.97 mmol, leq.) in dioxane (100 mL, 20 vol.) was added ((l-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (3b, 10.35 g, 44.9 mmol, 3 eq.), potassium acetate (2.94 g, 29.9 mmol, 2 eq.) followed by dichlorobis(tri-o-tolylphosphine)palladium(II) (1.765 g, 2.246 mmol, 0.15 eq.) at rt under an atmosphere of argon. The resulting mixture was stirred at 75 °C for 16 h. The progress of the reaction was monitored by TLC/LCMS. Upon complete consumption of starting materials, the reaction mixture was filtered through a celite® pad which was washed with EtOAc (2 x 50 mL). The filtrate was directly concentrated. The resulting crude compound was purified by silica gel flash column chromatography, eluting with 5-10% of EtOAc in hexane to afford tert-butyl 2-(6- bromoquinolin-3-yl)acetate (3c, 2 g, 4.31 mmol, 29% yield). LCMS: m/z MM+ES+APCI, positive [M+2]+ 324.2; >H NMR (400 MHz, DMSO-de) 5 ppm: 8.84 (d, J = 2.1 Hz, 1H), 8.27 (d, J= 2.3 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.96 (d, J= 8.9 Hz, 1H), 7.86 (dd, J = 2.3, 9.0 Hz, 1H), 3.85 (s, 2H), 1.42 (s, 9H).
Step 3: Synthesis of 2-(6-bromoquinolin-3-yl)acetic acid (3d)
To a stirred solution of tert-butyl 2-(6-bromoquinolin-3-yl)acetate (3c, 8.5 g, 26.4 mmol, 1 eq.) in MeOH (85 mL) added K2CO3 (7.29 g, 52.8 mmol, 2 eq.) at rt under an atmosphere of nitrogen and the resulting mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC/LCMS. The reaction mixture was then concentrated under reduced pressure. The obtained crude compound was dissolved in water and the pH of the aqueous mixture was adjusted to ~ 1-2 with 1.5 N HC1. A solid precipitated which was filtered and washed with water (2 x 60 mL) and followed by hexane (2 x 50 mL). The resultant solid was then triturated with EtOAc (10 mL), stirred for 10 min, filtered, and dried under reduced pressure to afford 2-(6-bromoquinolin-3-yl)acetic acid (3d, 7.5 g, 21.03 mmol, 80% yield). LCMS: m/z MM+ES+APCI, positive [M+2]+ 268.1 ; >H NMR (400 MHz, DMSO-rfc) 5 ppm: 12.87-12.46 (m, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.27 (d, 7= 2.1 Hz, 1H), 8.22 (d, 7 = 1.5 Hz, 1H), 7.96 (d, 7 = 8.9 Hz, 1H), 7.89-7.80 (m, 1H), 3.86 (s, 2H).
Step 4: Synthesis of methyl 2-(6-bromoquinolin-3-yl)acetate (3e)
To a stirred solution of 2-(6-bromoquinolin-3-yl)acetic acid (3d, 13 g, 48.9 mmol, 1 eq.) in MeOH (130 mL) was added sulfuric acid (3.91 mL, 73.3 mmol, 1.5 eq.) at room temperature under an atmosphere of nitrogen and the resulting mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature (monitored by TLC) and concentrated under reduced pressure. The obtained crude compound was dissolved in water and the aqueous phase was washed with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (2 x 100 mL) and brine solution (1 x 100 mL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The obtained crude compound was triturated with hexane (2 x 15 mL), and the precipitated solid was filtered and dried under reduced pressure to provide methyl 2-(6-bromoquinolin-3-yl)acetate (3e, 7 g, 20.79 mmol, 43% yield). LCMS: m/z MM+ES+APCI, positive [M+H]+ 280.1; >H NMR (400 MHz, DMSO-r/s) 5 ppm: 8.89-8.84 (m, 1H), 8.28-8.25 (m, 1H), 8.25-8.22 (m, 1H), 7.99-7.93 (m, 1H), 7.90-7.83 (m, 1H), 3.98 (s, 2H), 3.67 (s, 3H).
Step 5: Synthesis of 3-(6-bromoquinolin-3-yl)piperidine-2, 6-dione (INT-3)
To a stirred solution of 60% wt NaH (0.493 g, 12.32 mmol, 1.5 eq.) in THE (70 mL) was added methyl 2-(6-bromoquinolin-3-yl)acetate (3e, 2.3 g, 8.21 mmol, 1 eq.) and acrylamide (2e, 0.584 g, 8.21 mmol, 1 eq.) at -20 °C under an atmosphere of nitrogen and the resulting mixture was stirred at the same temperature for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (60 mL) at -20 °C. The aqueous mixture was washed with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The obtained crude compound was purified by reverse phase column chromatography using a Cl 8 column (330 g snap) eluting with 40% ACN/0.1 % of formic acid in water. The pure fractions containing the desired product were concentrated under reduced pressure to provide 3-(6-bromoquinolin-3-yl)piperidine-2, 6-dione (INT- 3, 1.1 g, 3.16 mmol, 39% yield). LCMS: m/z MM+ES+APCI, positive [M+2]+ 320.9, *H NMR (400 MHz, DMSO-de) 5 ppm: 11.00 (s, 1H), 8.86 (d, J = 2.25 Hz, 1H), 8.27 (d, J = 2.25 Hz, IH), 8.21 (d, J = 2.00 Hz, IH), 8.00-7.94 (m, IH), 7.87 (dd, 7 = 9.01, 2.25 Hz, IH), 4.18 (dd, 7 = 12.51, 4.88 Hz, IH), 2.84-2.72 (m, IH), 2.70-2.57 (m, IH), 2.46-2.32 (m, IH), 2.20-2.10 (m, IH). Example 4: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C)
0
EtO' Br >
O EtOH, 65 °C EtO o9e e /ns/te
Step 3a v' 4 0; d
O O ©
F AJL F
2.5 M n-BuLi in F O
Cl F3C o CF3 ci n-hexane, DMF Cl EtOH/Pyridine Cl 4b O H
NH2 Na2CO3. MTBE, N ■CF3 THF, -78 °C to 80 °C, 16 h ,OEt
NH
H 2 rt, 3 h -40 °C, 2 h
4a Step 1 4c Step 2 4d Step 3b
F F
Conc HCI, 0 °C, 1h,
Cl 50% H2SO4 Cl NH Cl
Morpholine 2 Aq. NaNO2, ,OEt 110 °C, 16 h
EtOH, 80 °C, N then KI, 0 °C, N 2.5 h, (2 steps) RT, 2h
I ep 3c 4j NT-4A
St Step 5
.OBn
F
Cl N
Pd(tBu3P)2, K2CO3, dioxane, OBn H2O, 60 °C, 12 h N'
INT-4C
Step 6
Step 1: Synthesis of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (4c)
To a stirred solution of 4-chloro-3-fluoroaniline (4a, 25 g, 172 mmol, 1 eq.) in MTBE (500 mL, 20 vol.) was added 2,2,2-trifluoroacetic anhydride (4b, 46.9 g, 223 mmol, 1.3 eq.) and sodium carbonate (54.6 g, 515 mmol, 3 eq.) at 10 °C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred for 3 h. The reaction mixture was quenched with water (500 mL) and the aqueous layer was washed with EtOAc (2 x 1000 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (l x 450 mL) and brine (l x 450 mL), dried over anhydrous Na2SC>4 and filtered. The solvent was concentrated under reduced pressure to afford N-(4- chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (4c, 40 g, 1.65 mmol, 96% yield), which was carried onto the next step without further purification. LCMS: m/z MM+ES+APCI, negative [M-H]+ 239.9; *H NMR (400 MHz, CDCh) 5 ppm: 7.95 (br s, 1H), 7.66 (dd, /= 10.19, 2.44 Hz, 1H), 7.49-7.40 (m, 1H),
7.27-7.21 (m, 1H).
Step 2: Synthesis of 6-amino-3-chloro-2-fluorobenzaldehyde (4d) n-BuLi (109 mL, 2.5 M in n-hexane, 273 mmol, 2.2 eq.) was added drop-wise to a stirred solution of N-(4-chloro-3-fhrorophenyl)-2,2,2-trifluoroacetamide (4c, 30 g, 124 mmol, 1 eq.) in THF (500 mL, 16 vol.) at -78 °C under an atmosphere of nitrogen and the resulting mixture was stirred at -78 °C for 20 min. N, N-dimethylformamide (27.2 g, 373 mmol, 3 eq.) was then added drop-wise at -50 °C and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was quenched with water (200 mL) at -40 °C and washed with EtOAc (2 x 250 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 6-amino-3-chloro-2-fluorobenzaldehyde (4d, 31 g, 100 mmol, 81% yield), which was carried onto the next step without further purification. LCMS: m/z MM+ES+APCI, positive [M+H]+ 173.9; >H NMR (400 MHz, DMSO-de) 5 ppm: 10.15 (s, 1H), 7.61 (br s, 2H), 7.46-7.40 (m, 1H), 6.63 (d, J = 9.13 Hz, 1H).
Step 3: Synthesis of ethyl 3-amino-6-chloro-5-fluoroquinoline-2-carboxylate (4i)
Step 3a- Pyridine (4f, 13.98 mL, 173 mmol, 1.5 eq.) was added to ethanol (200 mL, 20 vol.) under continuous nitrogen bubbling, followed by ethyl bromopyruvate (4e, 20.30 mL, 161 mmol, 1.4 eq.) at room temperature. The resulting mixture was then heated to 65 °C and stirred at 65 °C for 2 h to provide 4g.
Step 3b- The reaction mixture containing 4g was cooled to room temperature sparged with nitrogen. 6-amino-3-chloro-2-fluorobenzaldehyde (4d, 20 g, 115 mmol, 1 eq.) and pyridine (23.30 mL, 288 mmol, 2.5 eq.) were added at room temperature and the resulting mixture was stirred at 80 °C for 16 h to form 4h.
Step 3c- Morpholine (28.1 mL, 323 mmol, 2.8 eq.) was added drop-wise at 70 °C to the reaction mixture containing 4h and the resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was then cooled to room temperature, poured into cold water (500 mL), and stirred for 15 min. A solid precipitated which was filtered and washed with water (200 mL) and dried under reduced pressure to provide ethyl 3-amino-6-chloro-5-fluoroquinoline-2-carboxylate (4i, 25 g, 81 mmol, 70% yield). 4i was earned onto the next step without further purification. LCMS: m/z MM+ES+APCI, positive [M+H]+ 268.9, 'H NMR (400 MHz, DMSO-de) 5 ppm: 7.75 (d, 7 = 9.13 Hz, 1H), 7.61 (s, IH), 7.46 (dd, J = 9.07, 8.07 Hz, IH), 6.76 (s, 2H), 4.41 (q, 7 = 7.13 Hz, 2H), 1.37 (t, 7 = 7.07 Hz, 3H).
Step 4: Synthesis of 6-chloro-5-fluoroquinolin-3-amine (4j)
Ethyl 3-amino-6-chloro-5-fluoroquinoline-2-carboxylate (4i, 30 g, 112 mmol) was added portionwise to sulfuric acid (50%, 150 mL, 112 mmol, 5 vol.)/water (125 mL, 4.2 vol.) at room temperature and the resulting mixture was stirred at 110 °C for 16 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was cooled to room temperature and the pH was adjusted to ~10 with 50% aqueous sodium hydroxide solution to promote precipitation of a solid. The precipitated solid was filtered and washed the solid with water (2 x 10 mL) and dried under reduced pressure to afford 6-chloro-5-fluoroquinolin-3-amine (16 g, 67.5 mmol, 61% yield), which was carried onto the next step without further purification. LCMS: m/z MM+ES+APCI, positive [M+H]+ 197.9; *H NMR (400 MHz, DMSO-A) 5 ppm: 8.59-8.30 (m, IH), 7.64 (d, 7 = 9.01 Hz, IH), 7.37 (t, 7 = 8.44 Hz, IH), 7.19 (d, 7 = 2.38 Hz, IH), 6.13 (s, 2H). Step 5: Synthesis of 6-chloro-5-fluoro-3-iodoquinoline (INT-4A)
Sodium nitrite (6.67 g, 97 mmol, 1.9 eq.) dissolved in water (30 mL, 3 vol.) was added at to a suspension of 6-chloro-5-fluoroquinolin-3-amine (4j, 10 g, 50.9 mmol, 1 eq.) in concentrated HC1 (60 mL, 6 vol.) at 0 °C and the resulting mixture was stirred at 0 °C for 1 h. KI (21.11 g, 127 mmol, 2.5 eq.) dissolved in water (30 ml, 3 vol.) was then added drop-wise to the pre-stirred reaction mixture at 0 °C and stirring was continued at room temperature for 2 h. The reaction mixture was then poured into a saturated sodium bicarbonate solution (200 mL) and the aqueous layer was washed with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure to provide the crude compound (15 g). The crude compound was then purified by Biotage Isolera® using a 330 g silica gel cartridge and eluting with 2-4% EtOAc in hexane to afford 6-chloro-5- fluoro-3-iodoquinoline (INT-4A, 6.1 g, 19.42 mmol, 38% yield). LCMS: m/z MM+ES+APCI, positive [M+2]+ 309.8, *H NMR (400 MHz, DM SO- A) 5 ppm 9.16 (d, 7 = 2.00 Hz, 1H), 8.91 (d, J = 1.63 Hz, 1H), 8.10-7.61 (m, 2H).
Step 6: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C)
To a stirred solution of 6-chloro-5-fluoro-3-iodoquinoline (INT-4A, 7.5 g, 24.39 mmol, 1 eq.) in dioxane (70 mL, 9 vol.)/water (7.5 mL. 1 vol.) were added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 12.21 g, 29.3 mmol, 1.2 eq.) and potassium carbonate (4.05 g, 29.3 mmol, 1.2 eq.), bis(tri-t-butylphosphine)palladium(0) (0.623 g, 1.220 mmol, 0.05 eq.) at 25 °C under continuous bubbling of argon. The resulting mixture was stirred at 60 °C for 12 h. After complete consumption of starting material (confirmed by LCMS), the reaction mixture was filtered through a celite® pad, and the filter cake was washed thoroughly with EtOAc (30 mL). The obtained filtrate was concentrated under reduced pressure to afford the crude compound (13 g). The crude compound was purified by Biotage Isolera ® using a 330 g silica gel cartridge and eluting with 20-30% EtOAc in hexane to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fhroroquinoline (INT-4C, 9.5 g, 18.58 mmol, 76% yield). LCMS: m/z MM+ES+APCI, negative [M-H]+ 469.0; *H NMR (400 MHz, DMSO-t/e) 5 ppm:
9.23 (d, 7 = 2.13 Hz, 1H), 8.62 (d. 7 = 1.88 Hz, 1H), 8.09 (d. 7 = 8.13 Hz, 1H), 7.94-7.84 (m, 2H), 7.54-
7.24 (m, 10H), 6.68 (d. 7 = 8.13 Hz, 1H), 5.47 (d, 7 = 6.38 Hz, 4H).
Example 5: Synthesis of l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5)
Figure imgf000335_0001
Step 1: Synthesis of l-(6-chloro-5-fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydro-pyrimidine- 2,4(lH,3H)-dione (5a)
To a stirred solution of 6-chloro-5-fluoro-3-iodoquinoline (INT-4A, 2 g, 6.50 mmol, 1 eq.) and 3- (2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 2.063 g, 7.81 mmol, 1.1 eq.) in DMSO (40 mL, 20 vol.) was added potassium phosphate tribasic (2.266 g, 13.0 mmol, 2 eq.) and Cui (0.124 g, 0.650 mmol, 0.1 eq.) and (R,R)-(-)-N,N’-dimethyl-l,2-diamino-cyclohexane (0.093 g, 0.650 mmol, 0.1 eq.) under continuous bubbling of nitrogen at room temperature. The resulting mixture was stirred at 100 °C for 16 h. Upon complete consumption of starting material, the reaction mixture was cooled to room temperature, and then poured into cold water (500 mL). The aqueous mixture was washed with EtOAc (2 x 250 mL) and the combined organic phases were dried over anhydrous Na2SC>4 filtered, and concentrated in vacuo. The crude product was purified by Biotage Isolera® on a silica-gel cartridge (330 g) and eluting with 50-55% of EtOAc/hexane to provide l-(6-chloro-5-fluoroquinolin-3-yl)-3-(2,4-dimethoxy- benzyl)dihydropyrimidine-2,4(lH,3H)-dione (5a, 1g, 2.25 mmol, 34% yield). LCMS: m/z MM+ES+APCI, positive [M+H]+ 444.3; *H NMR (400 MHz, DMSO-de) 5 ppm: 9.05 (d, J = 2.50 Hz, 1H), 8.39 (dd, J = 2.38, 0.63 Hz, 1H), 7.97-7.82 (m, 2H), 6.96 (d, J = 8.38 Hz, 1H), 6.56 (d, J = 2.38 Hz, 1H), 6.49-6.40 (m, 1H), 4.82 (s, 2H), 4.15-4.05 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.03 (t, J= 6.57 Hz, 2H).
Step 2: l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5)
To a stirred solution of l-(6-chloro-5-fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione (5a, 5 g, 11.26 mmol, 1 eq.) in DCM (100 mL, 20 vol.) was added trifluoroacetic acid (19.93 g, 175 mmol, 15.52 eq.) followed by the drop-wise addition of trifluoromethanesulfonic acid (3.38 g, 22.53 mmol, 2 eq.) at 0 °C under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by LCMS. Upon complete consumption of starting material, the reaction mixture was concentrated under reduced pressure. The obtained crude residue was dissolved in dichloromethane (50 mL) and the pH ~8 was adjusted with saturated sodium bicarbonate solution (100 mL). The resulting precipitate was filtered. The filtered solid was triturated with MTBE (100 mL), stirred for 10 min, filtered, and dried under reduced pressure to provide l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5, 2 g, 6.81 mmol, 60% yield), LCMS: m/z MM+ES+APCI, negative [M-H]+ 292.2; *H NMR (400 MHz, DMSO-Aj 5 ppm: 10.82-10.42 (m, 1H), 9.06 (d, 7 = 2.38 Hz, 1H), 8.32 (d, 7 = 2.00 Hz, 1H), 8.02- 7.60 (m, 2H), 4.02 (t, 7= 6.63 Hz, 2H), 2.79 (t, 7= 6.63 Hz, 2H).
Example 6: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoroquinoline (INT-6B)
Figure imgf000336_0001
Step 1: Synthesis of 6-bromo-5-fluoroquinoline (6d)
To a suspension of 4-bromo-3-fluoroaniline (6a, 50 g, 263 mmol, 1 eq.) in sulfuric acid (50 mL, 263 mmol, 1 vol.) was added glycerol (6b, 38.5 mL, 526 mmol, 2 eq.), sodium iodide (3.94 g, 26.3 mmol, 0.1 eq.) and nitrobenzene (16.2 mL, 158 mmol, 0.6 eq.) at room temperature under an atmosphere of nitrogen and the resulting mixture was stirred at 100 °C for 5 h. Upon complete consumption of starting material (monitored by LCMS), the reaction mixture was neutralized with aqueous ammonia (300 mL) and washed with EtOAc (2 x 750 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to afford the crude compound (200 g). The crude compound was purified by flash silica gel column chromatography on 100-200 mesh silica gel eluting with 25-30% of EtOAc/hexane to afford the mixture of regioisomers 6c & 6d (140 g). The 6c and 6d mixture was refluxed in hexane (600 mL) for 30 min, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to afford the crude compound (100 g), which was further purified by reverse phase chromatography using a Cl 8 column (330 g snap) and eluting with 60% of 0.1% formic acid in FLO /Acetonitrile, flow rate: 35 mL/min. The pure fractions were concentrated under reduced pressure to afford 6-bromo-5 -fluoroquinoline (6d, 5.5 g, 24.3 mmol, 9%), LCMS: m/z MM+ES+APCI, positive [M]+ 225.9 & [M+2]+ 227.5; *H NMR (400 MHz, DMSO-Aj 0 ppm: 9.12-8.94 (m, 1H), 8.52 (d, 7 = 8.38 Hz, 1H), 8.01 (dd, J = 9.01, 7.63 Hz, 1H), 7.87 (d, 7= 9.01 Hz, 1H), 7.71 (dd, 7 = 8.51, 4.25 Hz, 1H).
Step 2: Synthesis of 6-bromo-5-fluoro-3-iodoquinoline (INT-6A) To a stirred solution of 6-bromo-5 -fluoroquinoline (6d, 9 g, 39.8 mmol, 1 eq.) in acetonitrile (180 mL, 20 vol.) was added iodine (12.13 g, 47.8 mmol, 1.2 eq.) and tert-butyl hydroperoxide (41.0 g, 319 mmol, 70% wt, 8 eq.) at room temperature under an atmosphere of argon and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature, quenched with saturated sodium thiosulfate solution (-100 mL), and concentrated (to remove acetonitrile) under reduced pressure. The aqueous layer was washed with EtOAc (2 x 75 mL) and the combined organic phases were dried over anhydrous Na2SC>4, filtered, concentrated in vacuo. The obtained crude compound was purified by flash silica gel column chromatography on 100-200 mesh silica gel eluting with 2% EtOAc in hexane to afford 6-bromo-5-fluoro-3-iodoquinoline (INT-6A, 8.5 g, 24.15 mmol, 61% yield). LCMS: m/z MM+ES+APCI, positive [M]+ 351.7 & [M+2]+ 353.7; *H NMR (400 MHz, DMSO-de) 5 ppm: 9.17 (d, J = 2.00 Hz, 1H), 8.91 (d, J= 1.38 Hz, 1H), 8.02 (dd, 7= 9.01, 7.50 Hz, 1H), 7.83 (d, J = 9.01 Hz, 1H).
Step 3: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoroquinoline (INT-6B)
In a 250 mL mini clave, to a solution of 6-bromo-5-fluoro-3-iodoquinoline (INT-6A, 5 g, 14.2 mmol, 1 eq.) in dioxane (45 mL, 9 vol.)/water (5 mL, 1 vol.) was added 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 6.52 g, 15.65 mmol, 1.1 eq.) and DIPEA (2.97 mL, 10.23 mmol, 2 eq.) followed by the addition of bis(tri-t-butylphosphine)-palladium(0) (0.365 g, 0.71 mmol, 0.05 eq.) at room temperature under continuous bubbling of argon for 15 min. The resulting mixture was stirred at room temperature for 16 h. Upon complete consumption of starting material (monitored by LCMS), the reaction mixture was filtered through a celite® pad, and the celite® cake was washed with EtOAc (-150 mL). The filtrate was concentrated in vacuo to provide the crude compound, which was purified by reverse phase chromatography using a 330 g C18 cartridge and eluting with 90% ACN/0.1 % formic acid in water at a 35 mL/min flow rate. The ACN/water mixture was removed under reduced pressure to afford 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoroquinoline (INT-6B, 3.75 g, 7.18 mmol, 51% yield). LCMS: m/z MM+ES+APCI, positive [M]+ 515.0 & [M+2]+ 516.9; *H NMR (400 MHz, DMSO-A) 5 ppm: 9.35-9.12 (m, 1H), 8.62 (d, 7 =1.63 Hz, 1H), 8.12-8.05 (m, 1H), 8.02-7.92 (m, 1H), 7.88-7.82 (m, 1H), 7.52-7.31 (m, 10H), 6.72-6.63 (m, 1H), 5.47 (d, 7 = 6.75 Hz, 4H).
Example 7: Synthesis of l-(6-chloro-l,5-naphthyridin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione (INT-7)
Figure imgf000338_0001
Step 1: Synthesis of 7-bromo-2-chloro-l,5-naphthyridine (7b)
To a stirred solution of 2-chloro-l,5-naphthyridine (7a, 4.5 g, 27.3 mmol, 1 eq.) and sodium acetate (4.5 g, 54.7 mmol, 2.0 eq.) in acetic acid (22 mL, 4.8 vol.) was added bromine (1.831 mL, 35.5 mmol, 1.3 eq.) in acetic acid (4 mL) drop-wise over a period of 15 min at 85 °C under an atmosphere of nitrogen and the resulting mixture was stirred at 85 °C for 3 h. After complete consumption of the starting material, the reaction mixture was cooled to ambient temperature and treated with aq. 6M sodium hydroxide solution (100 mL). The resulting solid was collected by filtration, washed with methanol (20 mL), and dried. The resulting crude compound was purified by Biotage Isolera® on a silica-gel cartridge (120 g) eluting with 13-20% of EtOAc/hexane to obtain 7-bromo-2-chloro-l,5-naphthyridine (7b, 3.3 g, 11.93 mmol, 44% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 243.0; >H NMR (400 MHz, DMSO-cL. 298 K) 5 (ppm): 9.07-9.19 (m, 1H), 8.76 (d, J= 1.3 Hz, 1H), 8.52 (d, 7= 8.8 Hz, 1H), 7.91 (d, 7= 8.9 Hz, 1H).
Step 2: Synthesis of l-(6-chloro-l,5-naphthyridin-3-yl)-3-(2,4-dimethoxybenzyl) dihydropyrimidine- 2,4(lH,3H)-dione (7c)
To a stirred solution of 7-bromo-2-chloro-l,5-naphthyridine (7b, 2.5 g, 10.27 mmol. 1.0 eq.) and 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 2.71 g, 10.27 mmol, 1.0 eq.) in DMSO (50 mL, 20 vol.) was added potassium phosphate tribasic (2.83 g, 13.35 mmol, 1.3 eq.), copper(I) iodide (0.098 g, 0.513 mmol, 0.05 eq.) and (R, R)-(-)-N, N’ -dimethyl- 1 ,2-diaminocyclohexane (0.073 g, 0.513 mmol, 0.05 eq.) at room temperature under continuous bubbling of argon. The resulting mixture was stirred at 80 °C for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with ice-cold water (100 mL), washed with EtOAc (2 X 300 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude product was purified by Biotage Isolera® with a 120 g silica-gel cartridge and eluting with 35-40% of EtOAc/hexane to afford l-(6-chloro-l,5-naphthyridin-3-yl)-3-(2,4- dimethoxybenzyl) dihydropyrimidine-2,4(lH,3H)-dione (7c, 1.6 g, 3.70 mmol, 36% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 427.0; 'H NMR (400 MHz, DMSO-rk 298 K) 6 (ppm): 9.12 (d, 7 = 2.5 Hz, IH), 8.49 (dd, 7 = 0.7, 8.8 Hz, 1H), 8.29 (dd, 7 = 0.8, 2.4 Hz, IH), 7.83 (d. 7 = 8.8 Hz, 1H), 6.97 (d, 7
= 8.4 Hz, 1H), 6.56 (d. 7 = 2.4 Hz, 1H), 6.46 (dd, 7 = 2.4, 8.4 Hz, 1H), 4.82 (s, 2H), 4.20-3.99 (m, 2H),
3.80 (s, 3H), 3.74 (s, 3H), 3.07-3.00 (m, 2H).
Step 3: Synthesis of l-(6-chloro-l,5-naphthyridin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione (INT-
7)
To a stirred solution of l-(6-chloro-l,5-naphthyridin-3-yl)-3-(2,4-dimethoxybenzyl) dihydropyrimidine-2,4(lH,3H)-dione (7c, 1.6 g, 3.75 mmol, 1.0 eq.) in DCM (16 mL, 10 vol.) were added trifluoroacetic acid (4.48 mL, 58.2 mmol, 15.5 eq.) and triflic acid (0.666 mL, 7.50 mmol, 2.0 eq.) at 0 °C under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material, all volatiles were removed under reduced pressure. The crude compound was treated with saturated sodium bicarbonate solution (50 mL) at 0 °C, and the precipitated solid was collected by filtration, washed with water (3 x 150 mL), and dried to obtain the crude product. The crude product was then triturated with DCM (100 mL), filtered, and dried under reduced pressure to afford l-(6-chloro-l,5-naphthyridin-3-yl) dihydropyrimidine -2, 4(lH,3H)-dione (INT- 7, 0.7 g, 2.024 mmol, 54% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 277.0. 'H NMR (400 MHz, DMSO-A,. 298 K) 8 (ppm): 10.70 (br s, 1H), 9.12 (s, 1H), 8.47 (d, J= 8.5 Hz, 1H), 8.23 (s, 1H), 7.81 (d. J = 8.3 Hz, IH), 4.03 (s, 2H), 2.80 (s, 2H).
Example 8: Synthesis of 7-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloro-l,5-naphthyridine (INT-8)
Figure imgf000339_0001
To a stirred solution of 7-bromo-2-chloro-l,5-naphthyridine (7b, 3 g, 12.32 mmol, 1.0 eq.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 5.66 g, 13.55 mmol, 1.1 eq.) in dioxane (27 mL, 9.0 vol.)/water (3.00 mL, 1.0 vol.) was added DIPEA (4.76 g, 6.44 mL, 37.0 mmol, 3.0 eq.) at room temperature under continuous bubbling of argon which was continued for 15 mins. Bis(tri-t-butyl phosphine)palladium(O) (0.630 g, 1.232 mmol, 0.01 eq.) was then added and the resulting mixture was stirred at room temperature for 12 h. After complete consumption of the starting material, the reaction mixture was filtered through a celite® pad and the filter cake was washed thoroughly with EtOAc (100 mL). The filtrate was then washed with water (1 x 50 mL) and brine (1 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to get the crude compound. The crude was purified by Biotage Isolera® with 330 g silica-gel cartridge eluting with 15- 20% EtOAc/hexane to afford 7-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloro-l,5-naphthyridine (INT-8, 3.7 g, 8.10 mmol, 66% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 454.2; *H NMR (400 MHz, DMSO-cL. 298 K) 5 (ppm): 9.43-9.10 (m, 1H), 8.56-8.38 (m, 2H), 8.07 (d, J= 8.1 Hz, 1H), 7.82 (d, / = 8.8 Hz, 1H), 7.56-7.21 (m, 10H), 6.68 (d, J= 8.1 Hz, 1H), 5.49 (s, 2H), 5.44 (s, 2H).
Example 9: Synthesis of 6-chloro-3-iodo-5-methylquinoline (57a)
Figure imgf000340_0001
Step 1: Synthesis of 2-bromo-4-chloro-3-methylaniline (9b)
To a solution of 2-bromo-3-methylaniline (9a, 50 g, 269 mmol) in ACN (2000 mL) was added N- chlorosuccinimide (37.7 g, 282 mmol) in portions at room temperature and the resulting mixture was stirred at 60 °C for 16 h under an atmosphere of nitrogen. The reaction mixture was cooled and concentrated under reduced pressure. The crude material was partitioned between water (500 mL) and EtOAc (500 mL). The organic phase was dried over anhydrous NazSCL filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 2% EtOAc in n-hexane to afford 2- bromo-4-chloro-3-methylaniline (9b, 44 g, 186 mmol, 69% yield). LCMS: m/z MM- ES+APCI, Positive [M+H, M+2+H]+ 220.0, 222.0. ’H-NMR (400 MHz, CDCh): 57.12 (d, J = 8.40 Hz, 1H), 6.60 (d, J =
8.40 Hz, 1H), 4.08 (br s, 2H), 2.51 (s, 3H).
Step 2: Synthesis of N-(2-bromo-4-chloro-3-methylphenyl)-2,2,2-trifluoroacetamide (9c)
To a stirred solution of 2-bromo-4-chloro-3-methylaniline (9b, 3.5 g, 15.87 mmol) in MTBE (20 ml) was added 2,2,2-trifluoroacetic anhydride (2.87 ml, 20.64 mmol) and NazCCL (5.05 g, 47.6 mmol) at 10 °C and the resulting mixture was stirred at room temperature for 3 h. Ice-cold water (50 mL) was added and the aqueous mixture extracted with EtOAc (2 x 250 mL). The combined organic phases were washed with sat. NaHCCL (250 mL) and brine (250 mL), dried over anhydrous NazSCL filtered and concentrated under reduced pressure to afford N-(2-bromo-4-chloro-3-methylphenyl)-2,2,2- trifluoroacetamide (9c, 4.8 g, 14.56 mmol, 92% yield). The product was carried onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M-, M-2]+ 314.0, 316.0. ’H-NMR (400 MHz, CDCh): 5 8.54 (hr s, 1H), 8.15 (d, J = 8.80 Hz, 1H), 7.43 (d, J = 8.80 Hz, 1H), 2.60 (s, 3H).
Step 3: Synthesis of 6-amino-3-chloro-2-methylbenzaldehyde (9d)
To a stirring solution of N-(2-bromo-4-chloro-3-methylphenyl)-2,2,2-trifluoroacetamide (9c, 10 g, 31.6 mmol) in THE (200 ml) was added n-BuLi (27.8 ml, 69.5 mmol) at -78 °C and the resulting mixture was stirred for 30 min. N, N-dimethylformamide (14.11 g, 193 mmol) was then added dropwise at -78 °C and stirring was continued for 1 h at -78 °C. After complete consumption of starting materials, as confirmed by LCMS, the reaction mixture was poured in ice-chilled water (50 mL) and partitioned with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na?SO4, filtered, and concentrated under reduced pressure to afford 6-amino-3-chloro-2-methylbenzaldehyde (9d, 8 g, 12.26 mmol, 39% yield). The product was carried onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H, M+2+H]+ 170.1, 172.1.
Step 4: Synthesis of ethyl 3-amino-6-chloro-5-methylquinoline-2-carboxylate (9e)
To a stirring solution of ethanol (100 ml) was added pyridine (7.00 g, 88 mmol) with purging with nitrogen and the resulting mixture was stirred for 10 min. Ethyl bromopyruvate (16.10 g, 83 mmol) was then added dropwise at room temperature, and stirring was continued at 65 °C for 2 h. The reaction mixture was cooled to room temperature and 6-amino-3-chloro-2-methylbenzaldehyde (9c, 10 g, 59.0 mmol) was added followed by pyridine (11.66 g, 147 mmol) and the resulting mixture was heated to 80 °C and stirred for 16 h. The mixture was then cooled to 70 °C, and morpholine (14.38 g, 165 mmol) was added slowly at 70 °C. The reaction mixture was heated at 80 °C for 3 h and then cooled to room temperature. Water (500 mL) and stirring was continued for 15 min. The resulting precipitated solid was filtered, washed with water (200 mL) and dried to afford ethyl 3-amino-6-chloro-5-methylquinoline-2- carboxylate (9e, 5 g, 17.38 mmol, 30% yield). The product was carried onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H, M+2+H]+ 264.9, 266.9. ’H-NMR (400 MHz, CDCh): 57.71 (d, J = 9.20 Hz, 1H), 7.68 (s, 1H), 7.38 (d, J = 9.20 Hz, 1H), 6.58 (hr s, 2H), 4.40 (q, J = 7.20 Hz, 2H), 2.56 (s, 3H), 1.37 (q, J = 7.20 Hz, 3H).
Step 5: Synthesis of 6-chloro-5-methylquinolin-3-amine (9f)
To a stirred solution of H2SO4 (8 ml, 15.11 mmol) in water (5 ml) was added ethyl 3-amino-6- chloro-5-methylquinoline-2-carboxylate (9e, 4 g, 15.11 mmol) at 0 °C and the resulting mixture was heated at 100 °C and stirred for 48 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to ~10 using 50% NaOH solution (with cooling using an ice bath). The aqueous mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 6-chloro-5-methylquinolin-3-amine (9f, 2 g, 4.05 mmol, 27% yield). The product was earned onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H, M+2+H]+ 192.9, 194.9.
Step 6: Synthesis of 6-chloro-3-iodo-5-methylquinoline (57a)
To a stirred solution of 6-chloro-5-methylquinolin-3-amine (9f, 2.7 g, 14.02 mmol) in concentrated HC1 (16 mL) was added sodium nitrite (1.837 g, 26.6 mmol) dissolved in water (12 mL) at 0 °C, and the resulting mixture was stirred for 1 h at 0 °C. KI (5.82 g, 35.0 mmol) dissolved in water (12 ml) was then added and stirring was continued at room temperature for 2 h. The reaction mixture was poured into 10% NaHCCL solution (slowly) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 2% EtOAc in n-hcxanc to afford 6-chloro-3-iodo-5-methylquinoline (57a) 1.7 g, 3.86 mmol, 28% yield). LCMS: m/z MM- ES+APCI, Positive [M+H, M+2+H]+ 304.1, 306.1. ’H-NMR (400 MHz, CDCh): 5 9.08 (d, J = 2.00 Hz, 1H), 8.96 (d, J = 2.00 Hz, 1H), 7.87 (d, J = 8.80 Hz,
1H), 7.80 (d, J = 8.80 Hz, 1H), 2.70 (s, 3H).
Example 10: Synthesis of 3-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) piperidine-2, 6-dione (INT-
10)
Figure imgf000342_0001
Step 1: Synthesis of (3-amino-6-chloropyridin-2-yl) methanol (10b)
To a stirred solution of 3-amino-6-chloropicolinic acid (10a, 10 g, 57.9 mmol, 1.0 eq.) in THF (100 mL, 10 vol.) was added IM BHs.THF (500 mL, 500 mmol, 8.0 eq.) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at room temperature for 24 h. After complete consumption of the starting material, MeOH (150 mL) was added, followed by 2M HC1 solution (75 mL). The pH of resulting mixture was adjusted to pH ~ 8 with 20% potassium carbonate solution (150 mL) and the aqueous mixture was washed with DCM (3 x 200 mL). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford (3-amino-6-chloropyridin- 2-yl) methanol (10b, 9.5 g, 57.4 mmol, 99% yield). The desired product was carried onto the next step without further purification. LCMS: m/z: MM-ES+APCI positive [M+H]+ 158 90; *H NMR (400 MHz DMSO-oL 298 K) 5 (ppm): 7.10-7.03 (m, 2H), 5.35 (s, 2H), 5.20 (t, J= 5.8 Hz, 1H), 4.44 (d, 7 = 5.8 Hz, 2H).
Step 2: Synthesis of 3-amino-6-chloropicolinaldehyde (10c)
To a stirred solution of (3-amino-6-chloropyridin-2-yl) methanol (10b, 5 g, 31.5 mmol, 1.0 eq.) in DCE (100 mL, 10 vol.) was added manganese dioxide (8.22 g, 95 mmol, 3.0 eq.) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at 80 °C for 24 h. The reaction mixture was filtered through a bed of celite®, and the filter cake was washed with DCM (2 x 100 mL). The filtrate was concentrated under reduced pressure to afford 3-amino-6-chloropicolinaldehyde (10c, 4.5 g, 28.7 mmol, 91% yield), which was carried onto the next step without further purification. LCMS: m/z: MM- ES+APCI, positive [M+H]+ 157.1; *H NMR (400 MHz, DMSO-tfc, 298 K) 5 (ppm): 9.79 (s, 1H), 7.42- 7.31 (m, 4H).
Step 3: Synthesis of 2-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) acetic acid (lOd)
2M aq. potassium hydroxide solution (2.150 g, 38.3 mmol, 1.99 eq.) was added to a solution of 3- amino-6-chloropicolinaldehyde (10c, 3 g, 19.16 mmol, 1.0 eq.) and 4-oxopentanoic acid (2b, 2.023 mL, 19.16 mmol, 1.0 eq.) in ethanol (15 mL, 5 vol.) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at 65 °C for 15 min. The reaction mixture was then cooled to ambient temperature, and volatiles were removed under reduced pressure. The crude residue was diluted with water (50 mL) and acidified with acetic acid (pH = ~2). The precipitated solid was collected by filtration and dried under reduced pressure to afford 2-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) acetic acid (lOd, 1.7 g, 6.71 mmol, 35% yield), which was carried onto the next step without further purification. LCMS: m/z: MM- ES+APCI, positive [M+H]+ 236.9; >H NMR (400 MHz, DMSO-tfc): 5 ppm 12.95-12.43 (m, 1H), 8.38 (d, J= 8.76 Hz, 1H), 8.19 (s, 1H), 7.77 (d, J= 8.75 Hz, 1H), 3.95 (s, 2H), 2.65 (s, 3H).
Step 4: Synthesis of methyl 2-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) acetate (lOe)
To a stirred a solution of 2-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) acetic acid (lOd, 9.5 g, 40.1 mmol, 1.0 eq.) in DMF (47.5 mL, 5 vol.) was added potassium carbonate (6.66 g, 48.2 mmol, 1.3 eq.) and methyl iodide (2.59 mL, 40.1 mmol, 1.0 eq.) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at room temperature for 2 h. After complete consumption of the starting material, as confirmed by LCMS, ice water (50 mL) was added and the resulting precipitated solid was collected by filtration and dried under reduced pressure to afford methyl 2-(6-chloro-2-methyl-l,5- naphthyridin-3-yl) acetate (10c, 6 g, 22.31 mmol, 56% yield). The desired product was carried onto the next step without further purification. LCMS: m/z: MM-ES+APCI, positive [M+H]+ 250.9; *H NMR (400 MHz, DMSO-de, 298 K) 5 (ppm): 8.38 (dd, J= 0.7, 8.8 Hz, 1H), 8.21 (s, 1H), 7.79 (d, J= 8.7 Hz, 1H), 4.06 (s, 2H), 3.68 (s, 3H), 2.63 (s, 3H).
Step 5: Synthesis of 3-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) piperidine-2, 6-dione (INT-10) To a stirred solution of methyl 2-(6-chloro-2-methyl-l,5-naphthyridin-3-yl) acetate (lOe, 3 g, 11.97 mmol, 1.0 eq.) in THF (15 mL, 5 vol.) was added 60% wt NaH (0.345 g, 14.36 mmol, 1.0 eq.) at - 20 °C under an atmosphere of nitrogen and stirred at the same temperature for 1 h. Acrylamide (2e, 0.851 g, 11.97 mmol, 1.0 eq.) was then added at -20 °C to the pre-stirred reaction mixture and stirring was continued at room temperature for 1 h. After complete consumption of the starting material, aq. ammonium chloride solution (10 mL) was added and the resulting aqueous mixture was washed with EtOAc (3 x 200 mL). The combined organic phases were dried over anhydrous Na2SC>4 filtered, and concentrated under reduced pressure. The crude compound was purified by reverse phase column chromatography using a 330 g C18 cartridge and eluting with 30-40% ACN in 0.1% ammonium acetate in water. Pure fractions were collected and concentrated under reduced pressure afforded 3-(6-chloro-2- methyl-l,5-naphthyridin-3-yl) piperidine-2, 6-dione (INT-10, 1.5g, 5.2 mmol, 43% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 289.9, negative [M-H]+ 288.0; *H NMR (400 MHz, DMSO-tfc, 298 K) 5 (ppm): 11.27-10.61 (m, 1H), 8.39 (d, J= 8.8 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 4.38 (dd, J = 4.6, 12.7 Hz, 1H), 2.91-2.74 (m, 1H), 2.71 (s, 3H), 2.68-2.57 (m, 2H), 2.21-2.02 (m, 1H).
Example 11: Synthesis of 3-(6-bromo-5-fluoro-2-methylquinolin-3-yl) piperidine-2, 6-dione (INT-11)
Figure imgf000344_0001
Step 1: Synthesis of (6-amino-3-bromo-2-fluorophenyl) methanol (11b)
To a stirred solution of 6-amino-3-bromo-2-fluorobenzoic acid (Ila, 13 g, 55.5 mmol, 1.0 eq.) in THF (220 mL, 17 vol.) was added IM BH3.THF (278 mL, 278 mmol, 5.0 eq.) dropwise at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with methanol (50 mL). All volatiles were concentrated under reduced pressure. The crude compound was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over anhydrous Na2SC)4 filtered, and concentrated under reduced pressure to afford (6-amino-3-bromo-2-fluorophenyl) methanol (11b, 11.5 g, 52.3 mmol, 94% yield). The product was carried onto the next step without further purification. LCMS: m/z: mass was not ionized. *H NMR (400 MHz, DMSO-76, 298 K) 5 (ppm): 7.20 (t, J= 8.4 Hz, 1H), 6.45 (dd, 7= 0.9, 8.8 Hz, 1H), 5.48 (s, 2H), 5.05 (t, J = 5.6 Hz, 1H), 4.46 (dd, J = 2.0, 5.6 Hz, 2H). Step 2: Synthesis of 6-amino-3-bromo-2-fluorobenzaldehyde (lie)
To a stirred solution of (6-amino-3-bromo-2-fluorophenyl) methanol (11b, 11.5 g, 52.3 mmol, 1.0 eq.) in DCM (530 mL, 46 vol.) was added manganese dioxide (27.3 g, 314 mmol, 6.0 eq.) portion wise at room temperature under an atmosphere of nitrogen and the resulting mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material, the reaction mixture was filtered through a bed of celite® and the filter cake was washed thoroughly with DCM. The filtrate was concentrated under reduced pressure to afford 6-amino-3-bromo-2-fluorobenzaldehyde (11c, 10.5 g, 40.2 mmol, 77% yield), which carried onto the next step without further purification. LCMS: m/z: MM- ES+APCI, positive [M+H]+ 218.0; *H NMR (400 MHz, DMSO-tfc 298 K) 5 (ppm): 10.14 (s, 1H), 7.63 (br s, 2H), 7.50 (dd, 7= 7.9, 9.1 Hz, 1H), 6.59 (d, 7 = 9.1 Hz, 1H).
Step 3: Synthesis of 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetic acid (lid)
To a stirred solution of 6-amino-3-bromo-2-fhiorobenzaldehyde (11c, 10 g, 45.9 mmol, 1.0 eq.) in methanol (92 mL, 9.2 vol.) was added 4-oxopentanoic acid (2b, 5.33 g, 45.9 mmol, 1.0 eq.) and 2M sodium hydroxide solution (2.201 g, 55.0 mmol, 1.2 eq., dissolved in 27.5 mL of water) at room temperature. The resulting mixture was stirred at 65 °C for 16 h. Upon complete consumption of the starting material, all volatiles were concentrated under reduced. The crude compound was diluted with water (50 mL) and acidified with acetic acid. The resulting solid was collected by filtration and dried under reduced pressure to afford 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetic acid (lid, 13.5 g, 42.2 mmol, 92% yield), which carried onto the next step without further purification. LCMS: m/z: MM- ES+APCI, positive [M+H]+ 298.0, >H NMR (400 MHz, DMSCM. 298 K) 5 (ppm): 8.24 (s, 1H), 7.87 (dd, 7= 7.6, 9.0 Hz, 1H), 7.75-7.69 (m, 1H), 3.86 (s, 2H), 2.61 (s, 3H).
Step 4: Synthesis of ethyl 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetate (lie)
To a stirred solution of 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetic acid (lid, 17 g, 57.0 mmol, 1.0 eq.) in ethanol (170 mL, 10 vol.) was added sulfuric acid (4.58 mL, 86 mmol, 1.5 eq.) dropwise at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at 85 °C for 16 h. Upon complete consumption of the starting material, all volatiles were concentrated under reduced pressure. The crude compound was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over anhydrous Na2SC>4 filtered and concentrated under reduced pressure to afford ethyl 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetate (lie, 15 g, 28.3 mmol, 50% yield). The product was carried onto the next step without further purification. LCMS: m/z: MM- ES+APCI, positive [M+H]+ 326.0, *H NMR (400 MHz, DMSO-de, 298 K) 5 (ppm): 8.33 (s, 1H), 7.91 (dd, 7= 7.7, 8.9 Hz, 1H), 7.75 (d, 7= 8.9 Hz, 1H), 4.14 (q, 7= 7.1 Hz, 2H), 4.05 (s, 2H), 2.61 (s, 3H), 1.21 (t, 7= 7.1 Hz, 3H).
Step 5: Synthesis of 3-(6-bromo-5-fluoro-2-methylquinolin-3-yl) piperidine-2, 6-dione (INT-11) To a stirred solution of ethyl 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl) acetate (lie, 5 g, 15.33 mmol, 1.0 eq.) in THF (77 mL, 15 vol.) was added IM LiHMDS in THF (18.40 mL, 18.40 mmol, 1.2 eq.) drop- wise at -78 °C under an atmosphere of nitrogen and the resulting mixture was stirred at -78 °C for 1 h. Acrylamide (2e, 1.308 g, 18.40 mmol, 1.2 eq.) was then added to the pre-stirred reaction mixture at -78 °C and stirring was continued at room temperature for Ih. Upon complete consumption of the starting material, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude compound was triturated with acetonitrile (2 x 100 mL), filtered, and dried under reduced pressure to afford 3-(6-bromo-5-fluoro-2-methylquinolin-3- yl) piperidine-2, 6-dione (INT-11, 2.3 g, 6.50 mmol, 42% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 351.2, 'H NMR (400 MHz, DMSO-de, 298 K) 5 (ppm): 11.46-10.56 (m, IH), 8.26 (s, IH), 7.92 (dd, 7= 7.6, 9.1 Hz, IH), 7.76 (d, 7= 9.1 Hz, IH), 4.39 (dd, 7= 4.6, 12.8 Hz, IH), 2.91-2.77 (m, IH),
2.68 (s, 3H), 2.66-2.53 (m, 2H), 2.18-2.05 (m, 1H).
Example 12: Synthesis of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
(INT-4B)
Figure imgf000346_0001
Step 1: Synthesis of 2,6-bis(benzyloxy)pyridine (12c)
2,6-bis(benzyloxy)pyridine (12c) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2022/261250.
To potassium terf-butoxide (284 g, 2534 mmol, 2.5 eq.) in a 5 L three neck RB flask equipped with a condenser and thermal socket, under an atmosphere of nitrogen was added THF (1.5 L, 5.2 vol.). The resulting mixture was cooled to 0 °C, and phenyl methanol (12b, 232 mL, 2230 mmol, 2.2 eq.) was added dropwise at 0 °C. The reaction mixture was then stirred at the same temperature for 15 min. A solution of 2,6-dichloropyridine (12a, 150 g, 1014 mmol, 1.0 eq.) in THF (1 L, 6 vol.) was added dropwise at 0 °C to the pre-stirred reaction mixture and stirring was continued at 75 °C for 12 h. The reaction mixture was then cooled to room temperature and poured into ice-cold water (2L). The aqueous mixture was extracted with EtOAc (2 x IL). The combined organic phases were washed with brine (IL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford 2,6- bis(benzyloxy)pyridine (12c, 290 g, 936 mmol, 92% yield), which was carried onto the next step without further purification. LCMS: m/z: MM-ES+APCI, positive [M+H]+ 292.7; *H NMR (400 MHz, DMSO-c/s, 298 K) 5 (ppm): 7.64 (t, J = 7.9 Hz, 1H), 7.48-7.26 (m, 10H), 6.43 (d, J = 7.9 Hz, 2H), 5.33 (s, 4H).
Step 2: Synthesis of 2,6-bis(benzyloxy)-3-bromopyridine (INT-12)
2.6-bis(benzyloxy)-3-bromopyridine (INT-12) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2022/261250.
To 2,6-bis(benzyloxy)pyridine (12c, 240 g, 824 mmol, 1 eq.) in a 5 L three neck RB flask equipped with a condenser and thermal socket, under an atmosphere of nitrogen was added acetonitrile (2.5 L, 10.4 vol.) at 25 °C. NBS (148 g, 832 mmol, 1.01 eq.) was then added portion-wise at 25 °C and stirring was continued at 85 °C for 16 h. Upon complete consumption of starting material as monitored by LCMS, the reaction mixture was cooled to room temperature. Three fourths of the volume of the acetonitrile was removed in vacuo. The thick mixture was quenched with cold water (I L), and the aqueous layer was extracted with EtOAc (2 x 2 L). The combined organic phases were washed with brine (1 L), dried over anhydrous NazSCh filtered, and concentrated under reduced pressure to afford 2,6- bis(benzyloxy)-3-bromopyridine (INT-12, 300 g, 810 mmol, 98% yield). The product was carried onto the next step without further purification. LCMS: m/z: MM-ES+APCI, positive [M+H]+ 370.1; *H NMR (400 MHz, DMSO+% 298 K) 8 (ppm): 7.90 (d, J = 8.3 Hz, 1H), 7.52-7.25 (m, 10H), 6.45 (d, J= 8.4 Hz, 1H), 5.46-5.20 (m, 4H).
Step 3: Synthesis of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B)
2.6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B) was prepared according to the procedures and examples as reported in Org. Lett., 2014, 16(11), 2916-2919.
To 2,6-bis(benzyloxy)-3-bromopyridine (INT-12, 250 g, 675 mmol, 1 eq.) in dioxane (2 L, 8 vol.) was added triethyl amine (281 mL, 2026 mmol, 3 eq.) at room temperature under continuous bubbling of nitrogen. 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (122 mL, 844 mmol, 1.25 eq.) was added drop-wise via cannula at 25 °C under an atmosphere of nitrogen, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (18.96 g, 27.0 mmol, 0.04 eq.) (18.96 g, 27.0 mmol, 0.04 eq.) at room temperature. The resulting mixture was heated to 90 °C and stirring was continued for 3 h. The reaction mixture was cooled to room temperature, and the dioxane was removed under reduced pressure to provide the crude compound. The crude product was purified by silica gel flash column chromatography eluting with 5-15% of EtOAc in hexane to afford 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 135 g, 323 mmol, 48% yield). LCMS: m/z: MM- ES+APCI, positive [M+H]+ 418.1 & [M+H]+ 335.6; ’H NMR (400 MHz, DMSO-A, 298 K) 5 (ppm): 7.85 (d, 7 = 7.9 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 1A1-1.T1 (m, 8H), 6.43 (d, 7 = 7.9 Hz, 1H), 5.39 (d, 7 = 6.0 Hz, 4H), 1.29 (s, 12H).
Example 13: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A) and 3- (2,6-bis(benzyloxy)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (INT-13B)
Figure imgf000348_0001
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A)
3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2017/197046.
To a pressure-released screw-cap vial containing a stirred solution of 6-bromo-3-iodoquinoline (la, 2 g, 5.99 mmol, 1 eq.) in dioxane (15 mL, 7.5 vol.)/water (1.667 mL, 0.83 vol.) was added 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 2.75 g, 6.59 mmol, 1.1 eq.) and DIPEA (1.255 mL, 7.19 mmol, 1.2 eq.) followed by the addition of bis(tri-t- butylphosphine)palladium(O) (0.153 g, 0.299 mmol, 0.05 eq.) at ambient temperature under continuous bubbling of nitrogen. Bubbling of nitrogen was continued for 15 min and the resulting mixture was stirred at ambient temperature for 12 h. The reaction mixture was filtered through a bed of celite® and the filter cake was washed with EtOAc (100 mL). The filtrate was washed with water (2 x 30 mL) and brine (30 mL). The organic phase was dried over anhydrous Na2SO4 filtered, and concentrated under reduced. The crude product was then purified via Biotage Isolera® on a 120 g silica-gel cartridge eluting with 15-20% EtOAc in hexane to provide 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 1.2 g, 2.407 mmol, 40% yield). LCMS: m/z: MM-ES+APCI, positive [M+2]+ 499.1 ; *H NMR (400 MHz, DMSO-tfc, 298 K) 5 (ppm): 9.15 (d, 7= 2.3 Hz, 1H), 8.48 (d, 7= 2.1 Hz, 1H), 8.27 (d, 7= 2.3 Hz, 1H), 8.00-7.92 (m, 2H), 7.87 (dd, 7 = 2.3, 8.9 Hz, 1H), 7.50-7.30 (m, 10H), 6.67 (d, 7= 8.1 Hz, 1H), 5.45 (d, 7 = 11.3 Hz, 4H).
Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline (INT-13B)
To a stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 3.5 g, 7.04 mmol. 1 eq.) in dioxane (35 mL, 10 vol.) was added potassium acetate (2.072 g, 21.11 mmol, 3 eq.) and bis(pinacolato)diboron (5.36 g, 21.11 mmol, 3 eq.) followed by PdCh(dppf).DCM adduct (0.575 g, 0.704 mmol, 0.1 eq.) at 25 °C under continuous bubbling of nitrogen. The resulting mixture was stirred at 100 °C for 16 h. Upon consumption of starting material, the reaction mixture was cooled to room temperature and filtered through a bed of celite®. The filter cake was washed thoroughly with EtOAc
(150 mL). The filtrate was washed with water (50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na3SO4 filtered, and concentrated under reduced pressure. The crude was purified via
Biotage Isolera® on a 330 g silica-gel cartridge eluting with 25-40% EtOAc in hexane to afford 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (INT-13B, 2.375 g,
2.93 mmol, 42% yield). LCMS: m/z: MM-ES+APCI, positive [M+l]+ 545.1 & [M+l]+ 463.1; 'H NMR
(400 MHz, DMSO-rfc 298 K) 5 (ppm): 9.27-9.06 (m, 1H), 8.58 (d, 7= 2.0 Hz, 1H), 8.38 (s, 1H), 8.12-
7.82 (m, 3H), 7.61-7.29 (m, 10H), 6.67 (d, J= 8.1 Hz, 1H), 5.45 (d, J= 15.0 Hz, 4H), 1.36 (s, 12H).
Example 14: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-4- methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-22) and l-(6-(4-hydroxy-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
(1-29)
F
F
Figure imgf000349_0001
1-22 and 1-29
Step 1: Synthesis of l-(6-bromo-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione and 1-
(6-bromo-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (14a) and (14b) l-(6-bromo-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione and l-(6-bromo-2- methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (14a) and (14b) were prepared according to the procedures and examples as reported in Nature, 2015, 525, 87-90.
To a vial with a stir bar was added l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-1, 0.32 g, 1.0 mmol) and PTSA (0.38 g, 2.0 mmol), MeOH (4 mL) and DMSO (2 mL). (4,4’-Di-t- butyl-2,2’-bipyridine)bis[2-(2-pyridinyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (9 mg, 0.01 mmol) and the resulting mixture was sparged with argon for 5 min. Ethyl 2-mercaptopropanoate (0.033 g, 33pL, 0.25 mmol) was then added and the vial was sealed and subjected to blue light irradiation at 456 nm for 48 h. The obtained crude product mixture containing l-(6-bromo-4-methylquinolin-3- yl)dihydropyrimidine-2,4( lH,3H)-dione and 1 -(6-bromo-2-methylquinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (14a) and (14b) was concentrated and purified directly by reverse phase ISCO chromatography (eluting with 0-100% MeCN in H2O w/0.1% FA) to afford desired product as a mixture of regioisomers (140 mg, 0.42 mmol, 42%). LCMS: m/z HESI, positive [M+H]+ = 334.17 [calcd for Ci4Hi3BrN3O2 +: 334.02]
Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4-methylquinolin-6-yl)- 3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)-2-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (14c) and (14d)
The mixture of l-(6-bromo-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione and 1- (6-bromo-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (14a and 14b) (140 mg, 0.42 mmol) was dissolved in 1,4-dioxane (3.7 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 0.19 g, 0.63 mmol), Pd(dppf)Cl2 eDCM (0.033 g, 0.04 mmol) and K2CO3 (0.087 g, 0.63 mmol) in H2O (370 pLi were added and the resulting mixture was sparged with argon for 4 min (with sonication), sealed, and heated at 90 °C overnight (conventional heating). The reaction mixture was concentrated in vacuo and re -dissolved in DMSO for reverse phase purification (eluting with 0% to 100% MeCN in H2O) to afford desired products as a mixture of regioisomers (0.12 g, 0.28 mmol, 68% yield). LCMS: m/z HESI, positive [M+H]+ = 437.32 [calcd for C24H29N4O4 +: 437.22]
Step 3: Synthesis of the trifluoroacetic acid salt of l-(6-(4-hydroxypiperidin-4-yl)-4-methylquinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione and the trifluoroacetic acid salt of l-(6-(4- hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (14e) and (14f)
Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-4-methylquinolin-6-yl)-3,6- dihydropyridine- 1 (2H)-carboxylate and tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-2- methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (14c and 14d, 0.12 g, 0.28 mmol) were dissolved in DCE/iPrOH (1:1) (7 mL) and 10% (v/v) DMF. Oxygen was bubbled through the solution for 10 min. Tris(dipivaloylmethanato)manganese (0.05 g, 0.09 mmol) and phenylsilane (104 pL, 0.84 mmol) were then added and the resulting mixture was stirred for 5 h at rt with bubbling of oxygen through the solution. The erode material was filtered, concentrated, and purified by reverse phase column chromatography (eluting with 0% to 100% MeCN in water) to afford desired product as a mixture of regioisomers (100 mg, 77% yield). LCMS: m/z HESI, positive [M+H]+ = 455.36 [ealed for C24H31N4O5"1": 455.23], The product was dissolved in DCM (4 mL) and TEA (2 mL) and the resulting solution was stirred for 3 h and concentrated in vacuo to afford the desired product 14e and 14f as TEA salt of a mixture of regioisomers, which was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+ = 355.31 [ealed for C19H23N4O3"1": 355.18].
Step 4: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione and l-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-22) and (1-29)
The trifluoroacetic acid salt of l-(6-(4-hydroxypiperidin-4-yl)-4-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione and the trifluoroacetic acid salt of l-(6-(4-hydroxy-piperidin-4- yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (0.13 g, 0.36 mmol) was dissolved in DCE/DMF (10:1, lOmL), basified with DIPEA (0.31 pL. 1.8 mmol) at 0 °C. 4-(trifhroromethyl)- benzaldehyde (0.63 g, 3.6 mmol, 10 eq.), sodium triacetoxyborohydride (0.23 g, 1.1 mmol), and a few drops of acetic acid were added and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and purified by reverse phase chromatography (via ISCO, eluting with 0% to 100% MeCN in water) and prep. HPLC (Shimadzu, eluting with MeCN/water with 0.1% formic acid) to afford desired product 1-22 and 1-29 (42 mg, 0.082 mmol, 23%) as a mixture of regioisomers. LCMS: m/z HESI, positive [M+H]+ = 513.36 [ealed for C27H28F3N4O3L 513.21].
Step 5: Chiral SFC separation of mixture of (1-22) and (1-29) to provide l-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-22) and l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-2-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-29)
The mixture of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-22) and l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)- piperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-29, 40 mg, 0.078 mmol) was separated by chiral SFC using chiral Whelk-(R,R) column eluting with 0.2% FA in IP A as mobile phase A and acetonitrile as mobile phase B. The fractions containing peak 1 were collected and concentrated under reduced pressure to dryness to afford l-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-4-methyl-quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (I- 22, 6.7 mg, 0.013 mmol, 3.6%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 513.2. 1H-NMR (400
MHz, DMSO-de): 5 10.51 (s, 1H), 8.74 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 1.60 Hz, 1H), 8.00-7.90 (m, 2H),
7.71 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 5.13 (s, 1H), 3.92-3.85 (m, 1H), 3.68-3.64 (m, 3H),
3.27-3.23 (m, 1H), 2.93-2.76 (m, 2H), 2.69-2.67 (m, 2H), 2.57 (s, 4H), 2.16-2.10 (m, 2H), 1.69 (d, J =
12.40 Hz, 2H). The fractions containing peak 3 were collected and concentrated under reduced pressure to dryness to afford l-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-29, 15 mg, 0.029 mmol, 8%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 513.2. 1H-NMR (400 MHz, DMSO-d6): 5 10.53 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H),
7.98 (s, 1H), 7.91 (s, 2H), 7.71 (d, J = 8.00 Hz, 2H), 7.60 (d, J = 8.00 Hz, 2H), 5.06 (s, 1H), 3.98-3.91 (m,
1H), 3.69-3.66 (m, 1H), 3.65 (s, 2H), 2.91-2.65 (m, 5H), 2.56 (s, 4H), 2.08 (t, J = 9.20 Hz, 2H), 1.69 (d, J
= 12.40 Hz, 2H).
Example 15: Synthesis of 3-(6-(4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-15)
Figure imgf000352_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- methylpiperidine- 1-carboxylate (15b) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-methyl-piperidine-l- carboxylate (15b, 166 mg, 0.26 mmol, 52% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 0.5 mmol) and tert-butyl 3-methyl-4-oxopiperidine- 1-carboxylate (15a, 118 mg, 0.55 mmol). LCMS: m/z HESI, positive [M+H]+ = 632.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- methylpiperidine- 1-carboxylate (15c) tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-methylpiperidine- 1 - carboxylate (15c, 36 mg, 0.08 mmol, 30% yield) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- methylpiperidine-1 -carboxylate (15b, 166 mg, 0.26 mmol). LCMS: m/z HESI, positive [M+H]+ = 454.
Step 3: Synthesis of 3-(6-(4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-15)
3-(6-(4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-15, 14 mg, 0.04 mmol, quantitative yield) was synthesized according to General Procedure 1, Step C starting from tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-methyl-piperidine-l-carboxylate (15c, 18 mg, 0.04 mmol). LCMS: m/z HESI, positive [M+H]+= 354.
Example 16: Synthesis of 3-(6-(3,3-bis(ethyl-d5)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-48)
Figure imgf000353_0001
Step 1: Synthesis of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16b)
To a stirred solution of piperidin-4-one hydrochloride (16a, 4.1 g, 1 eq., 30 mmol) and 1- (bromomethyl)-4-(trifluoromethyl)benzene (16b, 5.1 mL, 1.1 eq, 33 mmol) in acetonitrile (76 mL, 0.4 molar, 1 eq., 30 mmol), was added DIPEA (11 mL, 2 eq, 61 mmol) and the resulting mixture was heated to reflux for 2 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via silica gel column chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated in vacuo to yield l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16b, 6.3 g, 25 mmol, 81% yield). LCMS: m/z HESI, positive [M+H]+ and [M+H+H20]+ = 258 and 276.
Step 2: Synthesis of 3,3-bis(ethyl-ds)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16c)
To an oven-dried reaction vial equipped with a stir bar was added l-(4- (trifluoromethyl)benzyl)piperidin-4-one (16b, 500 mg, 1 eq., 1.94 mmol) and the resulting mixture was sparged with argon. Toluene (5 mL) was then added and the reaction mixture was cooled to 0 °C. Hexamethyldisilazane potassium salt solution (3.89 mL, 1 molar, 2 eq., 3.89 mmol) was added and the resulting mixture was allowed to stir for 1 h at 0 °C l Iodoethane l l 2 2 2 d (311 pL 2 eq 3 89 mmol) was then added and stirring was continued with heating at 50 °C for 3 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was diluted with brine and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were dried over Na2SOr, filtered, and concentrated in vacuo. The crude material purified via silica gel column chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated under reduced pressure to yield 3,3-bis(ethyl-d5)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16c, 196 mg, 0.606 mmol, 31% yield). LCMS: m/z HESI, positive [M+H]+= 324.
Step 3: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-bis(ethyl-ds)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (16d)
4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-bis(ethyl-d5)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (16d, 78.1 mg, 0.11 mmol, 21% yield) was synthesized according to General Procedure 2, Step A starting from 3,3-bis(ethyl-d5)-l-(4-(trifluoromethyl)benzyl)piperidin-4- one (16c, 179 mg, 0.55 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 0.5 mmol). LCMS: m/z HESI, positive [M+H]+= 742 Step 4\ Synthesis of 3-(6-(3,3-bis(ethyl-</5)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-48)
3-(6-(3,3-bis(ethyl-r/5)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-48, 2.9 mg, 0.005 mmol, 5% yield) as a mixture of diastereomers was synthesized according to General Procedure 2, Step B starting from 4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)quinolin-6-yl)-3,3-bis(ethyl-c/5)-l-(4-(trifluoro-methyl)benzyl)piperidin-4-ol (16d, 78.1 mg, 0.11 mmol). LCMS: m/z HESI, positive [M+H]+= 564. >H NMR (499 MHz, DMSO-de) 8 (ppm) = 10.97- 10.94 (m, 1H), 8.74-8.72 (m, 1H), 8.44-8.41 (m, 1H), 8.20-8.17 (m, 1H), 8.03-8.00 (m, 1H), 7.98-7.94 (m, 1H), 7.92-7.88 (m, 1H), 7.73-7.68 (m, 2H), 7.61-7.57 (m, 2H), 4.16-4.08 (m, 1H), 3.58-3.54 (m, 2H), 2.92-2.82 (m, 2H), 2.81-2.72 (m, 1H), 2.69-2.60 (m, 2H), 2.44-2.32 (m, 4H), 2.18-2.09 (m, 1H), 1.50- 1.43 (m, 1H).
Example 17: Synthesis of 3-(6-(4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-20)
Figure imgf000355_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- methoxypiperidine-l-carboxylate (17b) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-methoxypiperidine-l- carboxylate (17b, 150 mg, 0.23 mmol, 46% yield) was synthesized according to General procedure 1, Step A starting from tert-butyl 3 -methoxy-4-oxopiperidine-l -carboxylate (17a, 127 mg 0.55 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 0.5 mmol). LCMS: m/z HESI, positive [M+H]+= 648.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- methoxypiperidine-l-carboxylate (17c) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-methoxypiperidine-l- carboxylate (17c, 35 mg, 0.07 mmol, 32% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- methoxypiperidine-1 -carboxylate (17b, 150 mg, 0.23 mmol). LCMS: m/z HESI, positive [M+H]+= 470. Step 3: Synthesis of 3-(6-(4-hydroxy-3-methoxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (17d)
3-(6-(4-Hydroxy-3-methoxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (17d, 14 mg, 0.04 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-methoxypiperidine-l-carboxylate (17c, 17.5 mg, 0.04 mmol). LCMS: m/z HESI, positive [M+H]+ = 370. Step 4: Synthesis of 3-(6-(4-hydroxy-3-methoxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-20)
3-(6-(4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-20, 5.6 mg, 0.01 mmol, 28% yield) as a mixture of diastereomers was synthesized according to General procedure 1, Step D starting from 4-(trifluoromethyl)benzaldehyde (17e, 10.2 uL, 0.075 mmol) and 3-(6-(4-hydroxy-3-methoxypiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (17d, 14 mg, 0.04 mmol). LCMS: m/z HESI, positive [M+H]+ = 528. *H NMR (499 MHz, DMSO- de) 5 (ppm) = 10.98-10.95 (m, 1H), 8.75-8.73 (m, 1H), 8.42-8.38 (m, 1H), 8.20-8.16 (m, 1H), 7.97-7.90 (m, 3H), 7.74-7.69 (m, 2H), 7.63-7.57 (m, 2H), 4.18-4.10 (m, 1H), 3.82-3.72 (m, 1H), 3.69-3.58 (m, 2H),
2.96 (d, J = 0.8 Hz, 1H), 2.94-2.88 (m, 1H), 2.86 (s, 2H), 2.81-2.72 (m, 1H), 2.70-2.66 (m, 1H), 2.65-2.60
(m, 1H), 2.60-2.55 (m, 2H), 2.47-2.34 (m, 2H), 2.17-2.10 (m, 1H), 2.05-1.94 (m, 1H), 1.73-1.57 (m, 1H)
Example 18: Synthesis of 3-(6-(3-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (INT-18)
Figure imgf000356_0001
Step 1: Synthesis of tert-butyl 3-(cyclopropylmethyl)-4-oxopiperidine-l-carboxylate (18c)
To a reaction vial equipped with a stir bar was added tert-butyl 4-oxopiperidine-l -carboxylate (18a, 1.00 g, 1 eq., 5.02 mmol) and toluene (10 mL) and the resulting mixture was cooled to 0 °C using an ice-water bath. IM Hexamethyldisilazane potassium salt solution in THF (5.52 mL, 1.1 eq., 5.52 mmol) and the resulting mixture was allowed to stir for 1 h at 0 °C. (Bromomethyl)cyclopropane (18b, 813 mg, 584 pL, 1.2 eq., 6.02 mmol) was then added and stirring was continued overnight at rt. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was diluted with brine and the aqueous layer was extracted with EtOAc (2x). The combined organic phases were dried over anhydrous NazSCL, filtered, and concentrated in vacuo. The crude material purified via silica gel column chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated under reduced pressure to yield tert-butyl 3-(cyclopropylmethyl)-4- oxopiperidine-1 -carboxylate (18c, 178 mg, 0.70 mmol, 14% yield). *H NMR (499 MHz, DMSO-c/s) 5 (ppm) = 4.18-3.97 (m, 1H), 3.94-3.78 (m, 1H), 3.40-3.33 (m, 1H), 3.23-2.96 (m, 1H), 2.46 (br s, 2H), 2.34-2.27 (m, 1H), 1.58-1.49 (m, 1H), 1.43 (s, 9H), 1.19-1.07 (m, 1H), 0.73-0.63 (m, 1H), 0.47-0.33 (m, 2H), 0.09-0.06 (m, 2H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3- (cyclopropyhnethyl) -4-hydroxypiperidine- 1-carboxylate ( 18d) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(cyclopropylmethyl)-4- hydroxypiperidine- 1-carboxylate (18d, 142 mg, 0.21 mmol, 42% yield) was synthesized according to General procedure 1, Step A starting from tert-butyl 3-(cyclopropylmethyl)-4-oxopiperidine-l- carboxylate (18c, 140 mg, 0.55 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT- 13A, 250 mg, 0.50 mmol). LCMS: m/z HESI, positive [M+H]+ = 672.
Step 3: Synthesis of tert-butyl 3-(cyclopropylmethyl)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (18e) tert-butyl 3-(cyclopropylmethyl)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (18e, 64 mg, 0.13 mmol, 64% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6- yl)-3-(cyclopropylmethyl)-4-hydroxypiperidine- 1-carboxylate (18d, 142 mg, 0.21 mmol). LCMS: m/z HESI, positive [M+H]+ = 494.
Step 4: Synthesis of 3-(6-(3-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (INT-18)
3-(6-(3-(cyclopropylmethyl)-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT- 18, 26 mg, 0.07 mmol quantitative yield) was synthesized according to General procedure 1, Step C starting from tert-butyl 3-(cyclopropylmethyl)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (18e, 32 mg, 0.07 mmol). LCMS: m/z HESI, positive [M+H]+ = 394. Example 19: Synthesis of 3-(2,2-difluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (INT- 19)
Figure imgf000357_0001
To a reaction flask equipped with a stir bar was added l-(4-(trifluoromethyl)benzyl)-piperidin-4- one (16b, 4.000 g, 1 eq., 15.55 mmol) and THF (31.10 mL, 0.5M) and the resulting mixture was cooled to 0 °C using an ice-water bath. IM Hexamethyldisilazane potassium salt in THF solution (17.1 mL, 1.1 eq., 17.10 mmol) and the resulting mixture was allowed to stir for 1 h at 0 °C. 2-Bromo- 1,1 -difluoroethane (19a, 2.479 g, 1.36 mL, 1.1 eq., 17.1 mmol) was then added and the reaction mixture was allowed to want to room temperature and was then stirred for 5 min at room temperature. A condenser was then put onto the reaction flask and the reaction mixture was heated to 80°C overnight. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude material purified via silica gel column chromatography eluting with 0-100% EtOAc in heptane. The desired fractions were collected, combined, and concentrated in vacuo to yield 3-(2,2- difluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (INT-19, 307 mg, 0.96 pmol, 6% yield). LCMS: m/z HESI, positive [M+H]+ = 322.
Example 20: Synthesis of 3-(6-(3-(2,2-difhioroethyl)-4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-25)
Figure imgf000358_0001
Step 1: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (20a)
4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-l-(4-(trifluoromethyl)- benzyl)piperidin-4-ol (20a, 159 mg, 0.22 mmol, 43% yield) was synthesized according to General Procedure 2, Step A starting from 3-(2,2-difluoroethyl)-l-(4-(trifluoromethyl)benzyl)-piperidin-4-one (INT-19, 178 mg, 0.55 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 0.5 mmol). LCMS: m/z HESI, positive [M+H]+ = 740.
Step 2: Synthesis of 3-(6-(3-(2,2-difluoroethyl)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-25)
3-(6-(3-(2,2-difhioroethyl)-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-25, 8.7 mg, 0.02 mmol, 7% yield) as a mixture of diastereomers was synthesized according to General Procedure 2, Step B starting from 4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (20a, 159 mg, 0.22 mmol). LCMS: m/z HESI, positive [M+H]+ = 562. >H NMR (499 MHz, DMSO-de) 5 (ppm) = 11.01- 10.92 (m, 1H), 8.79-8.74 (m, 1H), 8.40-8.35 (m, 1H), 8.22-8.17 (m, 1H), 8.05-7.96 (m, 2H), 7.91-7.83
(m, 1H), 7.74-7.68 (m, 2H), 7.65-7.55 (m, 2H), 5.91-5.57 (m, 1H), 4.19-4.11 (m, 1H), 3.75-3.69 (m, 1H),
3.66-3.60 (m, 2H), 2.89-2.70 (m, 3H), 2.67-2.58 (m, 2H), 2.45-2.32 (m, 3H), 2.23-2.04 (m, 2H), 1.85-
1.61 (m, 1H), 1.44-1.34 (m, 1H), 1.19-1.03 (m, 1H).
Example 21: Synthesis of 3-(6-(3-(2,2-difluoroethyl)-3-ethyl-4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-12)
Figure imgf000359_0001
F. N E N
OH[|
F3C. Pd(OH)2, H2 'OH[|
F3C. F
N
'O' "O' EtOH, DMF N o'- N 0
Step 3 H
21c 1-12
Step 1: Synthesis of 3-(2,2-difluoroethyl)-3-ethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (21b)
To a reaction vial equipped with a stir bar was added 3-(2,2-difluoroethyl)-l-(4-(trifluoromethyl)- benzyl)piperidin-4-one (INT-19, 250 mg, 1 eq., 0.78 mmol) and DMF (3.9 mL, 0.2 M, 1 eq., 0.8 mmol) and the resulting mixture was cooled to 0 °C using an ice-water bath. Sodium hydride (34 mg, 60% wt, 1.1 eq., 0.86 mmol) was added and the reaction mixture was stirred for 30 min at 0 °C. lodoethane (21a, 63 pL, 1 eq., 0.78 mmol) was then added and stirring was continued for 3 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via silica gel column chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated in vacuo to yield 3-(2,2-difluoroethyl)-3- ethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (21b, 123 mg, 0.35 mmol, 45% yield). LCMS: m/z HESI, positive [M+H]+ = 350.
Step 2: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-3-ethyl- l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (21c)
4-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-3-ethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (21c, 91 mg, 0.12, mmol, 42% yield) was synthesized according to General Procedure 2, Step A starting from 3-(2,2-difluoroethyl)-3-ethyl-l-(4-(trifluoromethyl)benzyl)- piperidin-4-one (21b, 123 mg 0.35 mmol) and 3-(2,6-bis(benzyloxy)-pyridin-3-yl)-6-bromoquinoline (INT-13A, 140 mg, 0.28 mmol). LCMS: m/z HESI, positive [M+H]+ = 768.
Step 3: Synthesis of 3-(6-(3-(2,2-difhroroethyl)-3-ethyl-4-hydroxy-l- (4(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-12) 3-(6-(3-(2,2-difluoroethyl)-3-ethyl-4-hydroxy-l-(4(trifluoromethyl)-benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-12, 13 mg, 0.12 mmol, 18% yield) as a mixture of diastereomers was synthesized according to General Procedure 2, Step B starting from 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2-difluoroethyl)-3-ethyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-ol (21c, 91 mg, 0.12 mmol). LCMS: m/z HESI, positive [M+H]+ = 590. *H NMR (499 MHz, DMSO-rfe) 5 (ppm) = 10.99-10.93 (m, 1H), 8.79-8.74 (m, 1H), 8.45-8.38 (m, 1H), 8.23-8.19 (m, 1H), 8.08-8.04 (m, 1H), 7.95 (s, 2H), 7.72 (s, 2H), 7.62-7.55 (m, 2H), 6.06-5.74 (m, 1H), 5.15-5.09 (m,
1H), 4.19-4.10 (m, 1H), 3.73-3.66 (m, 1H), 3.55-3.48 (m, 1H), 2.90-2.70 (m, 3H), 2.68-2.55 (m, 4H),
2.55-2.52 (m, 1H), 2.45-2.34 (m, 1H), 2.19-2.10 (m, 1H), 1.60-1.37 (m, 4H), 0.61-0.49 (m, 3H).
Example 22: Synthesis of 3-(6-(8-hydroxy-5-azaspiro[2.5]octan-8-yl)quinolin-3-yl)piperidine-2,6- dione (INT-22)
Figure imgf000360_0001
N N
Pd(OH)2, H2 MSA
‘OH DCM, MeCN OH
EtOH, DMF HN
O' N O Step 3 0 N 0
Step 2 22c H INT-22 H
Step 1: Synthesis of tert-butyl 8-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-8-hydroxy-5- azaspiro[2.5]octane-5-carboxylate (22b) tert-Butyl 8-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-8-hydroxy-5-azaspiro-[2.5]octane- 5-carboxylate (22b, 106 mg, 0.16 mmol, 46% yield) was synthesized according to General procedure 1, Step A starting from tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (22a, 82 mg, 0.36 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 180 mg, 0.36 mmol). LCMS: m/z HESI, positive [M+H]+ = 644.
Step 2: Synthesis of tert-butyl 8-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-8-hydroxy-5- azaspiro[2.5]octane-5-carboxylate (22c) terf-Butyl 8-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-8-hydroxy-5-azaspiro[2.5]octane-5- carboxylate (22c, 48 mg, 0.1 mmol, 80% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 8-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-8-hydroxy-5-azaspiro[2.5]- octane-5-carboxylate (22b, 106 mg, 0.16 mmol). LCMS: m/z HESI, positive [M+H]+ = 466.
Step 3: Synthesis of 3-(6-(8-hydroxy-5-azaspiro[2.5]octan-8-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-22)
3-(6-(8-Hydroxy-5-azaspiro[2.5]octan-8-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-22, 38 mg, 0.10 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tert-butyl 8-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-8-hydroxy-5-azaspiro[2.5]octane-5-carboxylate (22c, 48 mg, 0.10 mmol). LCMS: m/z HESI, positive [M+H]+ = 366.
Example 23: Synthesis of 3-(6-(4-hydroxy-3-(trifluoromethyl)-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-13)
Figure imgf000361_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- (trifluoromethyl)piperidine-l-carboxylate (23b) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- (trifluoromethyl)piperidine-l -carboxylate (23b, 111 mg, 0.16 mmol, 35% yield) was synthesized according to General procedure 1, Step A starting from tert-butyl 4-oxo-3-(trifluoromethyl)piperidine- 1 -carboxylate (23a, 148mg, 0.55 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT- 13A, 250 mg, 0.5 mmol). LCMS: m/z HESI, positive [M+H]+ = 686.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- (trifluoromethyl)piperidine-l-carboxylate (23c) tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-(trifluoromethyl)piperidine- 1 -carboxylate (23c, 32 mg, 0.06 mmol, 39% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- (trifluoromethyl)piperidine-l -carboxylate (23b, 111 mg, 0.16 mmol). LCMS: m/z HESI, positive [M+H]+ = 508
Step 3: Synthesis of 3-(6-(4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (23d)
3-(6-(4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (23d, 13 mg, 0.03 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-(trifluoromethyl)piperidine- 1 - carboxylate (23c, 16 mg, 0.03 mmol). LCMS: m/z HESI, positive [M+H]+ = 408 Step 4: Synthesis of 3-(6-(4-hydroxy-3-(trifluoromethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-13)
3-(6-(4-hydroxy-3-(trifluoromethyl)-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-13, 3.7 mg, 0.007 mmol, 21% yield) as a mixture of diastereomers was synthesized according to General procedure 1, Step D starting from 4-(trifluoromethyl)benzaldehyde (17e, 14 mg, 11 uL, 0.08mmol) and 3-(6-(4-hydroxy-3-(trifluoromethyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (23d, 13 mg, 0.03 mmol). LCMS: m/z HESI, positive [M+H]+ = 566. *H NMR (499 MHz, DMSO-t/d) 5 (ppm) = 10.99-10.96 (m, 1H), 8.77-8.74 (m, 1H), 8.39-8.35 (m, 1H), 8.20-8.17 (m, 1H), 8.12-8.07 (m, 1H), 7.97-7.92 (m, 2H), 7.76-7.72 (m, 2H), 7.66-7.61 (m, 2H), 5.68-5.63 (m, 1H), 4.18-4.11 (m, 1H), 3.81-3.71 (m, 2H), 2.98-2.91 (m, 1H), 2.82-2.66 (m, 4H), 2.64-2.53 (m, 2H), 2.46- 2.37 (m, 1H), 2.20-2.11 (m, 2H), 1.67-1.59 (m, 1H).
Example 24: Synthesis of 3,3-diethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (INT-24)
Figure imgf000362_0001
To an oven-dried flask equipped with a stir bar was added l-(4-(trifluoromethyl)benzyl)- piperidin-4-one (16b, 1000 mg, 1 eq., 3.89 mmol) and toluene (0.4M) followed by KOtBu (963.9 mg, 2.21 eq, 8.59 mmol) and the resulting mixture was stirred for 1 h at room temperature. Bromoethane (931.9 mg, 634 pL, 2.2 eq., 8.55 mmol) was then added and the reaction mixture was heated to reflux at 100 °C. After 1 h, LCMS showed complete consumption of starting material. Saturated bicarbonate was added, and the aqueous mixture was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography on a 40 g silica gel column eluting with 0 to 10% MeOH in DCM to provide 3,3-diethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (INT-24, 238 mg, 0.76 mmol, 20% yield). 'H NMR (499 MHz, CDC13, 302 K) 5 (ppm) = 7.60 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 3.61 (s, 2H), 2.69 (t, /= 6.0 Hz, 2H), 2.49-2.45 (m, 4H), 1.86 (dd, 7 = 7.7, 14.2 Hz, 2H), 1.50 (dd, / = 7.4,
14.5 Hz, 2H), 0.72 (t. 7 = 7.7 Hz, 6H).
Example 25: Synthesis of 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-46)
Figure imgf000363_0001
Step 1: Synthesis of 4-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-diethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (25a)
4-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-diethyl-l-(4-(trifluoromethyl)benzyl)- piperidin-4-ol (25a, 28.3 mg, 0.39 mmol, 15% yield) was synthesized according to General Procedure 2, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-quinoline (INT-13A, 130.0 mg, 1 eq., 0.26 mmol) and 3,3-diethyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4-one (INT-24, 90.1 mg, 1.1 eq., 0.29 mmol). LCMS: m/z HESI, positive [M+H]+ = 732
Step 2: Synthesis of the 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-46)
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-46, 11 mg, 0.02 mmol, 50%, solid) as a mixture of diastereomers was synthesized according to General Procedure 2, Step B starting from l-(3-(2,6-bis(benzyloxy)-pyridin-3- yl)quinolin-6-yl)-2,2-diethyl-4-(4-(trifhroromethyl)-benzyl)cyclohexan-l-ol (25a, 28.3 mg, 1 eq., 0.039 mmol). LCMS: m/z HESI, positive [M+H]+ = 554; >H NMR (499 MHz, DMSO-tfc, 298 K) 5 (ppm) = 11.02 (s, 1H), 10.36 (br s, 1H), 8.97 (br s, 1H), 8.63 (br s, 1H), 8.14-8.08 (m, 2H), 8.04 (br d, J = 8.2 Hz, 3H), 7.89 (d, J = 8.2 Hz, 2H), 5.78 (br s, 1H), 4.63-4.52 (m, 1H), 4.46 (br dd, J = 6.3, 12.9 Hz, 1H), 4.22 (br dd, J = 4.7, 12.9 Hz, 1H), 3.46-3.41 (m, 2H), 3.23 (br t, 7= 11.8 Hz, 1H), 3.20-3.13 (m, 1H), 2.83- 2.72 (m, 2H), 2.68-2.59 (m, 1H), 2.48-2.40 (m, 1H), 2.22-2.09 (m, 2H), 1.79 (br d, J = 14.2 Hz, 1H), 1.63-1.50 (m, 1H), 1.19-1.07 (m, 2H), 0.48-0.36 (m, 6H). Example 26: Synthesis of tert- butyl 9-oxo-6-azaspiro[3.5]nonane-6-carboxylate (INT-26)
Figure imgf000364_0002
To a 40 mL vial equipped with a stir bar was added 6-azaspiro[3.5]nonan-9-one HC1 (26a, 1.00 g, 1 eq., 7.18 mmol) and sodium bicarbonate (1.20 g, 2 eq., 14.37 mmol) and THF (35.9 mL, 0.2 M) and water (8.9 mL, 0.8 M). Di-tert-butyl dicarbonate (1.82 mL, 1.1 eq., 7.90 mmol) was then added to the suspension and the resulting solution was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo and then diluted with DCM and saturated sodium bicarbonate. The phases were separated, and the aqueous phase was extracted one additional time with DCM. The combined organic phases were dried over Na2SC>4 and concentrated in vacuo. The crude material was purified via silica gel chromatography on an 80 g silica gel column eluting with 0 to 100% EtOAc in heptanes. The pure product containing fractions were collected and concentrated to yield a clear viscous solid, which was lyophilized from benzene to yield tert-butyl 9-oxo-6-azaspiro[3.5]nonane-6-carboxylate (INT-26, 1.27 g, 5.32 mmol, 74% yield). LCMS: m/z HESI, positive [M+H- tBu]+ = 184 and [M-Boc+H]+= 140.
Example 27: Synthesis of 3-(6-(9-hydroxy-6-(4-(trifluoromethyl)-benzyl)-6-azaspiro[3.5]nonan-9- yl)quinolin-3-yl)piperidine-2, 6-dione (1-36)
Figure imgf000364_0001
Step 1: Synthesis of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (27a) tert-Butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9-hydroxy-6-azaspiro[3.5]nonane- 6-carboxylate (27a, 167.4 mg, 0.25 mmol, 51% yield) was synthesized according to General procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-quinoline (INT-13A, 250 mg, 1 eq., 503 pmol) and tert-butyl 9-oxo-6-azaspiro[3.5]nonane-6-carboxylate (INT-26, 120 mg, 1 eq., 0.50 mmol). LCMS: m/z HESI, positive [M+H]+ = 658.
Step 2: Synthesis of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-9-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (27b) tert-Butyl 9-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-9-hydroxy-6-azaspiro[3.5]-nonane-6- carboxylate (27b, 43.2 mg, 0.09 mmol, 47% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate 27a, (127 mg, 1 eq., 0.19 mmol). LCMS: m/z HESI, positive [M+H]+ = 480.
Step 3: Synthesis of 3-(6-(9-hydroxy-6-azaspiro[3.5]nonan-9-yl)quinolin-3-yl)piperidine-2, 6-dione (27c)
3-(6-(9-hydroxy-6-azaspiro[3.5]nonan-9-yl)quinolin-3-yl)piperidine-2, 6-dione (27c, 34 mg, 0.09 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tertbutyl 9-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-9-hydroxy-6-azaspiro[3.5]-nonane-6-carboxylate (27b, 43 mg, 1 eq., 0.09 mmol). LCMS: m/z HESI, positive [M+H]+ = 380.
Step 4: Synthesis of 3-(6-(9-hydroxy-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[3.5]nonan-9- yl)quinolin-3-yl)piperidine-2, 6-dione (1-36)
3-(6-(9-hydroxy-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[3.5]-nonan-9-yl)quinolin-3- yl)piperidine-2, 6-dione (1-36, 48 mg, 0.034 mmol, 38% yield, amorphous solid) as a mixture of diastereomers was synthesized according to General procedure 1, Step D starting from 3-(6-(9-hydroxy- 6-azaspiro[3.5]nonan-9-yl)quinolin-3-yl)piperidine-2, 6-dione (27c, 34 mg, 1 eq., 0.090 mmol), 4- (trifhioromethyl)benzaldehyde (17e, 17 mg, 13 pL, 1.1 eq., 0.099 mmol). LCMS: m/z HESI, positive [M+H]+ = 538. >H NMR (499 MHz, DMSO-tL, 297 K) 5 (ppm) = 11.05 (s, IH), 10.73 (hr s, 1H), 9.04 (hr s, IH), 8.71 (br s, IH), 8.26-8.18 (m, 2H), 8.15 (br d, 7= 8.8 Hz, IH), 7.99 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 4.52 (br d, J = 4.9 Hz, 2H), 4.26 (br dd, J = 4.7, 12.9 Hz, IH), 3.41-3.25 (m, 5H), 2.93- 2.74 (m, 2H), 2.71-2.59 (m, IH), 2.48-2.35 (m, IH), 2.28-2.12 (m, 2H), 2.09-1.93 (m, IH), 1.92-1.74 (m, 2H), 1.50-1.40 (m, 2H), 0.67-0.55 (m, IH).
Example 28: Synthesis of tert-butyl 3-ethyl-3-methyl-4-oxopiperidine-l-carboxylate (INT-28)
.0 1. KOtBu,
.0 IBuOH
BocN BocN
2. Mel
28a INT-28
To a 100 mL oven dried round bottomed flask equipped with a stir bar was added tBuOH (5.50 mL, 0.4 molar) and KOtBu (247 mg, 1.0 eq., 2.20 mmol) followed by tert-butyl 3-ethyl-4-oxopiperidine- 1 -carboxylate (28a, 500 mg, 1 eq., 2.20 mmol) and the resulting mixture was stirred at 40 °C for 1 h. Mel (151 uL, 1.1 eq., 2.42 mmol) was then added in one portion. Instantly after adding the Mel, precipitate was observed, and the reaction mixture was stirred for an additional 2 h. Once LCMS indicated the formation of the desired product as well as undesired regioisomers, the reaction mixture was diluted with EtOAc and washed with water. 2 mL of 2 M HC1 was added to break the emulsion. The aqueous phase was extracted with EtOAc (3x) and the combined organic phases were dried over anhydrous NacSO^ filtered, and concentrated in vacuo. The crude material was via silica gel chromatography on a 40 g silica gel column eluting with 0 to 25% EtOAc in heptane. The pure product containing fractions were collected and concentrated to provide tert-butyl 3-ethyl-3-methyl-4-oxopiperidine-l-carboxylate (INT-28, 62.9 mg, 0.26 mmol, 12% yield). LCMS: m/z HESI, positive [M+H-Boc]+ = 142; >H NMR (499 MHz, CDCh, 297 K) 5 (ppm) = 4.21-4.08 (m, 1H), 3.82 (br d, J = 13.1 Hz, 1H), 3.40-3.23 (m, 1H), 3.06 (br s, 1H), 2.54 (br s, 1H), 2.35 (td, J = 4.6, 14.9 Hz, 1H), 1.70-1.62 (m, 1H), 1.49 (s, 10H), 1.00 (s, 3H), 0.82 (t, J = 7.7 Hz,
3H).
Example 29: Synthesis of 3-(6-(3-ethyl-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-
4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-62)
Figure imgf000366_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy- 3-methylpiperidine- 1 -carboxylate (29a) tert- Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methylpiperidine-1 -carboxylate (29a, 77.5 mg, 0.12 mmol, 29% yield) was synthesized according to General procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT- 13A, 200.0 mg, 1 eq., 0.40 mmol), tert-butyl 3 -ethyl-3-methyl-4-oxopiperidine-l -carboxylate (INT-28, 106.7 mg, 1.1 eq., 0.44 mmol). LCMS: m/z HESI, positive [M+H]+ = 660.
Step 2: Synthesis of the te/7-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methylpiperidine- 1-carboxylate (29b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3-methyl-piperidine-l- carboxylate (29b, 31.5 mg, 0.065 mmol, 56% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methylpiperidine- 1-carboxylate (29a, 77.5 mg, 1 eq., 0.12 mmol). LCMS: m/z HESI, positive [M+H]+ = 482. Step 3: Synthesis of 3-(6-(3-Ethyl-4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (29c)
3-(6-(3-Ethyl-4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (29c, 25 mg, 0.066 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tert-butyl 4-(3-(2,6.dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3-methylpiperidine-l- carboxylate (29b, 31.5 mg, 1 eq., 0.65 mmol). LCMS m/z: HESI, positive [M+H]+ = 382.
Step 4: Synthesis of 3-(6-(3-ethyl-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-62)
3-(6-(3-ethyl-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-62, 21 mg, 0.039 mmol, 59% yield, amorphous solid) as a mixture of diastereomers was synthesized according to General procedure 1, Step D starting from 3-(6-(3-ethyl-4- hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (29c, 25 mg, 1 eq., 0.066 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 13 mg, 9.8 pL, 1.1 eq., 0.072 nmol). LCMS: m/z HESI, positive [M+H]+ = 540. 'H NMR (499 MHz, DMSO-de, 298 K) 5 (ppm) = 11.03 (s, 1H), 10.39 (br s, 1H), 9.00 (br s, 1H), 8.65 (br s, 1H), 8.15-8.08 (m, 2H), 8.06-7.96 (m, 3H), 7.89 (d, J = 8.2 Hz, 2H), 5.73 (br s, 1H), 4.59-4.47 (m, 2H), 4.23 (dd, J = 4.9, 12.6 Hz, 1H), 3.36-3.19 (m, 3H), 3.17-3.02 (m, 2H), 2.85-2.72 (m, 1H), 2.69-2.59 (m, 1H), 2.48-2.40 (m, 1H), 2.21-2.14 (m, 1H), 1.91-1.73 (m, 2H), 1.02 (s, 3H), 0.97-0.84 (m, 1H), 0.56 (t, 7 = 7.7 Hz, 3H).
Example 30: Synthesis of 3-(6-(3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-50)
Figure imgf000367_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4- hydroxypiperidine- 1-carboxylate (30a) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-piperidine-l- carboxylate (30a, 192.3 mg, 0.29 mmol, 37% yield) was synthesized according to General procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 400 mg, 1 eq., 0.80 mmol) and tert-butyl 3-ethyl-4-oxopiperidine-l -carboxylate (28a, 238 mg, 1.3 eq., 1.05 mmol). LCMS: m/z HESI, positive [M+H]+ = 646.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyL4- hydroxypiperidine- 1-carboxylate (30b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxypiperidine- 1 - carboxylate (30b, 74.0 mg, 0.16 mmol, 53% yield) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy- piperidine- 1-carboxylate (30a, 192 mg, 1 eq., 0.29 mmol). LCMS: m/z HESI, positive [M+H]+ = 468. Step 3: Synthesis of 3-(6-(3-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (30c) 3-(6-(3-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (30c, 58 mg, 0.16 mmol, quantitative yield) was synthesized according to General procedure 1, Step C starting from tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxypiperidine- 1 -carboxylate (30b ,74 mg, 1 eq., 0.16 mmol). LCMS: m/z HESI, positive [M+H]+ = 368.
Step 4: Synthesis of 3-(6-(3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-50)
3-(6-(3-ethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (1-50, 18 mg, 0.034 mmol, 43% yield, amorphous solid) as a mixture of diastereomers was synthesized according to General procedure 1, Step D starting from 3-(6-(3-ethyl-4-hydroxypiperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (30c, 29 mg, 1 eq., 0.079 mmol) and 4- (trifhioromethyl)benzaldehyde (17e, 15 mg, 12 pL, 1.1 eq., 0.087 mmol). LCMS: m/z HESI, positive [M+H]+ = 526; >H NMR (499 MHz, DMSO-tfc, 297 K) 5 (ppm) = 11.44 (br s, 1H), 11.04 (s, 1H), 9.00 (br s, 1H), 8.60 (br s, 1H), 8.18 (d, 7 = 8.8 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J = 7.5 Hz, 2H), 7.93-7.91 (m, 1H), 7.91-7.87 (m, 2H), 4.61 (br dd, 7 = 4.1, 13.4 Hz, 1H), 4.48 (br dd, 7 = 5.7, 12.9 Hz, 1H), 4.25 (br dd, 7 = 4.9, 12.6 Hz, 1H), 3.49 (br d, 7 = 9.3 Hz, 1H), 3.45-3.33 (m, 2H), 3.30-3.26 (m, 1H), 3.13-3.02 (m, 1H), 2.84-2.73 (m, 1H), 2.70-2.58 (m, 3H), 2.47-2.32 (m, 1H), 2.22-2.11 (m, 1H), 1.82 (br d, 7 = 13.7 Hz, 1H), 1.10-0.91 (m, 2H), 0.59 (t, 7 = 7.4 Hz, 3H).
Example 31: Synthesis of 3-(6-(4-hydroxy-3-(methoxymethyl)-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-35)
Figure imgf000369_0001
Step 1: Synthesis of sodium (Z)-(l-(tert-butoxycarbonyl)-4-oxopiperidin-3-ylidene)-methanolate (31b)
To a stirred solution of sodium methoxide (5.42 g, 25.1 mmol) in methanol (5 mL) was added ethyl formate (31a, 2.79 g, 37.6 mmol) dropwise at 0 °C and the resulting mixture was warmed to room temperature. Tert-butyl 4-oxopiperidine-l -carboxylate (18a, 5.0 g, 25.1 mmol) was then added and stirring was continued at room temperature for 32 h. The reaction mixture was concentrated under reduced pressure to provide sodium (Z)-(l-(ter/-butoxycarbonyl)-4-oxopiperidin-3-ylidene)methanolate (31b, 5 g, 18.05 mmol, 72% yield) which was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H-Boc-Na]+ 127.9.
Step 2: Synthesis of tert-butyl (Z)-3-(methoxymethylene)-4-oxopiperidine-l-carboxylate (31c)
To a stirred solution of sodium (Z)-(l-(tert-butoxycarbonyl)-4-oxopiperidin-3- ylidene)methanolate (31b, 5 g, 20.06 mmol) in acetone (100 mL) were added K2CO3 (5.55 g, 40.1 mmol) followed by dimethyl sulfate (1.902 mL, 20.06 mmol) at 25 °C and the resulting mixture was stirred at 65 °C in an autoclave for 16 h. The reaction mixture was then cooled to room temperature, water was added, and the aqueous mixture was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over anhydrous NazSOr, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography on Biotage Isolera® on silica gel (100- 200 mesh) eluting with 0 to 60% EtOAc in /i-hcxanc to afford tert-butyl (Z)-3-(methoxymethylene)-4- oxopiperidine-1 -carboxylate (31c, 2.5 g, 6.22 mmol, 31% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 242.1, ’H-NMR (400 MHz, DMSO-zfc): 87.34 (s, 1H), 4.29 (s, 2H), 3.92 (s, 3H), 3.57 (t, J = 6.00 Hz, 2H), 2.35 (t, J = 6.00 Hz, 2H), 1.60-1.48 (m, 9H).
Step 3: Synthesis of tert-butyl 3-(methoxymethyl)-4-oxopiperidine-l-carboxylate (31d) To a stirred solution of tert-butyl (Z)-3-(methoxymethylene)-4-oxopiperidine-l -carboxylate (31c, 5 g, 20.72 mmol) in methanol (100 mL) at 25 °C under an atmosphere of nitrogen was added Pd/C (10- 50%, 4.4 g, 4.14 mmol) at room temperature and the resulting mixture was stirred under an atmosphere of hydrogen (hydrogen balloon) for 16 h. The reaction mixture was filtered through a pad of celite® and the filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography on Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 10% EtOAc in n-hexane to afford tert-butyl 3-(methoxymethyl)-4- oxopiperidine-1 -carboxylate (31d, 900 mg, 2.52 mmol, 12% yield). LCMS: m/z MM-ES+APCI, Positive [M+H-tBu]+ 188.1, ’H-NMR (400 MHz, DMSO-tfc): 54.01-3.85 (m, 3H), 3.57-3.53 (m, 1H), 3.39-3.32 (m, 2H), 3.25 (s, 3H), 2.75-2.72 (m, 1H), 2.33-2.50 (m, 2H), 1.44-1.15 (m, 9H).
Step 4: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- (methoxymethyl)piperidine-l-carboxylate (31e) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-(methoxy- methyl)piperidine-l -carboxylate (31e) was synthesized according to General procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 1.0 eq., 0.50 mmol) and tert-butyl 3-(methoxymethyl)-4-oxopiperidine-l -carboxylate (31d, 183 mg, 1.5 eq., 0.75 mmol). The crude compound was purified by silica gel flash column chromatography, eluting with 0-50% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- (methoxy-methyl)piperidine-l -carboxylate (31e, 60 mg, 0.07 mmol, 15% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 662.5, ’H-NMR (400 MHz, DMSO-tfc): 59.08 (d, J = 2.40 Hz, 1H), 8.48 (d, J = 2.00 Hz, 1H), 8.05 (d, J = 1.20 Hz, 1H), 8.00-7.96 (m, 2H), 7.88-7.84 (m, 1H), 7.48-7.31 (m, 11H), 6.66 (d, J = 8.00 Hz, 1H), 5.47 (s, 2H), 5.44 (s, 2H), 4.19-4.12 (br s, 1H), 3.86-3.78 (br s, 1H), 3.28-3.23 (m, 2H), 3.13 (t, J = 9.60 Hz, 1H), 3.00 (s, 3H), 2.87-2.67 (m, 1H), 2.28-1.98 (m, 3H), 1.45 (m, 9H).
Step 5: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- (methoxymethyl) piperidine- 1 -carboxylate (31f) tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-(methoxymethyl)-piperidine- 1 -carboxylate (31f) was synthesized according to General procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-(methoxymethyl)piperidine-l- carboxylate (31e, 190 mg, 1.0 eq., 0.29 mmol). The crude compound was purified by silica gel flash column chromatography using Biotage Isolera® (on Neutral alumina) eluting with 0-20% IP A in EtOAc to provide tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- (methoxymethyl)piperidine-l -carboxylate (31f, 80 mg, 0.14 mmol, 47% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 484.4, ’H-NMR (400 MHz, DMSO-&): 5 10.97 (s, 1H), 8.77 (d, J = 2.40 Hz, IH), 8.21 (s, IH), 8.03-7.97 (m, 2H), 7.87-7.85 (m, IH), 5.35 (s, IH), 4.17-4.13 (m, 2H), 3.97-3.78 (m, IH), 3.32-3.10 (m, 2H), 3.03 (s, 3H), 2.84-2.59 (m, 4H), 2.42-2.07 (m, 5H), 1.45 (s, 9H).
Step 6: Synthesis of 3-(6-(4-hydroxy-3-(methoxymethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione, HC1 (31g)
3-(6-(4-Hydroxy-3-(methoxymethyl)piperidin-4-yl)quinolin-3-yl)piperidine -2, 6-dione, HC1 (31g, 52 mg, 0.11 mmol, 98% yield) was synthesized according to General procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-(methoxymethyl)piperidine-l- carboxylate (31f, 75 mg, 1.0 eq., 0.11 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 384.3, *H- NMR (400 MHz, DMSO-ds): 5 11.03 (s, IH), 9.08-8.86 (m, 3H), 8.48 (s, IH), 8.15 (d, 3 = 8.80 Hz, IH),
8.08 (s, IH), 7.87 (d, 3 = 8.80 Hz, IH), 5.58 (s, IH), 4.25-4.21 (m, IH), 3.65-3.20 (m, 6H), 3.17 (s, 3H),
2.89-2.62 (m, 4H), 2.46-2.42 (m, 1H), 2.20-2.16 (m, 1H), 1.79 (d, J = 14.00 Hz, 1H).
Step 7: Synthesis of 3-(6-(4-hydroxy-3-(methoxymethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-35)
3-(6-(4-hydroxy-3-(methoxymethyl)-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-35) was synthesized according to General procedure 1, Step D starting from 3-(6-(4-hydroxy-3-(methoxymethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (31g, 55 mg, 1.0 eq., 0.13 mmol) and 4-(trifluoro-methyl)benzaldehyde (17e, 45 mg, 2.0 eq., 0.26 mmol). The crude compound was purified by preparative-HPLC [(Column: X select C18 (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford a mixture of diastereomers of 3-(6- (4-hydroxy-3-(methoxymethyl)-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (1-35, 22 mg, 0.04 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 542.6, *H- NMR (400 MHz, DMSO-de): 5 11.23 (s, 1H), 11.02 (s, 1H), 8.94 (s, 1H), 8.47 (s, 1H), 8.15 (d, J = 8.80
Hz, IH), 8.08 (s, 1H), 7.96-7.86 (m, 5H), 5.85 (s, 1H), 4.61-4.55 (m, 2H), 4.24-4.21 (m, 1H), 3.52-3.48 (m, IH), 3.37-3.22 (m, 3H), 3.15 (t, 3 = 9.20 Hz, IH), 3.04-2.99 (m, IH), 2.98 (s, 3H), 2.79-2.76 (m, 2H), 2.68-2.61 (m, 2H), 2.47-2.43 (m, IH), 2.19-2.14 (m, IH), 1.86-1.78 (m, IH).
Example 32: Synthesis of 3-(6-(3-fluoro-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-10)
Figure imgf000372_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-fluoro-4- hydroxypiperidine- 1-carboxylate (32b)
To a stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 0.5 g, 1.00 mmol) and tert- butyl 3-fluoro-4-oxopiperidine- 1-carboxylate (32a, 0.328 g, 1.51 mmol) in THE (2 mL) was added /i-buty 11 ithium (1.6M sol. in THF, 0.754 mL, 1.206 mmol) at -78 °C and the resulting mixture was stirred at -78 °C for 1 h. Saturated ammonium chloride was added and the aqueous mixture was extracted with EtOAc (2x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-20% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)quinolin-6-yl)-3-fluoro-4- hydroxypiperidine- 1-carboxylate (32b, 210 mg, 0.30 mmol, 30% yield). LCMS: m/z MM-ES+APCI, Positive | M+H |+ = 636.4, ’H-NMR (400 MHz, DMSO-t/s): 89.09 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.99-
7.94 (m, 3H), 7.49-7.29 (m, 9H), 6.67 (s, 1H), 5.98-5.76 (m, 2H), 5.48-5.44 (m, 4H), 5.05-5.02 (m, 2H),
4.12-3.82 (m, 5H), 1.42 (s, 9H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4- hydroxypiperidine- 1-carboxylate (32c) tert- Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxypiperidine- 1 - carboxylate (32c) was synthesized according to General procedure 1, Step B starting from tert-butyl 4- (3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxypiperidine-l-carboxylate (32b, 210 mg, 1.0 eq., 0.33 mmol). The crude material was purified by reverse phase column chromatography using a Cis cartridge (25 g) and eluting with 50 to 100% MeCN and 0.1% formic acid in water as mobile phase. The pure fractions were collected and lyophilized to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3- yl)quinolin-6-yl)-3-fluoro-4-hydroxypiperidine-l-carboxylate (32c, 0.1 g, 0.22 mmol, 66% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+= 458.4, 'H-NMR (400 MHz, DMSO-Jg): 8 10.98 (s, 1H), 8.78 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.98 (m, 2H), 5.85 (s, 1H), 5.02-4.85 (m, 1H), 4.19-4.14 (m, 2H), 3.84 (s, 1H), 3.21 (m, 1H), 2.77-2.73 (m, 1H), 2.44-2.40 (m, 1H), 2.17-2.13 (m, 1H). 1.82-1.71 (m, 1H), 1.45 (s, 9H), 1.35-1.16 (m, 2H), 0.87-0.84 (m, 1H).
Step 3: Synthesis of 3-(6-(3-fluoro-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (32d)
3-(6-(3-Fluoro-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (32d, 80 mg, 0.2 mmol, 93% yield) was synthesized according to General procedure 1, Step C stalling from tert-butyl 4- (3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxypiperidine-l-carboxylate (32c, 100 mg, 1.0 eq., 0.22 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 358.4, ’H-NMR (400 MHz, DMSO-d6): 5 11.02 (s, 1H), 9.27 (br s, 2H), 8.92 (s, 1H), 8.43 (s, 1H), 8.13 (d, J = 6.40 Hz, 2H), 7.93 (d, J = 8.80 Hz, 1H), 6.35-6.2 (br s, 1H), 5.42-5.24 (m, 1H), 4.24-4.20 (m, 1H), 3.57-3.51 (m, 4H), 3.33-3.18 (m, 3H), 2.82-2.70 (m, 1H), 2.25-2.15 (m, 1H), 2.1-1.95 (m, 1H).
Step 4: Synthesis of 3-(6-(3-fluoro-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-10)
3-(6-(3-fluoro-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (1-10) was synthesized according to General procedure 1, Step D starting from-(6-(3-fluoro-4- hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (32d, 80 mg, 1.0 eq., 0.20 mmol) and 4- (trifluoromethyl) -benzaldehyde (17e, 35 mg, 1.0 eq., 0.20 mmol). The crude product was purified by preparative-HPLC [X Select C18 (250* 19mm), eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 12.0] . The fractions containing pure product were collected and lyophilized to afford 3-(6-(3-fluoro-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-10, 21.90 mg, 0.04 mmol, 20% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 516.5, ’H-NMR (400 MHz, DMSO-t/e): 5 11.62 (s, 1H), 11.01 (s, 1H), 8.91 (s, 1H), 8.42 (s, 1H), 8.13 (d, J = 8.40 Hz, 2H), 7.92-7.89 (m, 5H), 6.38 (s, 1H), 5.55-5.46 (m, 1H), 4.63 (br s, 2H), 4.21 (m, 1H), 3.79-3.48 (m, 2H), 3.32 (m, 3H), 2.83-2.74 (m, 1H), 2.68-2.61 (m, 1H), 2.45- 2.40 (m, 1H), 2.22-2.1 (m, 1H), 2.09-1.95 (m, 1H).
Example 33: Synthesis of 3-(6-(4-hydroxy-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-55) 0 O
Br 33a
N
KHMDS (1 M in THF) THF, 25°C, 16 h
CF3 Step 1 CF3
33c
.0
N.
N
F3CY1 N OH
F3C.
BC _ 33b
I n-BuLi, THF, -78°C, 1 h N
BnO^N 'OBn
BnO' XN 'OBn 25°C, 1 h 33d
INT-13A Step 2
Nx
H2/Pd-C (1 atm) F. F OH ' I F
DMF, rt, 12 h N
O' N ‘0
Step 3
1-55 H
Step 1: Synthesis of 3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (33b)
To a stirred solution of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16b, 6.2 g, 24.1 mmol) in THF (40 mL) was added KHMDS (48.2 mL, 48.2 mmol; IM solution in THF) dropwise at 25 °C and the resulting mixture was stirred at 25 °C for 1 h. 1 -Bromopropane (8.89 g, 72.3 mmol) was then added and stirring was continued at 25 °C for 16 h. Saturated ammonium chloride solution was added and the aqueous mixture was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over anhydrous NajSCh, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0-5% EtOAc in n-hexane to afford as 3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (33b, 1.5 g, 4.72 mmol, 20% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 300.0, ’H-NMR (400 MHz, CDC13): 7.62 (d, J = 8.00 Hz, 2H), 7.51 (d, J = 8.00 Hz, 2H), 3.72 (d, J = 13.60 Hz, 1H), 3.63 (d, J = 13.60 Hz, 1H), 3.03-3.00 (m, 2H), 2.57-2.50 (m, 3H), 2.45-2.40 (m, 1H), 2.29 (t, J = 9.60 Hz, 1H), 1.84-1.79 (m, 1H), 1.32-1.23 (m, 3H), 0.91 (t, J = 7.20 Hz, 3H), and 3,3-dipropyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-one (33c, 1.0 g, 2.84 mmol, 12% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 342.7, ’H-NMR (400 MHz, DMSO-A): 57.62 (d, J = 8.00 Hz, 2H), 7.52 (d, J = 8.00 Hz, 2H), 3.62 (s, 2H), 2.71 (t, J = 6.40 Hz, 2H), 2.49 (s, 2H), 1.83-1.78 (m, 2H), 1.49-1.41 (m, 2H), 1.49- 1.41 (m, 2H), 1.39-1.05 (m, 4H), 0.90 (t, J = 2.40 Hz, 6H).
Step 2: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-propyl-l-(4-
( trifluoromethyl) benzyl) piperidin-4-ol (33d) 4-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-propyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-ol (33d) was synthesized according to General Procedure 2, Step A starting from 3- propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (33b, 226mg, 1.5 eq., 0.75 mmol) and 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 250 mg, 1.0 eq., 0.5 mmol). The crude compound was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-50% EtOAc in hexanes to afford 4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)quinolin-6-yl)-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (33d, 100 mg, 0.139 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 718.6, ’H-NMR (400 MHz, DMSO-cL): 9.06 (s, 1H), 8.46 (s, 1H), 8.03 (s, 1H), 7.96 (d, J = 6.40 Hz, 2H), 7.72 (d, J = 8.00 Hz, 2H), 7.62 (d, J = 8.40 Hz, 2H), 7.48-7.28 (m, 11H), 6.66 (d, J = 8.00 Hz, 1H), 5.45 (m, 4H), 4.92 (s, 1H), 3.74-3.57 (m, 2H), 2.81 (m, 1H), 2.78 (m, 1H), 2.51 (m, 1H), 2.34-2.16 (m, 1H), 2.13-1.62 (m, 3H), 1.12-0.92 (m, 4H), 0.58 (t, J = 7.20 Hz, 3H).
Step 3: Synthesis of 3-(6-(4-hydroxy-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl) piperidine-2, 6-dione (1-55)
3-(6-(4-Hydroxy-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)-piperidine- 2, 6-dione (1-55) was synthesized according to General Procedure 2, Step B starting from 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-propyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-ol (33d, 150 mg, 1.0 eq., 0.21 mmol). The crude material was purified by prep-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.1% Acetic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(4- hydroxy-3-propyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-55, 24.7 mg, 0.045 mmol, 22% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 540.4, ’H-NMR (400 MHz, DMSO-de): 10.97 (s, 1H), 8.75 (2, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.99-7.95 (m, 1H), 7.86-7.83 (m, 1H), 7.72 (m, 2H), 7.62 (d, J = 8.00 Hz, 2H), 4.90 (d, J = 1.60 Hz, 1H), 4.14 (m, 1H), 3.72 (d, J = 13.60 Hz, 1H), 3.62 (d, J = 13.60 Hz, 1H), 2.81-2.78 (m, 2H), 2.68-2.60 (m, 3H), 2.51 (m, 2H), 52.34-2.16 (m, 1H), 2.13-1.62 (m, 3H), 1.12-0.92 (m, 4H), 0.58 (t, J = 7.20 Hz, 3H).
Example 34: Synthesis of the acetic acid salt of 3-(6-(4-hydroxy-3,3-dipropyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-11)
Figure imgf000376_0001
Step 1: 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-dipropyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-ol (34a)
4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-dipropyl-l-(4-(trifluoromethyl)benzyl)- piperidin-4-ol (34a) was synthesized according to General Procedure 2, Step A stalling from 3,3- dipropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (33c, 412 mg, 1.2 eq., 1.21 mmol) and 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 500 mg, 1.0 eq., 1.0 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-50% EtOAc in hexanes to afford 4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)quinolin-6-yl)-3,3-dipropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (34a, 0.23 g, 0.30 mmol, 30% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 760.5, 'H-NMR (400 MHz, DMSO-rfc): 5 9.05 (d, J = 2.00 Hz, 1H), 8.48 (d, J = 2.00 Hz, 1H), 8.04 (s, 1H), 7.98-7.90 (m, 3H), 7.71 (d, J = 8.00 Hz, 2H), 7.60 (t, J = 8.00 Hz, 2H), 7.49-7.38 (m, 10H), 6.66 (d, J = 8.00 Hz, 1H), 5.47 (s, 2H), 5.44 (s, 2H), 3.59- 3.54 (m, 2H), 2.91-2.67 (m, 2H), 2.50-2.33 (m, 2H), 2.24-1.91 (m, 2H), 1.51-1.15 (m, 4H), 1.09-0.95 (m, 4H), 0.75-0.63 (m, 6H).
Step 2: Synthesis of the acetic acid salt of 3-(6-(4-hydroxy-3,3-dipropyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-11)
The acetic acid salt of 3-(6-(4-hydroxy-3,3-dipropyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-11) was synthesized according to General Procedure 2, Step B starting from 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3,3-dipropyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-ol (34a, 220 mg, 1.0 eq., 0.29 mmol). The crude was purified by prep-HPLC [Method info: column: X select (150 x 19 mm) 5 pm, mobile phase A: 0.05% ammonium acetate in H2O, mobile phase B: MeCN, Flow rate: 15 mL/min] and the pure fraction containing product was lyophilized to afford the acetic acid salt of 3-(6-(4-hydroxy-3,3-dipropyl-l-(4-(trifluoromethyl)benzyl) piperidin-4- yl)quinolin-3-yl)-piperidine-2, 6-dione (1-11, 11.2 mg, 0.02 mmol, 7% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 582.39; ’H-NMR (400 MHz, DMSO-rfc): 10.96 (s, 1H), 8.75 (d, J = 2.40 Hz, 1H), 8.21 (d, J = 1.60 Hz, 1H), 8.01-7.90 (m, 3H), 7.71 (d, J = 8.00 Hz, 2H), 7.58 (d, J = 8.00 Hz, 2H), 4.87 (s, 1H), 4.16-4.11 (m, 1H), 3.6-35 (m, 2H), 2.81 (m,lH), 2.75-2.7 (m, 1H), 2.68-2.6 (m, 2H), 2.5-2.45
(m, 2H), 2.4-2.3 (m, 1H), 2.2-2.1(m, 1H), 2.0-1.95 (m, 1H), 1.96 (s, 3H), 1.5-1.45 (m, 1H), 1.4-1.3 (m,
1H), 1.35-1.1 (m, 1H), 1.05-0.91 (m, 3H), 0.65-0.2 (m, 9H).
Example 35: Synthesis of 3-(2-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-95)
Figure imgf000377_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (35c)
To a microwave vial equipped with a stir bar was added 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6- bromo-2-chloroquinoline (35a, 338 mg, 0.64 mmol, 1 eq.), PdCh(dppf)eDCM (77.9 mg, 0.15 eq., 0.95 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 236 mg, 1.2 eq., 0.76 mmol), and 1,4-dioxane (2.54 mL, 0.25M) followed by a solution of 2M potassium carbonate (508 pL, 1.6 eq., 1.02 mmol). The resulting solution was degassed with argon before the vial was sealed and subjected to microwave irradiation for 1 h. At this point LCMS shows conversion to desired product. The solution was diluted with EtOAc and filtered through celite®. The celite® pad was washed with excess EtOAc and the filtrate was concentrated in vacuo. The crude material was via silica gel chromatography on a 40 g silica gel column eluting with 0 to 100% EtOAc in heptane. The desired fractions were combined and concentrated in vacuo to yield tert-butyl 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-2-chloroquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35c, 175 mg, 276 pmol, 43% yield). LCMS: m/z HESI, positive [M+H]+ = 634.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloroquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (35d)
To a vial equipped with a stir bar was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2- chloroquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35c, 180 mg, 1 eq., 0.28 mmol), dichloromethane (1.58 mL, 0.18M), propan-2-ol (1.58 mL, 0.18M) and A,A-dimethylformamide (526 pL, 0.54M). The resulting solution was sparged with oxygen for 5 minutes at 0 °C before phenylsilane (105 pL, 3 eq., 0.85 mmol) and Mn(dpm)s (85.8 mg, 0.14 mmol, 0.5 eq.) were added. After 24 h, the desired product was observed by LCMS and the reaction mixture was concentrated in vacuo. The crude residue was dissolved in 3 mL of DMSO and filtered to remove insoluble material before being purified on a 40 g C18 column eluting with water and 0%-100% MeCN. The desired fractions were combined and concentrated in vacuo to yield tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloroquinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (35d, 51 mg, 0.078 mmol, 28% yield). LCMS: m/z HESI, positive [M+H]+ = 652.
Step 3: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloroquinolin-6-yl)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (35e)
To a vial equipped with a stir bar was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2- chloroquinolin-6-yl)-4-hydroxypiperidine-l -carboxylate (35d, 95 mg, 1 eq., 0.15 mmol) and DCM (2.4 mL, 0.06 M), followed by methanesulfonic acid (38 pL, 4 eq., 0.58 mmol) and the resulting mixture was stirred for 30 min. Upon complete consumption of starting material, as confirmed by LCMS, triethylamine (80.8 pL, 4 eq., 0.58 mmol) was added and the aqueous mixture was concentrated under reduced pressure (quantitative yield assumed). The erode residue was then suspended in ethanol (580 pL, 0.25M) and acetic acid (8.30 pL, 1 eq., 0.15 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 23.7 pL, 1.2 eq., 0.17 mmol) was added. The resulting mixture was heated at 45 °C for 1 h before sodium cyanoborohydride (18.2 mg, 2 eq., 0.290 pmol) was added in one portion. The reaction was monitored by LCMS. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was cooled to ambient temperature and loaded directly onto a C18 column for purification eluting with MeCN (+0.1% formic acid) and H2O (+0.1% formic acid). The desired fractions were collected, combined, and concentrated via lyophilization to yield 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2- chloroquinolin-6-yl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (35e, 57.8 mg, 0.084 mmol, 56% yield). LCMS: m/z HESI, positive [M+H]+ = 710.
Step 4: Synthesis of 3-(2-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-95)
To a reaction vial equipped with a stir bar was added 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-2- chloroquinolin-6-yl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-ol (35e, (50.0 mg, 1 eq., 0.071 pmol) and 4:1 DMF:EtOH (1.75 mL, 0.04M). and the resulting mixture was sparged thoroughly with argon. Dihydroxypalladium (20% wt, 0.2 eq.) was then added and a balloon of hydrogen was placed on the vial. The reaction solution was sparged with hydrogen continuously for 2 h. Upon complete debenzylation, as confirmed by LCMS, the reaction mixture was filtered through a pad of celite® and the filtrate was concentrated in vacuo. The crude material was then dissolved in 4:1 DMF:EtOH (0.94 mL, 0.04M) and the resulting mixture was sparged thoroughly with argon. Platinum(IV) Oxide (0.2 eq.) was added and a balloon of hydrogen was placed on the vial. The reaction solution was sparged with hydrogen continuously. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was filtered through a pad of celite®, the filter cake was washed with EtOAc, and the filtrate was concentrated in vacuo. The crude material was purified on a C 18 column eluting with water 0.1% formic acid and 0 to 50% MeCN with 0.1% formic acid The desired fractions were collected, combined, and IM
HC1 was added and concentrated via lyophilization to yield 3-(2-chloro-6-(4-hydroxy-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-95, 1.7 mg, 0.003 mmol, 5% yield) was isolated as an amorphous solid. LCMS: m/z HESI, positive [M+H]+ = 532.
Example 36: Synthesis of 3-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-74)
Figure imgf000379_0001
Step 1: Synthesis of 6-bromo-3-iodoquinolin-4-ol (36c)
To a stirred solution of 6-bromoquinolin-4-ol (36a, 5 g, 22.32 mmol) in acetic acid (120 mL) was added 1 -iodopyrrolidine-2, 5-dione (36b, 5.02 g, 22.32 mmol) at room temperature and the resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was then concentrated under reduced. The crude product was purified by silica gel flash column chromatography using a Biotage Isolera® on a silica gel (100-200 mesh) cartridge (40 g) eluting with EtOAc in n-hexane (70%). The pure product containing fractions were collected and concentrated under reduced pressure to afford 6 bromo 3 iodoquinolin-4-ol (36c, 6.5 g, 16.72 mmol, 75% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 349.8, 351.7. 'H-NMR (400 MHz, DMSO-t/s): 5 12.36 (s, 1H), 8.56 (s, 1H), 8.19 (d. 7 = 2.40 Hz, 1H), 7.84 (dd, J = 2.40, 8.80 Hz, 1H), 7.57 (d, J = 8.80 Hz, 1H).
Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (36d)
A solution of 6-bromo-3-iodoquinolin-4-ol (36c, 10 g, 28.6 mmol) in POCh (4.38 g, 28.6 mmol) was stirred at 100 °C for 11 h. The reaction mixture was then cooled to room temperature and slowly poured into ice-cooled water. A solid precipitated which was filtered and washed with ice-cold water (2 x 10 mL) followed by hexane (2 x 10 mL) to afford 6-bromo-4-chloro-3-iodoquinoline (36d, 9 g, 23.45 mmol, 82% yield). The product was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, [M+H, M+2+H]+ 369.6, 371.6. 'H-NMR (400 MHz, DMSO-rfc): 5 9.21 (s, 1H), 8.38 (s, 1H), 8.02 (d, 7 = 1.20 Hz, 2H).
Step 3: Synthesis of ethyl 2-(6-bromo-4-chloroquinolin-3-yl)acetate (36f)
To the stirred solution of triethylamine (2.75 g, 27.10 mmol) in MeCN (30 mL) was added formic acid (0.75 g, 16.29 mmol) followed by ethyl 2-diazoacetate (36e, 3.10 g, 27.1 mmol) at room temperature and the resulting mixture was degassed with nitrogen for 10 min. To this solution was added 6-bromo-4- chloro-3-iodoquinoline (36d, 4 g, 10.86 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.381 g, 0.54 mmol) at room temperature and the reaction mixture was degassed again with nitrogen for 10 min. The resulting mixture was stirred at 70 °C for 12 h and then was concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography using a Biotage Isolera® on a silica gel (100-200 mesh) cartridge (80 g) eluting with EtOAc in n-hexane (70%). The pure product containing fractions were collected and concentrated under reduced pressure to afford ethyl 2-(6- bromo-4-chloroquinolin-3-yl)acetate (36f, 1.2 g, 2.48 mmol, 23% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 327.9, 329.9, 'H-NMR (400 MHz, DMSO-de): 5 8.80 (s, 1H), 8.44 (d, 7 = 2.00 Hz, IH), 8.00 (d, 7 = 8.80 Hz, 1H), 7.86-7.83 (m, 1H), 4.26-4.09 (m, 2H), 4.01 (s, 2H), 1.33-1.27 (m, 3H).
Step 4: 3-(6-bromo-4-chloroquinolin-3-yl)piperidine-2, 6-dione (36g)
To the stirred solution of sodium hydride (60% in mineral oil) (91 mg, 2.28 mmol) in THE (10 mL) was added ethyl 2-(6-bromo-4-chloroquinolin-3-yl)acetate (36f, 500 mg, 1.52 mmol) and acrylamide (2e, 108 mg, 1.52 mmol) at -20 °C and the resulting mixture was stirred at -20 °C for 5 h. IN HC1 aqueous solution was added to quench the reaction and the resulting aqueous mixture was extracted with EtOAc (2 xlO mL). The combined organic phases were dried over anhydrous NaiSOr. filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Combi-Flash silica gel (100-200 mesh size) eluting with 70-80% of EtOAc in hexane to afford 3- (6-bromo-4-chloroquinolin-3-yl)piperidine-2, 6-dione (36g, 380 mg, 1.06 mmol, 70% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 352.9, 354.9. ’H-NMR (400 MHz, DMSO-^): 5 11.06 (s, 1H),
8.91 (s, 1H), 8.40 (d, J = 2.00 Hz, 1H), 8.07-8.01 (m, 2H), 4.57 (dd, J = 5.20, 13.00 Hz, 1H), 2.93-2.84
(m, 1H), 2.68-2.57 (m, 1H), 2.51-2.50 (m, 1H), 2.11-2.08 (m, 1H).
Step 5: Synthesis of tert-butyl 4-(4-chloro-3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (36h) tert-Butyl 4-(4-chloro-3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (36h) was synthesized according to General procedure 4 starting from 3-(6-bromo-4- chloroquinolin-3-yl)piperidine-2, 6-dione (36g, 190 mg, 1.0 eq., 0.54 mmol) and tert-butyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 166 mg, 1.0 eq., 0.54 mmol). The crude compound was purified by flash column chromatography using Combi-Flash silica gel (100-200 mesh size) eluting with 70-80% of EtOAc in hexane to afford tert-butyl 4-(4-chloro-3-(2,6- dioxopiperidin-3-yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (36h, 350 mg, 0.44 mmol, 83% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 456.2. ’H-NMR (400 MHz, DMSO-tfc): 5 11.06 (s, 1H), 8.80 (s, 1H), 8.13-8.03 (m, 3H), 6.52-6.49 (m, 1H), 4.57-4.52 (m, 1H), 4.09 (s, 2H), 3.63-
3.60 (m, 2H), 2.93-2.83 (m, 1H), 2.68-2.60 (m, 3H), 2.51-2.50 (m, 1H), 2.10-2.07 (m, 1H), 1.45 (s, 9H).
Step 6: Synthesis of 3-(4-chloro-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2,6-dione (36i)
To a stirred solution of tert-butyl 4-(4-chloro-3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (36h, 350 mg, 0.77 mmol) in DCM (10 mL) was added 4M HC1 in 1,4-dioxane (4 mL, 0.77 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was then concentrated under reduced pressure at room temperature and the crude material was washed with n-hexane and dried to afford 3-(4-chloro-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (36i, 150 mg, 0.39 mmol, 50% yield). The product was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 356.1, ’H-NMR (400 MHz, DM SO- A): 5 11.07 (s, 1H), 9.20 (hr s, 2H), 8.85 (s, 1H), 8.13-8.04 (m, 3H), 6.53 (s, 1H), 4.57 (dd, J = 4.80, 12.80 Hz, 1H), 3.85 (s, 2H), 3.39 (s, 2H), 2.92-2.87 (m, 3H), 2.68-2.60 (m, 2H), 2.11-2.08 (m, 1H). Step 7: Synthesis of 3-(4-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (36j)
To a stirred solution of 3-(4-chloro-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (36i, 120 mg, 0.34 mmol) in DMF (2 mL) was added 4-(trifluoromethyl)benzaldehyde (17e, 0.073 mL, 0.51 mmol) at 25 °C and the resulting mixture was stirred for 1 h at 25 °C. Sodium triacetoxyborohydride (179 mg, 0.84 mmol) was then added at 25 °C and stirring was continued at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure at room temperature. The crude compound was purified by flash column chromatography using Combi-Flash (neutral Alumina) eluting with 4-7% of IPA/DCM to afford 3-(4-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (36j, 120 mg, 0.22 mmol, 65% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 514.1, ’H-NMR (400 MHz, DMSO-c/e): 8 11.06 (s, IH), 8.79 (s, IH), 8.08- 7.96 (m, 3H), 7.72 (d, 7 = 8.00 Hz, 2H), 7.62 (d, 7 = 8.00 Hz, 2H), 6.52 (d, 7= 12.00 Hz, IH), 4.54 (dd, J = 5.20, 12.80 Hz, IH), 3.74 (s, 2H), 3.20-3.19 (m, 2H), 2.90-2.88 (m, 2H), 2.77-2.74 (m, 2H), 2.68-2.50
(m, 3H), 2.10-2.09 (m, 1H).
Step 8: Synthesis of 3-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-74)
3-(4-Chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione (1-74) was synthesized according to General Procedure 3, Step C starting from 3-(4-chloro-6- (l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2,6-dione (36j, 110 mg, 1.0 eq., 0.21 mmol). The crude compound was purified by preparative-HPLC [(Column: ZORBAX (150*21) 2.5 pm, eluting with Mobile phase A: 0.1% NtUOAc in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3- (4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (I- 74, 31 mg, 0.06 mmol). To a solution of 3-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)- piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (30 mg) in water (0.4 mL) and ACN (0.4 mL) was added 0.5 N aq. HC1 (1 mL) solution and this resulting mixture was lyophilized to afford the ide salt of 3- (4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (1-74, 31 mg, 0.053 mmol, 25% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 532.4. >H- NMR (400 MHz, DMSO-de): 8 11.05 (s, 1H), 10.27 (s, 1H), 8.85 (d, 7 = 9.60 Hz, 1H), 8.33 (d, J = 1.60 Hz, IH), 8.13 (d, 7 = 8.80 Hz, 1H), 7.95-7.88 (m, 5H), 5.89 (s, 1H), 4.56-4.53 (m, 3H), 3.40-3.35 (m, 4H), 2.91-2.84 (m, IH), 2.61-2.46 (m, 4H), 2.12-2.07 (m, IH), 1.93-1.76 (m, 2H).
Example 37: Synthesis of l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-18)
Figure imgf000383_0001
Step 5
Step 1: Synthesis of l-(6-(trimethylstannyl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (37b)
A solution of l-(6-bromoquinolin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione, HCI (INT-1, 500 mg, 1.40 mmol) and hexamethyl ditin (37a, 92 mg, 0.28 mmol) in 1,4-dioxane (5 mL) was sparged with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (162 mg, 0.14 mmol) was then added in one portion, and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, water (40 mL) was added and the resulting aqueous mixture was extracted with EtOAc (40 mL x 2). The combined organic phases were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude product was triturated with MTBE (10 mL x 2) and the resulting solid was filtered and dried under reduced pressure to afford l-(6-(trimethylstannyl) quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (37b, 500 mg, 0.84 mmol, 60% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 405.9. ’H-NMR (400 MHz, DMSO-cfc): 5 10.58 (s, 1H), 8.92 (d, J = 2.40
Hz, IH), 8.22 (d, J = 2.00 Hz, 1H), 8.09 (s, 1H), 7.97 (d, J = 8.40 Hz, 1H), 7.86-7.82 (m, 1H), 3.97 (t, J
= 6.40 Hz, 2H), 2.80 (t, J = 6.40 Hz, 2H), 0.36 (s, 9H).
Step 2: Synthesis of tert-butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl) quinolin-6-yl)-2- azaspiro [5.5]undec-4-ene-2-carboxylate (37d)
To the stirred solution of l-(6-(trimethylstannyl) quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (37b, 500 mg, 1.24 mmol) and tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[5.5]undec- 4-ene-2-carboxylate (37c, 494 mg, 1.24 mmol) in 1,4-dioxane (10 mL) in a vial under an atmosphere of nitrogen was added copper(I) iodide (47.1 mg, 0.25 mmol) at room temperature. The resulting mixture was sparged with nitrogen for 10 min, tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.25 mmol) was then added and stirring was continued at 65 °C for 5 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite®, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 50-100% EtOAc in hexanes to afford terf-butyl 5-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl) quinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (37d, 300 mg, 0.33 mmol, 27% yield). LCMS: m/z MM-ES+APCI, Negative [M-H]" 489.5, ’H-NMR (400 MHz, DMSO-t/s): 5 10.59 (s, 1H), 8.91 (d, J = 2.40 Hz, 1H), 8.25 (d, J = 2.00 Hz, 1H), 7.95 (d, J = 8.40 Hz,
1H), 7.70 (s, 1H), 7.41 (s, 1H), 5.58-5.53 (m, 1H), 4.06-3.94 (m, 4H), 3.61-3.57 (m, 2H), 2.80 (t, J = 6.40 Hz, 2H), 1.60-1.31 (m, 19H).
Step 3: l-(6-(2-azaspiro [5.5] undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
(37e)
(l-(6-(2- Azaspiro [5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (37e, 220 mg, 0.29 mmol, 47% yield) was synthesized according to General Procedure 6, Step A starting from tert-butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl) quinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (37d, 300 mg, 1.0 eq., 0.61 mmol). The product was taken onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 391.5; ’H-NMR (400 MHz, DMSO+L): 5 10.64 (s, 1H), 9.29 (s, 1H), 9.02 (d, J = 2.40 Hz, 1H), 8.42 (s, 1H), 8.06 (d, J = 8.80 Hz, 1H), 7.84-7.73 (m, 2H), 7.54 (d, J = 8.80 Hz, 1H), 5.58 (t, J = 3.20 Hz 1H), 4.02-3.95 (m, 2H), 3.69 (s, 1H), 3.57 (s, 2H), 3.38 (s, 1H), 2.81 (t, J = 6.40 Hz, 2H), 1.83-1.36 (s, 10H).
Step 4: l-(6-(2-(4-(trifluoromethyl) benzyl)-2-azaspiro [5.5]undec-4-en-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (37f) l-(6-(2-(4-(Trifluoromethyl) benzyl)-2-azaspiro [5.5]undec-4-en-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (37ff) was synthesized according to General Procedure 6, Step B starting from (l-(6-(2-azaspiro [5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione, HC1 (37e, 200 mg, 1.0 eq., 0.51 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 107 mg, 1.2 eq., 0.62 mmol). The crude compound was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 50-70% EtOAc in n-hexane as an eluent to afford 1- (6-(2-(4-(trifluoromethyl) benzyl)-2-azaspiro [5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (37f, 120 mg, 0.12 mmol, 24% yield). LCMS: m/z MM-ES+APCI, Positive | M+H|+ = 549.6; ’H-NMR (400 MHz, DMSO-de): 5 10.58 (s, 1H), 8.90 (s, 1H), 8.26-8.24 (m, 1H), 8.02-7.93 (m, 1H), 7.77-7.48 (m, 6H), 5.52 (t, J = 3.20 Hz, 1H), 4.00-3.94 (m, 2H), 3.74 (s, 2H), 3.11 (d, J = 2.80 Hz, 2H), 2.80 (t, J = 6.40 Hz, 2H), 2.59 (s, 2H), 1.74 (d, J = 12.00 Hz, 2H), 1.56-1.32 (m, 5H), 1.16-1.05 (m, 2H), 0.91-0.79 (m, 1H).
Step 5: Synthesis of l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-18) The acetic acid salt of l-(6-(5-hydroxy-2-(4-(trifluoromethyl) benzyl)-2-azaspiro[5.5]-undecan-5- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-18) was synthesized according to General Procedure 3, Step C starting from l-(6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (37f, 120 mg, 1.0 eq., 0.22 mmol). The crude material was purified by preparative-HPLC [(Column: X select (C18 150mm *19) 5 pm, eluting with Mobile phase A: 0.05% acetic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min for 30 minutes)]. The pure product containing fractions were collected and lyophilized to afford the acetic acid salt of l-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro [5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-18, 5.5 mg, 9.68 pmol, 6% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 567.3; 'H-NMR (400 MHz, DMSO-rfc): 5 10.51 (s, 1H), 8.89 (d, J = 2.40 Hz, IH), 8.27 (d, J = 2.40 Hz, 1H), 8.00-7.88 (m, 3H), 7.72 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 4.83 (s, IH), 3.97 (t, J = 6.40 Hz, 2H), 3.67 (d, J = 14.00 Hz, IH), 3.59 (d, J = 14.00 Hz, IH), 2.88- 2.80 (m, 5H), 2.78-2.62 (m, IH), 2.51-2.50 (m, IH), 2.34-2.29 (m, IH), 1.74 (t, J = 12.00 Hz, IH), 1.51 (t, J = 12.00 Hz, IH), 1.26-1.33 (m, 3H), 1.05-1.24 (m, 2H), 1.02-0.90 (m, IH), 0.89-0.68 (m, 2H).
Step 6: Synthesis of tert-butyl 5-oxo-2-azaspiro[5.5]undecane-2-carboxylate (37g)
To a stirred solution of tert-butyl 4-oxopiperidine-l -carboxylate (18a, 20 g, 100 mmol) in Toluene (200 mL) was added potassium tert-butoxide (22.53 g, 201 mmol) at 25 °C under nitrogen atmosphere and stirred for 1 h. To this resulting mixture was added 1,5-dibromopentane (34.5 g, 151 mmol) at 25 °C, and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled, quenched with ice-cold water, and extracted with (3 x 200 mL). The combined organic layer was dried over anhydrous Na2SC>4 filtered, and evaporated under reduced pressure to get a crude compound. The crude residue was purified by silica gel flash column chromatography, eluting with 0-4% EtOAc in hexanes to afford tert-butyl 5-oxo-2-azaspiro[5.5]undecane-2-carboxylate (11.1 g, 37.4 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H-56]+ 212.1, ’H-NMR (400 MHz, CDCh): 6 3.72 (s, 3H), 3.55 (s, 3H), 2.49 (t, J= 6.4 Hz, 2H), 1.78-1.71 (m, 2H), 1.59-1.42 (s, 17H).
Step 7: Synthesis of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[5.5]undec-4-ene-2- carboxylate (37c)
To a stirred solution of tert-butyl 5-oxo-2-azaspiro[5.5]undecane-2-carboxylate (10 g, 37.4 mmol) in THE (50 mL) was added NaHMDS (1.0 M in THE) (44.9 ml, 44.9 mmol) dropwise at -78 °C and the reaction mixture was stirred at the same temperature for 30 minutes. To this resulting solution was added N-(5-Chloropyridin-2-yl)-N-(methanesulfonyl)-methanesulfonamide (21.99 g, 56.1 mmol) dissolved in THE (40 mL) dropwise at -78 °C and the reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (350 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to dryness to obtain the crude. This crude material was purified by silica gel flash column chromatography, eluting with 0-12% EtOAc in hexanes to afford tert-butyl 5-(((trifhioromethyl)sulfonyl)oxy)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (9 g, 22.53 mmol, 60% yield). LCMS: m/z MM-ES+APCI, Negative [M-H]" 398.1, ’H-NMR (400 MHz, DMSO-d6): 55.89-5.85 (m, 1H), 4.05-4.01 (m, 2H), 3.57 (s, 2H), 1.69-1.58 (m, 3H), 1.52-1.42 (m, 15H), 1.12-1.09 (m, 1H).
Example 38: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-19)
Figure imgf000386_0001
Step 1: Synthesis of l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (38a)
To a stirred solution of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16b, 1 g, 3.89 mmol) in THF (20 ml) was added NaHMDS (1 M in THF) (7.77 ml, 7.77 mmol) at -78 °C under an atmosphere of nitrogen and the resulting mixture was stirred for 1 h. l,l,l-Trifhioro-N-(pyridin-2-yl)-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (2.089 g, 5.83 mmol) dissolved in THF (5 mL) was then added dropwise at -78 °C and stirring was continued at room temperature for 3 h. Saturated ammonium chloride solution was added and the resulting aqueous mixture was extracted with EtOAc (100 mL x 2). The combined organic phases were dried over anhydrous NaiSOr, filtered, and concentrated under reduced pressure. This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (38a, 0.9 g, 2.31 mmol, 60% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 389.9; ’H-NMR (400 MHz, DMSO-rfc): 5 7.72 (d, J = 8.00 Hz, 2H), 7.55 (d, J = 8.00 Hz, 2H), 5.96 (t, J = 3.00 Hz, 1H), 3.76 (s, 2H), 3.14 (t, J =
3.00 Hz, 2H), 2.74 (t, J = 5.60 Hz, 2H), 2.44 (t, J = 5.60 Hz, 2H).
Step 2: Synthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4-(trifluoromethyl)-benzyl)- 1 ,2,3,6-tetrahydropyridine
A solution of l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate, (38a 0 2 g 051 mmol) bis(pinacolato)diboron (0 196 g 077 mmol) and potassium acetate (0.151 g, 1.54 mmol) in 1, 4-dioxane (10 mL) was degassed with nitrogen at 25 °C for 10 min. Pd(dppf)CheDCM (0.021 g, 0.03 mmol) was then added in one portion, and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridine (38b, 0.1 g, 0.20 mmol, 39% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 368.0; ’H-NMR (400 MHz, DMSO-tfc): 57.68 (d, J = 8.00 Hz, 2H), 7.54 (d, J = 8.00 Hz, 2H), 6.38 (br s, 1H), 3.62 (s, 2H), 2.98-2.94 (m, 2H), 2.49-2.45 (m, 2H), 2.14-2.10 (m, 2H), 1.17 (s, 12H).
Step 3: Synthesis l-(6-(l-(4-(trifluoromethyl)benzyl)- 1,2,3, 6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (38c) l-(6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (38c) was synthesized according to General Procedure 4 starting from l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-1, 400 mg, 1.0 eq., 1.25 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4-(trifluoromethyl)-benzyl)-l,2,3,6- tetrahydropyridine (38b, 551 mg, 1.2 eq., 1.5 mmol). The crude compound was purified by reverse phase column chromatography eluting with 0-100% MeCN in 0.1% FA in water. The product containing fractions were collected and lyophilized to afford of l-(6-(l-(4-(trifhioromethyl)benzyl)-l, 2,3,6- tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (38c, 0.12 g, 0.22 mmol, 18% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 481.7; ’H-NMR (400 MHz. DMSO-rfc): 5 10.59 (s, 1H), 8.88 (d, J = 2.40 Hz, 1H), 8.21 (t, J = 2.40 Hz, 1H), 7.96-7.92 (m, 3H), 7.72 (d, J = 8.00 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 6.43 (s, 1H), 3.97 (t, J = 13.20 Hz, 2H), 3.74 (s, 2H), 3.18 (s, 2H), 2.80 (t, J = 13.20 Hz, 2H), 2.73 (d, J = 4.80 Hz, 2H), 2.66-2.62 (m, 2H).
Step 4: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-19) l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (1-19) was synthesized according to General Procedure 3, Step C starting from l-(6- (l-(4-(trifhioromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (38c, 200mg, 1.0 eq., 0.42 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-10% IP A in DCM followed by preparative-HPLC [(Column: X-SELECT CSH C18 (150 mm, 19 mm, 5pm), eluting with Mobile phase A: 0.05 N HC1 in water, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 9.65 min)]. The product containing fractions were collected and lyophilized to afford l-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-19, 29 mg, 0.05 mmol, 15% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 499.1, ’H-NMR (400 MHz, DMSO-t/s): 5 11.07 (s, 1H), 10.60 (s, 1H), 8.98 (d, J = 2.00 Hz, 1H), 8.37 (s, IH), 8.10-8.05 (m, 2H),
7.96-7.86 (m, 5H), 5.74 (br s, IH), 4.53 (d, J = 4.80 Hz, 2H), 3.94 (t, J = 6.40 Hz, 2H), 3.41-3.37 (m,
4H), 2.80 (t, J = 6.40 Hz, 2H), 2.51-2.29 (m, 2H), 1.91 (d, J = 13.60 Hz, 2H).
Example 39: Synthesis of l-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-76)
.0 OyN^O Mn(dpm)3,
BocN F
BocN^ 35b Phenylsilane
NH
Pd(tBu3P)2, DIPEA DCM:IPA:DMF 1 ,4-dioxane water (9:1 ), I NT O2, 0 °C-rt, 16 h 80 °C, 4 h. 39a Step 2 Step 1
O
F.
HCI (4M in 1,4 dioxane)
II 17e F.
1 ,4-dioxane, 0 °C, 7 h. NaBH(OAc)3, DMF I
Step 3 0 °C to rt, 3 h Step 4
Step 1: te/7-bulvl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (39a) tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (39a) was synthesized according to General Procedure 5 starting from l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5 300 mg, 1.0 eq., 1.02 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (35b, 316 mg, 1.0 eq., 1.02 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 78% EtOAc in n- hexane to afford tert-butyl 4-(3-(2,4-dioxotetrahydro-pyrimidin-l(2H)-yl)-5-fhioroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (39a, 250 mg, 0.53 mmol, 52% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 441.1; 'H-NMR (400 MHz, DMSO-tfc): 5 10.63 (s, 1H), 8.98 (s, 1H), 8.31 (s, 1H),
7.87-7.85 (m, IH), 7.76-7.71 (m, IH), 6.18 (s, IH), 4.10-3.99 (m, 4H), 3.59 (t, J = 5.20 Hz, 2H), 2.81 (t, J
= 6.60 Hz, 2H), 2.57-2.50 (m, 2H), 1.45 (s, 9H).
Step 2: tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (39b) tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (39b) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-5-fhioroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (39a, 220 mg, 1.0 eq., 0.5 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 100% EtOAc in n-hexane to afford tert-butyl 4-(3-(2,4-dioxo-tetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxypiperidine-l -carboxylate (39b, 40 mg, 0.07 mmol, 14% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 459.5.
Step 3: l-(5-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
(39c) l-(5-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (39c, 20 mg, 0.031 mmol, 36% yield) was synthesized according to General Procedure 6, Step A starting from tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (39b, 40 mg, 1.0 eq., 0.09 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 359.2; 'H-NMR (400 MHz, DMSO-tfc): 5 10.65 (s, 1H), 8.99 (d, J = 6.00 Hz, 1H), 8.34 (s, 1H), 8.05-8.01 (m, 1H), 7.95 (d, J = 9.20 Hz, 2H), 4.05-4.01 (m, 4H), 3.39 (m, 3H), 2.82 (t, J = 6.40 Hz, 2H), 1.90 (d, J = 12.80 Hz, 2H), 1.29 (d, J = 12.40 Hz, 2H).
Step 4: Synthesis of l-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4-yl)quinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-76) l-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-76) was synthesized according to General Procedure 6, Step B starting from l-(5-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (39c, 20 mg, 1.0 eq., 0.056 mmol) and 4-(trifhroromethyl)benzaldehyde (17e, 9.72 mg, 1.0 eq., 0.056 mmol). The crude material was purified by preparative-HPLC [X SELECT C18 (19*250MM) eluting with Mobile phase A: 0.5 HC1 in water, Mobile phase B: Acetonitrile, flow rate: 15 mL/min), Rt: 10.8]. The product containing fractions were collected and lyophilized to afford l-(5-fluoro-6-(4- hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, (1-76, 4.4 mg, 7.91 pmol, 15% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 517.5; ’H-NMR (400 MHz, DMSO-t/s): 5 10.63 (s, 1H), 10.38 (w, 1H), 8.99 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.04-7.89 (m, 6H), 6.12 (hr s, 1H), 4.53 (d, J = 5.20 Hz, 2H), 4.01 (t, J = 6.80 Hz, 2H), 3.44-3.37 (m, 4H), 2.81 (t, J = 6.80 Hz, 2H), 2.68-2.63 (m, 2H), 1.96 (d, J = 13.20 Hz, 2H).
Example 40: Synthesis of tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine- 1 (2H) -carboxylate (INT-40)
Figure imgf000389_0001
Step 1: Synthesis of tert-butyl 3,3-dimethyL4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- l(2H)-carboxylate (40b) To a stirred solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (40a, 10 g, 44.0 mmol) in THF (120 mL) was added potassium terf-butoxide (IM in THF) (52.8 mL, 52.8 mmol) dropwise at -78 °C and the resulting mixture was stirred at same temperature for 1 h. N-(5-chloropyridin- 2-yl)-l,l,l-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (20.73 g, 52.8 mmol) dissolved in THF (40 mL) was then added drop wise at -78 °C and stirring was continued at room temperature for 3 h. Saturated ammonium chloride solution was added and the resulting aqueous mixture was extracted with EtOAc (350 mL x 2). The combined organic phases were dried over anhydrous NazSOr. filtered, and concentrated to dryness under reduced pressure. This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-2.5% EtOAc in hexanes to afford tert-butyl 3,3-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- 1(2H) -carboxylate (40b, 10 g, 22.75 mmol, 64% yield). LCMS: m/z MM-ES+APCI, Negative [M-H] 358.0, 'H-NMR (400 MHz, DMSO-tfc): 55.67 (s, 1H), 4.10 (s, 2H), 3.40 (s, 2H), 1.50 (s, 9H), 1.17 (s, 6H).
Step 2: Synthesis of tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihy dropyridine- 1 (2H)-carboxylate (INT-40)
A solution of tert-butyl 3,3-dimethyl-4 ((trifluoromethyl)sulfonyl) oxy)-3,6-dihydropyridine- 1(2H) -carboxylate (5 g, 13.91 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (40b, 4.24 g, 16.70 mmol) and potassium acetate (2.048 g, 20.87 mmol) in THF (50 mL) was degassed with nitrogen at 25 °C for 10 min. Pd(dppf)C12-DCM (1.136 g, 1.391 mmol) was then in one portion and the resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-10% EtOAc in hexanes to afford tert-butyl 3,3- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (INT- 40, 2 g, 5.93 mmol, 43% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ Not ionized; ’H-NMR (400 MHz, CDC13): 5 6.38-6.31 (m, 1H), 3.95 (s, 2H), 3.18 (s, 2H), 1.48(s, 9H), 1.28 (s, 12H), 1.10 (s, 6H). Example 41: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-31) 41 b
Figure imgf000391_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)- 3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (41a) tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2H)-carboxylate (41a) was synthesized according to General Procedure 5 starting from l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5, 100 mg, 1.0 eq., 0.34 mmol) and tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (INT-40, 345 mg, 3.0 eq., 1.02 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 10% isopropanol in DCM to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fhioroquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (41a, 110 mg, 0.09 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 469.3.
Step 2: Synthesis of l-(6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (41b) l-(6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoroquinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (41b, 80 mg, 0.08 mmol, 33% yield) was synthesized according to General Procedure 6, Step A starting from tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)- 3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (41a, 110 mg, 1.0 eq., 0.24 mmol). LCMS: m/z MM-ES+APCI, Negative [M-H] - 367 1 Step 3: Synthesis of l-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (41c) l-(6-(3,3-dimethyl- 1 -(4-(trifluoromethyl)benzyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (41c) was synthesized according to General Procedure 6, Step B starting from l-(6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fhmroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (41b, 80 mg, 1.0 eq., 0.22 mmol) and 4- (trifluoromethyl)benzaldehyde (17e, 45 mg, 1.2 eq., 0.26 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 15% isopropanol in DCM to afford l-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l, 2,3,6- tetrahydropyridin-4-yl)-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (41c, 90 mg, 0.10 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 527.2.
Step 4: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-31) l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-31) was synthesized according to General Procedure 3, Step C starting from l-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (41c, 90 mg, 1.0 eq., 0.17 mmol). The crude material was purified by preparative-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.1% ammonium acetate in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford l-(5-fluoro-6-(4-hydroxy-3,3- dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-31, 2.2 mg, 4.03 pmol, 2% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 545.4; 'H-NMR (400 MHz, DMSO-A): 5 10.61 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.33 (d, J = 2.40 Hz, 1H), 8.09 (t, J = 8.80 Hz, 1H), 7.85 (d, J = 9.20 Hz, 1H), 7.72 (d, J = 8.40 Hz, 2H), 7.60 (d, J = 8.00 Hz, 2H), 5.16 (s, 1H), 4.00 (t, J = 7.20 Hz, 2H), 3.67 (d, J = 14.00 Hz, 1H), 3.56 (d, J = 14.00 Hz, 1H), 3.16 (t, J = Hz, 1H), 2.80 (t, J = 6.40 Hz, 2H), 2.68-2.60 (m, 2H), 2.51-2.50 (m, 1H), 2.17 (d, J = 10.00 Hz, 1H), 1.72 (d, J = 13.20 Hz, 1H), 1.02 (d, J = 2.80 Hz, 3H), 0.69 (d, J = 11.20 Hz, 3H).
Example 42: Synthesis of l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-43)
Figure imgf000393_0001
Step 1: Synthesis of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-azaspiro[5.5]undec- 4-ene-2-carboxylate (42b)
A solution of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[5.5]undec-4-ene-2- carboxylate (37c, 4 g, 10.01 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (3.05 g, 12.02 mmol) and potassium acetate (1.966 g, 20.03 mmol) in 1, 4-dioxane (30 rnL) was degassed with nitrogen at room temperature for 10 min. Pd(dppf)C12*DCM (0.818 g, 1.00 mmol) was then added in one portion, and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-6% EtOAc in hexanes to afford tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (42b, 1 g, 2.15 mmol, 21% yield). LCMS: m/z MM-ES+APCI, Positive [M+H-Boc]+ 277.6; 'H-NMR (400 MHz, DMSO-rfc): 5 6.3-6.25 (m, 1H), 3.84 (s, 2H), 3.35-3.32
(m, 2H), 1.72-1.64 (m, 3H), 1.45-1.43 (m, 12H), 1.30-1.17 (m, 16H).
Step 2: Synthesis of tert-butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)- 2-azaspiro[5.5]undec-4-ene-2-carboxylate (42c) tert-Butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (42c) was synthesized according to General Procedure 5 starting from l-(6-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-5, 500 mg, 1.0 eq., 1.7 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-azaspiro[5.5]undec-4- ene-2-carboxylate (42b, 642 mg, 1.0 eq., 1.7 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 90% EtOAc in hexane to afford tert-butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6- yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (42c, 0.350 g, 0.25 mmol, 15% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 509.2; ’H-NMR (400 MHz, DMSO-t/e): 5 10.67 (s, 1H), 9.00 (d, J = 2.40
Hz, IH), 8.36-8.31 (m, 1H), 7.94-7.83 (m, 1H), 7.51-7.45 (m, 1H), 5.63 (s, 1H), 4.05-3.99 (m, 5H), 3.63 (s, 3H), 2.80 (t, J = 6.40 Hz, 3H), 1.67-1.36 (m, 16H).
Step 3: Synthesis of l-(5-fluoro-6-(2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (42d)
To a stirred solution of tert-butyl 5-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin- 6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (42c, 350 mg, 1.0 eq., 0.69 mmol) in DCM (2 mL) was added HC1 in 4M 1, 4-dioxane (2.58 mL, 10.32 mmol) at 0 °C under an atmosphere of nitrogen atmosphere and the resulting mixture was allowed to stir at room temperature for 1 h. The solution was concentrated under reduced pressure and then further concentrated on high-vac to afford l-(5-fluoro-6-(2- azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (42d, 200 mg, 0.26 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 409.1.
Step 4: Synthesis of l-(5-fluoro-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (42e) l-(5-fluoro-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (42e) was synthesized according to General Procedure 6, Step B starting from l-(5-Fluoro-6-(2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione hydrochloride (42d). To a stirred solution of l-(5-fhioro-6-(2-azaspiro[5.5]undec-4-en- 5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (42d, 190 mg, 0.43 mmol) in DMF (2 mL) was added 4-(trifluoromethyl)benzaldehyde (17e, 89 mg, 0.51 mmol) at room temperature and the resulting reaction was stirred for 1 h. After 1 h, NaBH(OAc)3 (226 mg, 1.07 mmol) was added, and stirring was continued at room temperature for 32 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 80% EtOAc in hexane to afford l-(5-fluoro-6-(2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (42e, 100 mg, 0.08 mmol, 19% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 567.3.
Step 5: Synthesis of l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan- 5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-43) l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-43) was synthesized according to General Procedure 3, Step C starting from l-(5-fluoro-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (42e, 100 mg, 1.0 eq., 0.18 mmol). The crude material was purified by preparative-HPLC [X Select Cl 8 (250*19 mm), eluting with Mobile phase A: 0.05% HC1 In H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 12.5]. The pure fractions were collected and lyophilized to afford l-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan- 5-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-43,14 mg, 0.02 mmol, 11% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 585.2; 'H-NMR (400 MHz, DMSO-t/e): 5 10.62 (s, 1H), 10.05 (hr s, 1H), 9.00 (d, J = 2.00 Hz, 1H), 8.35 (d, J = 1.60 Hz, 1H), 8.04-7.88 (m, 6H), 5.87 (s, 1H), 4.57 (d, J =
3.60 Hz, 2H), 4.01 (t, J = 6.40 Hz, 2H), 3.58-3.36 (m, 3H), 3.20-3.14 (m, 1H), 2.80 (t, J = 6.40 Hz, 2H),
1.97-1.91 (m, 1H), 1.82 (d, J = 12.40 Hz, 1H), 1.42-0.82 (m, 9H).
Example 43: Synthesis of the acetic acid salt of l-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]-undecan-5- yl)-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-28)
Figure imgf000395_0001
Step 1: Synthesis of l-(6-chloro-5-fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)-dihydropyrimidine- 2,4(lH,3H)-dione (43a)
A solution of 6-chloro-5-fluoro-3-iodoquinoline (INT-4A, 0.75 g, 2.44 mmol), 3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 0.774 g, 2.93 mmol) and K3PO4 tribasic (1.035 g, 4.88 mmol) in DMSO (2 mL) was degassed with nitrogen for 10 min. Copper(I) iodide (0.046 g, 0.24 mmol) was then added followed by (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (0.035 g, 0.24 mmol) and the resulting mixture was degassed with nitrogen for 10 min. The reaction mixture was stirred at 100 °C for 18 h and then cooled to room temperature. Cold water (50 mL) was added and the resulting aqueous mixture was extracted with EtOAc (2 X 100 mL). The combined organic phases were dried over anhydrous N 3286)4. filtered, concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography, eluting with 0 to 50% EtOAc in hexane to afford l-(6-chloro-5- fluoroquinolin-3-yl)-3-(2,4-dimethoxy-benzyl)dihydropyrimidine-2,4(lH,3H)-dione (43a, 0.8 g, 1.66 mmol, 68% yield). LCMS: m/z MM ES+APCI Positive [M+H]+ 444 6 Step 2: Synthesis of tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoroquinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (43b) tert-Butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (43b) was synthesized according to General Procedure 5 starting from tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (42b, 408 mg, 1.2 eq., 1.08 mmol) and l-(6-chloro-5- fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (43a, 400 mg, 1.0 eq., 0.9 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 40% EtOAc in hexane to afford tert-butyl 5-(3-(3- (2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (43b, 0.3 g, 0.40 mmol, 45% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 659.3; ’H-NMR (400 MHz, DMSO-tfc): 5 8.98 (d, J = 18.40 Hz, 1H), 8.36 (d, J = 2.00 Hz, 1H), 7.85 (d, J = 8.80 Hz, 1H), 7.48 (t, J = 8.40 Hz, 1H), 6.96 (d, J = 8.40 Hz, 1H), 6.56 (d, J = 2.40 Hz, 1H), 6.46 (d, J = 8.40 Hz, 1H), 5.60 (s, 1H), 4.80 (s, 2H), 4.08 (t, J = 6.80 Hz, 2H), 4.03 (t, J = 7.20 Hz, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 3.63 (s, 2H), 3.03 (t, J = 6.40 Hz, 2H), 1.57-1.54 (m, 4H), 1.47 (s, 9H), 1.20-1.16 (m, 3H).
Step 3: Synthesis of tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (43c) tert-Butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (43c) was synthesized according to General Procedure 3, Step C starting from tert-butyl 5-(3-(3-(2,4-dimethoxy-benzyl)-2,4- dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (43b, 400 mg, 1.0 eq., 0.61 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 50% EtOAc in hexane followed by reverse phase column chromatography using a C18 cartridge (25 g) eluting with 5 to 100% MeCN and 0.1% formic acid in water. The pure product containing fractions were collected and lyophilized to obtain tert-butyl 5-(3-(3-(2,4-dimethoxy-benzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 5-fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (43c, 0.2 g, 0.28 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 677.5; ’H-NMR (400 MHz, DMSO-de): 5 8.98 (d, J = 2.40 Hz, 1H), 8.38 (d, J = 2.00 Hz, 1H), 8.07 (t, J = 8.80 Hz, 1H), 7.87 (d, J = 9.20 Hz, 1H), 6.95 (d, J = 8.40 Hz, 1H), 6.56 (d, J = 2.40 Hz, 1H), 6.46 (dd, J = 2.00, 8.40 Hz, 1H), 5.41 (s, 1H), 4.81 (s, 2H), 4.08 (t, J = 7.20 Hz, 4H), 3.81 (s, 3H), 3.74 (s, 3H), 3.03 (t, J = 6.40 Hz, 5H), 1.81-1.78 (m, 2H), 1.61- 1.51 (m, 2H), 1.44 (s, 9H), 1.38-1.35 (m, 3H), 1.24-1.21 (m, 1H), 0.89-0.80 (m, 2H), 0.65-0.62 (m, 1H). Step 4: Synthesis of l-(5-fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (43d)
To a stirred solution of tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- l(2H)-yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (43c, 100 mg, 0.15 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.177 mL, 2.29 mmol) followed by trifluoromethanesulfonic acid (0.026 mL, 0.30 mmol) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude material was basified with saturated NaHCCL solution and a solid precipitated. The precipitated solid was filtered and washed with water (2 x 10 mL) and DCM (2 x 80 mL) and dried to afford l-(5-fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (43d, 50 mg, 0.07 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 427.2; ’H-NMR (400 MHz, DMSO-de): 5 10.62 (s, 1H), 8.99 (d, J = 2.40 Hz, 1H), 8.34 (d, J = 2.00 Hz, 1H), 8.06 (t, J = 8.40 Hz, 1H), 7.87 (d, J = 9.20 Hz, 1H), 5.50 (s, 1H), 4.01 (t, J = 6.80 Hz, 2H), 3.76- 3.73 (m, 2H), 3.15-2.94 (m, 4H), 2.80 (t, J = 6.40 Hz, 2H), 1.82-1.18 (m, 10H).
Step 5: Synthesis of the acetic acid salt of l-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5- fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-28) l-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoroquinolin-3-yl)dihydro-pyrimidine- 2,4(1 H,3H)-dione (1-28) was synthesized according to General Procedure 6, Step B starting from l-(5- fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)dihydro-pyrimidine-2,4(lH,3H)-dione (43d, 40 mg, 1.0 eq., 0.086 mmol) and acetaldehyde (7.61 mg, 2.0 eq., 0.17 mmol). The crude material was purified by preparative-HPLC [X-select C18, 150mm X 19, eluting with Mobile phase A: 10 mM ammonium acetate in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 12.8]. The pure product containing fractions were collected and lyophilized with acetic acid to afford the acetic acid salt of l-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoroquinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (1-28, 10.20 mg, 0.02 mmol, 23% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 455.5; ’H-NMR (400 MHz, DMSO-tfe): 5 10.61 (s, 1H), 8.97 (d, J = 2.40 Hz, 1H), 8.33 (d, J = 2.00 Hz, IH), 8.08 (t, J = 8.80 Hz, 1H), 7.84 (d, J = 9.20 Hz, 1H), 5.03 (s, 1H), 4.01 (dd, J = 5.60, 6.40 Hz, 2H), 3.15 (m, IH), 2.98 (d, 7 = 11.20 Hz, IH), 2.80 (t, J = 6.40 Hz, 2H), 2.67 (dd, J = 2.00, 3.60 Hz, IH), 2.37 (q, J = 6.80 Hz, 3H), 2.14 (d, J = 11.20 Hz, 2H), 1.90 (s, 3H), 1.79-1.73 (m, 2H), 1.65-1.62 (m, IH), 1.45-1.30 (m, 4H), 1.05 (t, J = 7.2 Hz, 3H), 0.86 (m, IH), 0.68 (s, 2H).
Example 44: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-l,5- naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-21)
Figure imgf000398_0001
Step 1: Synthesis of tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l,5-naphthyridin-2-yl)- 3,6-dihydropyridine- 1 (2H) -carboxylate (44a)
Tert- butyl 4-(7-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l,5-naphthyridin-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (44a) was synthesized according to General Procedure 5 starting from l-(6-chloro-l,5-naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-7, 300 mg, 1.0 eq., 1.08 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (35b, 503 mg, 1.5 eq., 1.63 mmol). The crude material was purified by silica gel flash column chromatography Biotage Isolera® on a silica gel (100-200 mesh) cartridge (25 g) eluting with IP A in DCM (0-20%). The pure product containing fractions were collected and concentrated under reduced pressure to afford tert-butyl 4-(7-(2,4-dioxotetra-hydropyrimidin-l(2H)-yl)-l,5-naphthyridin-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (44a, 200 mg, 0.45 mmol, 42% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 424.4. ’H-NMR (400 MHz, DMSO-t/s): 5 10.65 (s, 1H), 9.00 (d, J = 2.40 Hz, 1H), 8.36 (dd, J = 8.80, Hz, 1H), 8.21 (d, J = 2.00 Hz, 1H), 8.07 (dd, J = 9.20 Hz, 1H), 6.94 (br s, 1H), 4.34
(br s, 2H), 4.06-4.01 (m, 3H), 3.61-3.58 (m, 2H), 2.82-2.74 (m, 3H), 1.45 (s, 9H).
Step 2: Synthesis of l-(6-(l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3-yl)dihydro-pyrimidine- 2,4(lH,3H)-dione (44b)
To a stirred solution of tert-butyl 4-(7-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l,5-naphthyridin- 2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (44a, 200 mg, 1.0 eq., 0.47 mmol) in DCM (5 mL) was added HC1 (4M in 1,4-dioxane) (1.0 mL, 4.00 mmol) at 0 °C and the resulting mixture was stirred for 2 h. After complete consumption of starting material was observed via LCMS, the reaction mixture was concentrated to obtain crude material. The crude material was triturated with MTBE, filtered, and dried under reduced pressure to afford l-(6-(l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (44b, 140 mg, 0.39 mmol, 82% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 324.3. ’H-NMR (400 MHz, DMSO-cfc): 5 10.60 (s, 1H), 9.42 (br s, 1H),
9.04 (d, J = 2.40 Hz, 1H), 8.43 (dd, J = 8.80, Hz, 1H), 8.25 (dd, J = 2.00, Hz, 1H), 8.13 (dd, J = 9.20, Hz, 1H), 7.58-6.93 (d, J = Hz, 1H), 4.05-4.01 (m, 2H), 3.95 (br s, 2H), 3.37-3.36 (m, 2H), 2.97 (br s, 2H), 2.81 (t, 7 = 6.80 Hz, 2H).
Step 3: Synthesis of l-(6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-l,5- naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (44c)
A solution of l-(6-(l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione, HC1 (44b, 150 mg, 1.0 eq., 0.42 mmol) and 4-(trifhroromethyl)benzaldehyde (17e, 87 mg, 1.2 eq., 0.5 mmol) in DMF (2 mL) was stirred at 25 °C for 2 h. Sodium triacetoxyborohydride (221 mg, 1.042 mmol) was then added at 25 °C and stirring was continued for 16 h. The reaction mixture was concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica gel flash column chromatography Biotage Isolera® on a silica gel (100-200 mesh) cartridge (25 g) eluting with IP A in DCM (0-20%). The pure product containing fractions were collected and concentrated under reduced pressure to afford l-(6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-l,5- naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (44c, 120 mg, 0.21 mmol, 51% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 482.3. ’H-NMR (400 MHz, DMSO-tfc): 5 10.60 (s, 1H), 8.98 (d,
J = 2.40 Hz, 1H), 8.29 (dd, J = 50.80, Hz, 1H), 8.19 (d, J = 0.80 Hz, 1H), 8.05 (dd, J = 8.80, Hz, 1H), 7.73-7.71 (m, 2H), 7.63-7.61 (m, 2H), 6.93 (d, J = Hz, 1H), 4.05-4.01 (m, 2H), 3.78-3.75 (m, 3H), 3.28 (d, J = 35.60 Hz, 2H), 2.82-2.73 (m, 3H), 2.68-2.67 (m, 2H).
Step 4: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-l,5-naphthyridin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-21) l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-l,5-naphthyridin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-21) was synthesized according to General Procedure 3, Step C starting froml-(6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (44c, 115 mg, 1 eq., 0.24 mmol). The crude material was purified by prepared ve-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-l,5- naphthyridin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-21, 37.4 mg, 0.07 mmol, 35% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 500.1. ’H-NMR (400 MHz, DMSO-tfc): 5 10.71 (br s, 1H), 10.67
(s, 1H), 9.07 (dd, J = 2.40, 9.20 Hz, 1H), 8.48 (d, J = 8.80 Hz, 1H), 8.19 (d, J = 1.60 Hz, 1H), 8.07 (dd, J
= 3.60, 8.80 Hz, 1H), 7.94-7.86 (m, 4H), 5.97 (s, 1H), 4.53 (d, J = 4.80 Hz, 2H), 4.04 (t, J = 6.80 Hz,
2H), 3.37 (s, 4H), 2.84-2.79 (m, 2H), 2.68-2.56 (m, 2H), 1.97 (d, J = 13.60 Hz, 2H).
Example 45: Synthesis of l-(4-chloro-6-(4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-30)
Figure imgf000400_0001
Step 1: Synthesis of l-(6-bromo-4-chloroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)-dihydropyrimidine- 2,4(lH,3H)-dione (45a)
To a stirred solution of 6-bromo-4-chloro-3-iodoquinoline (36d, 500 mg, 1.36 mmol), 3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 359 mg, 1.36 mmol) in DMSO (10 mL) were added sodium terf-butoxide (157 mg, 1.63 mmol) and copper (I) iodide (51.7 mg, 0.27 mmol) and the resulting mixture was degassed with nitrogen for 5 min. Trans-MN'-dimethylcyclohexane-l ,2-di amine (38.6 mg, 0.27 mmol) was then added at room temperature, and stirring was continued at 80 °C for 1 h. The reaction mixture was poured into ice-cold water and a solid precipitated. The resulting precipitated solid was filtered and dissolved in EtOAc. The EtOAc phase was dried over anhydrous NaiSCh. filtered, and evaporated under reduced pressure. The crude compound was purified by flash column chromatography using Combi-Flash (on Silica gel, 100-200 mesh) eluting with 22-25% EtOAc in hexane to afford l-(6-bromo-4-chloroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)- dione (45a, 550 mg, 0.71 mmol, 52% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 504.2, 506.2. ’H-NMR (400 MHz, DMSO-rfc): 59.03 (s, 1H), 8.27 (d, J = 2.00 Hz, IH), 8.08 (dd, J =
2.00, 8.80 Hz, IH), 7.97-7.91 (m, 1H), 6.96 (d, J = 8.40 Hz, 1H), 6.56 (d, J = 2.40 Hz, 1H), 6.49 (d, J =
6.00 Hz, IH), 4.81 (d. 7 = 6.40 Hz, 2H), 3.93 0, 7 = 6.40 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.09 (s, IH),
3.01 (d, J = 10.80 Hz, 1H).
Step 2: Synthesis of tert-butyl 4-(4-chloro-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetra- hydropyrimidin-l(2H)-yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (45b) tert- Butyl 4-(4-chloro-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (45b) was synthesized according to General Procedure 4 starting from l-(6-bromo-4-chloroquinolin-3-yl)-3-(2,4-dimethoxy- benzyl)dihydropyrimidine-2,4(lH,3H)-dione (45a, 780 mg, 1.0 eq., 1.55 mmol) and tert-butyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 478 mg, 1.0 eq., 1.55 mmol). The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with 80-85% EtOAc in hexane to afford tert-butyl 4-(4-chloro-3-(3-(2,4- dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)quinolin-6-yl)-3,6-dihydropyridine- 1 (2H)- carboxylate (45b, 900 mg, 1.16 mmol, 75% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 607.4. ’H-NMR (400 MHz, DMSO-rfc): 5 8.93 (s, 1H), 8.11 (d, J = 5.20 Hz, 3H), 6.97 (d, J= 8.40 Hz, 1H), 6.56 (d, J = 2.40 Hz, 1H), 6.49 (dd, J = 2.40, 8.40 Hz, 2H), 4.81 (d, J = 8.00 Hz, 2H), 4.10 (s, 1H), 3.94 (t, J = 2.40 Hz, 2H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 3.74 (s, 3H), 3.62 (t, J = 6.00 Hz, 2H), 3.11 (t, J = 7.20 Hz, 1H), 3.03-3.00 (m, 1H), 2.65 (s, 2H), 1.46 (s, 9H).
Step 3: Synthesis of l-(4-chloro-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydro-pyrimidine- 2,4(lH,3H)-dione (45c)
To a stirred solution of tert-butyl 4-(4-chloro-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetra- hydropyrimidin-l(2H)-yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (45b, 800 mg, 1.32 mmol) in DCM (10 mL) was added triflic acid (0.234 mL, 2.64 mmol) and TEA (0.254 mL, 3.29 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 3 h. The solvent was evaporated under reduced pressure and the resulting crude material was washed with MTBE and dried to afford l-(4-chloro-6- (l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (45c, 610 mg, 1.23 mmol, 93% yield), which was carried onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 356.9. ’H-NMR (400 MHz, DMSO-c/e): 5 10.79 (s, 1H), 8.90 (s, 1H), 8.11 (s, 3H), 6.58 (s, 2H), 3.00 (d, 7 = 5.60 Hz, 2H), 2.92 (d, 7 = 46.40 Hz, 2H), 1.28-1.25 (m, 4H), 0.88 (s, 2H).
Step 4: Synthesis of l-(4-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (45d)
To a stirred solution of l-(4-chloro-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (45c, 320 mg, 1.0 eq., 0.9 mmol) in DMF (7 mL) was added 4- (trifluoromethyl)benzaldehyde (17e, 156 mg, 1.0 eq., 0.9 mmol) at room temperature and the resulting mixture was stirred for 1 h. Sodium triacetoxyborohydride (475 mg, 2.24 mmol) was then added and stirring was continued at 25 °C for 16 h. The solvent was removed under reduced pressure to afford crude product. The crude compound was purified by flash column chromatography using Combi-Flash (on Silica gel, 100-200 mesh) and eluting with gradient of 85-90% of EtOAc in hexane to afford l-(4-chloro- 6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-
2,4(1 H,3H)-dione (45d, 220 mg, 0.31 mmol, 35% yield), which was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 515.1. ’H-NMR (400 MHz, DMSO- d6y. 5 10.67 (s, 1H), 8.90 (s, 1H), 8.11-8.09 (m, 3H), 7.72 (cl, 7 = 8.00 Hz, 2H), 7.62 (d. 7 = 8.40 Hz, 2H), 6.53 (s, 1H), 3.88-3.82 (m, 6H), 3.20 (s, 2H), 2.84 (t, 7= 6.00 Hz, 2H), 2.74 (d, 7 = 6.00 Hz, 1H), 2.68 (s,
1H).
Step 5: Synthesis of l-(4-chloro-6-(4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4-yl)quinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-30) l-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-30) was synthesized according to General Procedure 3, Step C starting from l-(4-chloro-6-(l-(4-(trifhroromethyl)-benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (45d, 130 mg, 1.0 eq., 0.25 mmol). The crude compound was purified by preparative-HPLC [X SELECT C18 (19*150)], eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford l-(4-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-30, 28.8 mg, 0.050 mmol, 21% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 533.2. ’H-NMR (400 MHz, DMSO-<fc): 10.98 (s, 1H), 10.67 (s, 1H), 8.95 (s, 1H), 8.35 (d, 7 = 1.60 Hz, 1H), 8.17 (d, 7 = 8.80 Hz, 1H), 7.99-7.88 (m, 5H), 5.98 (s, 1H), 4.54 (d. 7 = 5.20 Hz, 2H), 3.86 (dd, 7 = 6.00, 7.60 Hz, 2H), 3.38 (d, 7 = 12.00 Hz, 3H), 2.85 (t, 7= 6.40 Hz, 2H), 2.68-2.67 (m, 2H), 1.89 (d, 7 = 14.00 Hz, 2H).
Example 46: Synthesis of l-(5-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-57)
Figure imgf000403_0001
p
Step 1: Synthesis of 3-bromo-6-nitroquinoline (46c)
To a stirred solution of 4-nitroaniline (46a, 2 g, 14.48 mmol) in AcOH (30 mL) was added 2,2,3- tribromopropanal (46b, 6.40 g, 21.72 mmol) at room temperature and the resulting mixture was stirred at room temperature for 1 h and then at 115 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography Biotage Isolera® on silica gel (100-200 mesh) eluting with EtOAc in n- hexane (20-30%). The pure product containing fractions were collected and concentrated under reduced pressure to afford 3-bromo-6-nitroquinoline (46c, 0.34 g, 1.34 mmol, 9% yield). LCMS: Not ionized. *H-
NMR (400 MHz, DMSO-tfc): 89.20 (d, J = 2.40 Hz, 1H), 9.09 (d, J = 2.40 Hz, 1H), 9.06 (d, J = 2.80 Hz,
1H), 8.51 (dd, 7 = 2.80, 9.20 Hz, 1H), 8.26 (d, J = 9.20 Hz, 1H).
Step 2: Synthesis of 3-bromoquinolin-6-amine (46d)
To a stirred solution of 3-bromo-6-nitroquinoline (46c, 340 mg, 1.34 mmol) in ethanol (16 mL) and water (4 mL) was added iron (375 mg, 6.72 mmol) and ammonium chloride (719 mg, 13.44 mmol) at room temperature and the resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled, filtered through celite®, and the filter cake was washed with ethanol (30 mL). The filtrate was concentrated under reduced pressure and the crude compound was purified by silica gel flash column chromatography Biotage Isolera® on silica gel (100-200 mesh) eluting with EtOAc in n-hexane (20- 30%). The pure fractions were collected and concentrated under reduced pressure to afford 3- bromoquinolin-6-amine (46d, 145 mg, 0.55 mmol, 41% yield). LCMS: m/z MM-ES+APCI, [M+H, M+2+H]+ 222.9, 224.9. ’H-NMR (400 MHz, DMSO-A): 5 8.46 (d, J = 2.00 Hz, 1H), 8.25 (d, J = 2.00 Hz, 1H), 7.69 (d, J = 8.80 Hz, 1H), 7.18 (dd, J = 2.40, 8.80 Hz, 1H), 6.74 (d, 7 = 2.40 Hz, 1H), 5.82 (s,
2H, D2O exchangeable).
Step 3: Synthesis of 3-bromo-5-chloroquinolin-6-amine (46e)
To a stirred solution of 3-bromoquinolin-6-amine (46d, 490 mg, 2.20 mmol) in DCM (20 mL) was added 1 -chloropyrrolidine-2, 5-dione (352 mg, 2.64 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 4 h. Water (50 mL) was added and the resulting aqueous mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous NaiSCL, filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with a gradient of 20-25% of EtOAc in hexane to afford 3-bromo-5-chloroquinolin-6-amine (46e, 800 mg, 1.77 mmol, 81% yield). LCMS: m/z MM-ES+APCI, Positive [(M+H, M+2+HJL 258.9, 260.9. ’H-NMR (400 MHz, DMSO-&): 5 8.61 (d, J = 2.40 Hz, 1H), 8.36 (d, J = 2.00 Hz, 1H), 7.75 (d, J = 8.80 Hz, 1H), 7.40 (d, J = 8.80 Hz, 1H), 6.16 (s, 2H, D2O exchangeable).
Step 4: Synthesis of 3-bromo-5-chloro-6-iodoquinoline (46f)
To a stirred solution of 3-bromo-5-chloroquinolin-6-amine (46e, 1.1 g, 4.27 mmol) in 10% aq. HC1, (25 mL, 4.27 mmol) was added sodium nitrite (0.589 g, 8.54 mmol) at 0 °C and the resulting mixture was stirred for 1 h. Potassium iodide (1.418 g, 8.54 mmol) was then added and stirring was continued at room temperature for 6 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 x 300 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with gradient of 10% EtOAc in hexane to afford 3- bromo-5-chloro-6-iodoquinoline (46f, 1.1 g, 2.23 mmol, 52% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 367.9, 369.9. ’H-NMR (400 MHz, CDCh): 5 8.97-8.95 (m, 1H), 8.79-8.77 (m, 1H), 7.97-7.82 (m, 1H), 7.79-7.74 (m, 1H).
Step 5: Synthesis of 3-bromo-5-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinoline (46g)
To a stirred solution of 3-bromo-5-chloro-6-iodoquinoline (46f, 400 mg, 1.09 mmol) and 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(4-(trifhioromethyl)benzyl)-l,2,3,6-tetrahydropyridine (38a, 399 mg, 1.09 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added CS2CO3 (708 mg, 2.17 mmol) and the resulting mixture was sparged with N2gas for 10 minutes. Pd(dppf)C12eDCM (44.3 mg, 0.05 mmol) was added and stirring was continued at 75 °C for 16 h. The reaction mixture was cooled, poured in water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous NaiSCL. filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with an isocratic method of 10% EtOAc in hexane to afford 3-bromo-5-chloro-6-(l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinoline (46g, 250 mg, 0.52 mmol, 48% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 481.0, 483.0.
Step 6: Synthesis of l-(8-chloro-7-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)naphthalen-2-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (46h)
To a stirred solution of 3-bromo-5-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l, 2,3,6- tetrahydropyridin-4-yl)quinoline (46g, 250 mg, 0.52 mmol) in DMSO (4 mL) under an atmosphere of nitrogen was added copper (I) iodide (29.7 mg, 0.16 mmol), 3-(2,4-dimethoxybenzyl)dihydropyrimidine- 2,4(1 H,3H)-dione (lb, 178 mg, 0.68 mmol) and sodium terLbutoxide (100 mg, 1.04 mmol) at 25 °C. The resulting mixture was sparged with N2 for 10 min. Trans-A,A'-dimethylcyclohexane-l,2-diamine (22.15 mg, 0.16 mmol) was then added at 25 °C and the reaction mixture was again sparged with nitrogen for 5 min and stirring was continued at 100 °C for 1 h. The reaction mixture was cooled, water (15 ml) was added and the aqueous mixture was extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Grace reverse phase chromatography [(Column: Cl 8, eluting with Mobile phase A: 0.1% FA in H2O, Mobile phase B: Acetonitrile, flow rate: 20 mL/min)]. The pure product containing fractions were collected and lyophilized to afford l-(8-chloro-7-(l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)naphthalen-2-yl)-3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (46h, 40 mg, 0.03 mmol, 6% yield) LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 665.3.
Step 7: Synthesis of l-(5-chloro-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (46i)
To a stirred solution of l-(8-chloro-7-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)naphthalen-2-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (46h, 100 mg, 0.16 mmol) in DCM (2 mL) was added TEA (361 mg, 3.16 mmol) and triflic acid (47.5 mg, 0.32 mmol) at 0 °C the resulting mixture was allowed to stir at room temperature for 6 h. Since starting material was still present as indicated by LCMS, additional TFA (361 mg, 3.16 mmol) and triflic acid (47.5 mg, 0.316 mmol) were added and stirring was continued at 40 °C for 16 h. The reaction mixture was then cooled, and the solvent volume was reduced under reduced pressure. The resulting mixture was basified to pH = 8 using sat. aq. NaHCO s sol (10 mL) and extracted with DCM (2 x 20 mL). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and evaporated under reduced pressure to provide l-(5- chloro-6-(l-(4-(trifhroromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (46i, 20 mg, 0.02 mmol, 15% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 515.3.
Step 8: Synthesis of l-(5-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-
3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-57) l-(5-Chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-57) was synthesized according to General Procedure 3, Step C starting from-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione (46i, 20 mg, 1.0 eq., 0.04 mmol). The crude compound was purified by preparative-HPLC [(Column: Shimpak C18 (250*21), eluting with Mobile phase A: 0.05% FA in H2O, Mobile phase B: Acetonitrile, Rt-6.0 min, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford l-(5-chloro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-
4-yl)quinolin-3-yl)dihydro-pyrimidine-2,4(lH,3H)-dione (1-57, 2.2 mg, 4.09 pmol, 7% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 533.2. 'H-NMR (400 MHz, DMSO-tfc): 5 10.62 (s, 1H), 8.98 (d, J = 2.40 Hz, 1H), 8.54 (d, J = 2.00 Hz, 1H), 8.27 (d, J = 9.20 Hz, IH), 8.04 (d, J = 9.20 Hz, 1H), 7.72 (d, J= 8.00 Hz, 2H), 7.64 (d, J = 8.00 Hz, 2H), 6.56 (s, IH), 5.34 (s, IH), 4.02 (t, J = 6.80 Hz, 2H), 3.65 (s, 2H), 2.80-2.67 (m, 5H), 2.57-2.50 (m, 2H), 1.63 (d, J = 12.40 Hz, 2H).
Example 47: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-56)
Figure imgf000406_0001
Step 1: Synthesis of h/LButyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (47a) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate
(47a) was synthesized according to General Procedure 4 starting from 3-(6-bromoquinolin-3- yl)piperidine-2, 6-dione (INT-3, 400 mg, 1.0 eq., 1.26 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine l(2H) carboxylate (35b 554 mg 1 5 eq 1 88 mmol) The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-70% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3- yl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (47a, 400 mg, 0.87 mmol, 70% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 422.0. ’H-NMR (400 MHz, DMSO-tfc): 8 10.98 (s, 1H), 8.76 (s, 1H), 8.18 (s, 1H), 7.99-7.92 (m, 3H), 6.42 (s, 1H), 4.17-4.14 (m, 1H), 4.08-4.03 (m, 2H), 3.61 (t, J = 5.60
Hz, 2H), 2.63-2.61 (m, 4H), 2.46-2.39 (m, 1H), 2.46-2.39 (m, 1H), 1.45 (s, 9H).
Step 2: Synthesis of 3-(6-(l,2,3,6-Tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2,6-dione, HC1 (47b)
To a stirred solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (47a, 400 mg, 1.0 eq., 0.95 mmol) in DCM (8 mL) was added HC1 (4M in dioxane) (1.19 mL, 4.75 mmol) at 0 °C under an atmosphere of nitrogen and the resulting mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure and then further concentrated on high-vac to afford the crude compound. The crude compound was triturated with MTBE and hexane, filtered, and dried under reduced pressure to afford 3-(6-( 1,2,3, 6-tetrahydropyridin-4- yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (47b, 350 mg, 0.68 mmol, 71% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 322.2. ’H-NMR (400 MHz, DMSO-cfc): 8 11.06 (s, 1H), 9.34 (s, 2H), 9.04 (s, 1H), 8.62 (s, 1H), 8.21-8.14 (m, 3H), 6.53 (s, 1H), 4.31-4.27 (m, 1H), 3.87-3.83 (m, 2H), 3.41-3.37 (m, 2H), 2.89-2.73 (m, 3H), 2.68-2.63 (m, 1H), 2.47-2.40 (m, 1H), 2.22-2.19 (m, 1H).
Step 3: Synthesis of 3-(6-(l-(4-(Trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- nyl)piperidine-2, 6-dione (47c)
A solution of 3-(6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2,6-dione, HC1 (47b, 150 mg, 1.0 eq., 0.42 mmol) and 4-(trifhroromethyl)benzaldehyde (17e, 88 mg, 1.2 eq., O.SOmmol) in DMF (8 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (222 mg, 1.05 mmol) was then added in portions and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and then further concentrated on high-vac to afford crude product. This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with a linear gradient of 0-100% EtOAc in hexanes to afford 3-(6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2,6- dione (47c, 170 mg, 0.34 mmol, 81% yield). The product was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 480.7. ’H-NMR (400 MHz, DMSO-cL): 8 10.98 (s, 1H), 8.75 (s, 1H), 8.17 (d, J = 2.00 Hz, 1H), 7.96-7.91 (m, 3H), 7.72 (d, J = 8.00 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 6.42 (s, 1H), 4.17-4.13 (m, 1H), 3.73 (s, 2H), 3.17 (d, J = 2.80 Hz, 2H), 2.77-2.72 (m, 4H), 2.64-2.62 (m, 2H), 2.47-2.40 (m, 1H), 2.21-2.12 (m, 1H). Step 4: Synthesis of 3-(6-(4-Hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-56)
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione was synthesized according to General Procedure 3, Step C starting from 3-(6-( l-(4-
( trifluoromethyl) benzyl)-! ,2,3, 6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (47c, 170 mg, 1.0 eq., 0.36 mmol). The crude material was purified by preparative-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(4- hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-56, 84 mg, 0.15 mmol, 47% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 498.5. 'H-NMR (400 MHz, DMSO-r/s): <5 11.52 (s, 1H), 11.06 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.26-8.21 (m, 2H), 8.08 (d, J = 8.40
Hz, 1H), 7.97 (d, J = 8.00 Hz, 2H), 7.87 (d, J = 8.00 Hz, 2H), 5.80 (s, 1H), 4.52 (d, J = 2.80 Hz, 2H),
4.30 (d, J = 10.80 Hz, 1H), 3.35 (s, 4H), 2.83-2.77 (m, 1H), 2.67-2.64 (m, 3H), 2.46-2.43 (m, 1H), 2.15-
2.20 (m, 1H), 2.44 (d, J = 12.40 Hz, 2H).
Example 48: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-40)
Figure imgf000408_0001
Step 1: Synthesis of (3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)boronic acid (48a)
(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)boronic acid (48a) was synthesized according to General Procedure 3, Step A starting from 3-(6-bromoquinolin-3-yl)piperidine-2, 6-dione (INT-3, 300 mg, 1.0 eq., 0.94 mmol). This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford (3- (2,6-dioxopiperidin-3-yl)quinolin-6-yl)boronic acid (48a, 330 mg, 0.51 mmol, 54% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 285.0. 'H-NMR (400 MHz, DMSO-rfc): 5 10.99 (s, 1H), 8.85 (s, 1H), 8.33 (d, J = 12.00 Hz, 2H), 8.00-7.93 (m, 2H), 4.18-4.14 (m, 1H), 3.65-3.57 (m, 1H), 2.79-2.51 (m, 1H), 2.46-2.44 (m, 1H), 2.17-2.14 (m, 1H).
Step 2: Synthesis of 3-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (48b)
3-(6-(3,3-dimethyl- 1 -(4-(trifluoromethyl)benzyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (48b) was synthesized according to General Procedure 3, Step B starting from (3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)boronic acid (48a, 280 mg, 1.0 eq., l.Ommol) and 3,3-dimethyl- l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (INT-69, 494 mg, 1.2 eq., 1.18mmol). This crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford 3-(6-(3,3- dimethyl-l-(4-(trifluoromethyl)-benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (48b, 250 mg, 0.44 mmol, 45% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 508.2. ’H-NMR (400 MHz, DMSO-Jd): 5 10.97 (s, 1H), 8.77 (d, J = 2.00 Hz, 1H), 8.21 (d, J = 1.00 Hz, 1H), 7.95 (d, J =
8.80 Hz, 1H), 7.75-7.73 (m, 3H), 7.66-7.57 (m, 4H), 5.58 (t, J = 3.20 Hz, 1H), 4.17-4.12 (m, 1H), 3.72 (s,
2H), 3.11 (d, 7 = 2.80 Hz, 1H), 2.78-2.75 (m, 1H), 2.64-2.59 (m, 1H), 2.48-2.44 (m, 3H), 2.17-2.13 (m, 1H), 1.08 (s, 6H).
Step 3: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-40)
3-(6-(4-Hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-40) was synthesized according to General Procedure 3, Step C starting from 3-(6-(3,3-dimethyl-l-(4-(trifhroromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)piperidine- 2,6-dione (48b, 250 mg, 1.0 eq., 0.49 mmol). The crude material was purified by preparative-HPLC [X- SELECT C18 (250*19*5U), eluting with Mobile phase A: 0.1% formic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 11.6]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-40, 18.10 mg, 0.03 mmol, 7% yield). LCMS: m/z MM-ES+APCI, Positive | M+H |+ = 526.2. ’H-NMR (400 MHz, DMSO-rfe): 5 10.96 (s, 1H), 8.76 (d, 7 = 2.00 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.94 (s, 2H), 7.72 (d, 7 = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 4.85 (s, 1H), 4.16-
4.12 (m, 1H), 3.69-3.55 (m, 2H), 2.91-2.88 (m, 3H), 2.67-2.61 (m, 4H), 2.39-2.33 (m, 2H), 1.56 (d, J =
13.20 Hz, 1H), 0.93 (s, 3H), 0.69 (s, 3H).
Example 49: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]-undecan-5- yl)quinolin-3-yl)piperidine-2, 6-dione (1-27)
Figure imgf000410_0001
Step 1: Synthesis of 3-(6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3- yl)piperidine-2, 6-dione (49a)
3-(6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine-2,6- dione (49a) was synthesized according to General Procedure 3, Step B starting from (3-(2,6- dioxopiperidin-3-yl)quinolin-6-yl)boronic acid (48a, 300 mg, 1.0 eq., 1.06 mmol) and 2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl trifluoromethanesulfonate (INT-72, 580 mg, 1.2 eq., 1.27 mmol). The crude material was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) and eluting with 0-80% EtOAc in hexanes to afford 3-(6- (2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine-2, 6-dione (49a, 250 mg, 0.39 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 548.2. ’H-NMR (400 MHz, DMSO-de): 5 10.97 (s, 1H), 8.77 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 8.80 Hz, 1H), 7.75-7.63 (m, 5H), 7.52-7.49 (m, 1H), 5.51 (s, 1H), 4.17-4.12 (m, 1H), 3.77 (s, 2H), 3.11 (s, 2H), 2.51-2.64 (m, 4H), 2.44-2.33 (m, 2H), 1.89-1.72 (m, 2H), 1.42-1.32 (m, 8H).
Step 2: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5- yl)quinolin-3-yl)piperidine-2, 6-dione (1-27)
3-(6-(5-Hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)piperidine-2, 6-dione (1-27) was synthesized according to General Procedure 3, Step C starting from 3-(6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine-2, 6-dione (49a, 250 mg, 1.0 eq., 0.46 mmol). The crude compound was purified by preparative-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% acetic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(5-hydroxy-2-(4-(trifluoro-methyl)benzyl)-2-azaspiro[5.5]undecan-5- yl)quinolin-3-yl)piperidine-2, 6-dione (1-27, 7.2 mg, 0.01 mmol, 3% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 566.3., 'H-NMR (400 MHz, DMSO-tfe): 5 10.97 (s, 1H), 8.76 (s, 1H), 8.22 (s, 1H), 7.98-7.89 (m, 3H), 7.73-7.38 (m, 4H), 4.81 (s, 1H), 4.16-4.12 (m, 1H), 3.69-3.32 (m, 2H), 2.31-2.86 (m, 9H), 1.78-1.73 (m, 2H), 1.52 (m, 1H), 1.49 (m, 3H), 1.29-1.02 (m, 5H).
Example 50: Synthesis of 3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-89)
Figure imgf000411_0001
Step 5
50d 1-89
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,6- dihydropyridine- 1 ( 2// )-ca rboxy late (50a) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (50a) was synthesized according to General Procedure 5 starting from 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C, 500 mg, 1.0 eq., 1.06 mmol) and tertbutyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 657 mg, 2.0 eq., 2.12 mmol). The crude product was purified by silica gel flash column chromatography using Biotage Isolera® (on neutral alumina) eluting with 0-100% EtOAc in hexanes to afford tert-butyl 4-(3- (2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (50a, 0.3 g, 0.41 mmol, 39% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+= 618.2. ’H-NMR (400 MHz, DMSO-t/s): 59.15 (s, 1H), 8.60 (d, J = 1.60 Hz, 1H), 8.06 (d, J = 8.40 Hz, 1H), 7.89-7.85 (m, 1H), 7.76-
7.49 (m, 1H), 7.48-7.41 (m, 10H), 6.67 (d, J = 8.40 Hz, 1H), 6.17 (s, 1H), 5.47 (d, J = 10.00 Hz, 4H), 4.08-4.03 (m, 2H), 3.91 (s, 2H), 2.52-2.51 (m, 2H), 1.50-1.46 (m, 9H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)py ridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (50b) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (50b) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4- (3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (50a, 300 mg, 1.0 eq., 0.49 mmol). The crude product was purified by silica gel flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (50b, 0.18 g, 0.22 mmol, 44% yield) as liquid. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 636.4. 'H-NMR (400 MHz, DMSO-t/e): 5 9.14 (d, J = 2.00 Hz, IH), 8.61 (d, J = 1.60 Hz, IH), 8.03- 8.03 (m, 2H), 7.88 (d, J = 9.20 Hz, IH), 7.50-7.43 (m, 10H), 6.66 (s, IH), 5.62 (s, IH), 5.49-5.45 (m, 4H), 3.93 (s, 2H), 3.33-3.27 (m, 2H), 2.19-2.16 (m, 2H), 1.70-1.67 (m, 2H), 1.49 (s, 9H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (50c)
Tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine- 1 - carboxylate (50c) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2023/23255. tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (50c) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4- (3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (50b, 180 mg, 1.0 eq., 0.28 mmol). The crude material was purified by reverse phase chromatography C18 (12 g), eluting with Mobile phase A: 0.1% HCOOH in H2O: MeCN, Mobile phase B: Acetonitrile, flow rate: 15 mL/min], The pure product containing fractions were collected and lyophilized to afford tert-butyl 4-(3- (2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (50c, 0.08 g, 0.14 mmol, 49% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 458.2. 'H-NMR (400 MHz, DMSO- d6y. 5 10.97 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.06 (t, J = 8.80 Hz, 1H), 7.89 (d, J = 8.80 Hz, IH), 5.60 (s, 1H), 4.25-4.21 (m, 1H), 3.88-3.52 (m, 3H), 3.31-3.21 (m, 3H), 2.75-2.72 (m, 2H), 2.12- 2.00 (m, 4H), 2.00-1.67 (m, 3H), 1.43-1.36 (m, 6H).
Step 4: Synthesis of 3-(5-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (50d) 3-(5-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (50d, 30 mg, 0.07 mmol, 35% yield) was synthesized according to General Procedure 1, Step C starting from tert-butyl 4- (3-(2, 6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy -piperidine- 1 -carboxylate (50c, 80 mg, 1.0 eq., 0.18 mmol). The crude compound was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 358.2.
Step 5: Synthesis of 3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-89) 3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine-
2, 6-dione (1-89) was synthesized according to General Procedure 1, Step D starting from 3-(5-fluoro-6- (4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (50d, 30 mg, 1.0 eq., 0.066 mmol) and 4- (trifluoromethyl)benzaldehyde (17e, 17.7 mg, 1.5 eq., 0.10 mmol). The crude compound was purified by preparative-HPLC [(Column: X Select C18 (250*19mm) eluting with Mobile phase A: 0.05% HCI in H2O: MeCN, Mobile phase B: Acetonitrile, flow rate: 15 rnL/min, Rt:12.5 min)]. The pure product containing fractions were collected and lyophilized to afford 3-(5-fhioro-6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-89, 3 mg, 5.41 pmol. 9% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 516.3. 'H-NMR (400 MHz, DMSO-rT): 5 10.99 (s, 1H), 10.40 (s, 1H), 8.92 (s, 1H), 8.36 (s, 1H), 8.04 (t, 1 = 8.80 Hz, 1H), 7.96-7.90 (m, 5H), 6.01 (S,
1H), 4.53 (d, J = 5.20 Hz, 2H), 4.26-4.23 (m, 1H), 3.42-3.36 (m, 4H), 2.74-2.67 (m, 1H), 2.64-2.45 (m,
4H), 2.34-2.33 (m, 1H), 2.21-2.14 (m, 2H).
Example 51: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-82)
Figure imgf000413_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3- dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (51a) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2H)-carboxylate (51a) was synthesized according to General Procedure 5 starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C, 1.5 g, 1.0 eq., 3.18 mmol) and tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (INT-40, 2.15 g, 2.0 eq., 6.37 mmol). The crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-60% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-dimethyl- 3,6-dihydropyridine-l(2rt)-carboxylate (51a, 1.0g, 1.55mmol, 45% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 646.6. ’H-NMR (400 MHz, DMSO-cL): 59.17 (s, 1H), 8.59 (s, 1H), 8.06 (d, J = 8.00 Hz, 1H), 7.84 (d, J = 8.40 Hz, 1H), 7.53-7.51 (m, 3H), 7.49-7.42 (m, 4H), 7.36-7.32 (m, 4H), 6.67 (d, J = 8.00 Hz, 1H), 5.61 (s, 1H), 5.46 (d, J = 5.20 Hz, 4H), 4.04 (t, J = 7.20 Hz, 2H), 3.33 (s, 2H), 1.44 (s, 9H),
1.09 (s, 6H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate (51b) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate (51b) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fhioroquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2rt)-carboxylate (51a, 1.0 g, 1.0 eq., 1.55 mmol). The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 70% EtOAc in hexane to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate (51b, 0.33g, 0.5mmol, 31% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 664.7. ’H-NMR (400 MHz, DMSO-<fc): 89.15 (s, 1H), 8.63 (s, 1H), 8.08 (d, J = 8.40 Hz, 2H), 7.85 (d, J = 9.20 Hz, 1H), 7.46-7.36 (m, 9H), 6.67 (d, J = 8.00 Hz, 2H), 5.46 (s, 4H), 3.98 (d, J = 39.20 Hz, 1H), 3.93-2.50 (m, 4H), 1.69-1.66 (m, 2H), 1.70 (s, 9H), 1.26 (s, 3H), 0.79 (s, 3H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate (51c) tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethyl- piperidine-1 -carboxylate (51c, 550mg, 1.13mmol, 57% yield;) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5-fluoroquinolin-6- yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (51b, 1.0 g, 1.0 eq., 1.5 mmol). LCMS: m/z MM- ES+APCI, Positive | M+H |+ = 486.8. ’H-NMR (400 MHz, DMSO-tfc): 6 10.98 (s, 1H), 8.86 (s, 1H), 8.33 (d, J = 2.00 Hz, 1H), 8.09 (t, J = 4.8 Hz, 1H), 7.87 (d, J = 8.80 Hz, 1H), 5.45 (s, 1H), 4.24-4.20 (m, 1H), 4.03 (br s, 2H), 3.49-3.23 (m, 3H), 2.96-2.92 (m, 1H), 2.77-2.72 (m, 1H), 2.68-2.60 (m, 1H), 2.16-2.11 (m, 1H), 1.68 (d, J = 13.20 Hz, 1H), 1.41 (s, 9H), 0.86 (s, 3H). 0.68 (s, 3H).
Step 4: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (51d)
3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, (51d, 500 mg, 1.06 mmol, 93% yield) was synthesized according to General Procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate (51c, 550 mg, 1.0 eq., 1.13 mmol). The product obtained was taken onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 386.0. ’H-NMR (400 MHz, DMSO-c/s): 5 11.00 (s, 1H), 9.08 (d, J = 11.60 Hz, 1H), 8.90 (s, 1H), 8.38 (s, 2H), 8.08 (t, J = 8.40 Hz, 1H), 7.99-7.89 (m, 1H), 5.87 (s, 1H), 4.27-4.22 (m, 1H), 3.23-2.90 (m, 4H), 2.74-2.60 (m, 2H), 2.15-1.91 (m, 2H), 1.30-1.19 (m, 2H), 1.05 (s, 3H), 0.76 (s, 3H).
Step 5: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-82)
3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-82) was synthesized according to General Procedure 1, Step D starting from 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (51d, 100 mg, 1.0 eq., 0.24mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 41 mg, 1.0 eq., 0.24 mmol). The crude compound was purified by preparative-HPLC [(Column: X Select C18 (250*19mm) eluting with Mobile phase A: 0.05% HC1 in H2O: MeCN, Mobile phase B: Acetonitrile, flow rate: 15 mL/min], The pure product containing fractions were collected and lyophilized to afford 3-(5-fhioro-6-(4-hydroxy-3,3- dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-82, 14.99 mg, 0.03 mmol, 12% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 544.3. ’H-NMR (400 MHz, DMSO-r/s): 8 10.99 (s, 1H), 9.98 (s, 1H), 8.89 (d, J = 2.00 Hz, 1H), 8.38 (s, 1H), 8.07 (t, J = 8.80 Hz, 1H), 7.93-7.95 (m, 5H), 5.93 (s, 1H), 4.56-4.48 (m, 2H), 4.29 (d, J = 4.80 Hz, 1H), 3.61-3.33 (m, 4H), 2.82 (t, J = 4.40 Hz, 2H), 2.76-2.62 (m, 2H), 2.27-2.25 (m, 1H), 2.02-1.99 (m, 1H), 1.11 (s, 3H), 0.78 (s, 3H).
Example 52: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (1-34)
Figure imgf000415_0001
3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione (1-34) was synthesized according to General Procedure 1, Step D starting from 3-(5-fluoro-6-(4- hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (51d, 250 mg, 1.0 eq., 0.65 mmol) and acetaldehyde (0.073 mL, 2.0 eq., 1.3 mmol). The crude product was purified by reverse phase purification using Column: C18, eluting with Mobile phase A: 0.1% HCOOH in H2O, Mobile phase B: Acetonitrile, product eluted at 50% MeCN in water (0.1% HCOOH)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione (1-34, 21.1 mg, 0.05 mmol, 7% yield). LCMS: m/z MM-
ES+APCI, Positive [M+H]+ = 414.2. ’H-NMR (400 MHz, DMSO-cfc): 5 10.98 (s, 1H), 8.85 (d, J = 2.00
Hz 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.10 (t, J = 8.80 Hz, 1H), 7.84 (d, J = 8.80 Hz, 1H), 5.11 (s, 1H), 4.25-
4.20 (m, 1H), 3.14-3.07 (m, 1H), 2.68-2.51 (m, 4H), 2.44-2.42 (m, 4H), 2.39-2.37 (m, 1H), 2.32 (t, J =
12.80 Hz, 1H), 1.71 (d, J = 12.80 Hz, 1H), 1.23 (t, J = 7.20 Hz, 3H), 1.07 (s, 3H), 0.82 (s, 3H).
Example 53: Synthesis of 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-
5-fluoroquinolin-3-yl)piperidine-2, 6-dione (1-79)
Figure imgf000416_0001
Step 1: Synthesis of tert-butyl 3,3-diethyl-4-oxopiperidine-l-carboxylate (53a)
To a solution of tert-butyl 4-oxopiperidine-l -carboxylate (18a, 40 g, 201 mmol) in THF (480 mL) under an atmosphere of nitrogen was added KHMDS (1 M in THF) (500 mL, 500 mmol) at 0 °C and the resulting mixture was stirred for 1 h. lodoethane (125 g, 804 mmol) was then added and stirring was continued at 25 °C for 16 h. Water (500 mL) was added and the resulting aqueous mixture was extracted with EtOAc (2 x 500 mL). The combined organic phases were washed with water (50 mL) and brine solution (50 mL), dried over anhydrous NaiSOr. filtered, and concentrated under reduced pressure. This crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-
200 mesh) eluting with 0-10% EtOAc in hexanes to afford tert-butyl 3,3-diethyl-4-oxopiperidine-l- carboxylate (53a, 7 g, 23.03 mmol, 11% yield). LCMS: m/z MM-ES+APCI, Positive [M-Boc+H]+ 156.0. ’H-NMR (400 MHz, DMSO-t/e): 53.60 (t, J = 6.40 Hz, 2H), 3.40 (s, 2H), 2.39 (t, J = 6.40 Hz, 2H), 1.52- 1.37 (m, 13H), 0.72 (t, J = 7.60 Hz, 6H).
Step 2: Synthesis of tert-butyl 3,3-diethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- l(2H)-carboxylate (53b)
To a solution of tert-butyl 3,3-diethyl-4-oxopiperidine-l-carboxylate (4 g, 15.66 mmol) in THF (40 mL) was added KHMDS (1 M in THF) (31.32 mL, 31.32 mmol) under an atmosphere of nitrogen at - 78 °C and the resulting mixture was stirred at -78 °C for 1 h. N-phenylbis(trifluoromethanesulfonimide) (11.18 g, 31.32 mmol) dissolved in THF (10 mL) was then added dropwise at -78 °C and stirring was continued at 25 °C for 6 h. Water (100 mL) was added and the resulting aqueous mixture was extracted with EtOAc (150 mL). The organic phases were washed with water (50 mL) and brine solution (10 mL), dried over anhydrous NaiSO^ filtered, and concentrated under reduced pressure. This crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-50% EtOAc in hexanes to afford tert-butyl 3,3-diethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-l(2H)-carboxylate (53b, 4.5 g, 11.57 mmol, 74% yield) as gum, LCMS: m/z MM- ES+APCI, Positive [M-tBu+H]+ 332.2. ’H-NMR (400 MHz, DMSO-ds): 55.96 (s, 1H), 4.01 (s, 2H), 3.42 (s, 2H), 1.48-1.37 (m, 13H), 0.85 (t, J = 7.20 Hz, 6H).
Step 3: Synthesis of tert-butyl 3,3-diethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (53c)
A solution of tert-butyl 3,3-diethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-pyridine- 1(2H) -carboxylate (53b, 5 g, 12.9 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(l,3,2-dioxaborolane) (4.91 g, 19.35 mmol) and potassium acetate (3.8 g, 38.7 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen at 25 °C for 10 min. Pd(dppf)C12,DCM(1.05 g, 1.29 mmol) was then added and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-7% EtOAc in hexanes to afford tert-butyl 3 ,3-diethyl-4-(4,4,5 ,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (53c, 2.5 g, 6.84 mmol, 53% yield). LCMS: m/z MM-ES+APCI, Positive [M— tBu+H]+ 310.32. 1H-NMR (400 MHz, CDCh): 5 6.55- 6.45 (m, 1H), 3.95-3.85 (m, 2H), 3.3-3.25 (m, 2H), 1.48 (br s, 4H), 1.27 (m, 21H), 0.81 (t, J = 7.60 Hz,
6H).
Step 4: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3- diethyl-3,6-dihydropyridine-l(2H)-carboxylate (53d) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-3,6- dihydropyridine-l(2H)-carboxylate (53d) was synthesized according to General Procedure 5 starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C, 500mg, 1.0 eq., 1.06 mmol) and tert-butyl 3,3-diethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (53c, 582 mg, 1.5 eq., 1.59 mmol). The crude material was purified by flash column chromatography Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 20% EtOAc in n-hexane to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-3,6- dihydropyridine-l(2H)-carboxylate (53d, 0.3 g, 0.37 mmol, 34% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 674.4. ’H-NMR (400 MHz, DMSO-t/s): 59.16 (d, J = 2.40 Hz, 1H), 8.60 (d, J = 1.60 Hz, IH), 8.07 (d, J = 8.00 Hz, 1H), 7.83 (d, J = 8.80 Hz, 1H), 7.52-7.37 (m, 11H), 6.67 (d, J = 8.40 Hz, 1H), 5.77 (m, IH), 5.46 (m, 4H), 4.06-4.01 (m, 2H), 3.46 (s, 2H), 1.46 (s, 9H), 1.43-1.41 (m, 4H), 0.80 (s, 6H).
Step 5: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3- diethyl-4-hydroxypiperidine-l-carboxylate (53e) tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4- hydroxypiperidine-1 -carboxylate (53e) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-3,6- dihydropyridine-l(2H)-carboxylate (53d, 400 mg, 1 eq., 0.59 mmol). The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 50% EtOAc in hexane to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3- diethyl-4-hydroxypiperidine-l -carboxylate (53e, 140 mg, 0.20 mmol, 34% yield). LCMS: m/z MMES+APCI, Positive [M+H]+ 692.6. ’H-NMR (400 MHz, DMSO-J6): 59.14 (d, J = 2.00 Hz, IH), 8.63 (s, IH), 8.19-0.15 (m, IH), 8.07 (d, J = 8.40 Hz, IH), 7.84 (d, J = 9.20 Hz, IH), 7.44-7.35 (m, 10H), 6.67 (d, J = 8.40 Hz, IH), 5.50-5.42 (m, 5H), 4.06-4.01 (m, 2H), 3.11-3.00 (m, 4H), 1.73-1.59 (m, 4H), 1.45 (s, 9H), 1.24-1.05 (m, 6H).
Step 6: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4- hydroxypiperidine- 1-carboxylate (531) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxy- piperidine- 1-carboxylate (53f) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxypiperidine- 1 -carboxylate (53e, 200 mg, 1.0 eq., 0.29 mmol). The crude product was purified by reverse phase column chromatography eluting with 5 to 100% MeCN in 0.1% formic acid in water. The pure product containing fractions were collected and lyophilized to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5- fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxypiperidine-l-carboxylate (53f, 100 mg, 0.18 mmol, 61% yield) as gum. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 514.4. ’H-NMR (400 MHz, DMSO-ds): 5 10.98 (s, IH), 8.85 (d, J = 2.40 Hz, IH), 8.32 (s, IH), 8.18 (t, J = 8.80 Hz, IH), 7.85 (d, J = 9.20 Hz, IH), 5.47 (s, 1H), 4.25-4.21 (m, 1H), 3.95-3.67 (m, 2H), 3.32-2.98 (m, 3H), 2.76-2.63 (m, 2H), 2.33-2.13 (m, 1H), 1.72 (s, 1H), 1.60 (m, 2H), 1.44 (s, 9H), 1.41 (s, 2H), 1.19 (s, 1H), 0.75-0.72 (m, 4H), 0.52-0.45 (m, 2H). Step 7: Synthesis of 3-(6-(3,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione, HC1 (53g)
3-(6-(3,3-Diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione, HC1 (53g, 80 mg, 0.14 mmol, 89% yield) was synthesized according to General Procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3,3-diethyl-4-hydroxypiperidine-l- carboxylate (53f, 80 mg, 1.0 eq., 0.16 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 414.6. *H- NMR (400 MHz, DMSO-ds): 5 11.00 (s, 1H), 9.06 (hr s, 1H), 8.90 (d, J = 2.00 Hz, 1H), 8.39 (s, 1H),
8.19-0.15 (m, 1H), 7.92-7.86 (m, 1H), 5.92 (s, 1H), 4.27-4.22 (m, 1H), 3.23-2.96 (m, 5H), 2.77-2.61 (m,
2H), 2.34-2.13 (m, 2H), 1.85-1.83 (m, 1H), 1.64-1.60 (m, 1H), 1.44 (s, 1H), 1.24-1.20 (m, 2H), 0.74-0.52
(m, 3H), 0.49-0.45 (m, 3H).
Step 8: Synthesis of 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione (1-79)
3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2,6-dione (1-79) was synthesized according to General Procedure 1, Step D starting from 3-(6-(3,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione, HC1 (53g, 40 mg, 1.0 eq., 0.09 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 19 mg, 1.2 eq., 0.11 mmol). The crude product was purified by preparative-HPLC [X Select C18 (250* 19mm), eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min, Rt: 12.0] . The pure product containing fractions were collected and lyophilized to afford 3-(6-(3,3-diethyl-4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine -2, 6-dione (1-79, 10.6 mg, 0.02 mmol, 20% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 572.6. 'H-NMR (400 MHz, DMSO- d6): 5 11.00 (s, 1H), 9.85 (s, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.14 (t, J = 8.80 Hz, 1H), 8.00 (m, 2H), 7.89 (d, J = 3.60 Hz, 3H), 5.98 (s, 1H), 4.57-4.52 (m, 2H), 4.29 (m, 2H), 3.25-3.20 (m, 4H), 2.77-2.73 (m, 2H), 2.68-2.64 (m, 1H), 2.13 (m, 2H), 1.93 (m, 1H), 1.63 (m, 1H), 1.18-1.12 (m, 2H), 0.52 (t, J = 7.20 Hz, 3H), 0.45 (t, J = 7.60 Hz, 3H).
Example 54: Synthesis of 3-(5-fluoro-6-(l,3,3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-68)
Figure imgf000419_0001
3-(5-fluoro-6-(l, 3, 3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-68) was synthesized according to General Procedure 1, Step D starting from 3-(6-(3,3-diethyl-4- hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione, HC1 (53g, 40 mg, 1.0 eq., 0.09mmol) and acetaldehyde (4.26 mg, 1.1 eq., O.lmmol).. The crude product was purified by preparative-HPLC [X SELECT C18 (19*250MM), eluting with Mobile phase A: 0.05% HC1 in water, Mobile phase B: Acetonitrile, flow rate: 14.0 mL/min) Rt:l 1.5]. The pure product containing fractions were collected and lyophilized to afford 3-(5-fluoro-6-( 1 ,3,3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (1-68, 9.5 mg, 0.02 mmol, 22% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 442.6. ’H- NMR (400 MHz, DMSO-ds): 5 11.00 (s, 1H), 9.42 (s, 1H), 8.91 (d, J = 2.00 Hz, 1H), 8.41 (s, 1H), 8.18
(m, 1H), 7.92 (m, 1H), 5.98 (s, 1H), 4.25 (m, 1H), 3.37-3.21 (m, 6H), 3.20-3.11 (m, 2H), 2.68-2.61 (m,
2H), 2.17-2.15 (m, 2H), 1.93 (m, 1H), 1.69-1.67 (m, 1H), 1.33 (t, J = 7.20 Hz, 3H), 1.26-1.20 (m, 2H),
0.72 (m, 3H), 0.51 (m, 3H).
Example 55: Synthesis of 3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoro-methyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-64)
Figure imgf000420_0001
Step 1: Synthesis of tert-butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (55a) tert-butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-2-azaspiro[5.5]-undec-4- ene-2-carboxylate (55a) was synthesized according to General Procedure 5 starting from 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-chloro-5-fluoroquinoline (INT-4C, 250mg, 1.0 eq., 0.53 mmol) and tertbutyl 5-(4,4,5,5-tetramethyl-l,3 2-dioxaborolan-2-yl)-2-azaspiro[5 5]undec-4-ene-2-carboxylate (42b 240 mg, 1.2 eq., 0.64 mmol). This crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-100% EtOAc in hexanes to afford tert- butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-quinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (55a, 150 mg, 0.19 mmol, 36% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 686.5. ’H-NMR (400 MHz, DMSO-t/s): 89.16 (s, 1H), 8.60 (s, 1H), 8.06 (d, J = 8.40 Hz, 1H), 7.83 (d, J = 8.40 Hz, 1H),
7.41-7.37 (m, 11H), 6.67 (d, J = 8.00 Hz, 1H), 5.65-5.58 (m, 1H), 5.47 (s, 2H), 5.46 (s, 2H), 4.06-4.01
(m, 2H), 3.64 (s, 2H), 1.47-1.16 (m, 19H).
Step 2: Synthesis of tert-butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-5- hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (55b) tert-Butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2- azaspiro[5.5]undecane-2-carboxylate (55b) was synthesized according to General Procedure 3, Step C starting from tert-butyl 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (55a, 500 mg, 1.0 eq., 0.73 mmol). The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 100% EtOAc in hexane to afford tert-butyl 5-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5- fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (55b, 0.2 g, 0.22 mmol, 31% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 704.4, 'H-NMR (400 MHz, DMSO-tfc): 3 9.15 (s, 1H), 8.62 (s, 1H), 8.08 (d, J = 8.00 Hz, 2H), 7.91-7.83 (m, 1H), 7.43-7.39 (m, 10H), 6.67 (d, J = 8.00 Hz, 1H), 5.42-5.39 (m, 5H), 4.19-4.01 (m, 2H), 3.07-2.96 (m, 2H), 1.82-1.45 (m, 4H), 1.20-1.14 (m, 17H). Step 3: Synthesis of tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2- azaspiro[5.5]undecane-2-carboxylate (55c) tert-Butyl 5-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro- [5.5]undecane-2-carboxylate (55c, 170 mg, 0.27 mmol, 64% yield) was synthesized according to General Procedure 1, Step B starting from tert-butyl 5-(3-(2,6-bis(benzyloxy)-pyridin-3-yl)-5-fluoroquinolin-6- yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (55b, 300 mg, 1.0 eq., 0.43 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 526.3.
Step 4: Synthesis of 3-(5-fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine- 2, 6-dione (55d)
3-(5-Fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (55d) was synthesized according to General Procedure 1, Step C starting from tert-butyl 5-(3-(2,6- dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (55c, 170 mg, 1.0 eq., 0.32 mmol). The crude compound was triturated with hexane 10 mL, filtered, and dried to afford 3-(5-fluoro-6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (55d, 120 mg, 0.21 mmol, 64% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 426.1. Step 5: Synthesis of 3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoro-methyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-64) 3-(5-fluoro-6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3- yl)piperidine-2, 6-dione (1-64) was synthesized according to General Procedure 1, Step D starting from 3-(5-fhioro-6-(5-hydroxy-2-azaspiro[5.5]-undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (55d, 60 mg, 1.0 eq., 0.13 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 23 mg, 1.0 eq., 0.13 mmol). The crude compound was purified by preparative-HPLC [(Column: X Select C18 (250*19mm) eluting with Mobile phase A: 0.05% HC1 in H2O: MeCN, Mobile phase B: Acetonitrile, flow rate: 15 mL/min], The pure product containing fractions were collected and lyophilized to afford 3-(5-fluoro-6-(5-hydroxy-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-64, 4.5 mg, 7.23 pmol, 6% yield) as solid. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 584.2. 'H-NMR (400 MHz, DMSO-de): 5 11.00 (s, IH), 9.50 (s, IH), 8.89 (s, IH), 8.36 (s, IH), 8.03 (t, J = 8.80 Hz, IH), 7.93-
7.89 (m, 5H), 5.88 (s, IH), 4.60 (s, 2H), 4.26-0.21 (m, IH), 3.67-3.61 (m, 2H), 3.19-3.17 (m, 2H), 2.77-
2.64 (m, 2H), 2.45-2.39 (m, 2H), 2.15-2.12 (m, IH), 1.97-1.92 (m, 1H), 1.83 (d, J = 13.20 Hz, 1H), 1.44-
1.24 (m, 4H), 1.08-0.84 (m, 5H).
Example 56: Synthesis of 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]-undecan-5-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (1-92)
H
O. N .0 CH3CHO, STAB, H
HN O. N .0
.OH 1? DMF, rt, 18 h N OH 1?
JI Step 1 If
55d 1-92
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoro-quinolin-3-yl)piperidine-2,6- dione (1-92) was synthesized according to General Procedure 1, Step D starting from 3-(5-fluoro-6-(5- hydroxy-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (55d, 150mg, 1.0 eq., 0.35 mmol) and acetaldehyde (15mg, 1.0 eq., 0.35mmol). The crude compound was purified by prep-HPLC [X SELECT C18 (19*150), eluting with Mobile phase A: 0.1% formic acid, Mobile phase B: Acetonitrile, flow rate: 15 mL/min), Rt: 9.3 min]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione (1-92, 7.5 mg, 0.02 mmol, 3% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 454.2. ’H- NMR (400 MHz, DMSO-ds): 5 10.98 (s, 1H), 8.85 (s, 1H), 8.34 (s, IH), 8.18 (s, 1H), 8.09 (d, J = 8.80 Hz, IH), 7.84 (d, J = 8.80 Hz, 1H), 5.06 (s, 1H), 4.24-4.20 (m, 1H), 2.80 (d, J = 4.1 Hz, 1H), 2.76 (d, J = 4.40 Hz, IH), 2.64-2.59 (m, 3H), 2.46-2.42 (m, 2H), 2.33 (m, IH), 2.16 (t, J = 5.20 Hz, 3H), 1.77 (d, J = 8.80 Hz, IH), 1.65 (d, 7 = 9.20 Hz, IH), 1.26-1.30 (m, 6H), 1.07 (t, J = 7.20 Hz, 3H), 0.87 (t, 7 = 6.8 Hz, IH), 0.70 (m, 2H).
Example 57: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- methylquinolin-3-yl)piperidine-2, 6-dione (1-45)
Figure imgf000423_0001
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-5-methylquinoline (57b)
A solution of 6-chloro-3-iodo-5 -methylquinoline (57a, 180 mg, 0.59 mmol) and 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 297 mg, 0.71 mmol) in 1 ,4-dioxane: water (4:1), 5 mL was degassed with nitrogen gas for 10 min. After 10 min, DIPEA (0.259 mL, 1.48 mmol) and Pd(tBu3P)2 (30.3 mg, 0.06 mmol) were added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was evaporated to dryness. The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with 0-10% of EtOAc in hexane to afford 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-chloro-5-methylquinoline (57b, 130 mg, 0.23 mmol, 38% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 467.7. ‘H-NMR (400 MHz, DMSO-tfc): 59.12 (d, 7 = 2.4 Hz,
1H), 8.64 (d, 7 = Hz, 1H), 8.08 (d, J = 8.40 Hz, IH), 7.88 (d, 7 = 8.80 Hz, 1H), 7.74 (d, 7 = 8.80 Hz, 1H),
7.43-7.37 (m, 10H), 6.69 (d, 7 = 8.00 Hz, IH), 5.46 (d, 7 = 7.60 Hz, 4H), 2.64 (s, 3H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (57c) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-3,6-dihydro-pyridine- 1(2H) -carboxylate (57c) was synthesized according to General Procedure 5 starting from 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-chloro-5-methylquinoline (57b, 100 mg, 1 eq., 0.21 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (132 mg, 2.0 eq. 0.43 mmol). The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with 0-20% of EtOAc in hexane to afford tert-butyl 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (57c, 60 mg, 0.09 mmol, 44% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 614.3. ’H-NMR (400 MHz, DMSO-t/s): 59.07 (d, J = 2.4 Hz 1H), 8.59 (s, 1H), 8.05 (d, J = 8.00 Hz, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.48-7.37 (m, 11H), 6.68 (d, J = 8.00 Hz, 2H), 5.64 (s, 1H), 5.46 (d, J = 4.40 Hz, 4H), 4.03 (s, 2H), 3.92 (s, 5H), 1.46 (s, 10H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (57d) tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (57d) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4- (3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (57c), 80 mg, 1.0 eq., 0.13mmol). The crude compound was purified by flash column chromatography using Combi-Flash (on silica gel, 100-200 mesh) eluting with 0-20% of EtOAc in hexane to afford tert- butyl 4- (3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (57d, 60 mg, 0.06 mmol, 49% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 632.3.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (57e)
To a stirred solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-methyl-quinolin-6-yl)- 4-hydroxypiperidine- 1-carboxylate (57d, 60 mg, 0.10 mmol) in DMF (4 mL) was added Pd/C (505 mg, 0.48 mmol) at room temperature and the resulting mixture was sparged with hydrogen and stirred under an atmosphere of hydrogen using a balloon at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was evaporated to dryness to afford tert-butyl 4-(3-(2,6- dioxopiperidin-3-yl)-5-methylquinolin-6-yl)-4-hydroxy-piperidine- 1-carboxylate (57e, 40 mg, 0.04 mmol, 46% yield). The product was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 454.4.
Step 5: Synthesis of 3-(6-(4-hydroxypiperidin-4-yl)-5-methylquinolin-3-yl)piperidine-2, 6-dione (57f) 3-(6-(4-Hydroxypiperidin-4-yl)-5-methylquinolin-3-yl)piperidine-2, 6-dione HC1 (57f, 30 mg, 0.05 mmol, 64% yield) was synthesized according to General Procedure 6, Step A starting from tert- butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-methylquinolin-6-yl)-4-hydroxy-piperidine-l -carboxylate (57e, 50 mg, 1 eq., 0.08 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 354.2.
Step 6: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin- 3-yl)piperidine-2, 6-dione (1-45) 3-(6-(4-Hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin-3-yl)piperidine- 2,6-dione (1-45) was synthesized according to General Procedure 6, Step B starting from 3-(6-(4- hydroxypiperidin-4-yl)-5-methylquinolin-3-yl)piperidine-2, 6-dione HC1 (57f, 30 mg, 1.0 eq., 0.085 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 18 mg, 1.2 eq., 0.1 mmol). The crude material was purified by prepared ve-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% acetic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were combined and lyophilized to afford 3-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin-3-yl)piperidine-2, 6-dione (1-45, 1.2 mg, 2.32 mmol, 4% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 512.2. ’H-NMR (400 MHz, DMSO- de): 5 10.95 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.90 (d, J = 9.20 Hz, 1H), 7.82 (d, 7 = 8.80 Hz, 1H), 7.71
(d, J = 8.00 Hz, 2H), 7.59 (d, 7 = 8.00 Hz, 2H), 5.00 (s, 1H), 4.20-4.15 (m, 1H), 3.63 (s, 2H), 2.93 (s, 3H), 2.82-2.76 (m, 2H), 2.65-2.48 (m, 4H), 2.19-2.10 (m, 3H), 1.99-1.88 (m, 3H). 19F-NMR (400 MHz, DMSO-<7>): 5 -60.736.
Example 58: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-58)
Figure imgf000425_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (58a) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (58a) was synthesized according to General Procedure 4 starting from 3-(6-bromo-2- methylquinolin-3-yl)piperidine 2 6 dione (INT 2 90 mg 1 eq 0 27 mmol) and tert butyl 4 (4 4 5 5 tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 92 mg, 1.1 eq., 0.30 mmol). The reaction mixture was concentrated and loaded onto a silica gel column for purification eluting with heptanes and EtOAc. The compound did not elute with 100% EtOAc and 20% IP A was needed to elute the product. The desired fractions were collected, combined, and concentrated in vacuo to yield tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (58a, 118 mg, 0.27 mmol, 100% yield). LCMS: m/z HESI, positive [M+H]+= 436.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (58b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-4-hydroxypiperidine- 1 - carboxylate (58b) was synthesized according to General Procedure 3, Step B starting from tert-butyl 4- (3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (58a, 118 mg, 1 eq., 0.27 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via C18 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and lyophilized to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (58b, 94 mg, 0.21 mmol, 77% yield). LCMS: m/z HESI, positive [M+H]+ = 454
Step 3: Synthesis of 3-(6-(4-hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (58c)
3-(6-(4-Hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (58c) was synthesized according to General Procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin- 3-yl)-2-methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (58b, 94 mg, 1.0 eq., 0.21 mmol). Quantitative yield was assumed for the reaction and 3-(6-(4-hydroxy-piperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (58c, 73 mg, 0.21 mmol, quantitative yield) was carried onto the next step without further purification. HESI, positive [M+H]+ = 354.
Step 4: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-2-methylquinolin-
3-yl)piperidine-2, 6-dione (1-58)
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine- 2, 6-dione (1-58) was synthesized according to General Procedure 1, Step D starting from 3-(6-(4- hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (58c, 73 mg, 1.0 eq., 0.21 mmol) and
4-(trifluoromethyl)benzaldehyde (17e, 34 uL, 1.2 eq., 0.25 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Cl 8 column eluting with 0-100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and concentrated in vacuo to yield 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-58, 19.6 mg, 0.04 mmol, 19% yield) as a mixture of diastereomers. LCMS: m/z HESI, positive |M+H|+ = 512. *H NMR (499 MHz, DMSO-cL) 5 (ppm) = 10.96-10.92 (m, 1H), 8.23 (s, 1H), 8.11-8.07 (m, 1H), 7.95-7.92 (m, 1H), 7.85 (s, 2H), 7.72-7.67 (m, 2H),
7.61-7.57 (m, 2H), 5.06-4.96 (m, 1H), 4.31-4.23 (m, 1H), 3.65-3.61 (m, 2H), 2.87-2.77 (m, 1H), 2.67-
2.62 (m, 6H), 2.61-2.58 (m, 1H), 2.55-2.51 (m, 1H), 2.46-2.35 (m, 1H), 2.15-2.02 (m, 3H), 1.71-1.64 (m,
2H), 1.24-1.21 (m, 1H).
Example 59: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]-undecan-5- yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-63)
Figure imgf000427_0001
Step 1: Synthesis of 3-(2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-3- yl)piperidine-2, 6-dione (59a)
3-(2-Methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-3-yl)piperidine-2,6-dione (59a, 57 mg, 0.15 mmol, quantitative yield) was synthesized according to General Procedure 3, Step A starting from 3-(6-bromo-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-2, 50 mg, 1 eq., 0.15 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was earned as a solution in dioxane onto to the next step without further purification. Quantitative yield is assumed for the reaction. LCMS: m/z HESI, positive [M+H]+ = 381.
Step 2: Synthesis of 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5- yl)quinolin-3-yl)piperidine-2, 6-dione (59b)
3-(2-Methyl-6-(2-(4-(trifhioromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3- yl)piperidine-2, 6-dione (59b) was synthesized according to General Procedure 3, Step B starting from a dioxane solution of 3-(2-methyl-6-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)quinolin-3-yl)piperidine- 2, 6-dione (59a, 57 mg, 1 eq., 0.15 mmol) and 2-(4-(trifhioromethyl)-benzyl)-2-azaspiro[5.5]undec-4-en- 5-yl trifluoromethanesulfonate (INT-72, 75 mg, 1.1 eq., 0.16 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via C18 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and lyophilized to yield 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)- 2-azaspiro[5.5]-undec-4-en-5-yl)quinolin-3-yl)piperidine-2, 6-dione (59b, 41 mg, 0.07 mmol, 49% yield). LCMS: m/z HESI, positive | M+H|+ = 562.
Step 3: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-63)
3-(6-(5-Hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methyl-quinolin-
3-yl)piperidine-2, 6-dione (1-63) was synthesized according to General Procedure 3, Step C starting from 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3- yl)piperidine-2, 6-dione (59b, 41 mg, 1 eq., 0.07 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via CIS column eluting from 0 to 100% MeCN in H2O (10 mM NELOAc solution). The desired fractions were collected, combined and lyophilized to yield 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-63, 1.9 mg, 0.003 mmol, 5% yield) as a mixture of diastereomers. LCMS: m/z HESI, positive [M+H]+ = 580. ’H NMR (499 MHz, DMSO-ds) 5 (ppm) = 10.98-10.89 (m, 1H), 8.15-8.10 (m, 1H), 7.93-7.87 (m, 1H), 7.86-7.79 (m, 2H), 7.70 (s, 2H), 7.61 (s, 2H), 4.32-4.23 (m, 1H), 3.69-3.64 (m, 1H), 3.61-3.55 (m, 1H), 2.90-2.78 (m, 3H), 2.71-2.67 (m, 1H), 2.66-2.62 (m, 3H), 2.62-2.56 (m, 1H), 2.46-2.41 (m, 1H), 2.32-2.26 (m, 2H), 2.17- 2.09 (m, 1H), 2.03-1.94 (m, 1H), 1.75-1.69 (m, 1H), 1.59-1.55 (m, 1H), 1.50-1.44 (m, 1H), 1.26-1.21 (m, 3H), 1.09-0.97 (m, 2H), 0.91-0.82 (m, 1H), 0.71-0.62 (m, 1H), 0.55-0.47 (m, 1H).
Example 60: Synthesis of 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (1-24)
Figure imgf000428_0001
Step 1: Synthesis of /e/7- butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (60a) tert-Butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2- carboxylate (60a) was synthesized according to General Procedure 3, Step B starting from 3-(2-methyl- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-3-yl)piperidine-2,6-dione (59a, 57 mg, 1 eq., 0.15 mmol) and tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (37c, 66 mg, 1.1 eq., 0.16 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated purified via C18 column eluting 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and concentrated in vacuo to yield tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-2- azaspiro[5.5]undec-4-ene-2-carboxylate (60a, 45 mg, 0.09 mmol, 60% yield). LCMS: m/z HESI, positive [M+H]+ = 504.
Step 2: Synthesis of tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-5-hydroxy-2- azaspiro[5.5]undecane-2-carboxylate (60b) tert-Butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-5-hydroxy-2- azaspiro[5.5]undecane-2-carboxylate (60b) was synthesized according to General Procedure 3, Step C starting from tert-Butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin-6-yl)-2-azaspiro[5.5]undec-4- ene-2-carboxylate (60a, 45 mg, 1 eq., 0.09 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via Cl 8 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and lyophilized to yield tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-2-methylquinolin- 6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (60b, 47 mg, 0.09 mmol, 100% yield). LCMS: m/z HESI, positive [M+H]+= 522.
Step 3: Synthesis of 3-(6-(5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)piperidine- 2, 6-dione (60c)
3-(6-(5-Hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (60c) was synthesized according to General Procedure 1, Step C starting from tert-butyl 5-(3-(2,6-dioxo- piperidin-3-yl)-2-methylquinolin-6-yl)-5-hydroxy-2-azaspiro[5.5]undecane-2-carboxylate (60b, 47 mg, 1 eq., 0.09 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo. The material was carried onto the next step without step without further purification. 3-(6-(5-hydroxy-2-azaspiro[5.5]-undecan-5-yl)-2-methylquinolin-3-yl)piperidine-2,6- dione (60c, 38 mg, 0.09 mmol, quantitative yield). LCMS: m/z HESI, positive | M+H ]+ = 422.
Step 4: Synthesis of 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (1-24)
3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2-methyl-quinolin-3-yl)piperidine-2,6- dione (1-24) was synthesized according to General Procedure 1, Step D starting from 3-(6-(5-hydroxy- 2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (60c, 38 mg, 1 eq., 0.09 mmol) and acetaldehyde (10 uL, 2 eq., 0.18 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Cl 8 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and concentrated via lyophilization to yield 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-24, 0.6 mg, 0.001 mmol, 1% yield). LCMS: m/z HESI, positive |M+H |+= 450.
Example 61: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2,4- dimethylquinolin-3-yl)piperidine-2, 6-dione (1-75)
Figure imgf000430_0001
Step 1: Synthesis of 3-(6-(4-hydroxypiperidin-4-yl)-2,4-dimethyl-quinolin-3-yl)piperidine-2, 6-dione (61a)
3-(6-(4-hydroxypiperidin-4-yl)-2,4-dimethylquinolin-3-yl)piperidine-2, 6-dione (61a) was prepared according to the procedures and examples as reported in Nature, 2015, 525, 87-90.
To a reaction vial equipped with a stir bar were added tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2- methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (58b, 55.6 mg, 1 eq., 0.12 mmol), 4- methylbenzenesulfonic acid hydrate (47 mg, 2 eq., 0.25 mmol), and Ir(ppy)2(dtbbpy)PFe (1.1 mg, 0.01 eq., 0.001 mmol) and DMSO (490 pL, 0.25 molar) and methanol (490 pL, 0.25 molar), followed ethyl 2- mercaptopropanoate (4 pL, 0.25 eq., 0.03 mmol) and the reaction vial was sealed and irradiated under blue light (456 nM) for 48 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via Cl 8 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and lyophilized to yield 3-(6- (4-hydroxypiperidin-4-yl)-2,4-dimethylquinolin-3-yl)piperidine-2, 6-dione (61a, 45 mg, 0.12 mmol, quantitative yield). LCMS: m/z HESI, positive [M+H]+ = 368.
Step 2: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-2,4- dimethylquinolin-3-yl)piperidine-2, 6-dione (1-75)
To a reaction vial equipped with a stir bar were added 3-(6-(4-hydroxypiperidin-4-yl)-2,4- dimethylquinolin-3-yl)piperidine-2, 6-dione (61a, 45 mg, 1 eq., 0.12 mmol), 4-(trifluoro- methyl)benzaldehyde (17e, 20 pL, 1.2 eq., 0.15 mmol), DCE (500 uL, 0.25 molar) and DMF (500 uL, 0.25 molar), followed by the addition of sodium triacetoxyborohydride (52 mg, 2 eq., 0.24 mmol) and acetic acid (14 uL, 2 eq., 0.24 mmol). The resulting mixture was allowed to stir for 2 h. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via C18 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and lyophilized to yield 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)- benzyl)-piperidin-4-yl)-2,4-dimethyl-quinolin-3-yl)piperidine-2, 6-dione (1-75, 1.2 mg, 0.002 mmol, 2% yield). LCMS: m/z HESI, positive [M+H]+ = 526.
Example 62: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-38)
Figure imgf000431_0001
Step 1: Synthesis of 3-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydro-pyridin-4- yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (62a)
3-(6-(3,3-Dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (62a) was synthesized according to General Procedure 3, Step B starting from 3-(2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-3-yl)piperidine-2,6- dione (59a, 51 mg, 1 eq., 0.13 mmol) and 3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6- tetrahydropyridin-4-yl trifluoromethanesulfonate (INT-69, 62 mg, 1.1 eq., 0.15 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via C18 column eluting 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and concentrated in vacuo to yield 3-(6-(3,3-dimethyl-l- (4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-methylquinolin-3-yl)piperidine-2,6-dione (62a, 0.027 g, 0.05 mmol, 39% yield). LCMS: m/z HESI, positive [M+H]+= 522.
Step 2: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-38)
3-(6-(4-Hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl-quinolin-3- yl)piperidine-2, 6-dione (1-38) was synthesized according to General Procedure 3, Step C starting from 3-(6-(3,3-dimethyl-l-(4-(trifhroromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (62a, 27 mg, 1 eq., 0.052 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via Cl 8 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and lyophilized to yield 3-(6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)-piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-38, 1.8 mg, 0.003 mmol, 6% yield) as a mixture of diastereomers. LCMS: m/z HESI, positive [M+H]+ = 540. *H NMR (499 MHz, DMSO-de) 5 (ppm) = 10.97-10.92 (m, 1H), 8.14-8.08 (m, 1H), 7.95-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.73-7.68 (m, 2H), 7.62-7.56 (m, 2H), 4.32-4.23 (m, 1H), 2.90-2.77 (m, 3H), 2.74-2.69 (m, 1H),
2.64 (s, 4H), 2.60-2.55 (m, 2H), 2.46-2.34 (m, 2H), 2.17-2.07 (m, 2H), 1.57-1.50 (m, 1H), 1.28-1.21 (m,
1H), 0.90 (s, 3H), 0.67 (s, 3H).
Example 63: Synthesis of 3-(6-bromo-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-63)
Figure imgf000432_0001
Step 1: Synthesis of 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)acetic acid (63a)
To a reaction vial equipped with a stir bar was added 6-amino-3-bromo-2-fluorobenzaldehyde (11c, 1.00 g, 1 eq., 4.59 mmol) and methanol (9.2 mL, 0.5 molar), followed by levulinic acid (63a, 533 mg, leq., 4.59 mmol) and aqueous solution of NaOH (2.8 mL, 2 molar, 1.2 eq., 5.5 mmol). The resulting mixture was refluxed overnight. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated and diluted with H2O. The aqueous solution was then acidified to pH = 2 with acetic acid, sonicated for 10 min, and filtered. The resulting precipitate was washed with diethyl ether and dried under reduced pressure to yield 2-(6-bromo-5-fluoro-2- methylquinolin-3-yl)acetic acid (63a, 1 g, 3 mmol, 70% yield). The product was carried onto to the next step without further purification. LCMS: m/z HESI, positive [M+H]+= 297.
Step 2: Synthesis of tert-butyl 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)acetate (63b)
To a reaction vial equipped with a stir bar was added dicyclohexylcarbodiimide (761.3 mg, 1.1 eq., 3.69 mmol) and DCM (3.7 mL, 0.91 molar) and the resulting mixture was cooled to 0 °C using an ice-water bath. DMAP (328 mg, 0.8 eq., 2.68 mmol), 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)acetic acid (63a, 1.0 g, 1 eq., 3.35 mmol) and tert-butyl alcohol (2 55 mL 8 eq 26 84 mmol) were then added and stirring was continued at room temperature overnight. Upon complete consumption of starting material, as confirmed by LCMS, water was added and the aqueous mixture was extracted twice with EtOAc. The combined organic phases were dried over anhydrous NaiSCh, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated in vacuo to yield tert-butyl 2- (6-bromo-5-fluoro-2-methylquinolin-3-yl)acetate (63b, 870 mg, 2.46 mmol, 73% yield). LCMS: m/z HESI, positive [M+H]+ = 354.
Step 3: Synthesis of tert-butyl 2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-4-cyanobutanoate (63d)
To a reaction vial equipped with a stir bar was added tert-butyl 2-(6-bromo-5-fluoro-2- methylquinolin-3-yl)acetate (63b, 870 mg, 1 eq., 2.46 mmol) and DMF (9.8 mL 0.25 molar), followed benzyl(triethyl)ammonium chloride (560 mg, 1 eq., 2.46 mmol), potassium carbonate (340 mg, 1 eq., 2.46 mmol), and acrylonitrile (63c, 159 pL, 1 eq., 2.46 mmol) and the resulting mixture was stirred at room temperature overnight Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was diluted with water and the aqueous mixture was extracted twice with EtOAc. The combined organic phases were dried over Na2SOr, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 0 to 100% EtOAc in heptanes. The desired fractions were collected, combined, and concentrated in vacuo to yield tert-butyl 2-(6-bromo-5- fluoro-2-methylquinolin-3-yl)-4-cyanobutanoate (63c, 680 mg, 1.67 mmol, 68% yield). LCMS: m/z HESI, positive [M+H]+ = 407.
Step 4: Synthesis of tert-butyl 5-amino-2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-5-oxopentanoate (63e)
To a reaction vial equipped with a stir bar was added tert-butyl 2-(6-bromo-5-fluoro-2- methylquinolin-3-yl)-4-cyanobutanoate (63d, 680 mg, 1 eq., 1.67 mmol) and DMSO (5.48 mL, 0.305 molar) and the resulting mixture was cooled to 0 °C using an ice-water bath. Hydrogen peroxide (863 pL, 30% wt, 5 eq., 8.34 mmol) and potassium carbonate (23.1 mg, 0.1 eq., 0.17 mmol) were then added and stirring was continued for 5 h at room temperature. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was diluted with water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was then loaded onto a silica column for purification eluting with heptanes and EtOAc followed by 20% IP A (desired product will only elute upon the addition of 20% IP A). The desired product fractions were collected, combined, and concentrated in vacuo to yield tertbutyl 5-amino-2-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-5-oxopentanoate (63e, 466 mg, 1.10 mmol, 66% yield). LCMS: m/z HESI, positive [M+H]+ = 425.
Step 5: Synthesis of 3-(6-bromo-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-63) To a reaction vial equipped with a stir bar was added tert-butyl 5-amino-2-(6-bromo-5-fluoro-2- methylquinolin-3-yl)-5-oxopentanoate (63e, 466 mg, 1 eq., 1.10 mmol) and acetonitrile (3.0 mL, 0.36 molar), followed by p-toluenesulfonic acid monohydrate (943 mg, 5 eq., 5.48 mmol) and the resulting mixture was heated to 80 °C overnight. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and redissolved in DMSO and purified via Cl 8 column eluting with 0 to 100% MeCN (+0.1% formic acid) in HjO (+0.1% formic acid). The desired fractions were collected, combined, and concentrated via lyophilization to yield 3-(6-bromo-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (INT-63, 204 mg, 0.58 mmol, 53% yield). LCMS: m/z HESI, positive [M+H]+ = 351.
Example 64: Synthesis of 3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoro-methyl)benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-98)
Figure imgf000434_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (64a) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,6-dihydro-pyridine- 1(2H) -carboxylate (64a) was synthesized according to General Procedure 4 starting from 3-(6-bromo-5- fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-63, 50mg, 1 eq., 0.14mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 48 mg, 1.1 eq., 0.16 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via C18 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and concentrated in vacuo to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)- 3,6-dihydropyridine-l(2H)-carboxylate (64a, 41 mg, 0.09 mmol, 63% yield). LCMS: m/z HESI, positive [M+H]+ = 454.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (64b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-piperidine- 1 -carboxylate (64b) was synthesized according to General Procedure 3, Step C starting from tert- butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (64a, 41 mg, 1.0 eq., 0.09 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and loaded onto a CIS column for purification eluting with 0% to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and lyophilized to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2- methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (64b, 43 mg, 0.09 mmol, quantitative yield). LCMS: m/z HESI, positive [M+H]+ = 472.
Step 3: Synthesis of 3-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2,6- dione (64c)
3-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (64c) was synthesized according to General Procedure 1, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin- 3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (64b, 43 mg, 1 eq., 0.09 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was cooled to 0 °C using an ice -water bath, and triethylamine was then added. The reaction mixture was then concentrated in vacuo to provide 3-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (64c, 34mg, 0.09 mmol, quantitative yield). The product was carried onto the next step without further purification. LCMS: m/z HESI, positive [M+H]+ = 372.
Step 4: Synthesis of 3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-98)
3-(5-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione (1-98) was synthesized according to General Procedure 1, Step D starting from 3-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (64c, 34 mg, 1 eq., 0.09 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 15 uL, 1.2 eq., 0.11 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was purified via C18 column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% Formic acid). The desired fractions were collected, combined, and concentrated via lyophilization to yield 3-(5-fluoro-6-(4-hydroxy- 1 -(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-98, 15.5 mg, 0.029 mmol, 32% yield) as a mixture of diastereomers. LCMS: m/z HESI, positive [M+H]+ = 530. *H- NMR (499 MHz, DMSO-rL) 5 (ppm) = 10.98-10.95 (m, 1H), 8.28-8.23 (m, 1H), 8.22-8.18 (m, 1H), 8.01- 7.95 (m, 1H), 7.79-7.74 (m, 1H), 7.73-7.68 (m, 2H), 7.62-7.56 (m, 2H), 5.38-5.16 (m, 1H), 4.38-4.32 (m,
1H), 3.65-3.61 (m, 2H), 2.87-2.77 (m, 1H), 2.66 (s, 3H), 2.65 (br s, 3H), 2.56-2.51 (m, 2H), 2.49-2.45 (m,
1H), 2.38-2.28 (m, 2H), 2.15-2.07 (m, 1H), 1.72-1.63 (m, 2H).
Example 65: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-59)
Figure imgf000436_0001
Step 1: Synthesis of (3-(2,6-dioxopiperidin-3-yl)-5-fhioro-2-methylquinolin-6-yl)boronic acid (65a) (3-(2,6-Dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)boronic acid (65a) was synthesized according to General Procedure 3, Step A starting from 3-(6-bromo-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione (INT-63, 40 mg, 1 eq., 0.11 mmol). The reaction mixture was carried onto the next step as a solution in dioxane without further purification and quantitative yield was assumed (3-(2,6- dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)boronic acid (65a, 36 mg, 0.11 mmol, quantitative yield.) LCMS: m/z HESI, positive [M+H]+ = 317.
Step 2: Synthesis of 3-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (65b)
3-(6-(3,3-dimethyl- 1 -(4-(trifluoromethyl)benzyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (65b) was synthesized according to General Procedure 3, Step B starting from a dioxane solution of (3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)boronic acid (65a, 36 mg, 1 eq., 0.11 mmol) and 3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6- tetrahydropyridin-4-yl trifluoromethanesulfonate (INT-69, 52 mg, 1.1 eq., 0.13 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via Cl 8 column for purification eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined and concentrated via lyophilization to yield 3-(6-(3,3-dimethyl- 1 -(4-(trifluoromethyl)benzyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (65b, 30 mg, 0.056 mmol, 49% yield). LCMS: m/z HESI, positive [M+H]+ = 540.
Step 3: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-59) 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-59) was synthesized according to General Procedure 3, Step C starting from 3-(6-(3,3-dimethyl-l-(4-(trifhioro-methyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-5- fhioro-2-methylquinolin-3-yl)piperidine-2, 6-dione (65b, 30 mg, 1.0 eq., 0.056 mmol). Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was concentrated in vacuo and purified via CIS column eluting with 0 to 100% MeCN (+0.1% formic acid) in H2O (+0.1% formic acid). The desired fractions were collected, combined, and lyophilized to yield 3-(5-fluoro-6-(4-hydroxy- 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione (I- 59, 2.5 mg, 0.005 mmol, 8% yield) as a mixture of diastereomers. LCMS: m/z HESI, positive [M+H]+ = 558. 'H-NMR (499 MHz, DMSO-de) 5 (ppm) = 11.00-10.92 (m, 1H), 8.24-8.18 (m, 1H), 8.07-7.99 (m, 1H), 7.76-7.67 (m, 3H), 7.62-7.53 (m, 2H), 4.40-4.30 (m, 1H), 3.69-3.62 (m, 2H), 3.57-3.53 (m, 2H), 3.19-3.09 (m, 2H), 2.88-2.79 (m, 1H), 2.66 (s, 3H), 2.64-2.55 (m, 2H), 2.48-2.46 (m, IH), 2.18-2.14 (m, 1H), 2.13-2.07 (m, IH), 1.72-1.66 (m, IH), 1.27-1.21 (m, IH), 1.02-0.97 (m, 2H), 0.69-0.64 (m, 2H).
Example 66: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-67)
Figure imgf000437_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3- dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (66a) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine- l(2H)-carboxylate (66a) was synthesized according to General Procedure 4 starting from 3-(6-bromo-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (INT-63, 250 mg, 1.0 eq., 0.71 mmol) and tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (INT-40, 480 mg, 2.0 eq., 1.42 mmol). The crude material was purified by reverse phase purification using Column: C18, eluting with Mobile phase A: 0.1% HCOOH in H2O, Mobile phase B: Acetonitrile. The product eluted with 50% ACN in water (0.1% HCOOH)]. The pure product containing fractions were collected and lyophilized to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5- fluoro-2-methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (66a, 111 mg, 0.23mmol, 32% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 482.4. ’H-NMR (400 MHz, DMSO-t/s): 5 10.96 (s, 1H), 8.21 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H), 7.45 (t, J = 8.40 Hz, 1H), 5.59 (s, 1H), 4.37 (d, J = 4.40 Hz, 1H), 4.02 (s, 2H), 3.35 (s, 2H), 2.88-2.79 (m, 1H), 2.68 (s, 3H), 2.64-2.49 (m, 2H), 2.14-2.11 (m, 1H), 1.46-1.28 (m, 9H), 0.99 (s, 6H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine- 1-carboxylate (66b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1-carboxylate (66b) was synthesized according to General Procedure 3, Step C starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fhmro-2-methylquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine- l(2H)-carboxylate (66a, 700 mg, 1.0 eq., 1.45 mmol). The crude material was purified by reverse phase column chromatography using Cl 8 cartridge (25 g) eluting with 5 to 100% ACN and 0.1% formic acid in water. The pure product containing fractions were collected and lyophilized to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1-carboxylate (66b, 310 mg, 0.534 mmol, 37% yield), m/z MM-ES+APCI, Positive [M+H]+ 500.4. ’H-NMR (400 MHz, DMSO-cfc): 5 10.95 (s, 1H), 8.22 (s, 1H), 8.03 (t, J = 8.80 Hz, 1H), 7.76 (d, J = 8.80 Hz, 1H), 5.76 (s, 1H), 4.37-4.33 (m, 1H), 3.99 (br s, 1H), 3.42-3.08 (m, 4H), 2.88-2.79 (m, 1H), 2.72 (s, 3H), 2.63-2.52 (m, 2H), 2.13-1.09 (m, 2H), 1.43 (s, 9H), 0.83 (s, 3H), 0.72 (s, 3H).
Step 3: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3- yl)piperidine-2, 6-dione, HC1 (66c)
3-(5-Fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2,6- dione, HC1 (66c) was synthesized according to General Procedure 6, Step A starting from tert-butyl 4- (3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (66b, 310 mg, 1 eq., 0.64 mmol). The crude material was washed with n-pentane (10 x 2 mL) and dried under reduced pressure to afford 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2- methylquinolin-3-yl)piperidine-2, 6-dione, HCI (66c, 250 mg, 0.516 mmol, 80% yield). The product was earned onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 400.4. ’H-NMR not recorded.
Step 4: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fhioro-2-methylquinolin- 3-yl)piperidine-2, 6-dione (1-67)
3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine- 2, 6-dione (1-67) was synthesized according to General Procedure 6, Step B starting from 3-(5-fluoro-6- (4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3-yl)piperidine-2, 6-dione, HCI (66c, 250 mg, 1.0 eq., 0.63 mmol) and acetaldehyde (55 mg, 2.0 eq., 1.25 mmol). The crude compound was purified by preparative-HPLC [(ColummX select C18 (150mm *19) 5 um, eluting with Mobile phase A: 0.05% FA in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(l-ethyl-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-67, 73.4 mg, 0.155 mmol, 25% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 428.5. ’H-NMR (400 MHz, DMSO-tfc): 5 10.95 (s, 1H), 8.21 (d, J = 5.20 Hz, 1H), 8.18 (s, 1H), 8.04 (t, J = 8.80 Hz, 1H), 7.74 (d, J = 10.40 Hz, 1H), 5.08 (s, 1H), 4.37-4.32 (m, 1H), 3.09 (t, J = 12.80 Hz, 1H), 2.86-2.74 (m, 2H), 2.67 (s, 3H), 2.66-2.51 (m, 2H), 2.48-2.28 (m, 4H), 2.14- 2.08 (m, 1H), 1.69 (d, J = 13.20 Hz, 2H), 1.05 (t, J = 7.60 Hz, 3H), 0.95 (s, 3H), 0.71 (s, 3H).
Example 67: Synthesis of 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)- 5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (1-1)
Figure imgf000439_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3- diethyl-3,6-dihydropyridine-l(2H)-carboxylate (67a) tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fhroro-2-methylquinolin-6-yl)-3,3-diethyl-3,6- dihydropyridine-l(2H)-carboxylate (67a) was synthesized according to General Procedure 3, Step B starting from (3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)boronic acid (65a, 408 mg, 1.0 eq., 1.29 mmol) and tert-butyl 3 3-diethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3 6-dihydropyridine-l(2H)- carboxylate (53b, 500 mg, 1.0 eq., 1.29 mmol). This crude material was purified by flash column chromatography using Biotage Isolera® (on silica gel 100-200 mesh) eluting with 0-80% EtOAc in hexanes to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-diethyl- 3,6-dihydropyridine-l(2H)-carboxylate (67a, 320 mg, 0.57 mmol, 44% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 510.8. ’H-NMR (400 MHz, DMSO-c/e): 5 10.95 (s, IH), 8.21 (s, IH), 7.74
(d, J = 8.80 Hz, IH), 7.48 (d, J = 7.20 Hz, 1H), 5.76 (s, 1H), 4.37-4.10 (m, 1H), 4.05-4.01 (m, 2H), 3.45 (s, 2H), 2.83-2.79 (m, 2H), 2.60-2.51 (m, 4H), 2.13 (s, 1H), 1.45-1.39 (m, 13H), 0.79 (s, 6H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3- diethyl-4-hydroxypiperidine-l-carboxylate (67b) tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-diethyl-4- hydroxypiperidine-1 -carboxylate (67b) was synthesized according to General Procedure 3, Step C starting from 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-diethyl-3,6- dihydropyridine- l(2H)-carboxylate (67a, 320 mg, 1.0 eq., 0.63 mmol). The crude material was purified by reverse phase column chromatography using (Cl 8) cartridge (25 g) eluting with 5 to 100% MeCN and 0.1% formic acid in water. The pure product containing fractions were collected and lyophilized to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-diethyl-4- hydroxypiperidine-1 -carboxylate (67b, 220 mg, 0.31 mmol, 50% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 528.6. ’H-NMR (400 MHz, DMSO-t/6): 8 10.98 (s, 1H), 8.42 (s, 1H), 8.12 (d, J = 7.60 Hz, IH), 7.76-7.74 (m, 1H), 5.42 (s, 1H), 4.42-4.39 (m, 1H), 4.19-3.93 (m, 3H), 2.83-2.80 (m, 2H), 2.65- 2.61 (m, 5H), 2.14-2.11 (m, IH), 1.59-1.57 (m, 2H), 1.43-1.33 (m, 13H), 0.96-0.80 (t, J = 7.40 Hz. 3H), 0.48-0.46 (t, J = 7.40 Hz, 3H).
Step 3: Synthesis of 3-(6-(3,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione, HC1 (67c)
3-(6-(3,3-Diethyl-4-hydroxypiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione, HC1 (67c, 190 mg, 0.35 mmol, 83% yield) was synthesized according to General Procedure 1, Step C was starting from tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-3,3-diethyl-4- hydroxypiperidine-1 -carboxylate (67b, 220 mg, 1.0 eq., 0.42 mmol). The product was taken onto the next step without further purification. LCMS: m/z MM-ES+APCI, Negative [M-H]" 426.1.
Step 4: Synthesis of 3-(6-(3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- fluoro-2-methylquinolin- 3- yl)piperidine-2, 6-dione (I- 1)
3-(6-(3,3-Diethyl -4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-1) was synthesized according to General Procedure 1, Step D starting from 3-(6-(3,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine- 2, 6-dione, HC1 (67c, 100 mg, 1.0 eq., 0.22 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 45 mg, 1.2 eq., 0.26 mmol). The crude compound was purified by preparative-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HCOOH in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6- (3,3-diethyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione (1-1, 15.6 mg, 0.03 mmol, 12% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 586.7. ’H-NMR (400 MHz, DMSO-c/e): 5 10.95 (s, 1H), 8.20 (d, J = 3.20 Hz, 1H), 8.12 (t, J =
8.80 Hz, 1H), 7.72 (d, J = 4.40 Hz, 3H), 7.63 (d, J = 8.00 Hz, 2H), 5.11 (s, 1H), 4.37-4.32 (m, 1H), 3.62-
3.55 (m, 3H), 3.33-3.17 (m, 1H), 2.83 (m, 2H), 2.66-2.61 (m, 6H), 2.39-2.34 (m, 2H), 2.12 (s, 2H), 1.62-
1.49 (m, 1H), 1.11-1.07 (m, 2H), 0.54 (t, J = 7.20 Hz, 3H), 0.44 (t, J = 7.60 Hz, 3H).
Example 68: Synthesis of 3-(5-fluoro-2-methyl-6-(l,3,3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-5)
Figure imgf000441_0001
3-(5-fhioro-2-methyl-6-(l, 3, 3-triethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine -2,6- dione (1-5) was synthesized according to General Procedure 1, Step D starting from 3-(6-(3,3-diethyl-4- hydroxypiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione, HC1 (67c, 120 mg, 1.0 eq., 0.26 mmol) and acetaldehyde (23 mg, 2.0 eq., 0.52mmol). The crude compound was purified by preparative-HPLC [(Column: X select (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HCOOH in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized afford 3-(5-fluoro-2-methyl-6-(l,3,3-triethyl-4-hydroxy- piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-5, 7.8 mg, 0.02 mmol, 6% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 456.5. ’H-NMR (400 MHz, DMSO-ds): 5 10.95 (s, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 8.12 (t, J = 8.40 Hz, 1H), 7.73 (d, J = 8.80 Hz, 1H), 5.06 (s, 1H), 4.37-4.32 (m, 1H), 3.33-3.15 (m, 1H), 2.83-2.66 (m, 1H), 2.52-2.50 (m, 6H), 2.47-2.41 (m, 3H), 2.34-2.33 (m, 1H), 2.23-2.20 (m, 1H), 2.11-2.09 (m, 2H), 1.59-1.53 (m, 2H), 1.18-1.16 (m, 1H), 1.07-1.03 (m, 4H), 0.68 (t, J = 7.20 Hz, 3H), 0.50 (t, J = 7.60 Hz, 3H).
Example 69: Synthesis of 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydro-pyridin-4-yl trifluoromethanesulfonate (INT -69) F3C.
.0 HCI (4 M in dioxane) .0 16b Br F3C .0
BocN HN 2 h K2CO3, D N
DCM, 0 °C to rt, 1 MF,
40a Step 1 69a rt, 12 h 69b
Step 2 o9o F
F F3C. •OTf
F F
NaHMDS, THF, N -78°C to rt, 3 h
INT-69 Step 3
Step 1: 3,3-dimethylpiperidin-4-one (69a)
To a stirred solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (40a, 5 g, 22.00 mmol) in DCM (25 mL) was added HC1 (4M in dioxane) (11.00 mL, 44.00 mmol) at 0°C under an atmosphere of nitrogen and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to afford 3,3- dimethylpiperidin-4-one (69a, 2.6 g, 20.03 mmol, 91% yield). The product was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 128.1.
Step 2: 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (69b)
To a stirred solution of 3,3-dimethylpiperidin-4-one (69a, 2.6 g, 20.44 mmol) in DMF (25 mL) were added potassium carbonate (5.65 g, 40.90 mmol) and l-(bromo-methyl)-4-(trifluoromethyl)benzene (16b, 5.38 g, 22.49 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 12 h. Ice-cold water (50 mL) was then added and the aqueous mixture was extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na?SO4 and concentrated under reduced pressure. The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0-10% EtOAc in //-hexane to afford 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (69b, 3.6g, 12.61 mmol, 62% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 286.1. ’H-NMR (400 MHz, DMSO-de): 57.72 (d, J = 8.00 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 3.67 (s, 2H), 2.70 (t, J = 6.00 Hz, 2H), 2.46 (t, J = 6.00 Hz, 2H), 2.40 (s, 2H), 1.06 (d, J = Hz, 6H).
Step 3: 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (INT -69)
To a stirred solution of 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (69b, 3.3 g, 11.57 mmol) in THF (20 mL) was added NaHMDS (IM in THF) (23.13 mL, 23.13 mmol) at -78 °C and the resulting mixture was stirred at -78 °C for 35 min. 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (5.37 g, 15.04 mmol) dissolved in THF (5 mL) was then added dropwise at -78 °C and stirring was continued at room temperature for 3 h. Aqueous ammonium chloride solution (50 mL) was added and aqueous mixture extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0-10% EtOAc in //-hexane to afford 3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (INT-69, 3.2 g, 6.36 mmol, 55% yield). LCMS: m/z ES+APCI, Positive [M+H]+ = 418.1. ’H-NMR (400 MHz, DMSO-r/e): 5 (d, J = 8.00 Hz, 2H), 7.58 (d, J = 8.00 Hz, 2H), 5.79-5.76 (m, 1H), 3.70 (s, 2H), 3.11 (s, 2H), 2.33
(s, 2H), 1.09 (s, 6H).
Example 70: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-2-methyl- l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-16)
Figure imgf000443_0001
Step 1: Synthesis of tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-6-methyl-l,5-naphthyridin-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (70a) tert-Butyl 4-(7-(2,6-dioxopiperidin-3-yl)-6-methyl-l,5-naphthyridin-2-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (70a) was synthesized according to General Procedure 5 starting from 3-(6-chloro-2- methyl-l,5-naphthyridin-3-yl)piperidine -2, 6-dione (INT-10, 200 mg, 1.0 eq., 0.69mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 256 mg, 1.2 eq., 0.83mmol). The crude compound was purified by Biotage Isolera® (on a 40g silica gel cartridge) eluting with 95% EtOAc in hexane. The pure product containing fractions were collected and concentrated under reduced pressure to afford tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-6-methyl-l,5- naphthyridin-2-yl)-3,6-dihydropyridine l(2H) carboxylate (70a 325 mg 0 67 mmol 97% yield) LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 437.3. ‘H-NMR (400 MHz, DMSO-tfc): 5 10.96 (s, 1H), 8.27(d, J = 8.86 Hz, 1H), 8.10 (s, 1H), 6.89 (s, 1H), 5.76 (s, 1H), 4.36-4.32 (m, 1H), 4.13-4.04 (m, 2H), 3.58 (t, 7 = 5.20 Hz, 2H), 2.87-2.74 (m, 6H), 2.16 (s, 2H), 2.08 (s, 1H), 1.51 (s, 9H).
Step 2: Synthesis of 3-(2-methyl-6-(l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3- yl)piperidine-2, 6-dione (70b)
3-(2-methyl-6-(l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3-yl)piperidine-2,6-dione (70b) was synthesized according to General Procedure 6, Step A starting from tert-butyl 4-(7-(2,6- dioxopiperidin-3-yl)-6-methyl-l,5-naphthyridin-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (70a, 350 mg, 1 eq., 0.80 mmol). The crude product was washed by MTBE to afford 3-(2-methyl-6-(l, 2,3,6- tetrahydropyridin-4-yl)-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (70b, 250 mg, 0.62 mmol, 78% yield), which was carried onto the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 337. ‘H-NMR (400 MHz, DMSO-de): 5 11.01 (s, 1H), 8.29 (br s, 2H), 8.46 (d, 7 = 8.80 Hz, 1H), 8.33 (s, 1H), 8.20 (d, J = 8.80 Hz, 1H), 6.96 (s, 1H), 4.44-4.42 (m, 1H), 4.39-3.75 (m, 2H), 3.37 (s, 2H), 2.98-2.92 (m, 2H), 2.90-2.81 (m, 1H), 2.81 (s, 3H), 2.68-2.57 (m, 2H), 1.69-1.61 (m, 1H).
Step 3: Synthesis of 3-(2-methyl-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)- l,5-naphthyridin-3-yl)piperidine-2, 6-dione (70c)
3-(2-Methyl-6-(l-(4-(trifhroromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3- yl)piperidine-2, 6-dione (70c) was synthesized according to General Procedure 6, Step B starting from 3-(2-methyl-6-( 1 ,2,3,6-tetrahydropyridin-4-yl)- 1 ,5-naphthyridin-3-yl)piperidine-2, 6-dione (70b, 200 mg, 1.0 eq., 0.60 mmol) and 4-(trifhroromethyl)benzaldehyde (17e, 124 mg, 1.2 eq., 0.71mmol). The erode compound was purified by silica gel flash column chromatography, eluting with 65% EtOAc in hexane to afford 3-(2-methyl-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-l,5-naphthyridin-3- yl)piperidine-2, 6-dione (70c, 200 mg, 0.35 mmol, 59% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 495.4. ’H-NMR (400 MHz, DMSO-cfc): 5 10.96 (s, 1H), 8.24 (d, J = 8.40 Hz, 1H), 8.08 (s, 1H), 8.01 (d, 7 = 9.20 Hz, 1H), 7.72 (d, 7 = 8.00 Hz, 2H), 7.61 (d, 7 = 8.00 Hz, 2H), 6.87 (s, 1H), 4.35- 4.31 (m, 1H), 3.74 (s, 2H), 3.22-3.21 (m, 3H), 2.72-2.63 (m, 4H), 2.52 (s, 3H), 2.51-2.50 (m, 2H), 2.16- 2.13 (m, 1H).
Step 4: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-2-methyl-l,5- naphthyridin-3-yl)piperidine-2, 6-dione (1-16)
3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl-l,5-naphthyridin-3- yl)piperidine-2, 6-dione (1-16) was synthesized according to General Procedure 3, Step C starting from 3-(2-methyl-6-( 1 -(4-(trifluoromethyl)benzyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)- 1 ,5-naphthyridin-3- yl)piperidine-2, 6-dione (70c, 180 mg, 1 eq., 0.36 mmol). The crude compound was purified by preparative-HPLC using X SELECT C18 [19*250MM] column, eluting with Mobile phase A: 0.1% Ammonium Acetate, Mobile phase B: Acetonitrile, flow rate: 15 ml/min)], RT:12.8. The pure product containing fractions were collected and lyophilized to afford 3-(6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-16, 70 mg). This compound was dissolved in acetonitrile, 0.5 M HC1 (1.0 eq.) was added and the resulting mixture was lyophilized to afford 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)-2- methyl-l,5-naphthyridin-3-yl)piperidine -2, 6-dione, HC1 (1-16, 56.7 mg, 0.10 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 513.5. 'H-NMR (400 MHz, DMSO-r/e): 5 11.00 (s, 1H), 10.40 (s,
1H), 8.39 (d, 7 = 8.80 Hz, 1H), 8.07-8.02 (m, 2H), 7.87 (d, 7 = 16.80 Hz, 4H), 5.99 (s, 1H), 4.53 (d, 7 =
4.80 Hz, 2H), 4.39-4.35 (m, 1H), 3.37 (s, 4H), 2.89-2.83 (m, 1H), 2.71 (s, 3H), 2.65-2.59 (m, 4H), 2.16-
2.13 (m, 1H), 1.94 (d, J = 14.00 Hz, 2H).
Example 71: 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl- l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-49)
Figure imgf000445_0001
Step 1: Synthesis of 3-(2-methyl-6-(trimethylstannyl)-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (71a)
To a stirred solution of 3-(6-chloro-2-methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (INT- 10, 200 mg, 0.69 mmol) in 1,4-dioxane (7 mL) under an atmosphere of nitrogen was added hexamethyl ditin (37a, 407 mg, 1.24 mmol) at 25 °C and the resulting mixture was sparged with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol) was then added at 25 °C and the reaction mixture was sparged with nitrogen for 10 min and stirring was continued at 80 °C for 2 h. The reaction mixture was filtered through a pad of celite®, and the filtrate was concentrated under reduced pressure to afford 3-(2-methyl-6-(trimethylstannyl)-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (71a, 300 mg, 0.47 mmol, 68% yield), which was carried onto the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 420.0. Step 2: Synthesis of 3-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (71b)
To a stirred solution of 3-(2-methyl-6-(trimethylstannyl)-l,5-naphthyridin-3-yl)-piperidine-2,6- dione (71a, 200 mg, 0.48 mmol) and 3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6- tetrahydropyridin-4-yltrifluoromethanesulfonate (INT-69, 200 mg, 0.48 mmol) in DMF (5 mL) was added copper(I) iodide (18.22 mg, 0.10 mmol) followed by tetrakis(triphenyl-phosphine)palladium(0) (55.3 mg, 0.05 mmol) at 25 °C under an atmosphere of nitrogen atmosphere and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered through a pad of Celite® to remove the inorganic salts. The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography on Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 85% EtOAc in n-hexane to afford 3-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin- 4-yl)-2-methyl-l,5 naphthyridin-3-yl)piperidine-2, 6-dione (71b, 170 mg, 0.27 mmol, 57% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 523.3. ’H-NMR (400 MHz, DMSO-tfc): 5 10.95 (s, 1H), 8.22 (d, J = 8.80 Hz, 1H), 8.11 (s, 1H), 7.91-7.78 (m, 4H), 7.64 (d, J = 8.00 Hz, 1H), 6.24 (t, J = 3.60 Hz, 1H), 3.74 (d, J = 7.60 Hz, 2H), 3.21 (d, J = 3.60 Hz, 1H), 2.69 (t, J = 4.40 Hz, 4H), 2.51 (t, J = 2.00 Hz, 2H), 2.35 (s, 1H), 2.20-2.13 (m, 2H), 1.33 (d, J = 10.40 Hz, 5H), 1.11 (s, 3H).
Step 3: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2- methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-49)
3-(6-(4-Hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl-l,5- naphthyridin-3-yl)piperidine-2, 6-dione (1-49) was synthesized according to General Procedure 3, Step C starting from afford 3-(6-(3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-2- methyl-1,5 naphthyridin-3-yl)piperidine-2, 6-dione (71b, 170 mg, 1 eq., 0.325 mmol). The crude material was purified by preparative-HPLC [(Column: X select Cl 8 [19*250 mm], eluting with Mobile phase A: 0.1% ammonium acetate, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-49, 3.7 mg, 6.63 pmol, 22% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 541.5. ’H-NMR (400 MHz, DMSO-t/s): 5 10.97 (s, 1H), 8.28 (d, J = 8.80 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J = 2.00, 9.00 Hz, 1H), 7.71 (d, J = 8.00 Hz, 2H), 7.60 (d, J = 8.00 Hz, 2H), 5.25 (d, J = 10.00 Hz, 1H), 4.35 (dd, J = 4.40, 12.20 Hz, 1H), 3.62 (dd, J = 14.00, 34.00 Hz, 2H), 3.11 (s, 1H), 2.86-2.81 (m, 4H), 2.77 (t, J = 9.60 Hz, 3H), 2.69 (t, J = 1.60 Hz, 2H), 2.16 (d, J = 10.40 Hz, 2H), 1.53 (d, J = 13.60 Hz, 1H), 0.92 (d, J = 2.40 Hz, 3H), 0.72 (d, J = 3.20 Hz, 3H).
Example 72: Synthesis of 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl trifluoromethanesulfonate (INT -72)
Figure imgf000447_0001
Step 1: Synthesis of 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-one (72b)
To a stirred solution of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (16b, 5 g, 19.44 mmol) in toluene (50 mL) was added potassium terLbutoxide (4.80 g, 42.8 mmol) at 25 °C and the resulting mixture was stirred for 1 h. 1,5-dibromopentane (72a, 4.47 g, 19.44 mmol) then added dropwise over 5 min at 25 °C. and stirring was continued at 110 °C for 3 h. The reaction mixture was cooled to room temperature, saturated solution of NH4CI in water (300 mL) was added, and the aqueous mixture was extracted with EtOAc (3 x 250 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography using Biotage Isolera® on silica gel (100-200 mesh) eluting with 0-15% EtOAc in n- hexane to afford 2-(4-(trifhioro-methyl)benzyl)-2-azaspiro[5.5]undecan-5-one (72b, 2.5 g, 7.38 mmol, 38% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 326.6. ’H-NMR (400 MHz, DMSO-A): 5 7.73 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 3.82 (s, 2H), 2.69 (t, J = 6.00 Hz, 2H), 2.51-2.45 (m, 2H), 2.43-2.33 (m, 2H), 2.33-2.00 (m, 2H), 1.75 (m, 8H).
Step 2: Synthesis of 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl trifluoromethanesulfonate (INT -72)
To the stirred solution of 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-one (72b, 1 g, 3.07 mmol) in THF (2 mL) was added NaHMDS (1 M in THF) (3.07 mL, 3.07 mmol) at -78 °C under an atmosphere of nitrogen and the resulting mixture stirred for 30 min at -78 °C and at 25 °C for 1 h. This reaction mixture was again cooled to -78 °C and N-phenyl-bis(trifluoromethanesulfonimide) (2.196 g, 6.15 mmol) dissolved in THF (2 mL) was then added dropwise at -78 °C and stirring was continued at room temperature for 16 h. Water (20 mL) was added and the aqueous mixture was extracted with EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (on silica gel 100-200 mesh, Isolera, flow rate of 35 mL/min, eluting with 5-6% EtOAc in pet ether) to afford 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl trifluoromethanesulfonate (INT-72, 1 g, 1.51 mmol, 49% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 458.7. ’H-NMR (400 MHz, DMSO-tfc): 87.72 (d, J = 8.00 Hz, 2H), 7.58 (d, J = 8.00 Hz, 2H), 5.83-5.76 (m, 1H), 3.73 (s, 2H), 3.13 (s, 2H), 2.51 (t, J = 1.60 Hz, 2H), 1.63 (d, J = 12.80 Hz, 2H), 1.53- 1.40 (m, 6H), 1.10-1.07 (m, 2H). Example 73: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5- yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-37)
Figure imgf000448_0001
Step 1: Synthesis of 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)- l,5-naphthyridin-3-yl)piperidine-2, 6-dione (73a)
To the stirred solution of 3-(2-methyl-6-(trimethylstannyl)-l,5-naphthyridin-3-yl)piperidine -2,6- dione (71a, 200 mg, 0.48 mmol) and 2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl trifluoromethanesulfonate (INT-72, 219 mg, 0.48 mmol) in DMF (5 mL) was added tetrakis(tripbenylphosphine)palladium(0) (55.3 mg, 0.05 mmol), followed by copper(I) iodide (18.22 mg, 0.10 mmol) at 25 °C under nitrogen atmosphere and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered through a pad of celite® to remove the inorganic salts and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography Biotage Isolera® on silica gel (100-200 mesh) eluting with 0 to 80% EtOAc in n-hexane to afford 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undec-4-en-5-yl)-l,5-naphthyridin- 3-yl)piperidine-2, 6-dione (73a, 150 mg, 0.21 mmol, 45% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 563.4. 'H-NMR (400 MHz, DMSO-tfc): 5 10.96 (s, 1H), 8.23 (d, J = 8.80 Hz, 1H), 8.13 (s, 1H), 7.75-7.72 (m, 2H), 7.67-7.65 (m, 2H), 7.63-7.54 (m, 2H), 6.00 (s, 1H), 4.25-4.23 (m, 1H), 3.75 (s, 2H), 3.33 (s, 2H), 2.90 (s, 1H), 2.74 (d, J = 0.40 Hz, 3H), 2.69-2.62 (m, 3H), 2.16-2.15 (m, 2H), 1.39- 1.36 (m, 3H), 1.11-1.08 (m, 3H), 0.54-0.55 (m, 3H).
Step 2: Synthesis of 3-(6-(5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2- methyl-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-37)
3-(6-(5-Hydroxy-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methyl-l,5- naphthyridin-3-yl)piperidine-2, 6-dione (1-37) was synthesized according to General Procedure 3, Step C starting from 3-(2-methyl-6-(2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5 5]undec-4-en-5-yl)-l 5- naphthyridin-3-yl)piperidine-2, 6-dione (73a, 140 mg, 1 eq., 0.075 mmol). The crude material was purified by preparative-HPLC [(Column: X select C18 [19*250 mm], eluting with Mobile phase A: 0.1% ammonium acetate, Mobile phase B: Acetonitrile, flow rate: 15 mL/min), Rt 12.8 min]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(5-hydroxy-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)-2-methyl-l,5-naphthyridin-3-yl)piperidine-2,6- dione (1-37, 4.3 mg, 6.96 pmol. 24% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 581.7. *H- NMR (400 MHz, DMSO-ds): 5 10.97 (s, IH), 8.27 (d, J = 9.20 Hz, IH), 8.15 (s, IH), 8.01 (d, J = 4.80
Hz, IH), 7.71 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 5.23 (d, J = 14.80 Hz, 1H), 4.35-4.33 (m,
IH), 3.65-3.61 (m, 2H), 3.30 (s, 1H), 2.90-2.85 (m, 6H), 2.70-2.65 (m, 3H), 2.34-2.32 (m, 2H), 1.90 (s,
1H), 1.76 (m, 1H), 1.28-1.24 (m, 4H), 1.07-1.04 (m, 2H), 0.68-0.63 (m, 1H), 0.65-0.61 (m, 1H), 0.58-
0.53 (m, 1H).
Example 74: Synthesis of 3-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-
4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione (I- 122)
H "
W _VxN N'°, H
\= OyNyO
NH (/ / N N
ALD-107
STAB, DMF, r A N^/ w t, 12 h
51d 1-122
To a stirred solution of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione, HC1 (51d, 100 mg, 0.237 mmol) in DMF (3 mL) was added 4-(l,2,4-oxadiazol- 3-yl)benzaldehyde (ALD-107, 41.3 mg, 0.237 mmol) at room temperature and the resulting mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (151 mg, 0.711 mmol) was then added in portions, and stirring was continued at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and further on high-vac to obtain the crude material. The crude compound was purified by preparative-HPLC [X-SELECT CSH Cl 8 (250 xl9 x5u), eluting with Mobile phase A: 0.05% HC1 in H2O: 100% ACN, Mobile phase B: Acetonitrile, flow rate: 14 ml/min, RT: 12.9]. The pure product containing fractions were collected and lyophilized to afford 3-(6-(l -(4-( 1 ,2,4- oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione (1-122, 34.4 mg, 0.059 mmol, 25% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 544.54. 'H-NMR (400 MHz, DMSO-tfc): 5 11.00 (s, 1H). 10.27 (br s, 1H), 9.78 (s, 1H), 8.92 (s, 1H), 8.43 (s, 1H), 8.16 (d, J = 8.00 Hz, 2H), 8.08 (t, J = 8.40 Hz, 1H), 7.95-7.91 (m, 3H), 5.94 (br s, 1H), 4.52-4.44 (m, 2H), 4.28- 4.15 (m, 2H), 3.42 (s, 3H), 3.29 (t, J = 11.20 Hz, 1H), 2.90 (d, 7 = 11.60 Hz, 1H), 2.77-2.51 (m, 2H), 2.15-2.01 (m, 2H), 1.10 (s, 3H), 0.77 (s, 3H).
Example 75: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-2-chloroquinoline (35a)
Figure imgf000450_0001
Step 1: Synthesis of 6-bromo-2-chloro-3-iodoquinoline (75b)
6-Bromo-2-chloro-3-iodoquinoline (75b) was prepared according to the procedures and examples as reported in PCT Application Publication No. WO2011/090911.
To a dry round bottom flask under an atmosphere of argon at -78 °C (using a dry ice and acetone bath) was added IM LDA in THF (15mL), followed by the slow addition of a solution of 6-bromo-2- chloroquinoline (75a, 3.03 g, 12.5 mmol) in THF (40 mL) and the resulting mixture was stirred at -78°C for 2 h. A solution of I2 (3.16g, 12.5 mmol) in THF (35 mL) was then added and stirring was continued at -78 °C for 2 h. The reaction mixture was poured onto ice, concentrated to remove most of the THF, and diluted with EtOAc. The organic phase was washed with sat. NajSiOs solution and sat. NaHCCh solution. The organic phase was dried over Na^SCh. filtered, and concentrated under reduced pressure to afford crude material, which was purified by flash column chromatography (on silica gel and eluting with 20% to 60% EtOAc in heptanes). The product containing fractions were collected and the desired product was trituated using hexanes to afford 6-bromo-2-chloro-3-iodoquinoline (75b, 340 mg, 0.92 mmol, 7% yield) which was carried onto the next step without further purification. LCMS: m/z HESI, positive [M+H]+ = 368.2; [M+H+2]+=369.9; [calcd for C9H5BrClIN+ for 367.8],
Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-2-chloroquinoline (35a)
6-bromo-2-chloro-3-iodoquinoline (75b, 0.18g, l.Smmol), 2,6-bis(benzyloxy)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (INT-4B, 0.25g, 0.6mmol), and PdC12(dppf)-DCM (0.04g, 0.05 mmol) were weighed into lOmL MW tube and 1,4-dioxane (6 mL) was added, followed by the addition of an aqueous solution of K2CO3 (0.097g, 0.7mmol, in 600uL H2O). The resulting mixture was sparged with argon with sonication for 4 minutes. The MW tube was then sealed and heated at 85 °C under MW irradiation for 2 h. The reaction mixture was then directly loaded onto the silica gel cartridge, and purified by flash column chromatography (eluting with 10% to 100% EtOAc in heptanes) to afford 6- bromo-2-chloro-3-(2,6-dimethoxypyridin-3-yl)quinoline (35a, 128mg, 0.24mmol, 40% yield). LC-MS: m/z HESI, positive [M+H]+ = 531.5; [M+H+2]+=533.3 [calcd for C28H2iBrClN2O2+ for 531.1].
Example 76: General procedure C- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 ml) and the aldehyde (0.12 mmol, 1.2 eq.) at 25 °C is added acetic acid (0.1 mmol, 1.0 eq.) and the resulting mixture is stirred for 0.5 to 1 h. Sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.) is then added and stirring is continued for 16 h. The reaction mixture is then concentrated under reduced pressure to afford crude compound, which is purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 um, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 ml/min)]. The fractions containing pure product are combined and concentrated via lyophilization to afford the desired product the formic acid salt, the hydrochloride salt, or the free amine.
Example 77: General procedure D- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 ml) and the aldehyde (0.12 mmol, 1.2 eq.) at 25 °C was added sodium acetate (0.5 mmol, 5.0 eq.) and acetic acid (0.3 mmol, 3.0 eq.) and the resulting mixture was stirred for 30 min. MP-Cyanoborohydride (0.15 mmol) was then added and stirring was continued for 16 h. (If reaction was not complete after 16 h, temperature was raised to 60 °C). The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 um, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 ml/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 78: General procedure E- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mL) was added acetic acid (0.1 mmol, 0.1 eq.) and triethylamine (0.5 mmol, 5.0 eq.) followed by the aldehyde (0.12 mmol, 1.2 eq.) at 25°C. The resulting mixture was stirred for 4 h. Sodium cyanoborohydride (0.5 mmol, 5.0 eq.) was then added and stirring was continued for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 79: General procedure F- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mL) and the aldehyde (0.12 mmol, 1.2 eq.) and DIPEA (0.3 mmol, 3.0 eq.) was added at 25°C, and the reaction mixture was stirred at 25°C for 1 h. To this mixture was added sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.) and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 80: General procedure G- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in IP A (1 mF) was added the aldehyde (0.12 mmol, 1.2 eq.) followed by potassium acetate (0.15 mmol, 1.5 eq.) and sodium cyanoborohydride (0.2 mmol, 2.0 eq.) at 25°C. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mF/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 81: General procedure H- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mF) were added the aldehyde (0.12 mmol, 1.2 eq.) and TEA (0.2 mmol, 2.0 eq.) at 25°C, and the resulting mixture was stirred at 25 °C for 2 h. To this mixture was added sodium acetate (0.2 mmol, 2.0 eq.) followed by sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mF/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 82: General procedure I- Reductive amination (with ketones)
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) and the ketone (0.12 mmol, 1.2 eq.) in DMF (1 mF) was added titanium(IV) isopropoxide (0.5 mmol, 5.0 eq.), followed by DIPEA (0.3 mmol, 3.0 eq.) at 25 °C. The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, sodium cyanoborohydride (0.5 mmol, 5.0 eq.) was added, and the reaction mixture was heated at 80 °C for 3 h. The reaction mixture was cooled, water was added, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in FEO, Mobile phase B: Acetonitrile, flow rate: 15 mF/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine. Example 83: General procedure J- Alkylation
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mL) was added the alkyl halide or alkyl sulfonate (0.1 mmol, 0.1 eq.) and triethylamine (0.5 mmol, 5.0 eq.) at 0°C. The resulting mixture was allowed to stir at 25°C for 10 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 84: General procedure K- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mF) and the aldehyde (0.12 mmol, 1.2 eq.) was added MP-cyanoborohydride (0.1 mmol, 1.0 eq.) at 25°C. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 85: General procedure L- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) and the aldehyde (0.12 mmol, 1.2 eq.) in DMF (1 mL) was added acetic acid (0.1 mmol, 0.1 eq.) and triethylamine (0.2 mmol, 2.0 eq.) followed by MP cyanoborohydride (0.1 mmol, 1.0 eq.) at 25°C. The resulting mixture was stirred at 80 °C for 5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 86: General procedure M- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in IP A (1 mL) was added the aldehyde (0.12 mmol, 1.2 eq.) followed by potassium acetate (0.3 mmol, 3.0 eq.), and the reaction mixture was stirred at 25°C for 1 h. To this mixture was added sodium cyanoborohydride (0.3 mmol, 3.0 eq.) at 25 °C, and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 87: General procedure N- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 mL) and the aldehyde (0.12 mmol, 1.2 eq.) and DIPEA (0.3 mmol, 3.0 eq.) was added sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.) and the resulting mixture was stirred at 60°C for 1 h. The reaction mixture was cooled and filtered; the filtrate was concentrated under reduced pressure to afford the crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 pm, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 88: General procedure 0 - Reductive amination
Amine (1 Eq) and aldehyde (1.5 Eq) were charged into a reaction vial equipped with a stir bar and dissolved in N,N-dimethylformamide, followed by the addition of decaborane (0.4 Eq). The reaction was allowed to stir for 30mins at 70 - 80 °C before monitoring through LCMS. Upon completion, the reaction mixture was loaded onto a Cl 8 column for purification with MeCN (+0.1% formic acid) and H2O (+0.1% formic acid). The desired fractions were collected, combined and concentrated via lyophilization to yield the desired product.
Example 89: General procedure P- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 ml) and the aldehyde (0.12 mmol, 1.2 eq.) was added sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.) and the resulting mixture was stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to afford crude compound, which was purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 um, eluting with Mobile phase A: 0.05% FA or HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 ml/min)]. The fractions containing pure product were combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 90: General procedure Q- Reductive amination
To a stirred solution of the amine or the amine hydrochloride (0.1 mmol, 1.0 eq.) in DMF (1 ml) and the aldehyde (0.12 mmol, 1.2 eq.) and DIPEA (0.3 mmol, 3.0 eq.) is added sodium triacetoxyborohydride (0.3 mmol, 3.0 eq.) and the resulting mixture is stirred for 16 h. The reaction mixture is then filtered and the filtrate is concentrated under reduced pressure to afford the crude compound, which is purified by reverse phase chromatography [(Column: X select (150 mm x 19) 5 um, eluting with Mobile phase A: 0.05% FA or HC1 in HiO, Mobile phase B: Acetonitrile, flow rate: 15 ml/min)]. The fractions containing pure product are combined and concentrated via lyophilization to afford the desired product as the formic acid salt, the hydrochloride salt, or the free amine.
Example 91: General procedure R- Reductive amination
To a stirred solution of amine (1.0 eq.) and an aldehyde (1.2 eq.) in DMF (1 mL) in a reaction vial equipped with a stir bar was added sodium triacetoxyborohydride (1.4 eq.). The resulting mixture was stirred at either room temperature overnight or heated to 60 °C for 30 min. Upon complete consumption of starting material, as confirmed by LCMS, the reaction mixture was worked up and purified via the purification method stated in the table entry.
Table 3.
Aldehyde/ Synthesis
Compound Amine MS Other and
Name (Cmpd Starting observed, 1H-NMR Starting Purification
No.) Material MH+ Material Method
1H-NMR (400 MHz, DMSO-d6): 5 10.60 (s, 1H), 10.55 (s, 1H), 8.95 (d, J = 2.40 Hz, l-(6-(l-benzyl- 1H), 8.31 (d, J = 2.00 4- l-(6-(4- Hz, 1H), 8.06-8.02 (m, hydroxypiperid hydroxypiperi 2H), 7.85 (s, 1H), in-4- din-4- 7.68-7.66 (m, 2H), yl)quinolin-3- yl)quinolin-3- benzaldehyde 431.3 7.51-7.49 (m, 3H), yljdihydropyri yl)dihydropyri Q 5.74 (s, 1H), 4.42 (d, J midine- midine- = 5.20 Hz, 2H), 3.98 2,4(1H,3H)- 2,4(1H,3H)- (t, J = 6.80 Hz, 2H), dione, HC1 (I- dione INT-S1 3.47-3.34 (m, 4H), 306) 2.81 (t, J = 6.40 Hz, 2H), 2.51-2.50 (m, 2H), 1.93-1.90 (m, 2H).
1H-NMR (400 MHz, l-(6-(4- DMSO-d6): 5 10.58 hydroxy-l-(3- l-(6-(4- (s, 1H), 8.89 (d, J = (trifluoromethy hydroxypiperi 2.80 Hz. 1H), 8.24 (d, l)benzyl)piperi din-4- 3- J = 2.00 Hz, 1H), 8.04 din-4- yl)quinolin-3- (trifluorometh (d, J = 1.60 Hz, 1H),
499.4 yl)quinolin-3- yl)dihydropyri yl)benzaldehy 7.97 (d, J = 8.80 Hz, Q yljdihydropyri midine- de 1H), 7.91 (d, J = 2.00 midine- 2,4(1H,3H)- Hz, 1H), 7.68-7.59 (m, 2,4(1H,3H)- dione INT-S1 4H), 5.08 (s, 1H), 3.96 dione (1-885) (t, J = 6.80 Hz, 2H), 3 66 (s 2H) 2 80 (t J = 6.80 Hz, 2H), 2.67 (d, J = 6.80 Hz, 1H), 2.51-2.50 (m, 1H), 2.11 (t, J = 8.40 Hz, 2H), 1.70 (d, J = 12.40 Hz, 2H), 1.28-1.24 (m, 2H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.58 (s, 1H), 8.88 (d, J =
2.80 Hz, 1H), 8.24 (d, J = 2.40 Hz, 1H), 8.02 (d, J = 2.00 Hz, 1H), l-(6-(l- 7.97 (d, J = 8.80 Hz, (cyclohexylmet l-(6-(4- 1H), 7.90 (d, J = 2.00 hyl)-4- hydroxypiperi Hz, 1H), 5.02 (s, 1H), hydroxypiperid din-4-
3.96 (t, J = 6.80 Hz, in-4- yl)quinolin-3- cyclohexanec
437.5 2H), 2.80 (t, J = 6.80 yl)quinolin-3- yl)dihydropyri arbaldehyde Q Hz, 2H), 2.68 (d, J = yljdihydropyri midine- 1.60 Hz, 1H), 2.41- midine- 2,4(1H,3H)- 2.36 (m, 2H), 2.15 (d, 2,4(1H,3H)- dione INT-S1 J = 7.20 Hz, 2H), 2.04 dione (1-919) (t, J = 8.80 Hz, 2H), 1.76 (m, 2H), 1.69- 1.64 (m, 6H), 1.53 (d, J = Hz, 1H), 1.28- 1.19 (m, 3H), 0.86 (q, J = 11.60 Hz, 2H). 1H-NMR (400 MHz, DMSO-d6): 5 10.58 (s, 1H), 8.89 (d, J = 2.40 Hz, 1H), 8.24 (d,
4-((4-(3-(2,4- J = 2.40 Hz, 1H), 8.03 l-(6-(4- dioxotetrahydr (d, J = 1.60 Hz, 1H), hydroxypiperi opyrimidin- 7.97 (d, J = 8.80 Hz, din-4- 1(2H)- 1H), 7.91 (d, J = 1.60 yl)quinolin-3- 4- yl)quinolin-6- Hz, 1H), 7.82 (d, J = yl)dihydropyri formylbenzon 456.4 P yi)-4- 8.00 Hz, 2H), 7.58 (d, midine- itrile hydroxypiperid J = 8.00 Hz, 2H), 5.09 2,4(1H,3H)- in-1- (s, 1H), 3.97 (t, J = dione, HC1 yl)methyl)benz 6.80 Hz, 2H), 3.65 (s, INT-S1 onitrile (1-167) 2H), 2.81 (t, J = 6.80 Hz, 2H), 2.68-2.64 (m, 4H), 2.15-2.12 (m, 2H), 1.70 (d, J = 11.60 Hz, 2H). _ l-(6-(4- l-(6-(4- 1H-NMR (400 MHz,
2- hydroxy-l-(2- hydroxypiperi DMSO-d6): 5 10.64
(trifluorometh (trifluoromethy din-4- 499.4 (s, 1H), 9.01 (d, J = P yl)benzaldehy l)benzyl)piperi yl)quinolin-3- 2.40 Hz, 1H), 8.42 (s, de din-4- yl)dihydropyri 2H) 8 08 (s 2H) yl)quinolin-3- midine- 7.94-7.91 (m, 3H), yljdihydropyri 2,4(1H,3H)- 7.71 (t, J = 7.60 Hz, midine- dione INT-S1 1H), 4.59 (d, J = 4.80 2,4(1H,3H)- Hz, 2H), 3.99 (t, J = dione, HC1 (I- 6.80 Hz, 3H), 3.48- 920) 3.35 (m, 4H), 2.81 (t, J = 6.80 Hz, 2H), 2.75- 2.68 (m, 2H), 1.90 (d, J = 13.60 Hz, 2H).
1H NMR (499 MHz, DMSO-d6) 5 ppm 10.97 (s, 1H) 8.75 (d, 1=2.19 Hz, 1H) 8.34 (s, 2H) 8.20 (d, 1=2.19 Hz, 1H) 8.02 (s, 1H)
3-(6-(8- 7.84-7.98 (m, 2H) 4.14 hydroxy-5- (dd, 1=12.59, 4.93 Hz, azaspiro[2.5]o 1H) 2.71-2.81 (m, 1H)
(1-916) ctan-8- acetaldehyde 394.4 C 2.55-2.68 (m, 3H) 2.42 yl)quinolin-3- (m, 1H) 2.26-2.38 (m, yl)piperidine- 3H) 2.10-2.18 (m, 1H) 2, 6-dione
1.95-2.10 (m, 2H) 1.72-1.88 (m, 1H) 1.23 (hr s, 2H) 0.99 (t, J=7.12 Hz, 3H) 0.38 (hr, 1H) 0.27-0.34 (m, 1H) 0.04-0.13 (m, 1H) 1H NMR (499 MHz, DMSO-d6) 5 = 10.97 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.00- 7.91 (m, 3H), 7.77- 7.66 (m, 3H), 7.63 (d,
3-(6-(3,3- J = 7.7 Hz, 2H), 4.50 bis(cycloprop (br s, 1H), 4.13 (dd, J ylmethyl)-4- 4- = 4.9, 12.6 Hz, 1H), hydroxypiperi (trifluorometh
(1-883) 606.5 3.71 (s, 2H), 3.01-2.94 0 din-4- yl)benzaldehy
(m, 2H), 2.77 (m, 1H), yl)quinolin-3- de 2.67-2.57 (m, 1H), yl)piperidine- 2.44 (m, 1H), 2.33- 2, 6-dione 2.07 (m, 5H), 1.05- 0.93 (m, 2H), 0.67- 0.44 (m, 2H), 0.36- 0.25 (m, 2H), 0.20- 0.04 (m, 4H), -0.33 (m, 2H), -0.50-0.61 (m, 2H) _
3-(6-(4- 1H NMR (499 MHz,
(1-886) hydroxy-3- acetaldehyde 382.4 DMSO-d6) 5 ppm 0 methylpiperid 10 94 10 99 (m 1H) in-4- 8.71-8.76 (m, 1H) yl)quinolin-3- 8.26-8.31 (m, 1H) yl)piperidine- 8.15-8.19 (m, 1H) 2, 6-dione 7.98-8.02 (m, 1H) 7.93-7.97 (m, 1H) 7.80-7.84 (m, 1H) 4.08-4.16 (m, 1H) 2.54-2.84 (m, 5H) 2.08-2.23 (m, 5H) 1.60-1.67 (m, 1H) 1.21-1.26 (m, 1H) 1.03-1.11 (m, 3H) 0.45-0.53 (m, 3H) (peaks overlap with solvent)
1H NMR (499 MHz, DMSO-d6) 5 ppm 10.96 (s, 1H) 8.75 (d, J=2.19 Hz, 1H) 8.19- 8.23 (m, 1H) 8.33 (s,
3-(6-(5- 2H) 7.87-7.96 (m, 3H) hydroxy-2- 4.11-4.17 (m, 1H) azaspiro[5.5]u 2.94-3.00 (m, 1H)
(1-176) ndecan-5- acetaldehyde 436.5 2.68-2.84 (m, 3H) 0 yl)quinolin-3- 2.58-2.65 (m, 1H) yl)piperidine- 2.31-2.46 (m, 4H) 2, 6-dione 2.11-2.23 (m, 3H) 1.71-1.78 (m, 1H) 1.38-1.50 (m, 2H) 1.20-1.34 (m, 4H) 1.05 (s, 3H) 0.99 - 0.83 (m, 1H) 0.51-0.67 (m, 2H)
3-(6-(l-ethyl-4-
3-(6-(4- hydroxy-3- hydroxy-3- methoxypiperid methoxypiperi in-4- din-4- acetaldehyde 398.3 N/A 0 yl)quinolin-3- yl)quinolin-3- yljpiperidine- yl)piperidine- 2, 6-dione (I- 2, 6-dione 899)
1H NMR (499 MHz, DMS0-d6) 5 ppm
3-(6-(l-ethyl-4- 3-(6-(4- 10.95-10.99 (m, 1H) hydroxy-3- hydroxy-3- 8.73-8.76 (m, 1H) (trifluoromethy (trifluorometh 8.21-8.25 (m, 1H) l)piperidin-4- yl)piperidin- acetaldehyde 436.4 8.15-8.19 (m, 1H) 0 yl)quinolin-3- 4-yl)quinolin- 8.07-8.11 (m, 1H) yljpiperidine- 3-
7.91-7.96 (m, 2H) 2, 6-dione (I- yl)piperidine- 4.11-4.18 (m, 1H) 178) 2, 6-dione
3.15-3.21 (m, 1H)
2 92 2 98 (m 1H) 2.73-2.82 (m, 2H) 2.68-2.72 (m, 1H) 2.52-2.65 (m, 2H) 2.34-2.48 (m, 3H)
2.10-2.19 (m, 2H)
1.60-1.65 (m, 1H) 1.21-1.27 (m, 1H) 1.04-1.10 (m, 3H) 1H NMR (499 MHz, DMSO-d6) 5 ppm
10.95-10.98 (m, 1H) 8.80 (d, J = 2.2 Hz, 1H) 8.32-8.36 (m, 1H)
8.24-8.27 (m, 1H)
8.17-8.23 (m, 1H)
3-(6-(4-
7.98-8.03 (m, 1H) hydroxy-9-
7.60-7.65 (m, 2H) azadispiro[2.1 4- 7.44-7.49 (m, 2H) .25.33]decan- (trifluorometh d-911) 550.4 4.57-4.63 (m, 1H) 0
4-yl)quinolin- yl)benzaldehy 4.09-4.19 (m, 1H) 3- de 2.72-2.80 (m, 1H) yl)piperidine- 2.55-2.65 (m, 3H) 2, 6-dione 2.40-2.47 (m, 1H)
2.11-2.18 (m, 1H) 1.93-1.99 (m, 2H) 1.13-1.21 (m, 2H) 0.91-1.00 (m, 2H) 0.52-0.61 (m, 3H) 0.25-0.34 (m, 2H) 1H NMR (499 MHz, DMSO-d6) 5 ppm
10.95-10.97 (m, 1H) 8.75-8.78 (m, 1H)
3-(6-(4- 8.31-8.33 (m, 1H) hydroxy-9- 8.25-8.27 (m, 1H) azadispiro[2.1 8.18-8.21 (m, 1H) .25.33]decan- 7.98-8.02 (m, 1H)
(1-922) acetaldehyde 420.4 0
4-yl)quinolin- 2.70-2.82 (m, 2H)
3- 2.57-2.64 (m, 1H) 2.54 yl)piperidine- (s, 1H) 2.41-2.45 (m, 2, 6-dione 1H) 2.12-2.23 (m, 6H) 1.15-1.22 (m, 2H) 0.89-0.98 (m, 3H) 0.88 (s, 3H) 0.61-0.68 (m, 2H) 0.32-0.41 (m, 2H)
3-(6-(l-ethyl-4- 1H NMR (499 MHz,
3-(6-(4- hydroxy-3,3- DMSO-d6, 298 K) 5 hydroxy-3,3- dimethylpiperi (ppm) = 10.98 - 10.95 dimethylpiper acetaldehyde 396.4 0 din-4- (m, 1H). 8.77 - 8.73 idin-4- yl)quinolin-3- (m, 1H), 8.24 - 8.19 yl)quinolin-3- yljpiperidine- (m 2H) 8 00 7 96 2,6-dione (I- yl)piperidine- (m, 1H), 7.95 - 7.88
896) 2, 6-dione (m, 2H), 4.16 - 4.11 (m, 1H), 2.83 - 2.74 (m, 3H), 2.65 - 2.61 (m, 1H), 2.46 - 2.36 (m, 6H), 2.29 - 2.24 (m, 1H), 2.17 - 2.11 (m, 1H). 1.59 - 1.52 (m, 1H), 1.07 - 1.02 (m, 3H), 0.88 - 0.85 (m, 3H), 0.73 - 0.71 (m, 3H)
1H NMR (499 MHz, DMSO-d6) 5 ppm 10.97 - 11.00 (m, 1H) 8.81 - 8.85 (m, 1H) 8.31 - 8.34 (m, 1H) 8.01 - 8.07 (m, 1H) 7.85 - 7.89 (m, 1H)
7.69 - 7.73 (m, 2H)
3-(6-(3-ethyl- 7.59 - 7.63 (m, 2H)
4- 4.20 - 4.26 (m, 1H) hydroxypiperi 4-
3.69 - 3.75 (m, 1H) din-4-yl)-5- (trifluorometh
(1-250) 544.4 3.57 - 3.63 (m, 1H) 0 fluoroquinolin yl)benzaldehy 2.71 - 2.82 (m, 2H) -3- de
2.58 - 2.65 (m, 2H) yl)piperidine- 2.22 - 2.29 (m, 2H)
2, 6-dione 2.10 - 2.18 (m, 1H) 1.93 - 2.04 (m, 1H) 1.61 - 1.69 (m, 1H) 1.02 - 1.13 (m, 1H) 0.88 - 0.97 (m, 1H) 0.51 - 0.60 (m, 3H) (peaks overlap with solvent)
1H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s,
3-{5-fluoro-6- 3-(5-fluoro-6- 1H), 8.09 (t, J = 8.80 [4-hydroxy- (4-hydroxy- Hz, 1H), 7.84 (d, J =
3,3-dimethyl-l- 3,3-
2,2,2- 9.20 Hz, 1H), 5.20 (s, (2,2,2- dimethylpiper
Trifluoroethyl 1H), 4.23 (q, J = 4.40 trifluoroethyl)- idin-4- 468 J
Trifluorometh Hz, 1H), 3.22-3.09 (m,
4-piperidyl]-3- yl)quinolin-3- anesulfonate 3H), 2.95 (t, J = 4.00 quinolyl}-2,6- yl)piperidine- Hz, 2H), 2.89 (t, J = piperidinedione 2, 6-dione, 8.00 Hz, 2H), 2.51 (t, J (1-893) HC1 = 1.60 Hz, 1H), 2.34- 2.28 (m, 1H), 2.34- 2.28 (m, 1H), 2.16- 2 12 (m 1H) 1 70 (d
Figure imgf000461_0001
Figure imgf000462_0001
din-4-yl)-5- methylquinoli (hr t, J = 8.8 Hz, 1H), fluoro-2- n-3- 7.96 (hr d, J = 9.3 Hz, methylquinolin yl)piperidine- 1H), 7.00 - 6.85 (m, -3- 2, 6-dione, 1H), 6.31 (hr t, J = 3.6 yljpiperidine- HC1 Hz, 1H), 6.10 (q, J = 2, 6-dione (I- 2.7 Hz, 1H), 5.90 (hr 299) s, 1H), 4.43 (hr dd, J = 4.4, 12.6 Hz, 2H), 4.32 (br d, J = 4.4 Hz, 2H), 3.36 - 3.27 (m, 2H), 3.23 - 3.16 (m, 2H), 2.87 - 2.81 (m, 2H), 2.80 (s, 2H), 2.68 - 2.55 (m, 2H), 2.15 - 2.09 (m, 1H), 2.05 - 1.92 (m, 1H), 1.09 (s, 3H), 0.76 (s, 3H).
1H NMR (499 MHz, DMSO-d6) 5 (ppm) = 10.99 (s, lH), 9.16 (br s, 1H), 8.44 (br d, J = 7.1 Hz, 1H), 8.15 -
3-(5-fluoro-6- 3-(5-fluoro-6- 8.06 (m, 1H), 7.91 (br (4-hydroxy-l- (4-hydroxy- d, J = 9.3 Hz, 1H), isopropyl-3,3- 3,3- 5.94 (br s, 1H), 4.44 - dimethylpiperi dimethylpiper 4.38 (m, 1H), 3.55 - din-4-yl)-2- idin-4-yl)-2- 3.48 (m, 1H), 3.37 - acetone 442 0 methylquinolin methylquinoli 3.31 (m, 3H), 3.21 - -3- n-3- 3.15 (m, 2H), 3.07 - yl)piperidine- yl)piperidine- 3.00 (m, 1H), 2.88 - 2, 6-dione (I- 2, 6-dione, 2.80 (m, 1H), 2.76 (s, 868) HC1 3H), 2.66 - 2.60 (m, 1H), 2.16 - 2.08 (m, 1H), 2.07 - 1.96 (m, 1H), 1.42 - 1.26 (m, 6H), 1.11 (s, 3H), 0.84 - 0.79 (m, 3H).
1H NMR (499 MHz, DMSO-d6, 298 K) 5 (ppm) = 11.00 - 10.95 (m, 1H), 8.79 - 8.72
3-(6-(3- (m, 1H), 8.26 - 8.22 benzyl-4- (m, 2H), 8.15 - 8.12 hydroxypiperi (m, 1H), 8.07 - 7.99 d-14) din-4- acetaldehyde 458.5 0 (m, 1H), 7.98 - 7.92 yl)quinolin-3- (m, 1H), 7.22 - 7.14 yl)piperidine- (m, 2H), 7.13 - 7.07 2, 6-dione (m, 1H), 6.95 - 6.86 (m, 2H), 4.19 - 4.10 (m, 1H), 2.79 - 2.72 (m 2H) 2 66 2 58 (m, 1H), 2.47 - 2.40
(m, 3H), 2.38 - 2.32
(m, 3H), 2.27 - 2.11
(m, 5H), 1.72 - 1.65 (m, 1H), 0.93 (s, 3H)
1H NMR (499 MHz, DMSO-d6, 297 K) 5 (ppm) = 11.01 - 10.95 (m, 1H), 8.79 - 8.74 (m, 1H), 8.38 - 8.35 (m, 1H), 8.25 - 8.22 (m, 1H), 8.15 - 8.13 (m, 1H), 8.07 - 8.00 (m, 1H), 7.98 - 7.95 (m, 1H), 7.71 - 7.61 (m, 2H), 7.60 - 7.47
3-(6-(3- (m, 2H), 7.16 - 7.03 benzyl-4- (m, 2H), 6.99 - 6.87
4- hydroxypiperi (m, 2H), 6.75 - 6.62
(trifluorometh
(1-23) din-4- 588.5 (m, 1H), 5.18 - 5.15 0 yl)benzaldehy yl)quinolin-3- (m, 1H), 4.18 - 4.12 de yl)piperidine- (m, 1H), 3.64 - 3.60 2, 6-dione (m, 1H), 3.52 - 3.48 (m, 1H), 2.82 - 2.73 (m, 1H), 2.67 - 2.61 (m, 1H), 2.61 - 2.56 (m, 1H), 2.48 - 2.42 (m, 2H), 2.37 - 2.32 (m, 1H), 2.28 - 2.19 (m, 2H), 2.19 - 2.11 (m, 2H), 2.01 - 1.77 (m, 1H), 1.69 - 1.64 (m, 1H), 1.26 - 1.22 (m, 1H)
1H NMR (499 MHz, DMSO, 297 K) 5 ppm 10.99 - 10.93 (m, 1H), 8.33 - 8.28 (m, 1H), 8.24 - 8.20 (m, 1H),
3-(5-fluoro-6- 8.01 - 7.95 (m, 1H), (4- 7.77 - 7.73 (m, 1H), hydroxyazepa 4- 7.72 - 7.66 (m, 2H), n-4-yl)-2- (trifluorometh
1-688 544.4 7.63 - 7.56 (m, 2H), 0 methylquinoli yl)benzaldehy 4.40 - 4.31 (m, 1H), n-3- de 3.84 - 3.73 (m, 2H), yl)piperidine- 3.00 - 2.94 (m, 1H), 2, 6-dione 2.87 - 2.80 (m, 1H), 2.75 - 2.71 (m, 2H), 2.66 (s, 3H), 2.65 - 2.62 (m, 1H), 2.62 - 2 53 (m 2H) 2 42 2.35 (m, 2H), 2.15 - 2.00 (m, 2H), 1.83 -
1.71 (m, 2H), 1.68 -
I.59 (m, 1H) (peak overlap with solvent) 1H NMR (499 MHz, DMSO, 300 K) 5 ppm 10.99 - 10.90 (m, 1H),
8.29 (s, 1H), 8.21 - 8.18 (m, 1H), 8.00 -
7.94 (m, 1H), 7.77 - 7.73 (m, 1H), 4.38 - 4.31 (m, 1H), 3.12 -
3-(5-fluoro-6- 3.06 (m, 1H), 2.93 - (4- 2.87 (m, 1H), 2.87 - hydroxyazepa 2.78 (m, 2H), 2.77 - n-4-yl)-2-
1-872 acetaldehyde 414.3 2.71 (m, 1H), 2.70 - 0 methylquinoli
2.68 (m, 1H), 2.66 (s, n-3-
3H), 2.64 - 2.58 (m, yl)piperidine- 1H), 2.48 - 2.40 (m, 2, 6-dione 2H), 2.30 - 2.23 (m, 1H), 2.15 - 2.08 (m, 1H), 2.06 - 1.97 (m, 1H), 1.85 - 1.77 (m, 2H), 1.72 - 1.62 (m, 1H), 1.08 (s, 3H) (peak overlap with solvent) _
1H NMR (499 MHz, DMSO, 297 K) 5 ppm
II.02 - 10.94 (m, 1H),
8.88 - 8.83 (m, 1H), 8.33 (s, 2H), 8.10 -
3-(5-fluoro-6- 8.02 (m, 1H), 7.94 - (4-hydroxy-3- 7.89 (m, 1H), 6.00 - (trifluorometh 5.90 (m, 1H), 4.27 - yl)piperidin- 4.20 (m, 1H), 2.98 -
1-255 acetaldehyde 454.4 0
4-yl)quinolin- 2.92 (m, 1H), 2.81 - 3- 2.72 (m, 2H), 2.65 - yl)piperidine- 2.54 (m, 2H), 2.48 - 2, 6-dione 2.30 (m, 4H), 2.17 - 2.11 (m, 1H), 2.05 -
1.94 (m, 1H), 1.76 -
1.69 (m, 1H), 1.35 -
1.22 (m, 1H), 1.07 (s, 3H) _
1H NMR (499 MHz,
3-(6-(4- 4- DMSO-d6, 297 K) 5 hydroxyazepa (trifluorometh
1-853 512.3 ppm 10.98 - 10.95 (m, 0 n-4- yl)benzaldehy 1H), 8.74 (d, J = 2.2 yl)quinolin-3- de Hz 1H) 8 31 8 27 yl)piperidine- (m, 1H), 8.21 - 8.18 2, 6-dione (m, 1H), 7.94 (s, 2H), 7.91 - 7.87 (m, 1H),
7.69 (s, 2H), 7.63 - 7.56 (m, 2H), 4.17 - 4.10 (m, 1H), 3.78 - 3.73 (m, 2H), 2.96 - 2.89 (m, 1H), 2.81 -
2.70 (m, 3H), 2.64 - 2.61 (m, 1H), 2.60 - 2.53 (m, 1H), 2.46 - 2.35 (m, 1H), 2.25 - 2.18 (m, 2H), 2.17 - 2.09 (m, 1H), 2.06 - 1.95 (m, 1H), 1.88 - 1.77 (m, 2H), 1.68 - 1.58 (m, 1H)
1H NMR (499 MHz, DMSO-d6, 297 K) 5 ppml 1.00 - 10.94 (m, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H),
8.20 - 8.16 (m, 1H),
3-(6-(4- 8.00 - 7.94 (m, 2H), hydroxyazepa 7.92 - 7.86 (m, 1H), n-4- 4.16 - 4.11 (m, 1H),
1-910 acetaldehyde 382.4 0 yl)quinolin-3- 3.21 - 3.13 (m, 1H), yl)piperidine- 2.99 - 2.90 (m, 2H), 2, 6-dione 2.84 - 2.75 (m, 4H), 2.64 - 2.57 (m, 1H), 2.47 - 2.30 (m, 3H),
2.16 - 1.97 (m, 3H), 1.86 - 1.79 (m, 2H), 1.71 - 1.62 (m, 1H), 1.12 (s, 3H)
3-(6-(l-((4,4- difluorocyclohe 3-(5-fluoro-6- xyl)methyl)-4- (4-hydroxy- hydroxy-3,3- 3,3- dimethylpiperi dimethylpiper 4,4- din-4-yl)-5- idin-4-yl)-2- difluorocyclo
532 No NMR recorded 0 fluoro-2- methylquinoli hexane- 1- methylquinolin n-3- carbaldehyde -3- yl)piperidine- yl)piperidine- 2, 6-dione, 2, 6-dione (I- HC1 297) _
3-(5-fluoro-6- 3-(5-fluoro-6- 1H NMR (499 MHz, (4-hydroxy-l- (4-hydroxy- isobutyr aldeh DMS0-d6) 5 (ppm) =
456 0 isobutyl-3,3- 3,3- yde 10.94 (s, 1H), 8.20 (s, dimethylpiperi dimethylpiper 1H) 8 03 (t J = 8 8
Figure imgf000467_0001
2H), 2.46 - 2.30 (m, 3H), 2.22 - 2.17 (m, 2H), 2.17 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.87 - 1.76 (m, 1H), 1.74 - 1.67 (m, 1H), 1.26 - 1.21 (m, 1H), 0.92 - 0.88 (m, 5H). 0.89 - 0.86 (m, 1H) _
1H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, 1H), 10.64 (s, 1H), 8.92 (d, J = 1.60 Hz,
3-(6-(l-ethyl-4-
3-(6-(4- 1H), 8.43 (s, 1H), 8.13 hydroxy-3- hydroxy-3- (t, J = 7.20 Hz, 1H), (2,2,2- (2,2,2- ' 7.84 (s, 1H), 6.11 (s, trifluoroethyl)p trifluoroethyl) 1H), 4.25-4.20 (m, iperidin-4- acetaldehyde 450.4 P piperidin-4- 1H), 3.31-3.27 (m, yl)quinolin-3- yl)quinolin-3- 6H), 3.01 (t, J = 5.60 yl)piperidine- yl)piperidine- Hz, 1H), 2.75-2.67 (m, 2, 6-dione, HC1
2, 6-dione 4H), 2.50-2.46 (m, (1-313) 1H), 2.19-2.16 (m, 2H), 1.95-1.91 (m, 2H), 1.33 (t, J = 7.60 Hz, 3H). _
1H NMR (499 MHz, DMSO-d6) 5 (ppm) = 10.96 (s, 1H), 9.99 (hr d, J = 4.4 Hz, 1H), 8.31 (hr d, J = 8.8 Hz,
3-(5-fluoro-6- 1H), 8.03 (hr t, J = 8.5 (4-hydroxy- 3-(5-fluoro-6- Hz, 1H), 7.83 (d, J = 3, 3 -dimethyl- 1 - (4-hydroxy- 8.8 Hz, 1H), 7.53 (d, J (( 1 -methyl- 1H- 3,3- = 1.6 Hz, 1H), 6.67 (s, pyrazol-5- dimethylpiper
1 -methyl- 1H- 1H), 5.90 (hr s, 1H), yl)methyl)piper idin-4-yl)-2- pyrazole-5- 494 4.54 (hr d, J = 3.8 Hz, 0 idin-4-yl)-2- methylquinoli carbaldehyde 2H), 4.42 - 4.34 (m, methylquinolin n-3- 1H), 3.96 (s, 3H), 3.32 -3- yl)piperidine- - 3.24 (m, 3H), 3.05 - yljpiperidine- 2, 6-dione, 2.98 (m, 1H), 2.90 - 2, 6-dione (I- HC1 2.76 (m, 2H), 2.70 (s, 158) 3H), 2.65 - 2.52 (m, 2H), 2.15 - 2.05 (m, 1H), 2.05 - 1.96 (m, 1H), 1.07 (s, 3H), 0.79 (s, 3H). _
3-(6-(l-ethyl-4- 3-(6-(4- 1H-NMR (400 MHz, hydroxy-3- hydroxy-3- DMSO-d6): 5 11.01 acetaldehyde 450.4 P (2,2,2- (2,2,2- ' (s, 1H), 10.09 (s, 1H), trifluoroethyl)p trifluoroethyl) 8 90 (s 1H) 8 39 (s iperidin-4- piperidin-4- 1H), 8.11 (d, J = 8.80 yl)quinolin-3- yl)quinolin-3- Hz, 1H), 8.01-7.97 (m, yl)piperidine- yl)piperidine- 2H), 6.09 (s, 1H), 4.21 2, 6-dione, HC1 2, 6-dione (dd, 1 = 4.80, 12.40
(1-314) Hz, 1H), 3.66-3.63 (m, 2H), 3.29-3.19 (m, 6H), 2.79-2.75 (m, 1H), 2.68-2.61 (m, 2H), 2.46-2.41 (m, 1H), 2.34-2.15 (m, 2H), 1.50 (m, 1H), 1.33 (t, J = 7.20 Hz, 3H).
1H NMR (499 MHz, DMSO-d6, 298 K) 5 ppm 11.02 - 10.98 (m, 1H), 8.88 - 8.83 (m, 1H), 8.50 - 8.47 (m, 1H), 8.37 - 8.32 (m, 1H), 8.14 - 8.09 (m, 1H), 7.94 - 7.89 (m,
3-(6-(3- 1H), 7.66 - 7.61 (m, benzyl-4- 2H), 7.52 - 7.48 (m, hydroxypiperi 4- 2H), 7.12 - 7.07 (m, din-4-yl)-5- (trifluorometh 2H), 7.03 - 6.97 (m,
1-680 606.3 O fluoroquinolin yl)benzaldehy 1H), 6.88 - 6.83 (m, -3- de 2H), 4.28 - 4.22 (m, yl)piperidine- 1H), 3.66 - 3.60 (m, 2, 6-dione 1H), 3.52 - 3.47 (m, 1H), 2.71 - 2.57 (m, 3H), 2.42 - 2.30 (m, 4H), 2.24 - 2.12 (m, 3H), 2.02 - 1.95 (m, 1H), 1.74 - 1.67 (m, 1H), 1.29 - 1.20 (m, 3H) (one extra aliphatic proton)
1H NMR (499 MHz, DMSO-d6, 298 K) 5 ppm 11.04 - 10.97 (m,
3-(6-(3- 1H), 8.85 (s, 1H), 8.32 benzyl-4- (s, 2H), 8.16 - 8.07 (m, hydroxypiperi 1H), 7.91 (s, 1H), 7.13 din-4-yl)-5- isobutyr aldeh (s, 2H), 7.08 - 7.00 (m,
(1-780) 504.4 0 fluoroquinolin yde 1H), 6.87 (d, J = 7.1 -3- Hz, 2H), 4.28 - 4.21 yl)piperidine- (m, 1H), 2.82 - 2.73 2, 6-dione (m, 1H), 2.68 - 2.59 (m, 3H), 2.47 - 2.34 (m, 4H), 2.34 - 2.28 (m 1H) 2 23 2 13 (m, 3H), 2.08 - 2.02
(m, 1H), 2.02 - 1.95
(m, 1H), 1.75 - 1.60
(m, 2H), 1.27 - 1.20
(m, 1H), 0.83 - 0.73
(m, 6H)
1H NMR (499 MHz, DMSO-d6) 5 (ppm) = 11.01 (s, 1H), 10.54 -
10.38 (m, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 8.17 (t, J = 8.8 Hz, 1H), 8.01 - 7.93 (m, 3H), 7.92 - 7.88
3-(5-fluoro-6- (m, 2H), 6.07 - 5.77 (9-hydroxy-6-
3-(5-fluoro-6- (m, 1H), 4.58 - 4.49 (4- (9-hydroxy-6- (m, 2H), 4.27 (dd, J = (trifluoromethy azaspiro[3.5]n 4- 4.9, 12.6 Hz, 1H), 3.56 l)benzyl)-6- onan-9- (trifluorometh (d, J = 12.0 Hz, 1H), azaspiro[3.5]no 556 R yl)quinolin-3- yl)benzaldehy 3.38 - 3.37 (m, 1H), nan-9- yl)piperidine- de 3.34 - 3.24 (m, 2H), yl)quinolin-3- 2, 6-dione 3.22 - 3.10 (m, 1H), yl)piperidine- INT-S4 2.81 - 2.74 (m, 1H), 2, 6-dione (I- 2.78 - 2.74 (m, 1H), 238) 2.67 - 2.59 (m, 1H), 2.30 - 2.26 (m, 1H), 2.18 - 2.10 (m, 1H), 2.01 - 1.92 (m, 2H), 1.89 - 1.81 (m, 1H), 1.60 - 1.50 (m, 1H), 1.50 - 1.43 (m, 1H), 0.99 - 0.83 (m, 1H).
1H NMR (499 MHz, DMSO-d6, 298 K) 5 ppm 11.02 - 10.98 (m, 1H), 8.87 - 8.83 (m, 1H), 8.36 (s, 2H), 8.13 - 8.08 (m, 1H), 7.92 -
3-(6-(3- 7.88 (m, 1H), 7.26 - benzyl-4- 7.24 (m, 1H), 7.13 - hydroxypiperi
1 -methyl- 1H- 7.08 (m, 2H), 7.05 - din-4-yl)-5-
1-651 pyrazole-5- 542.3 6.99 (m, 1H), 6.87 - 0 fluoroquinolin carbaldehyde 6.83 (m, 2H), 6.07 (d, -3- J = 1.6 Hz, 1H), 5.51 - yl)piperidine- 5.37 (m, 1H), 4.27 - 2, 6-dione 4.20 (m, 1H), 3.75 (s, 3H), 3.56 - 3.51 (m, 2H), 2.81 - 2.73 (m, 1H), 2.66 - 2.57 (m, 3H), 2.43 - 2.28 (m, 4H) 2 24 2 10 (m 3H), 1.74 - 1.68 (m, 1H). 1.29 - 1.16 (m, 1H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.11 (bs, 1H),
8.91 (d, J = 1.60 Hz, 1H), 8.41 (s, 1H),
3-(5-fluoro-6-
3-[5-fluoro-6- 8.11-8.06 (m, 1H), (4-hydroxy- (4-hydroxy-l- 7.92 (d, J = 9.20 Hz, 3,3- isopropyl-3,3- 1H), 5.93 (bs, 1H), dimethylpiper dimethyl-4- 4.32-4.28 (m, 1H), idin-4- Propan-2-one 428.6 P piperidyl)-3- 3.54-3.40 (m, 1H), yl)quinolin-3- quinolyl]-2,6- 3.38-3.22 (m, 3H), yl)piperidine- piperidinedione 3.20 (t, J = 10.2 Hz, 2, 6-dione,
(1-202) 1H), 3.05 (d, J = 11.2 HC1 Hz, 1H), 2.76-2.50 (m, 3H), 2.16-2.01 (m, 2H), 1.36 (t, J = 2.00 Hz, 6H), 1.12 (s, 3H), 0.84 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.82 (s, 1H),
3-[5-fluoro-6- 8.90 (s, 1H), 8.45-8.39 (4-hydroxy-l- 3-(5-fluoro-6- (m, 2H), 8.08-7.89 (m, {[p-(lH- (4-hydroxy- 8H), 7.57-7.53 (m, indazol-1- 3,3-
4-(lH- 1H), 7.32 (t, J = 7.60 yl)phenyl]meth dimethylpiper indazol-1- Hz, 1H), 5.95 (s, 1H), yl}-3,3- idin-4- 592.5 P yl)benzaldehy 4.52 (t, J = 5.20 Hz, dimethyl-4- yl)quinolin-3- de 2H), 4.27-4.23 (m, piperidyl)-3- yl)piperidine- 1H), 3.66-3.34 (m, quinolyl]-2,6- 2, 6-dione, 4H), 3.01 (d, J = 12.00 piperidinedione HC1 Hz, 1H), 2.68-2.51 (m, (1-409) 3H), 2.15-2.05 (m, 2H), 1.11 (s, 3H), 0.81 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(5-fluoro-6- (s, 1H), 8.85 (d, J = (4-hydroxy- 3-(5-fluoro-6- 2.00 Hz, 1H), 8.31 (s, 3, 3 -dimethyl- 1 - (4-hydroxy- 1H), 8.09 (t, J = 8.80 (( 1 -methyl- 1 H- 3,3-
1 -methyl- 1 H- Hz, 1H), 7.84 (d, J = l,2,4-triazol-5- dimethylpiper 1,2,4-triazole- 8.00 Hz, 2H), 5.17 (s, yl)methyl)piper idin-4- 481.5 P 1H), 4.22 (dd, J = idin-4- yl)quinolin-3- carbaldehyde 4.80, 12.80 Hz, 1H), yl)quinolin-3- yl)piperidine- 3.94 (s, 3H), 3.69 (s, yljpiperidine- 2, 6-dione, 2H), 3.08 (t, J = 2.40 2, 6-dione (I- HC1 Hz, 1H), 2.78-2.72 (m, 918) 1H), 2.67-2.57 (m, 5H) 2 13 (d J = 4 00
Figure imgf000472_0001
dimethylpiperi idin-4-yl)-2- = 8.80 Hz, 1H), 7.74 din-4-yl)-5- methylquinoli (s, 1H), 5.11 (s, 1H), fluoro-2- n-3- 4.37-4.33 (m, 1H), methylquinolin yl)piperidine- 3.98 (s, 2H), 3.33-3.11 -3- 2, 6-dione, (m, 1H), 2.82-2.59 (m, yl)piperidine- HC1 8H), 2.24 (d, J = 10.40 2, 6-dione (I- Hz, 1H), 2.12-2.10 (m, 892) 1H), 1.89 (s, 1H), 1.69 (d, J = 12.80 Hz, 1H), 0.97 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.59 (s, 1H), 9.86 (s, 1H),
(R)-l-(6-(l-((5- 8.97 (d, J = 2.40 Hz, chloro-6- 1H), 8.73 (d, J = 1.60 (1,2,4- (R)-l-(5- Hz, 1H), 8.33 (d, J = oxadiazol-3- fluoro-6-(4- 2.00 Hz, 1H), 8.15 (d, yl)pyridin-3- hydroxy-3,3- J = 1.20 Hz, 1H), 8.09 yl)methyl)-4- dimethylpiper 5-chloro-6- (t, J = 8.80 Hz, 1H), hydroxy-3,3- idin-4- (1,2,4- 7.85 (d, J = 9.20 Hz, dimethylpiperi yl)quinolin-3- oxadiazol-3- 580.3 M 1H), 5.19 (s, 1H), 4.01 din-4-yl)-5- yl)dihydropyri yl)nicotinalde (t, J = 6.40 Hz, 2H), fluoroquinolin- midine- hyde 3.78-3.62 (m, 2H), 3- 2,4(1H,3H)- 3.19 (m, 1H), 2.8O (t, J yl)dihydropyri dione, HC1 = 6.80 Hz, 2H), 2.68- midine- INT-(R)-S2 2.67 (m, 2H), 2.21 (d, 2,4(1H,3H)- J = 10.40 Hz, 1H), dione (1-890) 1.91 (s, 1H), 1.76-1.73 (m, 1H), 1.02 (s, 3H), 0.70 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J =
(R)-l-(5- 2.40 Hz, 1H), 8.32 (d, fluoro-6-(l-((5-
(R)-l-(5- J = 2.00 Hz, 1H), 8.07 fluoro-1- fluoro-6-(4- (t, J = 8.80 Hz, 1H), methyl-lH- hydroxy-3,3- 7.83 (d, J = 9.20 Hz, pyrazol-4- dimethylpiper 1H), 7.38 (d, J = 2.40 yl)methyl)-4- 5-fluoro-l- idin-4- Hz, 1H), 5.93-5.91 (m, hydroxy-3,3- methyl-lH- yl)quinolin-3- 499.2 1H), 5.11 (s, 1H), (s, G dimethylpiperi pyrazole-4- yl)dihydropyri 2H), 4.00 (t, J = 6.40 din-4- carbaldehyde midine- Hz, 2H), 3.57 (s, 3H), yl)quinolin-3- 2,4(1H,3H)- 2.88 (t, J = 6.40 Hz, yl)dihydropyri dione INT- 1H), 2.76 (m, 2H), midine- (R)-S2 2.71-2.66 (m, 2H), 2,4(1H,3H)- 2.12 (d, J = 10.40 Hz, dione (1-913) 1H), 1.67 (d, J = 13.60 Hz, 1H), 0.85 (s, 3H), 0.67 (s, 3H).
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Hz, 3H), 1.82 (d, J = 5.60 Hz, 2H), 1.11 (d, J = 2.40 Hz, 3H), 0.79 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.62
(R)-l-(5- (s, 1H), 9.27 (s, 1H), fluoro-6-(4- 9.00 (d, J = 2.40 Hz, hydroxy-3,3- (R)-l-(5- 1H), 8.34 (d, J = 2.00 dimethyl-l-((4- fluoro-6-(4- Hz, 1H), 8.07 (t, J = methyl-6- hydroxy-3,3- 8.80 Hz, 1H), 7.95- (trifluoromethy dimethylpiper
4-methyl-6- 7.93 (m, 2H), 5.98 (s, l)pyridin-3- idin-4- (trifluorometh 1H), 4.63 (s, 2H), 4.01 yl)methyl)piper yl)quinolin-3- 558.5 G yl)nicotinalde (t, J = 7.60 Hz, 2H), idin-4- yl)dihydropyri hyde 3.57-3.51 (m, 3H), yl)quinolin-3- midine- 3.19 (d, J = 13.20 Hz, yljdihydropyri 2,4(1H,3H)- 1H), 2.80 (t, J = 6.40 midine- dione, HC1 Hz, 2H), 2.60 (s, 3H), 2,4(1H,3H)- INT-(R)-S2 2.53-2.52 (m, 2H), dione, HC1 (I- 2.02 (d, J = 14.00 Hz, 897) 1H), 1.09 (s, 3H), 0.86 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.60 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.32 (d, J = 2.00 Hz, 1H), 8.26 (s, 1H), 8.08 (t, J = l-{5-fluoro-6- 8.80 Hz, 1H), 7.84 (d, [(R)-4- (R)-l-(5- J = 9.20 Hz, 1H), 6.49 hydroxy-3,3- fluoro-6-(4- (d, J = 2.40 Hz, 1H), dimethyl-1- hydroxy-3,3- 5.92 (d, J = 2.80 Hz, [(5, 6,7,8- dimethylpiper 1H), 5.05 (s, 1H), 4.00
5, 6,7,8- tetrahydro-1- idin-4- (t, J = 6.80 Hz, 2H), tetrahydroind indolizinyl)met yl)quinolin-3- 520.5 3.87 (t, J = 6.40 Hz, G olizine-1- hyl]-4- yl)dihydropyri 2H), 3.36 (s, 2H), carbaldehyde piperidyl]-3- midine- 3.29-3.21 (m, 1H), quinolyl}hexah 2,4(1H,3H)- 2.80 (t, J = 6.80 Hz, ydro-2,4- dione INT- 2H), 2.69-2.66 (m, pyrimidinedion (R)-S2 3H), 2.53-2.50 (m, e (1-881) 2H), 2.33 (t, J = 1.60 Hz, 1H), 1.86 (1, 1 =
4.80 Hz. 2H), 1.75 (t, J = 5.20 Hz, 2H), 1.68 (d, J = 13.60 Hz, 1H), 0.95 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H).
3-{5-fluoro-6- 3-(5-fluoro-6- 1H-NMR (400 MHz,
4-(oxazol-5- [(R)-4- ((R)-4- DMSO-d6): 5 10.99 yl)benzaldehy 543.2 L hydroxy-3,3- hydroxy-3,3- (s, 1H), 8.85 (s, 1H), de dimethyl-1- dimethylpiper 8 47 (s 1H) 8 36 (s {[p-(l,3- idin-4- 1H), 8.14-8.07 (m, oxazol-5- yl)quinolin-3- 1H), 7.85 (d, J = 8.80 yl)phenyl]meth yl)piperidine- Hz, 1H), 7.74-7.68 (m, yi}-4- 2, 6-dione 3H), 7.51-7.49 (m, piperidyl]-3- 2H), 5.16 (s, 1H), quinolyl}-2,6- 4.16-4.06 (m, 1H), piperidinedione 3.64-3.42 (m, 2H),
(1-613) 3.15-3.05 (m, 1H), 2.86-2.53 (m, 6H), 2.45-2.21 (m, 2H), 1.92 (s, 1H), 1.02 (s, 3H), 0.69 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, 1H), 10.60 (s, 1H),
3-{5-fluoro-6- 9.83 (s, 1H), 8.96 (m, [(R)-l-{[3- 3-(5-fluoro-6- 1H), 8.54-8.49 (m, fluoro-4-( 1,2,4- ((R)-4- 1H), 8.18-8.13 (m, oxadiazol-3- hydroxy-3,3- 3-fluoro-4- 2H), 8.11-7.95 (m, yl)phenyl]meth dimethylpiper (1,2,4- 2H), 7.82 (t, J = 7.20 yl}-4-hydroxy- idin-4- oxadiazol-3- 562.4 Hz, 1H), 5.98 (s, 1H), L 3,3-dimethyl-4- yl)quinolin-3- yl)benzaldehy 4.56-4.28 (m, 2H), piperidyl]-3- yl)piperidine- de 4.28-3.44 (m, 1H), quinolyl}-2,6- 2, 6-dione, 3.81-3.72 (m, 4H), piperidinedione HC1 3.17 (t, J = 10.80 Hz,
(1-643) 1H), 2.88-2.57 (m, 3H), 2.35-2.01 (m, 2H), 1.12 (s, 3H), 0.77 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.34 (s,
3-{5-fluoro-6- 1H), 8.22 (s, 1H), [(R)-4- 3-(5-fluoro-6- 8.12-8.08 (m, 1H), hydroxy-l-{[p- ((R)-4- 7.89-7.83 (m, 3H), (3- hydroxy-3,3- 7.52 (d, J = 8.40 Hz, isoxazolyl)phe dimethylpiper 4-(isoxazol-3- 2H), 7.15 (s, 1H), 5.14 nyljmethyl}- idin-4- yl)benzaldehy 543.1 (s, 1H), 4.26-4.21 (m, L 3,3-dimethyl-4- yl)quinolin-3- de 1H), 3.65 (d, J = 14.00 piperidyl]-3- yl)piperidine- Hz, 1H), 3.52 (s, 1H), quinolyl}-2,6- 2, 6-dione, 3.18-3.16 (m, 2H), piperidinedione HC1 2.64-2.63 (m, 2H), (1-133) 2.61-2.59 (m, 2H), 2.34-2.33 (m, 3H), 1.73-1.71 (m, 1H), 1.02 (s, 3H), 0.68 (s, 3H). _
3-{6-[(R)-l- 3-(5-fluoro-6- 3-chloro-4- 1H-NMR (400 MHz, {[3-chloro-4- ((R)-4- (1,2,4- 578.3 DMSO-d6): 5 10.98 L (1,2,4- hydroxy-3 3 oxadiazol 3 (s 1H) 9 79 (s 1H)
Figure imgf000479_0001
 3.17-3.09 (m, 4H), 2.81-2.77 (m, 1H), 2.73-2.67 (m, 3H), 2.34-2.16 (m, 4H), 1.70 (d, J = 13.20 Hz, 1H), 1.24 (s, 3H), 0.65 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J=
3-{6-[(R)-l- 1.60 Hz, 1H), 8.37- { [p-(6-chloro- 8.33 (m, 2H), 8.15- 3- 3-(5-fluoro-6- 8.08 (m, 3H), 8.01 (d, pyridazinyl)phe ((R)-4- J = 8.80 Hz, 1H), 7.84
4-(6- nyl]methyl}-4- hydroxy-3,3- (d, J = 8.80 Hz, 1H), chloropyridaz hydroxy-3,3- dimethylpiper 7.57 (d, J = 8.00 Hz, in-3- 588.3 L dimethyl-4- idin-4- 2H), 5.14 (s, 1H), 4.24 yl)benzaldehy piperidyl]-5- yl)quinolin-3- (d, J = 7.60 Hz, 1H), de fluoro-3- yl)piperidine- 3.68 (d, J = 14.4 Hz, quinolyl}-2,6- 2, 6-dione 1H), 3.56 (d, J = 13.6 piperidinedione Hz, 1H), 2.72-2.64 (m, (1-931) 3H), 2.22-2.13 (m, 4H), 1.76-1.71 (m, 4H), 1.03 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 1H), 9.33 (s, 1H), 8.84 (d, J= 2.0 Hz, 1H), 8.33 (s, 1H), 8.19
3-{5-fluoro-6- (s, 1H), 8.12-8.10 (m, [(R)-4- 1H), 8.10-8.08 (m, hydroxy-3,3- 3-(5-fluoro-6- 2H), 7.84 (d, J = 9.2 dimethyl-1- ((R)-4- Hz, 1H), 8.02 (d, J = {[p-(l,3,4- hydroxy-3,3- 4-(l,3,4- 8.00 Hz, 2H), 7.61 (d, oxadiazol-2- dimethylpiper oxadiazol-2- 1 = 8.00 Hz, 2H), 5.15
544. K yl)phenyl]meth idin-4- yl)benzaldehy (s, 1H), 4.23 (dd, J = yi}-4- yl)quinolin-3- de 12.60, 4.40 Hz, 1H), piperidyl]-3- yl)piperidine- 3.67 (d, J = 14.00 Hz, quinolyl}-2,6- 2, 6-dione 1H), 3.17 (s, 2H), piperidinedione 2.90-2.80 (m, 3H), (1-389) 2.73 (d, J = 4.40 Hz, 2H), 2.44-2.20 (m, 2H), 1.72 (d, J = 12.80 Hz, 1H), 1.23 (s, 1H), 1.02 (s, 1H), 0.68 (s, 3H). _
3-{6-[(R)-l- 3-(5-fluoro-6- 4-(5- 1H-NMR (400 MHz, {[p-(5- ((R)-4- cyclopropyl- DMSO-d6): 8 10.99
584.4 L cyclopropyl- hydroxy-3,3- 1,2,4- (s, 1H), 9.87 (s, 1H), 1,2,4- dimethylpiper oxadiazol 3 8 89 (s 1H) 8 37 (s oxadiazol-3- idin-4- yl)benzaldehy 1H), 8.11-8.06 (m, yl)phenyl]meth yl)quinolin-3- de 3H), 7.91-7.82 (m, yl}-4-hydroxy- yl)piperidine- 3H), 5.92 (s, 1H), 4.50 3,3-dimethyl-4- 2, 6-dione (s, 2H), 4.37-4.29 (m, piperidyl]-5- 1H), 3.45-3.22 (m, fluoro-3- 2H), 2.96-2.92 (m, quinolyl}-2,6- 1H), 2.77-2.52 (m, piperidinedione 4H), 2.50-2.40 (m,
(1-1200) 2H), 2.11-2.02 (m, 2H), 1.32-0.94 (m, 4H), 1.20 (s, 3H), 0.78 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 50.98 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H),
3-{5-fluoro-6- 8.12-8.08 (m, 1H), [(R)-4- 7.84 (d, J = 8.80 Hz,
3-(5-fluoro-6- hydroxy-3,3- 1H), 7.74-7.72 (m, ((R)-4- dimethyl-1- 3H), 7.37 (d, J = 8.00 hydroxy-3,3- 4-(l-methyl- {[p-(l-methyl- Hz, 2H), 6.67 (s, 1H), dimethylpiper IH-pyrazol- 3- 5.11 (s, 1H), 4.25-4.21 idin-4- 3- 556.2 L pyrazolyl)phen (m, 1H), 3.88 (s, 3H), yl)quinolin-3- yl)benzaldehy yl] methyl } -4- 3.59 (d, J = 13.60 Hz, yl)piperidine- de piperidyl]-3- 1H), 3.46 (s, 2H), 2, 6-dione, quinolyl}-2,6- 3.19-3.13 (m, 2H), HC1 piperidinedione 2.73-2.72 (m, 2H), (1-938) 2.69-2.67 (m, 2H),
2.19-2.08 (m, 2H),
1.72-1.70 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-{5-fluoro-6- (s, 1H), 9.79 (s, 1H), [(R)-4- 8.85 (d, J = 2.00 Hz, hydroxy-3,3- 1H), 8.34 (s, 1H), 8.10
3-(5-fluoro-6- dimethyl-1- (t, J = 8.80 Hz, 1H), ((R)-4- ({p-[5- 4-(5- 7.92 (d, J = 7.60 Hz, hydroxy-3,3- (trifluoromethy (trifluorometh 1H), 7.84 (d, J = 9.20 dimethylpiper 1)- 1,2,4- yl)- 1,2,4- Hz, 1H), 7.69 (s, 1H), idin-4- 612.3 L oxadiazol-3- oxadiazol-3- 7.55 (d, J = 7.20 Hz, yl)quinolin-3- yl] phenyl} meth yl)benzaldehy lH), 5.16 (s, 1H), yl)piperidine- yl)-4- de 4.26-4.21 (m, 1H), 2, 6-dione, piperidyl]-3- 3.69 (d, J = 14.40 Hz, HC1 quinolyl}-2,6- 1H), 3.57 (d, J = 14.40 piperidinedione Hz, 1H), 3.32 (s, 1H), (1-1190) 2.74-2.68 (m, 5H), 2.33-2.18 (m, 2H),
1.86 (s, 1H), 1.76 (d, J = Hz, 1H), 1.04 (s, 3H), 0.69 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (d, 4.40 Hz, 2H),
3-{5-fluoro-6-
Figure imgf000482_0001
9-8.11 (m, 5H), [(R)-4- 7.84 (d, J = 9.20 Hz,
3-(5-fluoro-6- hydroxy-l-{[p- 1H), 7.53-7.46 (m, ((R)-4- (6-methoxy-3- 4-(6- 3H), 7.33-7.29 (m, hydroxy-3,3- pyridazinyl)phe methoxypyrid lH), 5.14 (s, 1H), 4.23 dimethylpiper nyl]methyl}- azin-3- 584.3 (dd, 1 = 4.80, 12.80 K idin-4- 3,3-dimethyl-4- yl)benzaldehy Hz, 1H), 4.10-4.07 (m, yl)quinolin-3- piperidyl]-3- de 4H), 3.66 (d, J = 14.00 yl)piperidine- quinolyl}-2,6- Hz, 1H), 3.54 (d, J = 2, 6-dione piperidinedione 14.00 Hz, 1H), 3.21- (1-941) 3.15 (m, 1H), 2.77-
2.68 (m, 2H), 2.64- 2.49 (m, 2H), 2.24- 2.13 (m, 1H), 1.78- 1.71 (m, 1H), 1.03 (s, 3H), 0.69 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.22 (d, 14.00 Hz, 1H), 8.24
Figure imgf000482_0002
, 1H),
3-{6-[(R)-l- 8.21 (s, 1H), 8.09 (t, J {[p-(l- = 8.80 Hz, 1H), 7.84 cyclopropyl-4- 3-(5-fluoro-6- (t, J = 8.80 Hz, 2H), pyrazolyl)phen ((R)-4- 4-(l- 7.54 (d, J = 8.40 Hz, yl] methyl} -4- hydroxy-3,3- cyclopropyl- 2H), 7.33 (d, J = 8.00 hydroxy-3,3- dimethylpiper IH-pyrazol-
582.4 Hz, 2H), 5.11 (d, J = K dimethyl-4- idin-4- 4- Hz, 1H), 4.23 (dd, J = piperidyl]-5- yl)quinolin-3- yl)benzaldehy 4.80, 12.60 Hz, 1H), fluoro-3- yl)piperidine- de 3.76-3.72 (m, 2H), quinolyl}-2,6- 2, 6-dione 3.45-3.15 (m, 2H), piperidinedione 2.72-2.63 (m, 2H),
(1-944) 2.47-2.33 (m, 2H), 2.21-2.15 (m, 2H),
1.69 (d, J = 12.40 Hz, 1H), 1.09-1.05 (m, 2H), 0.99-0.97 (m, 5H), 0.67 (s, 3H).
3-{5-fluoro-6- 3-(5-fluoro-6- bi1H-NMR (400 MHz, [(R)-4- ((R)-4- isopropyl- 1H- DMSO-d6): 5 10.98 hydroxy-l-{[p- hydroxy-3,3- pyrazol-4- 584.3 (s, 1H), 8.85 (s, 1H), L (l-isopropyl-4- dimethylpiper yl)benzaldehy 8.33 (s, 1H), 8.22-8.19 pyrazolyl)phen idin-4- de (m 2H) 8 10 (t J =
Figure imgf000483_0001
  1.10-1.07 (m, 2H), 0.95-0.92 (m, 5H), 0.67 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.75 (s, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.07
3-{6-[(R)-l- (t, J = 8.40 Hz, 1H), {[3-chloro-4- 7.93-7.92 (m, 3H), (l-methyl-4- 3-(5-fluoro-6- 7.74 (d, J = 8.00 Hz, pyrazolyl)phen ((R)-4- 3-chloro-4- 1H), 7.66 (d, J = 8.00 yl] methyl} -4- hydroxy-3,3- (1-methyl- Hz, 1H), 5.93 (s, 1H), hydroxy-3,3- dimethylpiper IH-pyrazol-
590.6 4.42 (s, 2H), 4.24 (dd, K dimethyl-4- idin-4- 4- J = 4.80, 12.80 Hz, piperidyl]-5- yl)quinolin-3- yl)benzaldehy 1H), 3.92 (s, 3H), fluoro-3- yl)piperidine- de 3.38-3.27 (m, 5H), quinolyl}-2,6- 2, 6-dione
2.99 (d, J = 11.20 Hz, piperidinedione
1H), 2.77 (m, 1H),
(1-956) 2.68-2.63 (m, 1H), 2.33-2.14 (m, 1H), 2.03-2.00 (m, 1H), 1.09 (s, 3 H), 0.80 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J =
3-{6-[(R)-l- 2.00 Hz, 1H), 8.34 (s, { [p-(5-chloro- 1H), 8.14-8.08 (m, 3- 3-(5-fluoro-6- 1H), 7.84 (t, J = 3.20 isoxazolyl)phe ((R)-4-
4-(5- Hz, 3H), 7.54 (d, J = nyl]methyl}-4- hydroxy-3,3- chloroisoxazo 7.60 Hz, 2H), 7.35 (s, hydroxy-3,3- dimethylpiper
1-3- 577.2 lH), 5.14 (s, 1H), 4.23 L dimethyl-4- idin-4- yl)benzaldehy (dd, J = 4.40, 12.60 piperidyl]-5- yl)quinolin-3- de Hz, 1H), 3.64-3.55 (m, fluoro-3- yl)piperidine- 2H), 3.32-3.12 (m, quinolyl}-2,6- 2, 6-dione 2H), 2.79-2.57 (m, piperidinedione 5H), 2.18-2.13 (m, (1-1197) 2H), 1.92-1.71 (m, 1H), 0.93 (s, 3H), 0.68 (s, 3H). _
3-{5-fluoro-6- 1H-NMR (400 MHz, [(R)-l-({p-[5- 3-(5-fluoro-6- DMSO-d6): 8 10.99 (1- ((R)-4- 4-(5-(l- (s, 1H), 8.85 (d, J = fluorocyclopro hydroxy-3,3- fluorocyclopr 2.40 Hz, 1H), 8.34 (d, pyl)- 1,2,4- dimethylpiper opyl)- 1,2,4- J = 2.40 Hz, 1H), 8.10
602.1 L oxadiazol-3- idin-4- oxadiazol-3- (t, J = 8.80 Hz, 1H), yl] phenyl} meth yl)quinolin-3- yl)benzaldehy 7.99 (d, J = 8.40 Hz, yl)-4-hydroxy- yl)piperidine- de 2H), 7.84 (d, J = 9.20 3,3-dimethyl-4- 2, 6-dione Hz, 1H), 7.58 (d, J = piperidyl]-3- 8 40 Hz 2H) 5 14 (s quinolyl} -2,6- 1H), 4.23 (dd, J = piperidinedione 4.40, 12.60 Hz, 1H),
(1-959) 3.67 (d, J = 14.00 Hz, 1H), 3.55 (d, J = 14.00 Hz, 1H), 3.33 (m, 1H),
2.73-2.68 (m, 2H), 2.67-2.49 (m, 3H), 2.20-2.18 (m, 2H), 1.90-1.85 (m, 3H),
1.74-1.71 (m, 1H),
1.63-1.60 (m, 2H), 1.02 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H), 8.70 (s, 1H), 8.33 (s,
3-{6-[(R)-l- 1H), 8.27 (s, 1H), ({p-[l- 8.18-7.84 (m, 4H), (difluoromethyl 7.68 (d, J = 8.40 Hz,
3-(5-fluoro-6- )-4- 2H), 7.40 (d, J = 8.00 (( 4-(l- pyrazolyl]phen R)-4- Hz, 2H), 5.12 (s, 1H), hydroxy-3,3- (difluorometh yl } methyl) -4- 4.23 (dd, J = 4.80, dimethylpiper yl)-lH- hydroxy-3,3- 592.1 12.60 Hz, 1H), 3.60 K idin-4- pyrazol-4- dimethyl-4- (d, J = 13.60 Hz, 1H), yl)quinolin-3- yl)benzaldehy piperidyl]-5- 3.47 (d, J = 13.60 Hz, yl)piperidine- de fluoro-3- 1H), 3.20-3.13 (m, 2, 6-dione quinolyl}-2,6- 1H), 2.77-2.70 (m, piperidinedione 3H), 2.51-2.51 (m, (1-962) 2H), 2.46-2.41 (m, 1H), 2.19-2.13 (m, 2H), 1.72 (d, J 13.60 Hz, 1H), 1.01
Figure imgf000485_0001
, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
3-{5-fluoro-6- DMSO-d6): 5 10.99 [(R)-4- (s, 1H), 8.85 (s, 1H), hydroxy-3,3- 8.34 (s, 1H), 8.17-8.10
3-(5-fluoro-6- dimethyl-1- (m, 4H), 7.85 (d, J = ((R)-4- ({p-[5- 4-(5- 9.20 Hz, 1H), 7.66 (d, hydroxy-3,3- (trifluoromethy (trifluorometh J = 8.00 Hz, 2H), 5.16 dimethylpiper 1)-1,3,4- yl)-l,3,4- (s, 1H), 4.23 (t, J = idin-4- 612.3 L oxadiazol-2- oxadiazol-2- 4.80 Hz, 1H), 3.71 (d, yl)quinolin-3- yl] phenyl} meth yl)benzaldehy J = 14.00 Hz, 1H), yl)piperidine- yl)-4- de 3.58 (d, J = 14.00 Hz, 2, 6-dione, piperidyl]-3- 1H), 3.18 (s, 1H), HC1 quinolyl}-2,6- 2.74-2.68 (m, 5H), piperidinedione 2.19 (s, 1H), 1.73 (d, J 12.80 Hz, 1H), 1.02
Figure imgf000485_0002
, 3H), 0.68 (s, 3H); 2 protons merged with solvent. _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J =
3-{5-fluoro-6- 1.60 Hz, 1H), 8.33 (s, [(R)-l-{[3- 1H), 8.14-8.08 (m,
3-(5-fluoro-6- fluoro-4-(l- 2H), 7.85 (t, J = 8.80 ((R)-4- methyl-4- Hz, 2H), 7.69-7.65 (m, hydroxy-3,3- 3-fluoro-4-(l- pyrazolyl)phen 1H), 7.25-7.20 (m, dimethylpiper methyl-lH- yl] methyl} -4- 2H), 5.14 (s, 1H), 4.23 idin-4- pyrazol-4- 574.6 K hydroxy-3,3- (dd, J = 4.80, 12.80 yl)quinolin-3- yl)benzaldehy dimethyl-4- Hz, 1H), 3.90 (s, 3H), yl)piperidine- de piperidyl]-3- 3.62-3.42 (m, 2H), 2, 6-dione, quinolyl}-2,6- 3.26-3.09 (m, 2H), HC1 piperidinedione 2.72-2.51 (m, 5H),
(1-965) 2.25-2.08 (m, 2H), 1.72 (d, J = 13.20 Hz, 1H), 1.02 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.49 (s,
3-{5-fluoro-6- 1H), 8.33 (s, 1H), 8.19 [(R)-4- (s, 1H), 8.12 (s, 1H), hydroxy-3,3- 3-(5-fluoro-6- 8.09 (d, J = 8.80 Hz, dimethyl-1- ((R)-4- 1H), 7.85-7.77 (m, {[p-(l-methyl- hydroxy-3,3- 4-(l-methyl- 3H), 7.45-7.41 (m, 1H-1,2,3- dimethylpiper 1H-1,2,3- 2H), 5.12 (s, 1H), 4.52 triazol-4- idin-4- triazol-4- 557.2 L (s, 1H), 4.25-4.21 (m, yl)phenyl]meth yl)quinolin-3- yl)benzaldehy 1H), 4.09 (d, J = 2.80 yi}-4- yl)piperidine- de Hz, 2H), 3.60 (d, J = piperidyl]-3- 2, 6-dione, 13.20 Hz, 2H), 2.77- quinolyl}-2,6- HC1 0.70 (m, 2H), 2.60- piperidinedione 2.51 (m, 2H), 2.16 (d, (1-968) J = 2.40 Hz, 4H), 1.71 (d, J = 12.80 Hz, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
3-{5-fluoro-6- DMSO-d6): 5 10.99 [(R)-4- 3-(5-(4- (s, 1H), 8.85 (d, J = hydroxy-l-{[p- hydroxy-3,3- 2.00 Hz, 1H), 8.33 (s, (1- dimethylpiper 4-(l- 1H), 8.10 (t, J = 9.20 methoxycyclop idin-4-yl)-l- methoxycyclo
546.1 Hz, 1H), 7.84 (d, J = K ropyl)phenyl]m oxoisoindolin- propyl)benzal 8.80 Hz, 1H), 7.33 (d, ethyl}-3,3- 2- dehyde J = 8.00 Hz, 2H), 7.24 dimethyl-4- yl)piperidine- (d, J = 8.00 Hz, 2H), piperidyl]-3- 2, 6-dione 5.11 (s, 1H), 4.25-4.21 quinolyl}-2,6- (m 1H) 3 56 3 43 (m piperidinedione 3H), 3.19 (s, 3H),
(1-975) 2.51-2.51 (m, 2H), 2.23-2.13 (m, 3H), 1.70 (d, J = 11.60 Hz, 1H), 1.45 (d, J = 12.00 Hz, 2H), 1.15-1.12 (m, 2H), 1.00 (s, 3H), 0.96 (t, J = 2.00 Hz, 2H), 0.84 (s, 1H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H),
3-{5-fluoro-6- 8.33 (s, 1H), 8.14-8.07 [(R)-4- (m, 1H), 7.85 (d, J =
3-(5-fluoro-6- hydroxy-3,3- 8.80 Hz, 1H), 7.64 (s, ((R)-4- dimethyl-1- 4-(2- 2H), 7.37 (s, 2H), 5.30 hydroxy-3,3- {[p-(2-oxo-l- oxopyrrolidin (s, 1H), 4.25-4.20 (m, dimethylpiper pyrrolidinyljph -1- 559.3 1H), 3.85 (t, J = 6.80 L idin-4- enyl] methyl } - yl)benzaldehy Hz, 2H), 3.61-3.39 (m, yl)quinolin-3-
4-piperidyl]-3- de 4H), 3.27-3.16 (m, yl)piperidine- quinolyl}-2,6- 3H), 2.93-2.77 (m, 2, 6-dione piperidinedione 2H), 2.76-2.68 (m,
(1-978) 2H), 2.15-2.09 (m, 4H), 1.81-1.24 (m, 1H). 0.99 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 8.09 (t, J = 8.80 Hz, 1H),
3-{5-fluoro-6- 7.83 (d, J = 9.20 Hz, [(R)-4- 1H), 7.54 (d, J = 8.40 hydroxy-3,3- 3-(5-fluoro-6- Hz, 2H), 7.37 (d, J = dimethyl-1- ((R)-4-
4-(2- 8.40 Hz, 2H), 5.11 (s, {[p-(2-oxo-l,3- hydroxy-3,3- oxooxazolidi 1H), 4.44 (t, J = 8.00 oxazolidin-3- dimethylpiper n-3- 561.3 Hz, 2H), 4.25-4.21 (m, L yl)phenyl]meth idin-4- yl)benzaldehy 1H), 4.07 (t, J = 7.60 yl}-4- yl)quinolin-3- de Hz, 2H), 3.57 (d, J = piperidyl]-3- yl)piperidine- 13.20 Hz, 1H), 3.43 quinolyl}-2,6- 2, 6-dione (d, J = 13.20 Hz, 1H), piperidinedione 3.14 (s, 1H), 2.76-2.70 (1-981) (m, 2H), 2.68-2.64 (m, 2H), 2.63-2.56 (m, 2H), 2.43-2.33 (m, 2H), 1.81-1.69 (m, 1H), 0.99 (s, 3H), 0.67 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.09
3-{5-fluoro-6- (t, J = 8.80 Hz, 1H), [(R)-4- 7.83 (d, J = 9.20 Hz, hydroxy-3,3- 3-(5-fluoro-6- 1H), 7.53 (d, J = 8.40 dimethyl-1- ((R)-4- 4-(3-methyl- Hz, 2H), 7.29 (d, J = { [p-(3-methyl- hydroxy-3,3- 2- 8.80 Hz, 2H), 5.11 (s, 2-oxo- 1- dimethylpiper oxoimidazoli
574.6 1H), 4.23 (dd, J = K imidazolidinyl) idin-4- din-1- 4.80, 12.80 Hz, 1H), phenyl] methyl} yl)quinolin-3- yl)benzaldehy
3.80-3.61 (m, 4H), -4-piperidyl]-3- yl)piperidine- de
3.18-3.10 (m, 2H), quinolyl}-2,6- 2, 6-dione
2.81-2.72 (m, 5H), piperidinedione 2.68-2.59 (m, 2H), (1-984) 2.49-2.38 (s, 2H),
2.19-2.12 (m, 2H),
1.70 (d, J = 13.20 Hz, 1H), 1.05 (s, 3H), 1.04 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 9.01 (s, 1H), 8.85 (d, J = 2.00 Hz,
3-{5-fluoro-6- 1H), 8.33 (s, 1H), [(R)-4- 8.12-8.05 (m, 1H), hydroxy-3,3-
3-(5-fluoro-6- 7.89-7.78 (m, 3H), dimethyl-1- ((R)-4- 7.49 (d, J = 8.40 Hz, ({p-[2- 4-(2- hydroxy-3,3- 2H), 5.13 (m, 1H), (trifluoromethy (trifluorometh dimethylpiper 4.23 (q, J = 4.80 Hz, l)-l,3-oxazol-4- yl)oxazol-4- 611.2 L idin-4- 1H), 3.63 (d, J = 13.60 yl] phenyl} meth yl)benzaldehy yl)quinolin-3- Hz, 1H), 3.50 (d, J = yi)-4- de yl)piperidine- 13.60 Hz, 1H), 3.17 (t, piperidyl]-3- 2, 6-dione J = 13.20 Hz, 1H), quinolyl}-2,6- 2.80-2.76 (m, 2H), piperidinedione 2.74-2.49 (m, 4H), (1-1050)
2.20-2.12 (m, 2H), 1.91 (s, 3H), 1.73 (t, J = 12.40 Hz, 1H), 1.01 (s, 3H), 0.67 (s, 3H). l-(6-{l-[(5- 1H-NMR (400 MHz, l-(5-fluoro-6- amino-1- DMSO-d6): 5 10.55 (4-hydroxy- phenyl-4- (s, 1H), 8.42 (s, 1H), 3,3- pyrazolyl)meth 5-amino-l- 8.15 (s, 1H), 8.08 (t, J dimethylpiper yl]-4-hydroxy- phenyl-lH- = 9.20 Hz, 1H), 7.80 idin-4-yl)-2- 572.4 K 3,3-dimethyl-4- pyrazole-4- (d, J = 9.20 Hz, 1H), methylquinoli piperidyl}-5- carbaldehyde 7.64-7.62 (m, 2H), n-3- fluoro-2- 7.50 (t, J = 8.40 Hz, yl)dihydropyri methyl-3- 2H), 7.36-7.32 (m, midine- quinolyl)hexah 2H) 5 37 (s 2H)
Figure imgf000489_0001
yl)phenyl]meth yl)piperidine- 7.89 (d, J = 8.80 Hz, yl}-4- 2, 6-dione 1H), 7.55 (d, J = 8.00 piperidyl]-3- Hz, 2H), 5.90 (s, 1H), quinolyl}-2,6- 4.44 (m, 2H), 4.23 (dd, piperidinedione 1 = 4.80, 12.80 Hz,
(1-446) 1H), 3.56-3.32 (m, 4H), 3.01 (d, J = 12.00 Hz, 1H), 2.79-2.67 (m, 2H), 2.13 (d, J = 5.60 Hz, 1H), 2.13 (d, J = 5.60 Hz, 1H), 1.24 (s, 1H), 1.03 (s, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.95 (s, 1H), 10.97 (s, 1H), 9.77 (s, 1H), 8.76 (d, J = 2.00 Hz, 1H), 8.22
3-[6-(l-{[3- (m, 1H), 8.14-8.01 (m, fluoro-4-( 1,2,4- 3-(6-(4- 2H), 7.94-7.90 (m, oxadiazol-3- hydroxy-3,3-
3-fluoro-4- 2H), 7.55-7.32 (m, yl)phenyl]meth dimethylpiper (1,2,4- 2H), 4.87 (s, 1H), yl}-4-hydroxy- idin-4- oxadiazol-3- 544.2 4.17-4.12 (m, 1H), K 3,3-dimethyl-4- yl)quinolin-3- yl)benzaldehy 3.69 (d, J = 14.40 Hz, piperidyl)-3- yl)piperidine- de 1H), 3.58 (d, J = 14.80 quinolyl]-2,6- 2, 6-dione, Hz, 1H), 2.91 (m, 1H), piperidinedione HC1 INT-S20 2.81 (m, 1H), 2.75-
(1-995) 2.60 (m, 4H), 2.33- 2.15 (m, 2H), 1.91 (s, 3H), 1.59-1.56 (m, 1H), 0.95 (s, 3H), 0.70 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J =
3-{6-[(R)-l- 2.00 Hz, 1H), 8.38 (s, {[p-(2- 1H), 8.33 (s, 1H), 8.10
3-(5-fluoro-6- cyclopropyl- (t, J = 8.80 Hz, 1H),
1.3-oxazol-4- ((R)-4- 7.84 (d, J = 9.20 Hz, hydroxy-3,3- 4-(2- yl)phenyl]meth 1H), 7.69 (d, J = 8.40 dimethylpiper cyclopropylo yl}-4-hydroxy- Hz, 2H), 7.39 (d, J = idin-4- xazol-4- 583.6 K
3.3-dimethyl-4- 8.00 Hz, 2H), 5.11 (s, yl)quinolin-3- yl)benzaldehy piperidyl]-5- 1H), 4.23 (q, J = 4.80 yl)piperidine- de fluoro-3- Hz, 1H), 3.60 (d, J = 2, 6-dione, quinolyl}-2,6- 13.20 Hz, 1H), 3.45 HC1 piperidinedione (d, J = 13.20 Hz, 1H), (1-1047) 3.33-3.18 (m, 2H), 2.78-2.31 (m, 5H), 2.19-2.13 (m, 3H), 1.71 (d, J = 14.40 Hz, 1H), 1.08-1.00 (m, 7H), 0.67 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 9.79 (s, 1H), 8.76 (s, 1H), 8.23 (s,
3-(6-(l-(3- 1H), 8.02 (s, 1H), chloro-4- 7.96-7.91 (m, 3H), (1,2,4- 3-(6-(4- 7.70 (s, 1H), 7.55 (d, J oxadiazol-3- hydroxy-3,3-
3-chloro-4- = 1.20 Hz, 1H), 4.88 yl)benzyl)-4- dimethylpiper (1,2,4- (s, 1H), 4.17-4.12 (m, hydroxy-3,3- idin-4- oxadiazol-3- 560.3 1H), 3.70-3.67 (m, K dimethylpiperi yl)quinolin-3- yl)benzaldehy 1H), 3.60-3.56 (m, din-4- yl)piperidine- de 1H), 2.97-2.83 (m, yl)quinolin-3- 2, 6-dione 1H), 2.78-2.75 (m, yljpiperidine- INT-S20 2H), 2.68-2.57 (m, 2, 6-dione (I- 2H), 2.45-2.33 (m, 996) 2H), 2.21-2.15 (m, 2H), 1.59-1.56 (m, 1H), 1.58 (s, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.93 (s, 2H),
3-(6-(l-benzyl- 3-(6-(4- 7.39-7.33 (m, 4H),
4-hydroxy-3,3- hydroxy-3,3- 7.26 (t, J = 6.40 Hz, dimethylpiperi dimethylpiper 1H), 4.86 (s, 1H), din-4- idin-4- benzaldehyde 458.1 4.16-4.12 (m, 1H), L yl)quinolin-3- yl)quinolin-3- 3.60-3.52 (m, 2H), yl)piperidine- yl)piperidine- 2.87-2.73 (m, 3H), 2, 6-dione (I- 2, 6-dione 2.68-2.58 (m, 2H), 997) INT-S20 2.45-2.41 (m, 2H), 2.22-2.13 (m, 2H), 1.58-1.55 (m, 1H), 0.91 (s, 3H), 0.69 (s, 3H). _
3-{6-[(R)-l- 1H-NMR (400 MHz, {[p-(5- DMSO-d6): 5 10.99 cyclopropyl- 3-(5-fluoro-6- (s, 1H), 8.85 (s, 1H), 1,3,4- ((R)-4- 8.34 (s, 1H), 8.10 (t, J
4-(5- oxadiazol-2- hydroxy-3,3- = 8.80 Hz, 1H), 7.94 cyclopropyl- yl)phenyl]meth dimethylpiper (d, J = 8.00 Hz, 2H), 1,3,4- yl}-4-hydroxy- idin-4- 584.4 7.84 (d, J = 9.20 Hz, L oxadiazol-2- 3,3-dimethyl-4- yl)quinolin-3- 1H), 7.56 (d, J = 10.00 yl)benzaldehy piperidyl]-5- yl)piperidine- Hz, 2H), 5.14 (s, 1H), de fluoro-3- 2, 6-dione, 4.23 (d, J = 4.80 Hz, quinolyl}-2,6- HC1 1H), 3.65-3.52 (m, piperidinedione 1H), 2.72-2.68 (m, (1-1019) 1H) 2 59 241 (m 2H), 2.19-2.14 (m, 3H), 1.43 (s, 1H), 1.24 (s, 2H), 1.19 (s, 1H), 1.19-1.16 (m, 5H), 1.11 (s, 3H), 1.02 (m, 1H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 8 10.97 (s, 1H), 8.76 (d, J =
3-[6-(4- 2.00 Hz, 2H), 8.21 (s, hydroxy-3,3-
3-(6-(4- 1H), 8.07 (d, J = 8.80 dimethyl-1- hydroxy-3,3- Hz, 1H), 8.00 (s, 1H), {[6- dimethylpiper 6- 7.94-7.89 (m, 3H), (trifluoromethy idin-4- (trifluorometh 4.88 (s, 1H), 4.15-4.12 l)-3- 527.2 K yl)quinolin-3- yl)nicotinalde (m, 1H), 3.73 (s, 1H), pyridyl] methyl yl)piperidine- hyde 3.63 (m, 1H), 2.78- }-4-piperidyl)- 2, 6-dione 2.73 (m, 3H), 2.64- 3-quinolyl]-
INT-S20 2.55 (m, 4H), 2.33 (d, 2,6- J = 2.00 Hz, 2H), piperidinedione 2.70-2.50 (m, 1H), 0.92 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 10.97 (s, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.93
3-(6-(l-(4-(2,2- (s, 2H), 7.35 (dd, J = dichlorocyclopr 3-(6-(4-
8.40 Hz, 2H), 7.28 opyl)benzyl)-4- hydroxy-3,3- (dd, J = 8.00 Hz, 2H), hydroxy-3,3- dimethylpiper 4-(2,2- 4.83 (s, 1H), 4.16-4.12 dimethylpiperi idin-4- dichlorocyclo
566.2 (m, 1H), 3.55 (d, J = L din-4- yl)quinolin-3- propyl)benzal
2.40 Hz, 1H), 3.49 (d, yl)quinolin-3- yl)piperidine- dehyde J = 2.40 Hz, 1H), yl)piperidine- 2, 6-dione, 3.12-3.09 (m, 1H), 2, 6-dione (I- HC1 INT-S20 2.78-2.67 (m, 3H), 999) 2.68-2.57 (m, 2H), 2.45-2.44 (m, 2H), 2.17-2.08 (m, 4H), 1.57 (m, 1H), 0.91 (s, 3H), 0.68 (s, 3H).
3-{6-[(R)-l- 1H-NMR (400 MHz, {[3-chloro-4- 3-(5-fluoro-6- DMSO-d6): 8 10.98 (l-methyl-3- ((R)-4- 3-chloro-4- (s, 1H), 8.85 (d, J = pyrazolyl)phen hydroxy-3,3- (1-methyl- 2.00 Hz, 1H), 8.34 (s, yl] methyl} -4- dimethylpiper IH-pyrazol- 1H), 8.10 (t, J = 8.80
590.2 L hydroxy-3,3- idin-4- 3- Hz, 1H), 7.84 (d, J = dimethyl-4- yl)quinolin-3- yl)benzaldehy 9.20 Hz, 1H), 7.78- piperidyl]-5- yl)piperidine- de 7.73 (m, 2H), 7.50 (s, fluoro-3- 2, 6-dione 1H), 7.38-7.35 (m, quinolyl}-2,6- 1H) 6 70 (d J = 2 40 piperidinedione Hz, 1H), 5.14 (s, 1H),
(1-1142) 4.25-4.21 (m, 1H), 3.91 (s, 3H), 3.62 (d, J = 13.60 Hz, 1H), 3.49 (d, J = 13.60 Hz, 1H),
3.20-3.14 (m, 1H), 2.78-2.71 (m, 3H),
2.68-2.62 (m, 3H),
2.34-2.21 (m, 2H), 1.81-1.71 (m, 1H), 1.02 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.06 (s, 1H), 8.85 (s, 1H), 8.33 (s,
3-{6-[(R)-l- 1H), 8.10 (1, 1 = 8.80 {[p-(3- Hz, 1H), 7.84 (d, J = cyclopropyl- 8.80 Hz, 1H), 7.77 (d,
3-(5-fluoro-6- 1H-1,2,4- 1 = 8.40 Hz, 2H), 7.51 ((R)-4- 4-(3- triazol-1- (d, J = 8.40 Hz, 2H), hydroxy-3,3- cyclopropyl- yl)phenyl]meth 5.14 (s, 1H), 4.25-4.21 dimethylpiper 1H-1,2,4- yl}-4-hydroxy- 583.5 (m, 1H), 3.63 (d, J = L idin-4- triazol-1- 3,3-dimethyl-4- 13.60 Hz, 1H), 3.51 yl)quinolin-3- yl)benzaldehy piperidyl]-5- (d, J = 13.60 Hz, 1H), yl)piperidine- de fluoro-3- 3.49-3.33 (m, 2H), 2, 6-dione quinolyl}-2,6- 2.77-2.70 (m, 2H), piperidinedione 2.68-2.60 (m, 2H), (1-1074) 2.21-2.11 (m, 4H), 1.72 (d, J = 12.40 Hz, 1H), 0.99-0.90 (m, 5H), 0.89-0.86 (m, 2H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H),
3-{6-[(R)-l- 8.33 (s, 1H), 8.10 (1, 1 { [p-(5-chloro- = 8.80 Hz, 1H), 7.97 1,3,4- 3-(5-fluoro-6- (d, J = 8.40 Hz, 2H), oxadiazol-2- ((R)-4- 7.84 (d, J = 9.20 Hz,
4-(5-chloro- yl)phenyl]meth hydroxy-3,3- 1H), 7.77-7.49 (m, 1,3,4- yl}-4-hydroxy- dimethylpiper 2H), 5.14 (s, 1H), oxadiazol-2- 578.2 K 3,3-dimethyl-4- idin-4- 4.25-4.21 (m, 1H), yl)benzaldehy piperidyl]-5- yl)quinolin-3- 3.68 (d, J = 14.00 Hz, de fluoro-3- yl)piperidine- 1H), 3.56 (d, J = 14.40 quinolyl}-2,6- 2, 6-dione Hz, 1H), 3.22-3.16 (m, piperidinedione 1H), 2.70-2.53 (m, (1-1034) 6H), 2.19-2.12 (m, 2H), 1.72 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0 68 (s 3H) 1H-NMR (400 MHz, DMSO-d6): 5 10.96 (s, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.19 (d, l-[p-({4-[3- J = 10.40 Hz, 2H), (2,6-dioxo-3- 7.99 (s, 1H), 7.93 (s,
3-(6-((S)-4- piperidyl)-6- 2H), 7.38 (d, J = 8.40 hydroxy-3,3- l-(4- quinolyl]-4- Hz, 2H), 7.30 (d, J = dimethylpiper formylphenyl hydroxy-3,3- 8.00 Hz, 2H), 4.83 (s, idin-4- )cyclopropan 523.3 K dimethyl-1- 1H), 4.16-4.12 (m, yl)quinolin-3- e-1- pipcridyl |mcth 1H), 2.86-2.82 (m, yl)piperidine- carbonitile yl)phenyl] cyclo 4H), 2.78-2.64 (m, 2, 6-dione propanecarboni 2H), 2.47-2.41 (m, tile (1-1002) 3H), 2.18-2.15 (m, 2H), 1.76-1.73 (m, 2H), 1.56-1.49 (m, 3H), 0.90 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 9.00 (s, 1H),
8.75 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.94
3-(6-(4- (s, 2H), 7.88 (d, J = hydroxy-l-(4- 3-(6-(4- 8.00 Hz, 2H), 7.52 (d, (isoxazol-3- hydroxy-3,3- J = 8.00 Hz, 2H), 7.15 yl)benzyl)-3,3- dimethylpiper
4-(isoxazol-3- (s, 1H), 4.85 (s, 1H), dimethylpiperi idin-4- yl)benzaldehy 525.3 4.16-4.12 (m, 1H), L din-4- yl)quinolin-3- de 3.67-3.63 (m, 1H), yl)quinolin-3- yl)piperidine- 3.55-3.51 (m, 1H), yljpiperidine- 2, 6-dione, 2.89-2.73 (m, 3H), 2, 6-dione (I- HC1 INT-S20
2.68-2.58 (m, 2H), 1006)
2.45-2.41 (m, 1H), 2.21-2.13 (m, 2H), 1.58-1.55 (m, 2H), 0.93 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.97
3-[6-(4- (s, 1H), 9.34 (s, 1H), hydroxy-3,3-
3-(6-(4- 8.76 (d, J = 2.40 Hz, dimethyl-1- hydroxy-3,3- 1H), 8.22 (s, 1H), 8.17 {[p-(l,3,4- dimethylpiper 4-(l,3,4- (s, 1H), 8.03-8.01 (m, oxadiazol-2- idin-4- oxadiazol-2- 3H), 7.94 (m, 2H), yl)phenyl]meth 526.2 K yl)quinolin-3- yl)benzaldehy 7.62 (d, J = 8.40 Hz, yi}-4- yl)piperidine- de 2H), 4.87 (s, 1H), piperidyl)-3- 2, 6-dione 4.17-4.12 (m, 1H), quinolyl]-2,6-
INT-S20 3.68 (d, J = 14.00 Hz, piperidinedione 1H), 3.58 (d, J = 14.40
(1-1009) Hz, 1H), 2.90-2.89 (m, 1H) 2 89 274 (m
Figure imgf000495_0001
Formic Acid 2.50-2.33 (m, 4H),
(1-1012) 2.20-2.05 (m, 4H), 1.80 (m, 1H), 1.55- 1.51 (m, 1H), O.91- 0.89 (m, 9H), 0.71 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.97 (s, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.20 (s,
3-(6-{4- 1H), 7.99 (s, 1H), 7.93 hydroxy-3,3- 3-(6-(4- (s, 2H), 7.32 (d, J = dimethyl-l-[(l- hydroxy-3,3- 1.60 Hz, 1H), 6.16 (d, methyl-5- dimethylpiper J = 2.00 Hz, 1H), 4.87
1 -methyl- 1H- pyrazolyl)meth idin-4- (s, 1H), 4.16-4.12 (m, pyrazole-5- 462.2 K yi]-4- yl)quinolin-3- 1H), 3.87 (s, 3H), 3.54 carbaldehyde piperidyl}-3- yl)piperidine- (s, 2H), 2.82-2.71 (m, quinolyl)-2,6- 2, 6-dione 2H), 2.68-2.55 (m, piperidinedione INT-S20 2H), 2.45-2.40 (m,
(1-1013) 2H), 2.16-2.13 (m, 2H), 1.91 (s, 1H), 1.54 (d, J = 8.6 Hz, 1H), 0.87 (s, 3H), 0.70 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 6 10.97 (s, 1H), 8.76 (d, J = 2.00 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.93
3-(6-((S)-4- (s, 2H), 7.72 (d, J = hydroxy-3,3- 3-(6-((S)-4- 8.00 Hz, 2H), 7.61 (d, dimethyl-l-(4- hydroxy-3,3- 1 = 8.00 Hz, 2H), 4.86 (trifluoromethy dimethylpiper 4- (s, 1H), 4.17-4.12 (m, l)benzyl)piperi idin-4- (trifluorometh 1H), 3.67 (d, J = 14.40
526.1 K din-4- yl)quinolin-3- yl)benzaldehy Hz, 1H), 3.57 (d, J = yl)quinolin-3- yl)piperidine- de 14.00 Hz, 1H), 2.89- yl)piperidine- 2, 6-dione, 2.88 (m, 1H), 2.75- 2, 6-dione (I- HC1 2.73 (m, 2H), 2.68- 42) 2.63 (m, 1H), 2.45- 2.42 (m, lH), 2.16 (d, J = 10.40 Hz, 2H), 1.58-1.55 (m, 2H), 1.24 (s, 1H), 0.93 (s, 3H), 0.69 (s, 3H).
3-[6-(4- 1H-NMR (400 MHz,
3-(6-((S)-4- hydroxy-3,3- DMSO-d6): 8 11.03 hydroxy-3,3- 6-( 1,2,4- dimethyl-1- (s, 1H), 10.40 (s, 1H), dimethylpiper oxadiazol-3- {[6-(l,2,4- 527.3 9.08 (s, 1H), 9.08 (s, K idin-4- yl)nicotinalde oxadiazol-3- 1H), 9.00 (s, 1H), 8.66 yl)quinolin-3- hyde yl)-3- (s, 1H), 8.45 (d, J = yl)piperidine- pyridyl] methyl 8 00 Hz 1H) 8 24 (d }-4-piperidyl)- 2,6-dione, J = 8.00 Hz, 1H), 8.13 3-quinolyl]- HC1 (d, J = 9.60 Hz, 2H), 2,6- 8.01 (d, J = 9.20 Hz, piperidinedione 1H), 5.80 (s, 1H), (1-1016) 4.59-4.55 (m, 2H), 4.26-4.22 (m, 1H), 3.47-3.32 (m, 3H), 3.06-2.94 (m, 2H), 2.78-2.47 (m, 3H), 2.19 (d, J = 5.60 Hz, 1H), 1.90 (d, J = 14.40 Hz, 1H), 1.00 (s, 3H), 0.80 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.12 (t, J = 8.80 Hz, 1H), 7.84 (d, J =
3-{6-[(R)-l- 9.20 Hz, 1H), 7.77 (d, {[p-(5- 1 = 7.60 Hz, 2H), 7.51 cyclopropyl-3- 3-(5-fluoro-6- (d, J = 8.00 Hz, 2H), isoxazolyl)phe ((R)-4-
4-(5- 6.75 (d, J = 2.80 Hz, nyl]methyl}-4- hydroxy-3,3- cyclopropylis lH), 5.13 (m, 1H), hydroxy-3,3- dimethylpiper oxazol-3- 583.3 4.22 (t, J = 4.80 Hz, K dimethyl-4- idin-4- yl)benzaldehy 1H), 3.63 (d, J = 13.60 piperidyl]-5- yl)quinolin-3- de Hz, 1H), 3.51-3.32 (m, fluoro-3- yl)piperidine- 2H), 2.68 (d, J = 2.00 quinolyl}-2,6- 2, 6-dione Hz, 2H), 2.55 (q, J = piperidinedione 2.00 Hz, 2H), 2.33 (t, J (1-1055) = 1.60 Hz, 2H), 2.18 (d, J = 10.80 Hz, 2H), 2.04 (d, J = 5.20 Hz, 2H), 1.07-1.01 (m, 5H), 0.83 (d, J = 2.00 Hz, 2H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(6-((R)-l-(4- (s, 1H), 9.44 (s, 1H), (4- 3-(5-fluoro-6- 8.85 (d, J = 2.00 Hz, chloroisoxazol- ((R)-4- 1H), 8.33 (s, 1H), 8.14 3-yl)benzyl)-4- hydroxy-3,3- 4-(4- (s, 1H), 8.10 (t, J = hydroxy-3,3- dimethylpiper chloroisoxazo 8.80 Hz. 1H), 7.86- dimethylpiperi idin-4- 1-3- 577.4 7.81 (m, 3H), 7.59 (d, L din-4-yl)-5- yl)quinolin-3- yl)benzaldehy 1 = 8.00 Hz, 2H), 5.16 fluoroquinolin- yl)piperidine- de (s, 1H), 4.25-4.21 (m, 3-yl)piperidine- 2, 6-dione, 1H), 3.67-3.60 (m,
2, 6-dione, HC1 2H), 3.32-3.15 (m, Formic Acid 1H), 2.81-2.74 (m,
(1-1056) 3H), 2.68-2.47 (m, 3H) 2 34 224 (m 1H), 2.16-2.12 (m, 1H), 1.75-1.72 (m, 1H), 1.03 (s, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.10 (1, 1 = 8.00
3-{5-fluoro-6- Hz, 2H), 7.95 (d, J = [(R)-4- 8.40 Hz, 2H), 7.84 (d, hydroxy-3,3- J = 9.20 Hz, 1H), 7.56
3-(5-fluoro-6- dimethyl-1- (d, J = 8.00 Hz, 2H), ((R)-4- ({p-[5- 4-(5- 5.14 (m, 1H), 4.23 (dd, hydroxy-3,3- (trifluoromethy (trifluorometh J = 4.80, 12.80 Hz, dimethylpiper l)-3- yl)isoxazol-3- 611.3 1H), 3.67 (d, J = 14.00 K idin-4- isoxazolyl]phe yl)benzaldehy Hz, 1H), 3.54 (d, J = yl)quinolin-3- nyl}methyl)-4- de 14.00 Hz, 1H), 3.19- yl)piperidine- piperidyl]-3- 3.16 (m, 1H), 2.77- 2, 6-dione quinolyl}-2,6- 2.71 (m, 2H), 2.68- piperidinedione 2.59 (m, 2H), 2.34- (1-1059) 2.21 (m, 2H), 1.72 (d, J = 12.00 Hz, 1H), 1.02 (s, 3H), 0.68 (s, 3H); 2 protons missing, merged with solvent. _
1H-NMR (400 MHz, DMSO-d6): 5 11.01
(s, 1H), 10.28 (s, 1H), 9.34-9.32 (m, 1H),
3-{6-[(R)-l- 8.93 (s, 1H), 8.45 (s, {[3-chloro-4- 1H), 8.10 (t, J = 6.00
3-(5-fluoro-6- (3- Hz, 2H), 8.05 (d, J = pyridazinyl)phe ((R)-4- 1.60 Hz, 1H), 8.03 (d, hydroxy-3,3- nyl]methyl}-4- 3-chloro-4- J = 1.60 Hz, 1H), dimethylpiper hydroxy-3,3- (pyridazin-3- 7.89-7.81 (m, 2H), idin-4- 588.5 L dimethyl-4- yl)benzaldehy 7.79 (d, J = Hz, 1H), yl)quinolin-3- piperidyl]-5- de 5.98 (s, 1H), 4.55-4.28 yl)piperidine- fluoro-3- (m, 2H), 3.43-2.98 (m, 2, 6-dione, quinolyl}-2,6- 4H), 2.76 (d, J = 12.80 HC1 piperidinedione Hz, 1H), 2.73-2.68 (m, (1-1065) 1H), 2.65-2.61 (m, 1H), 2.51-2.50 (m, 2H), 2.34-2.31 (m, 2H), 1.12 (s, 3H), 0.81 (s, 3H). _
3-(5-fluoro-6- 3-(5-fluoro-6- 1H NMR (499 MHz,
4-(3-fluoro-l- ((R)-l-(4-(3- ((R)-4- DMSO-d6) 5 ppm methyl-lH- 574.4 C fluoro-1- hydroxy-3,3- 10.98 (s, 1H) 8.84 (d, pyrazol-4- methyl-lH- dimethylpiper 1=2 19 Hz 1H) 8 32 pyrazol-4- idin-4- yl)benzaldehy (t, 1=2.46 Hz, 1H) yl)benzyl)-4- yl)quinolin-3- de ALD-114 8.06 - 8.12 (m, 2H) hydroxy-3,3- yl)piperidine- 7.83 (d, 1=9.31 Hz, dimethylpiperi 2, 6-dione, 1H) 7.48 (d, 1=8.21 din-4- HC1 Hz, 2H) 7.38 (d, yl)quinolin-3- 1=8.21 Hz, 2H) 5.10 yl)piperidine- (s, 1H) 4.22 (dd, 2, 6-dione (I- 1=13.14, 4.93 Hz, 1H) 1068) 3.76 (s, 3H) 3.50 - 3.62 (m, 1H) 3.45 (br d, 1=13.69 Hz, 1H)
3.14 (br, 1H) 2.67 - 2.80 (m, 2H) 2.53 -
2.65 (m, 2H) 2.46 (br d, J= 10.40 Hz, 2H) 2.10 - 2.21 (m, 2H) 1.70 (br d, 1=12.05 Hz, 1H) 1.00 (br s, 3H) 0.67 (s, 3H)
1H NMR (499 MHz, DMSO-d6) 5 ppm 10.97 (s, 1H) 8.84 (d, 1=1.64 Hz, 1H) 8.33 (t, 1=2.74 Hz, 1H) 8.09 (t, 1=8.76 Hz,
3-(5-fluoro-6- 1H) 7.94 (d, 1=4.93 ((R)-l-(4-(4- Hz, 1H) 7.83 (d, fluoro-1- 3-(5-fluoro-6- 1=9.31 Hz, 1H) 7.70 methyl-lH- ((R)-4- (d, 1=7.67 Hz, 2H) pyrazol-3- hydroxy-3,3- 4-(4-fluoro-l- 7.43 (d, 1=8.21 Hz, yl)benzyl)-4- dimethylpiper methyl-lH- 2H) 5.11 (d, 1=1.64 hydroxy-3,3- idin-4- pyrazol-3- 574.3 Hz, 1H) 4.22 (dd, c dimethylpiperi yl)quinolin-3- yl)benzaldehy 1=12.87, 4.65 Hz, 1H) din-4- yl)piperidine- de ALD-113 3.82 (s, 3H) 3.59 (d, yl)quinolin-3- 2, 6-dione, 1=13.69 Hz, 1H) 3.48 yljpiperidine- HC1 (d, 1=13.69 Hz, 1H) 2, 6-dione (I- 3.15 (m, 1H) 2.67 - 1071) 2.79 (m, 2H) 2.52 -
2.66 (m, 2H) 2.43 -
2.49 (m, 2H) 2.07 - 2.24 (m, 2H) 1.71 (br d, 1=11.50 Hz, 1H) 1.00 (s, 3H) 0.68 (s, 3H) _
3-{6-[(R)-l- 3-(5-fluoro-6- 1H-NMR (400 MHz, {[p-(6- ((R)-4- 4-(6- DMSO-d6): 5 10.99 cyclopropoxy- hydroxy-3,3- cyclopropoxy (s, 1H), 8.85 (d, J = 3- dimethylpiper pyridazin-3- 610.6 2.00 Hz, 1H), 8.34 (s, K pyridazinyl)phe idin-4- yl)benzaldehy 1H), 8.19 (t, J = 9.20 nyl]methyl}-4- yl)quinolin-3- de Hz, 1H), 8.12-8.06 (m, hydroxy-3,3- yl)piperidine 3H) 7 84 (d J = 9 20 dimethyl-4- 2,6-dione, Hz, 2H), 7.34 (d, J = piperidyl]-5- HC1 9.60 Hz, lH), 5.14 (s, fluoro-3- 1H), 4.46 (t, J = 2.80 quinolyl}-2,6- Hz, 1H), 4.24-4.21 (m, piperidinedione 1H), 3.66 (d, J = 14.00
(1-1183) Hz, 1H), 3.55 (d, J = 14.00 Hz, 1H), 3.22-
3.13 (m, 1H), 2.74- 2.57 (m, 5H), 2.48- 2.33 (m, 2H), 2.27-
2.13 (m, 1H), 1.68 (d, J = 8.00 Hz, 1H), 1.03 (s, 3H), 0.86 (t, J = 6.00 Hz, 2H), 0.79 (dd, J = 6.40, 7.60 Hz, 2H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.56 (d,
3-{6-[(R)-l- J = 4.00 Hz, 1H), 8.33 { [4-(2-chloro- (s, 1H), 8.10 (t, J = l,3-oxazol-4- 3-(5-fluoro-6- 8.80 Hz, 1H), 7.90- yl)-3- ((R)-4- 7.83 (m, 2H), 7.35- fluorophenyl]m hydroxy-3,3- 4-(2- 7.32 (m, 2H), 5.14 (s, ethyl } -4- dimethylpiper chlorooxazol- 1H), 4.23 (dd, J = hydroxy-3,3- idin-4- 4-yl)-3- 595.1 K 4.80, 12.80 Hz, 1H), dimethyl-4- yl)quinolin-3- fluorobenzald 3.64 (d, J = 14.40 Hz, piperidyl]-5- yl)piperidine- ehyde 1H), 3.51 (d, J = 14.00 fluoro-3- 2, 6-dione, Hz, 1H), 3.21-3.17 (m, quinolyl}-2,6- HC1 1H), 3.14-2.80 (m, piperidinedione 2H), 2.77-2.73 (m, (1-1062) 3H), 2.22-2.01 (m, 3H), 1.76-1.62 (m, 1H), 1.24 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-{6-[(R)-l- (s, 1H), 8.85 (d, J = { [p-(2-chloro- 3-(5-fluoro-6- 2.00 Hz, 1H), 8.74 (s,
1.3-oxazol-4- ((R)-4- 1H), 8.33 (s, 1H), 8.08 yl)phenyl]meth hydroxy-3,3- 4-(2- (t, J = 8.80 Hz, 1H), yl}-4-hydroxy- dimethylpiper chlorooxazol- 7.84 (d, J = 8.80 Hz.
3.3-dimethyl-4- idin-4- 4- 577.3 1H), 7.72 (d, J = 8.40 K piperidyl]-5- yl)quinolin-3- yl)benzaldehy Hz, 2H), 7.45 (d, J = fluoro-3- yl)piperidine- de 8.40 Hz, 2H), 5.12 (s, quinolyl}-2,6- 2, 6-dione, 1H), 4.28-4.17 (m, piperidinedione HC1 1H), 3.58-3.46 (m, (1-1082) 2H), 3.26-3.08 (m, 2H), 2.68-2.56 (m, 5H) 2 29 205 (m 2H), 1.81-1.62 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.10 (q, J =
3-{5-fluoro-6- 8.80 Hz, 1H), 7.84 (d, [(R)-4- J = 9.20 Hz, 1H), 7.72 hydroxy-3,3- 3-(5-fluoro-6- (d, J = 8.40 Hz, 2H), dimethyl-1- ((R)-4-
4-(2- 7.40 (d, J = 8.00 Hz, { [p-(2-methyl- hydroxy-3,3- methyloxazol 2H), 5.11 (s, 1H), 4.23 l,3-oxazol-4- dimethylpiper -4- 557.4 (dd, J =12.8, 4.80 Hz, L yl)phenyl]meth idin-4- yl)benzaldehy 1H), 3.60 (d, J = 13.60 yl}-4- yl)quinolin-3- de Hz, 1H), 3.47 (d, J = piperidyl]-3- yl)piperidine- 13.60 Hz, 1H), 3.32- quinolyl}-2,6- 2, 6-dione 3.16 (m, 1H), 2.77- piperidinedione 2.69 (m, 2H), 2.68- (1-1085) 2.63 (m, 2H), 2.58- 2.51 (m, 5H), 2.18-
2.13 (m, 2H), 1.71 (d,
J = 12.40 Hz, 1H), 1.01 (s, 3H), 0.68 (m, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.97
3-{6-[4- (s, 1H), 8.76 (s, 1H), hydroxy-3,3- 8.21 (s, 1H), 8.00 (s,
3-(6-(4- dimethyl-1- 1H), 7.93 (s, 2H), 7.45 hydroxy-3,3-
({p-[l- 4-(l- -7.36 (m, 4H), 4.84, s, dimethylpiper
(trifluoromethy (trifluorometh 1H), 4.17-4.12 (m, idin-4- l)cyclopropyl]p yl)cyclopropy 566.3 1H), 3.57-3.48 (m, L yl)quinolin-3- henyljmethyl)- l)benzaldehyd 2H), 2.85-2.52 (m, yl)piperidine-
4-piperidyl]-3- e 5H), 2.51-2.45 (m, 2, 6-dione quinolyl}-2,6- 2H), 2.22-2.15 (m,
INT-S20 piperidinedione 2H), 1.55 (d, J = 13.20
(1-1042) Hz, 1H), 1.35-1.31 (m, 2H), 1.13 (s, 2H), 0.92 (s, 3H), 0.69 (s, 3H).
3-{5-fluoro-6- 1H-NMR (400 MHz,
3-(5-fluoro-6- [(R)-4- DMSO-d6): 8 10.99 hydroxy-3,3- ((R)-4- (s, 1H), 8.85 (d, J = hydroxy-3,3- 4-(l-methyl- dimethyl-1- 2.00 Hz, 1H), 8.51 (s, dimethylpiper 1H-1,2,4- {[p-(l-methyl- 1H), 8.34 (s, 1H), 8.10 idin-4- triazol-3- 557.4 L 1H-1,2,4- (s, 1H), 7.96 (d, J = yl)quinolin-3- yl)benzaldehy triazol-3- 8.00 Hz, 2H), 7.84 (d, yl)piperidine- de yl)phenyl]meth J = 9.20 Hz, 1H), 7.45 2, 6-dione, yl}-4- (d, J = 8.40 Hz, 2H), HC1 piperidyl]-3- 5 13 (s 1H) 4 23 (dd quinolyl} -2,6- 1 = 4.80, 12.60 Hz, piperidinedione 1H), 3.92 (s, 3H), 3.61
(1-1173) (d, J = 13.60 Hz, 1H), 3.50 (d, J = 13.60 Hz, 1H), 3.20-3.16 (m, 1H), 3.16-2.70 (m, 3H), 2.69-2.60 (m, 3H), 2.16 (dd, J = 4.80, 9.00 Hz, 2H),
1.72 (d, J = 12.00 Hz,
1H), 1.02 (s, 3H), 0.68 (s, 3H). _
1H NMR (499 MHz, DMSO-d6) 5 ppm 10.98 (s, 1H) 8.84 (d, 1=2.19 Hz, 1H) 8.33
(t, 1=2.74 Hz, 1H) 8.08 - 8.15 (m, 2H) 7.84 (d, J=9.31 Hz,
3-(6-((R)-l-(4- 1H) 7.63 (d, 1=8.21 (4- Hz, 2H) 7.44 (d, (difluoromethyl 3-(5-fluoro-6- J=8.21 Hz, 2H) 6.95 - )-l -methyl- 1H- ((R)-4- 4-(4- 7.36 (t, J = 55Hz, 1H) pyrazol-3- hydroxy-3,3- (difluorometh 5.14 (hr s, 1H) 4.23 yl)benzyl)-4- dimethylpiper yl)-l-methyl- (dd, 1=12.59, 4.93 Hz, hydroxy-3,3- idin-4- IH-pyrazol- 606.4 1H) 3.91 (s, 3H) 3.58 - dimethylpiperi yl)quinolin-3- 3- 3.68 (m, 1H) 3.52 (hr, din-4-yl)-5- yl)piperidine- yl)benzaldehy 1H) 3.09 - 3.21 (m, fluoroquinolin- 2, 6-dione, de ALD US 1H) 2.68 - 2.82 (m, 3-yl)piperidine- HC1 2H) 2.55 - 2.67 (m, 2, 6-dione (I- 2H) 2.20 - 2.28 (m, 1210) 1H) 2.08 - 2.18 (m, 1H) 1.72 (br d, 1=11.50 Hz, 1H) 1.02 (s, 3H) 0.68 (s, 3H) (two protons partially overlapped with DMSO solvent) _
1H-NMR (400 MHz,
3-{5-fluoro-6- DMSO-d6): 8 10.99 [(R)-4- (s, 1H), 8.84 (s, 1H),
3-(5-fluoro-6- hydroxy-l-{2- 8.32 (s, 1H), 8.05 (t, J ((R)-4- methoxy-l-[p- 2-methoxy-l- = 8.40 Hz. 1H), 7.82 hydroxy-3,3- (trifluoromethy (4- (d, J = 9.20 Hz, 1H), dimethylpiper l)phenyl] ethyl} (trifluorometh 588.2 7.72 (t, J = 4.00 Hz, idin-4- -3,3-dimethyl- yl)phenyl)eth 2H), 7.60 (d, J = 5.20 yl)quinolin-3-
4-piperidyl]-3- an- 1 -one Hz, 2H), 5.01 (m, 1H), yl)piperidine- quinolyl}-2,6- 4.23 (d, J = 13.60 Hz, 2, 6-dione piperidinedione 1H), 3.76 (t, J = 9.20 (1-1093) Hz, 3H), 3.25 (d, J = 8 40 Hz 3H) 3 14
Figure imgf000502_0001
3.15 (m, 2H), 2.95- 2.73 (m, 4H), 2.51- 2.34 (m, 1H), 2.15- 2.05 (m, 2H), 1.72- 1.61 (m, 1H), 1.01- 0.95 (m, 3H), 0.68-
0.61 (m, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H), 8.35 (d, J = 2.80 Hz, 2H), 8.13 (d, J = 8.80
3-(6-((R)-l-(3- Hz, 1H), 7.89-7.73 (m, chloro-4-(l-
3-(5-fluoro-6- 3H), 7.45 (s, 1H), 7.43 (difluoromethyl ((R)-4- 3-chloro-4- (d, J = 1.20 Hz, 1H), )-lH-pyrazol- hydroxy-3,3- ( 6.97 (s, 1H), 6.53 (s, 3-yl)benzyl)-4- 1- dimethylpiper (difluorometh 1H), 5.15 (s, 1H), hydroxy-3,3- idin-4- yl)-lH- 626.3 4.26-4.21 (m, 1H), L dimethylpiperi yl)quinolin-3- pyrazol-3- 3.65 (d, J = 14.00 Hz, din-4-yl)-5- yl)piperidine- yl)benzaldehy 1H), 3.53 (d, J = 14.00 fluoroquinolin- 2, 6-dione, de Hz, 1H), 3.18 (t, J = 3-yl)piperidine- HC1 12.40 Hz, 1H), 2.81- 2, 6-dione (I- 2.77 (m, 2H), 2.68- 1149) 2.63 (m, 3H), 2.19- 2.13 (m, 2H), 1.73 (d, J = 13.20 Hz, 1H), 1.03 (s, 3H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 8.10 (t, J = 8.80 Hz, 1H),
3-(6-((R)-l-(3- 8.03 (d, J = 8.00 Hz, chloro-4-(l-
3-(5-fluoro-6- 1H), 7.84 (d, J = 9.20 methyl-lH- ((R)- Hz, 1H), 7.56 (s, 1H), l,2,3-triazol-4- 4- 3-chloro-4- hydroxy-3,3- 7.45 (d, J = 8.00 Hz, yl)benzyl)-4- (1-methyl- dimethylpiper 1H), 5.15 (s, 1H), hydroxy-3,3- 1H-1,2,3- idin-4- 591.3 4.26-4.21 (m, 1H), K dimethylpiperi triazol-4- yl)quinolin-3- 4.15 (s, 3H), 3.63 (d, J din-4-yl)-5- yl)benzaldehy yl)piperidine- = 14.00 Hz, 1H), 3.51 fluoroquinolin- de 2, 6-dione, (d, J = 14.00 Hz, 1H), 3-yl)piperidine- HC1 3.18 (t, J = 15.20 Hz, 2, 6-dione (I- 2H), 2.72-2.68 (m, 1128) 2H), 2.63-2.60 (m, 2H), 2.19-2.18 (m, 2H), 1.86 (s, 1H), 1.75 (d, 1 = 6.80 Hz, 1H), 1.03 (s, 3H), 0.69 (s, 3H) 1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.32 (t, J
3-(5-fluoro-6- = 2.40 Hz, 1H), 8.19 ((R)-4- (s, 1H), 8.09 (t, J = hydroxy-3,3- 3-(5-fluoro-6- 8.80 Hz, 1H), 7.84 (d, dimethyl-l-((l- ((R)-4- J = 9.20 Hz, 1H), 7.31 methyl-lH- hydroxy-3,3- (d, J = 2.00 Hz, 1H), pyrazol-5- dimethylpiper 1 -methyl- 1H- 6.16 (d, J =2.00 Hz, yl)methyl)piper idin-4- pyrazole-5- 480.2 1H), 5.15 (s, 1H), K idin-4- yl)quinolin-3- carbaldehyde 4.25-4.20 (m, 1H), yl)quinolin-3- yl)piperidine- 3.86 (s, 3H), 3.53 (s, yljpiperidine- 2, 6-dione, 2H), 3.17-3.09 (m, 2, 6-dione, HC1 1H), 2.76-2.72 (m, Formic Acid 1H), 2.68-2.58 (m, (1-1029) 3H), 2.51-2.47 (m, 2H), 2.18-2.12 (m, 2H), 1.70 (d, J = 12.80 Hz, 1H), 0.96 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.82 (s, 1H), 8.85 (d, J = 2.00 Hz,
3-(6-((R)-l-(3- 1H), 8.35 (s, 1H), (difluoromethyl 8.13-8.05 (m, 2H),
3-(5-fluoro-6- )-4-(l,2,4- 7.93 (s, 1H), 7.85 (d, J oxadiazol-3- ((R)-4- 3- = 8.80 Hz, 1H), 7.75 hydroxy-3,3- yl)benzyl)-4- (difluorometh (d, J = 8.00 Hz, 1H), dimethylpiper hydroxy-3,3- yl)-4-(l,2,4- 7.55 (m, lH), 5.17 (s, idin-4- 594.3 K dimethylpiperi oxadiazol-3- 1H), 4.26-4.21 (m, yl)quinolin-3- din-4-yl)-5- yl)benzaldehy 2H), 3.73 (m, 1H), yl)piperidine- fluoroquinolin- de 3.58 (d, J = 12.80 Hz, 2, 6-dione,
3-yl)piperidine- 1H), 3.33-3.24 (m, HC1 2, 6-dione (I- 1H), 2.82-2.74 (m, 1234) 3H), 2.68-2.60 (m, 2H), 2.20-2.14 (m, 2H), 1.75 (d, J = 13.60 Hz, 1H), 1.04 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
3-(5-fluoro-6-
3-(5-fluoro-6- DMSO-d6): 5 10.98 ((R)-4- ((R)-4- (s, 1H), 8.85 (d, J = hydroxy-1- hydroxy-3,3- 2.00 Hz, 1H), 8.33 (s, isobutyl-3,3- dimethylpiper isobutyr aldeh 1H), 8.19 (s, 1H), 8.10 dimethylpiperi 442.3 K idin-4- yde (t, J = 8.80 Hz, 1H), din-4- yl)quinolin-3- 7.84 (d, J = 8.80 Hz, yl)quinolin-3- yl)piperidine- 1H), 5.07 (s, 1H), yl)piperidine- 2, 6-dione 4.25-4.21 (m, 1H), 2, 6-dione, 3 36 3 12 (m 1H)
Figure imgf000505_0001
 hydroxy-3, 3- hydroxy-3, 3- ol-3- (s, 1H), 8.87 (d, J = dimethyl-l-(4- dimethylpiper yl)benzaldehy 12.80 Hz, 1H), 8.36 (s, (5- idin-4- de 1H), 8.08-7.76 (m, methylisoxazol yl)quinolin-3- 5H), 6.84-6.76 (m, -3- yl)piperidine- 1H), 6.53 (s, 1H), 5.92 yl)benzyl)piper 2, 6-dione, (s, 1H), 5.13 (s, 1H), idin-4- HC1 4.50 (s, 1H), 4.26-4.23 yl)quinolin-3- (m, 1H). 3.69-3.501 yl)piperidine- (m, 3H), 3.39-2.99 (m, 2, 6-dione (I- 4H), 2.61-2.52 (m, 1037) 3H), 2.33-2.04 (m, 3H), 1.04 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s,
3-(6-((R)-l-(4- 1H), 8.29 (s, 1H), 8.13 (1- (t, J = 8.80 Hz, 1H),
3-(5-fluoro-6- (difluoromethyl 7.86-7.84 (m, 3H), ((R)-4- )-lH-pyrazol- 4-(l- 7.45 (d, J = 8.00 Hz, hydroxy-3,3- 3-yl)benzyl)-4- (difluorometh 2H), 7.03 (d, J = 2.40 dimethylpiper hydroxy-3,3- yl)-lH- Hz, lH), 5.13 (s, 1H), idin-4- 592.4 K dimethylpiperi pyrazol-3- 4.25-4.22 (m, 1H), yl)quinolin-3- din-4-yl)-5- yl)benzaldehy 3.64-3.61 (m, 2H), yl)piperidine- fluoroquinolin- de 3.20 (m, 2H), 2.77- 2, 6-dione, 3-yl)piperidine- 2.71 (m, 2H), 2.68- HC1 2, 6-dione (I- 2.63 (m, 2H), 2.57- 1121) 2.50 (m, 2H), 2.21-
2.18 (m, 2H), 1.71 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0.67 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s,
3-(6-((R)-l-(4- 1H), 8.10 (1, 1 = 8.80 (1-cyclopropyl- 3-(5-fluoro-6- Hz, 1H), 7.84 (d, J = lH-pyrazol-3- ((R)-4-
4-(l- 9.20 Hz, 1H), 7.80 (d, yl)benzyl)-4- hydroxy-3,3- cyclopropyl- J = 2.40 Hz, 1H), 7.74 hydroxy-3,3- dimethylpiper IH-pyrazol- (d, J = 8.40 Hz, 2H), dimethylpiperi idin-4- 582.6 K 3- 7.37 (d, J = 8.00 Hz. din-4-yl)-5- yl)quinolin-3- yl)benzaldehy 2H), 6.66 (d, J = 2.40 fluoroquinolin- yl)piperidine- de Hz, 1H), 5.11 (s, 1H), 3-yl)piperidine- 2, 6-dione,
4.25-4.21 (m, 1H), 2, 6-dione (I- HC1 3.76-3.75 (m, 1H), 1156) 3.59 (d, J = 13.60 Hz, 1H), 3.46 (d, J = 13.20 Hz, 1H), 3.35 (t, J = 19 60 Hz 1H) 2 67
Figure imgf000507_0001
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H),
3-{6-[(R)-l- 8.43 (s, 1H), 8.34 (s, {[3-chloro-4- 1H), 8.12-8.07 (m, (1-cyclopropyl-
3-(5-fluoro-6- 1H), 7.87-7.83 (m,
4- 3-chloro-4- ((R)-4- 2H), 7.57 (d, J = 8.00 pyrazolyl)phen hydroxy-3,3- (1- Hz, 1H), 7.48 (s, 1H), yl] methyl} -4- cyclopropyl- dimethylpiper 7.34-7.32 (m, 1H), hydroxy-3,3- IH-pyrazol- 616.2 K idin-4- 5.13 (m, 1H), 4.31- dimethyl-4- 4- yl)quinolin-3- 4.25 (m, 1H), 3.82- piperidyl]-5- yl)benzaldehy yl)piperidine- 3.72 (m, 1H), 3.60- fluoro-3- de 2, 6-dione 3.32 (m, 2H), 3.20- quinolyl}-2,6- 3.11 (s, 1H), 2.92-2.48 piperidinedione (m, 6H), 2.22-2.12 (m, (1-1163) 2H), 1.76-1.65 (m, 1H), 1.11-0.98 (m, 7H), 0.69 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.34 (s, 1H), 8.10 (t, J = 8.80
3-(6-((R)-l-(4- Hz, 1H), 8.04 (s, 1H), (4-chloro-l- 7.84 (d, J = 9.20 Hz,
3-(5-fluoro-6- methyl-lH- 1H), 7.79 (d, J = 8.40 ((R)-4- pyrazol-3- Hz, 2H), 7.44 (d, J = hydroxy-3,3- 4-(4-chloro- yl)benzyl)-4- 8.00 Hz, 2H), 5.13 (s, dimethylpiper 1 -methyl- 1H- hydroxy-3,3- 1H), 4.26-4.21 (m, idin-4- pyrazol-3- 590.3 K dimethylpiperi 1H), 3.87 (s, 3H), 3.61 yl)quinolin-3- yl)benzaldehy din-4-yl)-5- (d, J = 13.60 Hz, 1H), yl)piperidine- de fluoroquinolin- 3.50 (d, J = 13.60 Hz, 2, 6-dione, 3-yl)piperidine- 1H), 3.17 (t, J = 4.00 HC1 2, 6-dione (I- Hz, 1H), 2.63-2.52 (m, 1166) 5H), 2.18 (d, J = 14.80 Hz, 1H), 2.15-2.13 (m, 1H), 1.84 (s, 1H), 1.72 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz,
3-{5-fluoro-6- DMSO-d6): 5 10.98 [(R)-4- 3-(5-fluoro-6- (s, 1H), 8.84 (s, 1H), hydroxy-3,3- ((R)-4-
4-(3-methyl- 8.34 (s, 1H), 8.10 (t, J dimethyl-1- hydroxy-3,3- IH-pyrazol- = 8.80 Hz, 1H), 7.84 { [p-(3-methyl- dimethylpiper
1- 556.3 (d, J = 9.20 Hz, 1H), K 1- idin-4- yl)benzaldehy 7.75 (d, J = 8.40 Hz, pyrazolyl)phen yl)quinolin-3- de 2H), 7.44 (d, J = 8.00 yl] methyl } -4- yl)piperidine- Hz, 2H), 6.32 (d, J = piperidyl]-3- 2, 6-dione 2.00 Hz, lH), 5.12 (s, quinolyl}-2,6- 1H) 4 23 (dd J = piperidinedione 4.80, 12.80 Hz, 1H),
(1-1180) 3.60 (d, J = 13.60 Hz, 1H), 3.48 (d, J = 13.60 Hz, 1H), 3.18-3.13 (m, 1H), 2.81-2.72 (m, 4H), 2.33-2.18 (m, 6H), 1.91 (s, 3H),
1.76-1.24 (m, 1H),
1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 8.10 (t, J = 8.80 Hz, 1H),
3-(6-((R)-l-(4- 7.84 (d, J = 9.20 Hz, (4-cyclopropyl- 3-(5-fluoro-6- 1H), 7.74 (d, J = 8.40 IH-pyrazol-l- ((R)-4- 4-(4- Hz, 2H), 7.55 (s, 1H), yl)benzyl)-4- hydroxy-3,3- cyclopropyl- 7.44 (d, J = 8.40 Hz, hydroxy-3,3- dimethylpiper IH-pyrazol- 2H), 5.12 (s, 1H), dimethylpiperi idin-4- 582.3 K 1- 4.30-4.20 (m, 1H), din-4-yl)-5- yl)quinolin-3- yl)benzaldehy 3.60 (d, J = 10.80 Hz, fluoroquinolin- yl)piperidine- de 1H), 3.48 (d, J = 13.60 3-yl)piperidine- 2, 6-dione, Hz, 1H), 3.18-3.12 m, 2, 6-dione (I- HC1 1H), 2.69-2.53 (m, 1227) 3H), 2.20-2.18 (m, 3H), 1.89 (s, 1H),
1.77-1.76 (m, 3H), 1.01 (s, 3H), 0.89-0.85 (m, 2H), 0.68 (s, 3H), 0.62-0.58 (m, 2H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J =
2-(4-(((4R)-4- 2.00 Hz, 1H), 8.33 (s, (3-(2,6- 1H), 8.21 (s, 1H), 8.09 dioxopiperidin- (d, J = 8.80 Hz, 1H),
3-(5-fluoro-6-
3-yl)-5- 7.84 (d, J = 8.80 Hz, ((R)-4- fluoroquinolin- 1H), 7.43-7.38 (m, hydroxy-3,3- 6-yl)-4- 2-ethyl-2-(4- 5H), 5.12 (s, 1H), dimethylpiper hydroxy-3,3- formylphenyl 571.3 4.25-4.21 (m, 1H), L idin-4- dimethylpiperi )butanenitrile 3.58 (d, J = 10.00 Hz, yl)quinolin-3- din-1- 1H), 3.53 (d, J = 19.20 yl)piperidine- yl)methyl)phen Hz, 1H), 3.32 (s, 1H), 2, 6-dione yi)-2- 2.68-2.67 (m, 1H), ethylbutanenitri 2.67-2.63 (m, 2H), le (1-1279) 2.05-2.02 (m, 7H), 1.69 (s, 1H), 1.00 (s, 3H), 0.80 (t, J = 7.20 Hz 6H) 0 68 (s 3H) 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, l-(4-(((4R)-4- 1H), 8.29 (s, 1H), 8.14 (3-(2,6- (s, lH), 8.16 (s, 1H), dioxopiperidin- 8.10 (t, J = 8.80 Hz, 3-yl)-5-
3-(5-fluoro-6- 1H), 7.84 (d, J = 8.80 fluoroquinolin- ((R)-4- Hz, 1H), 7.48 (d, J = 6-yl)-4- l-(4- hydroxy-3,3- 8.40 Hz, 2H), 7.41 (d, hydroxy-3,3- formylphenyl dimethylpiper 1 = 8.40 Hz, 2H), 5.12 dimethylpiperi )cyclopentane 569.3 K idin-4- (s, 1H), 4.21-4.24 (m, din-1- -1- yl)quinolin-3- 1H), 3.51-3.59 (m, yl)methyl)phen carbonitrile yl)piperidine- 1H), 3.33-3.47 (m, yljcyclopentan 2, 6-dione 2H), 2.68-2.69 (m, e-1- 1H), 2.64-2.67 (m, carbonitrile, 2H), 2.47-2.51 (m, Formic Acid 4H), 2.10-2.21 (m, (1-1286) 4H), 1.90-1.92 (m, 4H), 1.88-1.89 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 10.99 (s, 1H), 8.85 (s, 2H), 8.33
3-(6-((R)-l-(4- (s, 1H), 8.10 (1, 1 = (4- 8.80 Hz, 1H), 7.99 (s, (difluoromethyl 3-(5-fluoro-6- 1H), 7.84 (d, J = 8.40 )-lH-pyrazol- ((R)-4- 4-(4- Hz, 3H), 7.51 (d, J = l-yl)benzyl)-4- hydroxy-3,3- (difluorometh 8.80 Hz, 2H), 7.27- hydroxy-3,3- dimethylpiper yl)-lH- 6.99 (m, lH), 5.13 (s,
592.4 K dimethylpiperi idin-4- pyrazol-1- 1H), 4.25-4.21 (m, din-4-yl)-5- yl)quinolin-3- yl)benzaldehy 1H), 3.65-3.57 (m, fluoroquinolin- yl)piperidine- de 2H), 3.20-3.17 (m, 3-yl)piperidine- 2, 6-dione 1H), 2.77-2.71 (m, 2, 6-dione (I- 2H), 2.60-2.51 (m, 1220) 3H), 2.19-2.12 (m, 3H), 1.72 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0.69 (s, 3H). _
3-(4-(((4R)-4- 1H-NMR (400 MHz, (3-(2,6- DMSO-d6): 5 10.99
3-(5-fluoro-6- dioxopiperidin- (s, 1H), 8.85 (s, 1H), ((R)-4- 3-yl)-5- 3-(4- 8.62 (s, 1H), 8.34 (s, hydroxy-3,3- fluoroquinolin- formylphenyl 1H), 8.13 (1, 1 = 8.80 dimethylpiper 6-yl)-4- )-l-methyl- 581.4 Hz, 1H), 7.84 (d, J = K idin-4- hydroxy-3,3- IH-pyrazole- 8.40 Hz, 3H), 7.51 (d, yl)quinolin-3- dimethylpiperi 4-carbonitrile J = 8.40 Hz, 2H), 5.13 yl)piperidine- din-1- (s, 1H), 4.23 (q, J = 2, 6-dione yl)methyl)phen 4.80 Hz, 1H), 3.95 (s, yl)-l-methyl- 3H) 3 63 (d J = 14 00 lH-pyrazole-4- Hz, 1H), 3.52 (d, J = carbonitrile (I- 13.60 Hz, 1H), 3.23 (t,
1203) J = 13.20 Hz, 1H), 2.77-2.71 (m, 2H), 2.68-2.63 (m, 4H), 2.22 (m, 2H), 1.72 (d, J = 13.20 Hz, 1H), 1.02 (s, 3H), 0.69 (s, 3H).
Table 4.
Aldehyde/ Synthesis
Compound Amine MS
Cmpd Other and Name Starting observed, 1H-NMR No. Starting Purification (Cmpd No.) Material MH+ Material Method
1H-NMR (400 MHz, DMSO-d6): 5 10.58 (s, 1H), 8.88 (s, 1H), l-(6-(4- 8.24 (s, 1H), 8.03 (s, hydroxy-1- 1H), 7.97 (d, J = 8.80 (4- Hz, 1H), 7.90 (d, J = (trifluorome 1.60 Hz. 1H), 7.49 (d, thoxy)benzy
4- J = 8.40 Hz, 1H), l)piperidin-
(trifluorome 7.33 (d, J = 8.00 Hz, 4- 1-168 INT-S1 515.3 thoxy)benza 1H), 5.07 (s, 1H), Q yljquinolin- Idehyde 3.96 (t, J = 6.80 Hz, 3- 2H), 3.58 (s, 2H), yljdihydrop 3.32 (s, 1H), 2.80 (t, J yrimidine- = 6.80 Hz, 2H), 2.66 2,4(1H,3H)- (d, J = 11.60 Hz, 2H), dione 2.14-2.05 (m, 2H), 1.91 (s, 1H), 1.71 (t, J = 12.40 Hz, 2H). l-(6-(4- hydroxy-1- (3-methoxy- 4- (trifluorome
3-methoxy- thoxy)benzy
4- l)piperidin-
1-169 INT-S1 (trifluorome 545.4 Tha C 4- thoxy)benza yljquinolin- Idehyde 3- yl)dihydrop yrimidine- 2,4(1H,3H)- dione 1H-NMR (400 MHz, DMSO-d6): 5 10.95 (s, 1H), 8.41 (s, 1H), 8.10 (t, J = 8.80 Hz,
3-(6-(3,3- 1H), 7.74-7.71 (m, diethyl-4- 3H), 7.60 (d, J = 8.00 hydroxy-1- Hz, 2H), 5.11 (s, 1H), (4- 4.36-4.32 (m, 1H), (trifluorome
4- 3.57 (q, J = 13.20 Hz, thyljbenzyl)
(trifluorome 2H), 3.32 (m, 1H), piperidin-4- 1-1 67c 586.7 P thyl)benzald 2.83 (m, 1H), 2.64- yl)-5-fluoro- ehyde 2.52 (m, 6H), 2.39- 2- 2.33 (m, 3H), 2.15- methylquino 2.12 (m, 2H), 1.60 (d, lin-3- J = 13.60 Hz, 1H), yljpiperidin 1.52-1.49 (m, 1H), e-2, 6-dione 1.13-1.09 (m, 2H), 0.55 (t, J = 7.20 Hz, 3H), 0.44 (t, J = 7.60 Hz, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.95 (s, 1H), 8.22-8.20 (m, 2H), 8.12 (t, J = 8.80 Hz, 1H), 7.73 (d, J = 8.80 Hz, 1H), 5.06 (s,
3-(5-fluoro- 1H), 4.34 (dd, J =
2-methyl-6- 4.40, 12.60 Hz, 1H), (1,3,3- 3.27-3.21 (m, 1H), triethyl-4- 2.83 (m, 1H), 2.68- hydroxypipe acetaldehyd 2.61 (m, 5H), 2.53- ridin-4- 1-5 67c 456.5 P e 2.50 (m, 2H), 2.47- yl)quinolin- 2.41 (m, 3H), 2.39-
3- 2.33 (m, 1H), 2.21 (d, yljpiperidin J = 11.20 Hz, 1H), e-2, 6-dione, 2.10 (d, J = 2.40 Hz, Formic Acid 2H), 1.62-1.51 (m, 2H), 1.18-1.16 (m, 1H), 1.06-1.01 (m, 4H), 0.68 (t, J = 7.20 Hz, 3H), 0.50 (t, J = 7.60 Hz, 3H).
3-(5-fluoro- 1H-NMR (400 MHz,
2-methyl-6- DMSO-d6): 5 10.94 (1,3,3- (s, 1H), 8.22-8.20 (m, triethyl-4- 2H), 8.11 (t, J = 8.80 acetaldehyd hydroxypipe 1-8 67c 456.6 Hz, 1H), 7.73 (d, J = P e ridin-4- 9.20 Hz, 1H), 5.06 (s, yl)quinolin- 1H), 4.34 (dd, J =
3- 4.80, 12.80 Hz, 1H), yljpiperidin 3 27 3 21 (m 1H)
Figure imgf000513_0001
dimethyl- 1- = 8.80 Hz, 1H), 7.83 ((tetrahydro (d, J = 9.20 Hz, 1H), -2H-pyran- 5.07 (s, 1H), 4.25- 4- 4.24 (m, 1H), 3.86- yl)methyl)pi 3.84 (m, 2H), 3.32- peridin-4- 3.25 (m, 2H), 3.14- yl)quinolin- 3.06 (m, 1H), 2.68- 3- 2.68 (m, 1H), 2.65- yljpiperidin 2.62 (m, 2H), 2.35- e-2, 6-dione 2.32 (m, 2H), 2.20- 2.12 (m, 4H), 1.89 (s, 3H), 1.76 (s, 2H), 1.17-1.13 (m, 2H), 0.97 (s, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 510.98
3-(5-fluoro- (s, 1H), 8.84 (s, 1H), 6-(4- 8.31 (s, 1H), 8.08 (t, hydroxy- J = 8.80 Hz, 1H), 3,3- 7.83 (d, J = 8.80 Hz, dimethyl-1- 1H), 5.09 (s, 1H), (oxetan-3- oxetane-3- 4.69-4.65 (m, 2H), ylmethyl)pi 1-206 51d carbaldehyd 456.5 4.32-4.20 (m, 3H), P peridin-4- e 3.33-3.19 (m, 3H), yl)quinolin- 2.68-2.61 (m, 5H), 3- 2.59-2.50 (m, 2H), yljpiperidin 2.11-2.09 (m, 2H), e-2, 6-dione, 1.86 (s, 3H), 1.67 (d, AcOH J = 13.2 Hz, 1H), 0.93 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(6-(l- (s, 1H), 8.84 (s, 1H), ((4,4-
8.32 (s, 1H), 8.10- difluorocycl 8.08 (m, 1H), 7.85- ohexyl)meth 7.83 (m, 1H), 5.07 (s, yl)-4-
4,4- 1H), 4.25-4.21 (m, hydroxy- difluorocycl 1H), 3.32 (m, 1H), 3,3-
1-311 51d ohexane-1- 518.5 2.68-2.67 (m, 1H), P dimethylpip carbaldehyd 2.60-2.50 (m, 2H), eridin-4-yl)- e 2.344-2.37 (m, 1H), 5- 2.22-2.12 (m, 4H), fluoroquinol 2.02-1.78 (m, 2H), in-3-
1.70-1.55 (m, 8H), yl)piperidin 1.16-1.11 (m, 2H), e-2, 6-dione 0.98 (s, 3H), 0.71 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (s, 1H),
3-(5-fluoro- 8.59 (s, 1H), 8.10- 6-(4- 8.08 (m, 1H), 7.84 (d, hydroxy-1- J = 9.20 Hz, 1H), isobutyl- 4.25-4.21 (m, 1H), 3,3- 3.13 (m, 1H), 2.8O- isobutyr aide dimethylpip 1-203 51d 442.2 2.77 (m, 1H), 2.76- P hyde eridin-4- 2.74 (m, 1H), 2.74- yljquinolin- 2.72 (m, 2H), 2.37 (s, 3- 2H), 2.16-2.08 (m, yljpiperidin 5H), 1.80-1.79 (m, e-2, 6-dione 1H), 1.70-1.69 (m, 1H), 1.00 (s, 3H), 0.85 (s, 6H), 0.71 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s,
3-(6-(l- 1H), 8.10 (t, J = 8.80 (cyclopropy Hz, 1H), 7.84 (d, J = lmethyl)-4- 9.20 Hz, 1H), 5.06 (s, hydroxy- 1H), 4.25-4.21 (m, 3,3- 1H), 3.33-3.29 (m, dimethylpip cyclopropan 1H), 2.68-2.63 (m, eridin-4-yl)- 1-201 51d ecarbaldehy 440.1 P 2H), 2.56-2.50 (m, 5- de 1H), 2.47-2.44 (m, fluoroquinol 3H), 2.34-2.32 (m, in-3- 4H), 1.86 (s, 3H), yljpiperidin 1.69 (d, J = 14.00 Hz, e-2, 6-dione, 1H), 0.98-0.95 (m, AcOH 3H), 0.86-0.84 (m, 1H), 0.71 (s, 3H), 0.47 (d, J = 1.20 Hz, 2H), 0.10 (d, 2H).
1H-NMR (400 MHz,
3-((4-(3- DMSO-d6): 5 12.47 (2,6- (d, J = 2.00 Hz, 1H), dioxopiperi 10.99 (s, 1H), 8.88 (s, din-3-yl)-5- 1H), 8.36 (s, 1H), fluoroquinol
3-formyl- 8.29 (d, J = 8.00 Hz. in-6-yl)-4- IH-indole- 1H), 8.03 (t, J = 8.80 hydroxy- 1-243 51d 540.3 P 7- Hz, 1H), 7.90 (d, J = 3,3- carbonitrile 2.80 Hz, 2H), 7.73 (d, dimethylpip J = 7.20 Hz, 1H), eridin-1- 7.33 (t, J = 7.60 Hz, yl)methyl)- 1H), 5.81 (s, 1H), IH-indole- 4.61 (d, J = 3.20 Hz, 7- 2H) 4 26 421 (m carbonitrile, 1H), 3.39-3.36 (m, HC1 1H), 3.28-3.23 (m, 4H), 3.18-3.08 (m, 1H), 2.77-2.67 (m, 1H), 2.64-2.60 (m, 1H), 2.34-2.33 (m, 1H), 2.00-1.98 (m, 1H), 1.07 (s, 3H), 0.76 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 11.00 (s, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.06 (t, J = 8.80 Hz, 1H), 7.90
3-(6-(l-(4- (d, J = 8.80 Hz, 1H), chlorobenzy 7.71 (d, J = 8.00 Hz, l)-4- 2H), 7.59 (d, J = 8.40 hydroxy- Hz, 2H), 5.92 (s, 1H), 3,3- 4.42 (t, J = 7.60 Hz, dimethylpip 4- 1H), 4.26-4.22 (m, eridin-4-yl)- 1-228 51d chlorobenza 510.1 P 1H), 3.46-3.36 (m, 5- Idehyde 4H), 3.29-3.23 (m, fluoroquinol 1H), 2.92-2.89 (m, in-3- 1H), 2.77-2.68 (m, yljpiperidin 1H), 2.68-2.64 (m, e-2, 6-dione, 1H), 2.63-2.60 (m, HC1 1H), 2.51 (s, 1H), 2.50-2.34 (m, 1H), 2.33-2.33 (m, 1H), 1.06 (s, 3H), 0.78 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 11.00
3-(5-fluoro- (s, 1H), 9.86 (s, 1H), 6-(4- 8.90 (s, 1H), 8.39 (s, hydroxy- 1H), 8.08 (t, J = 8.80 3,3- Hz, 1H), 7.91 (d, J = dimethyl-1- 9.20 Hz, 1H), 7.55 (s, ((1-methyl- 1-methyl- 1H), 6.67 (s, 1H), IH-pyrazol- 1H- 5.94 (s, 1H), 4.56 (d, 5- 1-235 51d pyrazole-5- 480.4 J = 3.60 Hz, 2H), P yl)methyl)pi carbaldehyd 4.27-4.23 (m, 1H), peridin-4- e 3.97 (s, 3H), 3.61- yljquinolin- 3.41 (m, 2H), 3.37- 3- 3.31 (m, 2H), 3.06- yl)piperidin 3.03 (m, 1H), 2.77- e-2, 6-dione, 2.74 (m, 1H), 2.22- HC1 2.12 (m, 1H), 2.11- 2.01 (m, 1H), 1.11 (s, 3H), 0.81 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.45 (s, 1H), 8.91 (d, J = 1.60 Hz,
3-(5-fluoro- 1H), 8.40 (s, 1H), 6-(4- 8.08 (t, J = 8.80 Hz, hydroxy- 1H), 7.92-7.90 (m, 3,3- 1H), 7.72-7.70 (m, dimethyl-1- 1H), 7.41-7.32 (m, (2- 2- 3H), 5.94 (s, 1H), methylbenz
1-317 51d methylbenza 490.6 4.46-4.45 (m, 2H), P yljpiperidin- Idehyde 4.27-4.23 (m, 1H),
4- 3.50-3.31 (m, 3H), yljquinolin- 3.01-2.98 (m, 1H), 3- 2.78-2.73 (m, 1H), yljpiperidin 2.68-2.60 (m, 1H), e-2, 6-dione, 2.54-2.50 (m, 2H), HC1 2.49 (s, 3H), 2.15- 2.13 (m, 1H), 2.12- 2.00 (m, 1H), 1.10 (s, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.57 (s, 1H),
3-(5-fluoro- 8.90 (d, J = 2.00 Hz, 6-(4- 1H), 8.38 (s, 1H), hydroxy- 8.11-8.07 (m, 1H),
1,3,3- 7.92-7.90 (m, 1H), trimethylpip 5.94 (s, 1H), 4.27- paraformald eridin-4- 1-200 51d 400.4 4.23 (m, 1H), 3.42- P ehyde yljquinolin- 3.26 (m, 3H), 3.13- 3- 3.11 (m, 1H), 2.84- yljpiperidin 2.75 (m, 4H), 2.67- e-2, 6-dione, 2.60 (m, 1H), 2.51- HC1 2.48 (m, 2H), 2.16- 2.13 (m, 1H), 2.12- 2.00 (m, 1H), 1.08 (s, 3H), 0.80 (s, 3H).
3-(6-(l-((2- 1H-NMR (400 MHz, amino-6- DMSO-d6): 8 11.00 (trifluorome (s, 1H), 8.90 (d, J = thyl)pyridin 2.00 Hz, 1H), 8.39 (s, -3- 1H), 8.09 (t, J = 8.80
2-amino-6- yljmethyl)- Hz, 1H), 8.03-8.01 (trifluorome
4-hydroxy- 1-218 51d 560 (m, 1H), 7.93-7.90 P thyl)nicotina 3,3- (m, 1H), 7.08 (d, J = Idehyde dimethylpip 8.00 Hz, 1H), 5.96 (s, eridin-4-yl)- 1H), 4.37-4.26 (m,
5- 2H), 4.24-4.23 (m, fluoroquinol 1H), 3.46-3.38 (m, in-3- 4H) 3 08 3 05 (m yljpiperidin 1H), 2.68-2.67 (m, e-2, 6-dione 1H), 2.64-2.60 (m, 1H), 2.14-2.13 (m, 1H), 2.02 (m, 1H), 1.09 (s, 3H), 0.81 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 8.04 (t, J = 8.40 Hz, 1H), 7.90
3-(6-(l-(4- (d, J = 8.80 Hz, 1H), cyclopropyl 7.53 (d, J = 8.00 Hz, benzyl)-4- 2H), 7.19 (d, J = 8.00 hydroxy- Hz, 2H), 5.89 (s, 1H), 3,3-
4- 4.35-4.22 (m, 3H), dimethylpip cyclopropyl 3.66 (s, 3H), 3.37- eridin-4-yl)- 1-101 51d 516.5 P benzaldehyd 3.22 (m, 1H), 2.89 (d, 5- e J = 8.00 Hz, 1H), fluoroquinol 2.71-2.60 (m, 2H), in-3- 2.56-2.50 (m, 1H), yljpiperidin 2.45-2.33 (m, 1H), e-2, 6-dione, 2.31-2.25 (m, 1H), HC1 1.99-1.94 (m, 2H), 1.06 (s, 3H), 1.04 - 0.99 (m, 2H), 0.76(s, 3H), 0.74-0.71 (m, 2H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J =
3-(6-(l-(4- 2.00 Hz, 1H), 8.33 (s, (difluoromet 1H), 8.09-8.07 (m, hoxy)benzyl 1H), 7.84 (d, J = 9.20 )-4- Hz, 1H), 7.41 (d, J = hydroxy- 3.20 Hz, 2H), 7.40-
4- 3,3- 7.04 (m, 3H), 5.12 (s, (difluoromet dimethylpip 1-104 51d 542.8 1H), 4.25-4.21 (m, P hoxy)benzal eridin-4-yl)- 1H), 3.58-3.44 (m, dehyde 3H), 3.33-3.29 (m, fluoroquinol 1H), 2.68-2.67 (m, in-3- 2H), 2.64-2.63 (m, yl)piperidin 1H), 2.51-2.45 (m, e-2, 6-dione 2H), 2.18-2.16 (m, 2H), 1.72-1.69 (m, 1H), 0.99 (s, 3H), 0.67 (s, 3H). _
3-(6-(l- 1H-NMR (400 MHz, benzyl-4- benzaldehyd DMSO-d6): 5 10.98
1-210 51d 476.2 P hydroxy- e (s, 1H), 8.85 (s, 1H), 3,3- 8 33 (s 1H) 8 15
Figure imgf000519_0001
Figure imgf000520_0001
thyljpyridin 8.06 (m, 2H), 7.91 (d, -3- J = 9.20 Hz, 2H), yl)methyl)pi 5.97 (s, 1H), 4.58- peridin-4- 4.57 (m, 2H), 4.27- yljquinolin- 4.23 (m, 1H), 3.51- 3- 3.31 (m, 4H), 3.00- yl)piperidin 2.97 (m, 1H), 2.77- e-2, 6-dione, 2.67 (m, 1H), 2.64- HC1 2.60 (m, 1H), 2.15- 2.12 (m, 1H), 2.11- 2.00 (m, 1H), 1.10 (s, 3H), 0.89 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.73 (s, 1H), 8.93 (d, J = 1.60 Hz, 1H), 8.43 (s, 1H),
3-(5-fluoro- 8.08-8.04 (m, 1H), 6-(4- 7.93-7.90 (m, 1H), hydroxy-1- 7.64-7.62 (m, 1H), (2- 7.53-7.48 (m, 1H), methoxyben 7.19-7.17 (m, 1H), zyl)-3,3- 2- 7.10-7.06 (m, 1H), dimethylpip 1-335 51d methoxyben 506.5 P
5.98 (s, 1H), 4.37- eridin-4- zaldehyde
4.24 (m, 3H), 3.94- yl)quinolin-
3.78 (m, 3H), 3.42- 3- 3.20 (m, 4H), 2.97- yljpiperidin 2.95 (m, 1H), 2.81- e-2, 6-dione, 2.73 (m, 1H), 2.68- HC1 2.60 (m, 1H), 2.68- 2.60 (m, 1H), 2.53- 2.49 (2H), 2.15-1.97 (m, 2H), 1.10 (s, 3H), 0.77 (s, 3H). _
1H-NMR (400 MHz,
3-(6-(l- DMSO-d6): 5 11.00 ((1H- (s, 1H), 9.81 (s, 1H), pyrazol-4- 8.92 (d, J = 1.20 Hz, yl)methyl)- 1H), 8.42-8.42 (m,
4-hydroxy- 1H), 8.09-8.05 (m, 3,3- 1H- 1H), 7.92-7.88 (m, dimethylpip pyrazole-4- 3H), 5.87 (s, 1H),
1-234 51d 466.1 P eridin-4-yl)- carbaldehyd 4.28-4.17 (m, 3H),
5- e 3.38-3.14 (m, 4H), fluoroquinol 2.95-2.92 (m, 1H), in-3- 2.82-2.81 (m, 1H), yl)piperidin 2.79-2.73 (m, 1H), e-2, 6-dione, 2.52-2.47 (m, 2H), HC1 2.16-2.14 (m, 1H), 2.12-1.98 (m, 1H),
Figure imgf000522_0001
Figure imgf000523_0001
1.09 (s, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.75 (s,
5-((4-(3- 1H), 8.33 (s, 1H), (2,6- 8.12-8.01 (m, 3H), dioxopiperi
7.84 (d, J = 8.80 Hz, din-3-yl)-5- 1H), 5.17 (s, 1H), fluoroquinol
5- 4.23 (dd, J = 4.80, in-6-yl)-4-
1-247 51d formylpicoli 502.4 12.40 Hz, 1H), 3.72 P hydroxy- nonitrile (d, J = 14.40 Hz, 1H), 3,3- 3.61 (d, J = 14.40 Hz, dimethylpip 1H), 3.16 (t, J = eridin-1- 12.40 Hz, 1H), 2.76- yl)methyl)pi 2.63 (m, 5H), 2.15 (d, colinonitrile J = 10.40 Hz, 2H), 1.90 (s, 1H), 1.76- 1.70 (m, 1H), 1.00 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.32 (s,
6-amino-5- 1H), 8.10 (t, J = 8.80 ((4-(3-(2,6- Hz, 1H), 7.85 (d, J = dioxopiperi 9.20 Hz, 1H), 7.56- din-3-yl)-5- 7.54 (m, 1H), 7.13- fluoroquinol 7.12 (m, 1H), 6.84 (s,
6-amino-5- in-6-yl)-4- 2H), 5.22 (s, 1H),
1-242 51d formylpicoli 517 P hydroxy- 4.25-4.21 (m, 1H), nonitrile 3,3- 3.51-3.43 (m, 2H), dimethylpip 3.17-3.13 (m, 1H), eridin-1- 2.81-2.73 (m, 1H), yl)methyl)pi 2.64-2.60 (m, 2H), colinonitrile 2.52-2.50 (m, 2H),
2.18-2.12 (m, 2H),
1.89-1.71 (m, 1H), 0.97 (s, 3H), 0.70 (s, 3H). _
3-(6-(l- 1H-NMR (400 MHz, ((IH-pyrrol- DMSO-d6): 5 10.98 2- IH-pyrrole- (s, 1H), 10.59 (s, 1H), yljmethyl)- 2- 8.84 (s, 1H), 8.32 (s,
1-213 51d 465.2 P
4-hydroxy- carbaldehyd 1H), 8.17 (s, 1H), 3,3- e 8.09 (t, J = 8.80 Hz, dimethylpip 1H), 7.83 (d, J = 8.80 eridin-4-yl)- Hz, 1H), 6.64 (t, J = 5- 2.40 Hz, 1H), 5.94 fluoroquinol (dd, J = 2.40, 5.40 in-3- Hz, 2H), 5.06 (s, 1H), yljpiperidin 4.22 (dd, J = 4.80, e-2, 6-dione, 12.80 Hz, 1H), 3.46- 0.68Formic 3.42 (m, 3H), 3.06- Acid 3.02 (m, 1H), 2.68- 2.64 (m, 3H), 2.42 (d, J = 10.80 Hz, 2H), 2.34-2.33 (m, 2H),
I.68 (d, J = 12.40 Hz,
1H), 0.97 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 10.30 (s, 1H), 8.92 (s, 1H), 8.42 (s,
3-(5-fluoro- 1H), 8.09 (t, J = 8.80 6-(4- Hz, 1H), 7.82-7.78 hydroxy-1- (m, 1H), 7.72 (s, 1H), (3-methoxy-
7.40 (d, J = 8.00 Hz,
4- 1H), 7.40 (d, J = 8.00 (trifluorome 3-methoxy- Hz, 1H), 5.95 (s, 1H), thyljbenzyl) 4- 4.50 (d, J = 3.20 Hz,
1-129 51d (trifluorome 574.4 P 1H), 4.44 (d, J = 6.00 dimethylpip thyl)benzald Hz, 1H), 4.27-4.25 eridin-4- ehyde (m, 1H), 3.96 (s, 3H), yljquinolin- 3.47-3.44 (m, 3H), 3- 3.31-3.28 (m, 1H), yljpiperidin 2.86-2.83 (m, 2H), e-2, 6-dione, 2.78-2.60 (m, 2H), HC1 2.15 (d, J = 2.80 Hz, 1H), 2.02 (d, J =
12.40 Hz, 1H), 1.11 (s, 3H), 0.78 (s, 3H). 1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 11.00 6-(4- (s, 1H), 9.91 (s, 1H), hydroxy-1- 9.07 (d, J = 1.60 Hz, (4- 1H), 8.90 (d, J = 1.60
Synthesied (isoxazol-3- Hz, 1H), 8.40 (s, 1H), using 3-(4- yl)benzyl)- 8.09-8.02 (m, 3H), (bromometh 3,3- 7.92-7.83 (m, 3H),
1-132 51d yl)phenyl)is 543.49 J dimethylpip 7.23 (d, J = 1.60 Hz, oxazole eridin-4- 1H), 5.93 (s, 1H), using yljquinolin- 4.50-4.46 (m, 2H), alkylation 3- 4.25 (dd, J = 4.40, yljpiperidin 12.60 Hz, 1H), 3.41 e-2, 6-dione, (s, 3H), 3.05 (t, J = HC1 II.60 Hz, 1H), 2.93 (d J = 11 60 Hz 1H) 2.77-2.68 (m, 1H), 2.67-2.49 (m, 2H), 2.34-2.03 (m, 2H), 1.08 (s, 3H), 0.78 (s,
3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 10.01 (s, 1H), 8.91 (d, J = 10.00 Hz, 2H), 8.38-8.36 (m, 1H), 8.32 (d, J = 6.40
5-((4-(3- Hz, 1H), 8.30-8.26 (2,6- (dm, 1H), 8.15 (d, J = dioxopiperi 8.00 Hz, 1H), 8.07 (t, din-3-yl)-5- J = 8.40 Hz, 1H), fluoroquinol 7.90 (d, J = 9.20 Hz,
5- in-6-yl)-4- 1H), 7.76 (s, 1H),
1-441 51d formylpicoli 520.4 P hydroxy- 5.95 (s, 1H), 4.55 (s, nonitrile 3,3- 2H), 4.24 (dd, J = dimethylpip 4.80, 12.80 Hz, 1H), eridin-1- 3.49-3.37 (m, 3H), yl)methyl)pi 2.98 (d, J = 11.60 Hz, colinamide 1H), 2.77-2.68 (m, 1H), 2.68-2.64 (m, 1H), 2.60 (s, 1H), 2.33-2.14 (m, 1H), 2.02 (d, J = 12.00 Hz, 1H), 1.08 (s, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.83 (d, J = 2.00 Hz, 1H), 8.76 (s, 1H), 8.32 (s, 2H),
5-((4-(3- 8.18 (t, J = 8.80 Hz, (2,6- 1H), 8.06-8.02 (m, dioxopiperi 1H), 7.83 (d, J = 8.80 din-3-yl)-5- Hz, lH), 5.18 (s, 1H), fluoroquinol 5- 4.24-4.20 (m, 2H), in-6-yl)-3,3- 1-274 53g formylpicoli 530.4 P
3.68-3.57 (m, 2H), diethyl-4- nonitrile 3.33-3.31 (m, 1H), hydroxypipe
2.68-2.63 (m, 4H), ridin-1- 2.42-2.33 (m, 2H), yl)methyl)pi 2.16-2.12 (m, 2H), colinonitrile 1.65-1.45 (m, 2H), 1.14-1.11 (m, 2H), 0.53 (t, J = 7.20 Hz, 3H), 0.45 (t, J = 7.60 Hz, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.83 (d, J = 2.00 Hz, 1H), 8.76 (s,
3-(6-(3,3- 1H), 8.32 (s, 2H), diethyl-4- 8.17 (t, J = 8.80 Hz, hydroxy-1- 1H), 8.07 (d, J = 8.00 ((6- Hz, 1H), 7.91 (d, J = (trifluorome 8.00 Hz, 1H), 7.83 (d, thyljpyridin 6- J = 8.80 Hz, 1H), -3- (trifluorome 5.18 (s, 1H), 4.24-
1-268 53g 573.49 P yl)methyl)pi thyl)nicotina 4.20 (m, 1H), 3.69- peridin-4- Idehyde 3.58 (m, 2H), 3.34- yi)-5- 3.31 (m, 1H), 2.68- fluoroquinol 2.63 (m, 4H), 2.42- in-3- 2.33 (m, 2H), 2.16- yljpiperidin 2.12 (m, 2H), 1.65- e-2, 6-dione 1.45 (m, 2H), 1.14- 1.11 (m, 2H), 0.53 (t, J = 7.20 Hz, 3H), 0.45 (t, J = 7.60 Hz, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.81 (s, 1H), 9.07 (d, J = 1.60 Hz, 1H), 8.89 (d, J = 2.40 Hz, 1H), 8.39 (s, 1H),
3-(6-(3,3- 8.14 (t, J = 8.80 Hz, diethyl-4- 1H), 8.04 (d, J = 8.40 hydroxy-1- Hz, 2H), 7.91 (d, J = (4- Synthesied 4.80 Hz, 1H), 7.88 (d, (isoxazol-3- using 3-(4- J = 3.60 Hz, 2H), yl)benzyl)pi (bromometh 7.24 (d, J = 2.00 Hz, peridin-4- 1-139 53g yl)phenyl)is 570.8 J 1H), 5.98 (d, J = Hz, yi)-5- oxazole 1H), 4.56-4.21 (m, fluoroquinol using 3H), 2.96 (t, J = in-3- alkylation 12.40 Hz, 2H), 2.77- yljpiperidin 2.64 (m, 3H), 2.23- e-2, 6-dione, 2.12 (m, 3H), 1.97- HC1 1.93 (m, 2H), 1.63- 1.60 (m, 2H), 1.17- 1.10 (m, 2H), 0.51 (t, J = 7.20 Hz, 3H), 0.43 (t, J = 7.60 Hz, 3H).
3-(6-(3,3- 1H-NMR (400 MHz, tetrahydro- diethyl-4- DMSO-d6): 5 11.00 2H-pyran-4- hydroxy-1- 1-272 53g 512.3 (s, 1H) D2O P carbaldehyd ((tetrahydro Exachange, 8.90 (s, e -2H-pyran- 1H) D2O Exchange 4- 8.90 (s, 1H), 8.39 (s, yl)methyl)pi 1H), 8.17 (t, J = 8.80 peridin-4- Hz, 1H), 7.91 (d, J = yi)-5- 9.20 Hz, 1H), 5.98 (s, fluoroquinol 1H) D2O Exchange, in-3- 4.27-4.22 (m, 1H), yljpiperidin 3.88 (d, J = 11.60 Hz, e-2, 6-dione, 2H), 3.68-3.34 (m, HC1 5H), 3.18-3.15 (m, 3H), 3.14-3.05 (m, 1H), 2.78-2.61 (m, 1H), 2.52-2.50 (m, 1H), 2.21-2.13 (m, 3H), 1.91 (d, J =
13.20 Hz, 1H), 1.74- 1.65 (m, 3H), 1.34-
1.23 (m, 5H), 0.70 (t,
J = 7.20 Hz, 3H), 0.53 (t, J = 7.20 Hz, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H) D2O Exachange, 10.28 (s, 1H) D2O Exchange,
4-((4-(3- 8.91 (d, J = 1.60 Hz, (2,6- 1H), 8.42 (s, 1H), dioxopiperi 8.16 (t, J = 8.80 Hz, din-3-yl)-5- 1H), 8.03-7.90 (m, fluoroquinol 5H), 6.00 (s, 1H)
4- in-6-yl)-3,3- D2O Exchange, 4.58-
1-265 53g formylbenzo 529.53 G diethyl-4- 4.43 (m, 2H), 4.27- nitrile hydroxypipe 4.23 (m, 1H), 3.52- ridin-1- 3.94 (m, 4H), 3.23- yl)methyl)b 3.17 (m, 1H), 2.75- enzonitrile, 2.50 (m, 3H), 2.34- HC1 2.13 (m, 3H), 1.63- 1.59 (m, 1H), 1.17- 1.09 (m, 2H), 0.50 (t, J = 7.20 Hz, 3H), 0.42 (t, J = 7.60 Hz, 3H). _
3-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 11.93
7- hydroxy- (d, J = 2.00 Hz, 1H), (trifluorome 3,3- 10.99 (s, 1H), 9.84 (s, thyl)-lH- dimethyl-1- 1-149 51d 583.45 1H), 8.90 (d, J = 1.60 G indole-3- ((7- Hz, 1H), 8.39 (s, 1H), carbaldehyd (trifluorome 8.24 (d, J = 8.40 Hz, e thyl)-lH- 1H), 8.03 (t, J = 8.40 indol-3- Hz 1H) 7 89 (d J = yl)methyl)pi 9.20 Hz, 2H), 7.56 (d, peridin-4- J = 7.60 Hz, 1H), yljquinolin- 7.33 (t, J = 7.60 Hz, 3- 1H), 5.81 (s, 1H), yljpiperidin 4.61 (d, J = 2.80 Hz, e-2, 6-dione, 2H), 4.24 (q, J = 4.80 HC1 Hz, 1H), 3.60-3.34 (s, 4H), 3.26 (t, J =
11.20 Hz, 1H), 3.09 (d, J = 8.00 Hz, 1H), 2.75 (d, J = 12.80 Hz, 1H), 2.62 (t, J =
14.40 Hz, 1H), 2.13
(q, 1 = 4.80 Hz, 1H), 1.99 (d, J = 10.40 Hz, 1H), 1.10 (s, 3H), 0.76 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.28 (s, 1H), 8.85 (d, J = 2.00 Hz,
3-(6-(l-(4- 1H), 8.33 (s, 1H),
(1H-1,2,4- 8.23 (s, 1H), 8.10 (t, J triazol-1- = 8.80 Hz, 1H), 7.84 yljbenzyl)- (m, 3H), 7.55 (d, J =
4-hydroxy-
4-(lH-l,2,4- 8.40 Hz, 2H), 5.14 (s,
3,3- triazol-1- 1H), 4.23 (q, J = 4.80 dimethylpip 1-354 51d 543.52 yl)benzalde Hz, 1H), 3.65 (d, J = Q eridin-4-yl)- hyde 13.60 Hz, 1H), 3.52 (d, J = 13.60 Hz, 1H), fluoroquinol 3.17 (s, 2H), 2.77- in-3- 2.68 (m, 2H), 2.64 (d, yljpiperidin J = 3.20 Hz, 1H), e-2, 6-dione
2.20 (d, J = 10.40 Hz, 2H), 1.74 (q, J = 12.80 Hz, 3H), 1.02 (s, 3H), 0.68 (s, 3H).
3-(6-(3,3- 1H-NMR (400 MHz, diethyl-4- DMSO-d6): 5 11.00 hydroxy-1- (s, 1H) D2O ((1-methyl- exchanged, 8.90 (s, IH-pyrazol- 1H) D2O exchanged,
1-methyl- 8.897 (s, 1H), 8.34 (s, 1H- yl)methyl)pi 1H), 8.16 (1, 1 = 8.80
1-164 53g pyrazole-5- 508.54 P peridin-4- Hz, 1H), 7.91 (d, J = carbaldehyd yi)-5- 9.20 Hz, 1H), 7.55 (d, e fluoroquinol J = 1.60 Hz, 1H), in-3- 6.72 (s, 1H), 5.99 (s, yljpiperidin 1H) D2O exchanged, e-2, 6-dione, 4.59 (d, J = 4.80 Hz, HC1 2H) 4 27 422 (m 1H), 3.97 (s, 3H), 3.54-3.45 (m, 3H), 3.33-3.25 (m, 1H), 2.95-2.92 (m, 1H),
2.68-2.60 (m, 1H), 2.52-2.40 (m, 2H), 2.20-1.94 (m, 3H),
1.68-1.60 (m, 1H), 1.23-1.17 (m, 2H), 0.57 (t, J = 7.20 Hz, 3H), 0.48 (t, J = 7.60 Hz, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.94
3-(6-(l-((7- (d, J = 2.00 Hz, 1H), chloro-lH- 10.99 (s, 1H), 9.70 (s, indol-3- 1H), 8.89 (d, J = 1.60 yljmethyl)- Hz, 1H), 8.37 (s, 1H),
4-hydroxy- 8.02 (t, J = 8.80 Hz,
7-chloro- 3,3- 1H), 7.89-7.83 (m, IH-indole- dimethylpip 3H), 7.29 (d, J = 7.60
1-146 51d 3- 549.46 eridin-4-yl)- Hz, 1H), 7.16 (t, J = Q carbaldehyd
5- 8.00 Hz, 1H), 5.79 (s, e fluoroquinol 1H), 4.59 (d, J = in-3- 12.00 Hz, 2H), 4.26- yljpiperidin 3.42 (m, 1H), 3.27- e-2, 6-dione, 3.21 (m, 6H), 3.10- HC1 3.07 (m, 2H), 2.14- 1.91 (m, 2H), 1.08 (s, 3H), 0.75 (s, 3H).
1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 12.07 6-(4- (s, 1H), 10.99 (s, 1H), hydroxy- 8.85 (d, J = 2.00 Hz, 3,3- 1H), 8.33 (s, 1H), dimethyl-1-
6-oxo-S- 8.09 (t, J = 8.80 Hz, ((6-oxo-5- (trifluorome 1H), 7.92-7.83 (m, (trifluorome thyl)-l ,6- 2H), 6.37 (d, J = 7.20 thyl)-l ,6-
1-262 51d dihydropyri 561.4 Hz, lH), 5.18 (s, 1H), dihydropyri Q dine -2- 4.26-4.21 (m, 1H), din-2- carbaldehyd 3.51-3.38 (m, 2H), yl)methyl)pi e 3.21-3.18 (m, 1H), peridin-4- 2.68-2.51 (m, 5H), yl)quinolin-
2.21-2.12 (m, 2H), 3- 1.79-1.76 (m, 2H), yljpiperidin 1.74 (s, 3H), 0.69 (s, e-2, 6-dione 3H).
3-(6-(3,3- 1H-NMR (400 MHz, diethyl-4- isobutyr aide DMSO-d6): 5 11.00
1-271 53g 470.52 P hydroxy-1- hyde (s, 1H) D2O isobutylpipe Exchange 8 89 (d J
Figure imgf000531_0001
5- Hz, 1H), 3.17 (s, 1H), fluoroquinol 2.75 (d, J = 14.40 Hz, in-3- 1H), 2.68-2.64 (m, yljpiperidin 1H), 2.60-2.50 (m, e-2, 6-dione 2H), 2.40-2.33 (m, 1H), 2.15 (t, J = 3.60 Hz, 4H), 2.01 (s, 2H), 1.69-1.53 (m, 8H),
1.20-1.12 (m, 5H),
0.67 (t, J = 7.20 Hz, 3H), 0.49 (t, J = 7.60 Hz, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J =
3-(5-fluoro- 2.00 Hz, 1H), 8.33 (s, 6-(4- 1H), 8.10 (t, J = hydroxy- 10.80 Hz, 2H), 7.84 3,3- (t, J = 4.80 Hz, 2H), dimethyl-1- 7.52 (d, J = 8.00 Hz, (4-(l- 4-(l-methyl- 2H), 7.33 (d, J = 8.00 methyl-lH- IH-pyrazol- Hz, 2H), 5.10 (s, 1H), pyrazol-4- 1-400 51d 4- 556.5 4.23 (d, J = 4.80 Hz, Q yl)benzyl)pi yl)benzalde 1H), 3.87 (s, 3H), peridin-4- hyde 3.58-3.32 (m, 2H), yljquinolin- 3.20-3.11 (m, 1H), 3- 2.72-2.60 (m, 4H), yljpiperidin 2.44-2.41 (m, 2H), e-2, 6-dione, 2.18-2.13 (m, 2H), AcOH 1.86 (s, 3H), 1.70 (d, J = 13.60 Hz, 1H),
1.24 (s, 3H), 0.68 (s,
3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.83 (s, 1H),
3-(6-(3,3- 8.17 (t, J = -9.20 Hz, diethyl-4- H), 7.83 (d, J = 8.80 hydroxy-1- Hz, 1H), 7.39-7.34 (4-(oxetan- (m, 4H), 5.12 (s, 1H), 3- 4.96-4.92 (m, 2H),
4-(oxetan-3- yl)benzyl)pi 4.65-4.60 (m, 2H),
1-142 53g yl)benzalde 560.7 H peridin-4- 4.27-4.20 (m, 2H), hyde yi)-5- 3.52-3.41 (m, 2H), fluoroquinol 3.42-3.33 (m, 1H), in-3- 2.68-2.63 (m, 3H), yljpiperidin 2.51-2.50 (m, 2H), e-2, 6-dione 2.38-2.30 (m, 2H), 2.16-2.14 (m, 2H), 1.86 (s, 1H), 1.76- 1 24 (m 2H) 1 13 1.09 (m, 2H), 0.56 (1, J = 7.20 Hz, 3H), 0.44 (t, J = 7.60 Hz, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J =
3-(5-fluoro- 2.00 Hz, 1H), 8.33 (s, 6-((S)-4- 1H), 8.10 (1, 1 = 8.80 hydroxy- Hz, 1H), 7.84 (d, J = 3,3- 8.80 Hz, 1H), 7.72 (d, dimethyl-1- J = 8.00 Hz, 2H),
4- (4- 7.60 (d, J = 8.00 Hz, (trifluorome (trifluorome 1-83 (S)-51d 544.54 2H), 5.14 (s, 1H), P thyl)benzald thyljbenzyl) 4.23 (dd, J = 4.40, ehyde piperidin-4- 12.80 Hz, 1H), 3.69- yl)quinolin- 3.55 (m, 2H), 3.33- 3- 3.13 (m, 1H), 2.8O- yljpiperidin 2.68 (m, 3H), 2.64- e-2, 6-dione 2.51 (m, 3H), 2.19- 2.16 (m, 2H), 1.73- 1.70 (m, 1H), 1.02 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (d, J =
3-(5-fluoro- 2.00 Hz, 1H), 8.33 (s, 6-((R)-4- 1H), 8.10 (1, 1 = 8.80 hydroxy- Hz, 1H), 7.84 (d, J = 3,3- 9.20 Hz. 1H), 7.72 (d, dimethyl-1- J = 8.00 Hz, 2H),
4- (4- 7.60 (d, J = 8.00 Hz,
(trifluorome (trifluorome 1-84 (R)-51d 544.54 2H), 5.15 (s, 1H), P thyl)benzald thyl)benzyl) 4.23 (q, J = 4.80 Hz, ehyde piperidin-4- 1H), 3.69-3.55 (m, yl)quinolin- 2H), 3.17 (1, J = 3- 12.00 Hz, 1H), 2.76- yljpiperidin 2.51 (m, 6H), 2.34- e-2, 6-dione 2.16 (m, 2H), 1.72 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0.68 (s, 3H).
3-(6-(l-(4- 1H-NMR (400 MHz, (1H- DMSO-d6): 5 11.00 imidazol-1- (s, 1H), 10.69 (s, 1H),
4-(lH- yl)benzyl)- 9.76 (s, 1H), 8.90 (s, imidazol-1-
4-hydroxy- 1-365 51d 542.53 1H), 8.38 (1, J = P yl)benzalde 3,3- 12.40 Hz, 2H), 8.09- hyde dimethylpip 8.04 (m, 3H), 7.97- eridin-4-yl)- 7.89 (m, 4H), 5.95 (s, 1H) 4 55 442 (m fluoroquinol 2H), 4.26-4.22 (m, in-3- 1H), 3.28-2.73 (m, yljpiperidin 3H), 2.83-2.64 (m, e-2, 6-dione, 5H), 2.50-2.13 (m, HC1 2H), 1.10 (s, 3H), 0.77 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00
3-(6-(l-(4- (s, 1H), 10.32 (s, 1H), (1H- 9.54 (s, 1H), 8.89 (d, imidazol-1- J = 1.60 Hz, 1H), yljbenzyl)- 8.37 (s, 1H), 8.28 (s,
4-hydroxy- 1H), 8.08-8.00 (m, 3,3- 4-(lH- 7H), 5.93 (s, 1H), dimethylpip imidazol-1- 4.55-4.46 (m, 2H),
1-364 51d 542.53 P eridin-4-yl)- yl)benzalde 4.26-4.22 (m, 1H),
5- hyde 3.42-2.88 (m, 2H), fluoroquinol 2.88-2.85 (m, 1H), in-3- 2.77-2.74 (m, 1H), yljpiperidin 2.68-2.68 (m, 1H), e-2, 6-dione, 2.60-2.51 (m, 3H), HC1 2.14-2.02 (m, 2H), 1.10 (s, 3H), 0.77 (s, 3H). _
1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 11.01 6-(4- (s, 1H), 10.21 (s, 1H), hydroxy- 8.94 (s, 1H), 8.45 (s, 3,3- 1H), 8.29 (d, J = 0.40 dimethyl-1- Hz, 1H), 8.09 (m, (4-(oxazol- 3H), 7.94-7.87 (m,
4-(oxazol-2-
2- 3H), 7.44 (d, J = 0.80
1-366 51d yl)benzalde 543.55 P yl)benzyl)pi Hz, 1H), 5.95 (s, 1H), hyde peridin-4- 4.54-4.23 (m, 3H), yljquinolin- 3.31-3.25 (m, 4H),
3- 2.90-2.73 (m, 2H), yl)piperidin 2.66-2.43 (m, 2H), e-2, 6-dione, 2.25-2.00 (m, 2H), HC1 1.10 (s, 3H), 0.77 (s, 3H). _
3-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 11.00 hydroxy- (s, 1H), 10.12 (s, 1H), 3,3- 8.93 (s, 1H), 8.44 (s, dimethyl-1- 4-(thiazol-2- 1H), 8.09 (t, J = 8.00 (4-(thiazol- 1-394 51d yl)benzalde 559.53 Hz, 3H), 7.99 (d, J = P
2- hyde 3.20 Hz, 1H), 7.92 (d, yl)benzyl)pi J = 8.80 Hz, 1H), peridin-4- 7.87-7.83 (m, 3H), yljquinolin- 5.94 (s, 1H), 4.53-
3- 4 49 (m 3H) 3 42
Figure imgf000535_0001
Figure imgf000536_0001
2.18 (m, 2H), 1.84- 1.71 (m, 1H), 1.026 (s, 3H), 0.683 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.94 (s, 1H), 8.52 (s, 1H),
3-(5-fluoro- 8.21 (d, J = 6.00 Hz, 6-(4- 1H), 8.02 (t, J = 8.80 hydroxy-1- Hz, 1H), 7.74 (d, J = (isoxazol-5- 9.20 Hz, 1H), 6.41 (s, ylmethyl)- 1H), 5.08 (d, J = 3.60 3,3- isoxazole-5- Hz, 1H), 4.35 (dd, J = dimethylpip 1-433 66c carbaldehyd 481.5 4.80, 12.60 Hz, 1H), P eridin-4-yl)- e 3.75 (d, J = 1.60 Hz, 2- 2H), 3.22 (m, 1H), methylquino 2.85-2.82 (m, 1H), lin-3- 2.75-2.62 (m, 5H), yljpiperidin 2.60-2.49 (m, 3H), e-2, 6-dione 2.19-2.11 (m, 2H),
1.75-1.71 (m, 1H), 0.97 (s, 3H), 0.68 s, 3H).
1H-NMR (400 MHz,
3-(6-(l-(4- DMSO-d6): 5 11.01 (1H- (s, 1H), 10.54 (s, 1H), benzo[d]imi 9.39 (s, 1H), 8.93 (s, dazol-1- 1H), 8.44 (d, J = 2.40 yljbenzyl)- Hz, 1H), 8.09 (t, J =
4-(lH-
4-hydroxy- 8.40 Hz, 3H), 7.94- benzo[d]imi 3,3- 7.90 (m, 4H), 7.80 (d, dazol-1- dimethylpip 1-455 51d 592.59 J = 2.80 Hz, 1H), P yl)benzalde eridin-4-yl)- 7.55-7.53 (m, 2H), hyde ALD- 6.01 (s, 1H), 4.60- 13 fluoroquinol 4.47 (m, 2H), 4.28- in-3- 4.24 (m, 2H), 3.52- yl)piperidin 3.31 (m, 4H), 2.91- e-2, 6-dione, 2.65 (m, 3H), 2.16- HC1 2.03 (m, 2H), 1.24 (s, 3H), 0.80 (s, 3H).
3-(6-(l-(4- 1H-NMR (400 MHz, (3,5- DMSO-d6): 5 10.99 dimethyliso (s, 1H), 8.85 (d, J = xazol-4- 4-(3,5- 2.00 Hz, 1H), 8.33 (s, yljbenzyl)- dimethyliso 1H), 8.11 (1, 1 = 9.20
4-hydroxy- 1-342 51d xazol-4- 569.56 Hz, 1H), 7.84 (d, J = P 3,3- yl)benzalde 8.80 Hz, 1H), 7.47 (d, dimethylpip hyde J = 8.00 Hz, 2H), eridin-4-yl)- 7.37 (d, J = 8.00 Hz.
5- 2H), 5.14 (s, 1H), fluoroquinol 4.25-4.21 (m, 1H), in-3- 3.62-3.33 (m, 2H), yljpiperidin 3.20-3.17 (m, 1H), e-2, 6-dione 2.76-2.54 (m, 7H), 2.42 (s, 3H), 2.35- 2.32 (m, 4H), 1.72 (d, J = 14.40 Hz, 1H), 1.03 (s, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz, DMS0-d6): 5 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s,
3-(6-(l-(3- 1H), 8.25 (s, 1H),
(1H- 8.10 (t, J = 8.80 Hz, imidazol-1- 1H), 7.84 (d, J = 8.80 yljbenzyl)- Hz, 1H), 7.74 (s, 1H),
4-hydroxy- 3-(lH- 7.62 (s, 1H), 7.54-
3,3- imidazol-1- 7.48 (m, 2H), 7.39 (d, dimethylpip 1-369 51d yl)benzalde 542.56 J = 7.20 Hz, 1H), P eridin-4-yl)- hyde ALD- 7.12 (s, 1H), 5.15 (s,
5- 17 1H), 4.25-4.21 (m, fluoroquinol 1H), 3.70-3.57 (m, in-3- 2H), 3.21-3.15 (m, yl)piperidin 1H), 2.80-2.60 (m, e-2, 6-dione 4H), 2.51-2.47 (m, 2H), 2.24-2.12 (m, 2H), 1.75-1.71 (m, 1H), 1.02 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMS0-d6): 5 10.99 (s, 1H), 9.90 (s, 1H),
3-(5-fluoro- 9.25 (d, J = 2.00 Hz, 6-(4- 1H), 8.90 (d, J = 1.60 hydroxy- Hz, 1H), 8.40 (s, 1H), 3,3- 8.29 (d, J = 2.00 Hz, dimethyl-1- 1H), 8.13-8.04 (m, (4-(thiazol-
4-(thiazol-4- 3H), 7.90 (d, J = 8.80
4-
1-372 51d yl)benzalde 559.8 Hz, 1H), 7.76 (d, J = P yl)benzyl)pi hyde 8.40 Hz, 2H), 5.92 (s, peridin-4- 1H), 4.44-4.36 (m, yljquinolin- 2H), 4.27-4.22 (m, 3- 1H), 3.41-3.25 (m, yljpiperidin 4H), 2.93 (d, J = 8.00 e-2, 6-dione, Hz, 1H), 2.80- HC1 2.48(m, 3H), 2.15- 2.00 (m, 2H), 1.09 (s, 3H), 0.78 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 10.05 (s, 1H),
3-(6-(l-(4- 9.78 (s, 1H), 8.91 (s, (1,2,4- 1H), 8.41 (s, 1H), oxadiazol-3- 8.18-8.13 (m, 3H), yl)benzyl)- 8.01-7.97 (m, 2H), 3,3-diethyl- 7.92-7.90 (m, 1H),
4- 4-(l,2,4- 5.99 (s, 1H), 4.59- hydroxypipe oxadiazol-3- 4.45 (m, 2H), 4.27-
1-535 53g 570.62 P ridin-4-yl)- yl)benzalde 4.22 (m, 1H), 3.49- hyde 3.42 (m, 3H), 3.25- fluoroquinol 3.19 (m, 1H), 2.84- in-3- 2.77 (m, 2H), 2.68- yljpiperidin 2.48 (m, 2H), 2.16- e-2, 6-dione, 2.12 (m, 2H), 1.97- HC1 1.93 (m, 1H), 1.64- 1.61 (m, 1H), 1.18- 1.11 (m, 2H), 0.52- 0.40 (m, 6H).
1H-NMR (400 MHz,
3-(6-(l-(4- DMSO-d6): 5 11.00 (1,2,4- (s, 1H), 10.32 (s, 1H), oxadiazol-3- 9.78 (d, J = Hz, 1H), yljbenzyl)- 8.52 (d, J = 4.80 Hz,
4-hydroxy- 1H), 8.17-8.10 (m, 3,3- 4-(l,2,4- 3H), 7.93 (d, J = 7.60 dimethylpip oxadiazol-3- Hz, 3H), 5.97 (s, 1H),
1-526 51d 558.4 P eridin-4-yl)- yl)benzalde 4.55-4.40 (m, 3H),
5-fluoro-2- hyde 3.42 (s, sH), 3.32- methylquino 3.25 (m, 1H), 2.90- lin-3- 2.83 (m, 3H), 2.79 (s, yljpiperidin 3H), 2.68-2.49 (m, e-2, 6-dione, 2H), 2.14-2.00 (m, HC1 2H), 1.09 (s, 3H), 0.76 (s, 3H).
3-(6-(l- 1H-NMR (400 MHz, (d,4- DMSO-d6): 5 10.99 dimethyl- (s, 1H), 9.78 (s, 1H), IH-pyrazol- 8.44 (d, J = 5.20 Hz, 5- 1,4- 1H), 8.10 (1, 1 = 8.40 yl)methyl)- dimethyl- Hz, 1H), 7.91 (d, J =
4-hydroxy- 1H- 9.20 Hz. 1H), 7.41 (s,
1-799 51d 508.6 P 3,3- pyrazole-5- 1H), 5.94 (s, 1H), dimethylpip carbaldehyd 4.56-4.39 (m, 3H), eridin-4-yl)- e 3.89 (s, 3H), 3.38-
5-fluoro-2- 3.20 (m, 5H), 2.84- methylquino 2.54 (m, 6H), 2.05- lin-3- 1.98 (m, 5H), 1.10 (s, yljpiperidin 3H), 0.81 (s, 3H).
Figure imgf000540_0001
dimethylpip (m, 2H), 6.57 (d, J = eridin-4-yl)- 2.00 Hz, 1H), 5.88 (s, 5-fluoro-2- 1H), 4.43-4.38 (m, methylquino 4H), 3.91 (s, 3H), lin-3- 3.30 (t, J = 12.00 Hz, yljpiperidin 1H), 3.00 (d, J = 12.4 e-2, 6-dione, Hz, 1H), 2.85-2.77 HC1 (m, 4H). 2.67-2.60 (m, 2H), 2.14-2.11 (m, 1H), 1.99 (d, J =
9.60 Hz, 1H), 1.07 (s, 3H), 0.76 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99
3-(5-fluoro- (s, 1H), 9.93 (s, 1H), 6-(4- 8.41-8.39 (m, 1H), hydroxy- 8.06 (t, J = 8.40 Hz, 3,3- 1H), 7.89-7.81 (m, dimethyl-1- 2H), 6.55 (s, 1H), ((1-methyl-
1-methyl- 5.86 (s, 1H), 4.40 IH-pyrazol- 1H- (dd, 1 = 4.80, 12.60 3-
1-777 66c pyrazole-3- 494.5 Hz, 1H), 4.33-4.31 p yl)methyl)pi carbaldehyd (m, 2H), 3.90 (s, 3H), peridin-4- e 3.36 (s, 3H), 3.24 (t, J yD-2- = 11.60 Hz, 1H), methylquino 3.01-2.98 (m, 1H), lin-3- 2.84-2.80 (m, 1H), yljpiperidin
2.74 (s, 3H), 2.68- e-2, 6-dione, 2.58 (m, 2H), 2.13- HC1 2.00 (m, 2H), 1.07 (s, 3H), 0.76 (s, 3H). 1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 10.99 6-(4- (s, 1H), 9.07 (s, 1H), hydroxy- 8.50 (d, J = 8.00 Hz, 3,3- 1H), 8.43 (d, J = Hz, dimethyl-1- 1H), 8.12-8.07 (m, ((6- 2H), 7.89 (d, J = 8.80 (trifluorome
6- Hz, 1H), 5.97 (s, 1H), thyl)pyridin (trifluorome 557.55 4.57 (d, J = 3.60 Hz, -3- 1-155 66c P thyl)nicotina (Negative) 2H), 4.41 (q, J = 8.40 yl)methyl)pi Idehyde Hz, 1H), 3.55-3.31 peridin-4- (m, 4H). 2.99 (d, J = yl)-2- 10.80 Hz, 1H), 2.85- methylquino
2.75 (m, 4H), 2.68- lin-3-
2.61 (m, 2H), 2.13- yljpiperidin 2.10 (m, 1H), 2.08- e-2, 6-dione, 2.04 (m, 1H), 1.08 (s, HC1 3H), 0.79 (s, 1H). 1H-NMR (400 MHz,
3-(6-(l- DMSO-d6): 5 11.02 (d,3- (s, 1H), 10.38 (s, 1H), dimethyl- 8.61 (d, J = 6.40 Hz, IH-pyrazol- 1H), 8.17 (t, J = 8.40 5- Hz, 1H), 8.01 (d, J = yl)methyl)- 1,3- 8.80 Hz, 1H), 6.47 (s,
4-hydroxy- dimethyl- 1H), 5.99 (s, 1H), 3,3- 1H- 4.55-4.43 (m, 3H),
1-632 66c 508.54 P dimethylpip pyrazole-5- 4.05 (s, 3H), 3.42 (s, eridin-4-yl)- carbaldehyd 3H), 3.27 (t, J =
5-fluoro-2- e 11.20 Hz, 1H), 3.00 methylquino (d, J = 11.60 Hz, 1H), lin-3- 2.88-2.76 (m, 4H), yl)piperidin 2.62-2.56 (m, 2H), e-2, 6-dione, 2.14-2.01 (m, 5H), HC1 1.11 (s, 3H), 0.79 (s, 3H).
3-(5-fluoro-
1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 11.00 hydroxy- (s, 1H), 9.82 (s, 1H), 3,3- 8.45 (d, J = 6.40 Hz, dimethyl-1- 1H), 8.09 (t, J = 8.40 ((1-methyl-
1-methyl- Hz, 1H), 7.96-7.90 IH-pyrazol- 1H- (m, 2H), 7.66 (s, 1H),
4-
1-697 66c pyrazole-4- 494.6 5.89 (s, 1H), 4.43 (d, P yl)methyl)pi carbaldehyd J = 3.60 Hz, 1H), peridin-4- e 4.23-3.85 (m, 5H), yl)-2- 3.26-3.14 (m, 4H), methylquino 2.68-2.61 (m, 7H), lin-3- 2.13-1.97 (m, 2H), yljpiperidin 1.00 (s, 3H), 0.78 (s, e-2, 6-dione, 3H), HC1
1H-NMR (400 MHz,
3-(6-(l-((3- DMSO-d6): 5 11.00 cyclopropyl (s, 1H), 10.10 (s, 1H), -1-methyl- 8.48 (s, 1H), 8.06 (t, J IH-pyrazol- = 8.40 Hz, 1H), 7.93 5-
3- (d, 1 = 8.80 Hz, 1H), yljmethyl)- cyclopropyl- 6.38 (s, 1H), 5.95 (s,
4-hydroxy- 1-methyl- 1H), 4.45-4.40 (m, 3,3-
1-749 66c 1H- 534.58 2H), 3.93 (s, 3H), P dimethylpip pyrazole-5- 3.37-3.40 (m, 3H), eridin-4-yl)- carbaldehyd 3.08-3.04 (m, 1H),
5-fluoro-2- e ALD-44 2.78-2.68 (m, 1H), methylquino 2.68-2.66 (m, 4H), lin-3- 2.65-2.51 (m, 3H), yl)piperidin 2.15-1.86 (m, 3H), e-2, 6-dione, 1.09 (s, 3H), 0.89- HC1 0 85 (m 2H) 0 80 (s 3H), 0.67-0.63 (m, 2H).
1H-NMR (400 MHz, DMSO-d6): 5 11.02 (s, 1H), 10.23 (s, 1H), 9.00 (t, J = 2.00 Hz,
3-(5-fluoro- 1H), 8.74 (t, J = 4.00 6-(4- Hz, 1H), 8.54 (s, 1H), hydroxy- 8.14 (t, J = 8.80 Hz, 3,3- 1H), 8.02-7.96 (m, dimethyl-1- 2H), 7.74 (d, J = 8.00 (pyridin-2- Hz, 1H), 7.56-7.41 picolinaldeh ylmethyl)pi 1-221 51d 477.52 (m, 1H), 6.03 (s, 1H), P yde peridin-4- 4.57 (s, 2H), 4.53- yljquinolin- 4.42 (m, 2H), 3.51- 3- 3.34 (m, 3H), 2.99 (d, yljpiperidin J = 12.00 Hz, 1H), e-2, 6-dione, 2.79-2.75 (m, 1H), HC1 2.66-2.61 (m, 1H), 2.17-2.16 (m, 1H),
2.15-2.03 (m, 1H),
1.13 (s, 3H), 0.76 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 10.85 (s, 1H),
3-(5-fluoro- 8.92-8.80 (m, 3H), 6-(4-
8.42 (s, 1H), 8.11- hydroxy- 8.09 (m, 3H), 7.92 (d, 3,3- J = 8.80 Hz, 1H), dimethyl-1- 5.99 (s, 1H), 4.62- (pyridin-4- isonicotinal 4.55 (m, 2H), 4.28- ylmethyl)pi 1-225 51d 477.49 P dehyde 4.25 (m, 2H), 3.46- peridin-4- 3.40 (m, 3H), 3.32 (t, yl)quinolin- J = 11.20 Hz, 1H), 3- 2.84-2.75 (m, 2H), yljpiperidin 2.74-2.65 (m, 1H), e-2, 6-dione, 2.34-2.33 (m, 1H), HC1
2.15-2.01 (m, 1H),
1.12 (s, 3H), 0.76 (s, 3H). _
3-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 11.14
1-methyl- hydroxy- (s, 1H), 11.00 (s, 1H), 1H- 3,3- 9.23 (s, 1H), 8.52 (s,
1-793 66c imidazole-5- 494.6 P dimethyl-1- 1H), 8.15-8.11 (m, carbaldehyd ((1-methyl- 2H), 7.96 (s, 1H), e 1H- 6.02 (s, 1H), 4.56 (s, imidazol-5- 2H), 4.45-4.42 (m, yl)methyl)pi 1H), 3.84 (s, 3H), peridin-4- 3.58 (s, 3H), 3.47- yl)-2- 3.34 (m, 1H), 3.12 (d, methylquino J = 11.60 Hz, 1H), lin-3- 2.93-2.80 (m, 4H), yljpiperidin 2.68-2.51 (m, 2H), e-2, 6-dione, 2.14-2.11 (m, 1H), HC1 2.03-2.01 (m, 1H), 1.24 (s, 3 H), 0.80 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00
3-(6-(l- (s, 1H), 9.64 (s, 1H), (d,4- 8.91 (s, 1H), 8.39 (s, dimethyl-
1H), 8.07 (t, J = 8.80 IH-pyrazol- Hz, 1H), 7.91 (d, J = 9.20 Hz, 1H), 7.41 (s, yl)methyl)- 1,4- 1H), 5.93 (s, 1H),
4-hydroxy- dimethyl- 4.54 (q, J = 4.80 Hz, 3,3- 1H-
1-858 51d 494.55 2H), 4.25 (d, J = 4.80 P dimethylpip pyrazole-5- Hz, 1H), 3.95 (s, 3H), eridin-4-yl)- carbaldehyd 3.39-3.21 (m, 5H), e 2.77-2.73 (m, 1H), fluoroquinol 2.65 (t, J = 2.00 Hz, in-3- 1H), 2.51-2.48 (m, yl)piperidin 1H), 2.14-2.11 (m, e-2, 6-dione, 4H), 2.04-2.02 (m, HC1 1H), 1.12 (s, 3H), 0.83 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.00
3-(6-(l-(3- (s, 1H), 9.80 (s, 2H), (1,2,4- 8.92 (d, J = 1.60 Hz, oxadiazol-3- 1H), 8.39 (s, 2H), yl)benzyl)- 8.17 (d, J = 8.00 Hz,
4-hydroxy- 1H), 8.07 (d, J = 8.80
3-(l,2,4- 3,3- Hz, 1H), 7.95-7.90 oxadiazol-3- dimethylpip (m, 2H), 7.73 (t, J =
1-348 51d yl)benzalde 544.54 P eridin-4-yl)- 7.60 Hz, 1H), 5.94 (s, hyde ALD- 1H), 4.56 (d, J = 4.00 43 fluoroquinol Hz, 2H), 4.27-4.22 in-3- (m, 1H), 3.72-3.40 yl)piperidin (m, 4H), 3.01-2.98 e-2, 6-dione, (m, 1H), 2.78-2.51 HC1 (m, 3H), 2.14-2.00 (m, 2H), 1.08 (s, 3H), 0.79 (s, 3H). _ l-(6-(l-(4- 1H-NMR (400 MHz,
4-(l,2,4- (1,2,4- DMSO-d6): 5 10.61
1-337 INT-S2 oxadiazol-3- 545.53 P oxadiazol-3- (s, 1H), 9.71 (s, 1H), yl)benzalde yl)benzyl)- 8 97 (s 1H) 8 33 (s 4-hydroxy- hyde ALD- 1H), 8.09 (t, J = 8.80
3,3- 107 Hz, 1H), 8.03 (d, J = dimethylpip 8.00 Hz, 2H), 7.85 (d, eridin-4-yl)- J = 8.80 Hz. 1H),
5- 7.58 (d, J = 8.00 Hz, fluoroquinol 2H), 5.16 (s, 1H), in-3- 4.01 (t, J = 7.20 Hz, yl)di hydrop 2H), 3.67 (d, J = yrimidine- 14.00 Hz, 1H), 3.55 2,4(1H,3H)- (d, J = 14.00 Hz, 1H), dione 3.32 (s, 1H), 2.80 (t, J = 6.80 Hz, 2H), 2.71- 2.67 (m, 1H), 2.62-
2.59 (m, 2H), 2.20 (d, J = 10.40 Hz, 1H), 1.74 (d, J = 13.60 Hz, 1H), 1.03 (s, 3H), 0.69 (s, 3H).
1H-NMR (400 MHz,
3-(6-(l- DMSO-d6): 5 10.98 ((1,3- (s, 1H), 8.85 (s, 1H), dimethyl- 8.32 (s, 1H), 8.11- IH-pyrazol- 8.07 (m, 1H), 7.84 (d, J = 8.80 Hz, 1H),
1,3- yljmethyl)- 5.93 (s, 1H), 5.14 (s, dimethyl-
4-hydroxy- 1H), 4.23 (q, J = 4.80 1H- 3,3- 1-796 51d 492.53 Hz, 1H), 3.77 (s, 3H), P pyrazole-5- dimethylpip 3.46 (s, 2H), 3.12- carbaldehyd eridin-4-yl)- 3.05 (m, 1H), 2.80- e
5- 2.59 (m, 4H), 2.51- fluoroquinol 2.47 (m, 2H), 2.20- in-3- 1.96 (m, 5H), 1.69 (d, yljpiperidin J = 13.60 Hz, 1H), e-2, 6-dione 0.96 (s, 3H), 0.70 (s, 3H).
1H-NMR (400 MHz,
3-((4-(3- DMSO-d6): 5 11.49 (2,6- (s, 1H), 10.94 (s, 1H), dioxopiperi 8.23 (t, J = 5.60 Hz, din-3-yl)-5- 2H), 8.03 (t, J = 8.80 fluoro-2- Hz, 1H), 7.73 (d, J = methylquino
3-formyl- 9.20 Hz, 1H), 7.53 (d, lin-6-yl)-4- IH-indole- J = 8.40 Hz, 1H), hydroxy- 1-538 66c 554.4 M 7- 7.46-7.42 (m, 2H), 3,3- carbonitrile 5.02 (d, J = 4.40 Hz, dimethylpip 1H), 4.34 (dd, J = eridin-1- 4.40, 12.40 Hz, 1H), yl)methyl)- 3.70 (s, 2H), 3.13 (s, IH-indole- 1H), 2.84 (d, J = 7-
13.20 Hz, 2H), 2.75 carbonitrile (t J = 9 60 Hz 5H) 2.25 (d, J = 10.40 Hz, lH), 2.10 (d, J = 14.80 Hz, 1H), 1.86 (s, 2H), 1.76 (s, 1H), 0.95 (d, J = 3.20 Hz, 3H), 0.66 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99
3-(6-(l-(4- (s, 1H), 8.86 (s, 1H), (4- 8.34 (s, 1H), 8.07 (t, J acetylpipera = 8.40 Hz, 1H), 7.86 zin-1- (d, J = 8.80 Hz, 1H), yl)benzyl)- 7.40-7.29 (m, 2H),
4-(4-
4-hydroxy- 6.98-6.95 (m, 2H), acetylpipera 3,3- 5.08 (s, 1H), 4.23 (q,
1-438 51d zin-1- 602.63 P dimethylpip J = 4.80 Hz, 1H), yl)benzalde eridin-4-yl)- 3.68-3.58 (m, 4H), hyde
5- 3.37-3.32 (m, 2H), fluoroquinol 3.19-3.13 (m, 6H), in-3- 2.78-2.59 (m, 5H), yljpiperidin 2.48-2.33 (m, 2H), e-2, 6-dione 2.15-2.12 (m, 1H), 2.05 (s, 3H), 1.00 (s, 3H), 0.71 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J =
3-(5-fluoro- 2.00 Hz, 1H), 8.53 (d, 6-(4- J = 1.20 Hz, 1H), hydroxy-1- 8.33 (s, 1H), 8.08 (t, J (isoxazol-5- = 8.80 Hz, 1H), 7.84 ylmethyl)- (d, J = 9.20 Hz, 1H), isoxazole-5- 3,3- 6.42 (d, J = 1.60 Hz,
1-832 51d carbaldehyd 467.3 P dimethylpip lH), 5.13 (s, 1H), e eridin-4- 4.23 (q, J = 4.80 Hz, yl)quinolin- 1H), 3.76 (s, 2H), 3- 3.33-3.13 (m, 1H), yljpiperidin 2.78-2.59 (m, 6H), e-2, 6-dione 2.46-2.20 (m, 2H), 1.72-1.24 (m, 1H), 0.98 (s, 3H), 0.69 (s, 3H).
3-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 10.98 hydroxy- 1-methyl- (s, 1H), 8.85 (s, 1H), 3,3- 1H- 8.31 (s, 1H), 8.09 (t, J dimethyl-1- 1-847 51d imidazole-5- 480.52 = 8.80 Hz, 1H), 7.93 P ((1-methyl- carbaldehyd (s, 1H), 7.85 (d, J = 1H- e 9.20 Hz. 1H), 7.01 (s, imidazol-5- 1H), 5.22 (s, 1H), yl)methyl)pi 4 25 4 20 (m 1H) peridin-4- 3.75 (s, 3H), 3.57- yljquinolin- 3.33 (s, 4H), 3.12-
3- 3.06 (m, 1H), 2.80- yljpiperidin 2.72 (m, 2H), 2.64- e-2, 6-dione 2.47 (m, 2H), 2.34-
2.11 (m, 2H), 1.75- 1.71 (m, 1H), 0.95 (s, 3H), 0.71 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.95 (s, 1H), 8.20 (d, J =
3-(5-fluoro- 4.00 Hz, 1H), 8.04 (t, 6-(4- J = 8.80 Hz, 1H), hydroxy- 7.79-7.73 (m, 3H), 3,3-
7.39 (t, J = 7.60 Hz, dimethyl-1- 2H), 7.27 (t, J = 7.20 ((1-methyl- l-methyl-3- Hz, 1H), 6.63 (s, 1H), 3-phenyl- phenyl-lH- 5.12 (s, 1H), 4.37- IH-pyrazol-
1-635 66c pyrazole-5- 570.68 4.33 (m, 1H), 3.92 (s, P carbaldehyd 3H), 3.57 (s, 2H), yl)methyl)pi e 3.10 (s, 1H), 2.82 (d, peridin-4- J = 4.40 Hz, 1H), yi)-2- 2.65 (d, J = 12.40 Hz, methylquino 5H), 2.65 (s, 2H), lin-3-
2.34 (t, J = 1.60 Hz, yl)piperidin 1H), 2.11 (t, J = 4.80 e-2, 6-dione Hz, 1H), 1.70 (d, J = 13.20 Hz, 1H), 1.02 (s, 4H), 0.70 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 12.00 (bs, 1H), 10.98 (s, 1H), 10.13 (s, 1H),
3-(5-fluoro- 8.84 (d, J = 2.00 Hz, 6-(4- 1H), 8.33 (s, 1H), hydroxy-
8.10 (t, J = 8.80 Hz, 3,3- 1H), 7.84 (d, J = 9.20 dimethyl-1- Hz, 1H), 7.59 (d, J = (4-(thiazol-
8.40 Hz, 2H), 7.26-
2- 4-(thiazol-2- 7.24 (m, 3H), 6.89- ylamino)ben 1-415 51d ylamino)ben 574.51 P 6.88 (m, 1H), 5.09 (s, zyl)piperidi zaldehyde 1H), 4.25-4.21 (m, n-4- 1H), 3.53-3.137 (m, yl)quinolin- 2H), 3.19 (t, J =
3-
12.40 Hz, 1H), 2.76- yl)piperidin 2.59 (m, 3H), 2.49- e-2, 6-dione, 2.33 (m, 2H), 2.20- 0.61AcOH
2.12 (m, 2H), 1.91 (s, 3H), 1.72 (t, J = 12.40 Hz, 1H), 0.99 (s 3H) 0 67 (s 3H) 1H-NMR (400 MHz, DMSO-d6): 5 11.02 (s, 1H), 10.44 (s, 1H),
3-(6-(l-((3- 8.98 (s, 1H), 8.52 (s, cyclopropyl 1H), 8.13 (t, J = 8.80 -1-methyl- Hz, 1H), 7.96 (d, J = IH-pyrazol- 9.20 Hz, 1H), 6.41 (s, 5-
3- 1H), 5.96 (s, 1H), yl)methyl)- cyclopropyl- 4.76 (s, 2H), 4.44-
4-hydroxy- 1-methyl- 4.27 (m, 1H), 3.86 (s, 3,3-
1-418 51d 1H- 520.55 1H), 3.41 (s, 3H), P dimethylpip pyrazole-5- 3.27-3.24 (m, 1H), eridin-4-yl)- carbaldehyd 3.00 (d, J = 11.60 Hz,
5- e ALD-44 1H), 2.78-2.60 (m, fluoroquinol 5H), 2.16 (t, J = 5.20 in-3- Hz, 1H), 2.02 (d, J = yljpiperidin 12.00 Hz, 1H), 1.89- e-2, 6-dione, 1.85 (m, 1H), 1.12 (s, HC1 3H), 0.90-0.85 (m, 2H), 0.80 (s, 3H), 0.67-0.63 (m, 2H).
1H-NMR (400 MHz, DMSO-d6): 5 11.93 (s, 1H), 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz,
3-(5-fluoro- 1H), 8.33 (s, 1H), 6-(4- 8.10 (t, J = 8.80 Hz, hydroxy- 1H), 7.84 (d, J = 9.20 3,3- Hz, 1H), 7.46 (d, J = dimethyl-1- 8.40 Hz, 2H), 7.33- (4-(thiazol-
4-(thiazol-2- 7.30 (m, 3H), 7.23 (d,
2-
1-412 51d yloxy)benza 575.53 J = 3.60 Hz, 1H), P yloxy)benzy Idehyde 5.13 (s, 1H), 4.23 l)piperidin- (dd, 1 = 4.80, 12.80
4- Hz, 1H), 3.61-3.48 yljquinolin- (m, 2H), 3.36-3.16
3- (m, 1H). 2.76-2.48 yljpiperidin (m, 5H), 2.21-2.12 e-2, 6-dione (m, 2H), 1.92 (s, 3H), 1.76-1.72 (m, 1H), 1.01 (s, 3H), 0.69 (s, 3H).
3-(6-(l- 1H-NMR (400 MHz, ((1H- DMSO-d6): 5 12.60 pyrazol-5- (s, 1H), 10.98 (s, 1H),
1H- yl)methyl)- 8.84 (d, J = 2.00 Hz, pyrazole-5-
4-hydroxy- 1-822 51d 466.5 1H), 8.33 (t, J = 2.40 P carbaldehyd 3,3- Hz, 1H), 8.15 (s, 1H), e dimethylpip 8.08 (t, J = 8.80 Hz, eridin-4-yl)- 1H), 7.84 (d, J = 9.20 Hz 1H) 7 56 (s 1H) fluoroquinol 6.19 (s, 1H), 5.12 (s, in-3- 1H), 4.23 (d, J = 4.80 yl)piperidin Hz, 1H), 3.59 (s, 2H), e-2, 6-dione, 3.16-3.10 (m, 1H), 0.79Formic 2.81-2.72 (m, 2H), Acid 2.58 (d, J = 3.60 Hz, 2H), 2.47-2.43 (m, 2H), 2.26-2.20 (m, 1H), 2.15-2.08 (m, 1H), 1.72-1.69 (m, 1H), 0.97 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, 1H), 8.85 (s, 1H), 8.61 (s, 1H), 8.46 (s,
3-(5-fluoro- 1H), 8.33 (s, 1H), 6-(4-
8.10 (t, J = 8.80 Hz, hydroxy- 1H), 7.84 (d, J = 9.20 3,3- Hz, 1H), 7.77 (d, J = dimethyl-1- 8.40 Hz, 2H), 7.43 (d, (4-(oxazol-
4-(oxazol-4- J = 8.40 Hz, 2H),
4-
1-384 51d yl)benzalde 543.55 5.12 (s, 1H), 4.23 (d, P yl)benzyl)pi hyde J = 4.80 Hz, 1H), peridin-4- 3.63-3.59 (m, 1H), yl)quinolin-
3.49-3.46 (m, 1H), 3-
3.16 (m, 1H), 2.77- yljpiperidin 2.70 (m, 2H), 2.69- e-2, 6-dione, 2.60 (m, 2H), 2.46 O.VAcOH (m, 2H), 2.21-2.14 (m, 2H), 1.73-1.70 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 11.00 6-(4- (s, 1H), 10.07 (s, 1H), hydroxy- 8.90 (d, J = 2.00 Hz, 3,3- 1H), 8.39 (s, 1H), dimethyl-1- 8.08 (t, J = 8.40 Hz, ((1-methyl- l-methyl-3- 1H), 7.91 (d, J = 9.20 3- (trifluorome Hz, 1H), 7.18 (s, 1H), (trifluorome thyl)-lH- 5.96 (s, 1H), 4.62 (s, thyl)-lH- 1-851 51d 548.57 P pyrazole-5- 2H), 4.27-4.23 (m, pyrazol-5- carbaldehyd 1H), 4.07 (s, 3H), yl)methyl)pi e 3.50-3.35 (m, 4H), peridin-4-
3.15-3.12 (m, 1H), yl)quinolin- 2.77-2.67 (m, 2H), 3- 2.52-2.49 (m, 1H), yl)piperidin
2.15-2.05 (m, 2H), e-2, 6-dione,
1.10 (s, 3H), 1.10 (s, HC1 3H) 1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.87 (s, 1H),
3-(5-fluoro-
8.91 (s, 1H), 8.41 (s, 6-(4- 1H), 8.06 (t, J = 8.40 hydroxy- Hz, 1H), 7.91 (d, J = 3,3- 9.20 Hz, 1H), 7.82 (d, dimethyl-1- J = 2.00 Hz, 1H), ((1-methyl- 1-methyl- 6.55 (d, J = 2.00 Hz, IH-pyrazol- 1H- 1H), 5.87 (s, 1H), 3- 1-839 51d pyrazole-3- 480.52 4.34-4.41 (m, 3H), Q yl)methyl)pi carbaldehyd
3.91 (s, 3H), 3.37 (s, peridin-4- e 3H), 3.24 (t, J = yljquinolin- 11.60 Hz, 1H), 3.02- 3-
2.99 (m, 1H), 2.76- yljpiperidin 2.67 (m, 2H), 2.51- e-2, 6-dione, 2.48 (m, 1H), 2.16- HC1 2.14 (m, 1H), 2.08-
1.99 (m, 1H), 1.16 (m, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.98 (s, 1H), 11.00 (s, 1H),
3-(5-fluoro- 8.85 (s, 1H), 8.33 (s, 6-(4- 1H), 8.08 (t, J = 8.80 hydroxy- Hz, 1H), 7.84 (d, J = 3,3-
8.80 Hz, 1H), 7.60 (s, dimethyl-1- 1H), 7.34 (s, 1H), ((1-methyl- 1-methyl- 5.09 (s, 1H), 4.23 (d, IH-pyrazol- 1H- J = 4.80 Hz, 1H),
4- 1-752 51d pyrazole-4- 480.5 P 3.82 (s, 3H), 3.49- yl)methyl)pi carbaldehyd 3.34 (m, 2H), 3.12 (s, peridin-4- e 1H), 2.76 (t, J = 4.80 yljquinolin- Hz, 1H), 2.63 (d, J = 3-
2.80 Hz, 1H), 2.59- yl)piperidin 2.45 (m, 3H), 2.25- e-2, 6-dione, 2.11 (m, 2H), 1.92 (s, 0.75AcOH 3H), 1.72 (s, 1H), 0.97 (s, 3H), 0.70 (s, 3H).
3-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 11.00 hydroxy- (s, 1H), 10.19 (s, 1H), 3,3- l-methyl-3- 8.92 (s, 1H), 8.42 (s, dimethyl-1- phenyl-lH- 1H), 8.09 (1, 1 = 8.80 ((1-methyl- 1-419 51d pyrazole-5- 556.5 Hz, 1H), 7.92 (d, J = P 3-phenyl- carbaldehyd 8.80 Hz, 1H), 7.81 (d, IH-pyrazol- e J = 1.20 Hz, 2H), 5- 7.44 (t, J = 7.60 Hz, yl)methyl)pi 2H), 7.33 (t, J = 7.20 peridin-4- Hz 1H) 7 13 (s 1H) yl)quinolin- 5.96 (s, 1H), 4.59 (s, 3- 2H), 4.26 (d, J = 4.40 yljpiperidin Hz, 1H), 4.03 (s, 3H), e-2, 6-dione, 3.49-3.34 (m, 4H), HC1 3.16-3.13 (m, 1H), 2.76 (t, J = 4.40 Hz, 1H), 2.63 (d, J = 3.20 Hz, 1H), 2.51-2.49 (m, 1H), 2.16-2.12 (m, 1H), 2.06-2.02 (m, 1H), 1.13 (s, 3H), 0.83 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.43 (s, 1H), 9.16 (s, 1H), 8.85 (d,
3-(5-fluoro- J = 2.00 Hz, 1H), 6-(4- 8.33 (s, 1H), 8.10 (t, J hydroxy-1- = 8.80 Hz, 1H), 7.84 (4- (d, J = 9.20 Hz, 1H), (isoxazol-4- 7.68 (d, J = 8.00 Hz, yljbenzyl)- 4-(isoxazol- 2H), 7.43 (d, J = 8.00 3,3- 4-
1-375 51d 543.2 Hz, 2H), 5.12 (s, 1H), P dimethylpip yl)benzalde 4.25-4.24 (m, 1H), eridin-4- hyde 3.62 (d, J = 13.60 Hz, yl)quinolin- 1H), 3.51-3.46 (m, 3- 2H), 3.33-3.26 (m, yljpiperidin 1H), 2.80-2.45 (m, e-2, 6-dione, 4H), 2.20-2.15 (m, AcOH 3H), 1.87 (s, 3H),
1.74-1.69 (m, 1H),
1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 10.97 6-(4- (s, 1H), 8.85 (d, J = hydroxy- 2.00 Hz, 1H), 8.33 (s, 3,3- 1H), 8.16 (s, 1H), dimethyl-1- 8.10 (t, J = 8.40 Hz,
4-(l-methyl- (4-(l- 1H), 7.84 (d, J = 8.80
5- methyl-5- Hz, 1H), 7.40 (q, J = (trifluorome (trifluorome 8.00 Hz, 4H), 5.13 (s,
1-397 51d thyl)-lH- 624.2 P thyl)-lH- 1H), 4.25-4.21 (m, pyrazol-4- pyrazol-4- 1H), 3.96 (s, 3H), yl)benzalde yl)benzyl)pi 3.61-3.49 (m, 2H), hyde peridin-4- 3.19-3.16 (m, 1H), yljquinolin- 2.74-2.63 (m, 4H), 3- 2.34-2.16 (m, 2H), yljpiperidin 1.76-1.69 (m, 3H), e-2, 6-dione 1.02 (s, 3H), 0.69 (s, 3H) 1H-NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 10.16 (s, 1H),
3-(6-((R)-l- 9.78 (s, 1H), 8.91 (s, (4-(l,2,4- 1H), 8.42 (s, 1H), oxadiazol-3- 8.16 (d, J = 8.00 Hz, yl)benzyl)- 2H), 8.08 (t, J = 8.80
4-hydroxy- Hz, 1H), 7.92 (m,
4-(l,2,4- 3,3- 3H), 5.94 (s, 1H), oxadiazol-3- dimethylpip 4.52 (m, 2H), 4.26 (d,
1-124 (R)-51d yl)benzalde 544.54 eridin-4-yl)- J = 8.00 Hz, 1H), Q hyde ALD- 3.42 (s, 3H), 3.30 (t, J 107 fluoroquinol = 12.00 Hz, 1H), 2.91 in-3- (d, J = 12.00 Hz, 1H), yljpiperidin 2.82-2.70 (m, 1H), e-2, 6-dione, 2.68-2.52 (m, 1H), HC1 2.50-2.40 (m, 1H), 2.18-2.13 (m, 1H), 2.02 (m, 1H), 1.10 (s, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 9.70 (s, 1H),
3-(5-fluoro- 8.85 (d, J = 2.00 Hz, 6-(4- 1H), 8.34 (s, 1H), hydroxy- 8.17 (s, 1H), 8.10 (t, J 3,3- = 8.80 Hz, 1H), 7.93 dimethyl-1- (d, J = 8.00 Hz, 1H), (3-methyl- 7.84 (d, J = 9.20 Hz,
3-methyl-4-
4-( 1,2,4- 1H), 7.40 (d, J = 7.60 (1,2,4- oxadiazol-3- Hz, 2H), 5.14 (s, 1H),
1-378 51d oxadiazol-3- 556.5 P yl)benzyl)pi 4.25-4.21 (m, 1H), yl)benzalde peridin-4- 3.64 (d, J = 14.00 Hz, hyde yljquinolin- 1H), 3.51 (d, J = 3- 14.00 Hz, 1H), 3.33- yljpiperidin 3.15 (m, 1H), 2.8O- e-2, 6-dione, 2.71 (m, 2H), 2.68- O.VFormic 2.48 (m, 7H), 2.22- Acid 2.12 (m, 2H), 1.72 (d, J = 8.00 Hz, 1H), 1.03 (s, 3H), 0.68 (s, 3H).
3-(6-(l-((6- 1H-NMR (400 MHz, (1,2,4- DMSO-d6): 5 11.00 oxadiazol-3- (s, 1H), 9.78 (s, 1H),
6-(l,2,4- yljpyridin- 8.80 (m, 1H), 8.75 (s, oxadiazol-3-
3- 1-406 51d 545.53 1H), 8.34 (s, 1H), P yl)nicotinald yl)methyl)- 8.13-8.08 (m, 2H), ehyde
4-hydroxy- 8.02-8.00 (m, 1H), 3,3- 7.84 (d, J = 9.20 Hz, dimethylpip lH) 5 18 (s 1H) eridin-4-yl)- 4.25-4.21 (m, 1H), 5- 3.72 (d, J = 14.00 Hz, fluoroquinol 1H), 3.60 (d, J = in-3- 14.00 Hz, 1H), 3.29- yl)piperidin 3.17 (m, 1H), 2.77- e-2, 6-dione 2.64 (m, 2H), 2.63- 2.48 (m, 4H), 2.20-
2.10 (m, 2H), 1.76- 1.71 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.99
3-(6-(l-(4- (s, 1H), 9.61 (s, 1H), (1,2,3- 8.85 (d, J = 2.40 Hz, thiadiazol- 1H), 8.34 (s, 1H),
4-
8.11 (m, 3H), 7.84 (d, yljbenzyl)- J = 9.20 Hz, 1H),
4-hydroxy- 4-(l,2,3- 7.55 (d, J = 8.00 Hz, 3,3- thiadiazol-4- 2H), 5.14 (s, 1H), dimethylpip 1-381 51d yl)benzalde 560.9 P
4.26-4.21 (m, 1H), eridin-4-yl)- hyde ALD- 3.69-3.65 (m, 1H),
5- 69 3.56-3.52 (m, 1H), fluoroquinol 3.32-3.18 (m, 1H), in-3- 2.76-2.64 (m, 4H), yljpiperidin 2.34-2.16 (m, 2H), e-2, 6-dione,
I.90 (s, 2H), 1.74 (s, AcOH
2H), 1.03 (s, 3H), 0.69 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.62 (s, 1H), 10.04 (s, 1H),
(R)-l-(6-(l- 9.77 (s, 1H), 9.00 (d, (4-(l,2,4-
J = 2.40 Hz, 1H), oxadiazol-3- 8.35 (s, 1H), 8.15 (d, yljbcnzyl)- J = 5.60 Hz, 2H),
4-hydroxy- 8.04 (t, J = 8.80 Hz, 3,3- 4-(l,2,4- 1H), 7.92-7.88 (m, dimethylpip oxadiazol-3-
INT-(R)- 3H), 5.93 (s, 1H), eridin-4-yl)- 1-339 yl)benzalde 545.5 M
S2 4.55-4.48 (m, 2H),
5- hyde ALD- 4.00 (t, J = 6.40 Hz, fluoroquinol 107 2H), 3.41 (s, 3H), in-3- 3.30 (t, J = 11.60 Hz, yljdihydrop 1H), 2.92 (d, J = yrimidine-
II.60 Hz, 1H), 2.79 2,4(1H,3H)- (t, J = 6.80 Hz, 2H), dione, HC1 2.02 (d, J = 9.60 Hz, 1H), 1.08 (s, 3H), 0.77 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.62 (s, 1H), 9.77 (s, 1H), 9.00 (d, J = 2.40 Hz,
(S)-l-(6-(l- 1H), 8.35 (s, 1H), (4-(l,2,4- 8.09 (t, J = 8.80 Hz, oxadiazol-3- 2H), 8.03 (d, J = 8.00 yljbenzyl)- Hz, 1H), 7.85 (d, J =
4-hydroxy- 9.20 Hz, 1H), 7.58 (d, 3,3- 4-(l,2,4- J = 8.40 Hz, 2H), dimethylpip oxadiazol-3-
INT-(S)- 5.16 (s, 1H), 4.01 (t, J eridin-4-yl)- 1-338 yl)benzalde 545.5 M
S2 = 6.80 Hz, 2H), 3.67
5- hyde ALD- (d, J = 14.00 Hz, 1H), fluoroquinol 107 3.55 (d, J = 14.00 Hz, in-3- 1H), 3.20-3.14 (m, yl)di hydrop 1H), 2.79 (t, J = yrimidine- 22.00 Hz, 2H), 2.52- 2,4(1H,3H)- 2.50 (m, 3H), 2.20 (d, dione J = 10.80 Hz, 1H), 1.76 (d, J = 11.20 Hz, 1H), 1.01 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 10.99 (s, 1H), 9.62 (s, 1H),
3-(5-fluoro- 8.89 (d, J = 2.00 Hz, 6-((R)-4- 1H), 8.37 (s, 1H), hydroxy- 8.14-8.04 (m, 3H), 3,3- 4-(5-methyl- 7.91-7.84 (m, 3H), dimethylpip 1,2,4- 5.93 (s, 1H), 4.51 (s, eridin-4- 1-454 (R)-51d oxadiazol-3- 558.54 2H), 4.24 (dd, J = P yljquinolin- yl)benzalde 4.40, 12.60 Hz, 1H), 3- hyde 3.42-3.29 (m, 2H), yljpiperidin 2.98 (d, J = 11.60 Hz, e-2, 6-dione, 1H), 2.77-2.68 (m, HC1 5H), 2.60-2.50 (m, 3H), 2.14-2.00 (m, 2H), 1.07 (s, 3H), 0.79 (s, 3H).
3-(5-fluoro- 1H-NMR (400 MHz, 6-((R)-4- DMSO-d6): 5 10.99 hydroxy- (s, 1H), 8.85 (s, 1H), 3,3- 8.33 (s, 1H), 8.15-
4-(5-methyl- dimethyl-1- 8.07 (m, 2H), 7.96 (d, 1,3,4- (4-(5- J = 8.40 Hz, 2H),
1-324 (R)-51d oxadiazol-2- 558.54 P methyl- 7.84 (d, J = 8.40 Hz, yl)benzalde 1,3,4- 1H), 7.59 (d, J = 8.40 hyde oxadiazol-2- Hz, 2H), 5.15 (s, 1H), yl)benzyl)pi 4.21-4.26 (m, 1H), peridin-4- 3.65-3.69 (m, 1H), yljquinolin- 3 57 3 54 (m 1H)
Figure imgf000555_0001
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (s, 1H),
4-(4-(((4R)- 8.40 (s, 1H), 8.33 (s, 4-(3-(2,6- 1H), 8.12-8.08 (m, dioxopiperi 1H), 7.84 (d, J = 8.80 din-3-yl)-5- Hz, 1H), 7.62 (d, J = fluoroquinol
4-(4- 8.00 Hz. 2H), 7.48 (d, in-6-yl)-4- formylphen J = 8.00 Hz, 2H), hydroxy- yl)-l- 5.13 (s, 1H), 4.25- 3,3- 1-584 (R)-51d 581.51 P methyl-lH- 4.21 (m, 1H), 3.99 (s, dimethylpip pyrazole-3- 3H), 3.63-3.59 (m, eridin-1- carbonitrile 1H), 3.52-3.49 (m, yl)methyl)p 1H), 3.20-3.16 (m, henyl)-l- 1H), 2.77-2.60 (m, methyl-lH- 4H), 4.52-2.48 (m, pyrazole-3- 2H), 2.19-2.15 (m, carbonitrile 2H), 1.73-1.70 (m, 1H), 1.02 (s, 3H), 0.68 (s, 3H)
1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-l-(5- (s, 1H), 9.87 (s, 1H), fluoro-6-(4- 9.00 (d, J = 2.40 Hz, hydroxy- 1H), 8.35 (d, J = 2.00 3,3- Hz, 1H), 8.12 (d, J = dimethyl-1- 8.00 Hz, 2H), 8.05 (t, (4-(5- J = 8.80 Hz, 1H), methyl- 4-(5-methyl- 7.91-7.86 (m, 3H), 1,2,4- 1,2,4- 5.94 (s, 1H), 4.54-
INT-(R)- oxadiazol-3- 1-705 oxadiazol-3- 559.4 4.46 (m, 2H), 4.00 (t, G
S2 yl)benzyl)pi yl)benzalde J = 6.80 Hz, 2H), peridin-4- hyde 3.41 (s, 3H), 3.31 (t, J yljquinolin- = 11.20 Hz, 1H), 2.96
3- (d, J = 11.60 Hz, 1H), yl)di hydrop 2.80 (t, J = 6.80 Hz, yrimidine- 2H), 2.70-2.67 (m, 2,4(1H,3H)- 3H), 2.02 (d, J = dione, HC1 10.80 Hz, 1H), 1.08 (d, 1 = 2.80 Hz, 3H), 0.79 (s, 3H).
(R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 5 10.63 hydroxy- (s, 1H), 9.78 (s, 1H),
3-methyl-4- 3,3- 9.41 (s, 1H), 9.00 (s, (1,2,4- dimethyl-1- INT-(R)- 1H), 8.35 (d, J = 2.40
1-475 oxadiazol-3- 559.46 M (3-methyl- S2 Hz, 1H), 8.08-8.03 yl)benzalde 4-( 1,2,4- (m, 2H), 7.91 (d, J = hyde oxadiazol-3- 9.20 Hz, 1H), 7.70- yl)benzyl)pi 7.66 (m, 2H), 5.94 (s, peridin-4- 1H) 4 49 (d J = 4 00 yl)quinolin- Hz, 2H), 4.02-3.98
3- (m, 2H), 3.40-3.30 yljdihydrop (m, 4H), 3.03 (d, J = yrimidine- 12.00 Hz, 1H), 2.82-
2,4(1H,3H)- 2.79 (m, 2H), 2.63 (s, dione, HC1 3H), 2.05 (d, J =
13.60 Hz, 1H), 1.07 (s, 3H), 0.80 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.63 (s, 1H), 10.54 (s, 1H),
(R)-l-(6-(l- 9.84 (s, 1H), 9.09 (s, ((6-( 1,2,4- 1H), 9.01 (d, J = 2.40 oxadiazol-3- Hz, 1H), 8.45 (dd, J = yljpyridin- 2.00, 8.20 Hz, 1H),
3- 8.37 (d, J = 1.60 Hz, yljmethyl)- 1H), 8.24 (d, J = 8.40
4-hydroxy-
6-(l,2,4- Hz, 1H), 8.06 (t, J = 3,3-
INT-(R)- oxadiazol-3- 8.80 Hz, 1H), 7.91 (d, dimethylpip 1-473 546.2 G
S2 yl)nicotinald J = 9.20 Hz, 1H), eridin-4-yl)- ehyde 5.97 (s, 1H), 4.57 (q,
5- J = 6.00 Hz, 2H), fluoroquinol 4.01 (t, J = 6.80 Hz, in-3- 2H), 3.43-3.31 (m, yljdihydrop 4H), 2.96 (d, J = yrimidine-
11.60 Hz, 1H), 2.80 2,4(1H,3H)-
(t, J = 6.40 Hz, 2H), dione, HC1 2.03 (d, J = 9.20 Hz, 1H), 1.11 (s, 3H), 0.79 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-l-(6-(l- (s, 1H), 9.59 (s, 1H), (4-(lH- 9.00 (s, 1H), 8.35 (s, pyrazol-3- 1H), 8.06-8.04 (m, yljbenzyl)- 1H), 7.95-7.89 (m,
4-hydroxy- 3H), 7.78 (s, 1H), 3,3- 4-(lH- 7.70-7.68 (m, 2H), dimethylpip pyrazol-3-
INT-(R)- 6.80 (s, 1H), 5.92 (s, eridin-4-yl)- 1-734 yl)benzalde 543.46 M
S2 1H), 4.44-4.38 (m,
5- hyde ALD- 2H), 4.02-3.99 (m, fluoroquinol 80 3H), 3.28-3.25 (m, in-3- 4H), 2.96 (d, J = yljdihydrop 11.60 Hz, 1H), 2.80 yrimidine- (t, J = 6.80 Hz, 2H), 2,4(1H,3H)- 2.04-2.01 (m, 1H), dione, HC1 1.07 (s, 3H), 0.79 (s, 3H). 1H-NMR (400 MHz, DMS0-d6): 5 10.63 (s, 1H), 9.86 (s, 1H),
(R)-l-(6-(l- 9.00 (d, J = 2.40 Hz, (4-(3,5- 1H), 8.35 (d, J = 2.00 dimethyliso Hz, 1H), 8.05 (t, J = xazol-4- 8.40 Hz, 1H), 7.90 (d, yl)benzyl)- J = 9.20 Hz, 1H),
4-hydroxy- 7.78 (d, J = 8.40 Hz,
4-(3,5- 3,3- 2H), 7.53 (d, J = 8.40 dimethyliso dimethylpip INT-(R)- Hz, 2H), 5.95 (s, 1H),
1-471 xazol-4- 572.5 M eridin-4-yl)- S2 4.45 (s, 2H), 4.00 (t, J yl)benzalde
5- = 6.80 Hz, 2H), 3.81 hyde fluoroquinol (s, 3H), 3.31 (t, J = in-3- 11.20 Hz, 1H), 2.97 yljdihydrop (d, J = 11.60 Hz, 1H), yrimidine- 2.80 (t, J = 6.40 Hz, 2,4(1H,3H)- 2H), 2.45 (s, 3H), dione, HC1 2.28 (s, 3H), 2.03 (d, J = 9.60 Hz, 1H), 1.10 (s, 3H), 0.80 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.63 (4-(l,3- (s, 1H), 9.9 (bs, s), dimethyl- 9.01 (s, 1H), 8.36 (s, IH-pyrazol- 1H), 8.06-8.00 (m, 4- 2H), 7.95 (d, J = yljbenzyl)- 4-(l,3- 16.00 Hz, 1H), 7.68 4-hydroxy- dimethyl- (m, 2H), 7.55 (d, J = 3,3- IH-pyrazol- 7.20 Hz, 2H), 5.92 (s,
INT-(R)- dimethylpip 1-708 4- 571.5 1H), 4.44-4.38 (m, G
S2 eridin-4-yl)- yl)benzalde 2H), 4.02-3.99 (m, hyde ALD- 2H), 3.89-3.81 (m, fluoroquinol 55 3H), 3.39 (s, 3H), in-3- 3.27 (s, 1H), 2.95 (s, yl)di hydrop 1H), 2.80 (t, J = 6.80 yrimidine- Hz, 2H), 2.47 (s, 4H), 2,4(1H,3H)- 2.03 (d, J = 11.20 Hz, dione, HC1 1H), 1.09 (s, 3H), 0.79 (s, 3H).
(R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 5 10.63 hydroxy- (s, 1H), 10.09 (s, 1H),
4-(4- 3,3- 9.03 (s, 2H), 8.37 (s, methylthiaz dimethyl-1- INT-(R)- 1H), 8.05 (t, J = 8.80
1-479 ol-5- 574.44 M (4-(4- S2 Hz, 1H), 7.90 (d, J = yl)benzalde methylthiaz 9.20 Hz, 1H), 7.81 (d, hyde ol-5- J = 8.40 Hz, 2H), yl)benzyl)pi 7.64 (d, J = 8.00 Hz, peridin-4- 2H) 5 94 (s 1H) yl)quinolin- 4.47-4.43 (m,2H),
3- 4.01 (t, J = 6.40 Hz, yljdihydrop 2H), 3.41-3.27 (m, yrimidine- 4H), 2.94 (d, J = 2,4(1H,3H)- 11.20 Hz, 1H), 2.80 dione, HC1 (t, J = 6.80 Hz, 2H),
2.50 (s, 3H), 2.03 (d,
J = 11.20 Hz, 1H), 1.11 (s, 3H), 0.79 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (s, 1H),
(R)-4-(4- 8.84 (s, 1H), 8.32 (d, ((4-(3-(2,4-
J = 2.00 Hz, 1H), dioxotetrahy 8.09 (t, J = 8.80 Hz, dropyrimidi 1H), 7.84 (d, J = 8.40 n-l(2H)-yl)- Hz, 1H), 7.61 (d, J = 5- 8.40 Hz, 2H), 7.47 (d, fluoroquinol 4-(4- J = 8.00 Hz, 2H), in-6-yl)-4- formylphen 5.14 (s, 1H), 4.16- hydroxy- INT-(R)- yl)-l-
1-731 582.46 3.99 (m, 5H), 3.62 (d, M 3,3- S2 methyl-lH- J = 13.40 Hz, 1H), dimethylpip pyrazole-3-
3.51 (d, J = 13.40 Hz, eridin-1- carbonitrile 1H), 3.16 (t, J = yl)methyl)p 12.00 Hz, 1H), 2.80 henyl)-l- (t, J = 6.80 Hz, 2H), methyl-lH- 2.78-2.67 (m, 1H), pyrazole-3- 2.61-2.49 (m, 2H), carbonitrile, 2.01 (d, J = 11.20 Hz, HC1 1H), 1.72 (d, J =
13.20 Hz, 1H), 1.02 (s, 3H), 0.68 (s, 3H).
(R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 5 10.63 hydroxy- (s, 1H), 10.27 (s, 1H), 3,3- 9.08-9.00 (m, 2H), dimethyl-1- 8.50 (d, J = 8.00 Hz, ((6- 1H), 8.35 (d, J = 2.00 (trifluorome Hz, 1H), 8.10-8.04
6- thyljpyridin (m, 2H), 8.09 (d, J =
INT-(R)- (trifluorome -3- 1-819 546.43 8.00 Hz, 1H), 5.97 (s, M S2 thyl)nicotina yl)methyl)pi 1H), 4.59 (s, 2H), Idehyde peridin-4- 4.02-3.97 (m, 3H), yl)quinolin- 3.40-3.32 (m, 4H), 3- 3.00 (d, J = 11.60 Hz, yl)di hydrop 1H), 2.80 (t, J = 6.80 yrimidine- Hz, 2H), 1.09 (d, J = 2,4(1H,3H)- 2.80 Hz, 3H), 0.80 (s, dione, HC1 3H). 3-(6-((R)-l-
1H-NMR (400 MHz, ((6-( 1,2,4- DMSO-d6): 8 11.00 oxadiazol-3- (s, 1H), 9.84 (s, 2H), yljpyridin- 9.04 (s, 1H), 8.90 (s,
3- 1H), 8.38 (d, J = 6.40 yljmethyl)- Hz, 2H), 8.10-7.92
4-hydroxy- 6-(l,2,4- (m, 3H), 5.96 (s, 1H), 3,3- oxadiazol-3- 543.4
1-408 (R)-51d 4.24 (d, J = 8.40 Hz, dimethylpip yl)nicotinald (Negative) Q 2H), 3.96-3.92 (m, eridin-4-yl)- ehyde 1H), 3.39-3.05 (m,
5- 5H), 2.92-2.88 (m, fluoroquinol 1H), 2.67-2.60 (m, in-3- 2H), 2.04-2.01 (m, yljpiperidin 2H), 1.08 (s, 3H), e-2, 6-dione, 0.80 (s, 3H). HC1
1H-NMR (400 MHz, DMSO-d6; 10.99 (s, 1H), 9.41 (s, 1H),
3-(5-fluoro- 8.88 (d, J = 2.00 Hz, 6-((R)-4- 1H), 8.36 (s, 1H), hydroxy- 8.13 (d, J = 8.00 Hz, 3,3- 2H), 8.06 (t, J = 8.80 dimethyl-1- Hz, 1H), 7.90 (d, J = (4-(5- 9.20 Hz, 1H), 7.83 (d, (methyl- Synthesized J = 8.00 Hz, 2H), d3)-l,2,4- using 5.93 (s, 1H), 4.52 (d,
1-674 (R)-51d 561.47 J oxadiazol-3- alkylation J = 4.40 Hz, 2H), yl)benzyl)pi method 4.24 (dd, J = 4.40, peridin-4- 12.60 Hz, 1H), 3.01 yl)quinolin- (d, J = 12.00 Hz, 1H), 3- 2.51-2.77 (m, 3H), yl)piperidin 2.01-2.14 (m, 2H), e-2, 6-dione, 1.06 (s, 3H), HC1 0.0779(s, 3H), (Note: two aliphatic proton overlapped with deutorated solvent).
(R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 8 10.63 hydroxy- (s, 1H), 9.91 (s, 1H), 3,3- 9.01 (d, J = 2.40 Hz, dimethyl-1- 1-methyl- 1H), 8.36 (d, J = 1.60 ((1-methyl- 1H- Hz, 1H), 8.04 (t, J =
INT-(R)- IH-pyrazol- 1-856 pyrazole-4- 481.45 8.80 Hz, 1H), 7.95 (s, M
S2
4- carbaldehyd 1H), 7.90 (d, J = 8.80 yl)methyl)pi e Hz, 1H), 7.66 (d, J = peridin-4- Hz, 1H), 5.88 (s, 1H), yl)quinolin- 4.24 (s, 2H), 4.03 (t, J 3- = 6.40 Hz, 2H), 3.89 yljdihydrop (s 3H) 3 34 3 26 (m yrimidine- 4H), 2.94 (d, J = 2,4(1H,3H)- 11.60 Hz, 1H), 2.80 dione, HC1 (t, J = 6.40 Hz, 2H), 2.00 (d, J = 13.20 Hz, 1H), 1.08 (s, 3H), 0.79 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 2H), 8.84 (d, J =
1.60 Hz, 1H), 8.32 (s,
3-(5-fluoro- 1H), 8.15 (s, 1H), 6-((R)-4- 8.09 (t, J = 8.80 Hz, hydroxy- 1H), 7.85-7.81 (m, 3,3- 3H), 7.51 (t, J = 7.60 dimethyl-1- Hz, 1H), 7.41 (d, J = ((4-(3- 4-(3-
7.60 Hz, 1H), 7.33 (t, (trifluorome (trifluorome J = 2.00 Hz, 1H), thyljphenyl) thyljphenyl) 6.43 (s, lH), 5.10 (s, -IH-pyrrol- 1-572 (R)-51d -IH-pyrrole- 609.52 G 1H), 4.22 (dd, J =
2- 2- 4.40, 12.60 Hz, 1H), yl)methyl)pi carbaldehyd 3.51-3.47 (m, 2H), peridin-4- e 3.12 (t, J = 12.40 Hz, yljquinolin- 1H), 2.76-2.67 (m,
3- 3H), 2.64-2.58 (m, yljpiperidin 3H), 2.25 (d, J = e-2, 6-dione,
10.80 Hz, 1H), 2.15- HC1
2.08 (m, 1H), 1.71 (d, J = 12.00 Hz, 1H), 0.99 (s, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 10.63
(R)-l-(5- (s, 1H), 10.20 (s, 1H), fluoro-6-(4- 9.01 (d, J = 2.40 Hz, hydroxy- 1H), 8.36 (d, J = 2.00 3,3- Hz, 1H), 8.18-8.13 dimethyl-1- (m, 3H), 8.04 (t, J = ((3-(3-
3-(3- 8.80 Hz, 1H), 7.90 (d, (trifluorome (trifluorome J = 8.80 Hz, 1H), thyljphenyl) thyl)phenyl) 7.73 (t, J = 8.00 Hz, -1H- INT-(R)-
1-884 -1H- 611.5 2H), 7.18 (s, 1H), M pyrazol-5- S2 pyrazole-5- 5.89 (s, 1H), 4.45 (d, yljmethyljpi carbaldehyd J = 2.40 Hz, 2H), peridin-4- e 4.01 (t, J = 6.40 Hz, yljquinolin- 2H), 3.40-3.31 (m, 3- 4H), 3.10 (d, J = yljdihydrop
11.60 Hz, 1H), 2.68 yrimidine- (t, J = 1.60 Hz, 2H), 2,4(1H,3H)- 2.02 (d, J = 9.60 Hz, dione, HC1 1H), 1.13 (s, 3H), 0 81 (s 3H) 1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(4- (s, 1H), 9.63 (s, 1H), hydroxy- 9.00 (s, 1H), 8.35 (s, 3,3- 1H), 8.05 (t, J = 8.80 dimethyl-1- Hz, 1H), 7.90 (d, J = (4-(l- 4-(l-methyl- 9.20 Hz, 1H), 7.81 (s, methyl-5-
5- 1H), 7.73 (d, J = 8.00 (trifluorome (trifluorome Hz, 2H), 7.51 (d, J = thyl)-lH- INT-(R)-
1-484 thyl)-lH- 625.46 8.00 Hz, 2H), 5.94 (s, M pyrazol-4- S2 pyrazol-4- 1H), 4.46 (s, 2H), yl)benzyl)pi yl)benzalde 4.06 (s, 3H), 4.00 (t, J peridin-4- hyde = 6.80 Hz, 2H), 3.39- yljquinolin- 3.31 (m, 4H), 3.00 (d, 3- J = 12.00 Hz, 1H), yljdihydrop 2.80 (t, J = 6.40 Hz, yrimidine- 2H), 2.04 (s, 1H), 2,4(1H,3H)- 1.08 (s, 3H), 0.80 (s, dione, HC1 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.63 (s, 1H), 8.97 (d, J =
2.40 Hz, 1H), 8.75 (d,
(R)-5-((4- J = Hz, 1H), 8.33 (d, (3-(2,4- J = 2.00 Hz, 1H), dioxotetrahy 8.10-8.01 (m, 3H), dropyrimidi 7.85 (d, J = 9.20 Hz, n-l(2H)-yl)- 1H), 5.18 (s, 1H), 5- 4.01 (t, J = 6.40 Hz,
5- fluoroquinol INT-(R)- 2H), 3.72 (d, J =
1-841 formylpicoli 503.43 M in-6-yl)-4- S2 14.40 Hz, 1H), 3.61 nonitrile hydroxy- (d, J = 14.40 Hz, 1H), 3,3- 3.16 (s, 1H), 2.80 (t, J dimethylpip = 6.40 Hz, 2H), 2.68 eridin-1- (t, J = 1.60 Hz, 1H), yl)methyl)pi 2.34 (t, J = 1.60 Hz, colinonitrile 2H), 2.15 (d, J =
10.40 Hz, 1H), 1.74 (t, J = 13.20 Hz, 1H), 1.08 (s, 3H), 0.68 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, ((1,3- DMSO-d6): 8 10.63 dimethyl- 1,3- (s, 1H), 10.12 (s, 1H), IH-pyrazol- dimethyl- 9.01 (d, J = 2.40 Hz, 5- INT-(R)- 1H- 1H), 8.36 (d, J = 2.00
1-855 495.47 M yljmethyl)- S2 pyrazole-5- Hz, 1H), 8.05 (t, J = 4-hydroxy- carbaldehyd 8.40 Hz, 1H), 7.91 (d, 3,3- e J = 9.20 Hz, 1H), dimethylpip 6.45 (s, 1H), 5.93 (s, eridin-4-yl)- 1H) 4 48 (d J = 4 00 5- Hz, 2H), 4.08-3.99 fluoroquinol (m, 2H), 3.87 (s, 3H), in-3- 3.42 (s, 3H), 3.28 (t, J yl)di hydrop = 1 1.20 Hz, 1H), 3.02 yrimidine- (d, J = 11.60 Hz, 1H), 2,4(1H,3H)- 2.80 (t, J = 6.80 Hz, dione, HC1 2H), 2.03 (s, 3H), 2.01 (d, J = 5.20 Hz. 1H), 1.10 (s, 3H), 0.80 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 11.55
(R)-l-(5- (s, 1H), 10.63 (s, 1H), fluoro-6-(4- 9.91 (s, 1H), 9.00 (d, hydroxy- J = 2.40 Hz, 1H), 3,3- 8.35 (d, J = 2.00 Hz, dimethyl-1- 1H), 8.28 (t, J = ((4-(3- 83.20 Hz, 1H), 8.03
4-(3- (trifluorome (t, J = 8.40 Hz, 3H),
(trifluorome thyljphenyl) 7.90 (d, J = 4.40 Hz, thyl)phenyl) -IH-pyrrol- INT-(R)- 2H), 7.88 (d, J = 4.00
1-569 -IH-pyrrole- 610.4 G
2- S2 Hz, 1H), 6.84 (d, J = 2- yl)methyl)pi 14.00 Hz, 1H), 5.88 carbaldehyd peridin-4- (s, 1H), 4.37 (d, J = e yljquinolin- 3.20 Hz, 2H), 4.00 (t,
3- 1 = 6.80 Hz, 2H), yl)di hydrop 3.25-3.02 (m, 5H), yrimidine- 3.00 (d, J = 12.00 Hz, 2,4(1H,3H)- 1H), 2.79 (t, J = 6.80 dione, HC1 Hz, 2H), 1.11 (s, 3H), 0.77 (t, J = 30.40 Hz, 3H). _
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.63 (d- (s, 1H), 10.06 (s, 1H), cyclopropyl 9.01 (d, J = 2.40 Hz, -1H- 1H), 8.36 (d, J = 2.00 pyrazol-5- Hz, 1H), 8.07-8.03 yljmethyl)- (m, 1H), 7.91 (d, J =
4-hydroxy- 8.80 Hz, 1H), 7.51 (d, cyclopropyl- 3,3- J = 1.60 Hz, 1H),
INT-(R)- 1H- dimethylpip 1-870 507.48 6.71 (d, J = 1.60 Hz, S2 pyrazole-5- Q eridin-4-yl)- 1H), 5.95 (s, 1H), carbaldehyd
5- 4.68-4.65 (m, 2H), e ALD-78 fluoroquinol 4.02-3.99 (m, 2H), in-3- 3.96-3.91 (m, 1H), yl)di hydrop 3.48-3.31 (m, 4H), yrimidine- 3.06-3.03 (m, 1H), 2,4(1H,3H)- 2.81 (t, J = 6.40 Hz, dione, HC1 2H), 2.04 (d, J = 13 60 Hz 1H) 1 20 1.09 (m, 7H), 0.81 (s, 3H).
1H-NMR (400 MHz,
3-(5-(((4R)- DMSO-d6): 5 10.98
4-(3-(2,6- (s, 2H), 8.85 (d, J = dioxopiperi 2.00 Hz, 1H), 8.33 (s, din-3-yl)-5- 1H), 8.11 (t, J = 9.20 fluoroquinol Hz, 1H), 7.99 (s, 1H), in-6-yl)-4- 3-(5-formyl- 7.87-7.83 (m, 3H), hydroxy- IH-pyrrol- 7.50-7.45 (m, 2H), 3,3- 1-559 (R)-51d 3- 566.49 7.35 (s, 1H), 6.45 (s, G dimethylpip yl)benzonitr lH), 5.12 (s, 1H), eridin-1- ile ALD-103 4.24-4.00 (m, 1H), yl)methyl)- 3.53 (s, 2H), 3.17- IH-pyrrol- 3.11 (m, 1H), 2.67- 3- 2.50 (m, 5H), 2.34- yljbenzonitr 2.14 (m, 2H), 1.82- ile 1.77 (m, 1H), 0.99 (s, 3H), 0.70 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, 1H), 10.45 (s, 1H), 8.96 (s, 1H), 8.48 (s,
3-(6-((R)-l- 1H), 8.11 (t, J = 8.40 (d- Hz, 1H), 7.94 (d, J = cyclopropyl
9.20 Hz, 1H), 7.50 (d, -1H- J = 1.60 Hz, 1H), pyrazol-5- 6.74 (d, J = 1.20 Hz, yljmethyl)- 1H), 5.90 (s, 1H),
4-hydroxy- cyclopropyl- 4.64 (s, 2H), 4.27 (d, 3,3- 1H-
1-835 (R)-51d 506.46 J = 4.80 Hz, 1H), G dimethylpip pyrazole-5- 3.99-3.95 (m, 2H), eridin-4-yl)- carbaldehyd 3.47 (m, 3H), 3.32 (t, e ALD-78 J = 7.20 Hz, 1H), fluoroquinol 3.01 (d, J = 5.60 Hz, in-3- 1H), 2.78-2.74 (m, yljpiperidin 1H), 2.63 (t, J = 7.20 e-2, 6-dione, Hz, 1H), 2.15 (d, J = HC1
5.20 Hz, 1H), 2.04 (d,
J = 9.60 Hz, 1H), 1.18-1.07 (m, 7H), 0.80 (s, 3H). _
(S)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- 3-(5-formyl- DMSO-d6): 5 11.48 hydroxy- IH-pyrrol- (s, 1H), 10.63 (s, 1H),
INT-(R)- 3,3- 1-689 3- 567.48 9.45 (s, 1H), 9.00 (d, N S2 dimethylpip yl)benzonitr J = 2.40 Hz, 1H), eridin-4- ile 8.34 (d, J = 2.40 Hz, yljquinolin- 1H), 8.07-8.00 (m, 3- 2H), 7.94-7.89 (m, yl)di hydrop 2H), 7.52-7.63 (m, yrimidine- 3H), 6.80 (s, 1H), 2,4(1H,3H)- 5.88 (s, 1H), 4.37 (d, dione, HC1 J = 2.00 Hz, 2H), 4.00 (t, J = 6.80 Hz, 2H), 3.52-3.34 (m, 3H), 3.04 (d, J = 11.60 Hz, 1H), 2.80 (t, J = 6.40 Hz, 2H), 2.19 (d, J = 10.40 Hz, 1H), 2.00 (d, J = 13.20 Hz, 1H), 1.08 (s, 3H), 0.82 (s, 3H). 1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 11.00 6-((R)-4- (s, 1H), 9.67 (s, 1H), hydroxy- 8.89 (s, 1H), 8.37 (s, 3,3- 1H), 8.19-8.12 (m, dimethyl-1- 3H), 8.04 (d, J = 8.40 ((3-(3- 3-(3- Hz, 1H), 7.85 (t, J = (trifluorome (trifluorome 52.40 Hz, 2H), 7.14 thyljphenyl) thyl)phenyl) (s, 1H), 5.89 (s, 1H), -1H- 1-852 (R)-51d -1H- 610.48 4.47 (s, 2H), 4.26- G pyrazol-5- pyrazole-5- 4.22 (m, 2H), 3.15 (d, yl)methyl)pi carbaldehyd J = 11.60 Hz, 1H), peridin-4- e 2.77-2.73 (m, 3H), yljquinolin- 2.52-2.50 (m, 2H), 3- 2.15 (s, 1H), 2.11 (m, yljpiperidin 2H), 2.02 (d, J = e-2, 6-dione, 14.00 Hz, 1H), 1.27- HC1 1.09 (m, 3H), 0.81 (m, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 12.80 (s, 1H), 11.00 (s, 1H),
3-(6-((R)-l- 9.66 (s, 1H), 8.90 (s, (4-(lH- 1H), 8.39 (s, 1H), pyrazol-3- 8.06 (t, J = 8.80 Hz, yljbenzyl)- 1H), 7.92-7.89 (m,
4-hydroxy- 4-(lH- 3H), 7.78 (d, J = 1.60 3,3- pyrazol-3- Hz, 1H), 7.69 (d, J = dimethylpip 1-603 (R)-51d yl)benzalde 542.5 8.00 Hz, 2H), 6.80 (d, Q eridin-4-yl)- hyde ALD- J = 2.00 Hz, 1H), 80 5.91 (s, 1H), 4.44- fluoroquinol 4.38 (m, 2H), 4.25 in-3- (dd, J = 4.80, 12.80 yl)piperidin Hz, 1H), 3.39-3.35 e-2, 6-dione (m, 3H), 3.30-3.25 (m, 1H), 2.96-2.93 (m 1H) 2 77 273 (m, 1H), 2.68-2.60 (m, 1H), 2.40-2.34 (m, 1H), 2.14-2.13 (m, 1H), 2.02 (d, J = 9.20 Hz, 1H), 1.07 (s, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.56
(R)-l-(6-(l- (s, 1H), 9.78 (s, 1H), (4-(l,2,4- 9.70 (s, 1H), 8.47 (s, oxadiazol-3- 1H), 8.19-8.17 (m, yl)benzyl)- 2H), 8.05 (d, J = 8.80
4-hydroxy- Hz, 1H), 7.89-7.83 3,3-
4-(l,2,4- (m, 3H), 5.94-5.92 dimethylpip
INT-(R)- oxadiazol-3- (m, 1H), 4.52 (s, 2H), eridin-4-yl)- 1-543 559.49 G
S6 yl)benzalde 3.99 (m, 1H), 3.70-
5-fluoro-2- hyde 3.67 (m, 1H), 333- methylquino 3.25 (m, 1H), 2.97- lin-3- 2.87 (m, 2H), 2.79- yljdihydrop 2.75 (m, 1H), 2.60 (s, yrimidine- 3H), 2.50-2.47 (m, 2,4(1H,3H)- 2H)2.03-2.00 (m, dione, HC1 1H), 1.07-1.06 (m, 3H), 0.78 (s, 3H).
(R)-l-(5- fluoro-6-(4- 1H-NMR (400 MHz, hydroxy- DMSO-d6): 8 10.57 3,3- (s, 1H), 9.99 (s, 1H), dimethyl-1- 8.48 (s, 1H), 8.05 (t, J (4- = 8.80 Hz, 1H), 7.95- (trifluorome 4- 7.83 (m, 5H), 5.93 (s, thyljbenzyl) INT-(R)- (trifluorome 557.48 1H), 4.54 (s, 2H),
1-546 G piperidin-4- S6 thyl)benzald (Negative) 3.99 (s, 1H), 3.70- yl)-2- ehyde 3.68 (m, 1H), 3.49- methylquino 3.27 (m, 4H), 2.95- lin-3- 2.76 (m, 3H), 2.68 (s, yljdihydrop 3H), 2.01 (d, J = yrimidine- 10.40 Hz, 1H), 1.07 2,4(1H,3H)- (s, 3H), 0.77 (s, 3H). dione, HC1
(S)-l-(6-(l- 1H-NMR (400 MHz, (4-(l,2,4- DMSO-d6): 5 10.56 oxadiazol-3- (s, 1H), 9.78 (s, 1H), yljbenzyl)- 9.68 (s, 1H), 8.46 (s,
4-(l,2,4-
4-hydroxy- 1H), 8.17 (d, J = 8.40
INT-(S)- oxadiazol-3- 557.5 3,3- 1-542 Hz, 2H), 8.04 (t, J = G S6 yl)benzalde (Negative) dimethylpip 8.80 Hz, 1H), 7.89- hyde eridin-4-yl)- 7.83 (m, 3H), 5.93 (d,
5-fluoro-2- J = 7.20 Hz, 1H), methylquino 4.52 (s, 2H), 3.99- lin-3- 3 96 (m 1H) 3 70 yl)dihydrop 3.67 (m, 1H), 3.34- yrimidine- 3.28 (m, 4H), 2.97-
2,4(1H,3H)- 2.79 (m, 3H), 2.60 (s, dione, HC1 3H), 2.01 (d, J = 12.40 Hz, 1H), 1.06 (s, 3H), 0.78 (s, 3H).
(S)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 8 10.56 hydroxy- (s, 1H), 9.68 (s, 1H), 3,3- 8.46 (s, 1H), 8.05 (t, J dimethyl-1- = 8.40 Hz, 1H), 7.91 (4- (s, 4H), 7.84 (d, J = (trifluorome 4- 8.80 Hz, 1H), 5.93 (d, thyl)benzyl) INT-(S)- (trifluorome 557.42 J = 8.00 Hz, 1H),
1-545 G piperidin-4- S6 thyl)benzald (Negative) 4.54 (s, 2H), 3.98- yl)-2- ehyde 3.97 (m, 1H), 3.70- methylquino 3.67 (m, 1H), 3.34- lin-3- 3.28 (m, 4H), 2.96- yl)dihydrop 2.87 (m, 3H), 2.60 (s, yrimidine- 3H), 2.01 (d, J = 2,4(1H,3H)- 12.40 Hz, 1H), 1.06 dione, HC1 (s, 3H), 0.78 (s, 3H). 1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 8 10.63 (3-chloro-4- (s, 1H), 9.71 (s, 1H), (1,3- 9.01 (d, J = 2.40 Hz, dimethyl- 1H), 8.35 (d, J = 2.40 IH-pyrazol- Hz, 1H), 8.06 (t, J = 4- 3-chloro-4- 8.80 Hz, 1H), 7.92- yl)benzyl)- (1,3- 7.90 (m, 2H), 7.84 (s,
4-hydroxy- dimethyl- [M+H, 1H), 7.57 (m, 1H), 3,3- INT-(R)- IH-pyrazol- M+2+H]+ 7.27-7.02 (m, 1H),
1-616 M dimethylpip S2 4- 605.3, 5.95 (s, 1H), 4.44 (d, eridin-4-yl)- yl)benzalde 607.3. J = 4.00 Hz, 2H),
5- hyde ALD- 4.01 (t, J = 6.80 Hz, fluoroquinol 85 2H), 3.83 (m, 4H), in-3- 3.32-3.29 (m, 2H), yljdihydrop 3.03 (d, J = 11.60 Hz, yrimidine- 1H), 2.80 (t, J = 6.40 2,4(1H,3H)- Hz, 2H), 2.14-2.02 dione, HC1 (m, 5H), 1.10 (s, 3H), 0.81 (s, 3H). _
(R)-l-(6-(l- 1H-NMR (400 MHz, ((2,2- DMSO-d6): 8 10.63
2,2- difluoroben (s, 1H), 9.55 (s, 1H), difluorobenz zo[d][l,3]di 9.00 (d, J = 2.40 Hz,
INT-(R)- o[d] [1 ,3]dio oxol-5- 1-790 557.3 1H), 8.35 (d, J = 2.00 G S2 xole-5- yl)methyl)- Hz, 1H), 8.05 (t, J = carbaldehyd
4-hydroxy- 8.40 Hz. 1H), 7.91 (d, e 3,3- J = 8.80 Hz, 1H), dimethylpip 7 79 (s 1H) 7 58 eridin-4-yl)- 7.51 (m, 2H), 5.93 (s, 5- 1H), 4.44 (s, 2H), fluoroquinol 4.00 (t, J = 6.80 Hz, in-3- 2H), 3.48-3.36 (s, yljdihydrop 2H), 2.95 (d, J = yrimidine- 12.00 Hz, 1H), 2.80 2,4(1H,3H)- (t, J = 6.80 Hz, 2H), dione, HC1 2.60-2.55 (m, 1H), 2.03 (s, 1H), 1.06 (s, 3H), 0.79 (s, 3H). 1H-NMR (400 MHz, l-(6-(l-(4- DMSO-d6): 5 10.57 (1,2,4- (s, 1H), 9.78 (s, 1H), oxadiazol-3- 9.65 (s, 1H), 8.47 (s, yljbenzyl)- 1H), 8.18 (d, J = 8.40
4-hydroxy- Hz, 2H), 8.07-8.03 3,3- (m, 1H), 7.88-7.83
4-(l,2,4- dimethylpip (m, 3H), 5.93 (d, J = oxadiazol-3- 557.2 eridin-4-yl)- 1-541 INT-S6 7.20 Hz, 1H), 4.53 (s, G yl)benzalde (Negative)
5-fluoro-2- 2H), 3.98 (s, 1H), hyde methylquino 3.70-3.67 (m, 1H), lin-3- 3.53-3.29 (m, 4H), yljdihydrop 3.01-2.72 (m, 3H), yrimidine- 2.60 (s, 3H), 2.02 (d, 2,4(1H,3H)- J = 13.20 Hz, 1H), dione, HC1 1.06 (s, 1 = 2.80 Hz, 3H), 0.78 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-4-(2- (s, 1H), 9.63 (s, 1H), chloro-4- 9.01 (d, J = 2.40 Hz, ((4-(3-(2,4- 1H), 8.36 (d, J = 2.00 dioxotetrahy Hz, 2H), 8.06 (t, J = dropyrimidi 8.40 Hz, 1H), 8.01 (d, n-l(2H)-yl)-
4-(2-chloro- J = 1.20 Hz, 1H), 5- 4- 7.91 (d, J = 8.80 Hz, fluoroquinol formylphen [M+H, 1H), 7.76 (dd, J = in-6-yl)-4-
INT-(R)- M+2+HJ+ 1.20, 8.00 Hz, 1H), hydroxy- 1-675 M
S2 methyl-lH- 616.46, 7.67 (d, J = 8.00 Hz, 3,3- pyrazole-3- 618.44. 1H), 5.96 (s, 1H), dimethylpip carbonitrile 4.48 (d, J = 4.00 Hz, eridin-1- ALD-86 2H), 4.04-3.99 (m, yl)methyl)p 5H), 3.40-3.32 (m, henyl)-l- 4H), 3.07 (d, J = methyl-lH-
11.60 Hz, 1H), 2.80 pyrazole-3- (t, J = 6.80 Hz, 2H), carbonitrile, 2.03 (d, J = 12.80 Hz, HC1 1H), 1.10 (s, 3H), 0.82 (s, 3H).
Figure imgf000569_0001
3- 2H), 4.45 (s, 2H), yl)di hydrop 4.00 (t, J = 6.80 Hz, yrimidine- 2H), 3.37-3.26 (m, 2,4(1H,3H)- 4H), 2.98 (d, J = dione, HC1 11.60 Hz, 1H), 2.80 (t, J = 6.80 Hz, 2H), 2.01 (d, J = 12.40 Hz, 1H), 1.06 (s, 3H), 0.79 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 8 10.61 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 8.08 (1, J
(R)-l-(5- = 8.80 Hz, 1H), 7.85 fluoro-6-(4- (d, J = 9.20 Hz, 1H), hydroxy- 7.40-7.35 (m, 4H), 3,3- 5.14 (s, 1H), 4.94 (q, dimethyl-1- J = 6.00 Hz, 2H), (4-(oxetan- 4.63 (t, J = 6.40 Hz, 3- 4-(oxetan-3-
INT-(R)- 2H), 4.25 (t, J = 7.60 yl)benzyl)pi 1-662 yl)benzalde 533.4 G
S2 Hz, 1H), 4.01 (t, J = peridin-4- hyde
6.80 Hz, 2H), 3.53 yl)quinolin- (m, 2H), 3.14 (1, 1 = 3- 12.00 Hz, 1H), 2.80 yljdihydrop (t, J = 6.80 Hz, 2H), yrimidine- 2.56-2.50 (m, 2H), 2,4(1H,3H)- 2.68-2.68 (m, 1H), dione 2.21 (d, J = 10.00 Hz, 1H), 1.71 (d, J =
13.20 Hz, 1H), 1.00 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 8 10.61
(R)-5-((4- (s, 1H), 8.97 (d, J = (3-(2,4- 2.40 Hz, 1H), 8.33 (d, dioxotetrahy J = 2.40 Hz, 1H), dropyrimidi 8.14-8.07 (m, 1H), n-l(2H)-yl)-
7.90-7.81 (m, 3H), 7.65 (d, J = 8.80 Hz, fluoroquinol
5-formyl-l- 1H), 5.15 (s, 1H), in-6-yl)-4-
INT-(R)- methyl-lH- 4.20 (s, 3H), 4.01 (t, J hydroxy- 1-824 556.46 G
S2 indazole-3- = 6.40 Hz, 2H), 3.78- 3,3- carbonitrile 3.61 (m, 2H), 3.17 (1, dimethylpip J = 11.60 Hz, 1H), eridin-1-
2.90-2.80 (m, 1H), yljmethyl)-
2.80 (1, 1 = 6.40 Hz, 1-methyl- 2H), 2.53-2.49 (m, 1H- 2H), 2.19 (d, J = 8.80 indazole-3- Hz, 1H), 1.73 (d, J = carbonitrile
12.80 Hz, 1H), 1.01 (s 3H) 0 67 (s 3H) (R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(l- DMSO-d6): 5 10.61 (3-fluoro-4- (s, 1H), 9.41 (s, 1H), (1,3,4- 8.97 (d, J = 2.40 Hz, oxadiazol-2- 1H), 8.33 (s, 1H), yljbenzyl)- 3-fluoro-4- 8.11-8.02 (m, 2H), 4-hydroxy- (1,3,4- 7.85 (d, J = 9.20 Hz, 3,3- INT-(R)- oxadiazol-2- 1H), 7.47 (t, J = 7.20
1-787 563.2 G dimethylpip S2 yl)benzalde Hz, 2H), 5.18 (s, 1H), eridin-4- hyde ALD- 4.01 (t, J = 6.40 Hz, yljquinolin- 76 2H), 3.99-3.56 (m, 3- 2H), 2.80 (t, J = 6.80 yljdihydrop Hz, 2H), 1.74 (d, J = yrimidine- 16.00 Hz, 4H), 1.24 2,4(1H,3H)- (s, 2H), 1.03 (s, 3H), dione 0.69 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(4- (s, 1H), 9.44 (s, 1H), hydroxy-1- 9.00 (s, 1H), 8.35 (d, (2-methoxy- J = 2.00 Hz, 1H), 4- 8.03 (t, J = 8.80 Hz, (trifluorome 1H), 7.91-7.83 (m,
2-methoxy- thyl)benzyl) 2H), 7.48-7.47 (m,
4-
INT-(R)- 2H), 5.92 (s, 1H),
1-795 (trifluorome 575.3 G dimethylpip S2 4.45 (d, J = 4.00 Hz, thyl)benzald eridin-4- 2H), 4.02-3.99 (m, ehyde yljquinolin- 5H), 3.40 (s, 3H), 3- 3.38-3.27 (m, 1H), yl)di hydrop 3.02 (d, J = 12.00 Hz, yrimidine- 1H), 2.80 (t, J = 6.80 2,4(1H,3H)- Hz, 2H), 1.99 (d, J = dione, HC1 10.80 Hz, 1H), 1.09 (s, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz,
(R)-2- DMSO-d6): 5 10.62 (difluoromet (s, 1H), 8.98 (s, 1H), hoxy)-4-((4- 8.34 (s, 1H), 8.10 (t, J (3-(2,4- = 8.80 Hz, 1H), 7.92- dioxotetrahy 7.84 (m, 2H), 7.51 (s, dropyrimidi 2- 1H), 7.45-7.41 (m, n-l(2H)-yl)- (difluoromet 1H), 5.19 (s, 1H), 5- INT-(R)- boxy) -4-
1-732 568.2 4.01 (t, J = 6.80 Hz, G fluoroquinol S2 formylbenzo 2H), 3.73 (d, J = in-6-yl)-4- nitrile ALD- 15.20 Hz, 1H), 3.55 hydroxy- 97 (d, J = 14.80 Hz, 1H), 3,3- 3.19 (t, J = 13.20 Hz, dimethylpip 1H), 2.82-2.79 (m, eridin-1- 2H), 2.70-2.47 (m, yl)methyl)b 4H), 2.14 (d, J = enzonitrile 10 40 Hz 1H) 1 74 (d, J = 13.20 Hz, 1H), 1.03 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(l- (s, 1H), 10.23 (s, 1H), (3-fluoro-4- 9.84 (s, 1H), 9.01 (s, (1,2,4- 1H), 8.36 (s, 1H), oxadiazol-3- 8.36-8.16 (m, 1H), yljbenzyl)- 3-fluoro-4- 8.08-8.03 (m, 1H), 4-hydroxy- (1,2,4- 7.95-7.89 (m, 2H), 3,3- INT-(R)- oxadiazol-3- 7.77-7.75 (m, 1H),
1-723 563.45 G dimethylpip S2 yl)benzalde 5.96 (s, 1H), 4.57- eridin-4- hyde ALD- 4.48 (m, 2H), 4.02- yl)quinolin- 94 3.99 (m, 2H), 3.35- 3- 3.29 (m, 5H), 2.94 (d, yljdihydrop J = 11.60 Hz, 1H), yrimidine- 2.82-2.79 (m, 2H), 2,4(1H,3H)- 2.03 (d, J = 9.60 Hz, dione, HC1 1H), 1.10 (m, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.63 (s, 1H), 9.83 (s, 1H),
(R)-l-(6-(l- 9.00 (s, 1H), 8.35 (s, (4-chloro-3- 1H), 8.05 (1, 1 = 8.80 (difluoromet Hz, 1H), 7.90 (d, J = hoxy)benzyl 8.80 Hz, 1H), 7.78- )-4- 7.75 (m, 2H), 7.61 hydroxy- (dd, J = 8.00 Hz, 1.60 3,3- 4-chloro-3- [M+H,M+ Hz, 1H), 7.31 (t, J = dimethylpip INT-(R)- (difluoromet 2+HJ + 72.8 Hz, 1H), 5.95 (s,
1-748 G eridin-4-yl)- S2 hoxy)benzal 577.5, 1H), 4.46-4.44 (m, 5- dehyde 579.4 2H), 4.00 (t, J = 6.40 fluoroquinol Hz, 2H), 3.38 (m, in-3- 2H), 3.32-3.26 (m, yljdihydrop 1H), 2.91 (d, J = yrimidine- 12.00 Hz, 1H), 2.80 2,4(1H,3H)- (t, J = 6.40 Hz, 2H), dione, HC1 2.68-2.67 (m, 2H), 2.02 (d, J = 10.40 Hz, 1H), 1.07 (s, 3H), 0.79 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, (4- 4- DMSO-d6): 8 10.63 (difluoromet (difluoromet (s, 1H), 10.33 (s, 1H),
INT-(R)- hoxy)-3- 1-597 hoxy)-3- 587.51 9.01 (d, J = 2.40 Hz, G S2 ethoxvbenz ethoxybenza 1H), 8.36 (d, J = 2.00 yi)-4-' Idehyde Hz, 1H), 8.05 (t, J = hydroxy- 8.80 Hz, 1H), 7.90 (d, 3,3- J = 9.20 Hz, 1H), dimethylpip 7.73 (s, 1H), 7.33- eridin-4-yl)- 6.96 (m, 3H), 5.90 (s, 5- 1H), 4.33-4.28 (m, fluoroquinol 2H), 4.15 (q, J = 6.80 in-3- Hz, 2H), 4.01 (t, J = yljdihydrop 6.80 Hz, 2H), 3.49- yrimidine- 3.35 (m, 3H), 3.26 (t, 2,4(1H,3H)- J = 11.60 Hz, 1H), dione, HC1 2.80 (t, J = 6.80 Hz,
3H), 2.01 (d, J = 14.00 Hz, 1H), 1.38 (t, J = 7.20 Hz, 3H), 1.10 (s, 3H), 0.77 (s, 3H). _
(R)-l-(6-(l- 1H-NMR (400 MHz, (3-chloro-4- DMSO-d6): 5 10.63 (1,2,4- (s, 1H), 10.03 (s, 1H), oxadiazol-3- 9.86 (s, 1H), 9.01 (s, yljbenzyl)- 1H), 8.36 (s, 1H),
4-hydroxy- 3-chloro-4- 8.12-8.04 (m, 3H), 3,3- (1,2,4- 7.92-7.87 (m, 2H), dimethylpip INT-(R)- oxadiazol-3- 5.96 (s, 1H), 4.51 (s,
1-712 579.43 M eridin-4-yl)- S2 yl)benzalde 2H), 4.02-3.99 (m,
5- hyde ALD- 2H), 3.36-3.31 (m, fluoroquinol 96 4H), 3.00 (d, J = in-3- 12.00 Hz, 1H), 2.82- yljdihydrop 2.79 (m, 2H), 2.03 (d, yrimidine- J = 10.40 Hz, 1H), 2,4(1H,3H)- 1.10 (s, 3H), 0.80 (s, dione, HC1 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-4-((4- (s, 1H), 9.40 (s, 1H), (3-(2,4- 9.00 (d, J = 2.40 Hz, dioxotetrahy 1H), 8.34 (d, J = 2.00 dropyrimidi Hz, 1H), 8.03 (t, J = n-l(2H)-yl)-
8.80 Hz, 1H), 7.90 (d, J = 9.20 Hz, 1H), fluoroquinol 7.81-7.58 (m, 4H), in-6-yl)-4- 4-formyl-3-
INT-(R)- 5.92 (s, 1H), 4.44 (d, hydroxy- 1-791 methoxyben 532.47 M
S2 J = 4.00 Hz, 1H), 3,3- zonitrile 4.02-3.96 (m, 5H), dimethylpip 3.65 (s, 3H), 3.26 (t, J eridin-1- = 11.20 Hz, 1H), 2.99 yl)methyl)- (d, J = 11.60 Hz, 1H), 3-
2.80 (t, J = 6.40 Hz, methoxyben 2H), 2.65-2.55 (m, zonitrile, 2H), 1.99 (d, J = HC1 10.40 Hz, 1H), 1.07 (s 3H) 0 78 (s 3H) 1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-l-(5- (s, 1H), 9.44 (s, 1H), fluoro-6-(4- 9.00 (d, J = 2.00 Hz, hydroxy- 1H), 8.34 (d, J = 1.60 3,3- Hz, 1H), 8.04 (t, J = dimethyl-1- 8.80 Hz, 1H), 7.90 (d, (4-(l- J = 8.80 Hz, 1H),
4-(l- (trifluorome 7.64 (dd, J = 8.00, (trifluorome thyl)cyclopr 27.20 Hz, 4H), 5.93
INT-(R)- thyl)cyclopr opyl)benzyl 1-578 585.3 (s, 1H), 4.43 (d, J = G
S2 opyl)benzal )piperidin- 4.00 Hz, 2H), 4.00 (t, dehyde 4- J = 6.80 Hz, 2H), ALD-29 yljquinolin- 3.30-3.27 (m, 3H), 3- 3.01 (d, J = 12.00 Hz, yljdihydrop 1H), 2.80 (t, J = 6.80 yrimidine- Hz, 2H), 2.02 (d, J = 2,4(1H,3H)- 12.00 Hz, 1H), 1.41- dione, HC1 1.37 (m, 2H), 1.24- 1.18 (m, 3H), 1.06 (s, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.63 (3-chloro-4- (s, 1H), 9.53 (s, 1H), (1,3,4- 9.14 (s,lH), 9.00 (d, J oxadiazol-2- = 2.00 Hz, 1H), 8.34 yl)benzyl)- (d, J = 2.00 Hz, 1H),
4-hydroxy- 3-chloro-4- 8.16-8.03 (m, 3H), 3,3- (1,3,4- [M+H,M+ 7.85 (d, J = 9.20 Hz, dimethylpip INT-(R)- oxadiazol-2- 2+HJ + 1H), 7.81 (d, J = 9.20
1-776 G eridin-4-yl)- S2 yl)benzalde 579.3,581. Hz, 1H), 5.98 (s, 1H),
5- hyde ALD- 2 4.01 (t, J = 6.80 Hz, fluoroquinol 77 2H), 3.52-3.41 (m, in-3- 2H), 3.33-3.09 (m, yljdihydrop 3H), 2.80 (t, J = 6.80 yrimidine- Hz, 2H), 2.53-2.48 2,4(1H,3H)- (m, 2H), 2.06-2.02 dione,HCl (m, 1H), 1.07 (s, 3H), 0.83 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, (3- DMSO-d6): 5 10.61 (cyclopropy (s, 1H),9.72 (s, 1H), Imethoxy)- 3- 8.97 (s, 1H), 8.33 (s, 4- (cyclopropyl 1H), 8.14-8.06 (m, (difluoromet INT-(R)- methoxy)-4- 1H), 7.85 (d, J = 9.20
1-619 613.4 G hoxy)benzyl S2 (difluoromet Hz, 1H), 7.56 (s, 1H), )-4- hoxy)benzal 7.34-7.05 (m, 2H), hydroxy- dehyde 5.15 (s, 1H), 4.01 (t, J 3,3- = 6.80 Hz, 2H), 3.93 dimethylpip (d, 1 = 6.80 Hz, 2H), eridin-4-yl)- 3 60 3 57 (m 1H)
Figure imgf000575_0001
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(4- (s, 1H), 10.09 (s, 1H), hydroxy- 9.01 (d, J = 2.40 Hz, 3,3- 1H), 8.36 (d, J = 2.00 dimethyl-1- Hz, 1H), 8.15 (s, 1H), ((l-(2,2,2- 8.04 (t, J = 8.80 Hz, l-(2,2,2- trifluoroethy 1H), 7.91-7.71 (m, trifluoroethy 1)-1H- 2H), 5.90 (s, 1H),
INT-(R)- 1)-1H- pyrazol-4- 1-843 549.2 5.24 (q, J = 9.20 Hz, G
S2 pyrazole-4- yl)methyl)pi 2H), 4.36-4.24 (m, carbaldehyd peridin-4- 2H), 4.00 (t, J = 6.80 e yljquinolin- Hz, 2H), 3.35-3.16 3- (m, 3H), 2.92 (d, J = yl)di hydrop 12.00 Hz, 2H), 2.80 yrimidine- (t, J = 6.40 Hz, 2H), 2,4(1H,3H)- 2.00 (d, J = 13.60 Hz, dione, HC1 1H), 1.08 (d, J = 2.40 Hz, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 8 10.63 fluoro-6-(4- (s, 1H), 9.60 (s, 1H), hydroxy-1- 9.00 (d, J = 2.40 Hz, ((1- 1H), 8.35 (d, J = 2.00 isopropyl- Hz, 1H), 8.07-8.01 IH-pyrazol- (m, 2H), 8.03 (d, J = 4- 1-isopropyl- 3.60 Hz, 1H), 7.67 (s, yl)methyl)- 1H- 1H), 5.89 (s, 1H),
INT-(R)- 3,3- 1-864 pyrazole-4- 509.56 4.59-4.52 (m, 1H), G
S2 dimethylpip carbaldehyd 4.25 (d, J = 4.00 Hz, eridin-4- e 2H), 4.00 (t, J = 6.80 yl)quinolin- Hz, 2H), 3.31-3.17 3- (m, 5H), 2.80 (t, J = yljdihydrop 6.80 Hz, 2H), 2.02- yrimidine- 1.99 (m, 1H), 1.44 (d, 2,4(1H,3H)- 1 = 6.80 Hz, 6H), dione, HC1 1.07 (d, J = 2.80 Hz, 3H), 0.80 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, ((1- DMSO-d6): 8 10.64 cyclopropyl (s, 1H), 10.08 (s, 1H), -1H- 9.02 (d, J = 2.40 Hz, pyrazol-4- 1H), 8.37 (d, J = 2.00 cyclopropyl- yljmethyl)- Hz, 1H), 8.07-8.02
INT-(R)- 1H-
4-hydroxy- 1-866 507.5 (m, 2H), 7.90 (d, J = G
S2 pyrazole-4- 3,3- 9.20 Hz, 1H), 7.66 (s, carbaldehyd dimethylpip 1H), 5.90 (s, 1H), e eridin-4-yl)- 4.21 (s, 1H), 4.20-
5- 4.03 (m, 2H), 3.99- fluoroquinol 3.79 (m, 2H), 3.83- in-3- 3 77 (m 1H) 3 36
Figure imgf000577_0001
dimethyl- 1- J = 2.00 Hz, 1H), (4- 8.15 (m, 1H), 8.07 (d, morpholino J = 8.80 Hz, 1H), benzyl)piper 7.84 (d, J = 9.20 Hz, idin-4- 1H), 7.20 (d, J = 8.40 yljquinolin- Hz, 2H), 6.91 (d, J = 3- 8.80 Hz, 2H), 5.10 (s, yl)di hydrop 1H), 4.00 (t, J = 6.80 yrimidine- Hz, 2H), 3.75-3.73 2,4(1H,3H)- (m, 4H), 3.49-3.38 dione, (m, 3H), 3.15-3.08 0.85Formic (m, 5H), 2.82-2.78 Acid (m, 2H), 2.69-2.67 (m, 1H), 2.50-2.16 (m, 2H), 1.69 (d, J = 13.20 Hz, 1H), 0.98 (d, 1 = 2.80 Hz, 3H), 0.98 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.64
(R)-l-(6-(l- (s, 1H), 10.06 (s, 1H), ((1-ethyl- 9.02 (d, J = 2.40 Hz, IH-pyrazol- 1H), 8.38 (s, 1H), 4- 8.03 (dd, J = 7.60, yl)methyl)- 17.00 Hz, 2H), 7.90 4-hydroxy- (d, J = 9.20 Hz, 1H), 3,3- 1 -ethyl- 1H- 7.69 (s, 1H), 5.90 (s, dimethylpip INT-(R)- pyrazole-4-
1-862 495.6 1H), 4.24-4.18 (m, G eridin-4-yl)- S2 carbaldehyd 4H), 4.15-3.99 (m, e ALD-101 2H), 3.36-3.17 (m, fluoroquinol 4H), 2.93 (d, J = in-3- 12.00 Hz, 1H), 2.82- yljdihydrop 2.51 (m, 2H), 2.34- yrimidine- 1.98 (m, 1H), 1.39 (t, 2,4(1H,3H)- J = 7.20 Hz, 3H), dione, HC1 1.09 (s, 3H), 0.79 (s, 3H). _
(R)-l-(6-(l- 1H-NMR (400 MHz, ((3-chloro- DMSO-d6): 5 10.64 1-methyl- (s, 1H), 10.41 (s, 1H), IH-pyrazol- 9.02 (d, J = 2.40 Hz, 4- 1H), 8.37 (d, J = 2.00
3-chloro-l- yl)methyl)- Hz, 1H), 8.17 (s, 1H), methyl-lH-
4-hydroxy- INT-(R)- 8.04 (t, J = 8.80 Hz,
1-871 pyrazole-4- 515 M 3,3- S2 1H), 7.90 (d, J = 9.20 carbaldehyd dimethylpip Hz, 1H), 5.90 (s, 1H), e ALD-102 eridin-4-yl)- 4.24-4.17 (m, 2H),
5- 4.05-3.99 (m, 3H), fluoroquinol 3.89 (s, 2H), 3.41- in-3- 3.16 (m, 4H), 3.01 (d, yljdihydrop J = 11 60 Hz 1H) yrimidine- 2.80 (t, J = 6.80 Hz, 2,4(1H,3H)- 2H), 2.05 (d, J = dione, HC1 23.20 Hz, 1H), 1.12 (d, J = 2.40 Hz, 3H), 0.80 (s, 3H). l-(6-(4- hydroxy- 1H-NMR (400 MHz, 3,3- DMSO-d6): 8 10.61 dimethyl-1- (d, J = 7.20 Hz, 1H), (4- 9.43 (s, 1H), 8.93 (s, (trifluorome 1H), 8.34 (s, 1H),
4- thyljbenzyl) 8.02-7.83 (m, 7H), (trifluorome piperidin-4- 1-816 INT-S7 527.45 5.68 (s, 1H), 4.55 (s, G thyl)benzald yljquinolin- 2H), 3.97 (t, J = 6.80 ehyde 3- Hz, 2H), 3.00-2.97 yljdihydrop (m, 2H), 2.80 (t, J = yrimidine- 6.40 Hz, 2H), 1.84 2,4(1H,3H)- (m, 2H), 1.24 (s, 3H), dione, 0.87 (s, 3H). 0.86HC1
1H-NMR (400 MHz, DMSO-d6): 8 10.63
(R)-l-(5- (s, 1H), 9.75 (s, 1H), fluoro-6-(l- 9.00 (d, J = 2.40 Hz, (d-(3- 1H), 8.80 (s, 1H), fluoropheny 8.35 (d, J = 2.00 Hz, 1)-1H- 1H), 8.07-8.03 (m, pyrazol-4- 2H), 7.90 (dd, J = l-(3- yljmethyl)- 9.20, Hz, 1H), 7.78- fluoropheny 4-hydroxy- 7.73 (m, 2H), 7.63-
INT-(R)- 1)-1H- 3,3- 1-838 561.2 7.58 (m, 1H), 7.25- G
S2 pyrazole-4- dimethylpip 7.20 (m, 1H), 5.91 (s, carbaldehyd eridin-4- 1H), 4.36 (s, 2H), e ALD-58 yljquinolin- 4.00 (t, J = 6.40 Hz, 3- 2H), 3.41-3.31 (m, yl)di hydrop 5H), 3.26 (d, J = yrimidine- 11.60 Hz, 1H), 3.08 2,4(1H,3H)- (t, J = 12.00 Hz, 2H), dione, HC1 2.02 (d, J = 10.00 Hz, 1H), 1.09 (s, 3H), 0.83 (s, 3H). _
(R)-4-(4- 1H-NMR (400 MHz, ((4-(3-(2,4- DMSO-d6): 8 10.63 dioxotetrahy (s, 1H), 10.04 (s, 1H),
4-(4-formyl- dropyrimidi 9.01 (d, J = 2.40 Hz, IH-pyrazol- n-l(2H)-yl)- INT-(R)- 1H), 8.92 (s, 1H),
1-849 568.5 G 5- S2 8.36 (d, J = 2.00 Hz, yl)benzonitr fluoroquinol 1H), 8.10-8.02 (m, lie in-6-yl)-4- 6H), 7.96-7.89 (m, hydroxy- 1H), 5.91 (s, 1H), 3,3- 4 36 (s 2H) 4 01 (t J dimethylpip = 6.80 Hz, 2H), 3.39- eridin-1- 3.30 (m, 4H), 3.25 (d, yljmethyl)- J = 11.60 Hz, 1H), IH-pyrazol- 3.07 (t, J = 11.60 Hz, 1- 2H), 2.02 (d, J = yljbenzonitr 10.00 Hz, 1H), 1.11 lie (s, 3H), 0.82 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 11.96 (s, 1H), 10.62 (s, 1H),
(R)-4-((4- 8.97 (s, 1H), 8.33 (s, (3-(2,4- 1H), 8.09 (t, J = 8.80 dioxotetrahy Hz, 1H), 7.85 (t, J = dropyrimidi 9.20 Hz, 1H), 7.70 (s, n-l(2H)-yl)- 1H), 7.27 (s, 1H), 5- 7.11 (d, J = 7.60 Hz, fluoroquinol 4-formyl-2- 1H), 5.17 (s, 1H), in-6-yl)-4- (2- 4.33-4.23 (m, 2H),
INT-(R)- hydroxy- 1-717 methoxyeth 576.2 4.01 (t, J = 6.80 Hz, G
S2 3,3- oxy)benzoni 2H), 3.74-3.70 (m, dimethylpip trile 3H), 3.66 (d, J = Hz, eridin-1- 1H), 3.37-3.33 (m, yl)methyl)- 2H), 3.22-3.17 (m, 2-(2- 3H), 2.82-2.67 (m, methoxyeth 3H), 2.50-2.35 (m, oxy)benzoni 1H), 2.17-2.16 (m, trile, AcOH 1H), 1.92-1.85 (s, 3H), 1.80-1.70 (m, 1H), 1.03 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.63
(R)-l-(6-(l- (s, 1H), 9.99 (s, 1H), (d-(3- 9.01 (s, 1H), 8.84 (s, chloropheny 1H), 8.36 (s, 1H),
1)-1H- 8.05 (t, J = 9.20 Hz, pyrazol-4- 2H), 7.97 (s, 1H), yljmethyl)- l-(3- 7.92-7.85 (m, 2H),
4-hydroxy- chloropheny 7.59 (t, J = 8.00 Hz, 3,3-
INT-(R)- 1)-1H- 1H), 7.45 (d, J = 8.00 dimethylpip 1-844 577.4 M S2 pyrazole-4- Hz, 1H), 5.91 (s, 1H), eridin-4-yl)- carbaldehyd 4.35 (s, 2H), 4.00 (t, J
5- e ALD-59 = 6.80 Hz. 2H), 3.41- fluoroquinol 3.34 (m, 4H), 3.26 (d, in-3- J = 11.20 Hz, 1H), yljdihydrop 3.06 (t, J = 12.00 Hz, yrimidine- 1H), 2.81-2.80 (m, 2,4(1H,3H)- 1H), 2.02 (d, J = dione, HC1
11.20 Hz, 1H), 1.10 (s, 3H), 0.82 (s, 3H). 1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(4- (s, 1H), 9.36 (s, 1H), hydroxy- 9.01 (s, 1H), 8.35 (s, 3,3- 1H), 8.03 (t, J = 8.80 dimethyl-1- Hz, 1H), 7.90 (d, J = ((l-(2,2,2- 8.80 Hz, lH), 7.13 (s, l-(2,2,2- trifluoroethy 1H), 6.95 (s, 1H), trifluoroethy 1)-1H- 5.86 (s, 1H), 5.01-
INT-(R)- 1)-1H- pyrrol-3- 1-833 548.4 4.94 (m, 2H), 4.22 (s, G
S2 pyrrole-3- yl)methyl)pi 2H), 4.00 (t, J = 6.80 carbaldehyd peridin-4- Hz, 3H), 3.32 (s, 3H), e ALD-61 yljquinolin- 3.19 (t, J = 11.60 Hz, 3- 1H), 2.93 (d, J = yl)di hydrop 12.00 Hz, 1H), 2.80 yrimidine- (t, J = 6.40 Hz, 2H), 2,4(1H,3H)- 2.00 (d, J = 10.00 Hz, dione, HC1 1H), 1.05 (s, 3H), 0.78 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.61
(R)-l-(5- (s, 1H), 9.43 (bs, 1H), fluoro-6-(4- 8.97 (s, 1H), 8.51 (s, hydroxy- 1H), 8.33 (s, 1H), 3,3- 8.09 (t, J = 8.80 Hz, dimethyl-1- 1H), 7.86-7.83 (m, ((6-(l- 1H), 7.81-7.78 (m, (trifluorome
6-(l- 1H), 7.54 (d, J = 8.00 thyl)cyclopr (trifluorome Hz, 1H), 5.15 (s, 1H), opyl)pyridin INT-(R)-
1-784 thyl)cyclopr 586.52 4.02-3.99 (m, 2H), G -3- S2 opyl)nicotin 3.61-3.50 (m, 2H), yl)methyl)pi aldehyde 3.13 (1, J = 13.60 Hz, peridin-4- 1H), 2.82-2.79 (m, yljquinolin- 2H), 2.68 (s, 1H), 3- 2.17 (d, J = 6.40 Hz, yljdihydrop 1H), 1.92 (s, 1H), yrimidine- 1.73 (1, J = 12.80 Hz, 2,4(1H,3H)- 2H), 1.40 (d, J = dione, HC1 18.80 Hz, 4H), 0.99 (s, 3H), 0.68 (s, 3H).
(R)-l-(4- 1H-NMR (400 MHz, ((4-(3-(2,4- DMSO-d6): 6 10.61 dioxotetrahy (s, 1H), 8.96 (d, J = l-(4- dropyrimidi 2.40 Hz, 1H), 8.32 (d, formylphen n-l(2H)-yl)- J = 2.00 Hz, 1H),
INT-(R)- yl)cycloprop 5- 1-622 542.2 8.08 (1, J = 8.80 Hz, G S2 ane-1- fluoroquinol 1H), 7.84 (d, J = 8.80 carbonitrile in-6-yl)-4- Hz, 1H), 7.38 (d, J =
ALD-99 hydroxy- 8.00 Hz, 2H), 7.31 (d, 3,3- J = 8.00 Hz, 2H), dimethylpip 5 13 (s 1H) 4 04 eridin-1- 3.99 (m, 2H), 3.57 (d, yl)methyl)p J = 13.60 Hz, 1H), henyl)cyclo 3.46 (d, J = 13.60 Hz, propane- 1- 1H), 3.12-3.08 (m, carbonitrile 1H), 2.80 (t, J = 6.80 Hz, 2H), 2.68-2.51 (m, 1H), 2.47-2.34 (m, 2H), 2.17 (d, J =
10.40 Hz, 1H), 1.76-
1.73 (m, 3H), 1.51 (t, 1 = 2.80 Hz, 2H), 1.00 (s, 3H), 0.67 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J =
2.40 Hz, 1H), 8.32 (d,
(R)-5-((4- J = 2.00 Hz, 1H), (3-(2,4- 8.10-8.06 (m, 1H), dioxotetrahy 7.84 (d, J = 8.80 Hz, dropyrimidi 1H), 7.65-7.61 (m, n-l(2H)-yl)- 2H), 7.26 (d, J = 8.40 Hz, lH), 5.14 (s, 1H), fluoroquinol 5-formyl-2- 4.27 (t, J = 4.40 Hz, in-6-yl)-4- (2-
INT-(R)- 2H), 4.00 (t, J = 6.80 hydroxy- 1-821 methoxyeth 576.5 G
S2 Hz, 2H), 3.71 (t, J = 3,3- oxy)benzoni
4.40 Hz, 2H), 3.60- dimethylpip trile
3.41 (m, 3H), 3.34 (d, eridin-1- J = 7.60 Hz, 3H), yljmethyl)- 3.17-3.10 (m, 1H), 2-(2-
2.80 (t, J = 6.40 Hz, methoxyeth 2H), 2.68 (t, J = 1.60 oxy)benzoni Hz, 1H), 2.34 (m, trile lH), 2.14 (d, J =
10.80 Hz, 1H), 1.75- 1.69 (m, 1H), 0.99 (s, 3H), 0.68 (s, 3H).
(R)-l-(5- 1H-NMR (400 MHz, fluoro-6-(4- DMSO-d6): 5 10.63 hydroxy-1- (s, 1H), 9.42 (s, 1H), (3-(2- 9.01 (d, J = 2.40 Hz,
3-(2- methoxyeth 1H), 8.35 (d, J = 2.00 methoxyeth oxy)-4- Hz, 1H), 8.05 (t, J = oxy)-4- (trifluorome INT-(R)- 8.80 Hz, 1H), 7.91 (d,
1-771 (trifluorome 619.3 G thyljbenzyl) S2 J = 9.20 Hz, 1H), thyl)benzald 7.77 (d, J = 8.00 Hz, ehyde dimethylpip 1H), 7.63 (s, 1H), (ALD-93) eridin-4- 7.35 (d, J= 7.60 Hz, yljquinolin- 1H), 5.96 (s, 1H), 3- 4.47 (d, J = 5.60 Hz, yljdihydrop 2H) 4 30 (d J = 3 20 yrimidine- Hz, 2H), 4.00 (t, J = 2,4(1H,3H)- 6.40 Hz, 2H), 3.74 (t, dione, HC1 J = 4.40 Hz, 2H), 3.60-3.29 (m, 7H), 2.97 (d, J = 11.20 Hz, 1H), 2.80 (t, J = 6.80 Hz, 2H), 2.09-2.02 (m, 1H), 1.06 (d, J = 2.80 Hz, 3H), 0.80 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J =
2.40 Hz, 1H), 8.32 (t,
(R)-l-(5- J = 2.00 Hz, 1H), fluoro-6-(4- 8.10-8.06 (m, 1H), hydroxy- 7.84 (d, J = 9.20 Hz, 3,3- 1H), 7.34 (d, J = 8.00 dimethyl-1- Hz, 2H), 7.22 (d, J = (4-(3-
8.40 Hz, 2H), 5.13 (s, methyloxeta 4-(3- 1H), 4.81 (d, J = 5.20 n-3- methyloxeta
INT-(R)- Hz, 2H), 4.54 (d, J = yl)benzyl)pi 1-737 n-3- 547.48 G
S2 5.60 Hz, 2H), 4.01 (t, peridin-4- yl)benzalde 1 = 6.80 Hz, 2H), yl)quinolin- hyde 3.55 (d, J = 13.60 Hz, 3- 1H), 3.46 (d, J = yljdihydrop
13.60 Hz, 1H), 3.14 yrimidine- (t, J = 12.00 Hz, 1H), 2,4(1H,3H)-
2.80 (d, J = 13.60 Hz, dione, 2H), 2.52-2.50 (m, 0.65AcOH 1H), 2.21 (t, J =
10.80 Hz, 1H), 1.72- 1.69 (m, 6H), 1.24 (s, 3H), 0.70 (s, 3H). l-(5-fluoro-
1H-NMR (400 MHz, 6-((R)-4- DMSO-d6): 5 10.63 hydroxy- (s, 1H), 10.21 (s, 1H), 3,3- 9.00 (d, J = 2.40 Hz, dimethyl-1- 1H), 8.36 (d, J = 2.00 ((S)-l-(4- Hz, 1H), 8.00-7.87 (trifluorome l-(4- (m, 6H), 5.85 (s, 1H), thyl)phenyl) INT-(R)- (trifluorome
1-825 559.3 4.74 (s, 1H), 4.01 (t, J I ethyl)piperi S2 thyl)phenyl) = 6.40 Hz, 2H), 3.68- din-4- ethan-l-one 3.51 (m, 2H), 3.31- yl)quinolin- 3.13 (m, 2H), 2.82- 3- 2.79 (m, 3H), 2.01 yl)di hydrop (m, 1H), 1.79 (m, yrimidine- 3H), 1.11 (m, 3H),
2,4(1H,3H)- 0.73 (s, 3H). dione
Figure imgf000584_0001
2,4(1H,3H)- 2.68 (t, J = 1.60 Hz, dione, HC1 3H), 2.03 (d, J = 14.00 Hz, 1H), 1.12 (s, 3H), 0.80 (s, 3H),
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.32 (d,
(R)-l-(6-(l- J = 2.00 Hz, 1H), (4-(2- 8.18 (s, 2H), 8.08 (t, J (dimethyla = 8.80 Hz, 1H), 7.84 mino)ethox (d, J = 9.20 Hz, 1H), y)benzyl)-4- 7.26 (d, J = 8.40 Hz, hydroxy- 2H), 6.91 (d, J = 8.80 3,3-
4-(2- Hz, 2H), 5.13 (s, 1H), dimethylpip (dimethylam 4.06 (t, J = 5.60 Hz, eridin-4-yl)- INT-(R)-
1-818 ino)ethoxy) 564.3 2H), 4.00 (t, J = 7.20 G 5- S2 benzaldehyd Hz, 2H), 3.52 (d, J = fluoroquinol e ALD-66 12.80 Hz, 1H), 3.41 in-3- (d, J = 13.20 Hz, 1H), yljdihydrop 3.24 (m, 1H), 2.80 (t, yrimidine- 1 = 6.80 Hz, 2H), 2,4(1H,3H)- 2.73-2.68 (m, 3H), dione, 2.50-2.43 (m, 2H), 2Formic 2.29 (s, 6H), 2.26- Acid 2.20 (m, 1H), 1.71 (d, J = 13.20 Hz, 1H), 0.98 (m, 3H), 0.67 (s, 3H),
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.63 ((5- (s, 1H), 9.41 (s, 1H), chloropyraz 9.00 (d, J = 2.40 Hz, olo[l,5- 1H), 8.84 (d, J = 7.60 a]pyridin-3- Hz, 1H), 8.34 (t, J = yl)methyl)- 5- 2.40 Hz, 3H), 8.04 (t,
4-hydroxy- chloropyraz J = 8.80 Hz, 1H), 3,3- olo[l,5- 7.90 (dd, J = 9.20,
INT-(R)- dimethylpip 1-857 ajpyridine- 551.3 Hz, 1H), 7.09 (dd, J = G
S2 eridin-4-yl)- 3- 2.40, 7.60 Hz, 1H),
5- carbaldehyd 5.89 (s, 1H), 4.61 (s, fluoroquinol e 2H), 4.00 (t, J = 7.20 in-3- Hz, 2H), 3.95 -3.54 yl)di hydrop (m, 1H), 3.33-3.28 yrimidine- (m, 3H), 2.81 (dd, J = 2,4(1H,3H)- 6.40, Hz, 1H), 2.79 dione, HC1 (t, J = 6.80 Hz, 2H), 2.08-2.00 (m, 1H), 1.06 (s, 3 H), 0.80 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.63 (s, 1H), 8.97 (d, J = 2.40 Hz, 1H), 8.33 (q, J = 0.40 Hz, 1H),
(R)-l-(5- 8.09 (t, J = 8.80 Hz, fluoro-6-(l- 1H), 7.85 (d, J = 8.80 (4-(3- Hz, 1H), 7.53 (d, J = fluorooxeta 7.60 Hz, 2H), 7.47 (d, n-3- J = 8.40 Hz, 2H), yljbenzyl)- 5.15 (s, 1H), 4.99-
4-(3- 4-hydroxy- 4.96 (m, 2H), 4.94- fluorooxetan 3,3- INT-(R)- 4.90 (m, 3H), 4.01 (t,
1-591 -3- 551.5 G dimethylpip S2 J = 6.80 Hz, 2H), yl)benzalde eridin-4- 3.61 (d, J = 13.60 Hz, hyde yl)quinolin- 1H), 3.51 (d, J = 3- 13.60 Hz, 1H), 3.34 yljdihydrop (s, 1H), 2.80 (t, J = yrimidine- 6.80 Hz, 2H), 2.68 (q, 2,4(1H,3H)- J = 1.60 Hz, 1H), dione 2.56-2.51 (m, 1H), 2.19 (dd, J = 10.40, Hz, 1H), 1.78-1.70 (m, 1H), 1.01 (d, J =
3.60 Hz, 3H), 0.68 (s,
3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.60
(R)-l-(5- (s, 1H), 8.96 (d, J = fluoro-6-(4- 2.40 Hz, 1H), 8.31 (s, hydroxy- 1H), 8.21 (s, 1H), 3,3- 8.08 (s, 1H), 7.84 (d, dimethyl-1- J = 8.80 Hz, 1H), ((3- 7.31-7.19 (m, 5H),
3- phenylcyclo 5.13 (s, 1H), 3.99 (t, J phenylcyclo butyl)methy INT-(R)- = 6.40 Hz, 2H), 3.29
1-875 butane- 1- 531.3 G l)piperidin- S2 (s, 2H), 3.12 (q, J = carbaldehyd 4- 13.20 Hz, 2H), 2.80 e ALD-35 yljquinolin- (t, J = 6.40 Hz, 2H), 3- 2.69 (d, J = 11.60 Hz, yljdihydrop 1H), 2.47 (t, J = 5.60 yrimidine- Hz, 2H), 2.34 (s, 3H),
2,4(1H,3H)- 2.22 (t, J = 13.60 Hz, dione 3H), 1.75-1.67 (m, 2H), 0.97 (s, 3H), 0.71 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.72 (s, 1H), 10.63 (s, 1H),
(R)-l-(5- 9.01 (d, J = 2.40 Hz, fluoro-6-(4- 1H), 8.67 (s, 1H), hydroxy-1- 8.37 (d, J = 2.40 Hz, (isothiazol- 1H), 8.05 (t, J = 8.80 5-ylmethyl)- Hz, 1H), 7.90 (d, J =
3,3- isothiazole- 8.80 Hz, 1H), 7.78 (s, dimethylpip INT-(R)- 5-
1-794 484.4 1H), 5.96 (s, 1H), M eridin-4- S2 carbaldehyd 4.83 (q, J = 5.20 Hz, yljquinolin- e 2H), 4.03-3.99 (m,
3- 2H), 3.41-3.28 (m, yljdihydrop 4H), 2.91 (d, J = yrimidine- 11.60 Hz, 1H), 2.81 2,4(1H,3H)- (t, J = 6.40 Hz, 2H), dione, HC1 2.03 (d, J = 9.20 Hz, 1H), 1.10 (d, J = 2.40 Hz, 3H), 0.79 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.61 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.33 (d, J = 2.00 Hz, 1H),
(R)-l-(5-
8.20 (s, 1H), 8.09 (t, J fluoro-6-(4- = 8.80 Hz, 1H), 7.84 hydroxy-1- (d, 1 = 8.80 Hz, 1H), (4-(3- 7.57 (d, J = 8.40 Hz, hydroxyoxet 2H), 7.38 (d, J = 8.00 an-3- Hz, 2H), 6.29 (s, 1H), yljbenzyl)- 4-(3- 5.12 (s, 1H), 4.77 (d, 3,3- hydroxyoxet
INT-(R)- J = 6.40 Hz, 2H), dimethylpip 1-709 an-3- 549.6 M
S2 4.70 (q, J = 2.40 Hz, eridin-4- yl)benzalde 2H), 4.01 (t, J = 1.60 yljquinolin- hyde Hz, 2H), 3.57 (d, J = 3- 2.00 Hz, 1H), 3.48 (d, yl)di hydrop J = 13.60 Hz, 2H), yrimidine- 3.33 (s, 2H), 2.80 (t, J 2,4(1H,3H)- = 6.80 Hz, 2H), 2.48 dione, (t, J = 11.20 Hz, 2H), Formic Acid
2.20 (d, J = 10.80 Hz, 1H), 1.71 (d, J = 13.60 Hz, 1H), 1.01 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz,
2- (2- DMSO-d6): 8 10.61 cyclopropox cyclopropox INT-(R)- (s, 1H), 8.97 (d, J =
1-845 y-4- 601.2 G y-4- S2 2.40 Hz, 1H), 8.33 (d, (trifluorome (trifluorome J = 2.00 Hz, 1H), thyl)benzald thyljbenzyl) 8 08 (t J = 8 80 Hz -4-hydroxy- ehyde ALD- 1H), 7.85 (d, J = 9.20 3,3- 37 Hz, 1H), 7.64 (d, J = dimethylpip 7.60 Hz, 1H), 7.53 (s, eridin-4-yl)- 1H), 7.36 (d, J = 7.60 5- Hz, 1H), 5.13 (s, 1H), fluoroquinol 4.05-3.99 (m, 3H), in-3- 3.50 (m, 1H), 3.18- yl)di hydrop 3.15 (m, 1H), 2.79- yrimidine- 2.60 (m, 6H), 2.19 (d, 2,4(1H,3H)- J = 10.40 Hz, 1H), dione 1.92-1.69 (m, 1H), 1.02 (m, 3H), 0.88- 0.83 (m, 7H).
1H-NMR (400 MHz, DMSO-d6 10.99 (s,
3-(6-(l-((4- 1H), 9.84 (s, 1H), (1,2,4- 9.78 (s, 1H), 8.89 (d, oxadiazol-3- J = 2.00 Hz, 1H), yl)phenyl)m 8.38 (s, 1H), 8.17 (d, ethyl-d)-4- J = 8.40 Hz, 2H), hydroxy- 8.07 (t, J = 8.80 Hz, 3,3- 1H), 7.91-7.88 (m, dimethylpip 1-561 51d No 545.3 3H), 5.93 (s, 1H), J eridin-4-yl)- 4.50 (dd, J = 5.20, 5- 16.20 Hz, 1H), 4.24 fluoroquinol idd. J = 4.80. 12.80 in-3- Hz, 1H), 3.56-3.40 yljpiperidin (m, 4H), 3.31-3.28 (s, e-2, 6-dione, 1H), 2.67-2.98 (m, HC1 3H), 2.08-2.03 (m, 2H), 1.08 (s, 3H), 0.078 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.62
(R)-l-(5- (s, 1H), 8.98 (d, J = fluoro-6-(4- 2.40 Hz, 1H), 8.34 (d, hydroxy-1- J = 2.40 Hz, 1H), (2-hydroxy- 8.09 (t, J = 8.80 Hz, 4- 1H), 7.86 (d, J = 9.20 (trifluorome 2- Hz, 1H), 7.39 (d, J = thyljbenzyl) cyclopropox 7.60 Hz, lH), 7.12 (d,
INT-(R)- y-4-
1-861 561.2 J = 8.40 Hz, 1H), G dimethylpip S2 (trifluorome 7.04 (s, 1H), 5.34 (s, eridin-4- thyl)benzald 1H), 4.01 (t, J = 6.40 yl)quinolin- ehyde Hz, 2H), 3.78 (d, J = 3- 7.20 Hz, 2H), 3.33 (s, yljdihydrop 4H), 2.81 (t, J = 6.40 yrimidine- Hz, 3H), 1.79 (d, J = 2,4(1H,3H)- 8.00 Hz, 2H), 1.01 (d, dione J = 3.20 Hz, 3H), 0 73 (s 3H) 1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(4- (s, 1H), 10.40 (s, 1H), hydroxy-1- 9.42 (s, 1H), 9.01 (s, (isothiazol- 1H), 8.86 (s, 1H), 4-ylmethyl)- 8.36 (s, 1H), 8.05 (m, 3,3- isothiazole- 1H), 7.90 (d, J = 8.80 dimethylpip INT-(R)- 4-
1-733 484.4 Hz, 1H), 5.92 (s, 1H), G eridin-4- S2 carbaldehyd 4.50 (m, 2H), 4.01 yl)quinolin- e (m, 2H), 3.45 (m, 3- 2H), 3.40-3.20 (m, yljdihydrop 2H), 2.92 (m, 1H), yrimidine- 2.81 (m, 2H), 1.98 m,
2,4(1H,3H)- lH),1.10 (s, 3H), 0.79 dione, HC1 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J = 2.40 Hz, 1H), 8.32 (d, J = 2.00 Hz, 1H),
(R)-l-(5- 8.21 (s, 1H), 8.11- fluoro-6-(4- 8.07 (m, 1H), 7.84 (d, hydroxy-1- J = 8.80 Hz, 1H), (4-(l- 7.45 (d, J = 8.40 Hz, hydroxycycl 2H), 7.32 (d, J = 8.00 obutyl)benz Hz, 2H), 5.12 (s, 1H), yl)-3,3- 4-(l- 4.00 (t, J = 7.60 Hz, dimethylpip hydroxycycl
INT-(R)- 2H), 3.56 (d, J = eridin-4- 1-656 obutyl)benz 547 G S2 13.60 Hz, 1H), 3.45 yljquinolin- aldehyde (d, J = 13.60 Hz, 2H), 3- ALD-38 3.14 (s, 2H), 2.80 (t, J yl)di hydrop = 6.80 Hz, 2H), 2.68 yrimidine- (d, J = 1.60 Hz, 1H), 2,4(1H,3H)- 2.67 (d, J = 1.60 Hz, dione, 1H), 2.52-2.47 (m, 0.88Formic 2H), 2.44-2.37 (m, Acid- 2H), 2.29-2.19 (m, 3H), 1.92 (m, 1H), 1.72-1.65 (m, 2H), 1.00 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, (3-chloro-4- DMSO-d6): 5 10.61
3-chloro-4- (3- (br s, 1H), 8.97 (d, J hydroxyoxet (3- = 3.00 Hz, 1H), 8.33 hydroxyoxet an-3- INT-(R)- (d, J = 2.00 Hz, 1H),
1-785 an-3- 583.2 G yljbenzyl)- S2 8.09 (t, J = 8.80 Hz, yl)benzalde 4-hydroxy- 1H), 7.85 (d, J = 8.80 hyde ALD- 3,3- Hz, 1H), 7.44-7.32 20 dimethylpip (m, 3H), 6.24 (s, 1H), eridin-4-yl)- 5 15 (s 1H) 5 08 (d 5- J = 7.20 Hz, 2H), fluoroquinol 4.70 (d, J = 7.20 Hz, in-3- 2H) 4.00 (t, J = 8.80 yljdihydrop Hz, 2H), 3.62-3.47 yrimidine- (m, 2H), 3.18-3.12 2,4(1H,3H)- (m, 1H), 2.81-2.67 dione (m, 4H), 2.52-2.49 (m, 1H), 2.18 (d, J = 10.8 Hz, 1H), 1.72 (d, J = 10.8 Hz, 1H), 1.02 (d, J = 3.20 Hz, 3H), 0.69 (s, 3H). 1H-NMR (400 MHz, DMSO-d6 11.00 (s,
3-(6-((R)-l- 1H), 10.06 (s, 1H), ((4-(l,2,4- 9.78 (s, 1H), 8.91 (d, oxadiazol-3- J = 1.60 Hz, 1H), yl)phenyl)m 8.41 (s, 1H), 8.17 (m, ethyl-d2)-4- 2H), 8.08 (t, J = 8.80 hydroxy- Hz, 1H), 7.93-7.90 3,3- (m, 3H), 5.94 (s, 1H), dimethylpip 1-581 (R)-51d alkylation 546.2 4.25 (dd, J = 4.40, J eridin-4-yl)- 12.60 Hz, 1H), 3.42- 3.27 (m, 4H), 2.91- fluoroquinol 2.65 (m, 3H), 2.15- in-3- 1.96 (m, 2H), 1.09 (s, yl)piperidin 3H), 0.78 (s, 3H), e-2, 6-dione, (Note: one aliphatic HC1 proton overlapped with deuterated solvent). _
1H-NMR (400 MHz, DMSO-d6 11.00 (s,
3-(6-(l-((4- 1H), 10.26 (s, 1H), (1,2,4- 9.78 (s, 1H), 8.92 (d, oxadiazol-3- J = 1.20 Hz, 1H), yl)phenyl)m 8.43 (s, 1H), 8.16 (m, ethyl-d2)-4- 2H), 8.08-8.06 (m, hydroxy- 1H), 7.92-7.90 (m, 3,3- 3H), 5.94 (s, 1H), dimethylpip 1-579 51d alkylation 546.3 4.26 (dd, J = 4.80, J eridin-4-yl)- 12.80 Hz, 1H), 3.42- 3.27(m, 4H), 2.88- fluoroquinol 2.64 (m, 3H), 2.16- in-3- 2.01 (m, 2H), 1.10 (s, yljpiperidin 3H), 0.77 (s, 3H). e-2, 6-dione, (Note: one aliphatic HC1 proton overlapped with deuterated solvent).
Figure imgf000591_0001
thyljpyridin 7.91 (d, J = 8.40 Hz, -3- 2H), 5.98 (s, 1H), yl)methyl)pi 4.61 (s, 2H), 4.60- peridin-4- 4.02 (m, 2H), 3.60- yljquinolin- 3.42 (m, 4H),3.07 - 3- 3.10 (m, 1H), 2.81- yljdihydrop 2.70 (m, 5H), 2.04- yrimidine- 2.01(m, 1H), 1.00 2,4(1H,3H)- (s, 3H), 0.67 (s, 3H). dione, HC1
1H NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 8.11-
3-(5-flooro- 8.07 (m, 1H), 7.83 (d, 6-((R)-4- J = 8.0 Hz, 1H), 7.39- hydroxy- 7.34 (m, 4H), 5.10 (s, 3,3- 1H), 4.95-4.92 (m, dioiethyl-1- 2H), 4.64-4.61 (m, (4-(oxetan- 4-(oxetan-3- 2H), 4.26-4.20 (m, 3- 1-575 (R)-51d yl)benzalde 532.3 G 2H), 3.57-3.54 (m, yl)benzyl)pi hyde 1H), 3.51-3.47 (m, peridio-4- 1H), 3.46-3.44 (m, yljquioolin- 1H), 3.18-3.13 (m, 3- 2H), 2.76-2.63 (m, yl)piperidio 1H), 2.47-2.44 (m, e-2, 6-dione 2H), 2.19-2.15 (m, 2H), 1.71-1.68 (m, 2H), 0.99 (s, 3H), 0.67 (s, 3H).
1H NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 8.33 (s,
3-(6-((R)-l- 1H), 8.09 (s, 1H), (3-chloro-4- 7.84 (d, 1 = 8.0 Hz, (oxetan-3- 1H), 7.51 (d, J = 8.0 yljbenzyl)- Hz, 1H), 7.43 (s, 1H),
4-hydroxy- 3-chloro-4- 7.38 (d, J = 8.0 Hz, 3,3- (oxetan-3- lH), 5.12 (s, 1H), dimethylpip 1-625 (R)-51d yl)benzalde 566.4 4.96-4.92 (m, 2H), G eridin-4-yl)- hyde ALD- 4.73-4.70 (m, 2H), 50 3.60-3.56 (m, 1H), fluoroquinol 3.53-3.49 (m, 1H), in-3- 2.68-2.66 (m, 1H), yljpiperidin 2.56-2.52 (m, 2H), e-2, 6-dione 2.49-2.47 (m, 1H), 2.38-2.34 (m, 2H), 2.18-2.16 (m, 2H), 2.12-2.08 (io, 2H), 2 01 1 98 (s 1H) 1.90-1.86 (m, 1H), 1.00 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.61
(R)-l-(5- (s, 1H), 8.97 (d, J = fluoro-6-(4- 2.80 Hz, 1H), 8.59 (d, hydroxy-1- J = 1.20 Hz, 1H), ((6-(3- 8.33 (d, J = 2.00 Hz, hydroxyoxet 1H), 8.09 (t, J = 8.80 an-3- Hz, 1H), 7.86-7.78 yljpyridin- (m, 2H), 7.59 (d, J = 3- 6-(3- 8.00 Hz. lH), 5.16 (s, yl)methyl)- hydroxyoxet
INT-(R)- 1H), 4.93 (t, J = 5.20 3,3- 1-778 an-3- 550.3 G
S2 Hz, 2H), 4.66 (d, J = dimethylpip yl)nicotinald 6.00 Hz, 2H), 4.02- eridin-4- ehyde 3.99 (m, 2H), 3.65- yl)quinolin- 3.51 (m, 2H), 3.18- 3- 3.15 (m, 2H), 2.80 (t, yljdihydrop J = 6.80 Hz, 2H), yrimidine- 2.68-2.53 (m, 2H), 2,4(1H,3H)- 2.35-2.33 (m, 1H), dione, 1.76-1.70 (m, 5H), 1.33AcO- 1.00 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.63 fluoro-6-(l- (s, 1H), 9.27 (s, 1H), ((3-(4- 9.01 (d, J = 2.00 Hz, fluoropheny 1H), 8.36 (d, J = 2.40 l)cyclobutyl Hz, 1H), 8.07 (t, J = )methyl)-4- (lr,3r)-3-(4- 8.80 Hz. 1H), 7.91 (d, hydroxy- fluoropheny J = 8.80 Hz, 1H), 3,3- INT-(R)- l)cyclobutan
1-874 549.5 7.35-7.26 (m, 2H), G dimethylpip S2 e-1- 7.19-7.13 (m, 2H), eridin-4- carbaldehyd 5.95 (s, 1H), 4.03- yl)quinolin- e ALD-34 3.99 (m, 2H), 3.45- 3- 3.07 (m, 7H), 2.83- yljdihydrop 2.60 (m, 5H), 2.51- yrimidine- 2.50 (m, 1H), 1.99-
2,4(1H,3H)- 1.91 (m, 2H), 1.11 (s, dione, HC1 3H), 0.88 (s, 3H).
(R)-l-(6-(l- 1H-NMR (400 MHz, (4-chloro-3- 4-chloro-3- DMSO-d6): 5 10.60 (2- (2- (s, 1H), 8.97 (d, J = (dimethyla INT-(R)- (dimethylam 2.40 Hz, 1H), 8.33 (d,
1-770 599.2 G mino)ethox S2 ino)ethoxy) J = 2.00 Hz, 1H), y)benzyl)-4- benzaldehyd 8.09 (t, J = 8.80 Hz, hydroxy- e 1H), 7.85 (d, J = 9.20 3,3- Hz, 1H), 7.36 (t, J = dimethylpip 4.00 Hz, lH), 7.17 (s, eridin-4-yl)- 1H), 6.94 (d, J = 9.20 5- Hz, 1H), 5.15 (s, 1H), fluoroquinol 4.16-3.99 (m, 4H), in-3- 3.59-3.43 (m, 1H), yl)di hydrop 2.80-2.59 (m, 5H), yrimidine- 2.50-2.25 (m, 9H), 2,4(1H,3H)- 1.76-1.72 (m, 2H), dione 1.02 (s, 3H), 0.67 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.97 (d, J =
(R)-l-(5-
2.40 Hz, 1H), 8.34 (d, fluoro-6-(4- J = 2.00 Hz, 1H), hydroxy- 8.10 (t, J = 8.80 Hz, 3,3- 1H), 7.98 (s, 1H), dimethyl-1- 7.85 (d, J = 8.80 Hz, (3-(oxetan- 3-(oxetan-3- 1H), 7.69 (d, J = 8.40 3-yl)-4- yl)-4- Hz, 1H), 7.48 (d, J = (trifluorome INT-(R)- (trifluorome
1-628 601.3 8.40 Hz, 1H), 5.18 (s, G thyljbenzyl) S2 thyl)benzald
1H), 4.99-4.94 (m, piperidin-4- ehyde ALD- 2H), 4.72-4.66 (m, yljquinolin- 33 3H), 4.01 (t, J = 6.80 3- Hz, 2H), 3.79-3.57 yl)di hydrop (m, 2H), 3.33-3.21 yrimidine- (m, 2H), 2.80-2.67 2,4(1H,3H)- (m, 3H), 2.50-2.50 dione (m, 1H), 1.80-1.76 (m, 2H), 1.05 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.61 (4-chloro-3- (s, 1H), 8.97 (d, J = (1- 2.40 Hz, 1H), 8.34 (d, hydroxycycl J = 2.00 Hz, 1H), obutyl)benz 8.09 (t, J = 8.80 Hz, yl)-4- 1H), 7.85 (d, J = 9.20 hydroxy- Hz, 1H), 7.44 (d, J =
4-chloro-3- 3,3- 1.60 Hz, 1H), 7.34 (d, dimethylpip INT-(R)- (1- J = 8.00 Hz, 1H),
1-665 hydroxycycl 581.5 E eridin-4-yl)- S2 7.25 (d, J = 1.60 Hz, obutyl)benz 1H), 7.23 (d, J = 2.00 aldehyde fluoroquinol Hz, 1H), 5.36 (s, 1H), in-3- 5.15 (s, 1H), 4.01 (1, J yl)di hydrop = 6.40 Hz, 2H), 3.61 yrimidine- (d, J = 14.00 Hz, 1H), 2,4(1H,3H)- 3.44 (d, J = 14.00 Hz, dione, 1H), 3.33-3.17 (m, 0.77AcOH 1H), 2.80 (1, 1 = 6.80 Hz 2H) 2 79 2 67 (m, 1H), 2.67-2.49 (m, 3H), 2.36-2.29 (m, 2H), 2.20-2.18 (m, 1H), 2.17-2.05 (m, 1H), 1.81 (s, 3H), 1.76-1.71 (m, 1H), 1.60-1.58 (m, 1H), 1.03 (m, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.61 (s, 1H), 8.97 (d, J = 2.40 Hz, 1H), 8.34-
(R)-l-(6-(l- 8.31 (m, 1H), 8.09 (t, (4-chloro-3- J = 8.80 Hz, 1H), (oxetan-3- 7.85 (d, J = 9.20 Hz, yljbenzyl)- 1H), 7.55 (d, J = Hz,
4-hydroxy- 1H), 7.42 (d, J = 8.00 3,3-
4-chloro-3- Hz, 1H), 7.29 (t, J = dimethylpip
INT-(R)- (oxetan-3- 1.60 Hz, lH), 5.15 (s, eridin-4-yl)- 1-659 567.5 G
S2 yl)benzalde 1H), 4.99-4.96 (m,
5- hyde 2H), 4.74-4.68 (m, fluoroquinol 2H), 4.58-4.56 (m, in-3- 1H), 4.01 (t, J = 6.80 yljdihydrop Hz, 2H), 3.67-3.46 yrimidine- (m, 2H), 3.33-3.17 2,4(1H,3H)- (m, 2H), 2.82-2.60 dione (m, 4H), 2.33-2.19 (m, 1H), 1.75-1.72 (m, 1H), 1.03 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.61
(R)-l-(5- (s, 1H), 8.97 (d, J = fluoro-6-(l-
2.80 Hz, 1H), 8.33 (d, (3-fluoro-4- J = 1.60 Hz, 1H), (1- 8.09 (t, J = 8.80 Hz, hydroxycycl 1H), 7.85 (d, J = 8.80 obutyl)benz Hz, 1H), 7.37 (t, J = yi)-4- 3-fluoro-4- 8.00 Hz, 1H), 7.15- hydroxy-
INT-(R)- (1- 7.10 (m, 2H), 5.45 (s, 3,3- 1-668 hydroxycycl 565.5 G
S2 lH), 5.14 (s, 1H), dimethylpip obutyl)benz 4.01 (t, J = 6.80 Hz, eridin-4- aldehyde 2H), 3.58 (d, J = yl)quinolin- 13.60 Hz, 1H), 3.46 3- (d, J = 13.60 Hz, 1H), yljdihydrop 3.33-3.15 (m, 1H), yrimidine-
2.81 (t, J = 6.40 Hz, 2,4(1H,3H)- 2H), 2.59-2.52 (m, dione 2H), 2.28-2.21 (m, 4H) 2 05 1 95 (m 1H), 1.72-1.58 (m, 2H), 1.01 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H)
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.97 (d, J = 2.40 Hz, 1H), 8.33 (d, J = 1.60 Hz, 1H),
(R)-l-(5- 8.15 (s, 1H), 8.09 (t, J fluoro-6-(4- = 8.80 Hz, 1H), 7.84 hydroxy- (d, J = 9.20 Hz, 1H), 3,3- 7.44 (s, 1H), 7.28- dimethyl-1- 7.25 (m, 3H), 5.13 (s, (3-(oxetan- 1H), 4.98-4.94 (m, 3- 2H), 4.63-4.60 (m,
3-(oxetan-3- yl)benzyl)pi 2H), 4.27-4.25 (m,
INT-(R)- yl)benzalde peridin-4- 1-775 533.3 1H), 4.00 (t, J = 6.40 G
S2 hyde ALD- yljquinolin- Hz, 1H), 3.63 (d, J = 19 3- 13.60 Hz, 1H), 3.46 yljdihydrop (d, J = 13.60 Hz, 1H), yrimidine- 3.18-3.15 (m, 1H), 2,4(1H,3H)- 2.80 (t, J = 6.80 Hz, dione, 2H), 2.68-2.68 (m, 0.519Formi 1H), 2.68-2.68 (m, c Acid 1H), 2.50-2.47 (m, 1H), 2.19 (d, J =
10.80 Hz, 1H), 1.72 (d, J = 13.60 Hz, 1H), 1.01 (m, 3H), 0.67(d, J = Hz, 3H).
1H-NMR (400 MHz,
(R)-l-(6-(l- DMSO-d6): 5 10.61 (4-chloro-3- (s, 1H), 8.97 (d, J = (3- 2.40 Hz, 1H), 8.33 (d, hydroxyoxet J = 2.00 Hz, 1H), an-3- 8.26 (s, 1H), 8.09 (t, J yljbenzyl)- = 8.40 Hz, 1H), 7.85 4-hydroxy- 4-chloro-3- (d, 1 = 8.80 Hz, 1H), 3,3- (3- 7.42 (d, J = 8.00 Hz, dimethylpip INT-(R)- hydroxyoxet 1H), 7.35 (t, J = 8.40
1-747 583.5 G eridin-4-yl)- S2 an-3- Hz, 2H), 6.27 (s, 1H), yl)benzalde 5.16 (s, 1H), 5.07 (d, fluoroquinol hyde J = 6.80 Hz, 2H), in-3- 4.73-4.71 (m, 2H), yl)di hydrop 4.01 (t, J = 6.80 Hz, yrimidine- 2H), 3.61 (d, J = 2,4(1H,3H)- 14.00 Hz, 1H), 3.46 dione, (d, J = 14.00 Hz, 1H), Formic Acid 3.17-3.14 (m, 1H), 2.80 (t, J = 6.80 Hz, 2H), 2.68-2.67 (m, 1H), 2.51-2.51 (m, 1H), 2.33-2.17 (m, 1H), 1.74-1.71 (m, 1H), 1.24-1.02 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.09 (1, 1 = 8.80 Hz, 1H), 7.84 (d, J =
3-(5-fluoro- 8.80 Hz, 1H), 7.45 (d, 6-((R)-4- J = 8.40 Hz, 2H), hydroxy-1- 7.32 (d, J = 8.00 Hz, (4-(l- 2H), 5.42 (s, 1H), hydroxycycl 4-(l- 5.10 (s, 1H), 4.23 obutyl)benz hydroxycycl (dd, J = 4.80, 12.60 yl)-3,3- 1-556 (R)-51d obutyl)benz 546.4 Hz, 1H), 3.56 (d, J = G dimethylpip aldehyde 13.20 Hz, 1H), 3.46 eridin-4- ALD-38 (d, J = 13.20 Hz, 1H), yl)quinolin- 3.14 (1, J = 1.60 Hz, 3- 1H), 2.78-2.75 (m, yljpiperidin 1H), 2.72-2.60 (m, e-2, 6-dione 3H), 2.48-2.45 (m, 2H), 2.40-2.35 (m, 2H), 2.30-2.10 (m, 4H), 1.99-1.85 (m, 1H), 1.72-1.85 (m, 2H), 1.00 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 5 10.59 fluoro-6-(4- (s, 1H) 8.96 (d, J = hydroxy-1- 2.40 Hz, 1H), 8.49 (d, ((6-(l- J = 1.60 Hz, 1H), hydroxycycl 8.32 (d, J = 2.00 Hz, obutyl)pyrid 1H), 8.08 (1, 1 = 8.80 in-3- Hz, 1H), 7.84 (d, J =
6-(l- yljmethyl)- 9.20 Hz, 1H), 7.74-
INT-(R)- hydroxycycl 3,3- 1-698 548.3 7.71 (m, 1H), 7.55 (d, G S2 obutyl)nicot dimethylpip J = 8.00 Hz, 1H), inaldehyde eridin-4- 5.68 (s, lH), 5.14 (s, yl)quinolin- 1H), 4.00 (1, J = 6.80 3- Hz, 2H), 3.61-3.48 yl)di hydrop (m, 2H), 3.17-3.11 yrimidine- (m, 1H), 2.80 (1, J = 2,4(1H,3H)- 6.80 Hz, 2H), 2.67- dione 2.50 (m, 4H), 2.24- 2 17 (m 3H) 1 91 1.76 (m, 4H), 0.99 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.97 (d, J =
(R)-l-(6-(l- 2.40 Hz, 1H), 8.33 (d, (3-chloro-4- J = 2.00 Hz, 1H), (1- 8.18 (s, 1H), 8.08 (t, J hydroxycycl = 8.80 Hz, 1H), 7.85 obutyl)benz (d, J = 8.80 Hz, 1H), yi)-4- 7.39-7.37 (m, 2H), hydroxy- 7.29-7.26 (m, 1H),
3-chloro-4- 3,3- 5.33 (s, lH), 5.14 (s, dimethylpip (1- 1H), 4.01 (t, J = 7.20
INT-(R)- hydroxycycl eridin-4-yl)- 1-759 581.5 Hz, 2H), 3.57 (d, J = G
S2 obutyl)benz 13.60 Hz, 1H), 3.46 aldehyde fluoroquinol (d, J = 14.00 Hz, 1H), ALD-20 in-3- 3.44-3.33 (m, 1H), yl)di hydrop 2.80 (t, J = 6.80 Hz, yrimidine- 2H), 2.68-2.60 (m, 2,4(1H,3H)- 1H), 2.68-2.60 (m, dione, 3H), 2.50-2.46 (m, 0.72Formic 1H), 2.34-2.19 (m, Acid 2H), 2.18 (d, J =
10.40 Hz, 1H), 1.73- 1.70 (m, 1H), 1.01 (m, 3H), 0.68 (s, 3H)
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 10.54 (s, 1H),
1-(6-(l- 8.42 (d, J = 2.40 Hz. ((IH-pyrrol- 1H), 8.16 (s, 1H),
2- 8.06 (d, J = 8.80 Hz, yl)methyl)- 1H), 7.78 (d, J = 9.20
4-hydroxy- Hz, 1H), 6.66 (dd, J = 3,3- 2.80, 4.20 Hz, 1H),
IH-pyrrole- dimethylpip 5.96-5.91 (m, 2H), 2- eridin-4-yl)- 1-598 INT-S6 480.2 5.09 (d, J = 8.40 Hz, G carbaldehyd
5-fluoro-2- 1H), 4.05-3.95 (m, e methylquino 1H), 3.70-3.65 (m, lin-3- 1H), 3.49-3.45 (m, yljdihydrop 1H), 3.10-3.10 (m, yrimidine- 1H), 2.86-2.68 (m, 2,4(1H,3H)- 2H), 2.67 (s, 3H), dione 2.47-2.44 (m, 2H), 2.24-2.22 (m, 2H), 0.96 (d, J = 3.20 Hz, 3H), 0.68 (s, 3H), 1H-NMR (400 MHz, DMSO-d6): 5 10.54 (s, 1H), 8.41 (s, 1H), l-(6-(l- 8.21 (s, 1H), 8.08 (t, J (cyclohexyl = 8.80 Hz, 1H), 7.78 methyl)-4- (d, J = 9.20 Hz, 1H), hydroxy- 5.06 (d, J = 8.00 Hz, 3,3- 1H), 4.05-3.95 (m, dimethylpip cyclohexane 1H), 3.71-3.67 (m, eridin-4-yl)-
1-859 INT-S6 carbaldehyd 497.3 1H), 3.10-3.09 (m, G 5-fluoro-2- e 2H), 2.86-2.68 (m, methylquino 3H), 2.67 (s, 3H), lin-3- 2.46-2.33 (m, 2H), yl)di hydrop 2.20-2.08 (m, 3H), yrimidine- 1.83-1.75 (m, 6H), 2,4(1H,3H)- 1.23-1.17 (m, 4H), dione 0.97 (d, J = 3.20 Hz, 3H), 0.88-0.85 (m, 2H), 0.70 (s, 1H).
1H-NMR (400 MHz, DMSO-d6): 8 10.57
((4,4- (s, 1H), 9.01-8.95 (m, difluorocycl 1H), 8.49 (d, J = 3.20 ohexyl)meth Hz, 1H), 8.07 (d, J = yl)-4- 8.80 Hz, 1H), 7.86 (d, hydroxy- J = 8.80 Hz, 1H),
4,4- 3,3- 5.99 (s, 1H), 4.05- difluorocycl dimethylpip 3.95 (m, 1H), 3.72-
1-837 INT-S6 ohexane-1- 533.2 G eridin-4-yl)- 3.68 (m, 4H), 3.22- carbaldehyd 5-fluoro-2- 3.20 (m, 3H), 3.18- e methylquino 3.16 (m, 1H), 2.88- lin-3- 2.68 (m, 2H), 2.67 (s, yl)di hydrop 2H), 2.08-2.00 (m, yrimidine- 4H), 1.97-1.85 (m, 2,4(1H,3H)- 4H), 1.32-1.24 (m, dione 2H), 1.12 (d, J = 2.40 Hz, 3H), 0.83 (s, 3H). l-(6-(l- 1H-NMR (400 MHz, ((3,3- DMSO-d6): 6 10.57 difluorocycl (s, 1H), 8.47 (s, 1H), obutyl)meth 8.07 (t, J = 8.40 Hz, yl)-4- 1H), 7.85 (d, J = 9.20
3,3- hydroxy- Hz, 1H), 5.92 (s 1H), difluorocycl 3,3- 3.99-3.71 (m, 1H),
1-860 INT-S6 obutane-1- 505.2 G dimethylpip 3.71-3.68 (m, 1H), carbaldehyd eridin-4-yl)- 3.68-3.34 (m, 6H), e 5-fluoro-2- 3.32-3.24 (m, 1H), methylquino 3.21-3.09 (m, 1H), lin-3- 2.84-2.75 (m, 4H), yljdihydrop 2.60-2.51 (m, 3H), yrimidine- 2 50 2 40 (m 1H) 2,4(1H,3H)- 2.00-1.98 (m, 1H), dione 1.09 (s, 3H), 0.81 (s,
3H), l-(5-fluoro- 6-(4- 1H-NMR (400 MHz, hydroxy- DMSO-d6): 5 10.57 3,3- (s, 1H), 8.85 (s, 1H), dimethyl-1- 8.49 (s, 1H), 8.08 (d, ((tetrahydro J = 8.80 Hz, 1H),7.86 -2H- tetrahydro- (d, J = 9.20 Hz, 1H), thiopyran-4- 2H- 5.93 (s, 1H), 3.99- yl)methyl)pi 1-831 INT-S6 thiopyran-4- 515.2 4.11 (m, 1H), 3.71- G peridin-4- carbaldehyd 3.68 (m, 1H), 3.40- yl)-2- e 3.38 (m, 3H), 3.24- methylquino 3.02 (m, 4H), 2.89- lin-3- 2.68 (m, 8H), 2.07- yl)dihydrop 0.00 (m, 5H), 1.32- yrimidine- 1.41 (m, 2H), 1.10 (s, 2,4(1H,3H)- 3H), 0.81 (s, 3H) dione
1H-NMR (400 MHz, DMSO-d6): 5 10.54 l-(5-fluoro- (s, 1H), 8.42 (d, J = 6-(4-
2.80 Hz, 1H), 8.08 (t, hydroxy-
J = 8.80 Hz, 1H), 3,3- 7.78 (d, J = 8.80 Hz, dimethyl-1- 1H), 5.12 (d, J = 9.60 (3,3,3- Hz, 1H), 4.00-3.96 trifluoropro 3,3,3- (m, 1H), 3.75-3.64 pyl)piperidi 1-854 INT-S6 trifluoropro 497.4 G (m, 1H), 3.09-3.06 n-4-yl)-2- panal (m, 1H), 2.85-2.68 methylquino (m, 3H). 2.67-2.64 lin-3- (m, 5H), 2.57-2.52 yl)di hydrop (m, 4H), 2.50-2.44 yrimidine- (m, 1H), 2.34 (d, J =
2,4(1H,3H)- 2.00 Hz, 1H), 1.70 (d, dione J = 13.20 Hz, 3H), 0.71 (s, 3H). _ l-(6-(l- 1H-NMR (400 MHz, (cyclopropy DMSO-d6): 5 10.55 lmethyl)-4- (s, 1H), 8.44 (d, J = hydroxy- 2.40 Hz, 1H), 8.24 (s, 3,3- 1H), 8.08 (t, J = 8.80 cyclopropan dimethylpip Hz, 1H), 7.80 (d, J =
1-850 INT-S6 ecarbaldehy 455.2 G eridin-4-yl)- 8.80 Hz, 1H), 5.50 (s, de 5-fluoro-2- 1H), 4.00-3.98 (m, methylquino 1H), 3.18-3.17 (m, lin-3- 1H), 3.04-3.01 (m, yl)di hydrop 1H), 2.68-2.86 (m, yrimidine- 5H), 2.43-2.54 (m,
Figure imgf000601_0001
l-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 5 10.54 hydroxy- (s, 1H), 8.41 (s, 1H), 3,3- 8.15 (s, 1H), 8.08 (t, J dimethyl-1- = 8.40 Hz, 1H), 7.78 ((tetrahydro (d, J = 8.80 Hz, 1H), furan-3- 5.12 (d, J = Hz, 1H), yl)methyl)pi tetrahydrofu 4.00 (m, 1H), 3.78- peridin-4- ran-3- 3.71 (m, 6H), 3.46-
1-840 INT-S6 485.3 G yD-2- carbaldehyd 3.44 (m, lH), 3.10 (t, methylquino e J = Hz, 1H), 2.90 (m, lin-3- 1H), 2.79-2.78 (m, yljdihydrop 2H), 2.68 (s, 3H), yrimidine- 2.40-2.31 (m, 3H), 2,4(1H,3H)- 1.96 (m, 1H), 1.71- dione, 1.68 (m, 2H), 0.96 (q, Formic J = 3.60 Hz, 3H), Acid- 0.70 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.54 l-(5-fluoro- (s, 1H), 8.41 (s, 1H), 6-(4- 8.18 (s, 1H), 8.07 (t, J hydroxy- = 8.80 Hz, 1H), 7.78 3,3- (d, J = 9.20 Hz, 1H), dimethyl-1- 5.50-5.00 (m, 1H), (oxetan-3- 4.69-4.65 (m, 2H), ylmethyl)pi 4.65-4.29 (m, 2H), peridin-4- oxetane-3- 4.29 (s, 1H), 4.00- yi)-2- 1-873 INT-S6 carbaldehyd 471.2 G 3.96 (m, 1H), 3.70- methylquino e 3.67 (m, 1H), 3.24- lin-3- 3.21 (m, 1H), 3.06 (s, yljdihydrop 1H), 2.86-2.78 (m, yrimidine- 7H), 2.70-2.61 (m, 2,4(1H,3H)- lH), 2.14 (d, J = dione, 10.40 Hz, 1H), 1.68 Formic (d, J = 13.20 Hz, 1H), Acid- 0.93 (s, 3H), 0.69 (s, 3H). l-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 8 10.54 hydroxy- (s, 1H), 8.42 (s, 1H), 3,3- 8.31 (d, J = Hz, 1H), dimethyl-1- 8.09-8.08 (m, 1H), propylpiperi 7.79-3.71 (m, 1H), propionalde din-4-yl)-2- 1-836 INT-S6 443.2 5.05 (s, 1H), 4.05- G hyde methylquino 3.95 (m, 1H), 3.72- lin-3- 3.65 (m, 1H), 3.72- yljdihydrop 3.68 (m, 1H), 3.18- yrimidine- 3.16 (m, 1H), 2.88- 2,4(1H,3H)- 2.68 (m, 2H), 2.67 (s, dione, 3H) 2 08 200 (m
Figure imgf000603_0001
yl)methyl)pi 3.85 (m, 2H), 3.70- peridin-4- 3.63 (m, 1H), 3.19- yi)-2- 3.11 (m, 1H), 2.92- methylquino 2.81 (m, 2H), 2.59 (s, lin-3- 3H), 2.51 (t, J = 1.60 yljdihydrop Hz, 1H), 2.29-2.09 yrimidine- (m, 3H), 1.70-1.59 2,4(1H,3H)- (m, 4H). 1.20-1.11 dione (m, 4H), 0.96 (d, J = 2.80 Hz, 3H), 0.70 (s, 3H). _
1H-NMR (400 MHz,
1-(5-fluoro- DMSO-d6): 5 10.54 6-(4- (s, 1H), 8.42 (s, 1H), hydroxy-1- 8.15 (s, 1H), 8.08 (t, J isobutyl- = 8.80 Hz, 1H), 7.78 3,3- (d, 1 = 8.80 Hz, 1H), dimethylpip 5.09 (s, 1H), 4.02- eridin-4-yl)- 3.96 (m, 1H), 3.72-
2- Isobutyralde 3.67 (m, 1H), 3.21-
1-783 INT-S6 457.3 G methylquino hyde 3.15 (m, 1H), 2.94- lin-3- 2.64 (m, 3H), 2.58 (s, yljdihydrop 3H), 2.51-2.33 (m, yrimidine- 2H), 2.25-2.09 (m, 2,4(1H,3H)- 3H), 1.82-1.68 (m, dione, 2H), 1.13 (d, J = 8.00 Formic Hz, 3H), 0.98 (d, J = Acid- 4.00 Hz, 6H), 0.80 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.96 (d, J =
(R)-l-(5- 2.40 Hz, 1H), 8.33 (d, fluoro-6-(4- J = 2.00 Hz, 1H), hydroxy-1- 8.07 (d, J = 8.80 Hz, (4-(2- 1H), 7.84 (d, J = 8.80 hydroxypro Hz, 1H), 7.43 (d, J = pan-2- 4-(2- 8.40 Hz, 2H), 7.27 (d, yljbenzyl)- hydroxypro J = 8.40 Hz, 2H), 3,3- INT-(R)- pan-2- 5.12 (s, 1H), 4.95 (s,
1-760 535.4 G dimethylpip S2 yl)benzalde 1H), 4.01 (t, J = 6.80 eridin-4- hyde ALD- Hz, 2H), 3.56-3.43 yl)quinolin- 46 (m, 2H). 3.43-3.33 3- (m, 1H), 2.80 (t, J = yljdihydrop 6.40 Hz, 2H), 2.68- yrimidine- 2.67 (m, 2H), 2.51- 2,4(1H,3H)- 2.51 (m, 1H), 2.21- dione 2.19 (m, 1H). 1.72- 1.69 (m, 1H), 1.43 (s, 6H), 1.01 (s, 3H), 0 68 (s 3H) 1H-NMR (400 MHz,
(R)-2-(4- DMSO-d6): 8 10.61 ((4-(3-(2,4- (s, 1H), 8.97 (d, J = dioxotetrahy 2.40 Hz, 1H), 8.11 (s, dropyrimidi 1H), 8.08 (d, J = 8.80 n-l(2H)-yl)- Hz, 1H), 7.85 (d, J = 5- 2-(4- 8.80 Hz, 1H), 7.50 (d, fluoroquinol formylphen J = 8.40 Hz, 2H), in-6-yl)-4- INT-(R)- yl)-2- 7.42 (d, J = 8.40 Hz,
1-720 544.4 G hydroxy- S2 methylpropa 2H), 5.14 (s, 1H), 3,3- nenitrile 4.01-3.99 (m, 2H), dimethylpip ALD-45 3.59-3.47 (m, 2H), eridin-1- 3.33-3.15 (m, 1H), yl)methyl)p 2.82-2.79 (m, 2H), henyl)-2- 2.68-2.67 (m, 3H), methylpropa 2.21-2.18 (m, 1H), nenitrile 1.71 (s, 7H), 1.02 (s, 3H), 0.68 (s, 3H).
(R)-5-((4-
1H-NMR (400 MHz, (3-(2,4- DMSO-d6): 8 10.6 (s, dioxotetrahy 1H), 8.92 (d, J = 2.40 dropyrimidi Hz, 1H), 8.33 (d, J = n-l(2H)-yl)-
1.60 Hz, 2H), 8.05 (t, J = 8.40 Hz, 1H), fluoroquinol 7.83-7.74 (m, 3H), in-6-yl)-4- 2-fluoro-5-
INT-(R)- 7.48-7.44 (m, 1H), hydroxy- 1-817 formylbenzo 520.2 G
S2 5.04 (s, 1H), 4.00 (t, J 3,3- nitrile = 6.80 Hz, 2H), 3.36- dimethylpip 3.22 (m, 3H), 2.82- eridin-1- 2.79 (m, 2H), 2.68- yl)methyl)-
2.60 (m, 3H), 2.34- 2- 2.33 (m, 1H), 1.98- fluorobenzo 1.95 (m, 1H), 1.01 (s, nitrile, 3H), 0.64 (s, 3H). Formic Acid
1H-NMR (400 MHz,
(R)-l-(5- DMSO-d6): 8 10.61 fluoro-6-(4- (s, 1H), 8.96 (d, J = hydroxy-1- 2.40 Hz, 1H), 8.32 (d, (4-(l- J = 2.00 Hz, 1H), methoxycyc 8.08 (d, J = 8.80 Hz, lobutyl)benz 4-(l- 1H), 7.86-7.83 (m, yi)-3,3- methoxycyc
INT-(R)- 1H), 7.38 (s, 4H), dimethylpip 1-640 lobutyl)benz 561.2 G
S2 5.13 (s, 1H), 4.02- eridin-4- aldehyde 3.99 (m, 2H), 3.58- yljquinolin- ALD-39 3.47 (m, 3H), 3.47- 3- 3.32 (m, 2H), 2.83 (s, yl)di hydrop 3H), 2.82-2.80 (m, yrimidine- 2H), 2.79 (s, 3H), 2,4(1H,3H)- 2.51-2.50 (m, 3H), dione 2 35 2 34 (m 1H) 2.33-2.30 (m, 1H), 2.28-2.27 (m, 1H), 1.02 (s, 3H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.60 (s, 1H), 8.96 (d, J =
2.40 Hz, 1H), 8.32 (d,
(R)-l-(5- J = 2.00 Hz, 1H), fluoro-6-(4- 8.08 (t, J = 8.40 Hz, hydroxy-1- 1H), 7.84 (d, J = 9.20 (4-(3- Hz, 1H), 7.11 (dd, J = hydroxy-3- 4.80, 16.20 Hz, 2H), methylazeti 6.41 (d, J = 8.40 Hz, din-1- 4-(3- 2H), 5.46 (s, 1H), yl)benzyl)- hydroxy-3- 5.08 (s, 1H), 4.00 (t, J 3,3- INT-(R)- methylazeti = 6.80 Hz, 2H), 3.72
1-789 562.4 G dimethylpip S2 din-1- (t, J = 6.00 Hz, 2H), eridin-4- yl)benzalde 3.58 (d, J = 7.20 Hz, yljquinolin- hyde 2H), 3.57-3.47 (m, 3- 1H), 3.33-2.82 (m, yljdihydrop 1H), 2.82-2.79 (m, yrimidine- 2H), 2.55-2.51 (m, 2,4(1H,3H)- 1H), 2.50-2.38 (m, dione, 1H), 2.34-2.33 (m, Acetic acid 1H), 1.91 (s, 3H), 1.76 (s, 1H), 1.71 (s, 1H), 1.46 (s, 3H), 0.97 (s, 3H), 0.67 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (s, 1H),
3-(6-((R)-l- 8.33 (s, 1H), 8.25 (s, (4-(3,3- 1H), 8.09 (t, J = 8.80 difluoroazet Hz, 1H), 7.83 (d, J = idin-1- 9.20 Hz, 1H), 7.21 (d, yljbenzyl)- J = 8.40 Hz, 2H),
4-hydroxy- 4-(3,3- 6.55 (d, J = 8.40 Hz, 3,3- difluoroazeti 2H), 5.08 (s, 1H), dimethylpip 1-740 (R)-51d din-1- 567.3 L 4.25 (t, J = 8.00 Hz, eridin-4-yl)- yl)benzalde 5H), 2.77-2.74 (m,
5- hyde 1H), 2.68-2.64 (m, fluoroquinol 2H), 2.50-2.47 (m, in-3- 1H), 2.34-2.18 (m, yljpiperidin 2H), 1.70-1.67 (m, e-2, 6-dione, 1H), 0.97 (s, 3H), Formic Acid 0.67 (s, 3H). (Note: 4 protons overlapped with solvent peak). 1H-NMR (400 MHz, DMSO-d6): 5 10.99
1-(4-(((4R)- (s, 1H), 8.85 (s, 1H), 4-(3-(2,6- 8.34 (s, 1H), 8.09 (t, J dioxopiperi = 9.60 Hz, 1H), 7.84 din-3-yl)-5- (d, J = 9.20 Hz, 1H), fluoroquinol l-(2-fluoro- 7.43 (t, J = 7.60 Hz, in-6-yl)-4- 4- 1H), 7.28-7.21 (m, hydroxy- formylphen 2H), 5.14 (s, 1H), 3,3-
1-692 (R)-51d yl)cycloprop 559.2 4.26-4.21 (m, 1H), L dimethylpip ane-1- 3.61-3.57 (m, 2H), eridin-1- carbonitrile 3.47-3.39 (m, 1H), yl)methyl)- ALD-106 3.18-3.17 (m, 2H),
2- 2.77-2.73 (m, 2H), fluoropheny 2.68-2.64 (m, 2H), l)cyclopropa 2.35-2.34 (m, 2H), ne-1- 1.69 (m, 3H), 1.46 carbonitrile (m, 2H). 1.02 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.98 (s, 1H), 8.90 (s, 1H), 8.41 (d, J = 6.00 Hz, 2H),
4-(((4R)-4- 8.07 (t, J = 8.80 Hz, (3-(2,6- 1H), 7.91 (d, J = 8.80 dioxopiperi Hz, 1H), 7.71 (t, J = din-3-yl)-5- 7.60 Hz, 2H), 7.57 (d, fluoroquinol J = 7.60 Hz, 1H), in-6-yl)-4- N-ethyl-2- 4.48-4.44 (m, 2H), hydroxy- fluoro-4-
1-769 (R)-51d 565.4 4.25 (dd, J = 4.80, K 3,3- formylbenza 12.80 Hz, 1H), 3.68 dimethylpip mide (s, 3H), 3.33-3.26 (m, eridin-1- 3H), 2.90 (d, J = yljmethyl)- 11.20 Hz, 1H), 2.77- N-ethyl-2- 2.74 (m, 1H), 2.66 (d, fluorobenza J = 13.60 Hz, 1H), mide 2.13 (d, J = 5.20 Hz, 1H), 2.02 (d, J = 11.20 Hz, 2H), 1.15- 1.09 (m, 6H), 0.78 (s, 3H).
2-(4-(((4R)- 1H-NMR (400 MHz, 4-(3-(2,6- DMSO-d6): 5 10.99
2-(4- dioxopiperi (s, 1H), 8.85 (d, J = formylphen din-3-yl)-5- 2.00 Hz, 1H), 8.33 (s, yl)-2- fluoroquinol 1-678 (R)-51d 543.4 1H), 8.22 (s, 1H), D methylpropa in-6-yl)-4- 8.25 (s, 1H), 7.84 (d, nenitrile hydroxy- J = 8.80 Hz, 1H),
ALD-45
3,3- 7.50 (d, J = 8.40 Hz, dimethylpip 2H) 7 42 (d J = 8 00
Figure imgf000608_0001
1H-NMR (400 MHz, DMSO-d6): 5 10.98
5-(((4R)-4- (s, 1H), 8.85 (d, J = (3-(2,6- 2.40 Hz, 1H), 8.33 (s, dioxopiperi 1H), 8.15-8.07 (m, din-3-yl)-5- 2H), 7.81-7.77 (m, fluoroquinol 2H), 7.53 (t, J = 9.20 in-6-yl)-4- Hz, lH), 5.14 (d, J = hydroxy- 1.20 Hz, 1H), 4.23
2-fluoro-5- 3,3- ( dd. J = 4.80. 12.80
1-786 (R)-51d formylbenzo 519.5 L dimethylpip Hz, 1H), 3.60 (d, J = nitrile eridin-1- 14.00 Hz, 1H), 3.18- yl)methyl)- 3.12 (m, 1H), 2.78- 2- 2.76 (m, 1H), 2.68- fluorobenzo 2.63 (m, 3H), 2.16- nitrile, 2.13 (m, 2H), 1.71 (d, 0.562Formi J = 13.60 Hz, 1H), c Acid 1.97-1.94 (m, 2H), 1.00 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.85 (s, 1H), 8.33 (s, 1H), 8.10 (t, J
3-(6-((R)-l- = 9.20 Hz, 1H), 7.84 (4-(l,l- (d, J = 9.20 Hz, 1H), difluoroethy 7.55 (d, J = 8.00 Hz, l)benzyl)-4- 2H), 7.48 (d, J = 8.40 hydroxy- Hz, 2H), 5.13 (d, J =
4-(l,l- 3,3- 1.20 Hz, 1H), 4.23 difluoroethy dimethylpip 1-650 (R)-51d 540.2 (dd, J = 4.80, 12.60 F l)benzaldeh eridin-4-yl)- Hz, 1H), 3.62 (d, J = yde 5- 14.00 Hz, 1H), 3.52 fluoroquinol (d, J = 14.00 Hz, 1H), in-3- 3.16 (t, J = 8.00 Hz, yljpiperidin 2H), 2.80-2.70 (m, e-2, 6-dione 5H), 2.21-2.10 (m, 2H), 1.99-1.97 (m, 3H), 1.73-1.63 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H).
3-(5-fluoro- 1H-NMR (400 MHz, 6-((R)-4- DMSO-d6): 5 10.99 hydroxy-1- 4-(2- (s, 1H), 8.84 (d, J = (4-(2- hydroxypro 2.00 Hz, 1H), 8.32 (d, hydroxypro pan-2- J = 7.60 Hz, 2H),
1-726 (R)-51d 534.6 K pan-2- yl)benzalde 8.10 (t, J = 8.80 Hz, yljbenzyl)- hyde ALD- 1H), 7.84 (d, J = 9.20 3,3- 46 Hz, 1H), 7.43 (d, J = dimethylpip 8.00 Hz, 2H), 7.27 (d, eridin-4- J = 8 00 Hz 2H) yl)quinolin- 5.10 (s, 1H), 4.97 (s,
3- 1H), 4.25-4.21 (m, yljpiperidin 1H), 2.68-2.60 (m, e-2, 6-dione, 4H), 2.34-2.09 (m, Formic Acid 4H), 1.70 (d, J =
12.40 Hz, 1H), 1.42
(d, 1 = 6.80 Hz, 6H), 1.24 (s, 1H), 1.24 (s, 3H), 0.68 (s, 3H) l-(5-fluoro- 1H-NMR (400 MHz, 6-(4- DMSO-d6): 8 10.55 hydroxy- (s, 1H), 8.41 (s, 1H), 3,3- 8.17 (s, 1H), 8.09 (t, J dimethyl-1- = 8.40 Hz, 1H), 7.78 ((4- (d, J = 9.20 Hz, 1H), (trifluorome 5.07 (d, J = 8.00 Hz,
4- thyljcyclohc 1H), 4.15-3.91 (m,
(trifluorome xyl)methyl) 1H), 3.80-3.60 (m, thyl)cyclohe piperidin-4- 1-834 INT-S6 565.6 1H), 3.35-3.10 (m, G xane-1- yi)-2- 1H), 2.95-2.81 (m, carbaldehyd methylquino 3H), 2.80-2.52 (m, e lin-3- 3H), 2.49-2.41 (m, yljdihydrop 1H), 2.31-2.13 (m, yrimidine- 4H), 1.91-1.85 (m, 2,4(1H,3H)- 2H), 1.71-1.63 (m, dione, 7H), 1.32-1.26 (m, 0.55Acetic 1H), 0.95-0.92 (m, acid 4H), 0.70 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 8 10.98
3-(6-((R)-l- (s, 1H), 8.84 (d, J = (4-(3,3- 2.00 Hz, 1H), 8.33 (s, difluorocycl 1H), 8.09 (t, J = 8.80 obutyl)benz Hz, 1H), 7.84 (d, J = yl)-4- 8.80 Hz, 1H), 7.34- hydroxy- 4-(3,3- 7.27 (m, 4H), 5.10 (s, 3,3- difluorocycl
1-716 (R)-51d 566.4 1H), 4.25-4.21 (m, D dimethylpip obutyl)benz 1H), 3.57-3.40 (m, eridin-4-yl)- aldehyde 4H), 3.01-2.98 (m, 5- 3H), 2.72-2.68 (m, fluoroquinol 5H), 2.52-2.50 (m, in-3- 2H), 2.22-2.11 (m, yljpiperidin 2H), 1.70-1.68 (m, e-2, 6-dione 1H), 0.99 (s, 3H), 0.67 (s, 3H). _ l-(4-(((4R)- l-(4- 1H-NMR (400 MHz, 4-(3-(2,6- formylphen DMSO-d6): 8 10.99 dioxopiperi yl)cyclobuta (s, 1H), 8.85 (d, J =
1-701 (R)-51d 555.6 D din-3-yl)-5- ne-1- 2.40 Hz. 1H), 8.33 (s, fluoroquinol carbonitrile 1H), 8.10 (t, J = 8.80 in-6-yl)-4- ALD 23 Hz 1H) 7 84 (d J = hydroxy- 9.20 Hz, 1H), 7.44 (s, 3,3- 4H), 5.12 (s, 1H), dimethylpip 4.22 (d, J = 4.80 Hz, eridin-1- 1H), 3.57-3.51 (m, yl)methyl)p 1H), 3.51-3.49 (m, henyl)cyclo 1H), 3.35-3.31 (m, butane- 1- 1H), 2.77-2.63 (m, carbonitrile 7H), 2.34-2.04 (m, 7H), 1.92-1.76 (m, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(5-fluoro- (s, 1H), 8.84 (d, J = 6-((R)-4- 2.00 Hz, 1H), 8.34 (d, hydroxy-1- J = 10.00 Hz, 2H), (4-(l- 8.11 (t, J = 8.40 Hz, methoxycyc 1H), 7.84 (d, J = 9.20 lobutyl)benz 4-(l- Hz, 1H), 7.48-7.38 yl)-3,3- methoxycyc (m, 4H), 5.12 (s, 1H), dimethylpip 1-594 (R)-51d lobutyl)benz 560.6 D
4.23 (q, J = 4.80 Hz, eridin-4- aldehyde
1H), 2.83 (s, 3H), yljquinolin- ALD-39 2.41-2.20 (m, 7H), 3- 1.90-1.85 (m, 2H), yl)piperidin 1.30 (s, 1H), 1.01 (s, e-2, 6-dione, 3H), 0.70 (s, 3H). 0.61 Formic (Note: 7 protons Acid overlapped with solvent peak). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.85 (d, J =
3-(5-fluoro- 2.00 Hz, 1H), 8.45 (s, 6-((R)-l-(3- 1H), 8.33 (s, 1H), fluoro-4-(l- 8.10 (t, J = 8.80 Hz, hydroxycycl 1H), 7.84 (d, J = 8.80 obutyl)benz
3-fluoro-4- Hz, 1H), 7.37 (t, J = yi)-4- (1- 7.60 Hz, 1H), 7.14- hydroxy-
1-743 (R)-51d hydroxycycl 564.6 7.09 (m, 1H), 5.45 (s, G 3,3- obutyl)benz lH), 5.12 (s, 1H), dimethylpip aldehyde 4.25-4.21 (m, 1H), eridin-4- 3.59-3.44 (m, 2H), yljquinolin- 2.37 (s, 2H), 2.34- 3- 2.33 (m, 7H), 2.14- yljpiperidin 2.01 (m, 3H), 1.69- e-2, 6-dione 1.63 (m, 3H), 1.24 (s, 1H), 1.01 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(5-fluoro- (s, 1H), 8.85 (s, 1H), 6-((R)-4- 8.75 (s, 1H), 8.33 (s, hydroxy- 1H), 8.12-8.06 (m, 3,3- 2H), 7.91 (d, J = 8.00 dimethyl-1- Hz, 1H), 7.84 (d, J = ((6- 6- 8.80 Hz. lH), 5.17 (s, (trifluorome (trifluorome 1H), 4.25-4.21 (m, thyljpyridin 1-519 (R)-51d 545.2 E thyl)nicotina 1H), 3.73 (d, J = -3- Idehyde 14.00 Hz, 1H), 3.63 yl)methyl)pi (d, J = 14.00 Hz, 1H), peridin-4- 3.17 (t, J = Hz, 1H), yljquinolin- 2.69-2.67 (m, 5H), 3- 2.18-2.13 (m, 2H), yljpiperidin 1.87 (s, 1H), 1.76- e-2, 6-dione 1.71 (m, 1H), 1.01 (s, 3H), 0.69 (m, 3H).
1H-NMR (400 MHz,
(R)-l-(4- DMSO-d6): 5 10.61 ((4-(3-(2,4- (s, 1H), 8.91 (s, 1H), dioxotetrahy 8.33 (t, J = 0.80 Hz, dropyrimidi 1H), 8.09 (t, J = 8.40 n-l(2H)-yl)- Hz, 1H), 7.85 (d, J = 5- l-(4- 9.20 Hz, 1H), 7.47- fluoroquinol formylphen 7.42 (m, 4H), 5.17 (s, in-6-yl)-4- INT-(R)- yl)cyclobuta 1H), 4.01 (t, J = 7.20
1-679 556.2 K hydroxy- S2 ne-1- Hz, 2H), 3.63 (m, 3,3- carbonitrile 2H), 3.33 (t, J = Hz, dimethylpip ALD-23 1H), 2.79-0.75 (m, eridin-1- 5H), 2.68-2.65 (m, yl)methyl)p 3H), 2.33-2.30 (m, henyl)cyclo 3H), 2.04-2.01 (m, butane- 1- 1H), 1.76-1.71 (m, carbonitrile 1H), 1.01 (s, 3H), 0.69 (m, 3H).
1H-NMR (400 MHz,
3-(5-fluoro- DMSO-d6): 5 10.97 6-((R)-4- (s, 1H), 8.84 (d, J = hydroxy- 2.00 Hz, 1H), 8.33 (s, 3,3- 1H), 8.09 (s, 1H), dimethyl-1- 4-(l- 7.84 (t, J = 9.20 Hz, (4-(l- (trifluorome 1H), 7.45-7.36 (m, (trifluorome thyl)cyclopr
1-606 (R)-51d 584.2 4H), 5.10 (s, 1H), E thyl)cyclopr opyl)benzal 4.25-4.21 (m, 1H), opyl)benzyl dehyde 3.57-3.47 (m, 2H), )piperidin- ALD-29 3.18-0.11 (m, 2H),
4- 2.77-2.72 (m, 2H), yl)quinolin- 2.66 (d, J = 12.00 Hz, 3- 3H), 2.20 (d, J = yljpiperidin 10 40 Hz 2H) 1 89 e-2, 6-dione, (s, 3H), 1.74 (d, J = O.SAcO- 18.40 Hz, 1H), 1.33 (t, J = 5.20 Hz, 2H), 1.13 (s, 2H), 1.01 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 8.97 (d, J =
(R)-l-(4-
2.40 Hz, 1H), 8.33 (d, ((4-(3-(2,4-
J = 2.00 Hz, 1H), dioxotetrahy 8.08 (t, J = 8.80 Hz, dropyrimidi 1H), 7.85 (d, J = 8.80 n-l(2H)-yl)- Hz, 1H), 7.43 (t, J = 5- l-(2-fluoro- 7.60 Hz, 1H), 7.28- fluoroquinol 4- 7.21 (m, 2H), 5.15 (s, in-6-yl)-4- formylphen 1H), 4.01 (t, J = 6.80 hydroxy- INT-(R)-
1-774 yl)cycloprop 560.2 Hz, 2H), 3.59 (d, J = G 3,3- S2 ane-1- 14.00 Hz, 1H), 3.49 dimethylpip carbonitrile (d, J = 14.00 Hz, 1H), eridin-1- ALD-106 3.15 (t, J = 12.40 Hz, yl)methyl)- 1H), 2.82-2.68 (m, 2- 2H), 2.68-2.67 (m, fluoropheny 2H), 2.18 (d, J = l)cyclopropa 10.80 Hz, 1H), 1.73- ne-1- 1.68 (m, 3H), 1.47- carbonitrile 1.43 (m, 2H), 1.24 (s, 1H), 1.01 (s, 3H), 0.68 (s, 3H). _
1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(5-fluoro- (s, 1H), 8.85 (d, J = 6-((R)-l-(3- 2.00 Hz, 1H), 8.33 (s, fluoro-4-(l- 1H), 8.09 (t, J = 8.80 hydroxycycl Hz, 1H), 7.85 (d, J = opropyl)ben Hz, 1H), 7.46 (t, J = zyl)-4- 3-fluoro-4- 8.00 Hz, 1H), 7.14- hydroxy- (1- 7.09 (m, 2H), 5.87 (s, 3,3- hydroxycycl lH), 5.12 (s, 1H),
1-729 (R)-51d 550.2 K dimethylpip opropyl)ben 4.25-4.21 (m, 1H), eridin-4- zaldehyde 3.58-3.52 (m, 3H), yljquinolin- ALD-68 3.18-3.12 (m, 2H), 3- 2.77-2.72 (m, 1H), yl)piperidin 2.68-2.60 (m, 1H), e-2, 6-dione, 2.18-2.08 (m, 2H), 0.465Formi 1.70 (d, J = 14.40 Hz, c Acid 1H), 1.24 (s, 3H), 1.01-0.86 (m, 6H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-d6): 5 10.98
3-(5-fluoro- (s, 1H), 8.85 (d, J = 6-((R)-l-(3- 2.00 Hz, 1H), 8.33 (s, fluoro-4-(2- 1H), 8.23 (s, 1H), hydroxypro 8.10 (t, J = 8.80 Hz, pan-2-
3-fluoro-4- 1H), 7.84 (d, J = 9.20 yl)benzyl)- oxy- (2 Hz, 1H), 7.58 (t, J =
4-hydr - hydroxypro 8.40 Hz, 1H), 7.15- 3,3-
1-763 (R)-51d pan-2- 552.3 7.06 (m, 2H), 5.21 (s, E dimethylpip yl)benzalde lH), 5.12 (s, 1H), eridin-4- hyde ALD- 4.26-4.21 (m, 1H), yl)quinolin- 92 3.57-3.44 (m, 6H), 3- 2.74-2.68 (m, 2H), yl)piperidin 2.20-2.14 (m, 2H), e-2, 6-dione, 1.71 (d, J = 12.80 Hz, 0.837Formi 1H), 1.49 (s, 6H), c Acid 1.01 (s, 3H), 0.68 (m, 3H).
Table 5. Characterization data of Exemplary compounds
Compound Name MS observed,
LCMS 1H-NMR (Cmpd No.) MH+
1H NMR (499 MHz, DMSO-d6, 297 K) 5 (ppm) = 11.07 - 10.85 (m, 1H), 8.24 - 8.15
LCMS: m/z (m, 1H), 8.05 - 7.96 (m, 1H), 7.75 - 7.68 (m, MM-ES+APCI, 3H), 7.63 - 7.58 (m, 2H), 4.42 - 4.30 (m,
(1-170) 300 Positive [M+H] 1H) 3.72 - 3.52 (m, 3H), 3.19 - 3.07 (m, 1H), + 300.0 (half 2.90 - 2.76 (m, 2H), 2.66 (s, 4H), 2.44 - 2.33 mass) (m, 1H), 2.30 - 2.23 (m, 1H), 2.18 - 1.91 (m, 2H), 1.76 - 1.59 (m, 2H), 1.36 - 1.21 (m, 4H), 1.18 - 0.96 (m, 2H), 0.89 - 0.52 (m, 3H)
1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 11.08 (s, 1H), 10.13 (hr s, 1H), 9.15 (hr s, 1H), 8.89 (hr s, 1H), 8.34 (hr s, 1H), 8.32 -
3-(6-(6-ethyl-9-
8.28 (m, 1H), 8.28 - 8.25 (m, 1H), 4.34 - hydroxy-6-
LCMS: m/z 4.28 (m, 2H), 3.64 - 3.57 (m, 1H), 3.40 - azaspiro[3.5]nona
408 HESI, positive 3.38 (m, 1H), 3.32 - 3.12 (m, 4H), 2.86 - n-9-yl)quinolin-3- [M+H]+= 408 2.75 (m, 2H), 2.71 - 2.62 (m, 1H), 2.49 - yl)piperidine-2,6- 2.40 (m, 1H), 2.28 - 2.16 (m, 2H), 2.07 - dione (1-908) 1.94 (m, 1H), 1.90 - 1.82 (m, 1H), 1.82 -
1.73 (m, 1H), 1.61 - 1.46 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.71 - 0.61 (m, 1H).
1H NMR (499 MHz, DMSO-d6) 5 ppm
LCMS: m/z 10.96 - 10.99 (m, 1H) 8.78 - 8.80 (m, 1H) MM-ES+APCI, 8.46 (s, 1H) 8.20 - 8.25 (m, 1H) 7.98 - 8.09 d-915) 626.4 Positive [M+H] (m, 2H) 7.71 (s, 2H) 7.73 (s, 1H) 7.59 - 7.64 + 626.4 (m, 2H) 5.61 - 5.89 (m, 2H) 4.12 - 4.18 (m, 1H) 2.83 - 2.88 (m, 2H) 2.73 - 2.82 (m, 1H) 2.58 - 2.65 (m, 1H) 2.34 - 2.45 (m, 4H) 2.08
- 2.19 (m, 1H) 1.92 - 2.03 (m, 1H) 1.46 - 1.68 (m, 3H) 1.21 - 1.37 (m, 4H) 1H NMR (499 MHz, DMSO-d6) 8 = 10.99 (s, 1H), 8.90 - 8.77 (m, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.02 (br t, J = 8.8 Hz, IH), 7.87 (d, J = 8.8 Hz, IH), 7.77 - 7.66 (m, 2H), 7.60 (br
LCMS: m/z d, J = 8.2 Hz, 2H), 4.22 (br dd, J = 4.9, 12.6 MM-ES+APCI,
(1-895) 582.5 Hz, IH), 3.69 (s 2H) 2.76 (m IH), 2.65 - Positive [M+H] 2.63 (m IH), 2.36 (m IH), 2.32 - 2.27 (m, + 582.5 IH), 2.25 - 2.19 (m, IH), 2.18 - 2.11 (m, IH), 2.04 - 1.96 (m, IH), 1.48 - 1.40 (m, IH), 0.88 - 0.84 (m, IH) (some peaks _ overlap with solvent) _ IH NMR (500 MHz, DMSO-d6) 8 (ppm) = 11.03 (s, IH), 9.79 (br s, IH), 9.09 - 8.88 (m,
3-(6-(3-ethoxy-4- IH), 8.57 (br s, IH), 8.21 - 8.08 (m, 2H), hydroxy-l-(4- 8.06 - 8.00 (m, IH), 7.98 - 7.94 (m, IH),
(trifluoromethyl)b LCMS: m/z 7.91 (s, 2H), 7.90 - 7.87 (m, IH), 6.21 - 6.01 enzyl)-piperidin- 542 HESI, positive (m, IH), 4.65 - 4.42 (m, 3H), 4.28 - 4.22 (m,
4-yl)quinolin-3- [M+H]+= 542 IH), 4.03 (q, J = 7.1 Hz, IH), 3.64 (br s, IH), yl)piperidine-2,6- 3.47 - 3.41 (m, IH), 3.37 - 3.31 (m, IH), dione (1-308) 3.31 - 3.19 (m, 2H), 2.91 - 2.74 (m, 2H), 2.69 - 2.60 (m, IH), 2.24 - 2.11 (m, IH), 2.05 - 1.98 (m, IH), 0.79 - 0.65 (m, 3H).
IH NMR (500 MHz, DMSO-d6) 8 (ppm) =
3-(6-((3S,5R)-4- 11.46 (br d, J = 6.0 Hz, IH), 11.04 (s, IH), hydroxy-3,5- 9.10 - 8.92 (m, IH), 8.83 (br s, IH), 8.27 (br dimethyl-l-(4- d, J = 8.8 Hz, IH), 8.02 (br d, J = 9.3 Hz, (trifluoromethyl)- LCMS: m/z IH), 8.00 - 7.93 (m, 2H), 7.91 - 7.85 (m, benzyl)piperidin- 540 HESI, positive 2H), 5.46 (br s, IH), 4.49 (br d, J = 4.4 Hz, 4-yl)-5- [M+H]+= 540 2H), 4.34 - 4.23 (m, IH), 3.21 - 3.03 (m, methylquinolin-3- 6H), 3.01 (s, IH), 2.90 (s, 3H), 2.84 - 2.72 yl)piperidine-2,6- (m, IH), 2.69 - 2.61 (m, IH), 2.21 - 2.11 (m, dione (1-921) _ IH), 0.68 - 0.50 (m, 6H). _ IH NMR (499 MHz, DMSO-d6, 297 K) 8 (ppm) 10.99 - 10.94 (m, IH), 8.78 - 8.75 (m, IH), 8.47 - 8.45 (m, 2H), 8.26 - 8.22 (m, IH), 8.06 - 8.02 (m, IH), 7.97 - 7.94 (m, IH), 7.93 - 7.89 (m, IH), 7.73 - 7.69 (m,
LCMS: m/z 2H), 7.61 - 7.57 (m, 2H), 6.20 - 5.91 (t, J = MM-ES+APCI,
(1-327) 576.5 55 Hz, IH) 4.14 (dd, J = 4.9, 12.6 Hz, IH), Positive [M+H] 3.68 - 3.59 (m, 2H), 2.91 (m, IH), 2.82 - + 576.5 2.72 (m, IH), 2.70 (m, IH), 2.66 - 2.60 (m, IH), 2.59 - 2.53 (m, IH), 2.47 - 2.33 (m, 2H), 2.20 - 2.07 (m, 2H), 2.04 - 1.93 (m, IH), 1.55 (br d, J = 13.1 Hz, IH), 1.49 - 1.32 (m, IH), 1.23 (br, 3H), 0.85 (m, IH)
LCMS: m/z IH NMR (499 MHz, DMSO-d6, 297 K) 8
(1-424) 586.6 MM-ES+APCI, ppm 11.03 - 10.96 (m, IH), 8.87 - 8.84 (m, Positive [M+H] 1H), 8.43 - 8.40 (m, 1H), 8.36 - 8.32 (m, + 586.6 1H), 8.10 - 8.04 (m, 1H), 7.89 - 7.83 (m, 1H), 7.71 (s, 2H), 7.61 - 7.57 (m, 2H), 5.31 - 5.24 (m, 1H), 4.26 - 4.19 (m, 1H), 3.72 - 3.67 (m, 1H), 3.64 - 3.59 (m, 1H), 3.52 - 3.45 (m, 2H), 3.19 - 3.10 (m, 4H), 3.10 - 3.05 (m, 2H), 2.81 - 2.71 (m, 1H), 2.71 - 2.66 (m, 1H), 2.65 - 2.58 (m, 2H), 2.39 - 2.34 (m, 1H), 2.27 - 2.22 (m, 1H), 2.17 -
2.10 (m, 1H), 1.72 - 1.67 (m, 1H), 1.48 - 1.42 (m, 1H), 1.30 - 1.20 (m, 2H), 1.19 - 1.07 (m, 1H)
1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 11.02 (s, 1H), 10.38 - 10.18 (m, 1H), 8.96 (s, IH), 8.58 (br s, IH), 8.15 - 8.07 (m, 2H),
3-(6-(10-hydroxy- 8.07 - 8.02 (m, IH), 7.98 (d, I = 8.2 Hz, 2H), 7-(4- 7.89 (d, J = 8.2 Hz, 2H), 5.73 (br s, IH), 4.58
(trifluoromethyl)b
LCMS: m/z - 4.47 (m, J = 4.9, 4.9 Hz, 2H), 4.22 (dd, J = enzyl)-7-
552 HESI, positive 4.7, 12.9 Hz, IH), 3.40 - 3.29 (m, 2H), 3.04 - azaspiro[4.5]decan [M+H]+= 552 2.87 (m, 3H), 2.84 - 2.72 (m, IH), 2.69 -
-10-yl)quinolin-3- 2.59 (m, IH), 2.48 - 2.43 (m, IH), 2.22 - yl)piperidine-2,6- 2.12 (m, IH), 2.12 - 2.02 (m, IH), 1.96 - dione (1-702) 1.88 (m, 2H), 1.44 (m, IH), 1.31 - 1.17 (m, 2H), 1.13 (m, IH), 0.95 - 0.82 (m, IH), 0.80
- 0.67 (m, IH).
IH NMR (500 MHz, DMSO-d6) 5 (ppm) = 11.01 (s, IH), 9.66 - 9.48 (m, IH), 8.96 (d, J = 2.2 Hz, IH), 8.48 (dd, J = 1.6, 7.1 Hz, IH),
3-(5-fluoro-6-(5- 8.11 (br t, J = 8.5 Hz, IH), 7.96 (d, J = 9.3 hydroxy-2- Hz, IH), 6.09 (br s, IH), 4.28 (dd, J = 4.9, isobutyl-9-oxa-2- LCMS: m/z 12.6 Hz, IH), 3.85 (br d, J = 12.6 Hz, IH), azaspiro[5.5]unde 484 HESI, positive 3.66 - 3.57 (m, IH), 3.54 - 3.41 (m, 4H), can-5-yl)quinolin- [M+H]+= 484 3.38 - 3.30 (m, IH), 3.28 - 3.09 (m, 2H), 3-yl)piperidine- 3.02 - 2.92 (m, IH), 2.82 - 2.71 (m, IH),
2, 6-dione (1-782) 2.68 - 2.51 (m, 3H), 2.41 - 2.28 (m, IH), 2.23 - 2.07 (m, IH), 2.05 - 1.88 (m, IH),
1.66 - 1.51 (m, IH), 1.40 - 1.27 (m, IH), 1.27 - 1.12 (m, 2H), 1.05 - 0.99 (m, 6H).
IH NMR (500 MHz, DMSO-d6) 5 (ppm) = l-(5-fluoro-6-(4- 10.63 (s, IH), 10.51 - 10.32 (m, IH), 9.01 (d, hydroxy-3,3- J = 2.7 Hz, IH), 8.38 (d, J = 2.2 Hz, IH), dimethyl-l-((l- 8.05 (t, J = 8.8 Hz, IH), 7.91 (d, J = 9.3 Hz, methyl-lH-
LCMS: m/z IH), 7.53 (d, J = 1.6 Hz, IH), 6.71 (d, J = 2.2 pyrazol-5-
481 HESI, positive Hz, IH), 6.04 - 5.84 (m, IH), 4.53 (br d, J = yl)methyl)piperidi |M+H |+= 481 4.4 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.97 (s, n-4-yl)quinolin-3- 3H), 3.48 - 3.38 (m, 3H), 3.37 - 3.20 (m, yl)dihydropyrimid IH), 2.98 (m, IH), 2.80 (t, J = 6.6 Hz, 2H), ine-2,4(lH,3H)- 2.02 (m, IH), 1.16 - 1.08 (m, 3H), 0.79 (s, dione (1-797) 3H). 1H NMR (500 MHz, DMSO-d6) 5 (ppm) = l-(6-(l-(4- 10.63 (s, 1H), 10.07 (br s, 1H), 9.00 (d, J = chlorobenzyl)-4- 2.2 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.03 (t, hydroxy-3,3- J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), dimethylpiperidin- LCMS: m/z 7.74 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 4-yl)-5- 511 HESI, positive 2H), 6.02 - 5.83 (m, 1H), 4.46 - 4.34 (m, fluoroquinolin-3- [M+H]+= 511 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.43 - 3.32 (m, yl)dihydropyrimid 3H), 3.28 - 3.19 (m, J = 11.5, 11.5 Hz, 1H), ine-2,4(lH,3H)- 2.89 - 2.82 (m, J = 11.5 Hz, 1H), 2.80 (t, J = dione (1-566) 6.6 Hz, 2H), 2.03 - 1.97 (m, J = 13.7 Hz, 1H), 1.07 (br s, 3H), 0.76 (s, 3H).
1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 10.64 (s, 1H), 9.83 (br s, 1H), 9.03 (d, J = 2.7 l-(5-fluoro-6-(9- Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.24 - 8.07 hydroxy-6- (m, 1H), 7.97 (d, J = 9.3 Hz, 1H), 5.93 (br s, methyl-6-
LCMS: m/z 1H), 4.06 - 3.97 (m, 2H), 3.72 - 3.66 (m, azaspiro[3.5]nona
413 HESI, positive 1H), 3.65 - 3.55 (m, 1H), 3.40 - 3.33 (m, n-9-yl)quinolin-3- [M+H]+= 413 IH), 3.10 - 2.99 (m, 1H), 2.86 (d, J = 4.4 Hz, yl)dihydropyrimid 3H), 2.81 (t, J = 6.6 Hz, 2H), 2.28 - 2.20 (m, ine-2,4(lH,3H)- IH), 2.01 - 1.93 (m, 2H), 1.87 - 1.73 (m, dione (1-877) 2H), 1.73 - 1.63 (m, IH), 1.56 - 1.35 (m, _ IH), 1.02 - 0.93 (m, IH). _
IH NMR (500 MHz, DMSO-d6) 5 (ppm) = l-(5-fluoro-6-(5- 10.79 (br s, IH), 10.63 (s, IH), 9.10 - 8.94 hydroxy-2-(4- (m, IH), 8.36 (d, J = 2.2 Hz, IH), 8.08 - 7.97 (trifluoromethyl)b (m, 3H), 7.94 - 7.87 (m, 3H), 6.00 (br s, IH), enzyl)-9-oxa-2-
LCMS: m/z 4.56 (br d, J = 4.4 Hz, 2H), 4.01 (t, J = 6.8 azaspiro[5.5]unde
587 HESI, positive Hz, 2H), 3.86 - 3.81 (m, IH), 3.59 - 3.47 (m, can-5-yl)quinolin- [M+H]+= 587 3H), 3.44 - 3.35 (m, 2H), 3.28 - 3.15 (m, 3- 2H), 2.84 - 2.75 (m, 2H), 2.70 - 2.61 (m, yl)dihydropyrimid IH), 2.02 - 1.91 (m, IH), 1.64 - 1.45 (m, ine-2,4(lH,3H)- IH), 1.37 - 1.21 (m, IH). 1.21 - 1.13 (m, dione (1-458) _ IH). _ IH NMR (500 MHz, DMSO-d6) 5 (ppm) = 10.63 (s, IH), 9.65 (br s, IH), 9.03 (d, J = 2.7 l-(5-fluoro-6-(5- Hz, IH), 8.38 (d, J = 2.2 Hz, IH), 8.06 (br t, hydroxy-2- J = 8.8 Hz, IH), 7.93 (d, J = 9.3 Hz, IH), isobutyl-9-oxa-2- 6.25 - 5.97 (m, IH), 4.04 - 3.99 (m, 2H), azaspiro[5.5]unde LCMS: m/z
3.88 - 3.83 (m, IH), 3.64 - 3.57 (m, IH), can-5-yl)quinolin- 485 HESI, positive
3.55 - 3.41 (m, 4H), 3.37 - 3.32 (m, IH),
3- [M+H]+= 485
3.27 - 3.08 (m, 2H), 3.03 - 2.90 (m, IH), yl)dihydropyrimid
2.80 (t, J = 6.6 Hz, 2H), 2.65 - 2.57 (m, IH), ine-2,4(lH,3H)- 2.40 - 2.29 (m, IH), 2.01 - 1.92 (m, IH), dione (1-814) 1.65 - 1.52 (m, IH), 1.42 - 1.28 (m, IH), 1.26 - 1.14 (m, IH), 1.02 (t, J = 6.8 Hz, 6H). l-(6-(2-(4-(l,2,4- IH NMR (500 MHz, DMSO-d6) 5 (ppm) = oxadiazol-3- LCMS: m/z 10.62 (s, IH), 9.70 (s, IH), 8.98 (d, J = 2.7 yl)benzyl)-5- 587 HESI, positive Hz, IH), 8.34 (d, J = 2.2 Hz, IH), 8.13 - 7.98 hydroxy-9-oxa-2- [M+H]+= 587 (m, 3H), 7.87 (d, J = 9.3 Hz, IH), 7.58 (d, J = azaspiro[5.5]unde 8.2 Hz, 2H), 5.28 (br s, IH), 4.01 (t, J = 6.6 can-5-yl)-5- Hz, 2H), 3.74 (br d, J = 13.7 Hz, 1H), 3.58 fluoroquinolin-3- (br d, J = 13.7 Hz, 1H), 3.51 - 3.45 (m, 1H), yl)dihydropyrimid 3.42 - 3.39 (m, 1H), 3.19 - 3.06 (m, 4H), ine-2,4(lH,3H)- 2.80 (t, J = 6.6 Hz, 2H), 2.76 - 2.70 (m, 1H), dione (1-460) 2.67 - 2.60 (m, 1H), 2.39 - 2.32 (m, 1H), 2.31 - 2.22 (m, 1H), 1.78 - 1.68 (m, 1H), 1.49 - 1.42 (m, 1H), 1.29 - 1.21 (m, 2H), 1.19 - 1.07 (m, 1H). (one extra aliphatic hydrogen, maybe salt?)
1H NMR (500 MHz, DMSO-d6) 5 (ppm) = 10.61 (s, IH), 8.98 (d, J = 2.2 Hz, 1H), 8.33 l-(5-fluoro-6-(5- (d, J = 2.2 Hz, IH), 8.06 (t, J = 8.8 Hz, IH), hydroxy-2-(4- 7.87 (d, J = 8.8 Hz, IH), 7.40 - 7.33 (m, 4H), (oxetan-3- 6.79 - 6.36 (m, IH), 5.24 (s, IH), 4.94 (dd, J yl)benzyl)-9-oxa- = 6.0, 8.2 Hz, 2H), 4.65 - 4.59 (m, 2H), 4.25
2- LCMS: m/z (quin, J = 7.5 Hz, IH), 4.01 (t, J = 6.6 Hz, azaspiro[5.5]unde 575 HESI, positive 2H), 3.67 - 3.55 (m, IH), 3.52 - 3.38 (m, can-5-yl)quinolin- [M+H]+= 575 3H), 3.22 - 3.05 (m, 3H), 2.80 (t, J = 6.6 Hz,
3- 2H), 2.73 - 2.66 (m, IH), 2.61 - 2.52 (m, yl)dihydropyrimid
IH), 2.34 - 2.27 (m, IH), 2.27 - 2.21 (m, ine-2,4(lH,3H)-
IH), 1.73 - 1.65 (m, IH), 1.51 - 1.38 (m, dione (1-730)
IH), 1.24 (dt, J = 5.2, 13.3 Hz, IH), 1.17 -
1.05 (m, IH)
IH NMR (500 MHz, DMSO-d6) 5 (ppm) = 10.60 (s, IH), 9.87 - 9.72 (m, IH), 8.63 (br d, l-(5-fluoro-6-(5- J = 11.0 Hz, IH), 8.16 - 8.10 (m, IH), 7.96 hydroxy-2- (br d, J = 9.3 Hz, IH), 6.26 - 5.96 (m, IH), isobutyl-9-oxa-2- 4.02 (dt, J = 5.5, 11.0 Hz, 2H), 3.90 - 3.79 azaspiro[5.5]unde LCMS: m/z (m, IH), 3.75 - 3.66 (m, IH), 3.64 - 3.56 (m, can-5-yl)-2- 499 HESI, positive IH), 3.55 - 3.39 (m, 5H), 3.25 - 3.09 (m, methylquinolin-3- |M+H |+= 499 2H), 3.00 - 2.85 (m, 2H), 2.82 - 2.73 (m, yl)dihydropyrimid IH), 2.70 - 2.62 (m, 4H), 2.42 - 2.27 (m, ine-2,4(lH,3H)- IH), 2.01 - 1.92 (m, IH), 1.62 - 1.54 (m, dione (1-669) IH), 1.36 - 1.27 (m, IH), 1.21 - 1.12 (m, IH), 1.05 - 0.99 (m, 6H).
IH NMR (500 MHz, DMSO-d6) 5 (ppm) = l-(5-fluoro-6-(5- 10.98 - 10.78 (m, IH), 10.58 (s, IH), 8.55 (br hydroxy-2-(4- d, J = 7.7 Hz, IH), 8.04 (br d, J = 8.2 Hz, (trifluoromethyl)b 3H), 7.89 (d, J = 8.2 Hz, 3H), 6.01 (br s, IH), enzyl)-9-oxa-2- 4.55 (br d, J = 3.8 Hz, 2H), 4.04 - 3.96 (m,
LCMS: m/z azaspiro[5.5]unde 3H), 3.87 - 3.78 (m, 2H), 3.73 - 3.66 (m,
601 HESI, positive can-5-yl)-2- IH), 3.58 - 3.52 (m, IH), 3.52 - 3.46 (m, [M+H]+= 601 methylquinolin-3- IH), 3.42 - 3.37 (m, IH), 3.28 - 3.14 (m, yl)dihydropyrimid 2H), 2.94 - 2.83 (m, IH), 2.80 - 2.64 (m, ine-2,4(lH,3H)- 2H), 2.63 (s, 3H), 2.02 - 1.91 (m, IH), 1.60 - dione (1-532) 1.48 (m, IH), 1.32 - 1.20 (m, IH), 1.20 - 1.07 (m, IH).
1H-NMR (400 MHz, DMSO-d6): 5 ppm
(1-517) 476.4 11.00 (s, IH), 9.41 (s, IH), 8.89 (s, IH), 8.37 (s, IH), 8.06 (t, J = 8.40 Hz, IH), 7.90 (d, J = 9.20 Hz, 1H), 7.65 (s, 2H), 7.51 (s, 2H), 5.90 (s, 1H), 4.47-4.42 (m, 2H), 4.26-4.22 (m, 1H), 3.38-3.25 (m, 4H), 2.94 (d, J = 10.20 Hz, 1H), 2.64-2.81 (m, 1H), 2.55-2.42 (m, 3H), 2.13-1.98 (m, 2H), 1.01 (s, 3H), 0.77 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 ppm 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.56 (d, J = 4.00 Hz, 1H), 8.33 (s, 1H), 8.10 (t, J =
8.80 Hz, 1H), 7.90-7.83 (m, 2H), 7.35-7.32 (m, 2H), 5.14 (s, 1H), 4.23 (dd, J = 4.80,
(1-1062) 595.1
12.80 Hz, 1H), 3.64 (d, J = 14.40 Hz, 1H), 3.51 (d, J = 14.00 Hz, 1H), 3.21-3.17 (m, 1H), 3.14-2.80 (m, 2H), 2.77-2.73 (m, 3H), 2.22-2.01 (m, 3H), 1.76-1.62 (m, 1H), 1.24
(s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.98 (s, IH), 8.85 (d, J = 2.0 Hz, 1H), 8.44 (s, IH), 8.33 (s, IH), 8.17 (s, IH), 8.10 (q, J = 8.80 Hz, IH), 7.84 (d, J = 9.20 Hz, IH), 7.72 (d, J = 8.40 Hz, 2H), 7.40 (d, J = 8.00
(1-1085) 557.4 Hz, 2H), 5.11 (s, IH), 4.23 (dd, 1 =12.8, 4.80 Hz, IH), 3.60 (d, J = 13.60 Hz, IH), 3.47 (d, J = 13.60 Hz, IH), 3.32-3.16 (m, IH), 2.77- 2.69 (m, 2H), 2.68-2.63 (m, 2H), 2.58-2.51 (m, 5H), 2.18-2.13 (m, 2H), 1.71 (d, J = 12.40 Hz, IH), 1.01 (s, 3H), 0.68 (m, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.98 (s, IH), 8.85 (d, J = 2.00 Hz, IH), 8.34 (s, IH), 8.10 (t, J = 8.80 Hz, IH), 7.84 (d, J = 9.20 Hz, IH), 7.78-7.73 (m, 2H), 7.50 (s, IH), 7.38-7.35 (m, IH), 6.70 (d, J = 2.40 Hz,
(1-1142) 590.2 IH), 5.14 (s, IH), 4.25-4.21 (m, IH), 3.91 (s, 3H), 3.62 (d, J = 13.60 Hz, IH), 3.49 (d, J = 13.60 Hz, IH), 3.20-3.14 (m, IH), 2.78-2.71 (m, 3H), 2.68-2.62 (m, 3H), 2.34-2.21 (m, 2H), 1.81-1.71 (m, IH), 1.02 (s, 3H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.98 (s, IH), 8.84 (s, IH), 8.34 (s, IH), 8.10 (t, J = 8.80 Hz, IH), 7.84 (d, J = 9.20 Hz, IH), 7.75 (d, J = 8.40 Hz, 2H), 7.44 (d, J = 8.00 Hz, 2H), 6.32 (d, J = 2.00 Hz, IH), 5.12
(1-1180) 556.3 (s, IH), 4.23 (dd, J = 4.80, 12.80 Hz, IH), 3.60 (d, J = 13.60 Hz, IH), 3.48 (d, J = 13.60 Hz, IH), 3.18-3.13 (m, IH), 2.81-2.72 (m, 4H), 2.33-2.18 (m, 6H), 1.91 (s, 3H), 1.76- 1.24 (m, IH), 1.01 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm
(1-1163) 616.2
10.99 (s, IH), 8.85 (s, IH), 8.43 (s, IH), 8.34 (s, 1H), 8.12-8.07 (m, 1H), 7.87-7.83 (m, 2H), 7.57 (d, J = 8.00 Hz, 1H), 7.48 (s, 1H), 7.34-7.32 (m, 1H), 5.13 (d, J = 1.20 Hz, 1H), 4.31-4.25 (m, 1H), 3.82-3.72 (m, 1H), 3.60- 3.32 (m, 2H), 3.20-3.11 (s, 1H), 2.92-2.48 (m, 6H), 2.22-2.12 (m, 2H), 1.76-1.65 (m, 1H), 1.11-0.98 (m, 7H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6):5 ppm 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.34 (s, 1H), 8.19 (t, J = 9.20 Hz, 1H), 8.12-8.06 (m, 3H), 7.84 (d, J = 9.20 Hz, 2H), 7.34 (d, J = 9.60 Hz, 1H), 5.14 (s, 1H), 4.46 (t, J = 2.80 Hz, 1H), 4.24-4.21 (m, 1H), 3.66 (d, J =
(1-1183) 610.6 14.00 Hz, 1H), 3.55 (d, J = 14.00 Hz, 1H), 3.22-3.13 (m, 1H), 2.74-2.57 (m, 5H), 2.48- 2.33 (m, 2H), 2.27-2.13 (m, 1H), 1.68 (d, J = 8.00 Hz, 1H), 1.03 (s, 3H), 0.86 (t, J = 6.00 Hz, 2H), 0.79 (dd, J = 6.40, 7.60 Hz, 2H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.99 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 8.05 (t, J = 8.40 Hz, 1H), 7.82 (d, J = 9.20 Hz, 1H), 7.72 (t, J = 4.00 Hz, 2H), 7.60 (d, J = 5.20 Hz, 2H), 5.01 (d, J = 14.80 Hz, 1H),
(1-1093) 588.2 4.23 (d, J = 13.60 Hz, 1H), 3.76 (t, J = 9.20 Hz, 3H), 3.25 (d, J = 8.40 Hz, 3H), 3.14-3.15 (m, 2H), 2.95-2.73 (m, 4H), 2.51-2.34 (m, 1H), 2.15-2.05 (m, 2H), 1.72-1.61 (m, 1H), 1.01-0.95 (m, 3H), 0.68-0.61 (m, 3H).
1H-NMR (400 MHz, DMSO-d6):8 ppm 10.97 (s, 1H), 8.75 (d, J = 2.40 Hz, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.95-7.92 (m, 4H), 7.57 (d, J = 8.40, Hz, 2H), 4.86 (s, 1H), 4.16-4.11 (m, 1H), 3.61 (d, J = 14.00
(1-1337) 566.2 Hz, 1H), 3.43 (d, J = 14.00 Hz, 1H), 2.95- 2.73 (m, 3H), 2.57-2.50 (m, 2H), 2.48-2.32 (m, 2H), 2.29-2.24 (m, 1H), 2.19-2.11 (m, 2H), 1.56 (d, J = 13.20 Hz, 1H), 1.19-1.11 (m, 4H), 0.92 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 3 ppm 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.96 (d, J = 8.00 Hz, 2H), 7.84 (d, J = 9.20 Hz, 1H), 7.45 (d, J = 8.40 Hz, 2H), 5.13 (s, 1H), 4.23
(1-1173) 557.4 (dd, J = 4.80, 12.60 Hz, 1H), 3.92 (s, 3H), 3.61 (d, J = 13.60 Hz, 1H), 3.50 (d, J = 13.60 Hz, 1H), 3.20-3.16 (m, 1H), 3.16-2.70 (m, 3H), 2.69-2.60 (m, 3H), 2.16 (dd, J = 4.80, 9.00 Hz, 2H), 1.72 (d, J = 12.00 Hz, 1H), 1.02 (s, 3H), 0.68 (s, 3H). 1H-NMR (400 MHz, DMSO-06): 5 ppm 10.98 (s, 1H), 8.83 (d, J = 2.00 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.05-7.99 (m, 1H), 7.81 (d, J = 9.20 Hz, 1H), 7.71 (d, J = 8.00 Hz, 2H), 7.54 (d, J = 8.00 Hz, 2H), 4.93 (d, J =
(1-1099) 629.3 15.20 Hz, 1H), 4.24-4.16 (m, 2H), 3.09-3.01 (m, 3H), 2.91-2.89 (m, 2H), 2.85-2.76 (m, 2H), 2.76-2.67 (m, 5H), 2.34-2.15 (m, 4H), 1.64 (d, J = 13.20 Hz, 1H), 1.24 (s, 1H), 0.95 (d, J = 7.20 Hz, 3H), 0.64 (s, 3H),
1H-NMR (400 MHz, DMSO-d6):8 ppm 10.97 (s, 1H), 8.76 (d, J = 2.00 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.40 Hz, 2H), 8.01 (s, 1H), 7.94 (s, 2H), 7.63 (d, J = 8.40 Hz, 2H),
(1-1003) 594.2 4.87 (s, 1H), 4.14 (dd, J = 4.80, 12.00 Hz, 1H), 3.70-3.67 (m, 2H), 2.89 (t, J = 2.40 Hz, 1H), 2.77-2.67 (m, 4H), 2.51-2.44 (m, 2H), 2.20-2.15 (m, 2H), 1.57 (d, J = 13.20 Hz, 1H), 0.93 (s, 3H), 0.69 (s, 3H).
’H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 8.08 (t, J = 8.40 Hz, 1H), 7.82 (d, J = 8.80
Hz, 1H), 7.71 (d, J = 7.60 Hz, 2H), 7.58 (d, J = 3.20 Hz, 2H), 5.00 (d, J = 20.00 Hz, 1H), 4.53 (s, 1H), 4.23 (d, J = 2.40 Hz, 1H), 3.80-
(1-1092) 574.3 3.79 (m, 3H), 3.59-3.54 (m, 1H), 3.15 (t, J
= Hz, 2H), 2.91-2.89 (m, 2H), 2.81-2.76 (m, 3H), 2.40-2.33 (m, 1H), 2.14 (d, J = 5.20 Hz, 1H), 1.64 (dd, J = 12.80, 40.20 Hz, 1H), 1.00 (d, J = 27.60 Hz, 3H), 0.65 (d, J = 35.20 Hz, 3H)
’H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 8.05 (t, J =
8.80 Hz, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.72 (d, J = 8.00 Hz, 2H), 7.59 (d, J = 8.00 Hz, 2H), 4.97 (s, 1H), 4.53 (s, 1H), 4.23 (q, J =
(1-1088) 574.2 4.80 Hz, 1H), 3.90 (s, 1H), 3.77 (t, J = 6.00 Hz, 1H), 3.59 (m, J = 6.40 Hz, 1H), 3.06 (t, J = 12.80 Hz, 1H), 2.77-2.73 (m, 1H), 2.66 (d, J = 13.20 Hz, 3H), 2.43 (d, J = 8.80 Hz, 3H), 2.16-2.12 (d, 1H), 1.63 (d, J = Hz, 1H), 1.03
(s, 3H), 0.69 (s, 3H)
’H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.05 (t, J =
8.80 Hz, 1H), 7.82 (d, J = 9.20 Hz, 1H), 7.71 (d, J = 8.40 Hz, 2H), 7.58 (d, J = 8.00 Hz,
(1-1089) 574.3 2H), 5.02 (s, 1H), 4.53 (s, 1H), 4.23 (d, J =
4.80 Hz, 1H), 3.80 (s, 2H), 3.54 (t, J = 5.60 Hz, 1H), 3.17 (t, J = Hz, 1H), 2.93 (d, J =
8.00 Hz, 1H), 2.77 (m, 1H), 2.65 (d, J = 3.60 Hz, 2H), 2.34 (d, J = 2.00 Hz, 2H), 2.14 (d, J = 4.80 Hz, 1H), 2.05 (d, J = 10.80 Hz, 1H), 1.71 (d, J = 12.80 Hz, 1H), 0.96 (s, 3H), 0.60 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 5 10.99 (s, 1H), 8.86 (s, 1H), 8.34 (s, 1H), 8.07 (d, J = 8.40 Hz, 2H), 8.14 (s, 1H), 7.85 (d, J = 8.40 Hz, 2H), 7.43 (d, J = -8.40 Hz, 2H), 5.12 (s,
(1-1237) 600.5 1H), 4.26-4.21 (m, 1H), 3.74-3.72 (m, 1H), 3.41-3.64 (m, 2H), 3.18-3.17 (m, 1H), 2.69- 2.67 (m, 6H), 2.16-2.12 (m, 2H), 1.64-1.74 (m, 1H), 1.09-1.00 (m, 7H), 0.68 (s, 3H).
’H-NMR (400 MHz, DMSO-de): 5 10.99 (s, 1H), 9.14 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.10 (t, J = 8.80 Hz, 1H), 7.85 (d, J = 8.80 Hz, 1H), 7.54-7.48 (m, 4H), 5.12 (s, 1H), 4.23 (dd, J = 4.40, 12.60 Hz, 1H),
(1-1338) 557.4 3.56 (m, 2H), 3.33 (m, 2H), 3.17 (t, J = 10.00 Hz, 1H), 2.80-2.76 (m, 2H), 2.72-2.67 (m, 2H), 2.41 (s, 3H), 2.34-2.33 (m, 1H), 2.16- 2.12 (m, 1H), 1.75 (d, J = 11.20 Hz, 1H), 1.02 (s, 3H), 0.70 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 1H), 9.09 (d, J = 6.80 Hz, 1H), 8.85 (d, J = 2.40 Hz, 1H), 8.84 (s, 1H), 8.13 (t, J = 8.80 Hz, 1H), 7.94 (d, J = 8.40 Hz, 1H), 7.49 (d, J = 8.40 Hz, 2H), 7.60 (d, J = 8.00 Hz, 2H),
(1-1339) 583.3 5.13 (s, 1H), 4.23 (dd, J = 4.80, 12.60 Hz, 1H), 3.62 (d, J = 13.60 Hz, 1H), 3.51 (d, J = 13.60 Hz, 1H), 3.33-3.16 (m, 1H), 2.74-2.50 (m, 7H), 2.22 (d, J = 10.40 Hz, 1H), 2.02- 1.98 (m, 2H), 1.73-1.70 (m, 1H), 1.07-1.02 (m, 6H), 0.69 (s, 3H).
’H-NMR (400 MHz, DMSO-de): 8 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.34 (d, J = 2.40 Hz, 1H), 8.20 (s, 1H), 8.12-8.08 (m, 2H), 7.84 (d, J = 9.20 Hz, 1H), 7.47 (d, J = 8.00 Hz, 2H), 7.40 (d, J = 8.40 Hz, 2H), 7.06
(1-1340) 606.3 (t, J = 53.60 Hz, 1H), 5.12 (s, 1H), 4.23 (dd, J = 4.80, 12.80 Hz, 1H), 3.92 (s, 3H), 3.60- 3.47 (m, 2H), 3.19-3.16 (m, 2H), 2.72-2.67 (m, 3H), 2.55-2.51 (m, 2H), 2.23-2.14 (m, 2H), 1.71 (d, J = 12.80 Hz, 1H), 1.02 (s, 3H), 0.69 (s, 3H).
1 H-NMR (400 MHz, DMSO-d6):8 ppm
10.98 (s, 1H), 8.85 (s, 1H), 8.84 (s, 1H), 8.22-7.98 (m, 2H), 7.84 (d, J = 9.20 Hz, 1H),
(1-1251) 624.4 7.58-7.56 (m, 4H), 5.13 (s, 1H), 4.25-4.21 (m, 1H), 3.96-3.57 (m, 2H), 3.49-3.32 (m, 2H), 3.16-3.13 (m, 1H), 2.77-2.72 (m, 2H), 2.67-2.63 (m, 2H), 2.34-0.20 (m, 4H), 1.91 (s, IH), 1.76-1.70 (m, 1H), 1.02 (s, 3H), 0.69 (s, 3H).
1H-NMR (400 MHz, DMSO-d6):3 ppm 10.98 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.12-8.07 (m, 1H), 7.84 (d, J = 9.20 Hz, 1H), 7.62 (dd, J = 8.00, Hz, 2H), 7.37 (dd, J = 8.00, Hz,
(1-1258) 609.4 2H), 5.11 (s, 1H), 4.25-4.21 (m, 1H), 3.62- 3.58 (m, 1H), 3.46-3.43 (m, 1H), 3.16 (m, 1H), 2.77-2.70 (m, 2H), 2.68-2.63 (m, 2H), 2.52-2.51 (m, 2H), 2.20-2.15 (m, 2H), 2.05 (s, 6H), 1.73-1.70 (m, 1H), 1.00 (s, 3H), 0.67 (s, 3H).
1H-NMR (400 MHz, DMSO-d6):3 ppm 10.99 (s, 1H), 8.85 (d, J = 2.40 Hz, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 8.80 Hz, 1H), 7.84 (d, J = 9.20 Hz, 1H), 7.51 (d, J = 8.00 Hz, 2H), 7.38 (d, J = 8.00 Hz, 2H), 5.11 (s, 1H), 4.25-4.21 (m, 1H), 3.67-3.65 (m,
(1-1265) 600.4 1H), 3.60-3.67 (m, 1H), 3.47-3.43 (m, 2H), 3.43-3.33 (m, 1H), 2.68-2.67 (m, 1H), 2.67- 2.64 (m, 2H), 2.47-2.45 (m, 2H), 2.34-2.17 (m, 2H), 1.72-1.67 (m, 1H), 1.06-1.05 (m, 2H), 1.04-1.00 (m, 2H), 0.97 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 1H), 8.84 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.09 (t, J = 8.80 Hz, 1H), 7.84 (d, J = 9.20 Hz, 1H), 7.36-7.31 (m, 4H), 5.86 (t, J = 56.40 Hz, 1H), 5.11 (s, 1H), 4.23 (dd, J =
(1-1272) 566.5 4.40, 12.60 Hz, 1H), 3.56-3.45 (m, 3H), 3.13-2.64 (m, 1H), 2.60-2.34 (m, 3H), 2.50- 2.34 (m, 2H), 2.14-2.12 (m, 2H), 1.69 (d, J = 12.80 Hz, 1H), 1.12-1.10 (m, 2H), 1.01-0.96 (m, 5H), 0.68 (s, 3H).
’H-NMR (400 MHz, DMSO-d6): 8 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.33 (s, 1H), 8.10 (t, J = 8.80 Hz, 1H), 7.84 (d, J = 9.20 Hz, 1H), 7.51-7.46 (m, 4H), 5.13 (s, 1H),
(1-1341) 591.2 4.23 (dd, J = 4.80, 12.60 Hz, IH), 3.58-3.52 (m, 6H), 3.15 (m, 2H), 2.77-2.68 (m, 3H), 2.64-2.59 (m, 2H), 2.21-2.13 (m, 2H), 1.85 (s, 3H), 1.76-1.60 (m, IH), 1.02 (s, 3H), 0.68 (s, 3H).
1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.99 (s, IH), 8.85 (d, J = 2.00 Hz, IH), 8.33
(1-1293) 561.1 (d, J =2.00 Hz, IH), 8.17 (d, J =8.80 Hz, IH), 8.12-8.08 (m, IH), 7.84 (d, J = 8.80 Hz, IH), 7.45 (t, J = 8.80 Hz, IH), 7.29-7.26 (m,
Figure imgf000624_0001
1H-NMR (400 MHz, DMSO-d6): 5 ppm 10.99 (s, 1H), 8.85 (d, J = 2.00 Hz, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.12 (d, J = 8.80 Hz, 1H), 8.05 (d, J = 8.40 Hz, 2H), 7.84 (d, J = 9.20 Hz, 1H), 7.52 (d, J = 8.40 Hz, 2H), 7.29 (d, J = 9.20 Hz, 1H), 5.14 (s, 1H), 4.54 (q, J
(1-1331) 598.4 = 6.80 Hz, 2H), 4.26-4.21 (m, 1H), 3.66 (d, J = 9.20 Hz, 1H), 3.55 (d, J = 9.20 Hz, 2H), 3.20-3.18 (m, 1H), 2.77-2.72 (m, 3H), 2.68- 2.64 (m, 2H), 2.24-2.22 (m, 1H), 2.16-2.16 (m, 1H), 1.73 (d, J = 4.00 Hz, 1H), 1.42 (t, J = 7.20 Hz, 3H), 1.03 (s, 3H), 0.69 (s, 3H).
Example 92: Synthesis of 4-hydroxy-6-(trifluoromethyl) nicotinaldehyde (ALD-1)
Figure imgf000625_0001
Step 1: Synthesis of 2-(trifluoromethyl)-5-vinylpyridin-4-ol
To a stirred solution of 5-bromo-2-(trifluoromethyl) pyridin-4-ol (0.2 g, 0.83 mmol) and trifluoro(vinyl)-14-borane, potassium salt (0.133 g, 0.99 mmol) in 1,4-dioxane (0.9 mL)/water (0.1 mL) was added cesium carbonate (0.539 g, 1.65 mmol) at room temperature. The reaction mixture was sparged with argon for 10 min., followed by the addition of Pd(dppf)Ch- DCM (0.067 g, 0.083 mmol). The mixture was sparged with argon for 10 min and then stirred at 80 °C for 23 h. After completion of reaction, the mixture was cooled and concentrated under reduced pressure. The combined crude compound was purified by flash column chromatography using Biotage Isolera (silica gel cartridge, 250 g) using 30% EtOAc in hexane as the eluent. The collected pure fractions were concentrated under reduced pressure to afford 2-(trifluoromethyl)-5-vinylpyridin-4-ol (150 mg, 0.76 mmol, 92% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 190.0. ’H-NMR (400 MHz, DMSO-&): 5 11.74 (s, 1H), 8.65 (s,
1H), 7.22 (s, 1H), 6.87 (dd, J= 17.8, 11.6 Hz, IH), 6.10 (d, J= 18.8 Hz, 1H), 5.49 (d, J= 11.6 Hz, 1H).
Step 2: Synthesis of 4-hydroxy-6-(trifluoromethyl) nicotinaldehyde (ALD-1)
To a stirred solution of 2-(trifluoromethyl)-5-vinylpyridin-4-ol (130 mg, 0.68 mmol) in 1,4- dioxane (4 mL) and water (1 mL) were added sodium periodate (294 mg, 1.38 mmol) and 4- methylmorpholine A-oxide (40.3 mg, 0.34 mmol) at room temperature. Osmium tetroxide was then added (437 mg, 0.069 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude residue. The crude residue was triturated with MTBE wash and dried under reduced pressure to yield 4-hydroxy- 6-(trifluoromethyl) nicotinaldehyde (ALD-1, 100 mg, 0.49 mmol, 72% yield). LCMS: m/z: MM- ES+APCI, [M+H]+ 192.1. ’H-NMR (400 MHz, DMSO-de): 5 10.34 (s, 1H), 8.77 (s, 1H), 7.32 (s, 1H),
3.57 (s, H).
Example 93: Synthesis of 5-chloro-6-(l,2,4-oxadiazol-3-yl) nicotinaldehyde (ALD-2)
Figure imgf000626_0001
Step 1: Synthesis of (Z)-5-bromo-3-chloro-A'-hydroxypicolinimidamide
To a stirred solution of 5-bromo-3-chloropicolinonitrile (5 g, 22.99 mmol) in ethanol (40 mL) and water (4 mL) was added hydroxylamine (4.79 g, 69.0 mmol) and potassium carbonate (K2CO3, 15.89 g, 115 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and stirred for 15 min. The resulting precipitate was filtered and washed with water (2 x 30 mL). The solid was dried under reduced pressure to afford (Z)-5-bromo-3-chloro-jV’-hydroxypicolinimidamide (3 g, 9.10 mmol, 39% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 249.8, 251.8. ’H-NMR (400 MHz, DMSO-r/6): 89.90 (s, 1H), 8.71
(s, 1H), 8.40 (s, 1H), 5.87 (s, 2H).
Step 2; Synthesis of 3-(5-bromo-3-chloropyridin-2-yl)-l,2,4-oxadiazole
To a stirred solution of 5 -bromo-3 -chloro- A-methylpicolinimidamide (3 g, 12.07 mmol) in triethyl orthoformate (89 g, 604 mmol) was added pyridinium p-toluene sulfonate (1.52 g, 6.04 mmol) at room temperature. The resulting reaction mixture was stirred at 120 °C for 12 h. The mixture was cooled to room temperature and quenched with ice-cold water (100 mL), then extracted with EtOAc (2 x 50 mL). The organic layer was dried over the Na2SC>4 filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using a Biotage Isolera system with a silica gel (230-400 mesh) cartridge (120 g), eluting with 18-20% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 3-(5-bromo-3-chloropyridin-2-yl)- 1,2,4- oxadiazole (700 mg, 2.39 mmol, 29% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 260.9, 261.9. ’H- NMR (400 MHz, DMSO-r/6): 8 9.88 (s, 1H), 8.91 (s, 1H), 8.65 (s, 1H).
Step 3: Synthesis of 3-(3-chloro-5-vinylpyridin-2-yl)-l,2,4-oxadiazole To a stirred solution of 3-(5-bromo-3-chloropyridin-2-yl)-l,2,4-oxadiazole (350 mg, 1.34 mmol) in 1,4-dioxane (9.5 mL) and water (0.5 mL) was added potassium trifluoroborate (254 mg, 2.016 mmol) and potassium carbonate (371 mg, 2.69 mmol) at room temperature. The reaction mixture was sparged with nitrogen for 10 min, and PdCh(dppf) (98 mg, 0.13 mmol) was added. The resulting reaction mixture was irradiated in the microwave at 85 °C for 1 h. The mixture was then concentrated under reduced pressure to obtain the crude product. The erode compound was extracted with EtOAc (2 x 100 mL) and washed with brine. The organic layer was dried over anhydrous NaiSO-i. filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexanes. The collected pure fractions were concentrated under reduced pressure to afford 3-(3-chloro-5-vinylpyridin-2-yl)-l,2,4-oxadiazole (135 mg, 0.57 mmol, 42% yield). LCMS: MM-ES+APCI, [M+H, M+2H]+208, 210. 'H-NMR (400 MHz, DMSO-rL): 5 9.85 (s, 1H), 8.85 (d, 7=1.60 Hz, 1H), 8.38 (d, 7=2.0 Hz, IH), 6.87 (dd, 7=17.8, 10.80 Hz, 1H), 6.28 (d, 7= 17.60 Hz,
IH), 5.63 (d, 7= 10.80 Hz, IH).
Step 4: Synthesis of 5-chloro-6-(l,2,4-oxadiazol-3-yl) nicotinaldehyde (ALD-2)
To a stirred solution of 3-(3-chloro-5-vinylpyridin-2-yl)-l,2,4-oxadiazole (120 mg, 0.578 mmol) in tetrahydrofuran (THE, 5 mL) and water (1.667 mL) were added potassium osmate dihydrate (5.32 mg, 0.014 mmol) and sodium periodate (185 mg, 0.867 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitor by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The water (50 mL) was added and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 5-chloro-6-(l,2,4-oxadiazol-3-yl) nicotinaldehyde (ALD-102, 60 mg, 0.23 mmol, 40% yield). The product was analyzed by ’H-NMR (400 MHz, DMSO-de): 5 10.19 (s, IH), 9.93 (s, IH), 9.19 (d, 7=1.60 Hz, IH), 8.63 (d, 7=1.60 Hz, IH).
Example 94: Synthesis of 3-chloro-5-fluoro-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-3)
Figure imgf000627_0001
Step 1: Synthesis of 4-bromo-2-chloro-6-fluorobenzamide To a stirred solution of 4-bromo-2-chloro-6-fluorobenzoic acid (5.0 g, 19.73 mmol) in DMF (40 mL) was added TEA (9.98 g, 99 mmol), HATU (9.00 g, 23.67 mmol), and ammonium chloride (3.17 g, 59.2 mmol) at room temperature and the reaction mixture was stirred for 16 h. After completion of reaction, the reaction mixture was quenched with water and extracted with DCM (2 x 100 mL). The organic layer was washed with sodium bicarbonate solution, dried over anhydrous NaiSCL, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified to afford 4-bromo-2-chloro-6-fluorobenzamide (2.5 g, 7.40 mmol, 38% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 253.99. 'H-NMR (400 MHz, DMSO-de): 5 8.14 (s, 1H), 7.91 (s, 1H), 7.70 (s, 2H).
Step 2: Synthesis of 4-bromo-2-chloro-6-fluorobenzonitrile
To a stirred solution of 4-bromo-2-chloro-6-fluorobenzamide (2.5 g, 9.90 mmol) in DCE (5 mL) was added POOL (7.59 g, 49.5 mmol) at room temperature and the resulting reaction mixture stirred at 60 °C for 5 h. The reaction mixture was cooled to room temperature and EtOAc (100 mL) was added. The EtOAc layer was washed with ice cold water. The combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtained crude compound. The crude was purified by normal phase column chromatography using (100-200 silica mesh) eluting with 15% of EtOAc in hexanes. The pure fractions were concentrated under reduced pressure to afford 4-bromo-2-chloro-6- fluorobenzonitrile (1.3 g, 5.54 mmol, 56% yield). ’H-NMR (400 MHz, CDCI3): 57.72 (s, 1H), 7.56 (s, 1H).
Step 3: Synthesis of (Z)-4-bromo-2-chloro-6-fluoro-N'-hydroxybenzimidamide
To a stirred solution of hydroxylamine (206 mg, 2.99 mmol) in ethanol (4 mL) was added sodium bicarbonate (627 mg, 7.46 mmol) at room temperature and stirred for 15 min. The 4-bromo-2-chloro-6- fluorobenzonitrile (700 mg, 2.99 mmol) in ethanol (4 mL) was added, and reaction mixture and stirred at 100 °C for 16 h. After completion of reaction, cooled the reaction mixture and filtered and washed with EtOAc (50 mL), filtrate was concentrated under reduced pressure to obtained as crude compound. The crude compound was purified by isolera biotage column chromatography using 100-200 silica gel mesh, eluted with 20% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to afford (Z)-4-bromo-2-chloro-6-fluoro-lV-hydroxybenzimidamide (270 mg, 1.009 mmol, 34% yield). 'H-NMR (400 MHz, DMSO-de): 59.57 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 5.98 (s, 2H).
Step 4: Synthesis of 3-(4-bromo-2-chloro-6-fluorophenyl)-l,2,4-oxadiazole
To a stirred solution of 4-bromo-2-chloro-6-fluoro-A-hydroxybenzimidamide (270 mg, 1.01 mmol) in triethyl orthoformate (449 mg, 3.03 mmol) was added TEA (115 mg, 1.01 mmol) at room temperature. The reaction mixture allowed to stir at 100 °C for 1 h. The reaction concentrated under reduced pressure and the crude compound was purified by silica gel flash column chromatography eluting with 50% EtOAc in hexanes. The collected pure fractions were concentrated under reduced pressure to afford 3-(4-bromo-2-chloro-6-fhrorophenyl)-l,2,4-oxadiazole (120 mg, 0.43 mmol, 43% yield). ’H-NMR (400 MHz, DMSO-A): 59.95 (s, 1H), 7.96-7.94 (m, 2H).
Step 5: Synthesis of 3-(2-chloro-6-fluoro-4-vinylphenyl)-l,2,4-oxadiazole
To a stirred solution of 3-(4-bromo-2-chloro-6-fluorophenyl)-l,2,4-oxadiazole (150 mg, 0.54 mmol) and trifluoro(vinyl)-14-borane potassium salt (109 mg, 0.81 mmol) in 1,4-dioxane (4 mL) and water (0.1 mL) was added potassium carbonate 149 mg, 1.08 mmol) at room temperature. The resulting reaction mixture was sparged with argon for 10 min and then PdCh(dppf)-CH2C12 adduct (44.1 mg, 0.054 mmol) was added. The mixture was sparged with argon again for 5 min and heated to 80 °C for 1 h. The reaction mixture was filtered through a pad of celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure and the crude compound was purified by silica gel flash column chromatography eluting with 20% EtOAc in hexanes. The collected pure fractions were concentrated under reduced pressure to afford 3-(2-chloro-6-fluoro-4-vinylphenyl)-l,2,4-oxadiazole (100 mg, 0.45 mmol, 82% yield). ’H-NMR (400 MHz, DMSO-de): 59.92 (s, 1H), 7.74 (s, 1H), 7.68 (dd, 1=10.6, 1.2 Hz, 1H), 6.82 (dd, 1=17.6, 11.2 Hz, 1H), 6.19 (d, 1= 17.60 Hz, 1H), 5.57 (d, 1= 10.80 Hz, 1H).
Step 6: Synthesis of 3-chloro-5-fluoro-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-3)
To a stirred solution of 3-(2-chloro-6-fluoro-4-vinylphenyl)-l,2,4-oxadiazole (100 mg, 0.45 mmol) in THE (1 mL) and water (0.2 mL) were added sodium periodate (143 mg, 0.67 mmol) and potassium osmate dihydrate (4.10 mg, 0.011 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, followed by addition of water (50 mL) and extraction with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4 filtered concentrated under reduced pressure, and purified by silica gel flash column chromatography eluting with 100% EtOAc. The collected pure fractions were concentrated under reduced pressure to afford 3-chloro-5-fluoro-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-3, 30 mg, 0.132 mmol, 30% yield). ’H-NMR (400 MHz, DMSO-t/s): 5 10.06 (s, 1H), 10.06 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H). Example 95: Synthesis of 4-methyl-6-(trifluoromethyl) nicotinaldehyde (ALD-4) n-BuLi, o' N DMF
,F
Toluene,
Figure imgf000629_0001
-78 °C, 2 h
Step 1
To a stirred solution of 5-bromo-4-methyl-2-(trifluoromethyl) pyridine (200 mg, 0.83 mmol) in toluene (2 mL) was added /z-buty 11 ithium in hexane (0.500 mL, 1.25 mmol) at -78 °C. The resulting reaction mixture was stirred at -78 °C for 30 min, and DMF (73.1 mg, 1.00 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography using a Biotage Isolera system with a silica gel (100-200 mesh) cartridge (1 g), eluting with 10% EtOAc in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 4-methyl-6-(trifluoromethyl) nicotinaldehyde (ALD-4, 80 mg, 0.28 mmol, 34% yield). LCMS m/z: MM-ES+APCI, positive [M+H]+ 189.9. 'H-NMR (400 MHz, DMSO-c/e): 5 10.40 (s, 1H), 9.06 (s, 1H), 7.64 (s, 1H), 2.80 (s, 3H).
Example 96: Synthesis of 5-fluoro-l-methyl-lH-pyrazole-4-carbaldehyde (ALD-5)
Figure imgf000630_0001
To a stirred solution of 4-bromo-5 -fluoro- 1 -methyl- 177-pyiazolc (300 mg, 1.68 mmol) in THF (3 mL) was added n-butyllithium (1.00 mL, 2.51 mmol) at -78 °C and the reaction mixture was stirred for 30 min. DMF (368 mg, 5.03 mmol) was then added at -78 °C. The resulting reaction mixture was stirred at - 78 °C for 1 h. After completion of the reaction, as confirmed by TLC and LCMS, the reaction mixture was quenched with water (10 mL) and extracted with 10% IP A in DCM (40 mL). The combined organic layers were concentrated under reduced pressure to afford 5-fluoro-l-methyl-lH-pyrazole-4-carbaldehyde (ALD-5, 300 mg, 2.34 mmol, quantitative yield). The crude aldehyde was used without further purification. 'H-NMR (400 MHz, CDCL): 59.771 (s, 1H), 7.799 (s, 1H), 3.724 (s, 3H).
Example 97: Synthesis of 4-(2,2-dichlorocyclopropyl) benzaldehyde (ALD-6)
B
Figure imgf000630_0002
Step 1: Synthesis of l-bromo-4-(2,2-dichlorocyclopropyl) benzene
To a stirred solution of l-bromo-4-vinylbenzene (3.57 mL, 27.3 mmol) in chloroform (60 mL) under a nitrogen atmosphere was added benzyltriethylammonium chloride (0.18 g, 0.82 mmol) at 0 °C. Sodium hydroxide (NaOH, 32.8 g, 819 mmol) was then added at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h After completion of reaction the reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over anhydrous Na2SOr and filtered. The solvent was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by flash column chromatography using hexane (100%) as the eluent to obtain the desired product, l-bromo-4-(2,2-dichlorocyclopropyl) benzene (4 g, 12.58 mmol, 46% yield). ’H-NMR (400 MHz, DMSO-t/e): 57.58 (dd, J = 14.20, 5.20 Hz, 2H), 7.40 (dd, 7 = 15.20, 2.80 Hz, 2H), 3.14 (t, J=
8.40 Hz, 1H), 2.20-2.12 (m, 1H), 2.10-2.07 (m, 1H).
Step 2: Synthesis of l-(2,2-dichlorocyclopropyl)-4-vinylbenzene
To a stirred solution of l-bromo-4-(2,2-dichlorocyclopropyl)benzene (2 g, 7.52 mmol), trifluoro(vinyl)-14-borane, potassium salt (1.51 g, 11.28 mmol), K2CO3 (3.12 g, 22.56 mmol) in 1,4- dioxane (20 mL) and water (2.22 mL) was added PdCh(dppf)-CH2C12 adduct (0.61 g, 0.75 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by flash column chromatography using hexane (100%) as the eluent to afford l-(2,2-dichlorocyclopropyl)-4-vinylbenzene (1.3 g, 4.99 mmol, 66% yield). ’H-NMR (400 MHz, DMSO- <Z6): 87.42 (d, J = 8.0 Hz, 2H), 7.23 (dd, 7 = 8.40, Hz, 2H), 6.73 (t, J= 17.6, 10.80 Hz, 1H), 5.78 (d, 7 = 17.6 Hz, 1H), 5.29 (d, J= 11.20 Hz, 1H), 2.93 (dd, 7=10.4, 8.4 Hz, 1H), 2.02-199 (m, 1H), 1.88-182 (m, 1H).
Step 3: Synthesis of 4-(2,2-dichlorocyclopropyl) benzaldehyde (ALD-6)
To a stirred solution l-(2,2-dichlorocyclopropyl)-4-vinylbenzene (0.50 g, 1.92 mmol), in water (0.056 mL) and acetonitrile (0.5 mL) was added sodium periodate (0.42 g, 1.92 mmol) and osmium (VIII) oxide (0.29 mL, 0.038 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL), extracted with DCM (3 x 50 mL). The combined organic layer was dried, over Na2SC>4 and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography, eluting with EtOAc in hexane (10 to 12%) to obtain 4-(2,2-dichlorocyclopropyl)benzaldehyde (ALD-6, 0.09 g, 0.36 mmol, 18% yield). LCMS m/z: MM-ES+APCI, positive [M+2H]+ 216.2. ’H-NMR (400 MHz, DMSO- d6y. 8 10.05 (s, 1H), 7.91 (dd, 7 = 8.00 Hz, 2H), 7.45 (dd, 7=8.40 Hz, 2H), 3.02-2.92 (m, 1H), 2.11-2.07
(m, 1H), 1.98-1.95 (m, 1H).
Example 98: Synthesis of 3-chloro-4-(l-(difluoro methyl)-lH-pyrazol-3-yl)benzaldehyde (ALD-7)
Figure imgf000632_0001
Step 1: Synthesis of 3-chloro-4-( l//-pyrazol-3-yl ) benzaldehyde
To a stirred solution of(2-chloro-4-formylphenyl) boronic acid (1.0 g, 5.32 mmol) and 3-bromo- IH-pyrazole (1.21 g, 7.97 mmol) in water (0.7 mL) and 1,4-dioxane (2 mL) under nitrogen atmosphere was added DIPEA (2.08 g, 15.95 mmol) at room temperature. The reaction mixture was sparged with nitrogen for 10 min, and bis (tri-tertbutyl phosphine) palladium (0) (0.27 g, 0.53 mmol) was added. The resulting reaction mixture was stirred at 100°C for 2 h. Water (50 mL) was added to quench and the aqueous solution was extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous NajSCL, concentrated under reduced pressure, and purified by Biotage using silica gel chromatography (100-200), eluting with 30% EtOAc in hexane. Fractions were concentrated to afford 3-chloro-4-(lH- pyrazol-3-yl) benzaldehyde (650 mg, 3.11 mmol, 59% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+ 207.2, 209.2. ’H-NMR (400 MHz, DMSO-de): 5 10.02 (s, 1H), 8.01 (d, J= 6.40 Hz, 2H), 7.92
(d, J = 57.20 Hz, 1H), 7.83 (s, 1H), 7.28 (s, IH), 6.97 (s, 1H).
Step 2: Synthesis of 3-chloro-4-( 1 -(difhioromethy I)- l//-pyrazol-3-yl (benzaldehyde (ALD-7)
To a stirred solution of 3-chloro-4-(lH-pyrazol-3-yl) benzaldehyde (300 mg, 1.45 mmol) in acetonitrile (5 mL) was added sodium carbonate (462 mg, 4.36 mmol), followed by bromotrifluoroethylene trimethyl silane (590 mg, 2.90 mmol) and the reaction mixture was stirred at 60 °C for 3 h. Water (50 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous NazSOr, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography, eluting with 10% EtOAc in hexane to afford 3-chloro-4-(l -(difluoro methyl)- lH-pyrazol-3-yl) benzaldehyde (ALD-7, 170 mg, 0.63 mmol, 43% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+ 257.0, 259.0. ’H-NMR (400 MHz, DMSO-d6): 8 10.07 (s, IH), 8.04 (d, J = 8.0 Hz, IH), 8.01 (d, J= 1.60 Hz, IH), 7.94 (d, J = 6.80 Hz, IH), 7.86 (dd, J = 8.0, 1.60 Hz, IH), 7.30 (t, 7= 53.6 Hz, IH), 7.11 (d, J = 1.60 Hz, IH).
Example 99: Synthesis of 3-(dimethylamino)-3-oxo-l-(4-(trifluoromethyl)phenyl)propyl methanesulfonate (ALD-8)
Figure imgf000633_0001
Step 1: Synthesis of V, V-dimethyl-3-oxo-3-(4-(trifluoromethyl (phenyl )propenamide
To a stirred solution of methyl 3-oxo-3-(4-(trifluoromethyl)phenyl)propanoate (2.0 g, 8.12 mmol) in toluene (20 mL) was added DMAP (0.099 g, 0.812 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction was then cooled, quenched with cold ice water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtained solid crude. The crude compound was purified by flash column chromatography (silica-gel, 230-400 mesh size) using 10% EtOAc in hexane as eluent. The pure fractions were evaporated and dried under high vacuum to afford as A,A-dimethyl-3-oxo-3-(4-(trifhioromethyl)phenyl)propanamide (500 mg, 1.72 mmol, 21% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 260.3.
Step 2: Synthesis of V,V-diinethyl-3-ox()-3-(4-(trifhioroinethyl (phenyl (propenamide
To a stirred solution of methyl 3-oxo-3-(4-(trifluoromethyl) phenyl) propanoate (2.0 g, 8.12 mmol) in toluene (20 mL) was added DMAP (0.099 g, 0.81 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4 filtered and concentrated. The crude residue was purified by flash column chromatography (silica-gel, 230-400 mesh size) using 10% EtOAc in hexane as eluent. The pure fractions were evaporated and dried under high vacuum to afford as N, A-dimethyl-3-oxo-3-(4- (trifluoromethyl)phenyl)-propenamide (500 mg, 1.72 mmol, 21% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 262.3. 'H-NMR (400 MHz, DMSO-t/e): 5 8.11-8.07 (m, 2H), 7.86-7.80 (m, 2H), 5.86 (s, 1H),
3.12 (s, 6H), 3.11-3.02 (m, 2H).
Step 3: Synthesis of 3-(dimethylamino)-3-oxo-l-(4-(trifluoromethyl)phenyl)propyl methanesulfonate
(ALD-8)
To a stirred solution of 3-hydroxy-Af^V-dimethyl-3-(4-(trifluoromethyl)phenyl)-propanamide (140 mg, 0.54 mmol) in DCM (3 mL), were added TEA (163 mg, 1.61 mmol) and methanesulfonyl chloride (0.062 mL, 0.804 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over anhydrous NaiSCL and filtered. The solvent was removed under reduced pressure and the crude compound was purified by silica gel flash column chromatography, eluting with 10% MeOH in DCM to afford 3-(dimethylamine)-3- oxo-l-(4-(trifluoromethyl) phenyl) propyl methane sulfonate (ALD-8, 130 mg, 0.146 mmol, 27% yield). ’H-NMR (400 MHz, DMSO-r/e): 57.68 (d, 7 = 8.40 Hz, 2H), 7.62 (d. 7 = 8.40 Hz, 2H), 6.15 (d, 7 = 8.60,
4.00 Hz, 1H), 3.39 (s, 1H), 3.17-3.12 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H).
Example 100: Synthesis of 3-chloro-4-(l-methyl-lH-l,2,3-triazol-4-yl)benzaldehyde (ALD-9)
Figure imgf000634_0001
Step 1: Synthesis of 4-(4-bromo-2-chlorophenyl)-lH-l,2,3-triazole
To a stirred solution of l-(4-bromo-2-chlorophenyl) ethan-l-one (2.0 g, 8.57 mmol) in DMSO (10 mL) were added 4-methylbenzenesulfonohydrazide (1.595 g, 8.57 mmol), 1 -aminopyridinium iodide (1.902 g, 8.57 mmol), and iodine (3.48 g, 13.71 mmol) at room temperature. The reaction was stirred at 90 °C for 16 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (10 mL) and diluted with brine (25 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extract was dried over anhydrous Na2SCU and filtered. The solvent was removed under reduced pressure and the crude compound was purified by silica gel flash column chromatography, eluting with 10% EtOAc in hexane to afford 4-(4-bromo-2-chlorophenyl)-lH-l,2,3-triazole (500mg, 1.65 mmol, 19% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+258, 260. ’H-NMR (400 MHz, CDC13): 5 8.28 (s, 1H), 7.88 (d, J = 7.20 Hz, 1H), 7.67 (d, J= 8.40 Hz, 1H), 7.28 (s, 1H).
Step 2: Synthesis of 4-(4-bromo-2-chlorophenyl )-l-methyl-l//-L2,3-triazole
To a stirred solution of 4-(4-bromo-2-chlorophenyl)-lH-l,2,3-triazole (0.5 g, 1.934 mmol) in DMF (5 mL) was added NaH (0.155 g, 3.87 mmol) at 0 °C and stirred for 10 min. Mel (0.181 mL, 2.90 mmol) was then added and the reaction mixture stirred at room temperature for 16 h. The reaction mixture quenched with water (100 mL), extracted with EtOAc (2x50 mL), and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel flash column chromatography, eluting with 10% EtOAc in hexane to afford 4-(4-bromo-2-chlorophenyl)-l- methyl-lH-l,2,3-triazole (0.2 g, 0.72 mmol, 37% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+ 272, 274. ’H-NMR (400 MHz, DMSO-</6): 5 8.67 (s, 1H), 8.03 (d, 7 =8.40 Hz, 1H), 7.86 (d, 7=2.0 Hz, 1H), 7.68 (dd, 7 =8.40, 2.00 Hz, 1H), 4.14 (s, 3H).
Step 3: Synthesis of 4-(2-chloro-4-vinylphenyl)-l-methyl-lH-l,2,3-triazole
To a stirred solution of 4-(4-bromo-2-chlorophenyl)-l-methyl-lH-l,2,3-triazole (150 mg, 0.55 mmol) in 1,4-dioxane (3 mL) and water (1.500 mL) under nitrogen atmosphere was added potassium trifluoro(vinyl)borate (111 mg, 0.83 mmol) and K2CO3 (114 mg, 0.83 mmol) at room temperature. The reaction mixture was sparged with nitrogen for 10 min, then PdCh(dppf)-DCM (45 mg, 0.055 mmol) was added, and the resulting reaction mixture was was heated at 80 °C for 2 h. The reaction was diluted with water, filtered through a pad of celite, and washed with EtOAc. The filtrate obtained was extracted with EtOAc (2x70 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using Biotage Isolera (silica gel cartridge 40 g) using 15% EtOAc in hexanes as eluent. Collected pure fractions were concentrated to afford 4-(2-chloro-4-vinylphenyl)-l-methyl-lH-l,2,3-triazole (100 mg, 0.41 mmol, 74% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+220, 222. ’H-NMR (400 MHz, DMSO+/J: 5 8.25 (d, 7 = 8.40 Hz, 1H), 8.20 (s, 1H), 7.75 (d, 7=1.60 Hz, 1H)7.74 (dd, 7 = 8.20, 2.0 Hz, 1H), 6.71 (dd, 7 = 17.4, 11.2 Hz, 1H), 5.84 (dd, 7 = 17.40, 0.80 Hz, 1H), 5.36 (d, 7=11.20, 0.40 Hz, 1H), 4.20 (s, 3H).
Step 4: Synthesis of 3-chloro-4-( 1 -methyl- l//-l,2,3-triazol-4-yl) benzaldehyde (ALD-9)
To a stirred solution of 4-(2-chloro-4-vinylphenyl)-l -methyl- 1H-1, 2, 3-triazole (100 mg, 0.46 mmol) in acetonitrile (2 mL) and water (0.5 mL) was added sodium periodate (97 mg, 0.46 mmol) followed by osmium tetroxide (0.014 mL, 0.046 mmol) at 0 °C. The reaction was stirred at room temperature for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 X 50 mL). The organic layer was dried over Na2SO4 filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography, eluting with 25% EtOAc in hexanes to afford 3-chloro-4-( I -methyl- 17/-1 ,2.3-triazol-4-yl) benzaldehyde (ALD-9, 50 mg, 0.22 mmol, 47% yield). LCMS: m/z: MM-ES+APCI, [M+H]+ 222.2. ’H-NMR (400 MHz, DMSO-c/e): 5 10.03 (s, 1H), 8.53 (d, 7= 8.00 Hz, 1H), 8.35 (s, 1H), 8.00 (d, 7=1.60 Hz, 1H), 7.90 (dd, 7= 8.0, 1.60 Hz, 1H). Example 101: Synthesis of 3-(difluoromethyl)-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-10)
Figure imgf000636_0001
Step 1: Synthesis of (Z)-4-bromo-2-(difluoromethyl)-A'-hydroxybenzimidamide
A solution of hydroxylamine (4.49 g, 64.6 mmol) and potassium carbonate (8.93 g, 64.6 mmol) in water (20 mL) and ethanol (100 mL) was stirred at room temperature for 30 min. 4-bromo-2-(difluoro methyl) benzonitrile (5 g, 21.55 mmol) was added, and the reaction mixture was heated at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel 100-200 mesh, Biotage Isolera, flow rate of 35 mL/min, 0-100% EtOAc in petroleum ether) to yield (Z)-4-bromo-2-(difluoro methyl)-A’-hydroxybenzimidamide (5.0 g, 18.30 mmol, 85% yield). LCMS: m/z: MM-ES+APCI, [M+H, M+2H]+ 265.1, 267.1. ’H-NMR (400 MHz, DMSO-t/s): 59.87 (s, 1H), 7.82 (s, 1H), 7.81 W. 7 = 3.60 Hz, 1H), 7.54 (d, 7= 3.60 Hz, 1H), 7.26 (t, 7=
54.80 Hz, 1H), 6.04 (s, 2H).
Step 2: Synthesis of 3-(4-bromo-2-(difluoromethyl) phenyl)-!, 2, 4-oxadiazole
To a stirred solution of (Z)-4-bromo-2-(difluoromethyl)-M-hydroxybenzimidamide (5 g, 18.86 mmol) in triethyl orthoformate (50 mL) was added p-TsOH (500 mg, 2.63 mmol) and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 x 150 mL). The organic layer was washed with water (150 mL), brine solution (150 mL) and dried over anhydrous Na2>SO4. filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel 100-200 mesh, Isolera, flow rate of 35 mL/min, 0- 100% EtOAc in petroleum ether) to afford 3-(4-bromo-2-(difhroromethyl) phenyl)- 1,2, 4-oxadiazole (4.0 g, 14.25 mmol, 76% yield). ’H-NMR (400 MHz, DMSO-t/e): 5 8.85 (s, 1H), 8.06-8.04 (m, 2H), 7.79-7.77 (m, 1H), 7.52 (t, J = 54.40 Hz, 1H).
Step 3: Synthesis of 3-(2-(difluoromethyl)-4-vinylphenyl)-l, 2, 4-oxadiazole
A stirred solution of 3-(4-bromo-2-(difluoro methyl)phenyl)- 1,2, 4-oxadiazole (500 mg, 1.818 mmol), trifluoro(vinyl)-14-borane, potassium salt (243 mg, 1.82 mmol) and potassium carbonate (K2CO3, 251 mg, 1.82 mmol) in 1,4-dioxane (15 mL) and water (2 mL) was sparged with nitrogen for 15 min. PdC12(dppf).CH2C12 adduct (742 mg, 0.91 mmol) was then added at room temperature. The resulting reaction mixture was stirred at 80 °C for 2 h The reaction was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with water (50 mL) and brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, Isolera, flow rate of 35 mL/min, 0-100% EtOAc in petroleum ether) to afford 3-(2-(difluoro methyl)-4-vinylphenyl)- 1,2,4- oxadiazole (200 mg, 0.78 mmol, 43% yield). ’H-NMR (400 MHz, DMSO-c/e): 5 8.83 (s, 1H), 8.14 (d, J = 8.00 Hz, 1H), 7.93 (s, 1H), 7.78-7.62 (m, 2H), 6.82 (dd, J = 17.6,10.80 Hz, IH), 5.97 (d, J = 17.60 Hz,
IH), 5.53 (d, 7= 10.80 Hz, IH).
Step 4: Synthesis of 3-(difluoromethyl)-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-10)
To a stirred solution of 3-(2-(difluoromethyl)-4-vinylphenyl)-l,2,4-oxadiazole (400 mg, 1.80 mmol) in THE (10 mL) and water (2 mL) at 0 °C was added sodium periodate (385 mg, 1.80 mmol), followed by osmium tetroxide (458 mg, 1.80 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, mesh size 100-200) using EtOAc in hexane (0 to 10%) as eluent to afford 3- (difhroromethyl)-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-10, 220 mg, 0.69 mmol, 38% yield). ’H- NMR (400 MHz, DMSO-drJ: 5 10.18 (s, IH), 8.91 (s, IH), 8.42 (s, IH), 8.38 (d, J= 8.0 Hz, IH), 8.33 (d, 7= 33.20 Hz, IH), 8.17 (dd, 7 =8.0, 0.8 Hz, IH), 7.68 (t, 7 = 54.80 Hz, IH).
Example 102: Synthesis of 4-(pyridazin-3-yl) benzaldehyde (ALD-11)
Ck o' o
B-OH Pd(PPh3)4, NaCO3,
OH EtOH/Toluene/H2O, ALD-11 80 °C, 16 h
To a stirred solution of 3-chloropyridazine (0.5 g, 4.37 mmol) and (4-formylphenyl)-boronic acid (1.178 g, 7.86 mmol) in ethanol (3 mL) and toluene (10 mL), IM aqueous NajCOa (13.1 mL, 13.1 mmol) was added at room temperature. The mixture stirred for 10 minutes under nitrogen. Then, Pd(PPh3)4 (0.303 g, 0.262 mmol) was added at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL), dried over anhydrous Na2SOr, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography, eluted with 50% acetonitrile in water, and the pure fraction was concentrated under reduced pressure to afford 4-(pyridazin-3-yl) benzaldehyde (ALD-11, 120 mg, 0.65 mmol, 15% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 185.1, ’H-NMR (400 MHz, CDCh): 8 10.15 (s, 1H), 9.26 (q, J = 1.60 Hz, 1H), 8.30 (d, J = 8.40 Hz, 2H), 8.08 (dd, J = 1.60, 6.80 Hz, 2H), 7.97 (dd, J = 1.60, 8.80 Hz, 1H), 7.66-7.62 (m, 1H).
Example 103: Synthesis of 4-( 1.3-di methyl -l//-pyraz(»l -4-yl ) benzaldehyde (ALD-12) 80 °C
Figure imgf000638_0001
To a stirred solution of l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (360 mg, 1.62 mmol) and 4-bromobenzaldehyde (250 mg, 1.351 mmol) in water (0.55 mL) and 1,4- dioxane (5 mL) under nitrogen purging, tripotassium phosphate (574 mg, 2.70 mmol) was added. The suspension was degassed with nitrogen for 5 minutes, then PdC12(dppf)-CH2C12 adduct (55.2 mg, 0.068 mmol) was added. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel 100-200 mesh, Isolera, flow rate of 35 mL/min, 40% EtOAc in petroleum ether to afford 4-(l,3-dimethyl-lH-pyrazol-4-yl) benzaldehyde (ALD-12, 240 mg, 1.18 mmol, 87% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 201.1, ’H-NMR (400 MHz, DMSO-de): 89.97 (s, 1H), 8.09 (s, 1H), 7.91 (d, J = 8.40 Hz, 2H), 7.66 (d, J = 8.00 Hz, 2H), 3.81 (s, 3H), 2.36 (s, 3H).
Example 104: Synthesis of 4-( l//-beiizo|(/|imidazol-l-yl)benzaldehyde (ALD-13)
Figure imgf000638_0002
To a stirred solution of 4-fluorobenzaldehyde (0.1 g, 0.81 mmol) in DMF (1 mL) were added K2CO3 (0.223 g, 1.61 mmol) and lH-benzo[d] imidazole (0.095 g, 0.81 mmol at room temperature. The reaction mixture was then stirred at 100 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na?SO4 filtered, and concentrated under reduced pressure. The crude product was purified by combi-flash chromatography (eluent: 30-50% EtOAc in n-hexane). The pure fractions were concentrated under reduced pressure to yield 4-(lH-benzo[d]imidazol-l-yl)benzaldehyde (ALD-13, 0.11 g, 0.46 mmol, 58% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 223.2, ’H-NMR (400 MHz, DMSO-iL.i: 8 10.11 (s, 1H), 8.72 (s, 1H), 8.17 (d, J = 6.80 Hz, 2H), 8.08 (d, J = 66.40 Hz, 2H), 7.83-7.76 (m, 2H), 7.42-7.34 (m,
2H). Example 105: Synthesis of 4-(thiazol-4-yl)benzaldehyde (ALD-14)
Figure imgf000639_0002
To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde (311 mg, 1.34 mmol) and 4-bromothiazole (0.110 mL, 1.22 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under nitrogen purging, tripotassium phosphate (518 mg, 2.44 mmol) was added. The suspension was degassed with nitrogen for 5 minutes, then PdCl2(dppf)-CH2Ch adduct (100 mg, 0.122 mmol) was added. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and tge crude residue was purified by Isolera (silica gel, 230-400 mesh) and eluted with 8% EtOAc in hexane to yield 4-(thiazol-4-yl) benzaldehyde (ALD-14, 200 mg, 0.83 mmol, 68% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 190.0, ’H-NMR (400 MHz, CDCh): 5 10.07 (s, 1H), 8.95 (d, J = 1.60 Hz, 1H), 8.14 (t, J = 1.60 Hz, 2H), 7.99 (t, J = 4.80 Hz, 2H), 7.75 (d, J = 2.00 Hz, 1H).
Example 106: Synthesis of 4-(3,5-dimethylisoxazol-4-yl)benzaldehyde (ALD-15)
Figure imgf000639_0001
100 C, 12 h
To a stirred solution of 4-bromo-3,5-dimethylisoxazole (0.5 g, 2.84 mmol) and (4- formylphenyl)boronic acid (0.767 g, 5.11 mmol) in ethanol (3 mL) and toluene (10 mL) was added NajCOs (8.52 mL, 8.52 mmol) at room temperature. The mixture was degassed with N2 for 10 min and Pd(PPh3)4 (0.197 g, 0.170 mmol) was then added at RT. The resulting reaction mixture was stirred at 100 °C for 12 h. The reaction was quenched with water and extracted with EtOAc (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography, eluting with 50% acetonitrile in H2O. The pure fractions were concentrated to afford 4-(3,5-dimethylisoxazol-4-yl) benzaldehyde (ALD-15, 0.1 g, 0.45 mmol, 16% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 202.1, ’H-NMR (400 MHz, CDCh): 5 10.08 (s, 1H), 7.99 (d, J = 2.00 Hz, 2H), 7.46 (d, J = 8.40 Hz, 2H), 2.48 (s, 3H), 2.33 (s, 3H).
Example 107: Synthesis of 3-(l//-pyrazol-l-yl)benzaldehyde (ALD-16)
Figure imgf000640_0001
To a stirred solution of IH-pyrazole (500 mg, 7.34 mmol) and (3-formylphenyl)boronic acid (2.20 g, 14.69 mmol) in DCM (20 mL), pyridine (1162 mg, 14.69 mmol) and copper(II) acetate (2.0 g, 11.02 mmol) were added. The mixture was stirred at room temperature under an oxygen bladder for 16 h. The reaction mixture was concentrated under reduced and the crude residue was purified by column chromatography (silica gel 100-200 mesh, Isolera, flow rate of 35 mL/min, 5-6% EtOAc in petroleum ether). The isolated product was re -purified using reverse phase column chromatography (Cl 8) cartridge (25 g), eluted with 5 to 100% acetonitrile in 0.1% formic acid in water. The pure fractions were collected and dried to afford 3-(lH-pyrazol-l-yl)benzaldehyde (ALD-16, 260 mg, 1.51 mmol, 21% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 173.0, ’H-NMR (400 MHz, DMSO-rL): 5 10.09 (s, 1H), 8.65 (d, J = 2.40 Hz, 1H), 8.38 (d, J = 2.00 Hz, 1H), 8.37-8.18 (m, 1H), 7.86-7.72 (m, 3H), 6.61-6.60 (m, 1H).
Example 108: Synthesis of 3-(lH-imidazol-l-yl)benzaldehyde (ALD-17)
Figure imgf000640_0002
Step 1
To a stirred solution of (3-formylphenyl)boronic acid (500 mg, 3.33 mmol) in DMSO (5 mL), IH-imidazole (454 mg, 6.67 mmol), tripotassium phosphate (1416 mg, 6.67 mmol), (E)-2-hydroxy-l,2- diphenylethan-l-one oxime (76 mg, 0.333 mmol), and copper(II) acetate (60.6 mg, 0.333 mmol) were added at room temperature. The mixture was then stirred at 80 °C for 16 h. The reaction mixture was added to EtOAc (100 mL) and water (100 mL), and the organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (100 mL) and brine solution (100 mL), dried over Na2SO4 filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by flash column chromatography using Biotage Isolera using a 100-200 mesh silica gel cartridge (100 g) with EtOAc in hexane (80%) as eluent. The isolated product was re-purified using a reverse phase Grace Cl 8 cartridge (40 g) with acetonitrile in water (0.1% formic acid) (40-50%) as the eluent. The pure fractions were collected and dried to obtain 3- (IH-imidazol-l-yl)benzaldehyde (ALD-17, 120 mg, 0.58 mmol, 17% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 173.0, ’H-NMR (400 MHz, DMSO-Je): 3 10.09 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.19-8.19 (m, 1H), 8.04-8.02 (m, 1H), 7.77 (t, J = 8.00 Hz, 2H), 7.16 (s, 1H). Example 109: Synthesis of 4-chloro-3-(l-hydroxy cyclobutyl) benzaldehyde (ALD-18)
OEt OEt TEA, DCM, HO.
Br triethyl orthoformate n-BuLi, cyclobutanone ' HO. 0 °C, 20 mi
O' Br n
EtO' EtO" ox
TI p-TSA, EtOH, toluene, -78 °C, 1.5 h 80 °C, 12 h 'Cl Hr Cl
Step 2 'Cl Step s
ALD-18
Step 1
Step 1: Synthesis of 2-bromo-l-chloro-4-(diethoxymethyl)benzene
To a stirred solution of 3-bromo-4-chlorobenzaldehyde (1 g, 4.56 mmol) in ethanol (10 mL), was added p-toluene sulfonic acid monohydrate (0.087 g, 0.46 mmol), followed by triethyl orthoformate (0.76 mL, 4.56 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over anhydrous NaiSCL filtered and concentrated under reduced pressure. The crude product was purified by neutral alumina column chromatography, eluting with 2% EtOAc in petroleum ether, to yield 2-bromo-l-chloro-4-(diethoxymethyl)benzene (1.1 g, 3.75 mmol, 82% yield). 1H-NMR (400 MHz, CDCh): 57.76 (d, J = 2.00 Hz, 1H), 7.45 (d, J = 8.40 Hz, 1H), 7.37 (dd, J = 2.00, 8.20 Hz, 1H), 5.48 (s,
1H), 3.60-3.57 (m, 4H), 1.26 (t, J = 7.20 Hz, 6H).
Step 2: Synthesis of l-(2-chloro-5-(diethoxymethyl)phenyl)cyclobutan-l-ol
To a stirred solution of 2-bromo-l-chloro-4-(diethoxymethyl) benzene (0.1 g, 0.34 mmol) in toluene (1 mL) was added n-BuLi (2.5 M in THF) (0.14 mL, 0.34 mmol) dropwise at -78 °C and the reaction was stirred at -78 °C for 20 minutes. After 20 minutes, cyclobutanone (0.024 g, 0.34 mmol) was added to the reaction mixture and stirred at -78 °C for 30 min. The reaction mixture was diluted with water (20 mL) and extracted with EtO Ac (2 x 25 mL). The combined organic layers were dried over Na2SO4. The crude compound was purified using 100-200 mesh silica gel, eluting with 20% EtOAc in hexane, to obtain l-(2-chloro-5-(diethoxymethyl)phenyl)cyclobutan-l-ol (70 mg, 0.25 mmol, 72% yield). 1H-NMR (400 MHz, DMSO-d6): 5 7.41-7.37 (m, 2H), 7.29-7.27 (m, 1H), 5.49 (s, 1H), 5.41 (s, 1H), 3.57-3.47 (m, 4H), 2.55-2.51 (m, 2H), 2.33-2.34 (m, 2H), 1.28-1.27 (m, 2H), 1.12 (t, J = 13.20 Hz, 6H).
Step 3: Synthesis of 4-chloro-3-(l-hydroxycyclobutyl)benzaldehyde (ALD-18)
To a stirred solution of l-(2-chloro-5-(diethoxymethyl)phenyl)cyclobutan-l-ol (70 mg, 0.26 mmol) in DCM (1 mL) was added TEA (0.114 mL, 1.48 mmol) dropwise at 0 °C and the reaction was stirred at 0 °C for 20 min. After completion, the reaction mixture was diluted with NaHCCL solution (20 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were dried and concentrated to obtain 4-chloro-3-(l -hydroxycyclobutyl) benzaldehyde (ALD-18, 40 mg, 0.190 mmol, 77% yield). *H- NMR (400 MHz, DMSO-de): 57.94-7.82 (m, 1H), 7.80 (d, J = 2.00 Hz, 1H), 7.62 (d, J = 8.80 Hz, 1H),
5.57 (s, 1H), 4.10 (s, 1H), 2.62-2.62 (m, 2H), 2.50-2.50 (m, 2H), 1.29-1.28 (m, 2H).
Example 110: Synthesis of 3-(oxetan-3-yl)benzaldehyde (ALD-19)
Figure imgf000642_0002
A stirred solution of (3-formylphenyl)boronic acid (500 mg, 3.33 mmol), 3-iodooxetane (1.23 g, 6.67 mmol), and CS2CO3 (2.17 g, 6.67 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen at room temperature for 15 minutes. After that, nickel (II) nitrate hexahydrate (79 mg, 0.33 mmol) and 4,4'-di-tert- butyl-2,2'-dipyridyl (90 mg, 0.33 mmol) were added and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The crude compound was purified by Isolera Biotage column chromatography using 100-200 mesh silica gel, eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 3-(oxetan-3-yl) benzaldehyde (ALD-19, 60 mg, 0.36 mmol, 11% yield). ’H-NMR (400 MHz, DMSO-r/e): 5 10.05 (s, 1H), 7.97 (s, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.76 (d, J = 7.60 Hz, 1H), 7.62 (t, J = 7.60 Hz, 1H), 4.99 (q, J = 6.00 Hz, 2H), 4.65 (t, J = 6.40 Hz, 2H), 4.37 (t, J = 7.20 Hz, 1H).
Example 111: Synthesis of 3-chloro-4-(l-hydroxycyclobutyl)benzaldehyde (ALD-20)
Figure imgf000642_0001
Step 1: Synthesis of (4-bromo-3-chlorophenyl)methanol
To a stirred solution of 4-bromo-3-chlorobenzaldehyde (1 g, 4.56 mmol) in methanol (15 mL) under a nitrogen atmosphere was added sodium borohydride (0.345 g, 9.11 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and quenched with ice water (30 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SOr and filtered. The solvent was removed under reduced pressure to afford the crude compound (4-bromo-3-chlorophenyl)methanol (1.00 g, 4.47 mmol, 98% yield). ’H-NMR (400 MHz, DMSO-de): 57.71 (d, J = 8.00 Hz, 1H), 7.55 (s, 1H), 7.23-7.21 (m, 1H), 5.40 (s, 1H), 4.48 (s, 2H).
Step 2: Synthesis of (4-bromo-3-chlorobenzyl)oxy)(tert-butyl)dimethylsilane To a stirred solution of (4-bromo-3-chlorophenyl)methanol (1.0 g, 4.52 mmol) in DMF(10 mL) under a nitrogen atmosphere was added imidazole (0.369 g, 5.42 mmol) and TBDMSC1 (0.817 g, 5.42 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Biotage Isolera (neutral alumina silica gel cartridge, 120 g) using 10% EtOAc in hexane as the eluent. The collected pure fractions were concentrated under reduced pressure to afford ((4-bromo-3 -chlorobenzyl) oxy)(tert-butyl)dimethylsilane (987 mg, 2.94 mmol, 65% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+336.9, 338.9; 'H-NMR (400 MHz, DMSO-tfc): 5 7.74 (d, J = 8.40 Hz, 1H), 7.53 (t, J = 0.80 Hz, 1H), 7.24-7.21 (m, 1H), 4.70 (s, 2H), 0.91 (s, 9H), 0.09 (s, 6H).
Step 3: Synthesis of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chlorophenyl)cyclobutan-l-ol
To a stirred solution of ((4-bromo-3-chlorobenzyl)oxy)(tert-butyl)dimethylsilane (650 mg, 1.94 mmol) in tetrahydrofuran (1.0 mL) was added n-butyllithium (1.33 mL, 2.13 mmol) at -78 °C. The reaction mixture was stirred at the -78 °C for 30 minutes, followed by the addition of cyclobutanone (149 mg, 2.13 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 12 h. The reaction was quenched with saturated NH4CI solution (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Biotage Isolera (silica gel cartridge 20 g, neutral alumina) using 0% to 10% EtOAc in hexane as the eluent. The collected fractions were concentrated under reduced pressure to yield l-(4-(((tert-butyldimethylsilyl) oxy)methyl)-2- chlorophenyl)cyclobutan-l-ol (225 mg, 0.68 mmol, 35% yield). ’H-NMR (400 MHz, DMSO-tfe): 5 7.39 (d, J = 8.00 Hz, 1H), 7.30 (s, 1H), 7.23-7.21 (m, 1H), 5.33 (s, 2H), 4.70 (s, 2H), 2.32-2.29 (m, 1H), 2.32- 2.29 (m, 1H), 2.29-2.00 (m, 1H), 1.50-1.58 (m, 1H), 0.93-0.87 (m, 10H), 0.13-0.09 (m, 6H).
Step 4: Synthesis of (4-bromo-3-chlorophenyl)methanol
To a stirred solution of l-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chlorophenyl)-cyclobutan- Lol (225 mg, 0.688 mmol) in tetrahydrofuran (1 mL), TBAF (0.69 mL, 0.69 mmol) was added at 0 °C and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated NH4CI solution and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude (90 mg). The crude compound was purified by flash column chromatography using Biotage Isolera (silica gel cartridge 20 g, neutral alumina) using 0% to 10% EtOAc in hexane as the eluent. The collected fractions were concentrated under reduced pressure to yield l-(2-chloro-4-(hydroxymethyl)phenyl)cyclobutan-l-ol (50 mg, 0.19 mmol, 27% yield). ’H-NMR (400 MHz, DMSO-d6): 57.37-7.32 (m, 1H), 7.31-7.30 (m, 1H), 7.23-7.21 (m, 1H), 5.31-5.27 (m, 2H), 4.48-4.47 (m, 2H), 2.53 (d, J = 3.60 Hz, 2H), 2.24-2.19 (m, 2H), 2.14-2.09 (m, 1H), 1.56 (m, 1H).
Step 5: Synthesis of 3-chloro-4-(l-hydroxycyclobutyl)benzaldehyde (ALD-20)
To a stirred solution of l-(2-chloro-4-(hydroxymethyl)phenyl)cyclobutan-l-ol (40 mg, 0.188 mmol) in DCM (2 mL) was added DMP (120 mg, 0.282 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at 25 °C for 1 h. The reaction mixture was quenched with NaiCOs solution, extracted with EtOAc (30 mL x 2), and the combined organic layer was dried over anhydrous Na2SO4 filtered, and concentrated. The crude obtained was washed with MTBE to get 3-chloro-4-(l- hydroxycyclobutyl)benzaldehyde (ALD-20, 39 mg, 0.19 mmol, quantitative yield). 'H-NMR (400 MHz, DMSO-rfc): 59.98 (s, 1H), 7.90-7.83 (m, 3H), 5.61 (s, 1H), 2.51-2.50 (m, 2H), 2.35-2.33 (m, 2H), 2.12-
2.08 (m, 1H), 1.91-1.62 (m, 1H).
Example 112: Synthesis of 4-chloro-3-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD-21)
Figure imgf000644_0001
Step 1: Synthesis of 2-bromo-l-chloro-4-(diethoxymethyl)benzene
To a stirred solution of 3-bromo-4-chlorobenzaldehyde (1 g, 4.56 mmol) in ethanol (10 mL), was added p-toluene sulfonic acid monohydrate (0.087 g, 0.46 mmol) and triethyl orthoformate (0.675 g, 4.56 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to obtain a crude residue. The crude product was purified by neutral alumina column chromatography, eluting with 2% EtOAc in pet ether, to yield 2-bromo-l-chloro-4-(diethoxymethyl)benzene (1.1 g, 3.75 mmol, 82% yield). ’H-NMR (400 MHz, DMSO-t/s): 57.76 (d, J = 2.00 Hz, 1H), 7.45 (d, J = 8.40 Hz, 1H), 7.38-7.36 (m, 1H), 5.48 (s, 1H), 3.61-3.55 (m, 4H), 1.26 (t, J = 7.20 Hz, 6H).
Step 2: Synthesis of 3-(2-chloro-5-(diethoxymethyl)phenyl)oxetan-3-ol
To stirred solution of 2-bromo-l-chloro-4-(diethoxymethyl)benzene (0.5 g, 1.70 mmol) in THE (2 mL) was added n-BuLi (1.6 M in hexane) (1.06 mL, 1.70 mmol) at -78 °C dropwise and stirred the reaction at -78 °C for 20 min. After 20 min, oxetan-3-one (0.123 g, 1.70 mmol) was added and the reaction stirred at -78 °C for 30 min. The reaction was quenched with NH4CI solution and extracted with EtOAc (2 x 25 mL). The combined organic layer was dried with anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude compound was purified through 100-200 silica gel column, 20% EtOAc in petroleum ether as eluent to get 3-(2-chloro-5-(diethoxymethyl)phenyl)oxetan-3- ol (70 mg, 0.17 mmol, 10% yield). 'H-NMR (400 MHz, DMSO-de): 57.45-7.42 (m, 3H), 6.31 (s, 1H), 5.56-5.49 (m, 2H), 5.05-4.03 (m, 2H), 4.38-4.29 (m, 2H), 4.70-4.72 (m, 2H), 4.30 (s, 1H), 1.16-1.14 (m, 6H).
Step 3: Synthesis of 4-chloro-3-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD-21)
To stirred solution of 3-(2-chloro-5-(diethoxymethyl)phenyl)oxetan-3-ol (0.07 g, 0.24 mmol) in DCM (1 mL) was added TFA (0.167 g, 1.465 mmol) at 0 °C dropwise and stirred at 0 °C for 20 min. The reaction was diluted with NaHCOs solution (20 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was dried and concentrated to get 4-chloro-3-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD- 21, 0.05 g, 0.24 mmol, 96% yield). ’H-NMR (400 MHz, DMSO-d6): 5 10.11 (s, 1H), 7.95-7.88 (m, 3H), 5.76 (s, 1H), 5.12-5.12 (m, 2H), 4.76-4.40 (m, 2H).
Example 113: Synthesis of 6-(l-hydroxycyclobutyl)nicotinaldehyde (ALD-22)
Figure imgf000645_0001
Step 1: Synthesis of 2-bromo-5-(diethoxymethyl)pyridine
To a stirred solution of 6-bromonicotinaldehyde (1 g, 5.38 mmol) in ethanol (10 mL) was added p-toluenesulfonic acid monohydrate (0.102 g, 0.538 mmol), followed by triethyl orthoformate (2.69 mL, 16.13 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (100 mL), extracted with EtOAc (2 x lOOmL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressue. The crude residue was purified by CombiFlash chromatography over neutral alumina, eluting with 30% EtOAc/hexane to afford 2-bromo-5- (diethoxymethyl)pyridine (1.25 g, 4.34 mmol, 81% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2H]+260.1, 262.2 1H-NMR (400 MHz, DMSO-tfc): 8 8.40 (d, J = 2.40 Hz, 1H), 7.75-7.72 (m, 1H),
7.67 (d, J = 0.40 Hz, 1H), 5.59 (s, 1H), 3.57-3.52 (m, 4H), 1.16 (t, J = 7.20 Hz, 6H).
Step 2: Synthesis of l-(5-(diethoxymethyl)pyridin-2-yl)cyclobutan-l-ol
To a stirred solution of 2-bromo-5-(diethoxymethyl)pyridine (353 mg, 1.36 mmol) in toluene (4 mL) was added n-butyllithium (0.542 mL, 1.355 mmol) at -78 °C and stirred for 1 h. Cyclobutanone (95 mg, 1.35 mmol) was then added at -78 °C and the reaction mixture was stirred for at -78 °C 1 h. The reaction was quenched with ammonium chloride solution (10 mL) and the compound was extracted with DCM (2 x 50 mL). The solvent was evaporated under reduced pressure and the crude product was purified by Combi Flash chromatography over neutral alumina, eluting with 30% EtOAc/hexane. Pure fractions were combined to yield l-(5-(diethoxymethyl)pyridin-2-yl)cyclobutan-l-ol (100 mg, 0.39 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 252.2, ’H-NMR (400 MHz, DMSO-d6): 8 8.54 (d, J = 2.00 Hz, 1H), 7.74 (d, J = 2.00 Hz, 1H), 7.57 (d, J = 0.40 Hz, 1H), 5.73 (s, 1H), 5.57 (s, 1H), 3.59- 3.55 (m, 4H), 2.23-2.20 (m, 2H), 1.93-1.91 (m, 2H), 1.87 (m, 2H), 1.16 (t, J = 6.80 Hz, 6H).
Step 3: Synthesis of 6-(l-hydroxycyclobutyl)nicotinaldehyde (ALD-22)
To a stirred solution of l-(5-(diethoxymethyl)pyridin-2-yl)cyclobutan-l-ol (90 mg, 0.36 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.55 mL, 7.16 mmol) at 0 °C and the reaction mixture was stirred for 6 h at room temperature. The reaction mixture was cooled to 0 °C and aqueous sodium bicarbonate solution (10 mL) was added. The mixture was extracted with DCM (2 x 20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to get 6-(l -hydroxycyclobutyl) nicotinaldehyde (ALD-22, 78 mg, 0.36 mmol, 99% yield). ’H-NMR (400 MHz, DMSO-de): 5 10.10 (s, 1H), 9.07 (d, J = 1.20 Hz, 1H), 8.24-8.21 (m, 1H), 7.79 (d, J = 8.00 Hz, 1H), 5.76 (s, 1H), 2.57-2.52 (m,
2H), 2.28-2.23 (m, 2H), 1.98-1.87 (m, 2H).
Example 114: Synthesis of l-(4-formylphenyl)cyclobutane-l-carbonitrile (ALD-23)
Figure imgf000646_0001
Step 1: Synthesis of l-(4-vinylphenyl)cyclobutane-l-carbonitrile
To a stirred solution of l-(4-bromophenyl)cyclobutane-l -carbonitrile (0.4 g, 1.69 mmol), trifluoro(vinyl)-L4-borane, potassium salt (0.340 g, 2.54 mmol), and K2CO3 (0.702 g, 5.08 mmol) in 1,4- dioxane (8 mL) and water (0.8 mL) was added PdChdppQ-CHoCL adduct (0.138 g, 0.169 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude product was purified by column chromatography using 100-200 mesh silica gel and 15% EtOAc in petroleum ether. The pure fractions were dried under reduced pressure to yield l-(4-vinyl-phenyl)cyclobutane-l -carbonitrile (0.23 g, 1.13 mmol, 67% yield). ’H-NMR (400 MHz, DMSO-tfc): 37.48-7.29 (m, 4H), 6.74 (dd, J = 10.80, 17.60 Hz, 1H), 5.79 (d, J = 0.80 Hz, 1H), 5.31 (d, J = 0.80 Hz, 1H), 2.89-2.82 (m, 2H), 2.68-2.60 (m, 2H), 2.49-2.42
(m, 1H), 2.14-2.08 (m, 1H).
Step 2: l-(4-formylphenyl)cyclobutane-l-carbonitrile (ALD-23)
To a stirred solution of l-(4-vinylphenyl)cyclobutane-l -carbonitrile (230 mg, 1.26 mmol) in water (0.5 mL) and acetonitrile (8 mL) was added sodium periodate (268 mg, 1.26 mmol) and 4% osmium tetroxide in water (0.197 mL, 0.025 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous NaoSOr, filtered, and concentrated under reduced pressure. The crude residue was purified by Combi Flash chromatography over neutral alumina, eluting with 30% EtOAc in hexane to afford l-(4-formylphenyl)cyclobutane-l -carbonitrile (ALD-23, 120 mg, 0.65 mmol, 52% yield). 'H-NMR (400 MHz, DMSO-rL): 5 10.06 (s, 1H), 7.95 (d, J = 6.40 Hz, 1H), 7.63 (d, J = 8.40 Hz, 1H), 7.40 (d, J = 9.60 Hz, 2H), 2.53-2.88 (m, 4H), 2.06-2.15 (m, 2H).
Example 115: Synthesis of 6-oxo-5-(trifluoromethyl)-l,6-dihydropyridine-2-carbaldehyde (ALD-24)
F
Figure imgf000647_0001
To a stirred solution of 6-(hydroxymethyl)-3-(trifluoromethyl)pyridin-2(lH)-one (0.20 g, 1.04 mmol) in DCM (5 mL) was added DMP (0.44 g, 1.04 mmol) at 0 °C and stirred at the same temperature for 3 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na^SOr. filtered, and concentrated to obtain the crude compound. The crude compound was purified by column chromatography, eluting with 4% MeOH in DCM, to afford 6-oxo-5-(trifluoromethyl)-l,6-dihydropyridine-2-carbaldehyde (ALD-24, 40 mg, 0.16 mmol, 16% yield). LCMS: m/z MM-ES+APCI, Negative [M-H] 190.7, 1H-NMR (400 MHz, DMSO-rfc): 5 12.57 (s, 1H), 9.69 (s, 1H), 8.18 (d, J = 6.80 Hz, 1H), 7.03 (br s, 1H).
Example 116: Synthesis of 7-(trifluoromethyl)-lH-indole-3-carbaldehyde (ALD-25)
Figure imgf000647_0002
A solution of POCI3 (0.497 g, 3.24 mmol) in DMF (5 mL) was stirred for 30 min. 7- (trifluoromethyl)-lH-indole (0.5 g, 2.70 mmol) in DMF (2 mL) was then added at 0 °C and stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction was diluted with 10% NaHCOr solution (25 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography using 60-120 silica gel and 40% EtOAc in hexane as the eluent to obtain 7-(trifluoromethyl)-lH-indole-3- carbaldehyde (ALD-25, 0.2 g, 0.94 mmol, 35% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 214.1, 'H-NMR (400 MHz, DMSO-rfc): 5 12.48 (s, 1H), 10.03 (s, 1H), 8.42 (t, J = 8.00 Hz, 2H), 7.64 (d, J = 7.60 Hz, 1H), 7.42 (t, J = 7.60 Hz, 1H).
Example 117: Synthesis of 4-(oxetan-3-yl)benzaldehyde (ALD-26) OH
Ni (NO A3)2-6H2O, 0
4,4'-Di-tert-butyl-2,2 -dipyridyl
H K2CO3 1 ,4 Dioxane, H
0 80°C, 16 h
O
Step 1
A stirred solution of (4-formylphenyl)boronic acid (250 mg, 1.67 mmol, 1 eq), 3-iodooxetane (614 mg, 3.33 mmol, 2 eq), and K2CO3 (691 mg, 5.00 mmol, 3 eq) in 1,4-dioxane (20 mL) was degassed with nitrogen for 15 minutes. Then, 4,4'-di-tert-butyl-2,2'-dipyridyl (44.8 mg, 0.17 mmol, 0.1 eq) and nickel(II) nitrate hexahydrate (39.6 mg, 0.17 mmol, 0.1 eq) were added at room temperature and degassed with nitrogen for 5 minutes. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and the aqueous portion was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04 filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, gradient EtOAc in hexane). The compound was eluted with 20% EtOAc in hexane. The pure fraction was concentrated under reduced pressure to yield 4-(oxetan-3-yl)benzaldehyde (ALD-26, 220 mg, 1.36 mmol, 81% yield). *H NMR (400 MHz. DMSO-d6): 8 10.00 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 4.99-4.94 (m, 2H), 4.66-4.61 (m, 2H), 4.40-4.32 (m, 1H).
Example 118: Synthesis of 4-(difluoromethoxy)-3-ethoxybenzaldehyde (ALD-27)
K2CO3 DMF, F. /F Water, 100 °C, 16 h
0.
Step 1 11
'O' CHO
To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (1 g, 6.02 mmol) in DMF (2 mL) and water (6 mL) was added sodium 2-chloro-2,2-difluoroacetate (1.37 g, 9.03 mmol) and K2CO3 (2.079 g, 15.04 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into ice-cold water (100 mL) and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 15% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 4-(difluoromethoxy)-3-ethoxybenzaldehyde (ALD-27, 190 mg, 0.87 mmol, 15% yield). 'H-NMR (400 MHz, CDCI3): 59.96 (s, 1H), 7.51 (d, J = 1.60 Hz, 1H), 7.47 (dd, J = 2.00, 8.00 Hz, 1H), 7.33 (d, J = 8.40 Hz, 1H), 7.28 (s, 1H), 4.21 (q, J = 6.80 Hz, 2H), 1.51 (t, J = 6.80 Hz, 3H).
Example 119: Synthesis of 4-bromo-lH-pyrrole-2-carbaldehyde (ALD-28)
Figure imgf000649_0002
Step 1: Synthesis of 4-bromo-lH-pyrrole-2-carbaldehyde
To a stirred solution of lH-pyrrole-2-carbaldehyde (100 mg, 1.05 mmol) in THF (4 mL) at 0 °C, was added 1 -bromopyrrolidine-2, 5-dione (187 mg, 1.05 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the crude residue was diluted with water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, gradient EtOAc in hexane). The compound was eluted with 10% EtOAc in hexane and the pure fractions were concentrated under reduced pressure to yield 4-bromo-lH-pyrrole-2-carbaldehyde (180 mg, 0.75 mmol, 72% yield). LCMS: m/z MM-ES+APCI, Negative [M-H, M-2H] 172.1 174.1; 'H-NMR (400 MHz, DMSO-t/s): 5 12.47 (s, 1H), 9.45 (s, 1H), 7.38 (s, 1H), 7.01 (s, 1H).
Step 2: Synthesis of 4-(3-(trifluoromethyl)phenyl)-lH-pyrrole-2-carbaldehyde (ALD-28)
To a stirred solution of 4-bromo-lH-pyrrole-2-carbaldehyde (25 mg, 0.14 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added (3-(trifluoromethyl)phenyl)boronic acid (32.7 mg, 0.17 mmol) and potassium phosphate tribasic (76 mg, 0.36 mmol) at 25 °C. The solution was then sparged with N2 for 10 min. Methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-l,T-biphenyl-2-yl)palladium(II) dichloromethane adduct (1.05 mg, 1.44 pmol) was added and then the mixture was sparged with N2 for 5 min. The reaction was heated at 100 °C for 16 h. The reaction was then filtered through a celite bed and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the crude was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh size; eluting 10-15% EtOAc in hexane) to afford 4-(3-(trifluoro-methyl)phenyl)-lH-pyrrole-2-carbaldehyde (ALD-28, 80 mg, 0.28 mmol, 58% yield). LCMS: m/z MM-ES+APCI, Negative [M-H] 238.3; 'H-NMR (400 MHz, CDCI3): 8 9.63 (s, 2H), 8.04 (s, 1H), 7.78 (s, 1H), 7.72 (t, J = 2.40 Hz, 1H), 7.53 (q, J = 2.00 Hz, 2H), 7.47 (t, J = 1.60 Hz, 1H).
Example 120: Synthesis of 4-(l-(trifluoromethyl)cyclopropyl)benzaldehyde (ALD-29)
Figure imgf000649_0001
Step 1: Synthesis of l-(l-(trifluoromethyl)cyclopropyl)-4-vinylbenzene
To a stirred solution of l-bromo-4-(l-(trifluoromethyl)cyclopropyl)benzene (0.10 g, 0.37 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added trifluoro(vinyl)-14-borane potassium salt (0.061 g, 0.45 mmol) and K2CO3 (0.078 g, 0.56 mmol) at 25 °C. The mixture was sparged with N2 for 5 minutes. To this reaction mixture, PdC12(dppf)-CH2C12 adduct (0.031 g, 0.038 mmol) was added and sparged with N2 for another 5 min. The resulting reaction mixture was heated at 80 °C for 1 h. After completion of the reaction as confirmed by TLC, the reaction mass was filtered through a Celite bed and washed with EtOAc (20 mL) and water (10 mL). The organic layer was concentrated under reduced pressure to afford the crude product l-(l-(trifluoromethyl)cyclopropyl)-4-vinylbenzene (100 mg, 0.47 mmol, quantitative yield) which was carried forward without purification. 'H-NMR (400 MHz, CDCL): 57.48-7.34 (m, 4H), 6.73 (q, J = 10.80 Hz, 1H), 5.78 (d, J = 17.60 Hz, 1H), 5.29 (d, J = 10.80 Hz, 1H), 1.37-1.37 (m, 2H), 1.04-1.02 (m, 2H).
Step 2: Synthesis of 4-(l-(trifluoromethyl)cyclopropyl)benzaldehyde (ALD-29)
To a stirred solution of l-(l-(trifluoromethyl)cyclopropyl)-4-vinylbenzene (100 mg, 0.47 mmol) in THF (0.6 mL) and water (0.2 mL) was added potassium osmate dihydrate (17.36 mg, 0.047 mmol) and sodium periodate (302 mg, 1.41 mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure and extracted with EtOAc (20 mL), then washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to afford the crude product 4-(l-(trifhmromethyl)cyclopropyl)benzaldehyde (ALD-29, 100 mg, 0.29 mmol, 62% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 215.
Example 121: Synthesis of 4-(3-methyloxetan-3-yl)benzaldehyde (ALD-30)
Figure imgf000650_0001
Step 1: Synthesis of 3-methyl-3-(4-vinylphenyl)oxetane
A solution of 3-(4-bromophenyl)-3-methyloxetane (200 mg, 0.88 mmol), trifluoro(vinyl)-14- borane, potassium salt (177 mg, 1.30 mmol), K2CO3 (243 mg, 1.76 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was degassed with N2 for 10 mins. Bis(diphenylphosphino)-ferrocenedichloro palladium(II) dichloromethane complex (64.4 mg, 0.088 mmol) was added into the reaction mixture. The reaction was stirred at 100 °C for 1 h. The reaction mixture was poured in cooled water (50 mL), extracted with EtOAc (2 x 50 mL), and the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Biotage Isolera column chromatography using 230-400 mesh silica gel mesh, eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to afford 3-methyl-3-(4- vinylphenyl)-oxetane (180 mg, 1.033 mmol, quantitative yield). ’H-NMR (400 MHz, CDCh): 57.49 (d, J = 2.00 Hz, 2H), 7.20 (d, J = 2.00 Hz, 2H), 6.77-6.70 (m, 1H), 5.79-5.74 (m, 1H), 5.26 (d, J = 0.80 Hz,
1H), 4.95 (s, 2H), 4.66 (s, 2H), 1.74 (s, 3H).
Step 2: Synthesis of 4-(3-methyloxetan-3-yl)benzaldehyde (ALD-30)
To a stirred solution of 3-methyl-3-(4-vinylphenyl)oxetane (150 mg, 0.86 mmol) in THF (1 mL) and water (0.2 mL) was added sodium periodate (276 mg, 1.29 mmol) and potassium osmate dihydrate (7.93 mg, 0.022 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography Biotage Isolera with silica gel using EtOAc in hexane (5-10%) as eluent. Pure fractions were concentrated under reduced pressure to afford 4-(3- methyloxetan-3-yl) benzaldehyde (ALD-30, 70 mg, 0.37 mmol, 43% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 177.0, ’H-NMR (400 MHz, CDC13): 5 10.03 (s, 1H), 7.91 (dd, J = 2.00, 5.00 Hz, 2H),
7.38 (dd, J = 1.60, 6.60 Hz, 2H), 4.97 (q, J = 5.60 Hz, 2H), 4.68 (q, J = 5.60 Hz, 2H), 1.76 (s, 3H).
Example 122: Synthesis of 4-chloro-3-(oxetan-3-yl)benzaldehyde (ALD-31) r-o
Br
Br 0 •o
0 NICIo .qlyme, TTMSS, dtbbpv, [I
(lr[dF(CF3)ppy2](dtbbpy))PF6
Cl I
Na2CO3,DME, Blue LED, 5 h
'Cl
DME, rt
Step 1
To a stirred solution of 3-bromo-4-chlorobenzaldehyde (250 mg, 1.14 mmol) and 3- bromooxetane (156 mg, 1.14 mmol) in DME (4 mL) was added Na2CO3 (241 mg, 2.28 mmol) at rt. The reaction mixture was sparged with argon for 5 min. Then, Ir[dF(CF3)ppyh(dtbbpy)PF6 (32.0 mg, 0.028 mmol), dichloronickel; 1 ,2-dimethoxyethane (7.51 mg, 0.034 mmol), 1,1, 1,3,3, 3-hexamethyl-2- (trimethylsilyl)trisilane (8.50 mg, 0.034 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl (9.17 mg, 0.034 mmol) were added and reaction mixture was stirred while being irradiated by blue LED lights at 25 °C for 5 h. The reaction mixture was filtered through a pad of celite, rinsed with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica gel mesh, eluting with 60% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to afford 4-chloro-3-(oxetan-3-yl)benzaldehyde (ALD-31, 30 mg, 0.13 mmol, 11% yield). ’H-NMR (400 MHz, DMSO-rL): 5 10.05 (s, 1H), 8.00 (d, J = 2.00 Hz, 1H), 7.85 (d, J = 9.20 Hz, 1H), 7.71 (d, J = 4.40 Hz, 1H), 4.98-4.82 (m, 2H), 4.81-4.63 (m, 2H), 3.71-3.69 (m, 1H). Example 123: Synthesis of 4-chloro-3-(2-(dimethylamino)ethoxy)benzaldehyde: (ALD-32)
Figure imgf000652_0002
To a stirred solution of 4-chloro-3-hydroxybenzaldehyde (150 mg, 0.96 mmol) in DMF (5 mL) was added K2CO3 (397 mg, 2.87 mmol) followed by 2-chloro-N,N-dimethylethan-l-amine (276 mg, 1.92 mmol) and potassium iodate (205 mg, 0.96 mmol). The reaction mixture was stirred in a microwave at 100 °C for 3 h. The reaction was quenched with water (5 mL) and extracted with 10% MeOH in DCM. The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using 230-400 mesh silica gel, eluting with 5% MeOH in DCM, to yield 4-chloro-3-(2-(dimethylamino)ethoxy)benzaldehyde (250 mg, 0.55 mmol, 57% yield). LCMS: m/z M-ES+APCI, Positive [M+H, M+2H]+ 228.0, 230.0. ’H-NMR (400 MHz, DMSO-d6): 59.98 (s, 1H), 7.70 (d, J = 8.00 Hz, 1H), 7.64 (d, J = 1.60 Hz, 1H), 7.53 (t, J = 1.60 Hz, 1H), 4.26 (t, J = 5.60 Hz, 2H), 3.17 (t, J = 8.40 Hz, 2H), 2.32 (s, 6H).
Example 124: Synthesis of 3-(oxetan-3-yl)-4-(trifluoromethyl)benzaldehyde (ALD-33) r
Figure imgf000652_0001
To a stirred solution of 3-bromo-4-(trifluoromethyl)benzaldehyde (250 mg, 0.99 mmol) and 3- bromooxetane (135 mg, 0.99 mmol) in DME (7 mL) was added NibCO; (209 mg, 1.98 mmol) at room temperature. The reaction mixture was degassed with argon for 5 min. Then, Ir[dF(CF3)ppy]2(dtbbpy)PF6 (27.7 mg, 0.025 mmol), dichloronickel; 1,2-dimethoxyethane (6.51 mg, 0.030 mmol), 1, 1,1, 3,3,3- hexamethyl-2-(trimethylsilyl)trisilane (7.37 mg, 0.030 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridyl (7.96 mg, 0.030 mmol) were added. The reaction mixture was stirred with irradiation from blue strip LED lights at 25 °C for 12 h. The reaction mixture was filtered through pad of celite, rinsed with EtOAc (100 mL), and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography using 100-200 silica gel mesh, eluted with 55% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to afford 3-(oxetan-3-yl)-4- (trifhioromethyl)benzaldehyde (30 mg, 0.099 mmol, 10% yield). LCMS: m/z M-ES+APCI, Positive [M+H]+ 231.2, ’H-NMR (400 MHz, DMSO-r/6): 5 10.15 (s, 1H), 8.20 (d, J = 12.80 Hz, 1H), 8.04-7.97 (m, 2H), 4.76-4.73 (m, 1H), 3.70 3 58 (m 4H) Example 125: Synthesis of 3-(4-fluorophenyl)cyclobutane-l-carbaldehyde (ALD-34)
CK
0
Li
Diethyl isocyanomethylphosphonate -78 °C- rt, THF, 16h
Step 1
F F
To a stirred solution of diethyl isocyanomethylphosphonate (108 mg, 0.61 mmol) in THF (10 mL) was added n-butyllithium (0.244 mL, 0.61 mmol) was added at -78 °C and stirred under a nitrogen atmosphere for 1 h. Then, 3-(4-fluorophenyl)cyclobutan-l-one (100 mg, 0.61 mmol) in THF (2 mL) was added to the reaction mixture at -78 °C and stirred at room temperature for 4 h. The reaction mixture was then quenched with concentrated HC1 and stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-(4- fluorophenyl)cyclobutane-l-carbaldehyde (70 mg, 0.39 mmol, 65% yield). ’H-NMR (400 MHz, DMSO- d6): 59.70 id J = 5.60 Hz, 1H), 7.27-7.25 (m, 2H), 7.14-7.11 (m, 2H), 3.92-3.90 (m, 2H), 3.67-3.57 (m, 4H).
Example 126: Synthesis of 3-phenylcyclobutane-l-carbaldehyde (ALD-35)
0
0 O' T° °1 n-BuLi ,THF, -78°C -rt, 16 h
Step 1
To a stirred solution of diethyl isocyanomethylphosphonate (0.121 g, 0.68 mmol) in THF (10 mL) was added n-butyllithium (0.27 mL, 0.68 mmol) at -78 °C and the mixture was stirred under a nitrogen atmosphere for 1 h. Then, a solution of 3-phenylcyclobutan-l-one (0.1 g, 0.68 mmol) in THF (2 mL) was added to the reaction mixture at -78 °C and allowed to warm to room temperature, stirring for an additional 4 h. The reaction was then treated with 1.5 N HC1 and stirred at room temperature for 16 h. The reaction was quenched by adding water (10 mL) and the mixture was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a 3-phenylcyclobutane-l-carbaldehyde (ALD-35, 20 mg, 0.68 mmol, 18% yield). ’H-NMR (400 MHz, CDCh): 5 7.32-7.28 (m, 5H), 9.71 (s, 1H), 3.53-3.51 (m, 4H), 2.07 (m, 2H).
Example 127: Synthesis of 4-(3-hydroxyoxetan- 3- yl) benzaldehyde (ALD-36)
Figure imgf000654_0001
Br ,0
Step-1 HO' Step-2
Step 1: Synthesis of 3-(4-(diethoxymethyl)phenyl)oxetan-3-ol
To a stirred solution of l-bromo-4-(ethoxy(methoxy)methyl)benzene (1 g, 4.08 mmol) in THF (10 mL), nBuLi (3.06 mL, 4.90 mmol) was added dropwise at -78 °C. The reaction was allowed to proceed for 20 minutes, after which oxetan-3-one (0.294 g, 4.08 mmol) was added at the same temperature and stirred for 1 h. The reaction mixture was quenched with water (50 mL) and the product was extracted with EtOAc (2 x 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This crude product was purified by normal phase column chromatography using 100-200 silica mesh and eluting with 11% EtOAc in hexane. The pure fractions were concentrated under reduced pressure to afford 3-(4-(diethoxymethyl)-phenyl)oxetan-3-ol (400 mg, 1.59 mmol, 39% yield). 1H-NMR (400 MHz, DMSO-ds): 5 7.60 (d, J = 2.00 Hz, 2H), 7.42 (d, J = 8.40 Hz, 2H), 6.34 (s, 1H), 5.49 (s, 1H), 4.77 (d, J = 6.80 Hz, 2H), 4.68 (d, J = 6.80 Hz, 2H), 3.57-3.53 (m, 4H), 1.17 (t, J = 2.40 Hz, 6H).
Step 2: Synthesis of 4-(3-hydroxyoxetan-3-yl)benzaldehyde
To stirred solution of 3-(4-(diethoxymethyl)phenyl)oxetan-3-ol (60 mg, 0.24 mmol) in DCM (1.5 mL) was added TEA (29.8 mg, 0.262 mmol) at 25 °C for 30 min. The reaction was quenched with NaHCCh (5 mL) and extracted with DCM (2 x 25 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get 4-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD-36, 40 mg, 0.238 mmol, 94% yield). 1H-NMR (400 MHz, CDCh): 5 10.07 (s, 1H), 7.97 (d, J = 2.00 Hz, 2H), 7.86 (s, 2H), 4.97-4.91 (m, 4H).
Example 128: Synthesis of 2-cyclopropoxy-4-(trifluoromethyl)benzaldehyde (ALD-37)
Figure imgf000654_0002
To a stirred solution of cyclopropanol (166 mg, 2.86 mmol) in DMSO (8 mL) under nitrogen atmosphere, 2-fluoro-4-(trifluoromethyl) benzaldehyde (500 mg, 2.60 mmol) was added at rt and stirred for 5 min. Then, K2CO3 (432 mg, 3.12 mmol) was added and stirred at rt for 5 min. Then reaction mixture was stirred under microwave at 100 °C for 1 h. The reaction mixture was poured in cooled water (100 mL), and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 50% EtOAc in hexane The collected pure fractions were concentrated under reduced pressure to get 2-cyclopropoxy-4- (trifhroromethyl)benzaldehyde (ALD-37, 50 mg, 0.22 mmol, 8% yield). alH-NMR (400 MHz, DMSO- d6): 5 10.48 (s, 1H), 7.87-7.78 (m, 3H), 4.23-4.22 (m, 1H), 0.49-0.48 (m, 4H).
Example 129: Synthesis of 4-(l-hydroxycyclobutyl)benzaldehyde (ALD-38)
Figure imgf000655_0002
Step 1: Synthesis of l-(4-(diethoxymethyl)phenyl)cyclobutan-l-ol
To a stirred solution of l-bromo-4-(diethoxymethyl)benzene (500 mg, 1.93 mmol) and cyclobutanone (0.147 mL, 1.93 mmol) in THF (2 mL) was added n-butyllithium in hexane (1.16 mL, 2.89 mmol) at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over anhydrous Na^SOr. filtered, and concentrated to afford crude l-(4-(diethoxymethyl)phenyl)cyclobutan-l-ol (300 mg, 1.198 mmol, 62% yield). LCMS: ES+APCI, Positive [M+HJ+ 251 1H-NMR (400 MHz, DMSO-d6): 5 7.49 (t, J = 3.60 Hz, 2H), 7.39-7.34 (m, 2H), 5.47 (s, 1H), 3.55-3.47 (m, 2H), 3.23 (s, 1H), 2.50 (t, J = 1.60 Hz, 2H), 2.37 (m, 2H), 2.27 (q, J = 2.40 Hz, 2H), 1.95 (s, 2H), 1.18-1.13 (m, 6H).
Step 2: Synthesis of 4-(l-hydroxycyclobutyl)benzaldehyde (ALD-38)
To a stirred solution of l-(4-(diethoxy methyl)phenyl)cyclobutan-l-ol (300 mg, 1.198 mmol) in DCM (2 mL) was added TEA (137 mg, 1.198 mmol) at 0 °C. The resulting reaction mixture was stirred at 25°C. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography Biotage Isolera with silica gel (100-200 mesh) cartridge (20 g) using EtOAc in hexane (5-10%) as eluent. Pure fractions were concentrated under reduced pressure to afford 4-(l -hydroxycyclobutyl) benzaldehyde (ALD-38, 60 mg, 0.297 mmol, 25% yield). LCMS: ES+APCI, Positive [M+HJ + 177, 1H-NMR (400 MHz, DMSO-d6): 5 10.00 (s, 1H), 7.89 (q, J = 1.60 Hz, 2H), 7.72 (d, J = 8.00 Hz, 2H), 2.52-2.50 (m, 1H), 2.33-2.28 (m, 2H), 1.99-1.91 (m, 2H), 1.73 (t, J = 6.80 Hz, 2H).
Example 130: Synthesis of 4-(l-methoxycyclobutyl)benzaldehyde (ALD-39)
Figure imgf000655_0001
Step 1: Synthesis of l-(4-(dimethoxymethyl)phenyl)cyclobutan-l-ol
To the stirred solution of l-bromo-4-(dimethoxymethyl)benzene (500 mg, 2.164 mmol) in THE (1.0 mL) was added n-butyllithium in hexane (2.028 mL, 3.25 mmol) at-78 °C. The resulting reaction mixture was stirred at -78 °C for 30 mins. Then, cyclobutanone (303 mg, 4.33 mmol) was added and the resulting reaction mixture was stirred at -78 °C to 25 °C. The reaction mixture was quenched with water (50 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extract was dried over anhydrous NaiSO4 and filtered the solvent was removed under reduced pressure to afford the crude compound. The crude compound was purified by silica gel flash column chromatography, eluting with 0-10% EtOAc in Hexane to afford l-(4-(dimethoxymethyl)phenyl)cyclobutan-l-ol (120 mg, 0.540 mmol, 25% yield. LCMS: m/z MM-ES+APCI, Positive [M+H]+ No ionization. 1H-NMR (400 MHz, DMSO-d6): 8 1H-NMR (400 MHz, DMSO-d6): 87.89 (d, J = 1.60 Hz, 2H), 7.72 (d, J = 8.40 Hz,
2H), 5.482 (s, 1H), 4.23 (1H), 3.324 (s, 6H), 2.38-2.34 (m, 2H), 2.00-1.92 (m, 2H), 1.66-1.61 (m, 2H).
Step 2: Synthesis of 4-(l-methoxycyclobutyl)benzaldehyde (ALD-39)
To stirred solution of l-(4-(dimethoxymethyl)phenyl)cyclobutan-l-ol (0.7 g, 3.15 mmol) in DMF (2.0 mL) was added NaH (0.091 g, 3.78 mmol) at 0 °C and continue for 30 min. Then was added Mel (0.591 mL, 9.45 mmol) then the reaction mixture was stirred at 80 °C for 12 h. The progress of reaction was monitored by TLC/LCMS. After completion of reaction, the reaction mass was quenched with ice cold water (50 mL) and the compound was extracted by EtOAc (30*3) and dried over anhydrous Na2SC>4, the organic layer concentrate under reduced pressure to afford gummy crude. The crude was purified by normal phase column chromatography using (100-200 silica mesh) eluting with 20% of ethyl in hexane as an eluent to afford 4-(l-methoxy-cyclobutyl) benzaldehyde (ALD-39) (150 mg, 0.788 mmol, 25% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ No ionization. 1H-NMR (400 MHz, DMSO-d6): 8 1H- NMR (400 MHz, DMSO-d6): 8 10.03 (s, 1H), 7.95 (dd, J = 2.00, 6.60 Hz, 2H), 7.65 (d, J = 8.00 Hz, 2H),
2.87 (s, 3H), 2.36 (t, J = 7.20 Hz, 2H), 1.92-1.89 (m, 2H), 1.69-1.62 (m, 2H).
Example 131: Synthesis of 4-(thiazol-2-yloxy) benzaldehyde (ALD-40)
Figure imgf000656_0001
Step 1: Synthesis of 1 ethyl 4-(thiazol-2-yloxy)benzoate
To the stirred solution of 2-bromothiazole (1.0 g, 6.10 mmoljin DMSO (10 mL) were added ethyl 4-hydroxybenzoate (1.013 g, 6.10 mmol), potassium carbonate (2.53 g, 18.29 mmol) at room temperature. The resulting reaction mixture was stirred at 120 °C for 4 h. The progress of reaction was monitored by TLC/LCMS. After completion of reaction, the reaction mixture was cooled to room temperature, diluted with hexane (200 mL), water (400 mL). The organic layer was separated, dried over anhydrous Na2SO4 solvents were removed by vacuum to obtained crude (1.5g). The obtained crude was purified by flash chromatography using 40g (230-400 mesh) column 0-10% EtOAc in hexane as eluent. Pure fractions were concentrated to afford ethyl 4-(thiazol-2-yloxy)benzoate (0.75 g, 2.99 mmol, 49% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 250.1. 1H-NMR (400 MHz, DMSO-d6): 5 8.15-8.11 (m, 2H), 7.38-
7.35 (m, 2H), 7.29 (t, J = 4.00 Hz, 1H), 6.92 (d, J = 4.00 Hz, 1H), 4.40 (q, J = 6.80 Hz, 2H), 1.42 (t, J = 6.80 Hz, 3H).
Step 2: Synthesis of 4-(thiazol-2-yloxy)benzaldehyde (ALD-40)
A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (257 mg, 2.95 mmol) and THE (5 mL). After cooling to 0°C, DIBAL-H (2.340 mL, 2.81 mmol) was added dropwise, and the mixture was stirred at 0°C for 3 h. Ethyl 4-(thiazol-2-yloxy)benzoate (350 mg, 1.404 mmol) in THE (5.00 mL) was added slowly to the reaction mixture, which was stirred for 20 min. Then, DIBAL-H (1.287 mL, 1.544 mmol) was added, and the mixture was stirred for 20 min. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with IN HC1 (20 mL), extracted with EtOAc (2 X 30 mL). The organic layer was separated, dried over anhydrous Na^SO^ solvents were removed by vacuum to obtained crude material. The crude material was purified by flash chromatography using 40g (230-400 mesh) column 0-15% EtOAc in hexane as eluent. Pure fractions were concentrated to afford 4-(thiazol-2-yloxy)benzaldehyde (ALD-40) (190 mg, 0.888 mmol, 63% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 206.1. 1H-NMR (400 MHz. DMSO-d6): 5 1H-NMR (400 MHz, DMSO-d6): 5 10.02 (s, 1H), 7.97 (dd, J = 2.00, 6.80 Hz. 2H), 7.48 (dd, J = 1.60, 6.80 Hz, 2H), 7.32 (d, J = 3.60 Hz, 1H), 6.96 (d, J = 4.00 Hz, 1H).
Example 132: Synthesis of 4-(thiazol-2-ylamino)benzaldehyde (ALD-41)
Figure imgf000657_0001
To a stirred solution of thiazol-2-amine (200 mg, 1.997 mmol) and 4-bromobenzaldehyde (370 mg, 1.997 mmol) in 1,4-Dioxane (5 mL) was added by K2CO3 (414 mg, 3.00 mmol) at RT. The reaction mixture was sparged with argon for 10 min and was added by Pd2(dba)s (183 mg, 0.200 mmol) followed by Xantphos (57.8 mg, 0.100 mmol) and sparged with argon for 10 min. Then reaction mixture was irradiated at 100 °C for 1 h. The progress of reaction was monitored by TLC/LCMS. After completion of reaction mixture, the reaction mixture was concentrated under reduced pressure to get crude. The crude compound was purified by silica gel flash column chromatography eluting with EtOAc to afford 4- (thiazol-2-ylamino)benzaldehyde (ALD-41) (150 mg, 0.700 mmol, 35% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 205.0. 1H-NMR (400 MHz, DMSO-d6): 8 1H-NMR (400 MHz, DMSO-d6):
8 10.77 (s, 1H), 9.83 (s, 1H), 7.87-7.82 (m, 4H), 7.37 (d, J = 3.60 Hz, 1H), 7.08 (d, J = 3.60 Hz, 1H).
Example 133: Benzyl 4-(4-acetylpiperazin- 1-yl) benzaldehyde (ALD-42)
Figure imgf000658_0001
To a stirred solution of 1 -(piperazin- l-yl)ethan- Lone (200 mg, 1.560 mmol) in DMF (5 mL) was added 4-fluorobenzaldehyde (232 mg, 1.872 mmol) followed by K2CO3 (323 mg, 2.341 mmol) at RTand the reaction mixture was stirred at 120 °C for 12 h. The progress of reaction was monitored by TLC/LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to get crude. The crude material was purified by silica gel flash column chromatography eluting with EtOAc to afford benzyl 4-(4-acetylpiperazin-Lyl)-benzaldehyde (180 mg, 0.649 mmol, 42% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 233.0. 1H-NMR (400 MHz, DMSO-d6): 8 1H-NMR (400 MHz, DMSO-d6): 89.73 (s, 1H), 7.74 (d, J = 8.80 Hz, 2H), 7.05 (d, J = 9.20 Hz, 2H), 3.59-3.17 (m, 8H), 2.05 (s, 3H).
Example 134: Synthesis of 3-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-43)
Figure imgf000658_0002
Step 1: Synthesis of 3-bromo-N-hydroxybenzimidamide
To a stirred solution of hydroxylamine hydrochloride, H2O (1.086 g, 12.41 mmol) in Water (2.5 mL) were added sodium bicarbonate (1.043 g, 12.41 mmol) at RT and resulting reaction mixture was stirred at RT for 10 min. Then followed by the addition a solution of methyl 3 -cyanobenzoate (1 g, 6.21 mmol) in MeOH (2.5 mL) at RT. Then resulting reaction mixture was stirred at RT for 16 h. The progress of reaction as confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give crude compound, the crude compound was dissolved in EtOAc (50 mL) and washed with water (2 x 20 mL), organic layer dried over anhydrous Na3SO4, filtered, and concentrated under reduced pressure to afford crude compound. The crude compound was washed with Hexane (2 x 10 mL) to afford methyl 3-(N-hydroxycarbamimidoyl)benzoate (1.0 g, 5.06 mmol, 81% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 194.9. 1H-NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): 5 9.77 (s, 1H), 8.30 (t, J = 1.60 Hz, 1H), 7.97-7.93 (m,
2H), 7.54 (t, J = 11.60 Hz, 1H), 5.94 (s, 1H), 3.88 (s, 3H).
Step 2: Synthesis of methyl 3-(l,2,4-oxadiazol-3-yl)benzoate
To a stirred solution of methyl 3-(N-hydroxycarbamimidoyl)benzoate (800 mg, 4.12 mmol) in triethyl orthoformate (9158 mg, 61.8 mmol) was added 4-methylbenzenesulfonic acid, H2O (78 mg, 0.412 mmol) at room temperature and resulting reaction mixture was stirred at 95 °C for 12 h. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give crude compound. The crude compound was purified by Isolera column chromatography (silica gel, 230- 400 mesh) and eluted with 10% EtOAc in Hexane to afford methyl 3-(l,2,4-oxadiazol-3-yl)benzoate (770 mg, 3.06 mmol, 74% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 204.9. 1H-NMR (400 MHz, DMSO-d6): 5 1H-NMR (400 MHz, DMSO-d6): 59.79 (s, 1H), 8.59 (d, J = 1.60 Hz, 1H), 8.32 (dd, J =
1.60, 4.60 Hz, 1H), 8.19 (dd, J = 1.20, 6.60 Hz, 1H), 7.77 (t, J = 7.60 Hz, 1H), 3.92 (s, 3H).
Step 3: Synthesis of 3-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-43)
A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.444 mL, 5.14 mmol) and THE (10 mL). After cooling to 0°C, DIBAL-H (4.08 mL, 4.90 mmol) was added dropwise, and the mixture was stirred for 3 h at the same temperature, methyl 3- (l,2,4-oxadiazol-3-yl)benzoate (500 mg, 2.449 mmol) in THE (5 mL) was added slowly to the reaction mixture, which was stirred for 20 min. Then, DIBAL-H (2.245 mL, 2.69 mmol) was added, and the mixture was stirred for 20 min. After completion of reaction, the reaction mixture was quenched with IN HC1 (40 mL), extracted with EtOAc (2 X 150 mL). The organic layer was separated, dried over anhydrous Na2SC>4 solvents were concentrated under reduced pressure to get crude residue. The crude was purified by flash chromatography using 40g (230-400 mesh) column 0-15% EtOAc in hexane as eluent to afford 3-(l,2,4-oxadiazol-3-yl)benzaldehyde (0.2 g, 1.068 mmol, 44% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ No ionisation. 1H-NMR (400 MHz, DMSO-d6): 5 1H-NMR (400 MHz, DMSO-d6): 5 10.14 (s, 1H), 9.80 (s, 1H), 8.54 (t, J = 1.60 Hz, 1H), 8.37-8.15 (m, 1H), 8.15-8.13 (m, 1H), 7.83 (t, J = 7.60 Hz, 1H).
Example 135: 3-cyclopropyl-l-methyl-lH-pyrazole-5-carbaldehyde (ALD-44)
Figure imgf000659_0001
Step 1: Synthesis of ethyl 4-cyclopropyl-2,4-dioxobutanoate To a stirred solution of sodium ethoxide (0.809 g, 11.89 mmol) in Ethanol (20 mL) was added 1- cyclopropylethan-l-one (1.0 g, 11.89 mmol) and diethyl oxalate (1.737 g, 11.89 mmol) dropwise at 0 °C, then reaction mixture was stirred at 0 °C-RT for 1 h. After Ih, reaction mixture was stirred at 80 °C for 45 min. After completion reaction mixture was cooled to room temperature, solvent was distilled out, then neutralized with 2N H2SO4 solution and extracted with EtOAc. The Organic layer was dried over anhydrous NaiSOr and concentrated under reduced pressure to afford ethyl 4-cyclopropyl-2,4- dioxobutanoate (1.5 g, 7.17 mmol, 60% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 185. 1H- NMR (400 MHz, DMSO-d6): 5 1H-NMR (400 MHz, DMSO-d6): 54.68 (s, 2H), 4.44-4.35 (m, 2H), 2.28-1.44 (m, 1H), 1.42-1.38 (m, 3H), 1.28-1.25 (m, 2H), 1.11-1.09 (m, 2H).
Step 2: Synthesis of ethyl 3-cyclopropyl-l-methyl-lH-pyrazole-5-carboxylate
To a stirred solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (1.5 g, 8.14 mmol) in Ethanol (15 mL) was added methylhydrazine (0.609 mL, 9.77 mmol) at -10 °C. Then reaction mixture was stirred at same temperature for 2 h. After completion reaction mixture was distilled out diluted with water and compound was extracted with EtOAc. The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get crude. The crude was purified by combi-flash chromatography (Eluent 0- 20% EtOAc in n-Hexane) to afford ethyl 3-cyclopropyl-l-methyl-lH-pyrazole-5-carboxylate (0.3 g, 1.455 mmol, 18% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 195.1. 1H-NMR (400 MHz, DMSO-d6): 8 1H-NMR (400 MHz, DMSO-d6): 8 6.56 (s, 1H), 4.27 (t, J = 7.20 Hz, 2H), 3.98 (s, 3H), 1.89-1.31 (m, 1H), 1.29 (t, J = 6.80 Hz, 3H), 0.88 (t, J = 2.40 Hz, 2H), 0.85 (t, J = 3.60 Hz, 2H).
Step 3: Synthesis of 3-cyclopropyl-l-methyl-lH-pyrazole-5-carbaldehyde (ALD-44)
To a stirred solution of morpholine (0.217 g, 2.487 mmol) in THE (2 mL) was added DIBAL-H (1.974 mL, 2.368 mmol) at 0 °C. Then reaction mixture was stirred at 0 CC for 3 h. After that ethyl 3- cyclopropyl-1 -methyl- lH-pyrazole-5-carboxylate (0.23 g, 1.184 mmol) in THE (2.000 mL) was added and stirred for 5 min then DIBAL-H (1.085 mL, 1.303 mmol) was added at 0 °C and resulting reaction mixture was stirred at 0 °C for 1 h. After completion reaction was quenched with saturated NH4CI solution (20 mL) and compound was extracted with EtOAc (2 x 30 mL). The organic layer was dried over anhydrous Na2SOr and concentrated under reduced pressure to get crude. The crude was purified by combi-flash chromatography (Eluent 5-10% EtOAc in n-Hexane to afford 3 -cyclopropyl- 1 -methyl- 1H- pyrazole-5-carbaldehyde (0.11 g, 0.635 mmol, 54% yield). 86.75. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 151.0. 1H-NMR (400 MHz, DMSO-d6): 8 1H-NMR (400 MHz, DMSO-d6): 89.79 (s, 1H), 6.56-6.50 (m, 1H), 4.36-4.29 (m, 3H), 1.99-1.94 (m, 1H), 0.99-0.96 (m, 2H), 0.77 (t, J = 2.00 Hz, 2H).
Example 136: Synthesis of 4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-45)
Figure imgf000661_0002
Step 1: Synthesis of Methyl 4-(l,2,4-oxadiazol-3-yl)benzoate
To a stirred solution of 2-(4-bromophenyl)-2-methylpropanenitrile (200 mg, 0.892 mmol) in 1 ,4- dioxane (3 mL) and water (0.333 mL) in a 20 mL vial under a nitrogen atmosphere, trifluoro(vinyl)borane potassium salt (239 mg, 1.785 mmol) and K2CO3 (370 mg, 2.68 mmol) were added at room temperature. The resulting reaction mixture was sparged with nitrogen for 10 minutes, then PdC^dppff Cl-hCh adduct (72.9 mg, 0.089 mmol) was added. The reaction mixture was irradiated under microwave at 80 °C for 1 h. After completion of the reaction as confirmed by LCMS/TLC, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (2 x 50 mL), dried over anhydrous NajSCL, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by combi flash chromatography on 230-400 silica, eluting with 10% EtOAc in hexane, to afford 4-bromo-3- chloro-2-fhmrobenzonitrile (450 mg, 1.862 mmol, 15% yield). ’H-NMR (400 MHz, DMSO-d6): 57.45 (s, 4H), 6.74 (dd, J = 11.20, 17.60 Hz, 1H), 5.81-5.77 (m, 1H), 5.32-5.29 (m, 1H), 1.75 (s, 6H).
Step 2: Synthesis of 2-(4-formylphenyl)-2-methylpropanenitrile (ALD-45)
To a stirred solution of 2-methyl-2-(4-vinylphenyl)propanenitrile (140 mg, 0.785 mmol) in water (0.600 mL) and tetrahydrofuran (3 mL), sodium periodate (168 mg, 0.785 mmol) and potassium osmate dihydrate (289 mg, 0.785 mmol) were added at room temperature and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SC>4, filtered, and concentrated to afford the crude product. The crude product was purified by combi flash chromatography over neutral alumina, eluting with 30% EtOAc in hexane, to afford 2-(4-formylphenyl)- 2-methylpropanenitrile (30 mg, 0.170 mmol, 22% yield). LCMS: ES+APCI, Positive [M+H]+ 174.13. *H- NMR (400 MHz, DMSO-d6): 5 10.06 (s, 1H), 7.95 (d, J = 4.80 Hz, 2H), 7.69 (d, J = 1.60 Hz, 2H), 1.79 (s, 6H).
Example 137: Synthesis of 4-(2-hydroxypropan-2-yl) benzaldehyde (ALD-46)
Figure imgf000661_0001
Step 1: Synthesis of 2-(4-vinylphenyl)propan-2-ol To a stirred solution of 2-(4-bromophenyl)propan-2-ol (500 mg, 2.325 mmol) in 1,4-dioxane (6 mL) and water (0.750 mL) in a 20 mL vial under a nitrogen atmosphere, vinyl trifluoroborate (320 mg, 1.262 mmol) and K2CO3 (964 mg, 6.97 mmol) were added at room temperature. The resulting reaction mixture was sparged with nitrogen for 10 minutes, then PdCbldppfl-CTLCL adduct (190 mg, 0.232 mmol) was added and the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (2 x 50 mL), and dried over anhydrous NaiSO^ filtered, and solvent was evaporated under reduced pressure to afford the crude product. The crude product was purified by combi flash chromatography on 230-400 silica, eluting with 10% EtOAc in hexane, to afford 2-(4-vinylphenyl) propan-2-ol (320 mg, 1.262 mmol, 54% yield). ’H-NMR (400 MHz, DMSO-d6): 57.47-0.40 (m, 4H), 6.71 (dd, J = 11.20, 17.80 Hz, 1H), 5.80-5.75 (m, 1H), 5.22-5.19 (m,
1H), 5.00 (s, 1H), 1.17 (s, 6H).
Step 2: Synthesis of 4-(2-hydroxypropan-2-yl)benzaldehyde (ALD-46)
To a stirred solution of 2-(4-vinylphenyl)propan-2-ol (321 mg, 1.266 mmol) in THF (2 mL) and water (0.400 mL), sodium periodate (298 mg, 1.393 mmol) and potassium osmate dihydrate (233 mg, 0.633 mmol) were added at room temperature and the reaction mixture was stirred at room temperature for 1 h. After completion as confirmed by TLC, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2 x 50 mL). The solvent was evaporated under reduced pressure to afford the crude product. The crude product was purified by combi flash chromatography over neutral alumina, eluting with 30% EtOAc in hexane, to afford 4-(2-hydroxypropan-2-yl)benzaldehyde (50 mg, 0.289 mmol, 23% yield). LCMS: ES+APCI, Positive [M+H]+ 165.0, ’H-NMR (400 MHz, DMSO-d6): 5 9.98 (s, 1H), 7.85 (d, J = 8.40 Hz, 2H), 7.70 (d, J = 8.40 Hz, 2H), 5.23 (s, 1H), 1.45 (s, 6H).
Example 138: Synthesis of 4-(3-hydroxy-3-methylazetidin-l-yl)benzaldehyde (ALD-47) o' K2CO3, BIN o'
CIHHN'T AP, Pd(OAc)2, lA-OH N'T
Toluene, 100 °C, 12 h VA-OH Step-1
To a stirred solution of 4-iodobenzaldehyde (500 mg, 2.155 mmol) in toluene (5 mL), 3- methylazetidin-3-ol (346 mg, 2.80 mmol) and K2CO3 (596 mg, 4.31 mmol) were added at room temperature. Then, BINAP (268 mg, 0.431 mmol) was added, followed by Pd(OAc)2 (48.4 mg, 0.215 mmol) at RTand the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2>SO4 filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to yield 4-(3-hydroxy-3-methylazetidin-l- yl)benzaldehyde (350 mg, 1.756 mmol, 81% yield). ’H-NMR (400 MHz, DMSO-d6): 59.89 (s, 1H), 7.29 (d, J = 2.00 Hz, 2H), 6.39 (d, J = 2.00 Hz, 2H), 5.52 (s, 1H), 3.68 (d, J = 6.00 Hz, 2H), 3.58 (d, J = 11.60 Hz, 2H), 1.36 (s, 3H).
Example 139: Synthesis of 6-(l,2,4-oxadiazol-3-yl)nicotinaldehyde (ALD-48)
Figure imgf000663_0001
Step 1: Synthesis of ethyl (Z)-6-(N'-hydroxycarbamimidoyl)nicotinate
To a stirred solution of methyl 6-cyanonicotinate (2 g, 12.33 mmol) in ethanol (20 mL) and water (20 mL), hydroxylamine hydrochloride (2.15 g, 24.67 mmol) and K2CO3 (3.41 g, 24.67 mmol) were added at room temperature and stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product. EtOAc (50 mL) and water (50 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified via chromatography to obtain ethyl (Z)-6-(N’-hydroxycarbamimidoyl) nicotinate (0.9 g, 2.94 mmol, 24% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 210.0, 'H-NMR (400 MHz, DMSO-de): 5 10.23 (d, J = 2.80 Hz, 1H), 9.06 (s, 1H), 8.30-8.27 (m, 1H), 8.00 (d, J = 8.40 Hz, 1H), 5.95 (s, 2H), 4.39-4.34 (m,
1H), 3.91 (s, 1H), 1.35 (t, J = 7.20 Hz, 3H).
Step 2: Synthesis of ethyl 6-(l,2,4-oxadiazol-3-yl)nicotinate
To a stirred solution of ethyl (Z)-6-(N’-hydroxycarbamimidoyl)nicotinate (0.9 g, 4.3 mmol) in triethyl orthoformate (14.33 mL, 86 mmol), 4-methylbenzenesulfonic acid monohydrate (0.082 g, 0.43 mmol) was added at room temperature. The resulting reaction mixture was stirred at 95 °C for 6 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product. EtOAc (50 mL) and water (50 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography using Biotage Isolera using a 50 g silica gel cartridge (100-200 mesh), eluting with 20% EtOAc in hexane. The pure fractions were concentrated to yield ethyl 6-(l,2,4-oxadiazol-3-yl) nicotinate (0.65 g, 2.48 mmol, 58% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 220.0, 'H-NMR (400 MHz, DMSO-rfc): 59.86 (s, 1H), 9.25 (d, J = 1.20 Hz, 1H), 8.55-8.51 (m, 1H), 8.28 (d, J = 8.00 Hz, 1H), 4.43-4.38 (m, 2H), 1.37 (t, J = 7.20 Hz, 3H).
Step 3: Synthesis of 6-(l,2,4-oxadiazol-3-yl)nicotinaldehyde (ALD-48)
To a stirred solution of morpholine (1.93 g, 22.18 mmol) in THF (10 mL), DIBAL-H (18.48 mL, 22.18 mmol) was added at 0 °C and stirred for 2 h. Methyl 6-(l,2,4-oxadiazol-3-yl)nicotinate (0.65 g, 3.17 mmol) in THF (5 mL) was then added and stirred for 30 min. Then, DIBAL-H (13.20 mL, 15.84 mmol) was added at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with 1.5 N HC1 solution and extracted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous NazSO^ filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography using Biotage Isolera using a 100 g silica gel cartridge (100-200 mesh), eluting with 10% IP A in DCM. The pure fractions were concentrated to yield 6-(l,2,4-oxadiazol-3- yl)nicotinaldehyde (ALD-48, 0.15 g, 0.78 mmol, 25% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 176.1, ’H-NMR (400 MHz, DMSO-rfc): 5 10.21 (s, 1H), 9.87 (s, 1H), 9.27 (d, J = 1.20 Hz, 1H), 8.50-8.48 (m, 1H), 8.34 (d, J = 8.00 Hz, 1H).
Example 140: Synthesis of isothiazole-4-carbaldehyde (ALD-49)
Figure imgf000664_0001
Step 1: Synthesis of methyl isothiazole-4-carboxylate
To a stirred solution of isothiazole-4-carboxylic acid (0.2 g, 1.549 mmol) in methanol (2 mL), SOCh (0.226 mL, 3.10 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was then concentrated and diluted with NaHCO s solution, followed by extraction with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude methyl isothiazole-4-carboxylate (0.2 g, 1.384 mmol, 89% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 143.9, 1H-NMR (400 MHz, DMSO-d6): 59.31 (s, 1H), 8.93 (s,
1H), 3.94 (s, 3H).
Step 2: Synthesis of isothiazol-4-ylmethanol
To a stirred solution of methyl isothiazole-4-carboxylate (0.2 g, 1.397 mmol) in tetrahydrofuran
(10 mL), LAH (2 M in THF, 1.746 mL, 3.49 mmol) was added at 0 °C and stirred for 3 h. After completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated Na2SCL solution, diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL) The combined organic layers were dried over anhydrous NazSCL. filtered, and concentrated under reduced pressure to get isothiazol-4-ylmethanol (60 mg, 0.427 mmol, 31% yield). 1H-NMR (400 MHz, DMSO-d6): 5 8.81 (t, J = 0.80 Hz, 1H), 8.52 (s, 1H), 5.29 (t, J = 5.60 Hz, 1H), 4.60 (d, J = 5.20 Hz, 2H).
Step 3: Synthesis of isothiazole-4-carbaldehyde (ALD-49)
To a stirred solution of isothiazol-4-ylmethanol (60 mg, 0.521 mmol) in dichloromethane (10 mL), Dess-Martin periodinane (332 mg, 0.782 mmol) was added at 0 °C and stirred for 3 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with saturated NaHCCL solution, stirred for 10 min, and extracted with dichloromethane (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get isothiazole-4-carbaldehyde (22 mg, 0.194 mmol, 37% yield). 1H-NMR (400 MHz, DMSO-d6): 5 10.14 (s, 1H), 9.36 (s, 1H), 8.99 (s, 1H).
Example 141: Synthesis of 3-chloro-4-(oxetan-3-yl)benzaldehyde (ALD-50)
Figure imgf000665_0002
To a stirred solution of (2-chloro-4-formylphenyl)boronic acid (100 mg, 0.542 mmol), 3- iodooxetane (200 mg, 1.085 mmol), and CS2CO3 (530 mg, 1.627 mmol) in 1,4-dioxane (2 mL), the mixture was degassed with nitrogen for 15 min. Then, Nickel (II) nitrate hexahydrate (12.89 mg, 0.054 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (14.56 mg, 0.054 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction as confirmed by TLC, the reaction mixture was concentrated under reduced pressure, and the compound was purified by silica gel flash column chromatography eluting with 20% EtO Ac in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 3-chloro-4-(oxetan-3-yl)benzaldehyde (30 mg, 0.125 mmol, 23% yield). 1H-NMR (400 MHz, DMSO-d6): 5 10.00 (s, 1H), 7.97-7.93 (m, 2H), 7.79 (d, J = 8.00 Hz, 1H), 5.01-4.97 (m, 2H), 4.75 (t, J = 6.40 Hz, 2H), 1.35-1.10 (m, 1H).
Example 142: Synthesis of 3-chloro-4-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD-51)
Figure imgf000665_0001
Step 1: Synthesis of l-bromo-2-chloro-4-(diethoxymethyl)benzene
To a stirred solution of 4-bromo-3-chlorobenzaldehyde (1 g, 4.56 mmol) in ethanol (10 mL), triethyl orthoformate (0.675 g, 4.56 mmol) and p-toluenesulfonic acid monohydrate (0.087 g, 0.456 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 2 h. The progress of the reaction was monitored by LCMS. After completion of the reaction as confirmed by LCMS, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were dried over anhydrous Na2SOr, filtered, and concentrated under reduced pressure to obtain the crude residue. The crude compound was purified by flash column chromatography using Biotage Isolera using a 40 g silica gel cartridge, eluting with 10% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to afford l-bromo-2-chloro-4- (diethoxymethyl)benzene (0.8 g, 2.398 mmol, 53% yield). 1H-NMR (400 MHz, DMSO-d6): 57.78 (d, J = 8.40 Hz, 1H), 7.58 (d, J = 2.00 Hz, 1H), 7.31-7.29 (m, 1H), 5.50 (s, 1H), 3.47-3.55 (m, 4H), 76.59 (m, 6H).
Step 2: Synthesis of 3-(2-chloro-4-(diethoxymethyl)phenyl)oxetan-3-ol
To a stirred solution of l-bromo-2-chloro-4-(diethoxymethyl)benzene (200 mg, 0.681 mmol) in THE (3 mL), butyllithium (0.511 mL, 0.817 mmol) was added at -78 °C. After 30 min, oxetan-3-one (54.0 mg, 0.749 mmol) was introduced at the -78 °C. The reaction mixture was then stirred at room temperature for 1 h. After completion of the reaction as confirmed by TLC, the reaction was quenched with ammonium chloride solution (5 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was concentrated under reduced pressure to yield crude 3-(2-chloro-4-(diethoxymethyl) phenyl)oxetan-3-ol (180 mg, 0.628 mmol, 92% yield). 1H-NMR (400 MHz, DMSO-d6): 57.42-7.40 (m, 3H), 6.27 (s, 1H), 5.05 (s, 1H), 4.37 (m. 2H), 3.58 (m, 2H), 3.50-3.33 (m, 4H), 1.18-1.14 (m, 6H).
Step 3: Synthesis of 3-chloro-4-(3-hydroxyoxetan-3-yl)benzaldehyde (ALD-51)
To a stirred solution of 3-(2-chloro-4-(diethoxymethyl)phenyl)oxetan-3-ol (200 mg, 0.697 mmol) in DCM (1 mL), TEA (0.059 mL, 0.767 mmol) was added at 0 °Cand the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to obtain a crude residue. This crude compound was then purified using a Biotage Isolera system with a 40 g silica gel cartridge, employing 40% EtOAc in hexane as the eluent. The collected pure fractions were concentrated under reduced pressure to yield 3-chloro-4-(3-hydroxyoxetan-3-yl) benzaldehyde (ALD-51, 80 mg, 0.35 mmol, 51% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 213.1, 215.1; 'H-NMR (400 MHz, DMSO-d6): 5 10.01 (s, 1H), 7.96 (d, J = 1.60 Hz, 1H), 7.90-7.88 (m, 1H), 7.65 (d, J = 8.00 Hz, 1H), 6.49 (s, 1H), 5.09 (d, J = 7.60 Hz, 2H), 4.73 (d, J = 8.00 Hz, 2H).
Example 143: Synthesis of 4-(4-chloroisoxazol-3-yl) benzaldehyde (ALD-52)
Figure imgf000667_0001
Cl
Step 1: Synthesis of (Z)-4-((hydroxyimino)methyl) benzonitrile
To a stirred solution of sodium carbonate (4.61 g, 43.5 mmol) in water (50 mL) was added hydroxylamine hydrochloride (3.02 g, 43.5 mmol), followed by the addition of 4-formylbenzonitrile (5 g, 36.2 mmol) in ethanol (50 mL) at room temperature and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the excess solvent was removed under reduced pressure, and water (100 mL) was added. The resulting emulsion was filtered and washed with water and hexanes, then dried under reduced pressure to afford the crude compound (Z)-4-((hydroxyimino)methyl) benzonitrile (4.0 g, 26.4 mmol, 73% yield). LCMS m/z: MM-ES+APCI, [M+H]+ 147. 'H-NMR (400 MHz, DMSO-de): 5 11.73 (s, 1H), 8.25 (s, 1H), 7.87 (dd, 7 = 6.60, 2.00, 2H), 7.78 (dd, 7 = 6.80, 1.20, 2H).
Step 2: Synthesis of 4-(5-(trimethylsilyl) isoxazol-3-yl) benzonitrile
To a stirred solution of (Z)-4-((hydroxyimino)methyl) benzonitrile (0.8 g, 5.47 mmol) in water (15 mL) was added lithium chloride (0.232 g, 5.47 mmol), Oxone (5.05 g, 8.21 mmol), and trimethylsilyl acetylene (1.152 mL, 8.21 mmol) at room temperature and the reaction mixture was stirred at 60 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was poured into cooled water (100 mL). The compound was extracted with EtOAc (2 x 100 mL), and the organic layer was dried over anhydrous NajSOr. filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexanes. The collected pure fractions were concentrated under reduced pressure to afford 4-(5-(trimethylsilyl) isoxazol-3-yl) benzonitrile (300 mg, 1.052 mmol, 19% yield). 'H-NMR (400 MHz, CDCh): 5 8.33 (dd, 7= 3.20 Hz, 2H), 7.97 (dd, 7 = 4.60, 2.40 Hz, 2H), 6.79 (s, 1H), 0.36 (s, 9H).
Step 3: Synthesis of 4-(isoxazol-3-yl) benzonitrile
To a stirred solution of 4-(5-(trimethylsilyl) isoxazol-3-yl) benzonitrile (2.4 g, 9.31 mmol) in methanol (30 mL) was added potassium carbonate (1.930 g, 13.96 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was poured into cooled water (100 mL). The compound was extracted with EtOAc (2 x 500 mL), and the organic layer was dried over anhydrous NaiSOr, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography eluting with 25% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 4-(isoxazol-3-yl) benzonitrile (1.2 g, 6.83 mmol, 73% yield). LCMS: m/z: MM- ES+APCI, [M+H]+ 171.0. 'H-NMR (400 MHz, CDCh): 5 8.56 (d, 7 = 1.60 Hz, 1H), 7.98 (dd, J= 6.0, 1.6
Hz, 2H), 7.79 (dd, J= 4.0, 0.80 Hz, 2H), 6.74 (d, 7 = 2.00 Hz, 1H).
Step 4: Synthesis of 4-(isoxazol-3-yl) benzaldehyde
To a stirred solution of 4-(isoxazol-3-yl) benzonitrile (0.4 g, 2.351 mmol) in dichloromethane (5 mL) was added diisobutylaluminum hydride (DIBAL-H, 2.351 mL, 2.351 mmol, 1 M in toluene) at 0 °C under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 h. Additional DIBAL-H (2.351 mL, 2.351 mmol, 1 M in toluene) was added portion wise, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 1.5 N HC1 solution (50 mL) and extracted with DCM (2 x 100 mL). The organic layer was dried over anhydrous Na2SOr and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography eluting with EtOAc in hexane (2-4%) to afford 4-(isoxazol-3-yl) benzaldehyde (0.2 g, 1.086 mmol, 46% yield) LCMS: m/z: MM-ES+APCI, [M+H]+ 174. iH-NMR (400 MHz, CDCb): 5 10.11 (s, 1H), 8.55 (d, 7= 1.60 Hz, 1H), 8.06 (dd, 7= 4.40, 3.80 Hz, 2H), 8.01 (dd, 7 = 0.80, 4.00 Hz, 2H), 6.77 (d, 7 = 1.60 Hz, 1H).
Step 5: Synthesis of 4-(4-chloroisoxazol-3-yl) benzaldehyde (ALD-52)
To a stirred solution of 4-(isoxazol-3-yl) benzaldehyde (200 mg, 1.155 mmol) in trifluoroacetic acid (TEA, 5 mL), cooled to 0 °C, was added A-chlorosuccinimide (771 mg, 5.77 mmol) at 0 °C. The resulting reaction mixture was stirred at 80 °C for 3 h. The reaction was concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexanes. The collected pure fractions were concentrated under reduced pressure to yield 4-(4-chloroisoxazol-3-yl) benzaldehyde (ALD-52, 90 mg, 0.41 mmol, 35% yield). 'H-NMR (400 MHz, CDCL): 5 10.13 (s, 1H), 8.61 (s, 1H), 8.11 (dd. 7 = 6.80. 1.60 Hz, 2H), 8.04 (dd, 7 = 6.60, 1.60 Hz, 2H).
Example 144: Synthesis of l-bromo-5-(trifluoromethyl)-2,3-dihydro-lH-indene: (ALD-53)
NaBH4 PBr3
MeOH, rt, DCM 0 °C to
0 30 min rt
Step-1 Step-2
Step 1: Synthesis of 5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-ol To a stirred solution of 5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-one (500 mg, 2.498 mmol) in methanol (5 mL) was added sodium borohydride (189 mg, 5.00 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with water (10 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous N 3286)4 filtered, and concentrated under reduced pressure to afford crude 5- (trifluoromethyl)-2,3-dihydro-lH-inden-l-ol (430 mg, 2.040 mmol, 82% yield). ’H-NMR (400 MHz, DMSO-t/e): 8 8.02 (s, 1H), 7.74 (d, J = 9.20 Hz, 1H), 7.53-7.31 (m, 1H), 5.45 (d, J = 6.00 Hz, 1H), 5.11-
5.09 (m, 1H), 3.00-2.97 (m, 1H), 2.81-2.77 (m, 1H), 2.42-2.40 (m, 1H), 1.79-1.79 (m, 1H).
Step 2: Synthesis of l-bromo-5-(trifluoromethyl)-2,3-dihydro-lH-indene (ALD-53)
To a stirred solution of 5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-ol (430 mg, 2.127 mmol) in dichloromethane (10 mL), cooled to 0 °C, phosphorus tribromide (0.261 mL, 2.76 mmol) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h and progress of reaction was monitored by (TLC). After completion of reaction, the reaction mixture was poured into cooled water (10 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na2S(>4 filtered, and concentrated under reduced pressure to yield crude l-bromo-5-(trifluoromethyl)-2,3-dihydro-lH- indene (90 mg, 0.301 mmol, 14% yield). ’H-NMR (400 MHz, DMSO-cfc): 87.55-7.51 (m, 3H), 5.57 (t, J = 4.00 Hz, 1H), 3.30-3.24 (m, 1H), 3.01-2.99 (m, 1H), 2.71-2.66 (m, 2H).
Example 145: Synthesis of 4-(5-methyl-l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-54)
Figure imgf000669_0001
Step 1: Synthesis of (Z)-4-bromo-N'-hydroxybenzimidamide
To a stirred solution of 4-bromobenzonitrile (500 mg, 2.75 mmol) in ethanol (5 mL) and water (0.5 mL), hydroxylamine hydrochloride (573 mg, 8.24 mmol) and K2CO3 (1898 mg, 13.73 mmol) were added at 25 °C. The resulting reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The crude residue was taken up in water (50 mL) and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield (Z)-4-bromo-N’-hydroxybenzimidamide (450 mg, 2.007 mmol, 73% yield). LCMS: m/z MM-ES+APCI, Positive [M+H2]+ 216.6, ’H-NMR (400 MHz, DMSO- d6): 5 9.74 (s, 1H), 7.62-7.56 (m, 4H), 5.87 (s, 2H). Step 2: Synthesis of 3-(4-bromophenyl)-5-methyl-l,2,4-oxadiazole
To a stirred solution of (Z)-4-bromo-N’-hydroxybenzimidamide (2 g, 9.30 mmol) in pyridine (2.21 g. 27.9 mmol) was added acetyl chloride (1.10 g, 14.0 mmol) and the mixture was stirred at 100 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure to obtain the crude product. Ethyl acetate (100 mL) and water (100 mL) were added to the crude product. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 10% ethyl acetate in hexane to yield 3-(4-bromophenyl)-5-methyl-l,2,4-oxadiazole (3 g, 10.86 mmol, 117% yield). LCMS: m/z MM-ES+APCI, Positive [M+H2]+ 240.8, 'H-NMR (400 MHz, DMSO-d6): 57.83 (dd, J = 8.80, 36.60 Hz, 4H), 2.71 (s, 3H).
Step 3: Synthesis of 5-methyl-3-(4-vinylphenyl)-l,2,4-oxadiazole
To a stirred solution of 3-(4-bromophenyl)-5-methyl-l,2,4-oxadiazole (500 mg, 2.091 mmol) in 1,4-dioxane (10 mL) and water (1 mL), trifluoro(vinyl)borane potassium salt (420 mg, 3.14 mmol) and K2CO3 (723 mg, 5.23 mmol) were added at 25 °C. The reaction mixture was degassed with nitrogen for 10 minutes. PdC^dppff CHjCL adduct (171 mg, 0.209 mmol) was then added, and the mixture was degassed again with nitrogen for 5 minutes. The reaction was irradiated under microwave at 85 °C for 2 h. The progress of the reaction was monitored by LCMS. After completion of the reaction as confirmed by LCMS, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography using Biotage Isolera using a 50 g silica gel cartridge (100-200 mesh), eluting with 50% EtOAc in hexane. The pure fractions were concentrated under reduced pressure to yield 5-methyl-3-(4-vinylphenyl)- 1,2,4- oxadiazole (320 mg, 1.414 mmol, 68% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 187.2, *H- NMR (400 MHz, DMSO-d6): 5 7.98 (d, J = 8.00 Hz, 2H), 7.67 (d, J = 8.40 Hz, 2H), 6.86-6.79 (m, 1H), 5.98 (d, J = 17.60 Hz, 1H), 5.41 (d, J = 11.20 Hz, 1H), 2.67 (s, 3H).
Step 4: Synthesis of 4-(5-methyl-l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-54)
To a stirred solution of 5-methyl-3-(4-vinylphenyl)-l,2,4-oxadiazole (320 mg, 1.718 mmol) in tetrahydrofuran (5 mL) and water (1 mL), sodium periodate (551 mg, 2.58 mmol) was added at 25 °C. Then, potassium osmate dihydrate (15.83 mg, 0.043 mmol) was added, and the resulting reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography using Biotage Isolera column chromatography using 100-200 mesh silica gel, eluting with 50% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to yield 4-(5-methyl-l,2,4-oxadiazol-3-yl) benzaldehyde (100 mg, 0.526 mmol, 31% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 189.2, *H-
NMR (400 MHz, CDC13): 8 10.12 (s, 1H), 8.27 (d, J = 8.00 Hz, 2H), 8.02 (d, J = 8.40 Hz, 2H), 2.71 (s,
3H).
Example 146: Synthesis of 4-(l,3-dimethyl-lH-pyrazol-4-yl)benzaldehyde (ALD-55)
Figure imgf000671_0001
To a stirred solution of (4-formylphenyl)boronic acid (1.5 g, 10.00 mmol) in 1,4-dioxane (12 mL) and water (1 .2 mL) at rt were added 4-bromo-l,3-dimethyl-lH-pyrazole (1.75 g, 10.0 mmol) and K2CO3 (2.77 g, 20.1 mmol). The reaction mixture was sparged with nitrogen for 5 min, then PdClildpptyCHzCL adduct (0.81 g, 1.00 mmol) was added and the reaction mixture was stirred at 80 °C under microwave irradiation for 2 h. The cooled reaction mixture was filtered through a Celite bed and concentrated under reduced pressure. The crude residue was purified by silica, gel flash chromatography, eluting with 34% ethyl acetate in hexane to afford 4-(l,3-dimethyl-lH-pyrazol-4-yl) benzaldehyde (800 mg, 3.81 mmol, 38% yield) as solid. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 201.0, ’H-NMR (400 MHz, CDC13): 8 10.02 (s, 1H), 7.91 (d, J = 8.00 Hz, 2H), 7.56 (t, J = 0.00 Hz, 3H), 3.92 (s, 3H), 2.47 (s, 3H).
Example 147: Synthesis of 4-(3-(trifluoromethyl)phenyl)-lH-pyrrole-2-carbaldehyde (ALD-56)
Figure imgf000671_0002
Step 1: Synthesis of 4-bromo-lH-pyrrole-2-carbaldehyde
To a stirred solution of 1 H-pyrrole-2-carbaldehyde (100 mg, 1.052 mmol) in THF (4 mL) at 0 °C was added NBS (187 mg, 1.05 mmol) and the reaction mixture was stirred at rt for 15 minutes. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water (10 mL) and the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product residue was purified by silica gel flash chromatography, eluting with 5% ethyl acetate in n-hexane to yield 4- bromo-lH-pyrrole-2-carbaldehyde (180 mg, 0.754 mmol, 72% yield). LCMS: m/z MM-ES+APCI, Positive [M-2, M-] 172.1, 174.1; ’H-NMR (400 MHz, DMSO-d6): 5 12.47 (s, 1H), 9.46 (d, J = 0.80 Hz, 1H), 7.21 (d, J = 1.60 Hz, 1H), 7.00 (d, J = 2.40 Hz, 1H).
Step 2: 4-(3-(trifluoromethyl)phenyl)-lH-pyrrole-2-carbaldehyde (ALD-56)
To a stirred solution of 4-bromo-lH-pyrrole-2-carbaldehyde (25 mg, 0.144 mmol) in dioxane (1 mL) and water (0.1 mL), (3-(trifluoromethyl)phenyl)boronic acid (32.7 mg, 0.172 mmol) and potassium phosphate tribasic (76 mg, 0.359 mmol) were added at 25 °C and the mixture was sparged with nitrogen for 10 min. Methanesulfonato(diadamantyl-n-butylphosphino)-2’-amino-l,r-biphenyl-2-yl)palladium(II) dichloromethane adduct (1.05 mg, 1.44 pmol) was then added, and the mixture was sparged with nitrogen for an additional 5 min. The reaction mixture was stirred at 100 °C for 16 h, then the cooled reaction mixture was filtered through a Celite bed and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 10-15% ethyl acetate in hexane to afford 4-(3-(trifluoromethyl)phenyl)-lH- pyrrole-2-carbaldehyde (80 mg, 0.278 mmol, 193% yield). LCMS: m/z MM-ES+APCI, Positive [M-H] 238.3, 1H-NMR (400 MHz, CDC13): 59.63 (s, 2H), 8.04 (s, 1H), 7.73 (s, 2H), 7.72 (d, J = 2.40 Hz, 2H),
7.53 (s, 1H).
Example 148: Synthesis of 4-(4-formyl-lH-pyrazol-l-yl)benzonitrile (ALD-57)
Figure imgf000672_0001
A stirred mixture of lH-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol), 4-iodobenzonitrile (1430 mg, 6.24 mmol), DMF (5 mL), CS2CO3 (2543 mg, 7.81 mmol) and copper(I) iodide (99 mg, 0.520 mmol) was sparged with nitrogen for 10 min. Copper(I) iodide (99 mg, 0.52 mmol) and (R, R)-(-)-N, N- dimethyl-l,2-cyclohexanediamine (74.0 mg, 0.520 mmol) were added, and the mixture was sparged with nitrogen for an additional 5 min. The reaction mixture was stirred at 80 °C for 12 h. The cooled reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel Hash chromatography eluting with 30% ethyl acetate in hexane to yield 4-(4-formyl-lH- pyrazol-l-yl)benzonitrile (0.15 g, 0.730 mmol, 14% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+
198.1, 1H-NMR (400 MHz, DMSO-d6): 5 10.02 (s, IH), 8.54 (s, IH), 8.24 (s, IH), 7.93-7.91 (m, 2H),
7.85-7.83 (m, 2H).
Example 149: Synthesis of l-(3-fluorophenyl)-lH-pyrazole-4-carbaldehyde (ALD-58)
Figure imgf000673_0001
To a stirred solution of lH-pyrazole-4-carbaldehyde (500 mg, 5.2 mmol) in DMF (5 mL) were added l-fluoro-3-iodobenzene (1386 mg, 6.24 mmol) and CS2CO3 (2543 mg, 7.81 mmol) at 25 °C, and the mixture was sparged with N2 for 10 min. To this reaction mixture were added copper(I) iodide (99 mg, 0.52 mmol) and (R,R)-(-)-N,N -Dimethyl- 1 ,2-cyclohexanediamine (74.0 mg, 0.52 mmol) and the mixture was again sparged with N2 for 5 min. The resulting reaction mixture was stirred at 80 °C for 12 h. Water (50 mL) was added, and the resulting solid precipitate was collected by filtration and dried to afford l-(3-fluorophenyl)-lH-pyrazole-4-carbaldehyde (300 mg, 1.577 mmol, 30% yield). LCMS: m/z MM-ES+APCI, Positive [M+H2]+ 191.0. 1H-NMR (400 MHz, DMSO-d6): 5 9.93 (s, 1H), 9.32 (s, 1H), 8.32 (s, IH), 7.85-7.81 (m, 2H), 7.64-7.59 (m, 1H), 7.64-7.59 (m, 1H), 3.32 (s, 1H).
Example 150: Synthesis of l-(3-chlorophenyl)-lH-pyrazole-4-carbaldehyde (ALD-59)
Figure imgf000673_0002
A stirred mixture of lH-pyrazole-4-carbaldehyde (500 mg, 5.2 mmol), DMF (5 mL), l-chloro-3- iodobenzene (1489 mg, 6.24 mmol) and C.S2CO3 (2543 mg, 7.81 mmol) was sparge with nitrogen for 10 min. Then, copper(I) iodide (99 mg, 0.52 mmol) and (R,R)-(-)-N,N-dimethyl-l,2-cyclohexanediamine (74.0 mg, 0.52 mmol) were added and the mixture was sparged with nitrogen for an additional 5 min. The reaction mixture was stirred at 80 °C for 1 h, then water was added to the cooled mixture. The resulting solid precipitate was collected via filtration and dried to afford l-(3-chlorophenyl)-lH-pyrazole-4- carbaldehyde (400 mg, 1.762 mmol, 34% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 207.0, 209.0. 1H-NMR (400 MHz, DMSO-d6): 59.93 (s, 1H), 9.33 (s, 1H), 8.31 (s, 1H), 8.05 (d, J = 1.60 Hz, IH), 7.97-7.92 (m, 1H), 7.61-7.51 (m, 1H), 7.50-7.48 (m, 1H).
Example 151: Synthesis of 4-formyl-2-(2-methoxyethoxy)benzonitrile (ALD-60)
Figure imgf000674_0001
Step 1: Synthesis of 4-bromo-2-(2-methoxy ethoxy) benzonitrile
A mixture of 4-bromo-2-hydroxybenzonitrile (2 g, 10.1 mmol), l-bromo-2-methoxy ethane (2.11 g, 15.2 mmol), acetonitrile (15 mL), and K2CO3 (1.40 g, 10.1 mmol) was stirred at 70 °C for 12 h. The cooled reaction mixture was poured into water, and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 50% EtOAc in petroleum ether to afford 4-bromo-2-(2-methoxyethoxy)benzonitrile (2.2 g, 7.82 mmol, 77% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 258.1. 1H-NMR (400 MHz, DMSO-d6): 57.69 (d, J = 8.40 Hz, 1H), 7.55 (d, J = 1.60 Hz, 1H), 7.33-7.31 (m, 1H), 4.33-4.31 (m, 2H), 3.71-3.68 (m, 2H), 3.33 (s, 3H).
Step 2: Synthesis of 2-(2-methoxyethoxy)-4-vinylbenzonitrile
A stirred mixture of 4-bromo-2-(2-methoxy ethoxy) benzonitrile (1 g, 3.9 mmol) and trifl uoro(vinyl) borane potassium salt (0.523 g, 3.9 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), was sparged with nitrogen. Then, potassium carbonate (1.08 g, 7.81 mmol) was added, and the mixture was sparged with nitrogen again. l,l’-Bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (0.286 g, 0.39 mmol) was added, and the reaction mixture was stirred at 100 °C for 1 h. The cooled reaction mixture was poured into water, and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 50% ethyl acetate in petroleum ether to yield 2-(2-methoxyethoxy)-4- vinylbenzonitrile (1.2 g, 4.84 mmol, 100% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 204.1. ‘H-NMR (400 MHz, DMSO-d6): 57.70 (d, J = 16.00 Hz, 1H), 7.32 (s, 1H), 7.28-7.19 (m, 1H), 6.87-6.69
(m, 1H), 6.58-6.49 (m, 1H), 6.16-6.02 (m, 1H), 5.59-5.40 (m, 1H), 4.40-4.25 (m, 2H), 3.80-3.69 (m, 2H),
3.38-3.29 (m, 3H).
Step 3: Synthesis of formyl-2-(2-methoxyethoxy)benzonitrile To a stirred solution of 2-(2-methoxyethoxy)-4-vinylbenzonitrile (600 mg, 2.95 mmol) in THF (5 mL) and water (0.5 mL) were added sodium periodate (947 mg, 4.43 mmol) and potassium osmate dihydrate (27.2 mg, 0.074 mmol) at rt. The resulting reaction mixture was stirred at rt for 30 min. The reaction mixture was poured into water, and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography, eluting with 30% EtOAc in pet ether to afford 4-formyl-2-(2-methoxyethoxy)benzonitrile (100 mg, 0.478 mmol, 16% yield). LCMS: m/z MM-ES+APCI, Positive [M-H]+ 206.12. 1H-NMR (400 MHz, DMSO-d6): 5 10.07 (s, 1H), 8.01 (d, J = 8.00 Hz, 1H), 7.73 (d, J = 0.80 Hz, 1H), 7.63 (d, J = 1.20 Hz, 1H), 4.40-4.38 (m, 2H), 3.76-3.73 (m, 2H), 3.33 (s, 3H).
Example 152: Synthesis of l-(2,2,2-trifluoroethyl)-lH-pyrrole-3-carbaldehyde (ALD-61)
F F F-X. zx _ o' o' N
NH V- F
CS2CO3,DMF,80 °C, 16 h.
F F
Step-1
To a stirred solution of lH-pyrrole-3-carbaldehyde (1 g, 10.52 mmol) and 2,2,2-trifluoroethyl 4- methylbenzenesulfonate (3.21 g, 12.62 mmol) in DMF (5 mL), cesium carbonate (6.85 g, 21.03 mmol) was added at ambient temperature. The resulting reaction mixture was stirred at 80 °C for 16 h. After completion, as confirmed by TEC, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 150 mL). The organic layer was concentrated under reduced pressure to obtain the crude compound, which was purified by flash column chromatography using Biotage Isolera column chromatography using 100-200 mesh silica gel, eluting with 20% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 1 -(2,2,2-trifluoroethyl)- 1H- pyrrole-3-carbaldehyde (600 mg, 3.39 mmol, 32% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 178.2, 1H-NMR (400 MHz, DMSO-d6): 59.72 (s, 1H), 7.74 (s, 1H), 7.01 (s, IH), 6.54-6.53 (m, 1H), 5.09-5.02 (m, 2H).
Example 153: Synthesis of 6-(l-(trifluoromethyl)cyclopropyl)nicotinaldehyde (ALD-62)
Figure imgf000676_0001
Step 1: Synthesis of 5-bromo-2-(3,3,3-trifhioroprop-l-en-2-yl)pyridine
To a stirred solution of 2,5-dibromopyridine (1.5 g, 6.33 mmol) and 4,4,6-trimethyl-2-(3,3,3- trifluoroprop-l-en-2-yl)-l,3,2-dioxaborinane (1.406 g, 6.33 mmol) in 1,4-dioxane (15 mL) and water (0.5 mL), K2CO3 (1.750 g, 12.66 mmol) was added. The reaction mixture was degassed with nitrogen gas for 5 min. Then, Pd (PPh3)4 (0.146 g, 0.127 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using Biotage Isolera column chromatography using 230-400 mesh silica gel, eluting with 5% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 5-bromo-2-(3,3,3-trifluoroprop-l-en-2-yl) pyridine (550 mg, 2.083 mmol, 33% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 252.2, 254.1. 1H-NMR (400 MHz, DMSO-d6): 5 8.80-8.79 (m, 1H), 8.19-8.17 (m, 1H), 7.68 (t, J = 2.40 Hz, 1H), 6.65-
6.64 (m, 1H), 6.32 (s, 1H).
Step 2: Synthesis of 5-bromo-2-(l-(trifluoromethyl)cyclopropyl)pyridine
To a stirred solution of 5-bromo-2-(3,3,3-trifluoroprop-l-en-2-yl)pyridine (550 mg, 2.182 mmol) in THF (15 mL), methyldiphenylsulfonium tetrafluoroborate (817 mg, 2.84 mmol) was added at 25 °C and stirred for 30 min. Then, sodium bis(trimethylsilyl)amide in THF (3.49 mL, 3.49 mmol) was then added at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into cooled water (100 mL) and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous NajSO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using Biotage Isolera column chromatography using 230-400 mesh silica gel, eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 5-bromo-2-(l- (trifluoromethyl)cyclopropyl)pyridine (230 mg, 0.733 mmol, 34% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 266.1, 268.1. 1H-NMR (400 MHz, DMSO-d6): 5 8.69 (d, J = 2.00 Hz, 1H), 8.10-8.08 (m, 1H), 7.52 (d, J = 8.40 Hz, 1H), 1.51-1.32 (m, 4H).
Step 3: Synthesis of 2-(l-(trifluoromethyl)cyclopropyl)-5-vinylpyridine
To a stirred solution of 5-bromo-2-(l-(trifluoromethyl)cyclopropyl)pyridine (210 mg, 0.789 mmol) and trifluoro(vinyl)borane potassium salt (127 mg, 0.947 mmol) in 1,4-dioxane (8 mL) and water (0.2 mL), K2CO3 (218 mg, 1.579 mmol) was added at 25 °C. The resulting reaction mixture was degassed with argon for 15 min. Then, PdCLlclpplFCI-LCL adduct (64.5 mg, 0.079 mmol) was then added at 25 °C, and the mixture was degassed with argon for an additional 5 minutesand the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using Biotage Isolera column chromatography using 230-400 mesh silica gel, eluting with 5% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 2-(l-(trifluoromethyl)cyclopropyl)-5- vinylpyridine (140 mg, 0.559 mmol, 71% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 214.0. 1H-NMR (400 MHz, DMSO-d6): 5 8.62 (d, J = 2.40 Hz, 1H), 7.97-7.95 (m, 1H), 7.52 (d, J = 8.00 Hz, 1H), 6.81-6.74 (m, 1H), 5.99 (dd, J = 0.80, 17.60 Hz, 1H), 5.42 (dd, J = 0.80, 10.80 Hz, 1H), 1.42-1.39 (m, 4H).
Step 4: Synthesis of 6-(l-(trifluoromethyl)cyclopropyl)nicotinaldehyde
To a stirred solution of 2-(l-(trifluoromethyl)cyclopropyl)-5-vinylpyridine (140 mg, 0.657 mmol) in THF (8 mL) and Water (2 mL) were added sodium periodate (211 mg, 0.985 mmol) and potassium osmate dihydrate (6.05 mg, 0.016 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured in cooled water (50 mL), compound was extracted in EtOAc (2 x 50 mL), organic layer was dried over anhydrous NajSO^ filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by isolera biotage column chromatography using neutral alumina mesh, eluted with 5% EtOAc in pet ether. The collected pure fractions were concentrated under reduced pressure to afford 6-(l-(trifluoromethyl)cyclopropyl)nicotinaldehyde (80 mg, 0.372 mmol, 57% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 216.0, 1H-NMR (400 MHz, DMSO-d6): 5 10.10 (s, 1H), 9.05 (d, J = 1.60 Hz, 1H), 8.29-8.27 (m, 1H), 7.76 (d, J = 8.40 Hz, 1H), 1.58-1.54 (m, 4H). Example 154: Synthesis of N-ethyl-5-formylpicolinamide (ALD-63)
Figure imgf000677_0001
Step 1: Synthesis of methyl 6-(ethylcarbamoyl)nicotinate To a stirred solution of 5-(methoxycarbonyl)picolinic acid (1) (500 mg, 2.76 mmol) in DMF (10 mL), DIPEA (1.446 mL, 8.28 mmol) and HATH (1574 mg, 4.14 mmol) were added, followed by ethanamine (2) (356 mg, 5.52 mmol)and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaiSO4, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Isolera using EtOAc/hexane (0-30%) to afford methyl 6-(ethyl carbamoyl)nicotinate (3) (50 mg, 0.240 mmol, 9% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 209.1, iH-NMR (400 MHz, DMSO-d6): 5 9.10 (d, J = 1.60 Hz, 1H), 8.99 (s, 1H), 8.49-8.46 (m, 1H), 8.17
(d, J = 8.00 Hz, 1H), 3.93 (s, 3H), 3.34 (t, J = 5.60 Hz, 2H), 1.14 (t, J = 7.20 Hz, 3H).
Step 2: Synthesis of N-ethyl-5-formylpicolinamide (ALD-63)
To a stirred solution of morpholine (0.961 mL, 11.05 mmol) in THF (2 mL), DIBAL-H (1.0 M in
THF, 10.57 mL, 10.57 mmol) was added at 0 °C, and the reaction mixture was stirred for 3 h. Then,
Methyl 6-(ethylcarbamoyl)nicotinate (1.0 g, 4.80 mmol) in THF (2 mL) was added to the reaction mixture and stirred at 0 °C for 10 min, followed by the addition of DIBAL-H (1.0 M in THF, 4.80 mL, 4.80 mmol) at 0 °Cand the reaction mixture was stirred at 25 °C for 15 min. The progress of the reaction was monitored by LCMS/TLC. After completion of the reaction as confirmed by LCMS/TLC, the reaction mixture was quenched with saturated NH4CI solution (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Isolera using EtOAc/hexane (0-40%) to afford N-ethyl-5-formylpicolinamide (ALD-63) (170 mg, 0.754 mmol, 16% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 179.12. 1H-NMR (400 MHz, DMSO-d6): 5 10.20 (s, 1H), 9.13-9.13 (m, 1H), 9.02 (s, 1H), 8.45-8.42 (m, 1H), 8.22 (d, J = 8.00 Hz,
1H), 3.33 (s, 2H), 1.15 (t, J = 7.20 Hz, 3H).
Example 155: Synthesis of 3-(4-formyl-lH-pyrazol-l-yl)benzonitrile (ALD-64)
Cl POCI3, DMF, Cl rt, 1 h k J 0 J
N Step-1 N
To a stirred solution of POCh (3.05 mL, 32.8 mmol) in DMF (30 mL) was stirred 10 mins at 0
°C. Then, a solution of 5-chloropyrazolo[l,5-a]pyridine (1.0 g, 6.55 mmol) in DMF was added to the reaction mixture at 0 °C. The resulting reaction mixture was stirred for 1 h. The reaction mixture was quenched with ice cold water (100 mL), then extracted with EtOAc (2 x 50 mL), and the combined organic layers were dried over anhydrous NazSO4. filtered, and concentrated to afford 5- chloropyrazolo[l,5-a]pyridine 3 carbaldehyde (301 mg 1 610 mmol 25% yield) LCMS: m/z MM ES+APCI, Positive [M+H, M+2+H]+ 181.1, 183.1; ’H-NMR (400 MHz, CDC13): 5 10.04 (s, 1H), 8.51 (dd, J = 0.40, 7.40 Hz, 1H), 8.41 (s, 1H), 8.35 (d, J = 2.00 Hz, 1H), 7.07 (dd, J = 2.40, 7.20 Hz, 1H).
Example 156: Synthesis of isothiazole-5-carbaldehyde (ALD-65)
Figure imgf000679_0001
Step 1: Synthesis of methyl isothiazole-5-carboxylate
To a stirred solution of isothiazole-5-carboxylic acid (100 mg, 0.774 mmol) in DMF (2 mL) was added potassium carbonate (214 mg, 1.549 mmol) at RT. After that, methyl iodide (0.058 mL, 0.929 mmol) was added at 25 °C and stirred the reaction mixture for 16 h. The reaction was monitored by LCMS. After completion of reaction as confirmed by LCMS, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (40 mL X 2), combine organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get erode compound methyl isothiazole-5-carboxylate (100 mg, 0.49 mmol, 63% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 144.2, 1H-NMR (400 MHz, DMSO-d6): 5 8.75 (d, J = 1.60 Hz, 1H), 7.97 (dd, J = 5.20 Hz, 1H), 3.90 (s, 3H).
Step 2: Synthesis of isothiazole-5-carbaldehyde (ALD-65)
To a stirred solution of Morpholine (140 mg, 1.607 mmol) in THF (2 mL) was added DIBAL-H (1.0M in THF) (1.537 mL, 1.537 mmol) at 0 °C and stirred for 3 h. After that methyl isothiazole-5- carboxylate (100 mg, 0.699 mmol) in THF (2 mL) was added to the above reaction mixture and stirred at 0 °C for 10 min, followed by DIBAL-H (1.0M in THF) (1.467 mL, 1.467 mmol) was added at same temperature. After completion of the reaction as confirmed by TLC, the rection mass quenched with IN HC1 in water and extracted with EtOAc (2 x 20 mL). The combined organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get isothiazole-5-carbaldehyde (ALD-65) (50 mg, 0.442 mmol, 63% yield). LCMS: Not recorded, ’H-NMR (400 MHz, DMSO-d6): 5 10.17 (s, 1H), 8.84 (dd, J = 2.00 Hz, 1H), 8.15 (dd, J = 2.00 Hz, 1H).
Example 157: Synthesis of 4-(2-(dimethylamino)ethoxy) benzaldehyde (ALD-66)
Figure imgf000679_0002
To a stirred solution of 4-hydroxybenzaldehyde (1 g, 8.19 mmol) in DMF (8 mL), 2- (dimethylamino)ethyl chloride hydrochloride (1.057 g, 9.83 mmol) and K2CO3 (2.263 g, 16.38 mmol) were added at 25 °C under a nitrogen atmosphere. The reaction mixture was then stirred at 80 °C for 16 h. After completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SOr, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Isolera using EtOAc/hexane (0-50%) to afford 4-(2- (dimethylamino)ethoxy)-benzaldehyde (200 mg, 0.963 mmol, 12% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 194.4. 1H-NMR (400 MHz, DMSO-d6): 5 9.87 (s, 1H), 7.96-7.85 (m, 2H), 7.16-7.12
(m, 2H), 4.17 (t, J = 5.60 Hz, 2H), 2.65 (t, J = 6.00 Hz, 2H), 2.22 (s, 6H).
Example 158: Synthesis of 4-(3-fluorooxetan-3-yl) benzaldehyde (ALD-67)
ALD-67
Figure imgf000680_0001
Step 1: Synthesis of 3-(4-(diethoxymethyl)phenyl)oxetan-3-ol
To a stirred solution of l-bromo-4-(ethoxy(methoxy)methyl) benzene (1 g, 4.08 mmol) in THF (10 mL), n-BuLi (3.06 mL, 4.90 mmol) was added dropwise at -78 °C. The reaction was stirred at -78 °C for 20 min, after which oxetan-3-one (0.294 g, 4.08 mmol) was added at the -78 °C, and stirred for 1 h. After completion, of the reaction as confirmed by TLC, the reaction mixture was quenched with water (100 mL), and the product was extracted with EtOAc (2 x 150 mL). The organic layer was dried over anhydrous N 3286)4. filtered, and concentrated under reduced pressure to yield a gummy crude product. This crude product was purified by normal phase column chromatography using 100-200 mesh silica gel, eluting with 11% EtOAc in hexane. The pure fractions were concentrated under reduced pressure to afford 3-(4-(diethoxymethyl)phenyl)oxetan-3-ol (400 mg, 1.585 mmol, 39% yield). 1H-NMR (400 MHz, DMSO-d6): 57.60 (d, J = 8.40 Hz, 2H), 7.42 (d, J = 8.00 Hz, 2H), 6.34 (s, 1H), 5.76 (s, 1H), 4.77 (d, J = 6.40 Hz, 2H), 4.68 (d, J = 6.40 Hz, 2H), 3.54-3.50 (m, 4H), 1.15 (s, 6H).
Step 2: Synthesis of 4-(3-fluorooxetan-3-yl) benzaldehyde
To stirred solution of 3-(4-(diethoxymethyl)phenyl)oxetan-3-ol (100 mg, 0.396 mmol) in DCM (3 mL) was added DAST (96 mg, 0.595 mmol) at 0 °Cand the reaction mixture was stirred at rt for 30 min. The Progress of reaction monitored by TLC. After completion of reaction of the reaction as confirmed by TLC, the reaction mass was quenched with NaHCCL solution (10 mL) and the compound was extracted by DCM (2 x 20 mL). The organic layer was dried over anhydrous Na2SOr, filtered, and concentrated under reduced pressure to afford gummy crude. The crude was purified by normal phase column chromatography using (100-200 silica mesh) eluting with 09% of ethyl in hexane as an eluent. Pure fractions were concentrated under reduced pressure to afford 4-(3-fluorooxetan-3-yl)benzaldehyde (35 mg, 0.194 mmol, 49% yield). 1H-NMR (400 MHz, DMSO-d6): 5 10.06 (s, 1H), 8.03 (d, J = 7.60 Hz, 2H), 7.81 (d, J = 8.00 Hz, 2H), 5.00-4.96 (m, 4H). Example 159: Synthesis of 3-fluoro-4-(l-hydroxycyclopropyl)benzaldehyde (ALD-68)
Figure imgf000681_0001
Step 1: Synthesis of l-(4-bromo-2-fluorophenyl)cyclopropan-l-ol
To a stirred solution of methyl 4-bromo-2-fluorobenzoate (5 g, 21.46 mmol) in THF (20 mL) under nitrogen at 25 °C, titanium(IV) isopropoxide (11.43 mL, 38.6 mmol) was added, followed by the dropwise addition of ethyl magnesium bromide (37.5 mL, 75 mmol) at 0 °C. The resulting reaction mixture was heated at 25 °C for 2 h. The progress of the reaction was monitored by LCMS/TLC. After completion of the reaction as confirmed by LCMS/TLC, the reaction was quenched with 1.5 N HC1 (100 mL) and diluted with EtOAc (500 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography using Biotage Isolera (silica gel 100-200 mesh) and a linear gradient of 0- 20% EtOAc in hexane as eluents to afford l-(4-bromo-2-fluorophenyl)cyclopropan-l-ol (2.8 g, 8.12 mmol, 38% yield). ’H-NMR (400 MHz, DMSO-d6): 57.47-7.42 (m, 2H), 7.39-7.32 (m, 1H), 6.02 (s, 1H), 1.18-1.10 (m, 4H).
Step 2: Synthesis of l-(2-fluoro-4-vinylphenyl)cyclopropan-l-ol
To a stirred solution of trifluoro(vinyl)-14-borane, potassium salt (417 mg, 3.12 mmol), l-(4- bromo-2-fluorophenyl)cyclopropan-l-ol (400 mg, 1.73 mmol), potassium salt (360 mg, 2.69 mmol) and K2CO3 (718 mg, 5.19 mmol) in 1,4-dDioxane (9 mL) and water (1 mL) was purged with N2 at room temperature over 10 min. To this resulting mixture PdC12(dppf)-CH2C12adduct (141 mg, 0.173 mmol) was added in one lot and the reaction mixture was again sparged with N2 for 10 min. The resulting reaction mixture was heated at 80°C for 16 h. The progress of the reaction was monitored by LCMS/TLC. After completion of the reaction as confirmed by LCMS/TLC, the reaction mixture was filtered through a pad of celite and washed with EtOAc (10 mL), the filtrate was concentrated under reduced pressure to get crude. The crude compound was purified by silica gel flash column chromatography, eluting with 0-20% EtOAc in hexane to afford l-(2-fluoro-4-vinylphenyl)-cyclopropan-l-ol (400 mg, 1.84 mmol, 106% yield). 'H-NMR (400 MHz, DMSO-d6): 5 7.49-7.44 (m, 1H), 7.43-7.40 (m, 1H), 7.39-7.32 (m, 1H), 6.74- 6.67 (m, 1H), 6.02 (s, 1H), 5.91 (d, J = 10.00 Hz, 2H), 1.20-1.14 (m, 4H).
Step 3: Synthesis of 3-fluoro-4-(l-hydroxycyclopropyl) benzaldehyde (ALD-68)
To a stirred solution of l-(2-fluoro-4-vinylphenyl) cyclopropan-l-ol (250 mg, 1.40 mmol) ACN (2.5 mL) and Water (0.25 mL) were added sodium iodide (50 mg, 0.33 mmol) at 25 °C. After 10 min osmium tetroxide 4% in water (0.07 mL, 0.223 mmol) was added at 0°C. The resulting reaction mixture was stirred at 25 °C for 6 h. The progress of the reaction was monitored by LCMS. After completion of the reaction as confirmed by LCMS, the reaction was quenched with water (10 mL) and diluted with DCM (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography using Biotag isolera (Neutral Alumina mesh) and a linear gradient of 0-30% EtOAc in hexane as eluents to afford 3-fluoro-4-(l-hydroxycyclopropyl)benzaldehyde (ALD-68) (37 mg, 0.168 mmol, 12% yield). ’H-NMR (400 MHz, DMSO-d6): 59.97 (d, J = 1.60 Hz, 1H), 7.81-7.73 (m, 2H), 7.62 (dd, J = 1.20, 11.40 Hz, 1H), 6.21 (s, 1H), 1.20-1.12 (m, 4H).
Example 160: Synthesis of 4-(l,2,3-thiadiazol-4-yl) benzaldehyde (ALD-69)
Figure imgf000682_0001
Step 1: Synthesis of 4-(4-vinylphenyl)-l,2,3-thiadiazole
To a stirred solution of 4-(4-bromophenyl)-l,2,3-thiadiazole (250 mg, 1.037 mmol) in dioxane (10 mL) and water (1 mL), potassium vinyl trifluoroborate (126 mg, 0.943 mmol) and K2CO3 (130 mg, 0.943 mmol) were added at room temperature. The reaction mixture was sparged with nitrogen for 10 minutes, followed by the addition of PdC12(dppf)-CH2C12 adduct (77 mg, 0.094 mmol) at room temperature. The mixture was then irradiated under microwave conditions at 80°C for 1 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion of the starting material, the reaction mixture was quenched with water, extracted with EtOAc (2 x 50 mL), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under reduced pressure to yield the crude product. Purification by combi flash chromatography on silica gel (230-400 mesh) using 5% EtOAc/hexane afforded 4-(4-vinylphenyl)-l,2,3-thiadiazole (150 mg, 0.576 mmol, 61% yield). LCMS: ES+APCI, Positive [M+H]+ 189. ’H-NMR (400 MHz, DMSO-d6): 89.70 (s, 1H), 8.15-7.78 (m, 2H), 7.68 (d, J = 8.00 Hz, 2H), 6.86-6.81 (m, 1H), 5.99-5.94 (m, 1H), 5.38-5.35 (m, 1H). Step 2: Synthesis of 4-(l,2,3-thiadiazol-4-yl) benzaldehyde (ALD-69)
To a stirred solution of 4-(4-vinylphenyl)-l,2,3-thiadiazole (150 mg, 0.797 mmol) in water (0.8 mL) and acetonitrile (3 mL), sodium periodate (168 mg, 0.785 mmol) and osmium tetroxide (0.020 mL, 0.080 mmol) were added at 0°C. The reaction mixture was then stirred at room temperature for 15 minutes. Upon completion, as confirmed by TLC and LCMS, the reaction mixture was quenched with hypo solution and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to yield the crude product. Purification by combi flash chromatography over neutral alumina, eluting with 5% EtOAc/hexane, afforded 4-(l,2,3-thiadiazol-4-yl) benzaldehyde (38 mg, 0.200 mmol, 25% yield). LCMS: ES+APCI, Positive [M+H]+ Not ionized; *H- NMR (400 MHz, DMSO-d6): 5 10.10 (s, 1H), 9.86 (s, 1H), 8.40 (d, J = 8.40 Hz, 2H), 8.10 (d, J = 2.00
Hz, 2H).
Example 161: Synthesis of 4-(oxetan-3-yl) benzaldehyde (ALD-70)
Figure imgf000683_0001
A stirred solution of (4-formylphenyl) boronic acid (0.4 g, 2.67 mmol), 3-iodooxetane (0.98 g, 5.34 mmol), and K2CO3 (1.11 g, 8.00 mmol) in 1,4-dioxane (1 mL) was degassed with nitrogen for 15 minutes. Nickel (II) nitrate hexahydrate (0.063 g, 0.27 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (0.072 g, 0.27 mmol) were then added at room temperature and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by column chromatography, eluting with 60-75% EtOAc in hexane. The pure fractions were concentrated to afford 4-(oxetan-3-yl) benzaldehyde (ALD-70, 0.4 g, 1.97 mmol, 74% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 163.3. ’H-NMR (400 MHz, DMSO-d6): 5 10.01 (s, 1H), 7.93 (dd, J = 8.40
Hz, 2H), 7.64 (dd, J = 8.00 Hz, 2H), 4.98 (d, J = 6.00 Hz, 2H), 4.41 (d, J = 0.80 Hz, 2H), 4.35-4.33 (m,
1H).
Example 162: Synthesis of cyclopropyl-l-methyl-lH-pyrazole-5-carbaldehyde (ALD-71)
Figure imgf000683_0002
Step 1: Synthesis of (ethyl 4-cyclopropyl-2,4-dioxobutanoate) To a stirred solution of sodium ethoxide (0.809 g, 11.89 mmol) in ethanol (20 mL), 1- cyclopropylethan-l-one (1.0 g, 11.89 mmol) and diethyl oxalate (1.737 g, 11.89 mmol) were added dropwise at 0 °C. The reaction mixture was then stirred at 0 °C to room temperature for 1 h. Subsequently, the reaction mixture was heated to 80 °C and stirred for 45 minutes. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled to room temperature, and the solvent was distilled off. The residue was neutralized with 2N H2SO4 solution and extracted with EtOAc. The organic layer was dried over anhydrous NazSO4 and concentrated under reduced pressure to yield ethyl 4-cyclopropyl-2,4-dioxobutanoate (1.5 g, 7.17 mmol, 60% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 185.1.
Step 2: Synthesis of ethyl 3-cyclopropyl-l-methyl-lH-pyrazole-5-carboxylate
To a stirred solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (1.5 g, 8.14 mmol) in ethanol (15 mL), methylhydrazine (0.609 mL, 9.77 mmol) was added at -10 °C. The reaction mixture was then stirred at the same temperature for 2 h. The progress of the reaction was monitored using TLC and LCMS. Upon completion, the reaction mixture was distilled, diluted with water, and the compound was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash chromatography (eluent: 0-20% EtOAc in n-hexane). The desired fractions were concentrated under reduced pressure to yield ethyl 3- cyclopropyl-1 -methyl- lH-pyrazole-5-carboxylate (0.3 g, 1.455 mmol, 18% yield), which solidified to a solid. LCMS: m/z MM-ES+APCI, Positive [M-H]+ 195.1.
Step 3: Synthesis of cyclopropyl-l-methyl-lH-pyrazole-5-carbaldehyde (ALD-71)
To a stirred solution of morpholine (0.217 g, 2.487 mmol) in THE (2 mL), DIBAL-H (1.974 mL, 2.368 mmol) was added at 0 °C and the reaction mixture was stirred at the same temperature for 3 h. Subsequently, ethyl 3-cyclopropyl-l-methyl-lH-pyrazole-5-carboxylate (0.23 g, 1.184 mmol) in THE (2.000 mL) was added and stirred for 5 minutes, followed by the addition of DIBAL-H (1.085 mL, 1.303 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with saturated ammonium chloride solution and the compound was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash chromatography (eluent: 5-10% EtOAc in n-hexane). The desired fractions were concentrated under reduced pressure to yield 3 -cyclopropyl- 1 -methyl- lH-pyrazole-5- carbaldehyde (0.11 g, 0.635 mmol, 54% yield). LCMS: m/z MM-ES+APCI, Positive [M-H]+ 151.0. 'H- NMR (400 MHz, CDCL3): 59.78 (s, 1H), 6.49 (s, 1H), 4.11 (s, 3H), 1.99-1.93 (m,lH), 0.99-0.97(m, 2H), 0.96-0.95 (m, 2H).
Example 163: Synthesis of 4-(thiazol-5-yl)benzaldehyde (ALD-72)
Figure imgf000685_0001
1,4 Dioxane, , ,
To a stirred solution of 4-bromobenzaldehyde (0.2 g, 1.081 mmol) in dioxane (2 mL) and water (0.4 mL) was added tripotassium phosphate (0.459 g, 2.162 mmol) and 5-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)thiazole (0.274 g, 1.297 mmol) at room temperature. The reaction mixture was sparged with nitrogen for 5 minutes. PdC^dppfl-Q-LCL adduct (0.044 g, 0.054 mmol) was then added, and the reaction mixture was stirred at 80 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was filtered through a Celite bed and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude compound was purified by combi-flash chromatography, eluting with 5-20% EtOAc in n-hexane. The desired fractions were concentrated under reduced pressure to yield 4-(thiazol-5-yl)benzaldehyde (0.18 g, 0.920 mmol, 85% yield). LCMS: m/z + 190.1; 1 H-NMR (DMSO): 1H-NMR (400 MHz, DMSO-d6): 5 10.03 (s, 1H), 9.21 (s, 1H), 8.53 (s, 1H), 8.00-7.94 (m, 4H).
Example 164: Synthesis of 4-(4-methylthiazol-5-yl) benzaldehyde (ALD-73)
Figure imgf000685_0002
To a stirred solution of 5-bromo-4-methylthiazole (300 mg, 1.685 mmol), (4- formylphenyl)boronic acid (278 mg, 1.853 mmol), and potassium phosphate, tribasic (894 mg, 4.21 mmol) in 1,4-dioxane (5 mL) and water (0.500 mL), degassed with N2 for 5 minutes, PdC12(dppf)-DCM adduct (138 mg, 0.168 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h.. The reaction mixture was concentrated under reduced pressure to obtain a crude residue. The crude compound was purified by flash column chromatography using Biotage Isolera (silica gel cartridge 40 g) using 11% EtOAc in hexane as the eluent. The pure fractions were concentrated under reduced pressure to afford 4- (4-methylthiazol-5-yl) benzaldehyde (240 mg, 0.897 mmol, 53% yield). LCMS: m/z [M+H]+ 204.0. 1H- NMR (400 MHz, DMSO-d6): 5 10.06 (s, 1H), 9.11 (s, 1H), 8.02-8.00 (m, 2H), 7.75 (d, J = 8.40 Hz, 2H), 2.53-2.50 (m, 3H).
Example 165: Synthesis of 3-methyl-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-75)
Figure imgf000686_0001
Step 1: Synthesis of (E)-4-bromo-N'-hydroxy-2-methylbenzimidamide
To a stirred solution of 4-bromo-2-methylbenzonitrile (5 g, 25.5 mmol) in ethanol (40 mL) and water (4 mL) was added hydroxylamine hydrochloride (5.32 g, 77 mmol) and K2CO3 (17.62 g, 128 mmol) at 25 °C. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was extracted with EtOAc (2 x 50 mL) and washed with brine solution. The organic layer was dried over anhydrous NaiSCL and concentrated under reduced pressure. The crude compound was triturated with hexane (10 mL) and dried under reduced pressure to afford (E)-4-bromo-N’-hydroxy-2-methylbenzimidamide (3.5 g, 14.58 mmol, 57% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 231.1; 'H-NMR (400 MHz, DMSOvL): 59.41 (s, 1H), 7.76-7.43 (m, 2H), 7.22 (d, J = 8.00 Hz, 1H), 5.77 (s, 2H), 2.34 (s. 3H).
Step 2: Synthesis of 3-(4-bromo-2-methylphenyl)-l,2,4-oxadiazole
To a stirred solution of (E)-4-bromo-N’-hydroxy-2-methylbenzimidamide (2 g, 8.73 mmol) in triethyl orthoformate (64.7 g, 437 mmol) at 25 °C was added pyridinium p-toluene sulfonate (1.09 g, 4.37 mmol). The resulting reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was extracted with EtOAc (2 x 100 mL) and washed with brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexane. The collected pure fractions were concentrated to yield 3-(4-bromo-2-methylphenyl)-l,2,4-oxadiazole (2.5 g, 9.83 mmol, quantitative yield). ’H-NMR (400 MHz, DMSO-t/e): 59.75 (s, 1H), 7.89 (dd, J = 8.00 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 2.57 (s, 3H), Step 3: Synthesis of 3-(4-bromo-2-methylphenyl)-l,2,4-oxadiazole
A stirred solution of 3-(4-bromo-2-methylphenyl)-l,2,4-oxadiazole (1.5 g, 6.27 mmol), potassium trifluoroborate (1.185 g, 9.41 mmol), K2CO3 (2.168 g, 15.69 mmol) in 1,4-dioxane (9.5 mL) and water (0.5 mL) was degassed with N2 at room temperature. PdC12(dppf)-CH2Ch adduct (0.512 g, 0.627 mmol) was added and the reaction mixture was stirred at 85 °C for 1 h in a microwave reactor. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was extracted with EtOAc (2 x 100 mL) and washed with brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to yield 3-(2-methyl-4-vinylphenyl)-l,2,4-oxadiazole (0.5 g, 2.28 mmol, 36% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 187.2; 'H-NMR (400 MHz, DMSO-tfc): 59.71 (s, 1H), 7.95 (d, J = 8.00 Hz, 1H), 7.54-7.50 (m, 2H), 6.79 (dd, J = 10.80, 17.60 Hz, 1H), 5.99 (d, J
= 0.40 Hz, 1H), 5.40 (d, J = 11.20 Hz, 1H), 2.59 (s, 1H),
Step 4: Synthesis of 3-methyl-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-75)
To a stirred solution of 3-(2-methyl-4-vinylphenyl)-l,2,4-oxadiazole (870 mg, 4.67 mmol) in THE (20 mL) and water (4.00 mL) was added sodium periodate (1499 mg, 7.01 mmol) at 25 °C. Potassium osmate dihydrate (43.0 mg, 0.12 mmol) was then added to the reaction mixture, which was stirred at 25 °C for 1 h. The reaction mixture was directly concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 5% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to yield 3-methyl-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-75, 365 mg, 1.75 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 189; 'H-NMR (400 MHz, DMSO-&): 8 10.09 (s, 1H), 9.81 (s, 1H), 8.17 (d, J = 8.00 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.00 Hz, 1H), 2.67 (s, 3H).
Example 166: Synthesis of 4-(4-formylphenyl)-l-methyl-lH-pyrazole-3-carbonitrile (ALD-75)
O
Br HCV 0
— N OH
N' — N
Pd(dppf)CI2 DCM adduct,
% N' K2CO3, dioxane, water, 80°C
N
To a stirred solution of (4-formylphenyl)boronic acid (300 mg, 2.001 mmol) and 4-bromo-l- methyl-lH-pyrazole-3-carbonitrile (372 mg, 2.001 mmol) in 1,4-dioxane (3 mL) and water (0.333 mL), potassium carbonate (415 mg, 3.00 mmol) was added at room temperature. The reaction mixture was sparged with argon for 10 minutes, followed by the addition of Pd(dppf)C12-DCM adduct (146 mg, 0.200 mmol) at room temperature. The reaction mixture was again sparged with argon for 10 minutes. The reaction mixture was then irradiated at 80 °C for 1.5 h. The progress of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Isolera using 100-200 mesh silica gel. The product eluted in EtOAc, and the pure fractions were collected and concentrated under reduced pressure to afford 4-(4-formylphenyl)-l- methyl-lH-pyrazole-3-carbonitrile (280 mg, 1.320 mmol, 66% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 212.0. 'H-NMR (400 MHz, DMSO-d6): 3 10.03 (s, 1H), 8.58 (s, 1H), 8.03 (d, J = 8.40 Hz, 2H), 7.88 (d, J = 8.40 Hz, 2H), 4.01 (s, 3H). Example 167: Synthesis of 3-nuoro-4-(l,3,4-oxadiazol-2-vl) benzaldehyde (ALD-76)
Figure imgf000688_0001
Step 1: Synthesis of 4-bromo-2- fluorobenzohydrazide
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.13 mmol) in DCM (20 mL) at 0 o. C under a nitrogen atmosphere, HOBt (2.098 g, 13.7 mmol) and EDC HC1 (2.63 g, 13.7 mmol) were added and the reaction mixture was stirred at the same temperature for 10 minutes, then hydrazine hydrate (0.488 mL, 10.05 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. Upon completion, as confirmed by TLC, the reaction mixture was poured into cooled water (100 mL), and the compound was extracted with EtOAc (2 x 300 mL). The organic layer was dried over anhydrous NazSCL, filtered, and concentrated under reduced pressure to obtain the crude compound. LCMS no ionization. ’H-NMR (400 MHz, DMSO-d6): 3 13.71 (s, 1H), 7.97 (d, J = 8.40 Hz, 1H), 7.71 (d, J = 8.40 Hz, 1H), 7.58-7.46 (m, 2H), 7.43 (t, J = 8.00 Hz, 1H). Step 2: Synthesis of 2-(4-bromo-2-fluorophenyl)-l,3,4-oxadiazole
To a stirred solution of 4-bromo-2-fluorobenzohydrazide (600 mg, 2.57 mmol) in triethoxymethane (382 mg, 2.57 mmol) at 0 CC, the reaction mixture was stirred at 100 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was added to water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a solid crude product. This was purified by flash column chromatography (silica gel, 100-200 mesh) using 100% EtOAc as the eluent. The pure fractions were evaporated and dried under high vacuum to afford 2-(4-bromo-2-fluorophenyl)-l,3,4-oxadiazole (200 mg, 0.823 mmol, 32% yield). LCMS: No ionization. ’H-NMR (400 MHz, DMSO-d6): 8 9.45 (s, 1H), 8.01 (t, J = 8.00 Hz, 1H), 7.92 (dd, J = 1.60, 10.40 Hz, 1H), 7.69 (dd, J = 1.60, 8.40 Hz, 1H).
Step 3: Synthesis of 2-(2-fluoro-4-vinylphenyl)-l,3,4-oxadiazole
To a stirred solution of 2-(4-bromo-2-fluorophenyl)-l,3,4-oxadiazole (200 mg, 0.82 mmol) in 1,4-dioxane (3 mL), trifluoro(vinyl)-14-borane, potassium salt (132 mg, 0.99 mmol) and K2CO3 (227 mg, 1.646 mmol) were added at 25 °C and degassed with N2 for 10 minutes. After 10 minutes, Pd(dppf)Ch-DCM (67.2 mg, 0.082 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 100% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to yield 2-(2-fluoro-4-vinylphenyl)-l,3,4-oxadiazole (90 mg, 0.46 mmol, 55% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 191.0; 'H-NMR (400 MHz, DMSO-d6): 8 8.55 (d, J = 6.80 Hz, 1H), 8.07 (t, J = 8.00 Hz, 1H), 7.35-7.30 (m, 2H), 6.75 (dd, J = 10.80, 17.60 Hz,
1H), 5.93 (d, J = 17.20 Hz, 1H), 5.50 (d, J = 10.80 Hz, 1H).
Step 4: Synthesis of 3-fhioro-4-(l,3,4-oxadiazol-2-yl) benzaldehyde
To a stirred solution of 2-(2-fluoro-4-vinylphenyl)-l,3,4-oxadiazole (60 mg, 0.315 mmol) in THF (0.6 mL) and water (0.2 mL), potassium osmate dihydrate (2.91 mg, 7.89 pmol) was added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 100% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to yield 3-fluoro-4-(l,3,4-oxadiazol-2-yl)benzaldehyde (35 mg, 0.159 mmol, 50% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 192.9. 'H-NMR (400 MHz, DMSO-d6): 8 10.10 (d, J = 1.60 Hz, 1H), 8.63 (s, 1H), 8.35 (dd, J = 6.40, 7.80 Hz, 1H), 7.87 (dd, J = 1.60, 8.00 Hz, 1H), 7.81 (dd, J = 1.20, 10.00 Hz, 1H). Example 168: Synthesis of 3-chloro-4-(l,3,4-oxadiazol-2-yl) benzaldehyde (ALD-77)
Figure imgf000689_0001
Step 1: Synthesis of 4-bromo-2-chlorobenzohydrazide
To a stirred solution of 4-bromo-2-chlorobenzoic acid (0.5 g, 2.123 mmol) in dichloromethane (10 mL) at 0 °C under a nitrogen atmosphere, EDC-HC1 (0.611 g, 3.19 mmol) and HOBt (0.488 g, 3.19 mmol) were added and the reaction mixture was stirred at room temperature for 5 minutes, then hydrazine hydrate (0.117 g, 2.336 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 40 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the solid crude product. This was purified by flash column chromatography (silica gel, 100-200 mesh) using 100% EtOAc as the eluent. The pure fractions were evaporated and dried under high vacuum to afford 4-bromo-2-chlorobenzohydrazide (0.5 g, 2.004 mmol, 94% yield). LCMS: no mass ionization. ’H-NMR (400 MHz, DMSO-d6): 57.95 (d, J = 8.40 Hz, 1H), 7.66 (d, J = 2.00 Hz, 1H), 7.50 (t, J = 7.60 Hz, 1H), 7.42 (t, J = 0.80 Hz, 1H), 4.48 (s, 2H), Step 2: Synthesis of 2-(4-bromo-2-chlorophenyl)-l,3,4-oxadiazole
Solution of 4-bromo-2-chlorobenzohydrazide (800 mg, 3.21 mmol) in triethoxymethane (475 mg, 3.21 mmol) was stirred at 100 °C for 12 h. After completion of starting material, as monitored by TLC/LCMS. After completion of reaction, reaction mixture was concentrated under reduced pressure to get crude. Crude was quenched with water (50 mL) diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to get crude compound, crude which was purified by flash column chromatography (silica-gel, 100-200 mesh size) using (100% EtOAc as an eluent). The pure fractions were evaporated and dried under high vacuum to afford 2-(4-bromo-2-chlorophenyl)- 1,3,4- oxadiazole (450 mg, 1.676 mmol, 52% yield). LCMS: m/z MM-ES+APCI, Positive [M+2]+ 258.8, 260.8. ’H-NMR (400 MHz, DMSO-d6): 89.48 (s, IH), 8.07 (s, 1H), 7.95 (d, J = 8.40 Hz, 1H), 7.82 (d, J = 2.00 Hz, IH),
Step 3: Synthesis of 2-(2-chloro-4-vinylphenyl)-l,3,4-oxadiazole
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-l,3,4-oxadiazole in 1,4-dioxane (3 mL), trifluoro(vinyl)-14-borane, potassium salt (49.6 mg, 0.370 mmol) and K2CO3 (85 mg, 0.617 mmol) were added at 25 °C and degassed with N2 for 10 minutes. After 10 minutes, Pd(dppf)C12- DCM (25.2 mg, 0.031 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 100% EtOAc in n- hexane. The collected pure fractions were concentrated under reduced pressure to yield 2-(2-chloro-4- vinylphenyl)-l,3,4-oxadiazole (60 mg, 0.199 mmol, 65% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 205.0, 207.0. ’H-NMR (400 MHz, DMSO-d6): 8 8.57 (s, IH), 8.01 (d, J = 8.40 Hz, 1H), 7.60 (s, IH), 7.46 (d, J = 1.60 Hz, IH), 6.77-6.70 (m, IH), 5.93 (d, J = 17.60 Hz, IH), 5.49 (d, J = 11.20 Hz, IH),
Step 4: Synthesis of 3-chloro-4-(l,3,4-oxadiazol-2-yl) benzaldehyde
Example 169: Synthesis of l-cyclopropyl-lH-pyrazole-5-carbaldehyde (ALD-78)
Figure imgf000691_0002
Step 1: Ethyl l-cyclopropyl-lH-pyrazole-5-carboxylate
To a stirred solution of lH-pyrazole-5-carboxylate (500 mg, 3.57 mmol) and cyclopropylboronic acid (613 mg, 7.14 mmol) in 1 ,2-dichloroethane (10 mL) were added bipyridinyl (111 mg, 0.714 mmol) and sodium carbonate (756 mg, 7.14 mmol) followed by copper(II) acetate monohydrate (142 mg, 0.714 mmol) at rt. The reaction mixture was stirred at 70 °C for 16 h. Water (50 mL) was added to the cooled reaction mixture, and the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were concentrated under reduced pressure and purified by silica gel flash column chromatography, eluting with EtOAc in hexane (10%) to afford ethyl l-cyclopropyl-lH-pyrazole-5-carboxylate (180 mg, 0.978 mmol, 27% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 181.3. 'H-NMR (400 MHz, DMSO-d6): 57.50 (d, J = 1.60 Hz, 1H), 6.87 (d, J = 2.00 Hz, 1H), 4.35-4.28 (m, 3H), 1.32 (t, J = 7.20 Hz, 3H), 1.15- 1.08 (m, 2H), 1.04-0.99 (m, 2H),
Step 2: l-cyclopropyl-lH-pyrazole-5-carbaldehyde (ALD-78)
To a stirred solution of morpholine (0.383 mL, 4.44 mmol) in THE (5 mL), DIBAL-H (3.70 mL, 4.44 mmol) was added at 0 °C and stirred for 2 h. Then, ethyl l-cyclopropyl-lH-pyrazole-5-carboxylate (160 mg, 0.888 mmol) in THE (2 mL) was added to the reaction mixture at 0 °C and stirred for 30 minutes. DIBAL-H (1.480 mL, 1.776 mmol) was added again at 0 °C and stirred for 1 h. The progress of the reaction was monitored by TLC and UPLC. Upon completion, as confirmed by TLC and UPLC, the reaction mixture was quenched with 1.5 N HC1 (5 mL) and extracted with water (20 mL) and EtOAc (2 x 25 mL). The organic layer was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 10% EtOAc in hexane to yield 1 -cyclopropyl- lH-pyrazole-5-carbaldehyde (100 mg, 0.625 mmol, 70% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 137.1. 'H-NMR (400 MHz, DMSO-d6): 5 10.05 (s, 1H), 7.56 (d, J =
2.00 Hz, 1H), 7.04 (d, J = 2.00 Hz, 1H), 4.25-4.22 (m, 1H), 1.18-1.16 (m, 2H), 1.08-1.06 (m, 2H).
Example 170: Synthesis of 6-(l-hydroxycyclobutyl)nicotinaldehyde (ALD-79)
Figure imgf000691_0001
Step 1: Synthesis of 2-bromo-5-(diethoxymethyl)pyridine
To a stirred solution of 6-bromonicotinaldehyde (2.5 g, 13.44 mmol) in ethanol (10 mL), p- toluene sulfonic acid monohydrate (0 256 g 1 344 mmol) and triethyl orthoformate (5 98 g 40 3 mmol) were added at room temperature. The reaction mixture was then stirred at 80 °C for 2 h. Upon completion, the reaction mixture was quenched with water (100 mL), and the compound was extracted with EtOAc (2 x 300 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to afford the crude compound. The crude product was purified by column chromatography using neutral alumina, eluted with 30% EtOAc/hexane. The collected pure fractions were evaporated under reduced pressure to afford 2-bromo-5-(diethoxymethyl)pyridine (2.45 g, 7.75 mmol, 58% yield). ’H-NMR (400 MHz, DMSO-d6): 5 8.47 (s, 1H), 7.68 (d, J = 2.40 Hz, 1H), 7.50 (d, J = 8.00 Hz, 1H), 5.55 (s, 1H), 3.65-3.60 (m, 4H), 1.28-1.26 (m, 6H).
Step 2: Synthesis of l-(5-(diethoxymethyl)pyridin-2-yl)cyclobutan-l-ol
To a stirred solution of 2-bromo-5-(diethoxymethyl)pyridine (1.3 g, 5.00 mmol) in toluene (4 mL), n-butyllithium (1.999 mL, 5.00 mmol) was added at -78 °C and stirred for 1 h. Cyclobutanone (0.350 g, 5.00 mmol) was then added at -78 °Cand the reaction mixture was stirred for 1 h at -78 °C. Upon completion, the reaction was quenched with water (50 mL) and the compound was extracted with DCM (2 x 250 mL) and dried over anhydrous Na2SC>4. The organic layer was concentrated under reduced pressure to afford the crude compound. The crude product was purified by column chromatography using neutral alumina, eluted with 30% EtOAc/hexane, and evaporated to yield l-(5-(diethoxymethyl)pyridin-2- yl)cyclobutan-l-ol (950 mg, 3.55 mmol, 71% yield). LCMS: m/z = (M+l) 252.5. ’H-NMR (400 MHz, DMSO-d6): 8 8.54 (s, 1H), 7.74 (d, J = 0.40 Hz, 1H), 7.57 (d, J = 0.80 Hz, 1H), 5.73 (s, 1H), 5.57 (s, 1H), 3.57-3.53 (m, 4H), 2.50 (m, 1H), 2.23-2.00 (m, 2H), 2.19-1.91 (m, 2H), 1.18-1.15 (m, 6H).
Step 3: Synthesis of 6-(l-hydroxycyclobutyl)nicotinaldehyde (ALD-79)
To a stirred solution of l-(5-(diethoxymethyl)pyridin-2-yl)cyclobutan-l-ol (100 mg, 0.37 mmol) in DCM (5 mL), trifluoroacetic acid (0.566 mL, 7.40 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 6 h. Upon completion, the reaction mixture was cooled to 0 °C and quenched with sodium bicarbonate solution (10 mL). The mixture was extracted with DCM (2 x 20 mL), dried over anhydrous Na2SC>4, filtered, and the solvent was evaporated under reduced pressure to obtain 6-(l-hydroxycyclobutyl)nicotinaldehyde (60 mg, 0.21 mmol, 57% yield). ’H-NMR (400 MHz, DMSO- d6): 8 10.10 (s, 1H), 9.07 (s, 1H), 8.21 (d, J = 2.00 Hz, 1H), 7.78 (d, J = 8.40 Hz, 1H), 6.07 (s, 1H), 2.52- 2.51 (m, 2H), 2.30-2.26 (m, 2H), 1.97-1.94 (m, 2H).
Example 171: Synthesis of 4-(lH-pyrazol-3-yl) benzaldehyde (ALD-80)
Figure imgf000692_0001
Step 1: 3-(4-bromophenyl)-lH-pyrazole To a stirred solution of l-(4-bromophenyl)ethan-l-one (1 g, 5.02 mmol) in DMF (5 mL) under nitrogen at 25 °C, l,l-dimethoxy-N,N-dimethylmethanamine (0.801 mL, 6.03 mmol) was added. The resulting reaction mixture was heated at 80 °C for 16 h. The reaction was quenched with water (10 mL) and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SC>4 and evaporated under reduced pressure to obtain the crude compound. The crude compound was dissolved in ethanol (5.0 mL) and stirred for 10 minutes. To this reaction mixture, hydrazine monohydrate (0.735 mL, 15.07 mmol) was added dropwise at 25 °C. The resulting reaction mixture was heated at 80 °C for 2 h. The reaction was quenched with ice- cold water (10 mL) and evaporated under reduced pressure to afford the crude compound, 3-(4- bromophenyl)-lH-pyrazole (1 g, 4.44 mmol, 88% yield). LCMS: m/z MM-ES+APCI, Positive [M+2]+ 223.1, 225.1; 'H-NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): 5 12.96 (s, IH), 7.78 (d, J = 8.80 Hz, 2H), 7.60-7.48 (m, 3H), 6.73 (d, J = 11.60 Hz, 1H).
Step 2: 3-(4-vinylphenyl)-lH-pyrazole:
3-(4-Vinylphenyl)-lH-pyrazole was prepared following a procedure similar to Example 168, ALD-77, Step 3.
Step 3: 4-(lH-pyrazol-3-yl) benzaldehyde
To a stirred solution of 3-(4-vinylphenyl)-lH-pyrazole (150 mg, 0.881 mmol) in THE (5 mL) and water (1 mL), potassium osmate dihydrate (64.9 mg, 0.176 mmol) and sodium periodate (565 mg, 2.64 mmol) were added at 25 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. The progress of the reaction was monitored by LCMS. The reaction was quenched with water (10 mL) and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel flash column chromatography eluting with 0-30% EtOAc in hexane to afford 4-(lH-pyrazol-3-yl) benzaldehyde (50 mg, 0.258 mmol, 29% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 172.8. ’H-NMR (400 MHz, DMSO-d6): 1H-NMR (400 MHz, DMSO-d6): 5 13.14 (s, 1H), 10.01 (s, IH), 8.06 (d, J = 8.00 Hz, 2H), 7.99-7.94 (m, 2H), 6.93- 6.88 (m, IH), 5.44 (t, J = 8.00 Hz, IH).
Example 172: Synthesis of 5-(3-(trifluoromethyl)phenyl)-lH-pyrazole-3-carbaldehyde (ALD-81)
Figure imgf000693_0001
Step 1: Synthesis of methyl 5-(3-(trifluoromethyl) phenyl)-lH-pyrazole-3-carboxylate To a stirred solution of methyl 5-bromo-lH-pyrazole-3-carboxylate (2 g, 9.76 mmol) in 1,4- dioxane (18 mL) and water (2 mL) under nitrogen purging, (3-(trifluoromethyl) phenyl) boronic acid (2.223 g, 11.71 mmol) was added, followed by sodium carbonate (2.068 g, 19.51 mmol) at room temperature. After 2 minutes, Pd (PPtnL (1.127 g, 0.976 mmol) was added under nitrogen purging and the reaction mixture was stirred at 100 °C for 3 h. Upon completion, the reaction mixture was filtered through a Celite pad, washed, and the filtrate was concentrated to obtain the crude compound. The crude product was purified by flash column chromatography using SiCL (100-200 mesh) and 45-50% EtOAc in hexanes. The pure fractions were concentrated under reduced pressure to afford methyl 5-(3- ( trifluoromethyl) phenyl)-lH-pyrazole-3-carboxylate (600 mg, 1.998 mmol, 21% yield). LCMS: m/z MM-ES+APCI, Positive [M]+ 271.4; 'H-NMR (400 MHz, DMSO-d6): 5 14.26 (s, 1H), 8.25-8.14 (m, 2H), 7.74-7.43 (m, 3H), 3.89 (s, 3H).
Step 2: Synthesis of (5-(3-(trifluoromethyl) phenyl)-lH-pyrazol-3-yl) methanol
To a stirred solution of methyl 5-(3-(trifluoromethyl) phenyl)- lH-pyrazole-3-carboxylate (1.5 g, 5.55 mmol) in THE (40 mL), LiAlH4 (IM in THE, 16.7 mL, 16.7 mmol) was added at 0 °C and the reaction mixture was stirred under a nitrogen atmosphere at 25 °C for 2 h. Upon completion, the reaction mixture was quenched with NH4Q solution (20 mL) and stirred for 15 minutes. The mixture was then extracted with EtOAc (50 mL). The organic layer was separated, dried over Na2$O4 and concentrated under reduced pressure to afford (5-(3-(trifluoromethyl) phenyl)-lH-pyrazol-3-yl)methanol (1.62 g, 4.10 mmol, 74% yield). LCMS: m/z MM-ES+APCI, Positive [M]+ 243.2; ’H-NMR (400 MHz, DMSO-d6): 5 12.95 (s, 1H), 8.13-8.07 (m, 2H), 7.86-7.82 (m, 2H), 6.34 (s, 1H), 5.39 (s, 1H), 4.79 (s, 2H).
Step 3: 5-(3-(trifluoromethyl) phenyl)-lH-pyrazole-3-carbaldehyde
To a stirred solution of (5-(3-(trifluoromethyl) phenyl)- lH-pyrazol-3-yl) methanol (500 mg, 2.064 mmol) in DCM (8 mL) under a nitrogen atmosphere, Dess-Martin periodinane (1313 mg, 3.10 mmol) was added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. Sodium bicarbonate solution was added and the mixture was extracted with DCM. The organic layer was separated and concentrated under reduced pressure to afford a crude residue. This crude product was triturated with MTBE and concentrated under reduced pressure to afford 5-(3-(trifluoromethyl) phenyl)-lH-pyrazole-3- carbaldehyde (46 mg, 0.134 mmol, 7% yield). LCMS: m/z MM-ES+APCI, Not ionized. ’H-NMR (400 MHz, DMSO-d6): 5 12.57 (s, 1H), 9.75 (s, 1H), 8.99 (s, 1H), 7.87-7.81 (m, 1H), 7.69-7.65 (m, 1H), 7.50- 7.44 (m, 1H), 6.76 (s, 1H).
Example 173: Synthesis of 3-(5-formyl-lH-pyrrol-3-yl)benzonitrile (ALD-82)
Figure imgf000695_0001
Step 1: 4-bromo-lH-pyrrole-2-carbaldehyde
To a stirred solution of lH-pyrrole-2-carbaldehyde (1 g, 10.52 mmol) in THF (20 mL) at 0 °C, 1- bromopyrrolidine-2, 5-dione (1.87 g, 10.52 mmol) was added as a single portion and the reaction mixture was stirred for 15 minutes at room temperature. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 5% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 4-bromo-lH-pyrrole-2-carbaldehyde (1.5 g, 6.16 mmol, 59% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 173.8, 175.8; ’H-NMR (400 MHz, DMSO-d6): 5 12.59 (s, 1H), 9.48-9.45 (s, 1H), 7.38-7.22 (s, 1H), 7.08-6.99 (s, 1H).
Step 2: 3-(5-formyl-lH-pyrrol-3-yl) benzonitrile
To a stirred solution of 4-bromo-lH-pyrrole-2-carbaldehyde (25 mg, 0.144 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL), (3-cyanophenyl)boronic acid (25.3 mg, 0.172 mmol) and potassium phosphate, tribasic (76 mg, 0.359 mmol) were added at 25 °C. The reaction mixture was degassed with N? for 10 minutes, followed by the addition of methanesulfonato-(diadamantyl-n-butylphosphino)-2’-amino- l,l’-biphenyl-2-yl)palladium(II) dichloromethane adduct (5.23 mg, 7.18 pmol). The reaction mixture was further degassed with N2 for 5 minutes. The resulting reaction mixture was allowed to stir at 100 °C for 16 h. The progress of the reaction was monitored by LCMS, which showed the desired product mass. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 5% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 3-(5-formyl-lH-pyrrol-3-yl) benzonitrile (50 mg, 0.245 mmol, 100% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 197.2; ’H-NMR (400 MHz, DMSO-d6): 5 12.42 (s, 1H), 9.54 (s, 1H), 8.07 (t, J = 8.00 Hz, 1H), 7.91-7.90 (m, 2H), 7.58-7.54 (m, 3H). Example 175: Synthesis of 3-chloro-4-(l,3-dimethyl-lH-pyrazol-4-yl)benzaldehyde (ALD-85)
Figure imgf000696_0001
To a stirred solution of (2-chloro-4-formylphenyl)boronic acid (150 mg, 0.814 mmol) and 4- bromo-l,3-dimethyl-lH-pyrazole (142 mg, 0.814 mmol) in 1,4-dioxane (0.9 mL)/water (0.1 mL) were added potassium carbonate (169 mg, 1.220 mmol), at 25 °C and degassed with N2 for 10 min. Pd(dppf)C12 • DCM adduct (59.5 mg, 0.081 mmol) was added at 25 °C and the mixture was again degassed with N2 for 10 min. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2 x 30 mL). The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (30%) to get 3-chloro-4-(l,3-dimethyl-lH-pyrazol-4- yl)benzaldehyde (100 mg, 0.413 mmol, 51% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 234.9, 236.8. 'H-NMR (400 MHz, DMSO-d6): 5 'H-NMR (400 MHz, DMSO-d6): 5 10.00 (s, 1H), 8.05 (d, J = 1.60 Hz, 1H), 7.93 (d, J = 2.00 Hz, 1H), 7.89-7.87 (m, 1H), 7.62-7.60 (m, 1H), 3.83 (s, 3H), 2.16 (s, 3H).
Example 176: Synthesis of 4-(2-chloro-4-formylphenyl)-l-methyl-lH-pyrazole-3-carbonitrile (ALD- 86)
Figure imgf000696_0002
To a stirred solution of (2-chloro-4-formylphenyl)boronic acid (100 mg, 0.542 mmol) and 4- bromo-l-methyl-lH-pyrazole-3-carbonitrile (101 mg, 0.542 mmol) in 1,4-Dioxane (0.9 mL)/Water (0.1 mL) was added potassium carbonate (112 mg, 0.814 mmol), at 25 °C and degassed with N2 for 10 min. Then, Pd(dppf)C12- DCM adduct (39.7 mg, 0.054 mmol) was added at 25 °C and degassed with N2 for 10 min and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture filtered through a pad of celite and washed with EtOAc (2 x 30 mL), organic layer concentrated under reduced pressure to get crude. The crude compound was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (30%) to get 4-(2-chloro-4-formylphenyl)-l-methyl-lH-pyrazole-3-carbonitrile (50 mg, 0.162 mmol, 30% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 246.1, 248.0. 1H-NMR (400 MHz, DMSO-d6): 5 10.04 (s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 8.00 Hz, 1H), 7.78 (d, J = 8.00 Hz, IH), 4.04 (s, 3H). Example 177: Synthesis of 3-(pyridazin-4-yl)benzaldehyde (ALD-87)
Figure imgf000697_0001
To a stirred solution of 4-bromopyridazine, HBr (80 mg, 0.333 mmol) and (3- formylphenyl)boronic acid (60.0 mg, 0.400 mmol) in 1,4-Dioxane (0.9 mL)/Water (0.1 mL) was added potassium phosphate (106 mg, 0.500 mmol), at 25 °C and degassed with N2 for 10 min. Then, XPhos (15.90 mg, 0.033 mmol) and XPhos Pd G3 (26.2 mg, 0.033 mmol) were added at 25 °C and degassed with
Figure imgf000697_0002
Step 1: Synthesis of 6-Vinylisoindolin-l-one
To a stirred solution of 6-bromoisoindolin-l-one (500 mg, 2.358 mmol) and trifluoro(vinyl)-14- borane, potassium salt (379 mg, 2.83 mmol) in 1,4-dioxane (0.9 mL)/water (0.1 mL) was added potassium phosphate tribasic (821 mg, 4.72 mmol) at 25 °C and degassed with N2 for 10 min. Then, Pd(dppf)C12 • DCM (193 mg, 0.236 mmol) was added at 25 °C and degassed with N2 for 10 min. Then reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2 x 30 mL). The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (30%) to afford 6-vinylisoindolin-l-one (500 mg, 2.82 mmol, 120% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 160.0, ’H-NMR (400 MHz, DMSO-d6): 5 7.95 (d, J = 1.20 Hz, 1H), 7.63 (dd, J = 1.60, 7.80 Hz, IH), 7.45 (d, J = 8.00 Hz, 1H), 6.86-6.72 (m, 2H), 5.88 (d, J = 17.60 Hz, 1H), 5.36 (d, J = 10.80 Hz, IH), 4.49 (d, J = 4.00 Hz, 2H).
Step 2: 3-oxoisoindoline-5-carbaldehyde To a stirred solution of 6-vinylisoindolin-l-one (200 mg, 1.26 mmol) in THF (3.0 mL), Water (1.0 mL) were added sodium periodate (403 mg, 1.89 mmol) and potassium osmate dihydrate (11.6 mg, 0.03 mmol), at 0 °C. Then, the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL), organic layer was concentrated under reduced pressure to get crude. The crude was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (100%) to afford 3-oxoisoindoline-5-carbaldehyde (55 mg, 0.29 mmol, 23% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 162.0. ‘H-NMR (400 MHz, DMSO-d6): 5 10.15 (s, 1H), 8.39 (s, 1H), 8.17 (dd, J = 1.20, 8.00 Hz, 1H), 7.67 (d, J = 7.60 Hz, 1H), 6.47 (s, 1H), 4.59
(s, 2H).
Example 180: Synthesis of 3-chloro-5-methyl-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-89)
KOH, H2O, THF, Cl Br NH4CI, HATU, MeOH, 80 °C, 12 h TEA, DCM, rt, 12 h
0.
Step-1 Step-2
OH
POCI3, DCE, NH2OH.HCI, K2CO3,
Cl Br Br TFA, CH(OEt)3,
60 °C EtOH, H2O, 80 °C 100 °C, 4 h
Step-3 NO Step-4
Step-5
Figure imgf000698_0001
K2OsO4-2H2O, NalO4.
^BF3K THF, H2O, 0 °C-rt, 30 min
PdCI2(dppf)-DCM, K2CO3, 1 ,4-dioxane, H2O, Step-7
Figure imgf000698_0002
1 h, 80 °C, MW
Figure imgf000698_0003
Step-6
Step 1: Synthesis of 4-bromo-2-chloro-6-methylbenzoic acid
To a stirred solution of methyl 4-bromo-2-chloro-6-methylbenzoate (3.8 g, 14.42 mmol) in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL), KOH (2.427 g, 43.3 mmol) was added at 0 °C. The reaction mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was extracted with EtOAc (2 x 1 mL). The aqueous layer was set aside, and the pH was adjusted to 4 with 1.5 M HC1 solution. The mixture was then extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous NazSCL filtered, and concentrated under reduced pressure to afford the crude product. The crude compound was purified to yield 4-bromo-2-chloro-6-methylbenzoic acid (2 g, 7.54 mmol, 52% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H] 248.8, 250.8; ‘H-NMR (400 MHz, DMSO-d6): 57.58 (s, 1H), 7.49 (s, 1H), 2.27 (s, 3H).
Step 2: Synthesis of 4-bromo-2-chloro-6-methylbenzamide To a stirred solution of 4-bromo-2-chloro-6-methylbenzoic acid (500 mg, 2.004 mmol) in dichloromethane (5 mL), TEA (811 mg, 8.02 mmol), HATU (914 mg, 2.405 mmol), and ammonium chloride (322 mg, 6.01 mmol) were added at room temperature. The mixture was stirred for 16 h at room temperature. Upon completion, the reaction mixture was quenched with water and extracted with DCM (2 x 100 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 50% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 4- bromo-2-chloro-6-methylbenzamide (900 mg, 3.62 mmol, 181% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 249.6, 251.8. ’H-NMR (400 MHz, DMSO-d6): 57.94 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 2.28 (s, 3H).
Step 3: Synthesis of 4-bromo-2-chloro-6-methylbenzonitrile
To a stirred solution of 4-bromo-2-chloro-6-methylbenzamide (700 mg, 2.82 mmol) in 1,2- dichloroethane (5 mL), POOL (1.317 mL, 14.08 mmol) was added at room temperature and stirred for 5 h at 80 °C. Upon completion, the reaction mixture was quenched with water and extracted with DCM (2 x 100 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 50% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 4- bromo-2-chloro-6-methylbenzonitrile (500 mg, 2.169 mmol, 77% yield). LCMS: No ionization; ’H-NMR (400 MHz, DMSO-d6): 8 7.94 (d, J = 1.20 Hz, 1H), 7.79 (s, 1H), 2.55 (s, 3H).
Step 4: Synthesis of (Z)-4-bromo-2-chloro-N'-hydroxy-6-methylbenzimidamide
To a stirred solution of hydroxylamine hydrochloride (150 mg, 2.169 mmol) in water (1 mL), K2CO3 (899 mg, 6.51 mmol) was added at room temperature and stirred for 15 minutes. Then, 4-bromo-2- chloro-6-methylbenzonitrile (500 mg, 2.169 mmol) in ethanol (4 mL) was added to the reaction mixture and stirred at 100 °C for 16 h. Upon completion, the reaction mixture was filtered, and the solid was collected. The solid was dried under reduced pressure to afford (Z)-4-bromo-2-chloro-N’-hydroxy-6- methylbenzimidamide (250 mg, 0.949 mmol, 44% yield). The crude product was used in the next step without purification. 1H-NMR (400 MHz, DMSO-d6): 67.49 (s, 1H), 7.65 (d, J = 55.20 Hz, 1H), 7.79 (s, 1H), 7.94 (s, 1H), 5.85 (s, 1H), 2.29 (s, 3H).
Step 5: Synthesis of 3-(4-bromo-2-chloro-6-methylphenyl)-l,2,4-oxadiazole
To a stirred solution of 4-bromo-2-chloro-N-hydroxy-6-methylbenzimidamide (200 mg, 0.759 mmol) in triethyl orthoformate (337 mg, 12711 mmol) at 25 °C, TEA (87 mg, 0.759 mmol) was added at 25 °C. The resulting reaction mixture was stirred at 100 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel flash column chromatography eluting with 50% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 3-(4-bromo-2-chloro-6-methylphenyl)- 1 ,2,4-oxadiazole (100 mg, 0.350 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H, M+4+H]+ 272.8, 274.9, 276.8; ’H-NMR (400 MHz, DMSO-d6): 59.90 (s, 1H), 7.83 (d, J = 1.20 Hz, 1H), 7.71 (d, J = 0.80 Hz, 1H), 2.14 (s, 3H).
Step 6: Synthesis of 3-(2-chloro-6-methyl-4-vinylphenyl)-l,2,4-oxadiazole
To a stirred solution of 3-(4-bromo-2-chloro-6-methylphenyl)-l,2,4-oxadiazole (200 mg, 0.731 mmol) and trifluoro(vinyl)-X4-borane, potassium salt (147 mg, 1.097 mmol) in 1,4-dioxane (5 mL) and water (0.2 mL), K2CO3 (202 mg, 1.462 mmol) was added at ambient temperature. The resulting reaction mixture was degassed with argon for 15 minutes, followed by the addition of PdCh(dppf)-CH2C12 adduct (59.7 mg, 0.073 mmol) at ambient temperature. The reaction mixture was degassed with argon for another 15 minutes. The reaction mixture was then irradiated in a microwave at 80 °C for 1 h. The progress of the reaction was monitored by TLC.
Upon completion, as confirmed by TLC, the reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel flash column chromatography eluting with 20% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to obtain 3-(2-chloro-6-methyl-4-vinylphenyl)-l,2,4-oxadiazole (190 mg, 0.373 mmol, 51% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 221.0, 223.0; ’H-NMR (400 MHz, CDC13): 3 8.92 (d, J = 2.80 Hz, 1H). 7.56 (d, J = 1.20 Hz, 1H), 7.42 (s, 1H), 6.8 (t, J = 4.20 Hz, 1H), 5.84 (d, J = 3.20 Hz, 1H), 5.43 (d. J = 3.20 Hz, 1H), 2.22 (s, 3H).
Step 7: Synthesis of 3-chloro-5-methyl-4-(l,2,4-oxadiazol-3-yl)benzaldehyde
To a stirred solution of 3-(2-chloro-6-methyl-4-vinylphenyl)-l,2,4-oxadiazole (180 mg, 0.816 mmol) in THE (0.6 mL) and water (0.2 mL), sodium periodate (262 mg, 1.224 mmol) and potassium osmate dihydrate (7.51 mg, 0.020 mmol) were added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 100% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 3-chloro-5-methyl-4-(l,2,4-oxadiazol- 3-yl) benzaldehyde (20 mg, 0.089 mmol, 11% yield). ’H-NMR (400 MHz, DMSO-d6): 8 10.05 (s, 1H), 9.95 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 2.24 (s, 3H).
Example 181: Synthesis of 5-formyl-l-methyl-lH-indazole-3-carbonitrile (ALD-90)
Figure imgf000701_0001
Step 1: Synthesis of 5-bromo-l-methyl-lH-indazole-3-carbonitrile
To a stirred solution of 5-bromo-lH-indazole-3-carbonitrile (1.0 g, 4.5 mmol) in 1,4-dioxane (18 mL), CS2CO3 (4.40 g, 13.51 mmol) was added at ambient temperature, and the resulting reaction mixture was stirred for 15 minutes. Methyl iodide (0.34 mL, 5.4 mmol) was then added at ambient temperature and the reaction mixture was stirred for 2 h at 25 °C. Upon completion of the reaction, ice-cold water was added to the reaction mixture, causing the solid to precipitate. The solid was filtered to obtain the crude product. The crude product was triturated with hexane to afford 5-bromo-l-methyl-lH-indazole-3- carbonitrile (1.05 g, 3.36 mmol, 75% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 236.06, 238.08; 'H-NMR (400 MHz, DMSO-d6): 8 8.17 (d, J = 1.20 Hz, 1H), 7.92-7.90 (m, 1H), 7.75- 7.73 (m, 1H), 4.20 (s, 3H).
Step 2: Synthesis of l-methyl-5-vinyl-lH-indazole-3-carbonitrile
To a stirred solution of 5-bromo-l-methyl-lH-indazole-3-carbonitrile (500 mg, 2.118 mmol) and potassium vinyl trifluoroborate (426 mg, 3.18 mmol) in 1,4-dioxane (10 mL), K2CO3 (585 mg, 4.24 mmol) was added at ambient temperature. The resulting reaction mixture was degassed with argon for 15 minutes, followed by the addition of PdCh(dppf)-DCM adduct (173 mg, 0.212 mmol) at ambient temperature. The reaction mixture was degassed with argon for another 15 minutes. The reaction mixture was then irradiated in a microwave at 90 °C for 2 h. Upon completion, as confirmed by TLC, the reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel flash column chromatography eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to obtain l-methyl-5-vinyl-lH-indazole-3- carbonitrile (320 mg, 1.568 mmol, 74% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 184. *H- NMR (400 MHz, CDC13): 8 7.80 (s, 1H), 7.67 (dd, J = 1.60, 8.80 Hz, 1H), 7.48 (d, J = 8.80 Hz, 1H),
6.90-6.83 (m, 1H), 5.85 (d, J = 9.20 Hz, 1H), 5.37 (d, J = 9.20 Hz, 1H), 4.18 (s, 3H).
Step 3: Synthesis of 5-formyl-l-methyl-lH-indazole-3-carbonitrile
To a stirred solution of l-methyl-5-vinyl-lH-indazole-3-carbonitrile (150 mg, 0.819 mmol) in THF (5 mL) and water (1.667 mL), potassium osmate dihydrate (7.54 mg, 0.020 mmol) and sodium periodate (263 mg, 1.228 mmol) were added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude compound was added to water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography eluting with 30% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to obtain 5-formyl-l-methyl-lH-indazole-3- carbonitrile (80 mg, 0.372 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 186. *H- NMR (400 MHz, DMSO-d6): 5 10.15 (s, 1H), 8.61 (s, 1H), 8.09-8.02 (m, 2H), 4.26 (s, 3H).
Example 182: Synthesis of 4-chloro-3-(difluoromethoxy)benzaldehyde (ALD-91)
Figure imgf000702_0001
Step 1: 4-bromo-l-chloro-2-(difluoro methoxy) benzene
To a stirred solution of 5-bromo-2-chlorophenol (2 g, 9.64 mmol) in acetonitrile (15 mL), KOH (12.44 g, 222 mmol) dissolved in water (10 mL) and diethyl (bromodifhroromethyl)-phosphonate (3.43 mL, 19.28 mmol) were added at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Upon completion, the reaction mixture was quenched with cooled water (100 mL) and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel flash column chromatography eluting with 20% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to obtain 4-bromo-l-chloro- 2-(difhioromethoxy) benzene (1.2 g, 3.84 mmol, 40% yield). LCMS: No mass ionization; ’H-NMR (400 MHz, CDC13): 57.43 (s, 1H), 7.34 (m, 2H), 6.74-6.38 (m, 1H).
Step 2: l-chloro-2-(difluoromethoxy)-4-vinylbenzene
To a stirred solution of 4-bromo-l-chloro-2-(difluoromethoxy) benzene (500 mg, 1.942 mmol) and trifluoro(vinyl)-74-borane, potassium salt (390 mg, 2.91 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL), K2CO3 (537 mg, 3.88 mmol) was added at ambient temperature. The resulting reaction mixture was degassed with argon for 15 minutes, followed by the addition of PdC12(dppf)-CH2C12 adduct (159 mg, 0.194 mmol) at ambient temperature. The reaction mixture was degassed with argon for another 15 minutes. The reaction mixture was then irradiated in a microwave at 80 °C for 1 h. Upon completion, as confirmed by TLC, the reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel flash column chromatography eluting with 30% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to obtain l-chloro-2-(difluoromethoxy)-4-vinylbenzene (230 mg, 0.727 mmol, 37% yield). LCMS: No mass ionization; ’H-NMR (400 MHz, CDC13): 57.43-7.42 (m, 1H), 7.40 (s, 1H), 7.23 (dd, J = 2.00, 8.40 Hz, 1H), 6.74-6.68 (m, 1H), 6.65 (s, 1H), 5.78 (d, J = 17.60 Hz, 1H), 5.36 (d, J = 10.80 Hz, 1H).
Step 3: 4-Chloro-3-(difluoromethoxy)benzaldehyde
To a stirred solution of l-chloro-2-(difluoromethoxy)-4-vinylbenzene (200 mg, 0.978 mmol) in THF (3 mL) and water (1 mL), sodium periodate (314 mg, 1.466 mmol) and potassium osmate dihydrate (9.00 mg, 0.024 mmol) were added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. Upon completion, as confirmed by TLC, the reaction mixture was poured into cooled water (100 mL) and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by Isolera Biotage column chromatography using 100-200 mesh neutral alumina, eluted with 0-100% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to obtain 4-chloro-3-(difluoromethoxy) benzaldehyde (45 mg, 0.190 mmol, 20% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 204.9, 206.9. ’H-NMR (400 MHz, CDC13): 5
10.00 (s, 1H), 7.77 (s, 1H), 7.73 (dd, J = 1.60, 8.20 Hz, 1H), 7.67 (dd, J = 8.00 Hz, 1H), 6.83-6.47 (m,
1H).
Example 183: Synthesis of 3-fluoro-4-(2-hydroxypropan-2-yl) benzaldehyde (ALD-92)
Figure imgf000703_0001
Step 1: 2-(4-bromo-2-fluorophenyl) propan- 2-ol
To a stirred solution of methyl 4-bromo-2-fluorobenzoate (200 mg, 0.858 mmol) in THF (10 mL), methyl magnesium bromide in THF (3.07 mL, 4.29 mmol) was added at 0°C. The reaction mixture was then stirred at 80°C for 5 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. Purification by silica gel flash column chromatography eluting with 5% EtOAc in petroleum ether, afforded 2-(4-bromo-2-fluorophenyl) propan-2-ol (70 mg, 0.247 mmol, 29% yield). *H- NMR (400 MHz, DMSO-d6): 8 7.57 (t, J = 8.80 Hz, 1H), 7.41-7.39 (m, 2H), 5.37 (s, IH), 1.46 (s, 6H). Step 2: 2-(2-fluoro-4-vinylphenyl) propan-2-ol
To a stirred solution of 2-(4-bromo-2-fluorophenyl) propan-2-ol (100 mg, 0.429 mmol) in 1,4- dioxane (3 mL) and water (0.333 mL), trifluoro(vinyl)-L4-borane, potassium salt (115 mg, 0.858 mmol) and K2CO3 (119 mg, 0.858 mmol) were added at room temperature. The reaction mixture was sparged with nitrogen for 10 minutes, followed by the addition of PdC12(dppf)-CH2Cl2 adduct (35.0 mg, 0.043 mmol). The resulting mixture was stirred at 80°C for 1 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, as confirmed by TEC, the reaction mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to yield the crude product. Purification by silica gel flash column chromatography eluting with 5% EtOAc in petroleum ether, afforded 2-(2-fluoro-4-vinylphenyl) propan-2-ol (30 mg, 0.108 mmol, 25% yield). 1H-NMR (400 MHz, DMSO-d6): 57.58 (t, J = 4.80 Hz, 1H), 7.44 (dd, J = 2.00 Hz, 1H), 7.41 (dd, J = 4.40 Hz, 1H), 7.26-7.23 (m, 1H), 6.71-6.67 (m, 1H), 5.86 (d, J = 17.60 Hz, 1H), 5.34 (s, 1H), 1.47 (s,
6H).
Step 3: 3-fluoro-4-(2-hydroxypropan-2-yl) benzaldehyde
To a stirred solution of 2-(2-fluoro-4-vinylphenyl) propan-2-ol (350 mg, 1.942 mmol) in THF (10 mL) and water (1.111 mL), sodium periodate (623 mg, 2.91 mmol) and potassium osmate dihydrate (35.8 mg, 0.097 mmol) were added at room temperature and the reaction mixture was stirred at 25 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, as confirmed by TLC, the reaction mixture was poured into cooled water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. Purification by Isolera Biotage column chromatography using neutral silica gel, eluting with 25% EtOAc in petroleum ether, afforded 3-fluoro-4-(2-hydroxypropan-2-yl) benzaldehyde (150 mg, 0.796 mmol, 41% yield). LCMS: m/z MM-ES+APCI, Positive [M+2]+ 183.2. ’H-NMR (400 MHz. DMSO-d6): 5 10.00 (s. 1H), 7.84 (t, J = 7.60 Hz, 1H), 7.68 (dd, J = 1.60, 8.00 Hz, 1H), 7.56 (dd, J = 1.60, 11.60 Hz, 1H), 2.08 (s, 1H), 1.68 (s, 6H).
Example 184: Synthesis of 3-(2-methoxyethoxy)-4-(trifluoromethyl)benzaldehyde (ALD-93)
Figure imgf000704_0001
2-(2-Methoxyethoxy)-l-(trifluoromethyl)-4-vinylbenzene was prepared in two steps using a procedure similar to that of Ex 151, ALD-60, Steps 1 and 2. To a stirred solution of 2-(2- methoxyethoxy)-! -(trifluoromethyl) -4- vinylbenzene (200 mg, 0.812 mmol) in THF (2 mL) and water (0.2 mL) (10:1), sodium periodate (261 mg, 1.218 mmol) and potassium osmate dihydrate (7.48 mg, 0.020 mmol) were added at room temperature. The resulting reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. Upon completion, as confirmed by TLC, the reaction mixture was diluted with EtOAc (150 mL) and passed through a Celite bed. The collected filtrate was poured into cooled water (100 mL), and the compound was extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by Isolera Biotage column chromatography using neutral silica gel (230-400 mesh), eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to yield 3-(2-methoxyethoxy)-4- ( trifluoromethyl) benzaldehyde (50 mg, 0.191 mmol, 24% yield). ’H-NMR (400 MHz, DMSO-d6): 5 10.08 (s, 1H), 7.88 (d, J = 8.00 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.00 Hz, 1H), 4.36 (t, J = 4.80 Hz, 2H),
3.71 (t, J = 8.80 Hz, 2H), 3.33 (s, 3H),
Example 185: Synthesis of 3-fluoro-4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-94)
Figure imgf000705_0001
Step 1: Synthesis of (Z)-4-bromo-2-fluoro-N'-hydroxybenzimidamide
To a stirred solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) in ethanol (20 mL) and water (2 mL), hydroxylamine hydrochloride (5.21 g, 75.0 mmol) and K2CO3 (17.27 g, 125 mmol) were added at 25 °C. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction was concentrated and quenched with ice water. The obtained solid was filtered and dried to yield (Z)-4- bromo-2-fluoro-N’-hydroxybenzimidamide (3.5 g, 15.02 mmol, 60% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2H]+ 232.8, 234.9, ’H-NMR (400 MHz, DMSO-rfc): 59.73 (s, 1H), 7.70-7.62 (m, 1H), 7.52-7.45 (m, 2H), 5.85 (s, 2H).
Step 2: Synthesis of 3-(4-bromo-2-fluorophenyl)-l,2,4-oxadiazole
To a stirred solution of 4-bromo-2-fluoro-N-hydroxybenzimidamide (500 mg, 2.15 mmol) in triethyl orthoformate (7 mL, 2.15 mmol) was added TEA (0.5 mL, 2.15 mmol) at room temperature. The resulting reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was poured into a saturated NaHCOs solution (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This crude product was purified by Isolera Biotage column chromatography using silica gel (100-200 mesh), eluting with 50% EtOAc in petroleum ether. The collected pure fractions were concentrated under reduced pressure to afford 3-(4- bromo-2-fluorophenyl)-l,2,4-oxadiazole (170 mg 0 68 mmol 32% yield) LCMS: m/z MM ES+APCI Positive [M+H, M+2H]+243, 245, ’H-NMR (400 MHz, DMSO-d6): 5 8.84 (s, 1H), 8.03-7.99 (m, 1H), 7.49 (d, J = 8.40 Hz, 2H).
Step 3: Synthesis of 3-(2-fluoro-4-vinylphenyl)-l,2,4-oxadiazole
To a stirred solution of 3-(4-bromo-2-fluorophenyl)-l,2,4-oxadiazole 3-(4-bromo-2- fluorophenyl)-l,2,4-oxadiazole (50 mg, 0.21 mmol) and potassium vinyltrifluoroborate (41.3 mg, 0.31 mmol) in 1,4-dioxane (2 mL) and water (0.25 mL) was added K2CO3 (56.9 mg, 0.41 mmol). The resulting reaction mixture was degassed with argon for 15 min. Then, PdC12(dppf)-CH2C12 adduct (16.80 mg, 0.021 mmol) was added and the mixture was degassed with argon for another 15 min. The reaction mixture was heated at 90 °C for 2 h. The reaction mixture was filtered through a celite bed, washed with EtOAc (50 mL), and extracted with water (2 x 20 mL). The organic layer was separated, dried over anhydrous Na2S(>4, filtered, and concentrated under reduced pressure. The crude product was purified by normal phase column chromatography using silica gel (100-200 mesh), eluting with 15% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to afford 3-(2-fluoro-4-vinylphenyl)- 1,2,4-oxadiazole (10 mg, 0.046 mmol, 22% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 191.0, ’H-NMR (400 MHz, DMSO-ds): 5 8.83 (s, 1H), 8.09-8.05 (m, 1H), 7.47-7.28 (m, 2H), 6.79-5.93 (m, 1H), 5.91 (d, J = 17.60 Hz, 1H), 5.46 (d, J = 10.80 Hz, 1H).
Step 4: Synthesis of 3-fluoro-4-(l,2,4-oxadiazoL3-yl)benzaldehyde (ALD-94)
To a stirred solution of 3-(2-fhioro-4-vinylphenyl)-l,2,4-oxadiazole (190 mg, 0.99 mmol) in THE (9 mL) and water (3 mL) was added sodium periodate (321 mg, 1.49 mmol) and potassium osmate dihydrate (9.20 mg, 0.025 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into cooled water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This crude product was purified by Isolera Biotage column chromatography using neutral alumina mesh, eluting with 30% EtOAc in petroleum ether. Pure fractions were concentrated under reduced pressure to afford 3-fluoro-4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-94, 55 mg, 0.27 mmol, 27% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 193.0, ’H-NMR (400 MHz, DMSO-cfc): 5 10.10 (s, 1H), 8.90 (s, 1H), 8.36-8.32 (m, 1H), 7.78 (d, J = 1.60 Hz, 1H), 7.28 (m 1H).
Example 186: Synthesis of 4-(3,3-difluoroazetidin-l-yl)benzaldehyde (ALD-95)
OMe HN^_p 0Me TFA, DCM,
M 0
F eO' 1 rt, 3 h r ii
MeO' 1
Pd(OAc)2, BINAP, N^p
Br Cs2CO3, PhMe, Step-2
ALD-95 F 100°C, 16 h F
Step-1
Step 1: l-(4-(dimethoxymethyl)phenyl)-3,3-difluoroazetidine To a stirred solution of l-bromo-4-(dimethoxy methyl) benzene (500 mg, 2.164 mmol) in toluene (8 mL) was added 3,3-difluoroazetidine hydrochloride (336 mg, 2.60 mmol) and cesium carbonate (1.41 g, 4.33 mmol). The reaction mixture was degassed with nitrogen for 10 minutes. Palladium (II) acetate (48.6 mg, 0.216 mmol) and BINAP (269 mg, 0.433 mmol) were then added, and the mixture was degassed with nitrogen for an additional 10 minutes. The resulting mixture was stirred at 100 °C for 12 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, as confirmed by TLC and LCMS, the reaction mixture was quenched; with water (50 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was dried over anhydrous Na2SC)4 and concentrated under reduced pressure to yield a crude residue. The crude compound was purified by silica gel flash column chromatography, eluting with 10% EtOAc in hexane to afford l-(4-(dimethoxy methyl) phenyl) -3 ,3 -difluoroazetidine (70 mg, 0.140 mmol, 6% yield). LCMS: No ionization. *H NMR (400 MHz, DMSO-de): 57.24 (d, J = 8.40 Hz, 2H), 6.56 (d, J = 8.40 Hz, 2H), 5.29 (s, 1H), 4.43 (t, J = 0.00 Hz, 2H), 4.27 (t, J = 7.20 Hz, 2H), 3.21
(s, 6H).
Step 2: 4-(3,3-difluoroazetidin-l-yl)benzaldehyde
To a stirred solution of l-(4-(dimethoxymethyl) phenyl) -3,3-difluoroazetidine (70 mg, 0.13 mmol) in DCM (2 mL), TEA (9.98 pL, 0.13 mmol) was added at 0 °C. The progress of the reaction was monitored by TLC. Upon completion, as confirmed by TLC, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford 4-(3,3-difluoroazetidin-l-yl) benzaldehyde (50 mg, 0.245 mmol, 189% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 198.1; *H NMR (400 MHz, DMSO- ck): 59.76 (s, 1H), 7.85 (d, J = 2.40 Hz, 2H), 6.66 (d, J = 8.40 Hz, 2H), 4.43 (t, J = 12.40 Hz, 4H).
Example 187: Synthesis of 3-chloro-4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-96)
Figure imgf000707_0001
Step 1: Synthesis of (Z)-4-bromo-2-chloro-N'-hydroxybenzimidamide
To a stirred solution of 4-bromo-2-chlorobenzonitrile (1 g, 4.62 mmol) in ethanol (10 mL) and water (1 mL), hydroxylamine hydrochloride (0.963 g, 13.86 mmol) and K2CO3 (3.19 g, 23.10 mmol) were added at 25 °C. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into water to precipitate the compound The precipitate was filtered through a Buchner funnel and washed with MTBE. LCMS: m/z MM-ES+APCI, Positive [M+H, M+2H]+ 248.9, 250.9, ’H-NMR (400 MHz, DMSO-de): 59.51 (s, IH), 7.66-7.57 (m, IH), 7.41-7.34 (m, 2H), 5.87 (s, 2H).
Step 2: Synthesis of 3-(4-bromo-2-chlorophenyl)-l,2,4-oxadiazole
To a stirred solution of 4-bromo-2-chloro-N-hydroxybenzimidamide (0.45 g, 1.80 mmol) in triethyl orthoformate (13.37 g, 90 mmol) was added TEA (0.206 g, 1.804 mmol). The resulting mixture was stirred at 120 °C for 12 h. The solvent was concentrated under reduced pressure. The crude product was quenched with NaHCCL (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (100-200 mesh), eluting with 12% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to afford 3-(4-bromo-2- chlorophenyl)-l,2,4-oxadiazole (200 mg, 0.58 mmol, 32% yield). ’H-NMR (400 MHz, DMSO-rL): 59.82 (s, IH), 8.02 (s, IH), 7.90 (d, J = 8.40 Hz, IH), 7.79 (d, J = 2.00 Hz, IH).
Step 3: Synthesis of 3-(2-chloro-4-vinylphenyl)-l,2,4-oxadiazole
To a stirred solution of 3-(4-bromo-2-chlorophenyl)-l,2,4-oxadiazole (500 mg, 1.93 mmol) and potassium trifluorovinyl borate (310 mg, 2.31 mmol) in 1,4-dioxane (7 mL) and water (0.7 mL), was added cesium carbonate (1.26 g, 3.85 mmol) at rt and the mixture was sparged with N2 gas for 10 min. Then, PdC12(dppf)-CH2C12 adduct (157 mg, 0.19 mmol) was added and the mixture was further sparged for 5 min. The reaction mixture was heated to 80 °C for 2 h. The solvent was concentrated under reduced pressure and purified by column chromatography using (100-200 silica mesh) eluting with 16% of ethyl in hexane. Pure fractions were concentrated under reduced pressure to afford 3-(2-chloro-4-vinylphenyl)- 1 ,2,4-oxadiazole (350 mg, 1.33 mmol, 68% yield). ’H-NMR (400 MHz, DMSO-cfc): 59.81 (t, J = 8.40 Hz, IH), 7.93 (t, J = 6.00 Hz, 1H), 7.68 (d, J = 1.20 Hz, 2H), 6.88-6.82 (m, 1H), 6.12-6.08 (m, 1H), 5.51- 5.48 (m, IH).
Step 4: Synthesis of 3-chloro-4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-96)
To a stirred solution of 3-(2-chloro-4-vinylphenyl)-l,2,4-oxadiazole (500 mg, 2.42 mmol) in THF (7 mL) and water (2.33 mL) was added sodium periodate (776 mg, 3.63 mmol) and potassium osmate dihydrate (22.29 mg, 0.060 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The solvent was concentrated under reduced pressure and the residue was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (100-200 mesh), eluting with 14% EtOAc in hexane. The collected pure fractions were concentrated under reduced pressure to afford 3-chloro-4-(l,2,4-oxadiazol-3-yl) benzaldehyde (ALD-96, 75 mg, 0.36 mmol, 15% yield). ’H-NMR (400 MHz, DMSO-ds): 5 10.10 (s, IH), 9.88 (s, IH), 8.19 (d, J = 8.00 Hz, 2H), 8.05 (d, J = 1.60 Hz, IH). Example 188: Synthesis of 2-(difluoromethoxy)-4-formylbenzonitrile (ALD-97)
Figure imgf000709_0001
Step 1: Synthesis of 4-bromo-2-(difluoromethoxy)benzonitrile
To a stirred solution of 4-bromo-2-hydroxybenzonitrile (2 g, 10.1 mmol) in ACN (15 mL), KOH (13.0 g, 232 mmol) dissolved in water (10 mL) and diethyl (bromodifluoromethyl)-phosphonate (3.6 mL, 20.2 mmol) were added at -78 °C. The resulting mixture was allowed to stir at rt for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SO4 filtered, and concentrated to yield a crude product. The crude product was purified by Isolera chromatography using silica gel (100-200 mesh), eluting with 40-50% EtOAc in hexane. The collected fractions were concentrated under reduced pressure to afford 4-bromo-2-(difluoro methoxy) benzonitrile (1.5 g, 6.05 mmol, 60% yield). 'H-NMR (400 MHz, DMSO-d6): 5 7.91 (d, J = 8.40 Hz, 1H), 7.79 (s, 1H), 7.69 (d, J = 1.60 Hz, 2H).
Step 2: Synthesis of 2-(difluoromethoxy)-4-vinylbenzonitrile
To a stirred solution of 4-bromo-2-(difluoromethoxy) benzonitrile (500 mg, 2.016 mmol) in dioxane (8 mL) and water (2 mL), II trifluoro(vinyl)-14-borane, potassium salt (405 mg, 3.02 mmol), and CS2CO3 (788 mg, 2.419 mmol) were added. The reaction mixture was sparged with N2 for 10 min, followed by the addition of PdCL (dppfpCtLCL adduct (32.9 mg, 0.040 mmol) at rt. The resulting reaction mixture was stirred at 80 °C for 1 h. The reaction mass was filtered through a celite pad. The filtrate was collected and concentrated under reduced pressure to yield a crude product. The crude product was purified by Isolera chromatography using silica gel (100-200 mesh), eluting with 20% EtOAc in hexane. The collected fractions were concentrated under reduced pressure to afford 2-(difluoromethoxy)- 4-vinylbenzonitrile (400 mg, 1.783 mmol, 88% yield). LCMS: m/z MM-ES+ APCI, Positive [M+H]+ 196.0, 'H-NMR (400 MHz, DMSO-d6): 5 7.79 (s, 1H), 7.79-7.67 (m, 1H), 7.57-7.48 (m, IH), 7.31 (d, J = 9.20 Hz, IH), 6.88-6.80 (m, IH), 6.13 (d, J = 17.60 Hz, IH), 5.57 (d, J = 10.80 Hz, IH).
Step 3: Synthesis of 2-(difluoromethoxy)-4-formylbenzonitrile
To a stirred solution of 2-(difluoromethoxy)-4-vinylbenzonitrile (200 mg, 1.025 mmol) in THF (2 mL) and water (1 mL), sodium periodate (329 mg, 1.537 mmol) was added at rt. Then, potassium osmate dihydrate (7.55 mg, 0.020 mmol) was added at room temperature. The resulting reaction mixture was stirred at rt for 1 h. After completion of reaction as confirmed by TLC, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude residue The crude compound was purified by silica gel flash column chromatography, eluting with 10% EtO Ac in hexane to afford 2- (difhioromethoxy)-4-formylbenzonitrile (40 mg, 0.203 mmol, 20% yield). ’H-NMR (400 MHz, DMSO- d6): 5 10.10 (s, 1H), 8.21 (d, J = 7.60 Hz, 1H), 7.97-7.95 (m, 1H), 7.91 (m, 1H), 7.65-7.47 (m, 1H).
Example 189: Synthesis of 6-(3-hydroxyoxetan-3-yl) nicotinaldehyde (ALD-98)
Figure imgf000710_0001
Step 1: 2-bromo-5-(diethoxymethyl)pyridine
To a stirred solution of 6-bromonicotinaldehyde (1.0 g, 5.38 mmol) in ethanol (20 mL) was added p-toluenesulfonic acid monohydrate (0.061 g, 0.323 mmol) at room temperature. Then, triethyl orthoacetate (4.96 mL, 26.9 mmol) was added at room temperature. The resulting reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to get crude residue. The crude was purified by silica gel flash column chromatography, eluting with EtO Ac in n- hexane (5-10%) to afford 2-bromo-5-(diethoxy methyl) pyridine (1.2 g, 1.409 mmol, 26% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 261.3. ’H-NMR (400 MHz, CDCL3): 5 8.47 (s, 1H), 7.68-7.66 (m,
1H), 7.52-7.49 (m, 1H), 5.54 (s, 1H), 3.65-3.62 (m, 4H), 1.29 (t, J = 0.40 Hz, 6H).
Step 2: 3-(5-(diethoxymethyl) pyridin-2-yl)oxetan-3-ol
To a stirred solution of 2-bromo-5-(diethoxymethyl)pyridine (500 mg, 1.92 mmol) and oxetan-3- one (139 mg, 1.92 mmol) in toluene (5 mL), n-butyllithium in hexane (1.15 mL, 2.88 mmol) was added at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtO Ac (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield crude 3-(5-(diethoxymethyl)pyridin-2-yl)oxetan-3-ol (180 mg, 0.63 mmol, 33% yield).
LCMS: m/z MM-ES+APCI, Positive [M+H]+ 254.4, ’H-NMR (400 MHz, CDCL3): 5 8.61-8.61 (m, 1H),
8.01 (d, J = 1.20 Hz, 2H), 6.01 (s, 1H), 5.62 (s, 1H), 5.13 (d, J = 1.20 Hz, 2H), 4.74 (d, J = 1.20 Hz, 2H),
3.67-3.65 (m, 4H), 1.30 (t, J = 1.60 Hz, 6H).
Step 3: 6-(3-hydroxyoxetan-3-yl) nicotinaldehyde
To a stirred solution of 3-(5-(diethoxymethyl)pyridin-2-yl)oxetan-3-ol (180 mg, 0.71 mmol) in DCM (2 mL), TEA (81 mg, 0.71 mmol) was added at 0 °C. The resulting reaction mixture was stirred at 0 °C for 1.5 h. After completion of reaction as confirmed by TLC, the reaction mixture was quenched with saturated NaHCOs solution (30 mL) and extracted with EtO Ac (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude product. The crude product was purified by silica gel flash column chromatography, eluting with 2.5% EtOAc in n-hexane to afford 6-(3-hydroxyoxetan-3-yl) nicotinaldehyde (75 mg, 0.42 mmol, 59% yield). ’H-NMR (400 MHz, DMSO-de): 5 10.14 (s, 1H), 9.16 (s, 1H), 8.29 (d, J = 2.00 Hz, 1H), 7.62 (d, J = 8.00 Hz, 1H), 5.61 (s, 1H), 4.39 (d, J = 6.40 Hz, 2H), 4.30 (d, J = 6.80 Hz, 2H).
Example 190: Synthesis of l-(4-formylphenyl) cyclopropane-l-carbonitrile (ALD-99)
Figure imgf000711_0001
Step 1: Synthesis of l-(4-vinylphenyl) cyclopropane-l-carbonitrile
To a stirred solution of 4-bromo-2-(2-methoxyethoxy) benzonitrile and trifluoro(vinyl)-74-borane, potassium salt (379 mg, 2.83 mmol) in 1,4-dioxane (0.9 mL) and water (0.1 mL), was added potassium carbonate (622 mg, 4.50 mmol) at room temperature and the mixture was degassed with N2 for 10 minutes. 1 , 1 ’ -bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane complex (165 mg, 0.23 mmol) was then added and the mixture was degassed with N2 for another 10 minutes. The reaction mixture was then stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (2 x 30 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel flash column chromatography, eluting with 2-5% EtOAc in hexane to obtain l-(4-vinylphenyl) cyclopropane-l-carbonitrile (200 mg, 1.18 mmol, 53% yield). ’H-NMR (400 MHz, DMSO-rfc): 57.52 (d, J = 10.00 Hz, 2H), 7.46 (d, I = 2.00 Hz, 2H), 6.68-6.75 (m, 1H), 5.77 (d, J = 9.60 Hz, 1H), 5.29 (d, J = 9.60 Hz, 1H), 1.71-1.78 (m, 2H), 1.39-1.44 (m, 2H).
Step 2: Synthesis of l-(4-formylphenyl) cyclopropane-l-carbonitrile (ALD-99)
To a stirred solution of l-(4-vinylphenyl) cyclopropane-l-carbonitrile (350 mg, 2.07 mmol) in THF (1 mL) and water (0.2 mL) was added sodium periodate (403 mg, 1.89 mmol) and potassium osmate dihydrate (19.05 mg, 0.052 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography, eluting with 5-10% EtOAc in n-hexane to afford l-(4-formylphenyl) cyclopropane-l-carbonitrile (ALD-99, 80 mg, 0.47 mmol, 23% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 172.0; ’H-NMR (400 MHz, DMSO-cL): 5 10.03 (s, 1H), 7.90 (d, J = 2.00 Hz, 2H), 7.46 (d, J = 1.60 Hz, 2H), 1.87-1.91 (m, 2H), 1.53-1.58 (m, 2H). Example 191: Synthesis of 4-(l-hydroxycyclobutyl) benzaldehyde (ALD-100)
Figure imgf000712_0001
Step 1: Synthesis of l-(4-(dimethoxymethyl)phenyl)cyclobutan-l-ol
To a stirred solution of l-bromo-4-(dimethoxymethyl) benzene (500 mg, 2.164 mmol) in THF (6 mL) under a nitrogen atmosphere, n-butyllithium 2.5M in hexane (1.039 mL, 2.60 mmol) was added dropwise at -78 °C. The resulting reaction mixture was stirred at -78 °C for 30 minutes. Cyclobutanone (0.163 mL, 2.164 mmol) was then added dropwise, and the mixture was stirred for 2 h at 25 °C. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue. This crude product was purified by silica gel flash column chromatography, eluting with 10% EtOAc in n-hexane to afford l-(4-(dimethoxymethyl)phenyl)cyclobutan-l-ol (180 mg, 0.527 mmol, 24% yield). LCMS: m/z MM-ES+APCI, Positive [M]+ = 223.0; ’H-NMR (400 MHz, DMSO-d6): 57.50 (d, J = -1.60 Hz, 2H), 7.48 (d, J = -1.60 Hz, 2H), 5.48 (s, 1H), 5.37 (s, 1H), 3.24 (s, 6H), 2.31-2.43 (m, 2H), 2.22-2.29 (m, 2H), 1.60-1.70 (m, 2H).
Step 2: 4-(l-hydroxycyclobutyl) benzaldehyde
To a stirred solution of l-(4-(dimethoxymethyl) phenyl)cyclobutan-l-ol (180 mg, 0.810 mmol) in CH2CI2 (3 mL) under a nitrogen atmosphere, TEA (0.062 mL, 0.810 mmol) was added dropwise at 0 °Cand the reaction mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a crude residue. This crude product was purified by silica gel flash column chromatography, eluting with 10% EtOAc in n-hexane to afford 4-(l -hydroxy cyclobutyl) benzaldehyde (80 mg, 0.454 mmol, 56% yield). LCMS: m/z MM- ES+APCI, [M-H] = 174.9. ’H-NMR (400 MHz, DMSO-A): 57.72 (d, J = -6.80 Hz, 2H), 7.61 (d, J = - 6.80 Hz, 2H), 5.74 (s, 1H), 2.39-2.45 (m, 4H), 1.93-1.99 (m, 2H).
Example 192: Synthesis of l-ethyl-lH-pyrazole-4-carbaldehyde (ALD-101)
Figure imgf000712_0002
To a stirred solution of lH-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol) in DMF (10 mL) under a nitrogen atmosphere, ethyl iodide (0.547 mL, 6.76 mmol) and CS2CO3 (1695 mg, 5.20 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into cooled water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to yield a crude gummy compound. This crude product was purified by column chromatography using silica gel (100-200 mesh), eluting with 50% EtOAc in n-hexane. The collected pure fractions were concentrated under reduced pressure to afford l-ethyl-lH-pyrazole-4-carbaldehyde (450 mg, 3.52 mmol, 68% yield). LCMS: m/z MM-ES+APCI, Positive [M+HJH25, ’H-NMR (400 MHz, DMSO-d6): 5 9.79 (s, 1H), 8.48 (s, 1H), 7.97
(d, J = 10.80 Hz, 1H), 4.23-4.17 (q, J = 7.20 Hz, 2H), 1.40 (t, J = 7.20 Hz, 3H).
Example 193: Synthesis of 3-chloro-l-methyl-/f7-pyrazole-4-carbaldehyde (ALD-102)
Figure imgf000713_0002
To a stirred solution of POCh (3.95 mL, 42.4 mmol) in DMF (2.5 mL) under nitrogen atmosphere was added l-methyl-7H-pyrazol-3-ol (1 g, 10.19 mmol) at 0 °C to -10 °C. Then, the reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction as confirmed by LCMS/TLC, the reaction mixture was diluted with EtOAc (100 mL) and reaction mixture was poured in 2M NaOH solution (~pH=8-9) (100 mL), compound was extracted in EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous NajSO^ filtered, and concentrated under reduced pressure to get crude residue. The crude residue was purified by flash column chromatography using (100-200 mesh silica gel) 30-60% EtOAc in n-hexane as an eluent. The pure fractions were evaporated and dried under a high vacuum to afford compound 3-chloro-l-methyl-77/-pyrazole-4-carbaldehyde (500 mg, 3.46 mmol, 34% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+145, ’H-NMR (400 MHz, DMSO-d6): 59.75 (s, 1H), 8.50 (s, 1H), 3.30 (s, 3H).
Example 194: Synthesis of 3-(4-forinyl-///-pyrazol-l-yl)benzonitrile (ALD-103)
Figure imgf000713_0001
Step 1: 3-(4-f(»rmyl-///-pyraz(»l- 1-yl) benzonitrile
To a stirred solution of 3 -iodobenzonitrile (100 mg, 0.437 mmol), 777-pyrazole-4-carbaldehyde (42.0 mg, 0.437 mmol) and cesium carbonate (356 mg, 1.092 mmol) in DMF (4 mL) was degassed for 15 min with N2 followed by the addition of (/?.7?)-(-)-A, N' -Dimethyl- 1 ,2-cyclohexanediamine (18.63 mg, 0.131 mmol) and copper(I) iodide (16.63 mg, 0.087 mmol) degassed with N2 atmosphere for 5 min. The resulting reaction mixture was stirred at 100 °C for 1 h. The reaction was monitored by LCMS. After completion of the reaction as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure to get crude. The crude residue which was purified by normal phase column chromatography using (100-200 silica mesh) eluting with 15-20% of EtOAC in Hexane as an eluent. Then, pure fractions were evaporated and dried under a high vacuum to afford 3-(4-formyl-7H-pyrazol-l-yl) benzonitrile (32 mg, 0.161 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 198.18, 'H-NMR (400 MHz, DMSO-d6): 5 10.02 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 1.60 Hz, 1H), 8.01-7.99 (m, 1H), 7.70-
7.67 (m, 2H).
Example 195: Synthesis of 4-(oxetan-3-yl)benzaldehyde (ALD-104) o
'OH >
H
4,4'-Di-tert-butyl-2,2'-dipyridyl, Ni(NO3)2 6H2O, K2CO3, 0 Dioxane, 80 °C, 16 h Step-1
Step 1: Synthesis of 4-(oxetan-3-yl)benzaldehyde
To a stirred solution of (4-formylphenyl)boronic acid (250 mg, 1.667 mmol), 3-iodooxetane (614 mg, 3.33 mmol) and K2CO3 (691 mg, 5.0 mmol) in 1,4-dioxane (20 mL) was degassed for 15 min with N3. Then were added 4,4'-Di-tert-butyl-2,2'-dipyridyl (44.8 mg, 0.17 mmol) and nickel (II) nitrate hexahydrate (39.6 mg, 0.17 mmol) at RT and degassed for 5 min with N2 and the reaction mixture was stirred at 80 °C for 16 h. The reaction was monitored by LCMS. After completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with EtOAc (50 mL), layers were separated, and aqueous portion was extracted with EtOAc (2 x 100 mL), The combine organic layers were dried over anhydrous Na2S(>4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, gradient EtOAc/Hexane) compound was eluted at 20% EtOAc/Hexane as eluent get pure fraction. The pure fraction was concentrated under reduced pressure to obtained 4-(oxetan-3-yl) benzaldehyde (220 mg, 1.356 mmol, 81% yield). *H NMR (400 MHz, DMSO- d6> 8 10.00 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 4.99-4.94 (m, 2H), 4.66-4.61 (m, 2H), 4.40-4.32 (m, 1H).
Example 196: Synthesis of 3-chloro-4-(oxetan-3-yl)benzaldehyde (ALD-105)
OH O
H H
'Cl 4,4'-Di-tert-butyl-2,2'-dipyridyl, 'Cl
0 Ni(NO3)2 6H2O, CS2CO3, 0 Dioxane, 80 °C, 2 h
Step-1
To a stirred solution of (2-chloro-4-formylphenyl)boronic acid (1 g, 5.4 mmol), 3-iodooxetane (1.996 g, 10.9 mmol) and CS2CO3 (5.30 g, 16.3 mmol) in 1,4-dioxane (2 mL) was degassed for 15 min with Nz.Were added nickel(II) nitrate hexahydrate (0.129 g, 0.54 mmol) and 4,4'-Di-tert-butyl-2,2'- dipyridyl (0.146 g, 0.54 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The progress of reaction was monitored by LCMS. After completion of reaction as confirmed by LCMS, the resulting reaction mixture was concentrated under reduced pressure and compound was purified by isolera biotag column chromatography using (100-200 mesh silica gel mess), eluted with 20% EtOAc in pet ether. The collected pure fractions were concentrated under reduced pressure to obtained 3-chloro-4-(oxetan-3- yl)benzaldehyde (0.1 g, 0.34 mmol, 6% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 197.0; *H NMR (400 MHz, DMSO-d6): 59.87 (s, 1H), 7.92 (d, J= 8.0 Hz, 2H), 7.48-7.44 (m, 1H), 4.97-4.75 (m, 2H), 4.28-4.25 (m, 2H), 4.17-4.11 (m, 1H).
Example 197: Synthesis of l-(2-fluoro-4-formylphenyl) cyclopropane- 1-carbonitrile (ALD-106)
Figure imgf000715_0001
Step 1: l-(2-fluoro-4-vinylphenyl) cyclopropane-l-carbonitrile
To a stirred solution of l-(4-bromo-2-fluorophenyl) cyclopropane-l-carbonitrile (200 mg, 0.833 mmol) in dioxane (2.8 mL) and water (0.2 mL) in a microwave vial under a nitrogen atmosphere, K2CO3 (173 mg, 1.250 mmol) was added at room temperature. The reaction mixture was sparged with nitrogen for 10 minutes, followed by the addition of PdCh(dppf)-CH2Ch adduct (68.0 mg, 0.083 mmol). The resulting mixture was irradiated under microwave conditions at 80°C for 30 minutes. The progress of the reaction was monitored by LCMS. Upon completion, as indicated by LCMS, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to yield the crude product. Th crude was purified by silica gel flash column chromatography, eluting with 5% EtOAc in hexane to afford l-(2-fluoro-4-vinylphenyl) cyclopropane-l-carbonitrile (150 mg, 0.801 mmol, 96% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 187.9 1H-NMR (400 MHz, DMSO-d6): 5 7.68 (d, J = 0.80 Hz, 2H), 7.30 (d, J = 1.60 Hz, 1H), 6.75 (t, J = 6.80 Hz, 1H), 5.96 (d, J = 17.20 Hz, 1H), 5.38 (d, J
= 11.20 Hz, 1H), 1.43 (t, J = 7.60 Hz, 2H), 1.23 (t, J = 16.00 Hz, 2H).
Step 2: l-(2-fluoro-4-formylphenyl) cyclopropane- 1-carbonitrile
To a stirred solution of l-(2-fluoro-4-vinylphenyl) cyclopropane- 1-carbonitrile (100 mg, 0.497 mmol) in acetonitrile (1.8 mL) and water (0.2 mL), sodium periodate (106 mg, 0.497 mmol) and osmium tetroxide (1.579 mL, 0.248 mmol) were added at 0°C and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield the crude product. Purification by Biotage Isolera (silica gel cartridge, 250 g) using 10% EtOAc in hexane as the eluent afforded l-(2-fluoro-4-formylphenyl) cyclopropane- 1 -carbonitrile (35 mg, 0.185 mmol, 37% yield). LCMS: No ionization; ’H-NMR (400 MHz, DMSO-d6): 5 10.02 (s, 1H), 7.81-7.74 (m, 3H), 1.80-1.77
(m, 4H).
Example 198: Synthesis of (ALD-107)
Figure imgf000716_0001
Step 1: Synthesis of methyl 4-(l,2,4-oxadiazol-3-yl)benzoate
To a stirred solution of hydroxylamine hydrochloride (8.56 g, 124 mmol) in water (25 mL) was added sodium hydrogen carbonate (10.42 g, 124 mmol) at room temperature and stirred for 15 min. After that methyl-4-cy anobenzoate (10 g, 62.1 mmol) in MeOH (100 mL) was added to the above reaction mixture and stirred at room temperature for 16 h. The reaction mixture was filtered, and the solid was collected. The solid was dried under reduced pressure to afford methyl 4-(N’-hydroxycarbamimidoyl)- benzoate (9 g, 45 mmol, 73% yield). LCMS: ES+APCI, Positive [M+H]+ 194.19. ’H-NMR (400 MHz, DMSO-r/s): 89.91 (s, 1H), 7.96 (d, J = 8.80 Hz, 2H), 7.82 (d, J = 8.80 Hz, 2H), 5.94 (s, 2H, 3.87 (s, 3H). Step 2: Synthesis of methyl 4-(l,2,4-oxadiazol-3-yl)benzoate
To the stirred solution of methyl 4-(N'-hydroxycarbamimidoyl)benzoate (9 g, 46 mmol) in THF (50 mL), trimethyl orthoformate (25.3 mL, 232 mmol) and toluene-4-sulfonic acid monohydrate (0.88 g, 4.63 mmol) were added at room temperature and the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was cooled and the excess solvent from the reaction mixture was evaporated under reduced pressure. Water was then added and precipitation was observed. The formed solid was filtered and dried under reduced pressure to afford methyl 4-(l,2,4-oxadiazol-3-yl)benzoate (8 g, 39.1 mmol, 84% yield). LCMS: ES+APCI, Positive [M+H]+ 205.10. ’H-NMR (400 MHz, DMSO-t/s): 69.80 (s, 1H), 8.21- 8.14 (m, 4H), 3.91 (s, 3H).
Step 3: Synthesis of 4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-107)
To a stirred solution of morpholine (0.98 g, 11.26 mmol) in THF (25 mL) was added DIBAL-H (1.0M in THF) (10.77 mL, 10.77 mmol) at 0 °C and stirred for 3 h. To this resulting mixture was added methyl 4-(l,2,4-oxadiazol-3-yl)benzoate (1 g, 4.90 mmol) in THF (25 mL) at 0 °C and stirred for 10 min. DIBAL-H (1.0M in THF) (5.88 mL, 5.88 mmol) was then added at 0 °C and the reaction mixture was stirred for 1 h. After completion of the reaction, the reaction was quenched with IN HC1 (100 mL) and excess THF was removed under reduced pressure. The resulting solid was collected by filtration and dried to afford 4-(l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-107, 400 mg, 2.29 mmol, 47% yield). LCMS: ES+APCI, Positive [M+H]+ 175.0. ’H-NMR (400 MHz, DMSO-cfc): 5 10.15 (s, 1H), 9.82 (s, 1H), 8.29 (t, J = 8.40 Hz, 2H), 8.11 (t, J = 6.80 Hz, 2H).
Example 199: Synthesis of 4-cyclopropoxybenzaldehyde (ALD-108):
Figure imgf000717_0001
To a stirred solution of 4-hydroxybenzaldehyde (0.5 g, 4.09 mmol) and bromocyclopropane (0.743 g, 6.14 mmol) in NMP (5 mL) was added cesium carbonate (2.67 g, 8.19 mmol) and the reaction mixture was irradiated under microwave at 200 °C for 2h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous NaACL. filtered and concentrated under reduced pressure. The crude compound was purified by Biotage column chromatography (100-200 silica) and EtOAc and hexane (0-100%) as eluent. The pure fractions containing product were collected and concentrated to afford 4-cyclopropoxybenzaldehyde (ALD-108, 0.4 g, 2.17 mmol, 53% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 163.1. ’H-NMR (400 MHz, DMSO-t/s): 59.89 (s, 1H), 7.89 (d, J = 2.40 Hz, 2H), 7.25 (d, J = 2.00 Hz, 2H), 4.01-3.98 (m, 1H), 0.88- 0.85 (m, 2H), 0.73-0.71 (m, 2H).
Example 200: Synthesis of 4-(3,3-difluorocyclobutyl)benzaldehyde (ALD-109)
Figure imgf000717_0002
Step 1: Synthesis of l-bromo-4-(3,3-difluorocyclobutyl)benzene
To a stirred solution of 3-(4-bromophenyl)cyclobutan-l-one (1.00 g, 4.44 mmol, 1 eq.) in DCM (30 mL) at -78 °C was added DAST (1.467 mL, 11.11 mmol, 2.5 eq.). The reaction mixture was then allowed to warm to 25 °C and stirred for 16 h. The reaction mixture was quenched with water and neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was then extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield l-bromo-4-(3,3-difluorocyclobutyl)benzene (1.10 g, 3.22 mmol, 72% yield). >H NMR (400 MHz, CDCh): 57.50-7.45 (m, 2H), 7.17-7.09 (m, 2H), 3.13-2.93 (m, 2H), 2.75-2.53 (m, 2H).
Step 2: Synthesis of l-(3,3-difluorocyclobutyl)-4-vinylbenzene
To a stirred solution of l-bromo-4-(3,3-difluorocyclobutyl)benzene (1.10 g, 4.45 mmol, 1 eq.) and potassium vinyl trifluoroborate (1.193 g, 8.90 mmol, 2 eq.) in 1,4-dioxane (10 mL) at 25 °C was added cesium carbonate (2.90 g, 8.90 mmol, 2 eq.). The reaction mixture was sparged with argon for 10 minutes. [l,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.182 g, 0.22 mmol, 0.05 eq.) was then added at 25 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to afford crude l-(3,3-difhiorocyclobutyl)-4-vinylbenzene (1.10 g, 2.83 mmol, 64% yield). 'H NMR (400 MHz, CDC13): 57.43-7.38 (m, 2H), 7.22 (d, J= 8.1 Hz, 2H), 6.73 (dd, 7 = 10.8, 17.6 Hz, 1H), 5.76 (dd, J
= 0.8, 17.6 Hz, 1H), 5.26 (dd, J= 0.8, 10.8 Hz, 1H), 3.10-2.93 (m, 2H), 2.78-2.57 (m, 2H).
Step 3: Synthesis of 4-(3,3-difluorocyclobutyl)benzaldehyde (ALD-109)
To a stirred solution of l-(3,3-difluorocyclobutyl)-4-vinylbenzene (1.10 g, 5.66 mmol, 1 eq.) in THF (25 mL) and water (8 mL) at 0 °C was added sodium periodate (1.817 g, 8.50 mmol) followed by potassium osmate dihydrate (0.125 g, 0.34 mmol, 0.06 eq.) at 0 °C. The reaction mixture was then stirred at 25 °C for 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to get the crude product. The crude product was purified by reverse-phase column chromatography using a C18 cartridge (120 g), eluted with a gradient of 30% acetonitrile in 0.1% formic acid in water. Pure fractions were concentrated under reduced pressure to afford 4-(3,3- difluorocyclobutyl)benzaldehyde (ALD-109, 0.35 g, 1.43 mmol, 25% yield). LCMS: m/z: MM- ES+APCI, positive [M+H]+ 196.9; >H NMR (400 MHz, DMSO-t/e): 5 10.00 (s, 1H), 7.93-7.86 (m, 2H), 7.56 (d, J = 8.3 Hz, 2H), 3.13-2.98 (m, 2H), 2.84-2.67 (m, 2H).
Example 201: Synthesis of 6-(l,2,4-oxadiazol-3-yl)nicotinaldehyde (ALD-110)
Figure imgf000718_0001
Step 7: Synthesis of methyl (Z)-6-(N'-hydroxycarbamimidoyl)nicotinate
To a stirred solution of hydroxylamine hydrochloride (0.429 g, 6.17 mmol, 2 eq.) in water (5 mL) at 25 °C was added sodium bicarbonate (0.518 g, 6.17 mmol, 2 eq.). The mixture was stirred for 15 min. A solution of methyl 6-cyanonicotinate (0.5 g, 3.08 mmol, 1 eq.) in methanol (5 mL) was then added at 25 °C. The reaction was stirred for 16 h and then filtered to remove the solid byproduct. The filtrate was concentrated under reduced pressure to afford methyl 6 (N hydroxycarbamimidoyl)nicotinate (0 55 g 2.79 mmol, 90% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 196.1; >H NMR (400 MHz, DMSO-cL): 5 10.24 (s, 1H), 9.06 (d, J= 1.4 Hz, 1H), 8.28 (dd. 7 = 2.2. 8.4 Hz, 1H), 8.00 (d. 7 = 8.4 Hz,
1H), 5.95 (br. s, 2H), 4.02-3.75 (m, 3H).
Step 2: Synthesis of methyl 6-(l,2,4-oxadiazol-3-yl)nicotinate
To a stirred solution of methyl 6-(N-hydroxycarbamimidoyl)nicotinate (2.00 g, 10.25 mmol, 1 eq.) in trimethyl orthoformate (8.50 mL, 77.0 mmol, 7.5 eq.) was added toluene-4-sulfonic acid monohydrate (0.195 g, 1.03 mmol, 0.1 eq.) at 25 °C. The reaction mixture was then heated to 90 °C and stirred for 3 h. The volatiles were evaporated under reduced pressure and the crude residue was was diluted with ice-cold water, resulting in the formation of a solid. This solid was filtered and dried under reduced pressure to afford methyl 6-(l,2,4-oxadiazol-3-yl)nicotinate (2.10 g, 10.09 mmol, 98% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 206.2; *H NMR (400 MHz, DMSO-rfc): 59.86 (s, 1H), 9.25 (d, 7 = 1.7 Hz, 1H), 8.53 (dd, 7 = 2.1, 8.2 Hz, 1H), 8.27 (d, 7= 8.1 Hz, 1H), 3.94 (s, 4H).
Step 3: Synthesis of 6-(l,2,4-oxadiazol-3-yl)nicotinaldehyde (ALD-110)
To a stirred solution of morpholine (0.97 mL, 11.21 mmol, 2.3 eq.) in THF (12.5 mL) at 0 °C was added DIBAL-H (10.72 mL, 10.72 mmol, 2.2 eq.). The reaction mixture was stirred at 0 °C for 2 h. Then, a solution of methyl 6-(l,2,4-oxadiazol-3-yl)nicotinate (1.00 g, 4.80 mmol, 1 eq.) in THF (12.5 mL) was added to the reaction mixture, which was then stirred at 0 °C for 1 h. After that, DIBAL-H (5.85 mL, 5.85 mmol, 1.1 eq.) was added and the reaction stirred at 0 °C for an additional 1 h. Upon completion, the mixture was slowly quenched with 1.5 N HC1 (-100 mL) at 0 °C and extracted with EtOAc (EtOAc, 2 x 100 mL). The pooled organic layer was dried over anhydrous NaiSCh, filtered, and concentrated under reduced pressure, The crude compound was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (40%-80%) to afford 6-(l,2,4-oxadiazol-3-yl)nicotinaldehyde (ALD-110, 0.210 g, 1.175 mmol, 24% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 176.0; >H NMR (400 MHz, DMSO-t/s): 5 *H NMR (401 MHz, DMSO-d6) 5 = 10.28-10.15 (m, 1H), 9.87 (s, 1H), 9.36-9.12 (m, 1H), 8.49 (dd, 7 = 2.1, 8.1 Hz, 1H), 8.34 (d, 7= 7.9 Hz, 1H).
Example 202: Synthesis of 6-(oxazol-4-yl)nicotinaldehyde (ALD-111)
Figure imgf000719_0001
Step 1: Synthesis of 6-acetylnicotinonitrile To a stirred solution of 6-bromonicotinonitrile (5.00 g, 27.3 mmol, 1.00 eq.) in toluene (40 mL) was added tributyl(l-ethoxyvinyl)stannane (10.15 mL, 30.1 mmol, 1.10 eq.) at 25 °C. The reaction mixture was degassed with argon for 5 min. Bis(triphenylphosphine)palladium(II) dichloride (0.959 g, 1.37 mmol, 0.05 eq.) was added at 25 °C, and the mixture was stirred at 120 °C for 8 h. The reaction mixture was then cooled to room temperature, and aqueous potassium fluoride (25 mL) was added and stirred for 30 min. Aqueous hydrochloric acid (50 mL) was then added, and the mixture was heated to 70 °C for 2 h. After cooling to room temperature, the mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (100-200 mesh) using a gradient of EtOAc in hexane (0-20%) as the eluent to afford 6- acetylnicotinonitrile (3.50 g, 23.33 mmol, 85% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 147.0; *H NMR (400 MHz, DMSO-de): 5 9.31-9.09 (m, 1H), 8.52 (dd, J = 2.1, 8.1 Hz, 1H), 8.08 (dd, J= 0.8, 8.1 Hz, 1H), 3.32 (s, 1H), 2.67 (s, 3H).
Step 2: Synthesis of 6-(2-bromoacetyl)nicotinonitrile
To a stirred solution of 6-acetylnicotinonitrile (3.40 g, 23.26 mmol, 1.00 eq.) in tetrahydrofuran (110 mL) was added pyridinium tribromide (7.44 g, 23.26 mmol, 1.00 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with aqueous saturated sodium thiosulfate (50 mL). The aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous NaaSCL, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (100-200 mesh) using a gradient of EtOAc in hexane (0-20%) as the eluent to yield 6-(2-bromoacetyl)nicotinonitrile (2.57 g, 9.09 mmol, 39% yield. LCMS: m/z: MM-ES+APCI, positive [M+2H]+ 224.9; >H NMR (400 MHz, DMSO-tfc): 5 9.22 (dd, 7= 1.0, 2.1 Hz, 1H), 8.57 (dd, J= 2.1, 8.1 Hz, 1H), 8.17 (dd, 7 = 0.9, 8.2 Hz, 1H), 5.04 (s, 2H).
Step 3: Synthesis of 6-(oxazol-4-yl)nicotinonitrile
To a stirred solution of 6-(2-bromoacetyl)nicotinonitrile (2.57 g, 11.42 mmol, 1.00 eq.) in DMF (12.5 mL) at 25 °C, formamide (12.79 mL, 322 mmol, 28.2 eq.) was added. The reaction mixture was heated to 130 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase column chromatography using a C18 cartridge (330 g), with a gradient elution of 0.1% ammonium acetate in water and acetonitrile. The pure fractions were concentrated under reduced pressure to afford 6-(oxazol-4-yl)nicotinonitrile (0.57 g, 3.11 mmol, 27% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 171.2; >H NMR (400 MHz, DMSO-de): 5 8.92 (d, 7 = 1.4 Hz, 1H), 8.25 (dd, 7= 2.1, 8.3 Hz, 1H), 8.00 (d, 7= 8.3 Hz, 1H), 7.87 (dd, 7= 0.8, 18.0 Hz, 2H). Step 4: Synthesis of 6-(oxazol-4-yl)nicotinaldehyde (ALD-111) To a stirred solution of 6-(oxazol-4-yl)nicotinonitrile (0.470 g, 2.47 mmol, 1 eq.) in DCM (15 mL) was added DIBAL-H in toluene (7.2 mL, 7.4 mmol, 3 eq.) at 0 °C and stirred at 25 °C for 1 h. The progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched with EtOAc (10 mL). The mixture was then concentrated under reduced pressure and the crude material was purified by reverse-phase column chromatography on a Cl 8 cartridge, eluted with a gradient of 0.1% ammonium acetate in water and acetonitrile. Pure fractions were concentrated under reduced pressure to yield 6-(oxazol-4-yl)nicotinaldehyde (ALD-111, 0.250 g, 0.919 mmol, 37% yield). LCMS: m/z: MM- ES+APCI, positive [M+H]+ 175.1.
Example 203: Synthesis of 4-(isoxazol-3-yl)benzaldehyde (ALD-112)
Figure imgf000721_0001
Step 1: Synthesis of (Z)-4-((hydroxyimino)methyl)benzonitrile
To a stirred solution of sodium carbonate (4.85 g, 45.8 mmol, 1.2 eq.) in water (50 mL) was added hydroxylamine hydrochloride (3.18 g, 45.8 mmol, 1.2 eq.), followed by the addition of 4- formylbenzonitrile (5 g, 38.1 mmol, 1 eq.) in ethanol (50 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to afford crude (Z)-4-((hydroxyimino)methyl)benzonitrile (4.5 g, 30.3 mmol, 79% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 147.0; *H NMR (400 MHz, DMSO-de): 5 8.25 (s, 1H), 7.90-7.83 (m, 2H), 7.81-7.72 (m, 2H).
Step 2: Synthesis of 4-(5-(trimethylsilyl)isoxazol-3-yl)benzonitrile
In a 100 mL two-neck round-bottom flask, trimethylsilyl acetylene (2.88 mL, 20.53 mmol, 1.5 eq.) was added to a solution of (Z)-4-((hydroxyimino)methyl)benzonitrile (2 g, 13.68 mmol, 1 eq.) in water (30 mL). Lithium chloride (0.580 g, 13.68 mmol, 1 eq.) was added portion-wise, followed by oxone (12.62 g, 20.53 mmol, 1.5 eq.) under a nitrogen atmosphere at 60 °C. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (100-200 mesh size) using (0 to 10%) hexane EtOAc as the eluent to obtain the desired product (2 g, 8.2 mmol, 62% yield). LCMS: m/z: MM-ES+APCI, positive [M+H]+ 243.0; *H NMR (400 MHz, DMSO-ds): 5 8.14-8.05 (m, 2H), 8.02-7.94 (m, 2H), 7.45 (s, 1H), 0.42-0.32 (m, 9H).
Step 3: Synthesis of 4-(isoxazol-3-yl)benzonitrile
To a stirred solution of 4-(5-(trimethylsilyl)isoxazol-3-yl)benzonitrile (1.3 g, 5.36 mmol, 1 eq.) in methanol (17 mL) at 0 °C under a nitrogen atmosphere, potassium carbonate (1.11 g, 8.05 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was then dissolved in water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over N 8286)4 and concentrated under reduced pressure to yield 4-(isoxazol-3-yl)benzonitrile. Quantitative yield was assumed. LCMS: m/z: MM-ES+APCI, positive [M+H]+ 170.9; *H NMR (400 MHz, DMSO-t/s): 5 9.19-9.00 (m, 1H), 8.14-8.07 (m, 2H), 8.04-7.98 (m, 2H), 7.30 (d, 7= 1.6 Hz, 1H).
Step 4: Synthesis of 4-(isoxazol-3-yl)benzaldehyde (ALD-112)
To a stirred solution of 4-(isoxazol-3-yl)benzonitrile (0.4 g, 2.35 mmol, 1 eq.) in DCM (5 mL) at 0 °C under a nitrogen atmosphere was added dropwise a solution of DIBAL-H (2.35 mL, 2.35 mmol, 1 M in toluene, 1 eq.). The reaction mixture was stirred at room temperature for 1 h, after which an additional portion of DIBAL-H (2.35 mL, 2.35 mmol, 1 M in toluene, 1 eq.) was added. The reaction mixture was stirred at room temperature for an additional 2 h. The reaction mixture was quenched with 1.5 N HC1 solution (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by silica gel flash column chromatography, eluting with EtOAc in hexane (2-4%) to afford 4-(isoxazol-3-yl)benzaldehyde (ALD-112, 0.2 g, 1.15 mmol, 49% yield). LCMS: m/z: MM- ES+APCI, positive [M+H]+ 174.0; >H NMR (400 MHz, DMSO-<M 5 10.10 (s, 1H), 8.55 (d, 7= 1.7 Hz, 1H), 8.17-7.75 (m, 4H), 6.77 (d, 7= 1.7 Hz, 1H).
Example 204: Synthesis of 4-(4-fluoro-l-methyl-lH-pyrazol-3-yl)benzaldehyde (ALD-113)
Figure imgf000722_0001
A stirred mixture of 3 -bromo-4-fluoro-l -methyl- IH-pyrazole (0.18 g, 1.0 mmol), (4- formylphenyl)boronic acid (0.18 g, 1.2 mmol), dioxane (3 mL), K2CO3 (0.21 g, 1.5 mmol, solution in 0.3 mL water), and PdCh(dppf)-DCM adduct (0.082 g, 0.1 mmol) was sparged with argon under sonication for 4 min, then the reaction vial was sealed and the mixture was stirred at 85 °C for 90 min under microwave irradiation. The cooled mixture was loaded onto silica gel and subject to purification via silica gel flash column chromatography, eluting with 20 to 80% EtOAc in heptane to afford 4-(4-fluoro-l- methyl- lH-pyrazol-3-yl) benzaldehyde (ALD-113, 0.115 g, 0.56 mmol, 56% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 205.0. >H NMR (500 MHz, DMSO-de) 5 ppm 10.01 (s, 1H), 8.03 Id, 7 = 4.38 Hz, IH), 7.94-8.00 (m, 4H), 3.87 (s, 3H).
Example 205: Synthesis of 4-(3-fluoro-l-methyl-lH-pyrazol-4-yl)benzaldehyde (ALD-114)
Figure imgf000723_0001
A mixture of 3-fluoro-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.23 g, 1.0 mmol), 4-bromobenzaldehyde (0.15 g, 0.8 mmol), dioxane (3 ml), PdCh(dppf)-DCM adduct (0.08 g. 0.1 mmol), and K2CO3 (0.21 g, 1.5 mmol, solution in 0.3 mL water) was sparged with argon under sonication for 5 min, then reaction mixture was stirred at 95 °C for 16h. The cooled mixture was loaded onto silica gel and subject to purification via silica gel flash column chromatography, eluting with 20 to 80% EtOAc in heptane to afford 4-(3-fluoro-l-methyl-lH-pyrazol-4-yl)benzaldehyde (ALD-114, 0.146 g, 0.71 mmol, 71% yield). 4-(3-fluoro-l -methyl- lH-pyrazol-4-yl)benzaldehy de. LCMS: m/z MM- ES+APCI, Positive [M+H]+ 205.1. >H NMR (500 MHz, DMSO-de) 5 ppm 9.97 (s, 1H), 8.33-8.34 (m, 1H), 8.30-8.32 (m, 1H), 7.88-7.99 (m, 2H), 7.74 (cl, 7 = 8.21 Hz, 2H), 3.79 (s, 3H).
Example 206: Synthesis of 4-(4-(difluoromethyl)-l-methyl-lH-pyrazol-3-yl)benzaldehyde (ALDUS)
Figure imgf000723_0002
F
A mixture of 3-bromo-4-(difluoromethyl)-l-methyl-lH-pyrazole (0.21 g, 1.0 mmol), (4- formylphenyljboronic acid (0.18 g, 1.2 mmol), dioxane (3 mL), K2CO3 (0.21 g, 1.5 mmol, solution in 0.3 mL water), and PdC12(dppf)-DCM adduct (0.082 g, 0.1 mmol) was sparged with argon under sonication for 4 min, then the reaction vial was sealed and the mixture was stirred at 90 °C for 3h under microwave irradiation. The cooled mixture was loaded onto silica gel and subject to purification via silica gel flash column chromatography, eluting with 20 to 80% EtOAc in heptane to afford 4-(4-(difluoromethyl)-l- methyl-lH-pyrazol-3-yl) benzaldehyde (ALD-115, 170 mg, 0.72 mmol, 72% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 237.1. >H NMR (500 MHz, DMSO-d6) 5 ppm 10.04 (s, IH), 8.20 (s, IH), 7.97-8.00 (m, 2H), 7.88-7.92 (m, 2H), 7.00-7.49 (t, J = 55 Hz, IH), 3.95 (s, 3H).
Example 207: Synthesis of l-(6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (INT-S1)
Figure imgf000724_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yi)-3,6- dihydropyridine- 1 ( 2// )-ca rboxy lat e
To a stirred solution of l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-1, 0.5 g, 1.56 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (35b, 0.580 g, 1.87 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added DIPEA (0.544 mL, 3.12 mmol) at rt. The reaction mixture was sparged with nitrogen for 15 minutes. Then, Bis(tri-tert-butylphosphine)palladium(0) (0.080 g, 0.156 mmol) was added, and the resulting reaction mixture was stirred at 100 °C in a sealed vial for 5 h. The reaction mixture was diluted with
EtOAc and passed through a Celite bed, and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA in water and acetonitrile to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (320 mg, 2.18 mmol, 40% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 423.0. ’H-NMR (400 MHz, DMSO-d6): 5 10.59 (s, 1H), 8.89 (d, J = 2.40 Hz, 1H), 8.24 (d, J = 2.40 Hz, 1H), 7.89-7.91 (m, 3H), 6.43 (s, 1H), 4.08 (s, 2h), 3.97 (t, J = 6.80 Hz, 2H), 3.61 (t, J = 5.60 Hz, 2H), 2.80 (t, 7= 6.40 Hz, 2H), 2.61 (d, J= 1.60 Hz, 2H), 1.45 (s, 9H).
Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)quinolin-6-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (0.65 g, 1.539 mmol) was treated according to General Procedure 3, Step C. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in EtOAc and passed through a Celite bed, and the filtrate was concentrated. The crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA in water and acetonitrile to afford tertbutyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (360 mg, 0.768 mmol, 50% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 441.0; 'H-NMR (400
MHz, DMSO-de): 5 10.59 (s, IH), 8.89 (d, J = 2.40 Hz, IH), 8.24 (d, 7 = 2.00 Hz, IH), 8.03 (d, 7 = 1.60
Hz, IH), 7.94 (d, 7 = 2.00 Hz, 1H), 7.88 (d, 7 = 2.00 Hz, 1H), 5.35 (s, 1H), 3.98-3.90 (m, 4H), 3.24-3.22
(m, 2H), 2.80 (t, /= 6.80 Hz, 2H), 1.93 (t, J= 8.40 Hz, 2H), 1.69 (d, J = 12.80 Hz, 2H), 1.44 (s, 9H).
Step 3: Synthesis of l-(6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (INT-S1)
To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (0.32 g, 0.726 mmol) in DCM (5 mL) was added 4M HC1 in dioxane (0.545 mL, 2.18 mmol) at 0 °C and the reaction mixture was allowed to stir at rt for 1 h. The reaction mixture was concentrated and dried under vacuum to afford l-(6-(4-hydroxypiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-S1, 0.28 g, 0.550 mmol, 76% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 341.2; 'H-NMR (400 MHz, DMSO-d6): 5 10.66 (s, 1H), 9.12-9.11 (m, 1H),
9.05 (d, 7 = 2.40 Hz, IH), 8.98-8.97 (m, IH), 8.50 (d, 7= 1.60 Hz, IH), 8.15-8.10 (m, 2H), 7.93 (dd, 7 =
2.00, 8.80 Hz, 1H), 4.00 (t, J= 6.80 Hz, 2H), 3.26 (s, 4H), 2.83-2.53 (m, 2H), 2.37-2.34 (m, 2H), 1.89-
1.86 (m, 2H).
Example 208: Synthesis of l-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT -S7)
Figure imgf000725_0001
Step 1: Synthesis of (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)boronic acid
To a stirred solution of l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-1, 600 mg, 1.874 mmol) in 1,4-dioxane (6 mL) were added 5,5,5’,5’-tetramethyl-2,2’-bi(l,3,2- dioxaborinane) (847 mg, 3.75 mmol) and potassium acetate (552 mg, 5.62 mmol) at 25 °C, then the mixture was sparged with nitrogen for 10 min. To this reaction mixture were added tertbutyldiphenylphosphine (91 mg, 0.375 mmol) and palladium(II) acetate (42.1 mg, 0.187 mmol), then the mixture was sparged with nitrogen for 5 min. The resulting reaction mixture was heated at 100 °C for 1 h. The cooled reaction mixture was filtered through a Celite bed and washed with EtOAc (60 mL). The filtrate was concentrated under reduced pressure to afford (3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)quinolin-6-yl)boronic acid (0.6 g, 1.60 mmol, 86% yield) which was used in the next step without purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 285.6. ’H-NMR (400 MHz, DMSO-de): 5 8.97 (s, 1H), 8.32 (s, 1H), 8.12-8.06 (m, 3H), 7.77 (s, 2H), 4.04 (t. 7 = 6.80 Hz, 2H), 2.96 (L 7 = 6.40 Hz, 2H).
(some NH resonances not observed)
Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-3,3- dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
To a stirred solution of (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)boronic acid (0.6 g, 2.11 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) were added tert-butyl 3,3-dimethyl-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (40b, 0.757 g, 2.11 mmol) and K2CO3 (0.582 g, 4.21 mmol) at room temperature, and the mixture was sparged with nitrogen for 10 min. To this reaction mixture was added PdCL(dppf).DCM adduct (0.086 g, 0.105 mmol), and the mixture was sparged with nitrogen for 5 min. The resulting reaction mixture was heated at 80 °C for 1 h. The cooled reaction mixture was filtered through a Celite bed and washed with EtOAc (2 x 50 mL). The filtrate was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (450 mg, 0.679 mmol, 32% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 451.8.
Step 3: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)quinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2H)-carboxylate (260 mg, 0.577 mmol) was treated according to General Procedure 3, Step C. The crude residue was purified by silica gel flash chromatography, eluting with 0-15% EtOAc in hexane to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (120 mg, 0.195 mmol, 34% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 469.3; ’H-NMR (400 MHz, DMSO-dg): 5 10.58 (s, 1H), 8.90 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.96-7.93 (m, 2H), 5.18 (s, H), 4.01 (m, 4H), 3.39-3.20 (m, 2H), 3.97 (t, 7 = 6.80 Hz, 2H), 2.82- 2.80 (m, 2H), 1.50 (s, 9H), 0.85 (s, 3H), 0.75 (s, 3H).
Step 4: Synthesis of l-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4i l//,3//i-dione (INT-S7)
To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate (120 mg, 0.256 mmol) in DCM (3 mL) was added HC1 (4M in dioxane) (0.256 mL, 1.024 mmol) at 0 °C and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with MTBE, filtered and dried to afford l-(6-(4-hydroxy-3,3-dimethyl-piperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (INT-S7, 110 mg, 0.173 mmol, 68% yield). LCMS: m/z MM-ES+APCI, Positive
[M+H]+ 369.3. ‘H-NMR (400 MHz, DMSO-d6): 5 10.63 (s, 1H), 9.11 (s, 1H), 8.60-8.43 (m, 2H), 8.14-
8.03 (m, 2H), 5.76 (s, 1H), 3.38-3.35 (m, 2H), 3.01-2.92 (m, 2H), 2.89-2.81 (m, 2H), 1.60 (m, 2H), 1.27-
1.24 (m, 2H), 0.96 (s, 3H), 0.80 (s, 3H).
Example 209: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT -S2)
Figure imgf000727_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2Z7)-yl)-5-fluoroquinolin-6-yl)- 4-hydroxy-3,3-dimethylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,3-dimethyl- 3,6-dihydropyridine-l(27/)-carboxylate (INT-41A, 1.1g, 2.348 mmol) was treated according to General Procedure 3, Step C. The reaction mixture was diluted with DCM and filtered through a Celite bed. The filtrate was concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA in water and 0.1% FA I\in acetonitrile to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (0.53 g, 1.04 mmol, 44% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 487.6: ’H-NMR (400 MHz, DMSO-t/6): 5 10.61 (s, 1H), 8.98 (d, 7 = 2.4 Hz, 1H), 8.33 (d. 7 = 2.4 Hz, IH), 8.06-8.10 (m, 1H), 7.87 (d. 7 = 8.8 Hz, 1H), 5.76 (s, 1H), 4.02-4.00 (m, 3H), 3.46-3.43 (m, 1H),
3.28-3.27 (m, 2H), 2.95-2.96 (m, IH), 2.82-2.80 (m, 2H), 1.70-1.67 (m, IH), 1.43 (s, 9H), 0.89 (s, 3H),
0.75 (s, 3H).
Step 2: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT -S2)
HCI (4M in 1,4-dioxane, 0.62 ml, 2.47 mmol) was added at 0 °C to a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate (80 mg, 0.164 mmol) in DCM (3 ml), and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to afford l-(5-fluoro-6-(4-hydroxy-3,3- dimethylpiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-S2, 60 mg, 0.134 mmol, 83% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 387.4; ‘H-NMR (400 MHz, DMSO-d6): 5 10.63 (s, 1H), 9.10 (d, J = 10.8 Hz, 1H), 9.00 (d, J= 2.4 Hz, 1H), 8.35 (m, 2H), 8.04-8.09 (m, 1H), 7.91 (d, J= 8.8 Hz, 1H), 5.88 (s, 1H), 4.02 (d, J = 6.4 Hz, 2H), 3.25-3.22 (m, 4H), 2.97-2.94 (m, 1H), 2.83- 2.81 (m, 2H), 1.91-1.91 (m, 1H), 0.99 (s, 3H), 0.79 (s, 3H).
Example 210: Synthesis of (R)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-(R)-S2) and (S)-l-(5-fluoro-6-(4-hydroxy-3,3- dimethylpiperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-(S)-S2)
Figure imgf000728_0001
Step 1: Chiral Separation of tert-butyl (R)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate and tert-butyl (S)-4-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate
Tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2F/)-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (from “Ex INT-S2”, Step 1, 0.53 g, 1.035 mmol) was subjected to chiral SFC chromatography using the following method:
Instrument: PIC 22-027
Column: CHIRALPAK AS-H 250 x 30 mm, 5 pm
Mobile Phase: CO2: 2-Propanol [70:30]
Total Flow: 120 mL/min
Back pressure: 120 bar
Wavelength: 254 nm
Cycle time: 6 min
Loading: 30 mg/injection
Two peaks obtained after chiral SFC were collected separately and lyophilized.
Fraction 1: Tert-butyl (R)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)- 4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (180 mg). Retention time: 4.82 min. Chiral purity: 100 %, [Analysis Method: SFC Chiralpak-AS-H; Flow: 4.00 mL/min, Co-Solvent: 30 % IPA, Oven Temperature : 40 °C, BPR Pressure : 102.0 kgf/cm], LCMS: m/z MM-ES+APCI, Positive [M+H] + 487.6: ’H-NMR (400 MHz, DMSO-t/6): 8 10.61 (s, 1H), 8.98 (d, J= 2.4 Hz, 1H), 8.33 (d, J= 2.4 Hz, 1H), 8.06- 8.10 (m, 1H), 7.87 (d, J = 8.8 Hz, 1H), 5.76 (s, 1H), 4.02-4.00 (m, 3H), 3.46-3.43 (m, 1H), 3.28-3.27 (m,
2H), 2.95-2.96 (m, 1H), 2.82-2.80 (m, 2H), 1.70-1.67 (m, 1H), 1.43 (s, 9H), 0.89 (s, 3H), 0.75 (s, 3H)
Fraction 2: Tert-butyl (S)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate (200 mg). Retention time: 7.14 min. Chiral purity: 98.29 %, [Analysis Method: SFC Chiralpak-AS-H; Flow: 4.00 mL/min, Co-Solvent : 30 % IPA, Oven Temperature : 40 oC, BPR Pressure : 102.0 kgf/cm], LCMS: m/z MM-ES+APCI, Positive [M+H] + 487.6: ’H-NMR (400 MHz, DMSO-t/e): 5 10.61 (s, 1H), 8.98 (d, 7= 2.4 Hz, 1H), 8.33 (d, J= 2.4 Hz, 1H), 8.06-
8.10 (m, 1H), 7.87 (d, J= 8.8 Hz, 1H), 5.76 (s, 1H), 4.02-4.00 (m, 3H), 3.46-3.43 (m, 1H), 3.28-3.27 (m,
2H), 2.95-2.96 (m, 1H), 2.82-2.80 (m, 2H), 1.70-1.67 (m, 1H), 1.43 (s, 9H), 0.89 (s, 3H), 0.75 (s, 3H).
Note: Absolute stereochemistry was assigned arbitrarily
Step 2: Synthesis of (l?)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)dihydro pyrimidine-2,4( l//,3//)-dione (INT-(R) S2)
To a stirred solution of tert-butyl (R)-4-(3-(2,4-dioxotetrahydropyrirnidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (the Fraction 1 product from Step 1, 50 mg, 0.103 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (176 mg, 1.54 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to afford (R)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(l//,3F/)-dione. LCMS: m/z MM-ES+APCI, Positive [M+H] + 387.4; ’H-NMR (400 MHz, DMS0v/6): 5 10.63 (s, 1H), 9.01 (d, J= 2.4 Hz, 1H), 8.35 (m 2H), 8.04-8.09 (m, 1H), 7.91 (d, J = 8.8 Hz, 1H), 5.88 (s, 1H), 4.02 (d, J= 6.4 Hz, 2H), 3.25-3.22 (m, 4H), 2.97-2.94 (m, 1H), 2.83-2.81 (m, 2H), 1.91-1.91 (m, 1H), 0.99 (s, 3H), 0.79 (s, 3H).
Similarly prepared was (S)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydro py rimidine-2, 4(1//, 3//)-dione (INT-(S) S2) starting from the Fraction 2 product from Step 1. LCMS: m/z MM-ES+APCI, [M+H] + 387; ’H-NMR (400 MHz, DMSO-t/e): 5 10.63 (s, 1H), 9.01-8.94 (m, 2H), 8.36-8.35 (m, 2H), 8.08 (d, J = 8.8 Hz, 1H), 7.90 (d, J= 8.8 Hz, 1H), 5.91 (s, 1H), 4.03-3.99 (m, 3H), 3.32-3.20 (m, 4H), 2.97-2.95 (m, 1H), 2.95-2.93 (m, 2H), 1.95-1.91 (m, 1H), 0.95 (s, 3H), 0.82 (s, 3H).
Example 211: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-S6)
Figure imgf000730_0001
Step 1: Synthesis of 6-bromo-5-fluoro-2-methylquinolin-3-amine
To a stirred solution of pyridine (50 mL) in ethanol (500 mL) under a nitrogen atmosphere at rt was added l-chloropropan-2-one (29.7 g, 321 mmol). The reaction mixture was heated to 65 °C for 3 h, then cooled to room temperature, and subjected to three cycles of vacuum followed by nitrogen backfill. Pyridine (50 mL) and 6-amino-3-bromo-2-fluorobenzaldehyde (50 g, 229 mmol) in ethanol (50 mL) were added. The reaction mixture was heated at 65 °C with stirring for 16 h and then was allowed to cool. Morpholine (55.9 g, 642 mmol) was added dropwise at rt, and the mixture was then stirred at 85 °C for 3 h. The reaction mixture was cooled to rt, water (500 mL) was added, and the mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were dried over NaiSCL, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-45 % ethyl acetate in hexane to afford 6-bromo-5-fluoro-2-methylquinolin-3-amine.
LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H] + 255.1, 257.1: 'H-NMR (400 MHz, DMSO+L): 5
7.63 (d, J = 1.2 Hz, 1H), 7.60 (d, 7= 1.2 Hz, 1H), 7.50 (s, 1H), 4.06 (s, 2H), 2.47 (s, 3H).
Step 2: Synthesis of N-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-2,2,2-trifluoroacetamide
To a stirred mixture of 6-bromo-5-fluoro-2-methylquinolin-3-amine (70 g, 274 mmol), MTBE
(2000 mL), and NaaCCT (87 g, 823 mmol) at 0 °C was added trifluoroacetic anhydride (53.5 mL, 357 mmol) dropwise, then the reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was diluted with ice-cold water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous NajSCL, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-60 % ethyl acetate in hexane to afford N-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-2,2,2- trifluoroacetamide (89 g, 243 mmol, 89% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H] + 351.2, 353.3: 1H-NMR (400 MHz, DMSO-d6): 5 11.43 (s, 1H), 8.49 (s, 1H), 7.97-8.01 (m, 1H), 7.80 (d, 7 = 8.8 Hz. I H). 2.63 (s, 3H).
Step 3: Synthesis of 4-(5-fluoro-2-methyl-3-(2,2,2-trifluoroacetamido)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
To a stirred solution of N-(6-bromo-5-fluoro-2-methylquinolin-3-yl)-2,2,2-trifluoroacetamide (5 g, 14.2 mmol) in THF (40 mL) at 0 °C was added sodium hydride (0.68 g, 17 mmol), and the mixture was stirred for 30 minutes. The reaction mixture was cooled to -78 °C, and n-butyllithium (1.6 M in hexanes, 9.79 mL, 15.7 mmol) was added slowly dropwise and the reaction mixture was stirred for 15 minutes. This was followed by the addition of a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (4.21 g, 18.5 mmol) in THF (10 mL) at -78 °C, and the mixture was stirred for 3 h. A saturated solution of ammonium chloride (50 mL) was added, and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 0-30 % ethyl acetate in hexane to afford tert-butyl 4-(5- fluoro-2-methyl-3-(2,2,2-trifluoroacetamido)quinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (4 g, 7.2 mmol, 51% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 500.4; H-NMR (400 MHz, DMSO-</6): 8 11.38 (s, 1H), 8.42 (s, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.81 (d, 7 = 8.8 Hz, 1H), 5.76 (s, 1H), 4.06-4.05 (m, 4H), 3.26-3.23 (m, 2H), 2.61 (s, 3H), 1.43 (s, 9H), 0.87 (s, 3H), 0.73 (s, 3H). Step 4: Synthesis of tert-butyl 4-(3-amino-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethyl piperidine- 1-carboxylate.
To a stirred solution of tert-butyl 4-(5-fluoro-2-methyl-3-(2,2,2-trifluoroacetamido)quinolin-6- yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (11 g, 22.0 mmol) in THF (110 mL) and water (110 mL) was added lithium hydroxide (1.58 g, 66 mmol) and the reaction mixture was heated to 60 °C for 3 h. The cooled reaction mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over NaiSOr. filtered and concentrated under reduced pressure. The crude residue was triturated with MTBE (50 mL), and the resulting solid was collected on a filter and dried to afford tertbutyl 4-(3-amino-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (6.9 g, 16.7 mmol, 76% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 404.5: ’H-NMR (400 MHz, DMSO-t/s): 87.63 (d, 7 = 8.8 Hz, 1H), 7.54 (d, 7= 8.8 Hz, 1H), 7.29 (s, 1H), 5.59 (s, 2H), 5.22 (s, 1H),
4.03-3.96 (m, 1H), 3.50-3.44 (m, 1H), 3.34-3.34 (m, 2H), 3.24-3.21 (m, 1H), 2.90-2.95 (m, 3H), 1.64-
1.61 (m, 1H), 1.43 (s, 9H), 0.81 (s, 3H), 0.71 (s, 3H).
Step 5: Synthesis of tert-butyl 4-(5-fluoro-3-iodo-2-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
To a stirred solution of tert-butyl 4-(3-amino-5-fhioro-2-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1-carboxylate (5 g, 12.4 mmol) in ACN (20 mL) was added copper(I) iodide (4.72 g, 24.8 mmol) at rt and the reaction mixture was stirred for 10 minutes. This was followed by the slow dropwise addition of a solution of tert-butyl nitrite (2.94 mL, 24.8 mmol) in ACN (3 mL) at rt. The reaction mixture was heated at 60 °C for 1 h. Water (30 mL) was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous NajSCL, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-40 % ethyl acetate in hexane to afford tert-butyl 4-(5-fluoro-3-iodo- 2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (2.1 g, 3.68 mmol, 30% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 515.5: 1H-NMR (400 MHz, DMSO-d6): 5 8.84 (s, 1H),
8.09 (d, J = 8.8 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 5.76 (s, 1H), 4.06-4.01 (m, 4H), 3.26-3.24 (m, 2H),
2.55 (s, 3H), 1.42 (s, 9H), 0.81 (s, 3H), 0.71 (s, 3H).
Step 6: Synthesis of tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate
A mixture of tert-butyl 4-(5-fluoro-3-iodo-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethyl- piperidine-1 -carboxylate (1.6 g, 3.1 mmol), 1,4-dioxane (10 mL), 3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione (lb, 0.82 g, 3.1 mmol), cesium carbonate (2.03 g, 6.22 mmol), (R,R)-(-)-N,N’ -Dimethyl- 1,2-diaminocyclohexane (0.133 g, 0.93 mmol) and copper iodide (0.178 g, 0.933 mmol) was stirred under an argon atmosphere at 100 °C for 16 h. The reaction mixture was cooled and filtered through a Celite bed, rinsing with ethyl acetate (100 mL). The combined filtrate was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography using a C-18 column, eluting with 50-55% acetonitrile in water to afford tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-5-fluoro-2- methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (0.93 g, 1.43 mmol, 46% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 651.5: ’H-NMR (400 MHz, DMSO-A): 5 8.46 (m, 1H),
8.07 (d, J = 8.8 Hz, 1H), 7.80 (d, J= 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.57-6.56 (m, 1H), 6.49 (m, 1H), 5.46 (s, 1H), 4.81-4.79 (m, 2H), 4.06-4.03 (m, 2H), 3.81-3.75 (m, 8H), 3.59-3.51 (m, 1H), 3.07-2.67 (m, 4H), 2.58 (s, 3H), 1.67 (d, J = 13.6 Hz, 1H), 1.43 (s, 9H), 0.83 (s, 3H), 0.72 (s, 3H).
Step 7: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (INT -S6)
To a stirred solution of tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- l(2H)-yl)-5-fhroro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (3.35 g, 5.15 mmol) in DCM (30 mL) were added TFA (33 mL, 43 mmol) and trifluoromethanesulfonic acid (0.91 mL,
10.3 mmol) at 0 °C, and the mixture was stirred at rt for 1 h. The mixture was then concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a C-18 column, eluting with 5-10% acetonitrile in water to afford l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)- 2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3F/)-dione, (INT-S6, 1.7 g, 3.3 mmol, 64% yield).
LCMS: m/z MM-ES+APCI, Positive [M+H] + 401.1; ’H-NMR (400 MHz, DMSO-A): 5 8.43 (d, J = 8.8
Hz, 1H), 8.08 (d, 7 = 8.8 Hz, 1H), 7.81 (d. 7 = 8. Hz, 1H), 4.02-4.01 (m, 1H), 3.71-3.70 (m, 1H), 3.00-
3.17 (m, 4H), 2.87-2.91 (m, 2H), 2.60 (s, 3H), 1.77-1.76 (m, 2H), 0.98 (s, 3H), 0.73 (s, 3H) (Note: 3 proton resonances appear to be obscured by the solvent peak).
Example 212: Synthesis of (7?)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2- methylquinolin-3-yl)dihydropyrimidine-2, 4(1//, 3//)-dione (INT-(R)-S6) and (S)-l-(5-fhioro-6-(4- hydroxy-3.3-dimethylpiperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4( l//,3//)-dione
(INT-(S)-S6)
Figure imgf000733_0001
Step 1: Chiral Separation of tert- butyl (R)-4-(3-(3-(2,4-dimethoxybenzyl)-2,4- dioxotet rahy d ropy ri midi n- 1( 2// )-yl)-5-fluoro-2-methy I qui noli n-6-y I )-4- hydroxy -3,3- dimethylpiperidine- 1 -carboxylate aanndd tert-butyl (S)-4-(3-(3-(2,4-dimethoxybenzyl)-2,4- dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2- methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (from “Ex INT-S6, Step 6, 1.0 g, 1.54 mmol) was subjected to chiral SFC chromatography using the following method:
Instrument: PIC 22-027
Column: Chiralpak-AS-H, IPA, 5 pm, 250 x 30 mm
Mobile Phase: CO2: 0.2% FA in 1:1 IPA:ACN [70:30]
Total Flow: 120 mL/min
Back pressure: 120 bar Wavelength: 220 nm Cycle time: 7 min Fraction 1: Tert-butyl (R)-4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2T/)- yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate. Retention time: 4.83 min. Chiral Purity : 99.36 %, [Analysis Method: SFC Chiralpak-AS-H; Flow : 4.00 mL/min, CoSolvent : 25 % IPA, Oven Temperature : 40 °C, BPR Pressure : 102.0 kgf/cm]. LCMS: m/z MM-ES+APCI, Positive [M+H] + 651.5; ’H-NMR (400 MHz, DMSO-de): 5 8.46 (d, J= 4.40 Hz, IH), 8.07 (d, J= 8.80 Hz,
IH), 7.80 (d, J = 8.80 Hz, IH), 6.95 (d, J = 8.80 Hz, IH), 6.57-6.56 (m, IH), 6.49-6.49 (m, IH), 5.46 (s,
IH), 4.81-4.79 (m, 2H), 4.03-4.06 (m, 2H), 3.81-3.75 (m, 8H), 3.59-3.51 (m, IH), 3.07-2.67 (m, 4H), 2.58
(s, 3H), 1.67 (d, J= 13.6 Hz, IH), 1.43 (s, 9H), 0.83 (s, 3H), 0.72 (s, 3H).
Fraction 2: Tert-butyl (>S)-4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2F0- yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate. Retention time: 6.86 min.. Chiral Purity : 98.16 %, [Analysis Method: SFC Chiralpak-AS-H; Flow : 4.00 mL/min, CoSolvent : 25 % IPA, Oven Temperature : 40 °C, BPR Pressure : 102.0 kgf/cm}. LCMS: m/z MM-ES+APCI, Positive [M+H] + 651.5: ’H-NMR (400 MHz, DMSO-rT): 5 8.46 (d, J= 4.40 Hz, IH), 8.07 (d, J= 8.80 Hz,
IH), 7.80 (d, J = 8.80 Hz, IH), 6.95 (d, J = 8.80 Hz, IH), 6.57-6.56 (m, IH), 6.49-6.49 (m, IH), 5.46 (s,
IH), 4.81-4.79 (m, 2H), 4.03-4.06 (m, 2H), 3.81-3.75 (m, 8H), 3.59-3.51 (m, IH), 3.07-2.67 (m, 4H), 2.58
(s, 3H), 1.67 (d, J= 13.6 Hz, IH), 1.43 (s, 9H), 0.83 (s, 3H), 0.72 (s, 3H).
Note: Absolute stereochemistry was assigned arbitrarily
Step 2: (R)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione((R)-S6)
To a stirred solution of tert-butyl (R)-4-(3-(3-(2,4-dimethoxybenzyl)-2,4- dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate (200 mg, 0.307 mmol) in DCM (3 ml) was added trifluoroacetic acid (350 mg, 3.07 mmol) followed by trifluoromethanesulfonic acid (138 mg, 0.922 mmol) at 0 °C under a nitrogen atmosphere and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was washed with hexane and then dried under vacuum to provide (R)-l-(5-fluoro-6-(4- hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, TFA (150 mg, 0.226 mmol, 73% yield). LCMS : m/z MM-ES+APCI, Positive [M+H] + 401.1; ’H-NMR (400 MHz, DMSO-d6): 5 10.67 (s, 1H), 8.43 (s, 1H), 8.08 (d, J = 8.80 Hz, 1H), 7.81 (d, J = 8.80 Hz, 1H), 5.80 (s, 1H), 4.02-4.01 (m, 1H), 3.81-3.60 (m, 3H), 3.17-3.00 (m, 3H), 2.91-2.87 (m, 2H), 2.68 (s, 3H), 1.95 (d, J = 10.40 Hz, IH), 1.25-1.16 (m, 1H), 0.98 (s, 3H), 0.73 (s, 3H).
Similarly prepared wwaass (S)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2- methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, TFA ((S)-S6), starting from /ert- butyl (S)- 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2-methylquinolin- 6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (the Fraction 2 product from Step 1). LCMS: m/z MM-ES+APCI, [M+HJ+ 401.3; 1H-NMR (400 MHz, DMSO-d6): 5 10.57 (s, 1H), 8.45 (s, 1H), 8.08 (t, J
= 8.40 Hz, 1H), 7.83 (d, J = 9.20 Hz, 1H), 5.81 (s, 1H), 4.01-3.98 (m, 1H), 3.81-3.67 (m, 3H), 3.19-3.11
(m, 2H), 2.98-2.79 (m, 2H), 2.68 (s, 3H), 1.93-1.82 (m, 1H), 1.28-1.23 (m, 1H), 1.02 (s, 3H), 0.78 (s, 3H).
Example 213: Synthesis of 3-(5-fluoro-6-((l?)-4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione ((R)-51d) and 3-(5-fluoro-6-((S)-4-hydroxy-3,3-dimethylpiperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione ((S)-51d)
Figure imgf000735_0001
Fraction 2 (S)-51c (S)-51d
(S)-51b
Step 1: Chiral Separation of tert-butyl ( /?)-4-(3-(2, 6-his( benzyloxy )pyridin-3-y I )-5-fluoroquinolin-6- yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate and tert-butyl (S)-4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (51b, 6.3 g, 9.5 mmol) was subjected to chiral SFC chromatography using the following method:
Instrument: PIC 22-027
Column: I-cellulose Z 250 x 30 mm, 5 pm
Mobile Phase: CO2: 0.2% FA in 1:1 IPA:ACN [70:30]
Total Flow: 120 ml/min
Back pressure: 120 bar
Wavelength: 220 nm
Cycle time: 7 min
Loading: 18 mg/injection
Two fractions obtained after chiral SFC were collected separately and lyophilized Fraction 1: Tert-butyl (R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate ((R)-51b, 2.5 g, 3.66 mmol, 40 % yield). Retention time: 3.15 min;. LCMS: m/z MM-ES+APCI, [M+H] + 664.7. ’H-NMR (400 MHz, DMSO-A; 9.14 (d. J = 2.0 Hz, IH), 8.63 (d, J= 1.6 Hz, 1H), 8.10-8.05 (m, 2H), 7.85 (d, T = 8.8 Hz, 1H), 7.30-7.45 (m, 10H), 6.67 (d, / = 8.4 Hz, IH), 5.50-5.42 (m, 5H), 3.99 (s, IH), 3.34-2.97 (m, 4H), 1.68 (d, J= 13.6 Hz, IH), 1.45
(m, 9H), 0.85 (s, 3H), 0.73 (s, 3H).
Fraction 2: Tert-butyl (S)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate ((S)-51b, 2.6 g, 3.73 mmol, 41 % yield). Retention time: 4.50 min; LCMS: m/z MM-ES+APCI, [M+H] + 664.8. ’H-NMR (400 MHz, DMSO-tfc 9.15 (d, J= 2.0 Hz, IH), 8.63 (d, J= 1.6 Hz, 1H), 8.16-8.06 (m, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.31-7.48 (m, 10H), 6.67 (d, J= 8.0 Hz, 1H), 5.50-5.42 (m, 5H), 3.99 (s, 1H), 3.34-2.97 (m, 4H), 1.68 (d, J= 13.6 Hz, 1H), 1.45 (s, 9H), 0.85 (s, 3H), -0.73 (s, 3H).
Step 2: Synthesis of tert-butyl (4R)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy- 3,3-dimethylpiperidine-l-carboxylate
A stirred solution of tert-butyl (R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)- 4-hydroxy-3,3-dimethylpiperidine-l-carboxylate ((R)-51b, the Fraction 1 product from Step 1, 1.25 g, 1.88 mmol) in N,N-dimethylformamide (15 mL) was sparged with nitrogen. Then palladium hydroxide (20% Pd(OH)2/C, wet basis) (0.66 g, 0.94 mmol) was added at rt. The mixture was stirred at rt for 8h under a hydrogen atmosphere (1 atm). The hydrogen source was removed, then the mixture was sparged with nitrogen and filtered through a Celite bed, rinsing with 1:9 DMF/THF. The combined filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography using a Cl 8 column, eluting with 50% acetonitrile in 0.1% FA in water to afford tert-butyl (4R)-4-(3- (2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (375 mg, 0.72 mmol, 38% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] +486.6; ’H-NMR (400 MHz, DMSO-cT; 10.98 (s, 1H), 8.86 (d, J= 2.4 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.09 (t, J= 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 5.45 (s, 1H), 4.23 (dd, J = 4.40, 12.6 Hz, 1H), 3.51-3.32 (m, 4H), 3.01-2.92 (m, 1H), 2.72-2.48 (m, 3H), 2.16-2.12 (m, 1H), 1.68 (d, J = 13.2 Hz, 1H), 1.43 (s, 9H), 0.84 (s, 3H), 0.73 (s, 3H).
Similarly prepared was tert-butyl (4S)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate, starting from tert-butyl (S)-4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate ((S)- 51b, the Fraction 2 product from Step 1). LCMS: m/z MM-ES+APCI, Positive [M+H] +486.2; ’H-NMR (400 MHz, DMSO-tfc 10.98 (s, 1H), 8.86 (d, J= 2.4 Hz, 1H), 8.33 (d, J = 2. Hz, 1H), 8.09 (t, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 5.45 (s, 1H), 4.23 (dd, / = 4.4, 12.6 Hz, 1H), 3.51-3.32 (m, 4H), 3.01-2.92 (m, 1H), 2.72-2.48 (m, 3H), 2.16-2.12 (m, 1H), 1.68 (d, J = 13.2 Hz, 1H), 1.43 (s, 9H), 0.84 (s, 3H), 0.73
(s, 3H).
Step 3: 3-(5-fluoro-6-((l?)-4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione ((R)-51d)
To a stirred solution of tert-butyl (4R)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxy-3, 3-dimethylpiperidine-l -carboxylate (120 mg, 0.25 mmol) in dichloromethane (5 ml) at 0 °C was added HCI (4M in 1,4-dioxane, 0.62 ml, 2.5 mmol) and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(5-fluoro-6-((R)-4-hydroxy-3,3- dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, 2HC1 (90 mg, 0.193 mmol, 78% yield).
LCMS: m/z MM-ES+APCI, Positive [M+H] +386.4; 'H-NMR (400 MHz, DMSO-tfc 11.01 (s, 1H), 9.39
(s, 1H), 8.96 (s, 1H), 8.73-8.47 (m, 2H), 8.13 (t, J = 8.4 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 5.90 (s, 1H),
4.30-4.16 (m, 1H), 3.22-3.15 (m, 4H), 2.68-2.89 (m, 3H), 2.16-2.13 (m, 1H), 1.93 (d, J= 11.6 Hz, 1H),
1.06 (s, 3H), 0.81 (s, 3H).
Similarly prepared was 3-(5-fluoro-6-((S)-4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione, 2HC1 ((S)-51d), starting from tert-butyl (45)-4-(3-(2,6-dioxopiperidin-3-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate. LCMS: m/z MM-ES+APCI, Positive [M+H] +386.4; 1H-NMR (400 MHz, DMSO-d6 : 11.01 (s, 1H), 9.31 (br s, 1H), 8.94 (s, 1H), 8.45
(s, 1H), 8.34 (s, 1H), 8.12 (t, J = 8.80 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 5.90 (s, 1H), 4.27 (dd, J = 4.4,
12.8 Hz, 1H). 3.23-3.08 (m, 4H), 2.65-2.77 (m, 3H), 2.15 (dd, J = 5.2, 9.2 Hz, 1H), 1.94-1.91 (m, 1H),
1.06 (s, 3H), 0.79 (s, 3H).
Example 214: Synthesis of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (INT-S20)
Figure imgf000737_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (3 g, 4.51 mmol, 45% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 5 g, 10.1 mmol) and tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (6.85 g, 30.2 mmol). LCMS: m/z MM-ES+APCI, Positive [M+H]+646.5. ’H-NMR (400 MHz, DMSO-rL; 9.06 (d. 7 = 2.00 Hz, 1H), 8.52
(d, 7 = 2.00 Hz, 1H), 8.01-7.93 (m, 4H), 7.33-7.45 (m, 10H), 6.67 (d. 7 = 8.00 Hz, 1H), 5.46 (m, 2H), 5.44
(s, 2H), 5.17 (s, 1H), 4.05-4.03 (m, 1H), 2.71-3.33 (m, 5H), 1.44 (s, 9H), 0.76-0.74 (m, 6H).
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (0.6 g, 1.21 mmol, 39% yield) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (2 g, 3.10 mmol) with a reaction time of lOh and using Workup/Purification Procedure (a). LCMS: m/z MM-ES+APCI, Positive [M+H]+468.4. ’H-NMR (400 MHz, DMSO-de; 10.97 (s, 1H), 8.77 (d, J = 2.00 Hz, 1H), 8.22 (d, J = 2.00 Hz, 1H), 8.00-7.94 (m, 3H),
5.16 (s, 1H), 4.17-4.12 (m, 5H), 2.17-3.41 (m, 6H), 1.53-1.43 (m, 9H), 0.76-074 (m, 6H).
Step 3: Synthesis of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-S20)
3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (INT-S20, 3.5 g, 7.89 mmol, 100% yield) was synthesized according to General Procedure 1, Step C starting from tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (3.7 g, 7.91 mmol) using HC1 in dioxane. The crude product was triturated with EtOAc to provide the title compound as an HC1 salt. LCMS: m/z MM-ES+APCI, Positive [M+H]+368.3. ’H-NMR (400 MHz, DMSO-r/s; 11.09 (s, 1H), 9.66 (s, 1H), 9.22 (s, 1H), 8.99-8.31 (m, 2H), 8.29-8.19 (m, 3H), 6.85 (s, 1H), 4.36 (d, 7 = 12.00 Hz, 1H), 3.57 (s, 1H), 2.78-3.26 (m, 7H), 1.83-2.24 (m, 2H), 0.97 (s, 3H), 0.79 (s, 3H). Example 215: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2- (trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione (1-887)
Figure imgf000738_0002
Figure imgf000738_0001
Step 1: Synthesis of ethyl 2-(6 bromo 2 (trifluoromethyl)quinolin 3 yl)acetate Sodium ethoxide (245 mg, 3.6 mmol) was added to a solution of 2-amino-5-bromobenzaldehyde (600 mg, 3.0 mmol) and ethyl 5,5,5-trifluoro-4-oxopentanoate (594 mg, 3.0 mmol) in ethanol (6 mL) under argon, and the mixture was heated at 80 °C for 16h. The reaction mixture was concentrated in 0 vacuo, then redissolved in ethanol (15 mL). Sulfuric acid (319 pL, 5.99 mmol) and 4 A mol sieves were added and the reaction mixture was stirred at 90 °C for Ih. The cooled reaction mixture was diluted with
EtOAc and filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate solution and brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to provide ethyl 2-(6-bromo-2-(trifluoromethyl)quinolin-3-yl)acetate (802 mg, 2.21 mmol, 74%). LCMS: m/z HESI, positive [M+H]+= 362.
Step 2: Synthesis of 3-(6-bromo-2-(trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione
LHMDS (2.65 mL, 1 molar, 2.65 mmol) was added to a solution of ethyl 2-(6-bromo-2- (trifluoromethyl)quinolin-3-yl)acetate (800 mg, 2.21 mmol) in anhydrous THE (11.0 mL, 0.2 molar) under an argon atmosphere at -78 °C. The mixture was stirred for 1 h at -78 °C before adding acrylamide (188 mg, 2.65 mmol), and the mixture was allowed to warm to rt and stirred for 2h. The reaction mixture was diluted with EtoAc and washed with 1 N HC1 (2 x 50 mL) and brine (50 mL). The combined aqueous washes were washed with EtOAc, and the combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 35% EtOAc in heptane to afford 3-(6-bromo-2-(trifluoromethyl)quinolin-3- yl)piperidine-2, 6-dione (683 mg, 1.76 mmol, 80%). LCMS: m/z HESI, positive [M+H]+ = 387.
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)quinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate
A solution of potassium carbonate in water (1.41 mL, 2 molar, 2.82 mmol) was added to a mixture of 3-(6-bromo-2-(trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione (683 mg, 1.76 mmol), [1,1 - PdCh(dppf)* DCM (216 mg, 265 pmol), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-l(2H)-carboxylate (35b, 655 mg, 2.12 mmol) in dioxane (7 mL). The mixture was sparged with argon, and the reaction vial was sealed and the mixture stirred under microwave irradiation for 3h at 85 °C. The cooled reaction mixture was concentrated under reduced pressure, then the residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to afford tertbutyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)quinolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (691 mg, 1.41 mmol, 80%). LCMS: m/z HESI, positive [M+H]+= 490.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)quinolin-6-yl)-4- hydroxypiperidine- 1 -carboxylate Tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-(trifluoromethyl)quinolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (690 mg, 1.41 mmol) was treated according to General Procedure 3, Step C. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to yield tert-butyl 4-(2-(2,6-dioxopiperidin-3- yl)-3-(trifluoromethyl)quinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (138 mg, 272 pmol, 19%). LCMS: m/z HESI, positive [M+H-Boc]+= 408.
Step 5: Synthesis of 3-(6-(4-hydroxypiperidin-4-yl)-2-(trifluoromethyl)quinolin-3-yl)piperidine-2,6- dione
To a stirred mixture of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)-quinolin-6- yl)-4-hydroxypiperidine-l -carboxylate (137 mg, 270 pmol) in DCM (4.5 mL) at rt was added methanesulfonic acid (70.1 pL, 1.1 mmol) and the mixture was stirred at rt for 3h. TEA (188 pL, 1.35 mmol) was added, and the mixture was concentrated in vacuo to yield crude 3-(6-(4-hydroxypiperidin-4- yl)-2-(trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione (110 mg), which was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+= 408.
Step 6: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-2- (trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione (1-887)
3-(6-(4-hydroxypiperidin-4-yl)-2-(trifluoromethyl)quinolin-3-yl)piperidine-2, 6-dione (110 mg, 270 pmol) was subjected to reaction with 4-(trifhioromethyl)benzaldehyde (41 pL, 297 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude was purified via Purification Method (a) followed by lyophilization with acctonitrilc/HCI (aq) to yield 3-(6-(4-hydroxy-l- (4-(trifluoromethyl)benzyl)piperidin-4-yl)-2-(trifluoromethyl)quinolin-3-yl)piperidine -2, 6-dione (1-887, 12 mg, 21 pmol, 8%). LCMS: m/z HESI, positive [M+H]+ = 566. *H NMR (500 MHz, DMSO-c/s) 5 ppm: 11.18 (br s, 1H), 11.05 (s, 1H), 8.71 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 8.12 (d, J= 1.6 Hz, 1H), 8.00-7.93 (m, 3H), 7.91-7.86 (m, 2H), 6.54 (br s, 1H), 5.83 (s, 1H), 4.59-4.45 (m, 2H), 4.37-4.25 (m, 1H), 3.54-3.38 (m, 1H), 2.98-2.86 (m, 1H), 2.66-2.51 (m, 4H), 2.48-2.32 (m, 2H), 2.20-2.10 (m, 1H), 1.94-1.85 (m, 2H). Example 216: Synthesis of 3-(6-((3R,5S)-4-hydroxy-3,5-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-917)
Figure imgf000740_0001
Step 1: Synthesis of tert-butyl (3R,5S)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4- hydroxy-3,5-dimethylpiperidine-l-carboxylate
Tert-butyl (3R,5S)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,5- dimethylpiperidine-1 -carboxylate (180 mg, 279 pmol, 56%) was synthesized according to General Procedure 1, Step A from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline INT-13A, (250 mg, 503 pmol) and tert-butyl (3R,5S)-3,5-dimethyl-4-oxopiperidine-l-carboxylate (149 mg, 653 nmol). The crude product was purified via silica gel chromatography eluting with 0 to 100% EtOAc in heptane. LCMS: m/z HESI, positive [M+H]+= 646.
Step 2; Synthesis of tert-butyl (3R,5S)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,5- dimethylpiperidine- 1 -carboxylate
Tert-butyl (3R,5S)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,5-dimethyl- piperidine-1 -carboxylate (94 mg, 200 pmol, 75%) was prepared from tert-butyl (3R,5S)-4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,5-dimethylpiperidine-l-carboxylate (173 mg, 268 pmol) according to General Procedure 1, Step B. The crude product was purified via preparative-HPLC [Method info: (Column: Phenomenex Luna Cl 8 column (50 x 21.2mm); 5 pm); eluting with 0.1% formic acid in H2O: 0.1% formic acid in MeCN. Flow rate: 50 mL/min], LCMS: m/z HESI, positive [M+H]+ = 468.
Step 3: Synthesis of 3-(6-((3R,5S)-4-hydroxy-3,5-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione
To a stirred mixture of tert-butyl (3R,5S)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy- 3,5-dimethylpiperidine-l-carboxylate (50 mg, 0.11 mmol) in DCM (1.8 mL) was added methanesulfonic acid (28 pL, 0.43 mmol) and the mixture was stirred at rt for 2h. TEA (74 pL, 0.53 mmol) was added, and the mixture was concentrated under reduced pressure to provide crude 3-(6-((3R,5S)-4-hydroxy-3,5- dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (39 mg), which was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+= 368.
Step 4: Synthesis of 3-(6-((3R,5S)-4-hydroxy-3,5-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-917)
Crude 3-(6-((3R,5S)-4-hydroxy-3,5-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (39 mg, 0.11 mmol) was subjected to reaction with 4-(trifluoromethyl) benzaldehyde (16 pL, 0.12 mmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via Purification Method (a) followed by lyophilization with acetonitrile/HCl (aq) to afford 3-(6-((3R,5S)- 4-hydroxy-3,5-dimethyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3-yl)piperidine -2, 6-dione (1-917, 30 mg, 58 pmol, 55%). LCMS: m/z HESI, positive [M+H]+ = 526. *H NMR (500 MHz, DMSO- d6) 5 (ppm) = 11.48 (hr s, 1H), 11.01 (s, 1H), 8.89 (s, 1H), 8.39 (s, 1H), 8.18-8.04 (m, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.88 (d, 7 = 8.2 Hz, 2H), 7.65 (d, 7 = 8.2 Hz, 1H), 5.39 (br s, 1H), 4.49 (d, J = 4.9 Hz, 2H),
4.21 (dd, J = 4.7, 12.9 Hz, 1H), 3.26-3.20 (m, 2H), 3.11-3.00 (m, 2H), 2.85-2.73 (m, 3H), 2.67-2.59 (m,
1H), 2.48-2.43 (m, 1H), 2.21-2.11 (m, 1H), 0.56-0.46 (m, 6H).
Example 217: Synthesis of 3-(6-(9,9-difluoro-5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-177)
Figure imgf000742_0001
Step 1: Synthesis of ethyl l-cyano-4,4-difluorocyclohexane-l-carboxylate
A solution of 4,4-difluorocyclohexane-l -carbonitrile (3.50 g, 24.1 mmol) in anhydrous THE (72 mL) was cooled to -78 °C was then treated with LHMDS (38.6 mL, 1 M in THE, 38.6 mmol). The mixture was stirred for 1 h at -78 °C, then ethyl chloroformate (3.69 mL, 38.6 mmol) was added and the mixture was allowed to warm to rt. Saturated aqueous sodium bicarbonate (100 ml) was added, and the mixture was extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 40% EtOAc in heptane to afford ethyl Lcyano-4,4- difluorocyclohexane-1 -carboxylate (3.96 g, 18.2 mmol, 76%). LCMS: m/z HESI, positive no ions observed.
Step 2: Synthesis of ethyl l-(aminomethyl)-4,4-difluorocyclohexane-l-carboxylate
A solution of ethyl l-cyano-4,4-difluorocyclohexane-l -carboxylate (5.24 g, 24.1 mmol) in EtOH
(66 mL) was added to platinum(IV) oxide (551 mg, 2.43 mmol) under an argon atmosphere. Acetic acid
(66 mL) was added, and the mixture was stirred under 1 atmosphere of hydrogen for 16h. The reaction mixture was filtered through a bed of celite and activated charcoal, and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 10 to 100% of 0.1% FA/acetonitrile in 0.1% FA/water to afford ethyl l-(aminomethyl)-4,4- difluorocyclohexane-1 -carboxylate (1.66 g, 7.50 mmol, 31%). LCMS: m/z HESI, positive | M+H ]+ = 222. Step 3: Synthesis of ethyl 4,4-difluoro-l-(((4-(trifluoromethyl)benzyl)amino)inethyl)-cyclohexane-l- carboxylate
A solution of ethyl l-(aminomethyl)-4,4-difluorocyclohexane-l -carboxylate (1.66 g, 7.50 mmol) and 4-(trifluoromethyl)benzaldehyde (1.13 mL, 8.25 mmol) in EtOH (30 mL) and AcOH (429 pL, 7.50 mmol), was stirred for 1 h at 45 °C. Sodium cyanoborohydride (942 mg, 15.0 mmol) was added and the mixture was stirred at 45 °C for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in saturate aqueous sodium bicarbonate solution and extracted with DCM (3 x 50 mL). The combine organic layers were washed with saturated aqueous sodium bicarbonate solution and with brine, then were dried over anhydrous Na2SC>4, filtered and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 10% MeOH in DCM to provide ethyl 4,4- difluoro-l-(((4-(trifhroromethyl)benzyl)amino)methyl)cyclohexane-l -carboxylate (1.74 g, 4.59 mmol, 61%). LCMS: m/z HESI, positive [M+H]+= 380.
Step 4: Synthesis of ethyl l-((3-ethoxy-3-oxo-N-(4-(trifluoromethyl)benzyl)propanamido)-methyl)- 4,4-difluorocyclohexane-l-carboxylate
A solution of ethyl 4,4-difhroro-l-(((4-(trifluoromethyl)benzyl)amino)methyl)-cyclohexane-l- carboxylate (1740 mg, 1 Eq, 4.59 mmol) and DIPEA (639 pL, 3.67 mmol) in DCM (23 mL) was added dropwise to a solution of ethyl 3-chloro-3-oxopropanoate (1.38 g, 9.17 mmol) in DCM (38 ml) at 0 °C with stirring. Following completion of the addition, the mixture was stirred for 90 min, then was diluted with DCM (50 mL) and poured into IN HC1 (aq) (200 mL). The aqueous layer was extracted with additional DCM (2 x 100 mL), then the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 80% EtOAc in heptane to provide ethyl l-((3-ethoxy-3-oxo-N-(4- (trifluoromethyl)benzyl)-propanamido)methyl)-4,4-difluorocyclohexane-l-carboxylate (1.91 g, 2.34 mmol, 51%) as a mixture with diethyl 2-(((l-(ethoxycarbonyl)-4,4-difluorocyclohexyl)methyl)(4- (trifluoro-methyl)benzyl)-carbamoyl)-3-oxopentanedioate. LCMS: m/z HESI, positive |M+H |+ = 494. Step 5: Synthesis of ethyl 9,9-difluoro-3,5-dioxo-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecane-4-carboxylate
A solution of sodium ethoxide (191 mg, 2.81 mmol) in ethanol (5.8 mL) was added to a solution of ethyl l-((3-ethoxy-3-oxo-N-(4-(trifluoromethyl)benzyl)propanamido)methyl)-4,4- difluorocyclohexane-1 -carboxylate (1.15 g, 2.34 mmol) in toluene (5.8 mL) under argon, and the mixture was stirred at 60 °C for 2h. The reaction mixture was concentrated under reduced pressure to give crude ethyl 9,9-difluoro-3,5-dioxo-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecane-4-carboxylate (1.05 g, 2.34 mmol) which was used in the next step without purification, assuming quantitative yield. LCMS: m/z HESI, positive [M+H]+= 448.
Step 6: Synthesis of 9, 9-difluoro-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecane-3, 5-dione
A solution of crude ethyl 9,9-difhroro-3,5-dioxo-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecane-4-carboxylate (1.05 g, 2.34 mmol) in acetonitrile (12 mL), water (1.7 mL, 94 mmol) and HC1 (aq) (994 pL, 2 M, 1.99 mmol) was heated at 115 °C (bath temp) for 1 h. The cooled reaction mixture was concentrated under reduced pressure, then the crude residue was taken up in DCM (100 mL) and the solution was filtered through a fritted filter. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to afford 9, 9-difhroro-2-(4-(trifhroromethyl)benzyl)-2-azaspiro[5.5]undecane-3, 5-dione (444 mg, 1.18 mmol, 51%). LCMS: m/z HESI, positive [M+H]+= 376.
Step 7: Synthesis of 9,9-difluoro-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-ol
To a stirred solution of 9,9-difluoro-2-(4-(trifhroromethyl)benzyl)-2-azaspiro[5.5]-undecane-3,5- dione (875 mg, 1 Eq, 2.33 mmol) in THE (12 mL) at 0 °C was added LAH (4.66 mL, 1 M solution in THE, 4.66 mmol). The mixture was stirred at 60 °C for 5h. The cooled reaction mixture was diluted with ether, then further cooled to 0 °C, and quenched by adding 0.26 mL of water, followed by 0.26 mL of 15% NaOH (aq), followed by 0.80 mL of water. The stirred mixture was allowed to warm to rt, then excess magnesium sulfate was added and the solids were removed by filtration. The filtrate was concentrated in vacuo and the crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 10 to 100% acetonitrile in water to provide 9,9-difluoro-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]-undecan-5-ol (366 mg, 1.01 mmol, 43%). LCMS: m/z HESI, positive [M+H]+= 364.
Step 8: Synthesis of 9,9-difluoro-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-one
To a solution of 9,9-difluoro-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-ol (73 mg, 0.20 mmol) in DCM (1 ml) was added DMP (94 mg, 0.22 mmol) at rt and the mixture was stirred at rt for 2h. Saturated sodium thiosulfate (aq) (10 mL) was added, and the mixture was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to yield 9,9-difluoro-2-(4-(trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-one (57 mg, 0.16 mmol, 79%). LCMS: m/z HESI, positive [M+H]+= 362.
Step 9: Synthesis of 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9,9-difluoro-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-ol 5-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9,9-difluoro-2-(4-(trifluoromethyl)-benzyl)- 2-azaspiro[5.5]undecan-5-ol (38.4 mg, 49.2 pmol, 26%) was synthesized from 3-(2,6- bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 93.0 mg, 187 nmol) and 9,9-difluoro-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-one (68 mg, 187 nmol) according to General Procedure 2, Step A. The crude product was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane. LCMS: m/z HESI, positive [M+H]+ = 780.
Step 10: Synthesis of 3-(6-(9,9-difluoro-5-hydroxy-2-(4-(trifluoromethyl)benzyl)-2- azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-177) l-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-9,9-difluoro-4-(4-(trifluoromethyl)- benzyl)spiro[5.5]undecan-l-ol (38.4 mg, 1 Eq, 49.3 ymol) was treated according to General Procedure 2, Step B, Purification Method (a), to provide 3-(6-(9,9-difhroro-5-hydroxy-2-(4- (trifluoromethyl)benzyl)-2-azaspiro[5.5]undecan-5-yl)quinolin-3-yl)piperidine-2, 6-dione (1-177, 5.0 mg, 8.4 pmol, 17%). LCMS: m/z HESI, positive [M+H]+ = 602. 1H NMR (500 MHz, DMSO-L) 5 ppm: 10.97 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.95-7.87 (m, 2H), 7.72 (d, J = 8.2 Hz,
2H), 7.61 (d, J = 7.7 Hz, 2H), 6.76 (br s, 1H), 5.02 (s, 1H), 4.14 (dd, J = 4.9, 12.6 Hz, 1H), 3.67 (d, J = 11.0 Hz, 2H), 2.87-2.79 (m, 2H), 2.79-2.68 (m, 2H), 2.65-2.56 (m, 2H), 2.47-2.36 (m, 3H), 2.20-2.11 (m, 1H), 1.87-1.78 (m, 1H), 1.74-1.63 (m, 2H), 1.57-1.49 (m, 2H), 1.23 (s, 1H), 1.03-0.92 (m, 1H). (No salt signals observed in *H NMR.)
Example 218: Synthesis of 3-(6-(3-ethyl-4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-179)
Figure imgf000745_0001
Step 1: Synthesis of tert-butyl 4,4-dimethoxy-3-oxopiperidine-l-carboxylate
To a solution of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-l -carboxylate (500 mg, 1.91 mmol) in DCM (10 ml) was added DMP (974 mg, 2.30 mmol) and the mixture was stirred at rt for 3h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to yield tert-butyl 4,4-dimethoxy-3- oxopiperidine-1 -carboxylate (273 mg, 1.05 mmol, 55%). LCMS: m/z HESI, positive |M+H-Boc|+ = 160.
Step 2: Synthesis of tert-butyl 3-ethyl-3-hydroxy-4,4-dimethoxypiperidine-l-carboxylate
Ethylmagnesium bromide (526 pL, 3 M solution in ether, 1.58 mmol) was added to a solution of tetrabutylammonium bromide (33.9 mg, 0.1 Eq, 105 pmol) and DME (109 pL, 1.05 mmol) in THE (1.6 mL), at 0 °C under an argon atmosphere. The solution was stirred for 30 min at 0 °C before adding a solution of tert-butyl 4,4-dimethoxy-3-oxopiperidine-l-carboxylate (273 mg, 1.05 mmol) in THE (1.05 mL) dropwise at 0 °C. After 3h, the reaction mixture was diluted with EtOAc (25 mL) and washed with IN HC1 (aq) (50 mL). The combined aqueous layers were back extracted once with EtOAc (25mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to provide tert-butyl 3-ethyl-3-hydroxy-4,4-dimethoxypiperidine-l -carboxylate (150 mg, 0.52 mmol, 49%). LCMS: m/z HESI, positive [M-OMe-Boc]+ = 158.
Step 3: Synthesis of tert-butyl 3-ethyl-3,4,4-trimethoxypiperidine-l-carboxylate
NaH (31 mg, 60% Wt, 780 pmol) was added at rt to a solution of tert-butyl 3 -ethyl- 3 -hydroxy - 4,4-dimethoxypiperidine- 1 -carboxylate (150 mg, 520 pmol) in DMF (1.7 mL) and the mixture was stirred at rt for 30 min before adding iodomethane (45 pL, 730 pmol). After 90 min, an additional aliquot of iodomethane (23 pL, 370 pmol) was added, and the mixture was stirred for an additional 90 min. The reaction was concentrated in vacuo to provide crude tert-butyl 3-ethyl-3,4,4-trimethoxypiperidine-l- carboxylate (160 mg), which was used in the next step without purification. LCMS: m/z HESI, positive [M-0Me-Boc]+= 172.
Step 4: Synthesis of tert-butyl 3-ethyl-3-methoxy-4-oxopiperidine-l-carboxylate
A solution of crude tert-butyl 3-cthyl-3.4.4-trimcthoxypipcridinc- 1 -carboxylate (160 mg, 517 pmol) and pTSOH (9.8 mg, 52 pmol) in acetone (2.7 mL) was stirred at rt for 16h. The reaction mixture was concentrated under reduced pressure and resuspended in MTBE (25 mL). The solution was washed with saturated aqueous sodium bicarbonate solution and the aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to provide tert-butyl 3-ethyl-3-methoxy-4-oxopiperidine-l-carboxylate (79 mg, 310 pmol, 59% (over 2 steps). LCMS: m/z HESI, positive [M+H-Boc]+ = 158.
Step 5: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy- 3-methoxypiperidine- 1 -carboxylate Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methoxypiperidine- 1 -carboxylate (93 mg, 0.14 mmol, 57%) was prepared according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 120 mg, 241 pmol) and tert-butyl 3-ethyl-3-methoxy-4-oxopiperidine-l-carboxylate (81 mg, 310 pmol). The crude product was purified by silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane. LCMS: m/z HESI, positive [M+H]+ = 676.
Step 6: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methoxypiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- methoxypiperidine- 1-carboxylate (93 mg, 0.14 mmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography using a C18 column, eluting with 10-100% of 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 4-(3- (2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3-methoxypiperidine- 1 -carboxylate (40 mg, 81 pmol, 59%). LCMS: m/z HESI, positive [M+H]+= 498.
Step 7: Synthesis of 3-(6-(3-ethyl-4-hydroxy-3-methoxypiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione
To a stirred mixture of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy- 3 -methoxypiperidine- 1 -carboxylate (40 mg, 81 pmol) in DCM (7 mL) at rt was added methanesulfonic acid (21 pL, 330 pmol). After 2h at rt, TEA (57 pL, 406 pmol) was added and the mixture was concentrated in vacuo to yield crude 3-(6-(3-ethyl-4-hydroxy-3-methoxy-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (32 mg). The crude product was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+ = 398.
Step 8: Synthesis of 3-(6-(3-ethyl-4-hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-179)
Crude 3-(6-(3-ethyl-4-hydroxy-3-methoxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (32 mg, 81 pmol) was subjected to reaction with 4-(trifluoromethyl)benzaldehyde (12 pL, 89 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via Purification Method (a) followed by lyophilization with acetonitrile/HCl (aq) to yield 3-(6-(3-ethyl-4- hydroxy-3-methoxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (I- 179, 26 mg, 47 pmol, 58%). LCMS: m/z HESI, positive [M+HJ+ = 556. *H NMR (500 MHz, DMSO-tfc) 5 ppm: 11.04 (s, 1H), 9.98 (hr s, 1H), 9.03 (s, 1H), 8.68 (s, 1H), 8.24 (s, 1H), 8.19-8.11 (m, 2H), 8.11- 8.05 (m, 1H), 8.00-7.97 (m, 1H), 7.93-7.87 (m, 2H), 6.17 (br s, 1H), 4.67-4.50 (m, 3H), 4.30-4.21 (m, 2H), 3.46-3.38 (m, 1H), 3.36-3.24 (m, 3H), 3.22-3.16 (m, 1H), 3.04 (s, 2H), 2.86-2.71 (m, 1H), 2.69-2.60 (m, IH), 2.25-2.10 (m, IH), 1.85-1.65 (m, IH), 1.59-1.47 (m, IH), 1.47-1.35 (m, IH), 1.09-0.98 (m, IH), 0.36-0.28 (m, 3H).
Example 219: Synthesis of 3-(6-(3-ethyl-3,4-dihydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-316)
Figure imgf000748_0001
Step 1: Synthesis of tert-butyl 3-ethyl-3-hydroxy-4-oxopiperidine-l-carboxylate
Tert-butyl 3-ethyl-3-hydroxy-4,4-dimethoxypiperidine-l -carboxylate (Prepared in 1-179, Step 2 above, 460 mg, 59 mmol) was treated with pTSOH in acetone according to the procedure of 1-179, Step 4 above, to yield tert-butyl 3-ethyl-3-hydroxy-4-oxopiperidine-l -carboxylate (280 mg, 1.15 mmol, 72%). LCMS: m/z HESI, positive [M+H-Boc]+= 144.
Step 2: Synthesis of tert-butyl 3-ethyl-4-oxo-3-((trimethylsilyl)oxy)piperidine-l-carboxylate
Chlorotrimethylsilane (150 pL, 1.18 mmol) was added to a solution of tert-butyl 3-ethyl-3- hydroxy-4-oxopiperidine-l -carboxylate (169 mg, 695 pmol) in DCM (3.5 ml) and pyridine (112 pL, 1.39 mmol) at rt and the mixture was stirred for Ih. Additional pyridine (2 eq) and TMSO (2 eq) were added, and the mixture was stirred at 37 °C for Ih. The reaction mixture was concentrated in vacuo, and the crude residue was purified via silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane to afford tert-butyl 3-ethyl-4-oxo-3-((trimethylsilyl)-oxy)piperidine-l-carboxylate (162 mg, 695 pmol, 74%). [M+H-Boc]+ = 216.
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy- 3-((trimethylsilyl)oxy)piperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- ((trimethylsilyl)oxy)piperidine-l -carboxylate (133 mg, 181 pmol, 50%) was prepared according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-quinoline (INT- 13A, 180 mg, 362 pmol) and ferf-butyl 3-ethyl-4-oxo-3-((trimethylsilyl)oxy)-piperidine-l-carboxylate (160 mg, 507 pmol). The crude product was purified using silica gel flash chromatography, eluting with 0 to 100% EtOAc in heptane. LCMS: m/z HESI, positive | M+H|+ = 734.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- ((trimethylsilyl)oxy)piperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- ((trimethylsilyl)oxy)piperidine-l -carboxylate (133 mg, 181 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography using a Cl 8 column, eluting with 10-100% of 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- ((trimethylsilyl)oxy)piperidine-l -carboxylate (60 mg, 0.11 mmol, 60%). LCMS: m/z HESI, positive [M+H]+ = 556.
Step 5: Synthesis of 3-(6-(3-ethyl-3,4-dihydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A mixture of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-ethyl-4-hydroxy-3- ((trimethylsilyl)oxy)piperidine-l -carboxylate (60 mg, 0.11 mmol), methanesulfonic acid (28 pL, 430 pmol) and DCM (1.8 ml) was stirred at rt for 2h. TEA (75 pL, 538 pmol) was added, and the mixture was concentrated in vacuo to yield crude 3-(6-(3-ethyl-3,4-dihydroxypiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (49 mg), which was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+= 384.
Step 6: Synthesis of 3-(6-(3-ethyl-3,4-dihydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-316)
Crude 3-(6-(3-ethyl-4-hydroxy-3-((trimethylsilyl)oxy)piperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (49 mg, 108 pmol) was subjected to reaction with 4-(trifluoromethyl)-benzaldehyde (26.2 pL, 1.4 Eq, 151 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via Purification Method (a) followed by lyophilization with acetonitrile/HCl (aq) to yield 3- (6-(3-ethyl-3,4-dihydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, (11 mg, 20 pmol, 19%). LCMS: m/z HESI, positive [M+H]+ = 542. 'H NMR (500 MHz, DMSO-de) 5 ppm 11.13 (br s, 1H), 11.08 (s, 1H), 9.17 (s, 1H), 8.90 (s, 1H), 8.26-8.17 (m, 3H), 8.07-8.03 (m, J= 8.2 Hz, 2H), 7.92-7.88 (m, J= 8.2 Hz, 2H), 5.97 (br s, 1H), 4.64-4.57 (m, 1H), 4.50-4.44 (m, 1H), 4.36-4.28 (m, 2H), 3.52-3.46 (m, 1H), 3.40-3.25 (m, 2H), 3.12-3.03 (m, 2H), 2.97-2.74 (m, 2H), 2.70-2.62 (m, 1H), 2.47-2.37 (m, 1H), 2.25-2.13 (m, 2H), 2.09-2.02 (m, 1H), 0.50 (t, J= 7.1 Hz, 3H).
Example 220: Synthesis of 3-(5-fluoro-6-(10-hydroxy-7-(4-(trifluoromethyl)benzyl)-7- azaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-560)
Figure imgf000750_0001
Step 1: Synthesis of tert-butyl 10-oxo-7-azaspiro[4.5]decane-7-carboxylate
To a stirred mixture of tBuOH (50 ml), KOtBu (4.73 g, 42.2 mmol) and tert-butyl 4- oxopiperidine-1 -carboxylate (4.00 g, 20.1 mmol) at 40 °C was added dropwise 1,4-dibromobutane (2.40 mL, 20.1 mmol). Following completion of the addition, the mixture was stirred at 40 °C for 2h. The cooled reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 X 100 mL). The combined aqueous layer was extracted with EtOAc (3 x 50 mL), and then the combine organic layers were concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography, eluting with 0 to 25% EtOAc in heptane to give tert-butyl 10-oxo-7- azaspiro[4.5]decane-7-carboxylate (851 mg, 3.36 mmol, 17%). LCMS: m/z HESI, positive [M+H- Boc]+ = 154.
Step 2: Synthesis of tert-butyl 10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-10- hydroxy-7-azaspiro[4.5]decane-7-carboxylate
Tert-butyl 10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fhioroquinolin-6-yl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate (314 mg, 456 pmol, 47%) was prepared according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoroquinoline (INT- 6B 500 mg, 1 Eq, 970 pmol) and tert-butyl 10-oxo-7-azaspiro[4.5]decane-7-carboxylate (369 mg, 1.46 mmol), with purification by silica gel flash chromatography with 0-100% EtOAc in heptane. LCMS: m/z HESI, positive [M+H]+= 690.
Step 3: Synthesis of tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate Tert-butyl 10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate (314 mg, 456 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography using a C18 column, eluting with 10-100% of 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 10-(3- (2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (87 mg, 0.170 mmol, 37%). LCMS: m/z HESI, positive [M+H]+ = 512.
Step 4: Synthesis of 3-(5-fluoro-6-(10-hydroxy-7-azaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine- 2, 6-dione
A mixture of tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-10-hydroxy-7- azaspiro[4.5]decane-7-carboxylate (87 mg, 0.17 mmol) and methanesulfonic acid (44 pL, 0.68 mmol) in DCM (2.8 mL) was stirred at rt for 2h. TEA (118 pL, 0.86 mmol) was added and the reaction mixture was concentrated in vacuo to yield crude 3-(5-fluoro-6-(10-hydroxy-7-azaspiro[4.5]decan-10-yl)quinolin-3- yl)piperidine-2, 6-dione (70 mg), which was used in the next step without further purification. LCMS: m/z HESI, positive [M+H]+ = 412.
Step 5: Synthesis of 3-(5-fluoro-6-(10-hydroxy-7-(4-(trifluoromethyl)benzyl)-7-azaspiro[4.5]decan- 10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-560)
Crude 3-(5-fluoro-6-(10-hydroxy-7-azaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (35 mg, 85 pmol) was subjected to reaction with 4-(ttifhroromethyl)benzaldehyde (16 pL, 120 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via Purification Method (a), followed by lyophilization with acctonitrilc/HCI (aq) to yield 3-(5-fluoro-6-(10- hydroxy-7-(4-(trifluoromethyl)benzyl)-7-azaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione, (I- 560, 10 mg, 18 pmol, 21%). LCMS: m/z HESI, positive [M+H]+ = 570. >H NMR (500 MHz, DM SO- A ) 5 ppm 10.99 (s, 1H), 10.05 (hr s, 1H), 8.90 (d, J= 1.6 Hz, 1H), 8.39 (t, 7= 2.5 Hz, 1H), 8.13 (t, J= 8.8 Hz, IH), 7.97-7.93 (m, 2H), 7.93-7.87 (m, 3H), 5.93 (hr s, 1H), 4.56-4.49 (m, 2H), 4.27-4.21 (m, 1H), 3.46-3.24 (m, 2H), 3.09-3.02 (m, IH), 2.82-2.69 (m, 2H), 2.67-2.58 (m, 2H), 2.24-2.18 (m, IH), 2.17- 2.09 (m, IH), 2.09-2.02 (m, IH), 1.92-1.71 (m, 2H), 1.41-1.26 (m, 3H), 1.21-1.11 (m, 2H), 0.87-0.75 (m, IH).
Example 221: Synthesis of 3-(7-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-912)
Figure imgf000752_0001
Step 1: Synthesis of 6-bromo-7-fluoro-3-iodoquinoline
A mixture of 6-bromo-7-fluoroquinoline (0.50 g, 2.21 mmol), acetonitrile (35 mL), tert-butyl hydroperoxide (3.42 g, 3.81 mL of 70% Wt, 26.5 mmol) and iodine (674 mg, 2.65 mmol) was refluxed for 16h. The reaction mixture was concentrated in vacuo and diluted with aqueous sodium thiosulfate solution. The mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with EtOAc in heptane to yield 6-bromo-7-fluoro-3-iodoquinoline (85 mg, 240 pmol, 11%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 351.9.
Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-7-fluoroquinoline
To a mixture of 6-bromo-7-fluoro-3-iodoquinoline (74 mg, 0.21 mmol), (2,6-bis(benzyloxy)- pyridin-3-yl)boronic acid (78 mg, 0.23 mmol), tetrakis(triphenylphosphine)-palladium(0) (49 mg, 42 pmol) and dioxane (2 mL) was added a solution of potassium carbonate (58 mg, 0.42 mmol) in water (0.2 mL). The reaction mixture was stirred for 50 min at 80 °C, then the cooled reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with EtOAc in heptane to yield 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-7-fluoroquinoline (77 mg, 0.15 mmol, 71%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 515.4.
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate
To a mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-7-fluoroquinoline (77 mg, 0.15 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (35b, 51 mg, 0.16 mmol), Pd(dppf)C12-DCM adduct (18 mg, 22 pmol), and dioxane (2 mL) was added a solution of potassium carbonate (31 mg, 0.22 mmol) in water (0.2 mL). The reaction mixture was sparged with argon and was then stirred at 80 °C for 50 min. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with EtOAc in heptane to provide tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoroquinolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (72 mg, 0.12 mmol, 78%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 618.5.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoroquinolin-6-yl)-3,6-dihydro-pyridine- l(2H)-carboxylate (0.072 g, 1 Eq, 0.12 mmol) was treated according to General Procedure 3, Step C. The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane to provide tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoro-quinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (57.1 mg, 89.8 pmol, 77%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 636.4.
Step 5: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoroquinolin-6-yl)-4- hydroxypiperidine- 1 -carboxylate
A mixture of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoroquinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (57.1 mg, 1 89.8 pmol), ethanol (5 mL), THE (7 mL) and Pd/C (9.6 mg, 90 pmol), was sparged with argon, then the mixture was sparged with hydrogen gas and then stirred under 1 atmosphere hydrogen pressure for 4h at rt. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The crude residue was purified via reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 4-(3-(2,6-dioxopiperidin- 3-yl)-7-fluoroquinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (10 mg, 22 pmol, 24%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 458.3.
Step 6: Synthesis of 3-(7-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoroquinolin-6-yl)-4-hydroxy- piperidine-1 -carboxylate (10 mg, 22 pmol) and methanesulfonic acid (8.4 mg, 87 pmol) in DCM (700 pL) and MeCN (700 pL) was stirred at rt for 30 min. The reaction mixture was cooled to 0 °C and triethylamine (15 mg, 0.15 mmol) was added. The reaction mixture was then concentrated under reduced pressure and the entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 358.2.
Step 7: Synthesis of 3-(7-fluoro-6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-912)
To a solution of 3-(7-fluoro-6-(4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (15 mg crude from previous step) and 4-(trifluoromethyl)benzaldehyde (8 mg, 6 pL 0.04 mmol) in DMF (1.5 mL) at 0 °C was added acetic acid (52 mg, 0.87 mmol) and sodium triacetoxyborohydride (9 mg, 0.04 mmol). The reaction mixture was stirred at rt for 3h, then was concentrated under reduced pressure. The crude residue was purified using reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to provide 3-(7-fluoro-6-(4-hydroxy-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1.2 mg, 2.3 pmol, 10%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 516.4.
Example 222: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3,3,5,5-tetramethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-909)
Figure imgf000754_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3, 3,5,5- tetramethylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3,5,5-tetramethyl- piperidine-1 -carboxylate was synthesized according to General Procedure 1, Step A, starting from 3- (2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-6B, 249 mg, 0.500 mmol) and tert-butyl 3,3,5,5-tetramethyl-4-oxopiperidine-l-carboxylate (128 mg, 500 pmol). The crude product was purified by silica gel chromatography, eluting with 0-100% EtOAc in heptane.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3, 3,5,5- tetramethylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3,5,5-tetramethyl- piperidine-1 -carboxylate (100 mg, 148 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was used in the next step without purification. LCMS: m/z MM- ES+APCI, Positive [M+H]+ 496.4.
Step 3: Synthesis of 3-(6-(4-hydroxy-3,3,5,5-tetramethylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione
A solution of tert-butyl 4-(3-(2, 6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3, 3,5,5- tetramethylpiperidine-1 -carboxylate (74 mg, 149 pmol) and methanesulfonic acid (57 mg, 594 pmol) in DCM (700 pL) and MeCN (700 pL) was stirred at rt for 2h. Triethylamine (150 mg, 1.49 mmol) was added, then the reaction mixture was concentrated in vacuo. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 396.3.
Step 4: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3,3,5,5-tetramethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-909) A mixture of 3-(6-(4-hydroxy-3,3,5,5-tetramethylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (59 mg, 148 pmol), acetaldehyde (6.5 mg, 150 pmol) DMF (1 mL), sodium triacetoxyborohydride (63 mg, 297 pmol) and acetic acid (52 mg, 0.87 mmol) was stirred at rt for 2h. The reaction mixture was filtered and directly loaded onto a Cl 8 column for purification by reverse phase chromatography, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield 3-(6-(l-ethyl-4-hydroxy-3,3,5,5-tetramethyl- piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1-909) (6.5 mg, 15 pmol, 10%) LCMS: m/z MM-ES+APCI, Positive [M+H]+ 424.3 *H NMR (500 MHz, DMSO-de) 5 ppm 10.96 (s, 1H), 8.74 (d, 1 = 2.2 Hz, 1H), 8.30 (s, 1H), 8.19-8.22 (m, 1H), 8.17 (s, 1H), 8.08 (hr d, J= 8.2 Hz, 1H), 7.91 (d, J = 8.8
Hz, IH), 4.13 (dd, J = 12.6, 4.9 Hz, 1H), 2.77 (m, 1H), 2.56-2.66 (m, 1H), 2.45-2.48 (m, 2H), 2.31-2.45
(m, 5H), 2.11-2.18 (m, 1H), 1.20-1.25 (m, 6H), 1.05 (t, 1 = 7.1 Hz, 3H), 0.75 (br s, 6H).
Example 223: Synthesis of 3-(6-(4-hydroxy-3-isopropyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-258)
Figure imgf000755_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- isopropylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-isopropyl-piperidine- 1 -carboxylate (130 mg, 197 pmol, 62%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-quinoline (INT-13A, 0.17 g, 320 pmol) and tert-butyl 3-isopropyl-4-oxopiperidine-l-carboxylate (100 mg, 416 pmol). The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane to yield LCMS: m/z MM- ES+APCI, Positive [M+H]+ 660.6.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- isopropylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-isopropylpiperidine- 1 -carboxylate (0.130 g, 197 pmol) was hydrogenated according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxy-3-isopropylpiperidine-l -carboxylate (70 mg, 0.15 mmol, 74%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 482.5.
Step 3: Synthesis of 3-(6-(4-hydroxy-3-isopropylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3-isopropyl- piperidine-1 -carboxylate (35 mg, 73 pmol) and methanesulfonic acid (28 mg, 0.29 mmol) in DCM (1 mL) and MeCN (1 mL) was stirred at rt for 30 min. The reaction mixture was cooled to 0 °C and triethylamine (74 mg, 0.73 mmol) was added.. The reaction mixture was concentrated under reduced pressure. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 382.3.
Step 4: Synthesis of 3-(6-(4-hydroxy-3-isopropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-258)
3-(6-(4-Hydroxy-3-isopropylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (0.028 g, pmol) was reacted with 4-(trifhioromethyl)benzaldehyde (26 mg, 0.15 mmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield 3-(6-(4- hydroxy-3-isopropyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (8.9 mg, 16 pmol, 22%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 540.4. 'H NMR (500 MHz, DMSO-d6) 8 10.96 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.36 (s, 1H), 8.20 (t, J= 2.5 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J= 8.8 Hz, 1H), 7.86 (hr s, 1H), 7.73-7.70 (m, J = 8.2 Hz, 2H), 7.62 (d, J= 8.2 Hz, 2H), 4.93 (hr s, 1H), 4.13 (dd, 7= 4.9, 12.6 Hz, 1H), 3.75 (hr d, J= 13.7 Hz, 1H), 3.62 (hr d, J= 13.7 Hz, 1H), 2.82-2.68 (m, 2H), 2.66-2.57 (m, 2H), 2.48-2.37 (m, 2H), 2.22-2.07 (m, 2H), 2.07-1.91 (m, 1H), 1.56 (hr d, J = 13.1 Hz, 2H), 1.36 (m, 1H), 0.79 (d, J= 6.6 Hz, 3H), 0.62-0.55 (d, J= 6.6 Hz, 3H).
Example 224: Synthesis of 3-(6-(2-ethyl-10-hydroxy-7-(4-(trifluoromethyl)benzyl)-2,7- diazaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-898)
Figure imgf000757_0001
Step 1: Synthesis of tert-butyl 2-benzyl-10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-10- hydroxy-2,7-diazaspiro[4.5]decane-7-carboxylate
Tert-butyl 2-benzyl-10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate (490 mg, 642 pmol, 64%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-quinoline (INT-13A, 0.5 g, 1.0 mmol) and tert-butyl 2-benzyl-10-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (416 mg, 1.21 mmol). The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane. LCMS: m/z MM-ES+sAPCI, Positive [M+H]+ 763.5.
Step 2: Synthesis of tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate
Tert-butyl 2-benzyl-10-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate (490 mg, 642 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with acetonitrile in water to afford tert-butyl 10-(3-(2,6-dioxopiperidin-3- yl)quinolin-6-yl)-10-hydroxy-2,7-diazaspiro[4.5]decane-7-carboxylate (90 mg, 0.18 mmol, 28%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 495.4.
Step 3: Synthesis of tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-2-ethyl-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate
Tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-10-hydroxy-2,7-diazaspiro[4.5]-decane- 7-carboxylate (45 mg, 91 pmol) was reacted with acetaldehyde (4.0 mg, 91 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a C18 column, eluting with acetonitrile in water to afford tert-butyl 10-(3-(2,6- dioxopiperidin-3-yl)quinolin-6-yl)-2-ethyl-10-hydroxy-2,7-diazaspiro[4.5]decane-7-carboxylate (21.2 mg, 40.6 pmol, 45%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 523.5.
Step 4: Synthesis of 3-(6-(2-ethyl-10-hydroxy-2,7-diazaspiro[4.5]decan-10-yl)quinolin-3- yl)piperidine-2, 6-dione
A solution of tert-butyl 10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-2-ethyl-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate (20 mg, 40.5 pmol) and methanesulfonic acid (15.6 mg, 162 pmol) in MeCN (1 mL) and DCM (1 mL) was stirred at rt for 30 min. The reaction mixture was cooled to 0 °C and then triethylamine (49.3 mg, 487 pmol) was added. The reaction mixture was concentrated in vacuo and the entire crude product was used in the next step without further purification. LCMS: m/z MM- ES+APCI, Positive [M+H]+ 423.4.
Step 5: Synthesis of 3-(6-(2-ethyl-10-hydroxy-7-(4-(trifluoromethyl)benzyl)-2,7- diazaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-898)
3-(6-(2-Ethyl-10-hydroxy-2,7-diazaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (17.1 mg, 1 Eq, 40.5 pmol) was reacted with 4-(trifluoromethyl)benzaldehyde (7.1 mg, 41 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to afford 3-(6-(2-ethyl-10-hydroxy-7-(4-(trifhioromethyl)-benzyl)-2,7-diazaspiro[4.5]decan-10-yl)quinolin- 3-yl)piperidine-2, 6-dione, formic acid (3.4 mg, 5.9 pmol. 14%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 581.5. >H NMR (500 MHz, DMSO-d6) 5 ppm 11.00-10.95 (m, 1H), 8.77-8.74 (m, 1H), 8.37-8.34 (m, 2H), 8.22-8.19 (m, 1H), 8.09-8.06 (m, 1H), 8.05-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.73-7.69 (m, 2H), 7.63-7.58 (m, 2H), 4.16-4.12 (m, 1H), 3.69-3.65 (m, 1H), 3.61-3.56 (m, 2H), 2.70-2.66 (m, 2H), 2.66- 2.62 (m, 3H), 2.61-2.57 (m, 2H), 2.46-2.42 (m, 2H), 2.30-2.26 (m, 1H), 2.11-2.07 (m, 1H), 2.04-1.97 (m,
2H), 1.93-1.85 (m, 2H), 1.83-1.77 (m, 1H), 1.64-1.59 (m, 1H), 0.78-0.73 (m, 3H).
Example 225: Synthesis of 3-(6-(4-hydroxy-3-phenyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-336)
Figure imgf000758_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3- phenylpiperidine- 1 -carboxylate
Tc/7-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-phenylpiperidine-l- carboxylate (261 mg, 376 pmol, 62%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 0.3 g, 603 pmol) and tertbutyl 4-oxo-3-phenylpiperidine-l-carboxylate (216 mg, 784 pmol). The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 694.6.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- phenylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3-phenylpiperidine-l- carboxylate (261 mg, 376 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography using a Cl 8 column, eluting with acetonitrile in water to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- phenylpiperidine-1 -carboxylate (120 mg, 233 pmol, 62%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 516.5.
Step 3: Synthesis of 3-(6-(4-hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- phenylpiperidine-1 -carboxylate (60 mg, 116 pmol) and methanesulfonic acid (44 mg, 466 pmol) in MeCN (1 mL) and DCM was stirred at rt for 30 min. Triethylamine (118 mg, 1.16 mmol) was added, and the reaction mixture was concentrated in vacuo. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 416.3.
Step 4: Synthesis of 3-(6-(4-hydroxy-3-phenyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-336)
3-(6-(4-hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (48 mg, 0.12 mmol) was reacted with 4-(trifhroromethyl)benzaldehyde (20 mg, 0.12 mmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield 3-(6-(4- hydroxy-3-phenyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1-336) (23.8 mg, 41.5 pmol, 36%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 574.6. 'H NMR (500 MHz, DMSO) 5 (ppm) 10.97-10.92 (m, 1H), 8.67 (d, I = 2.2 Hz, 1H), 8.36-8.31 (m, 1H), 8.07-8.04 (m, 1H), 7.87-7.83 (m, 1H), 7.82-7.74 (m, 2H), 7.72-7.68 (m, 2H), 7.66-7.59 (m, 2H), 7.08-7.02 (m, 2H), 6.99-6.91 (m, 3H), 5.27-5.21 (m, 1H), 4.13-4.03 (m, 1H), 3.77-3.68 (m, 2H), 2.95-2.87 (m, 1H), 2.84- 2.69 (m, 4H), 2.68-2.52 (m, 2H), 2.45-2.33 (m, 2H), 2.13-2.04 (m, 1H), 1.77-1.70 (m, 1H). Example 226: Synthesis of 3-(6-(l-ethyl-4-hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (1-47)
Figure imgf000760_0001
3-(6-(4-Hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (prepared in (1-336) step 3, 48 mg, 0.12 mmol) was reacted with acetaldehyde (5.1 mg, 0.12 mmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a C18 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield 3-(6-(l- ethyl-4-hydroxy-3-phenylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1-47, 18.7 mg, 42.2 pmol, 36%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 444.4 >H NMR (500 MHz, DMSO-d6) 5 10.94 (s, 1H), 8.67 (d, J= 2.2 Hz, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 7.80-7.74 (m, 2H), 7.08 (m, 2H), 7.02-6.91 (m, 3H), 4.08 (dd, J = 4.1, 12.3 Hz, 1H), 3.32 (m, 4H), 2.89-2.69 (m, 4H), 2.65-2.54 (m, 2H), 2.43-2.33 (m, 2H), 2.13-2.04 (m, 1H), 1.77-1.70 (m, 1H), 1.07 (t, J = 7.4 Hz, 3H). Example 227: Synthesis of 3-(6-(2-acetyl-10-hydroxy-7-(4-(trifluoromethyl)benzyl)-2,7- diazaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-900)
Figure imgf000760_0002
Step 1: Synthesis of tert-butyl 2-acetyl-10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate
Acetyl chloride (7.1 mg, 91 pmol) was added at 0 °C to a solution of tert-butyl 10-(3-(2,6- dioxopiperidin-3-yl)quinolin-6-yl)-10-hydroxy-2,7-diazaspiro[4.5]decane-7-carboxylate (prepared in Ex 224, Step 2, 45 mg, 91 pmol) and TEA (41 mg, 0.41 mmol) in DMF (1 mL). After 15 min, the reaction mixture was filtered and loaded directly onto a Cl 8 column for purification via reverse phase chromatography, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 2-acetyl-10-(3- (2,6-dioxopiperidin-3-yl)quinolin-6-yl)- 10-hydroxy-2,7-diazaspiro[4.5]decane-7-carboxylate (29 mg, 54 pmol, 59%) LCMS: m/z MM-ES+APCI Positive [M+H]+ 537 5 Step 2: Synthesis of 3-(6-(2-acetyl-10-hydroxy-2,7-diazaspiro[4.5]decan-10-yl)quinolin-3- yl)piperidine-2, 6-dione
A solution of ferLbutyl 2-acetyl-10-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-10-hydroxy-2,7- diazaspiro[4.5]decane-7-carboxylate (29 mg, 54 pmol) and methanesulfonic acid (21 mg, 0.22 mmol), in DCM (700 pL) and MeCN (700 pL) was stirred at rt for Ih. The reaction mixture was cooled to 0 °C and triethylamine (55 mg, 0.54 mmol) was added, then the reaction mixture was concentrated under reduced pressure. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 437.3.
Step 3: Synthesis of 3-(6-(2-acetyl-10-hydroxy-7-(4-(trifluoromethyl)benzyl)-2,7-diazaspiro- [4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (1-900)
3-(6-(2- Acetyl- 10-hydroxy-2,7-diazaspiro[4.5]decan-10-yl)quinolin-3-yl)piperidine-2, 6-dione (24 mg, 55 pmol) was reacted with 4-(trifluoromethyl)benzaldehyde (9.6 mg, 55 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to provide 3-(6- (2-acetyl-10-hydroxy-7-(4-(trifhioromethyl)benzyl)-2,7-diazaspiro[4.5]decan-10-yl)quinolin-3- yl)piperidine-2, 6-dione, formic acid (7.7 mg, 13 pmol, 24%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 595.5. 'H NMR (500 MHz, DMSO-d6) 5 ppm 11.01-10.94 (m, IH), 8.79-8.74 (m, IH), 8.47-8.41 (m, IH), 8.24-8.19 (m, IH), 8.12-8.08 (m, IH), 8.01-7.92 (m, 2H), 7.76-7.66 (m, 2H), 7.64-7.56 (m, 2H), 4.18-4.12 (m, IH), 3.76-3.57 (m, 3H), 2.92 (m, 3H), 2.85-2.70 (m, 4H), 2.67-2.56 (m, 4H), 2.45-2.36 (m, 2H), 2.18-2.10 (m, IH), 2.03-1.88 (m, IH), 1.76 (s, IH), 1.73-1.62 (m, 2H), 1.54-1.50 (m, IH).
Example 228: Synthesis of 3-(6-(3-(bicyclo[l.l.l]pentan-l-yl)-4-hydroxy-l-(4-(trifluoro- methyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-846)
Figure imgf000761_0001
Step 1: Synthesis of 3-(bicyclo[l.l.l]pentan-l-yl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one
A solution of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (1.17 g, 4.54 mmol) in THF (1.5 mL) was added to a solution of LDA (4.7 mL of 2 molar solution in THF/heptane/ethylbenzene, 9.38 mmol) at -78 °C, After 30 min, a solution of anhydrous zinc chloride (5.3 mL of 2M solution in THF, 10.6 mmol) was added and the mixture was stirred for 5 min at -78 °C. Tricyclo[1.1.1.01,3]pentane (0.20 g, 3.78 mL of 0.8 M solution in THF, 3.03 mmol) was then added and the reaction mixture was allowed to warm to rt and was stirred for Ih. Saturated aqueous NH4CI solution was added, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over NajSCL, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with EtOAc in heptane to yield 3-(bicyclo[l.l.l]pentan-l-yl)-l-(4-(trifhioromethyl)benzyl)piperidin-4-one (337 mg, 1.04 mmol, 34%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 324.3.
Step 2: Synthesis of 3-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)- l-(4-(trifluoromethyl)benzyl)piperidin-4-ol
3-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-l-(4- ( trifluoromethyl) benzyl)piperidin-4-ol (51 mg, 69 pmol, 34%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 100 mg, 201 pmol) and 3-(bicyclo[l.l.l]pentan-l-yl)-l-(4-(trifhioromethyl)benzyl)piperidin-4-one (78.0 mg, 241 pmol). The crude product was purified by silica gel flash chromatography, eluting with EtoAc in heptane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 372.0 (half mass).
Step 3: Synthesis of 3-(6-(3-(bicyclo[l.l.l]pentan-l-yl)-4-hydroxy-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-846)
3-(Bicyclo[l.l.l]pentan-l-yl)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-l-(4-(trifluoro- methyl)benzyl)piperidin-4-ol (51 mg, 69 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield 3-(6-(3-(bicyclo[l.l.l]pentan-l-yl)- 4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (2.1 mg, 3.7 pmol, 5.4%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 564.5 >H NMR (500 MHz, DMSO-d6) 5 ppm 10.98-10.94 (m, IH), 8.75-8.73 (m, IH), 8.45-8.43 (m, IH), 8.20-8.17 (m, IH), 8.07- 8.01 (m, IH), 7.96-7.91 (m, IH), 7.71 (s, 2H), 7.62-7.59 (m, 2H), 4.88-4.79 (m, IH), 4.18-4.09 (m, IH), 3.7 -3.71 (m, IH), 3.63-3.57 (m, IH), 2.81-2.73 (m, IH), 2.67-2.61 (m, 2H), 2.61-2.55 (m, 2H), 2.47-2.40 (m, 3H), 2.33-2.29 (m, IH), 2.19-2.12 (m, IH), 2.0-1.94 (m, IH), 1.34 (dd, J = 1.6, 9.6 Hz, 3H), 1.22 (s, 4H).
Example 229: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-piperidin-4- yl)-l,5-naphthyridin-3-yl)piperidine-2, 6-dione (1-181)
Figure imgf000763_0001
Step I; Synthesis of tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5-naphthyridin-2-yl)-3,3- dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
A solution of 7-(2,6-bis(benzyloxy)pyridin-3-yl)-2-chloro-l,5-naphthyridine (INT-8, 125 mg, 275 pmol), tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- l(2H)-carboxylate (INT-40, 111 mg, 330 pmol), and Pd(dppf)Ch-DCM adduct (33.7 mg, 41.3 pinol) in dioxane (1.1 mL) was sparged with argon for 3 min. A solution of potassium carbonate (46 pl, 2M in water, 0.33 mmol) was added and the mixture was again sparged with argon for 3 min, then was stirred at 100 °C for 2h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with EtOAc in heptane to provide tert-butyl 4-(7-(2,6- bis(benzyloxy)pyridin-3-yl)- 1 ,5-naphthyridin-2-yl)-3,3-dimethyl-3,6-dihydropyridine- 1 (2H) -carboxylate (72.8 mg, 116 pmol, 42%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 629.6.
Step 2: Synthesis of tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5-naphthyridin-2-yl)-4- hydroxy-3,3-dimethylpiperidine-l-carboxylate
Tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5-naphthyridin-2-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2H)-carboxylate (72 mg, 115 pmol) was treated according to General Procedure 3, Step C. The crude produce was purified by reverse phase chromatography using a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to yield tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5- naphthyridin-2-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (75 mg, 0.12 mmol, 100%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 647.6.
Step 3: Synthesis of tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-l,5-naphthyridin-2-yl)-4-hydroxy-3,3- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(7-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5-naphthyridin-2-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (75 mg, 0.12 mmol) was hydrogenated according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with acetonitrile/water to yield tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-l,5-naphthyridin- 2-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (10 mg, 21 pmol, 18%). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 469.6. Step 4: Synthesis of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-l,5-naphthyridin-3-yl)piperidine- 2, 6-dione
A solution of tert-butyl 4-(7-(2,6-dioxopiperidin-3-yl)-l,5-naphthyridin-2-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (10 mg, 21 pmol) and methanesulfonic acid (8.2 mg, 85 pmol) in MeCN (500 pL) and DCM (500 pL) was stirred at rt for 30 min, then was cooled to 0 °C and triethylamine (32 mg, 0.32 mmol) was added. The reaction mixture was concentrated in vacuo and the entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 369.3.
Step 5: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-l,5- naphthyridin-3-yl)piperidine-2, 6-dione (1-181)
3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)- 1 ,5-naphthyridin-3-yl)piperidine-2, 6-dione (8 g, 0.02 mmol) was reacted with 4-(trifluoromethyl)benzaldehyde (6 mg, 0.03 mmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to provide 3-(6- (4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-l,5-naphthyridin-3-yl)piperidine- 2,6-dione, formic acid (5.3 mg, 10 pmol, 50%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 527.5. *H NMR (500 MHz, DMSO, 298 K) 8 ppm 11.03-10.97 (m, 1H), 8.90-8.85 (m, 1H), 8.46-8.43 (m, 2H), 8.39-8.36 (m, 1H), 8.25-8.22 (m, 1H), 8.09-8.05 (m, 1H), 7.70 (s, 2H), 7.62-7.58 (m, 2H), 5.32-5.25 (m, 1H), 4.27-4.21 (m, 1H), 3.69-3.63 (m, 2H), 3.60-3.54 (m, 2H), 3.18-3.08 (m, 2H), 2.82-2.72 (m, 2H), 2.65-2.59 (m, 1H), 2.21-2.12 (m, 2H), 1.58-1.51 (m, 1H), 0.93-0.88 (m, 3H), 0.73 (s, 3H) Example 230: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((3-(trifluoromethyl)- bicyclo[l.l.l]pentan-l-yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-848)
Figure imgf000764_0001
F DMF
Step 1: Synthesis of 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carbaldehyde
DMP (26 mg, 60 pmol) was added to a solution of [3-(trifhroromethyl)bicyclo[ 1.1.1 Jpentan-1- yl]methanol (0.01 g, 60 pmol) in DCE (0.5 ml) and the mixture was stirred at rt for 2h. The reaction mixture was filtered, and the filtrate was used directly in the next step as a solution in DCE. Quantitative yield is assumed for the reaction.
Step 2: Synthesis of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-((3-(trifluoromethyl)- bicyclo[l.l.l]pentan-l-yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-848) To the stirred DCE solution of 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carbaldehyde (from
Step 1, 0.060 mmol) was added 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (8 mg, 0.02 mmol), followed by DMF (0.5 ml) and decaborane (1 mg, 8 pmol).
The reaction mixture was stirred for 15 min at 70 °C. The cooled reaction mixture was concentrated under reduced pressure, then the residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/acetonitrile in 0.1% FA/water to provide 3-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l- ((3-(trifluoromethyl)bicyclo[l.l.l-]pentan-l-yl)methyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (6.2 g, 12 pmol, 60%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 534.3. 1H NMR (500 MHz, DMSO-d6) 5 ppm 10.98 (s, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.44-8.36 (m, 1H), 8.35-8.28 (m, 1H), 8.11-8.06 (m, 1H), 7.86-7.81 (m, 1H), 5.11-5.06 (m, 1H), 4.25-4.19 (m, 1H), 3.14-3.06 (m, 2H), 2.79-2.71
(m, 1H), 2.68-2.61 (m, 2H), 2.61-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.16-2.09 (m, 1H), 1.94 (m, 5H), 1.68-
1.59 (m, 1H), 1.28-1.19 (m, 2H), 1.01-0.95 (m, 3H), 0.73-0.65 (m, 3H) (peaks overlap with solvent).
Example 231: Synthesis of 3-(6-(4-hydroxy-2-methyl-l-(4-(trifluoromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-903)
Figure imgf000765_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2- methylpiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2-methyl-piperidine-l- carboxylate (113 mg, 178 pmol, 29.5%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 0.3 g, 603 pmol) and tertbutyl 2-methyl-4-oxopiperidine- 1-carboxylate (154 mg, 724 pmol). The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 632.6.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2- methylpiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-Bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2-methyl-piperidine-l- carboxylate (0.11g, 178 pmol) was subjected to hydrogenation according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a C18 column, eluting with acetonitrile/water to yield tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2-methyl- piperidine-1 -carboxylate (48 mg, 0.11 mmol, 59%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 454.4. Step 3: Synthesis of 3-(6-(4-hydroxy-2-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2- methylpiperidine- 1 -carboxylate (24 mg, 53 pmol) and methanesulfonic acid (20 mg, 0.21 mmol) in MeCN (700 pL) and DCM (700 pL) was stirred at rt for 30 min, then was cooled to 0 °C. Triethylamine (80 mg, 0.79 mmol) was added, and the reaction mixture was concentrated. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 354.1. Step 4: Synthesis of 3-(6-(4-hydroxy-2-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin- 3-yl)piperidine-2, 6-dione (1-903) 3-(6-(4-Hydroxy-2-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (19 mg, 53 pmol) was reacted with 4-(trifhioromethyl)benzaldehyde (14 mg, 81 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via reverse phase chromatography on a Cl 8 column, eluting with 0 to 100% of 0.1% FA/MeCN in 0.1% FA/water to yield 3-(6-(4-hydroxy-2-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1.4mg, 2.7 pmol, 5%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 512.2 *H NMR (500 MHz, DMSO-d6) 8 10.98 (s, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.22 (m, 1H), 7.99 (m, 1H), 7.98-7.95 (s, 1H), 7.90 (dd, J = 1.9, 9.0 Hz, 1H), 7.67 (d, J= 8.2 Hz, 2H), 7.56 (d, 7= 8.2 Hz, 2H), 4.14 (dd, J = 4.7, 12.3 Hz, 1H). 3.92 (br d, 7= 14.2 Hz, 1H), 2.83-2.72 (m, 2H), 2.71-2.57 (m, 2H), 2.46-2.33 (m, 2H), 2.32-2.21 (m, 1H), 2.20-2.10 (m, 1H), 2.12-2.05 (m, 1H), 2.03-1.95 (m, 1H), 1.81-1.69 (m, 2H), 1.23 (m, 4H).
Example 232: Synthesis of 3-(6-(4-hydroxy-2,2-dimethyl-l-(4-(trifhioromethyl)benzyl)-piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-923)
Figure imgf000766_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2,2- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2,2-dimethyl- piperidine-1 -carboxylate (102 mg, 158 pmol, 26%) was synthesized according to General Procedure 1, Step A, starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 0.3 g, 603 pmol) and tert-butyl 2,2-dimethyl-4-oxopiperidine-l -carboxylate (165 mg, 724 pmol). The crude product was purified by silica gel flash chromatography, eluting with EtOAc in heptane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 646.6.
Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2,2- dimethylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-2,2-dimethyl- piperidine-1 -carboxylate (102 mg, 158 pmol) was hydrogenated according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a C18 column, eluting with acetonitrile/water to afford 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2,2- dimethylpiperidine-1 -carboxylate (32.3 mg, 69.1 pmol, 44%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 468.4.
Step 3: Synthesis of 3-(6-(4-hydroxy-2,2-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-2,2- dimethylpiperidine-1 -carboxylate (16 mg, 34 pmol) and methanesulfonic acid (13 mg, 0.14 mmol) in DCM (700 pL) and MeCN (700 pL) was stirred at rt for 30 min, then was cooled to 0 °C. Triethylamine (52 mg, 0.051 mmol) was added, and the reaction mixture was concentrated. The entire crude product was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 368.1. Step 4: Synthesis of 3-(6-(4-hydroxy-2,2-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-923) 3-(6-(4-Hydroxy-2,2-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (13 mg, 34 pmol) was reacted with 4-(trifhroromethyl)benzaldehyde (9.2 mg, 53 pmol) and decaborane according to General Procedure 1, Step D, Method A. The crude product was purified via reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA/MeCN in 0.1% FA/water to yield 3-(6-(4- hydroxy-2,2-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (2 mg, 4 pmol, 10%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 526.3.
Example 233: Synthesis of 3-(6-(2-benzyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)- 5-fluoroquinolin-3-yl)piperidine-2, 6-dione (1-987)
Figure imgf000768_0001
Step 1: Synthesis of tert-butyl 2-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)- 4-hydroxypiperidine-l -carboxylate (100a)
Tert-butyl 2-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (190.0 mg, 0.26 mmol, 26% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5- fluoroquinoline (INT-6B, 515 mg, 1.00 mmol) and tert-butyl 2-benzyl-4-oxopiperidine-l -carboxylate (347 mg, 1.20 mmol). LCMS: m/z HESI, positive [M+H]+ = 726.4.
Step 2: Synthesis of tert-butyl 2-benzyl-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine-l-carboxylate (100b)
Tert-butyl 2-benzyl-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (100b, 70 mg, 0.13 mmol, 77% yield) was synthesized according to General Procedure 1, Step B starting from tert-butyl 2-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (100a, 120 mg, 1.65 mmol). LCMS: m/z HESI, positive [M+H]+ = 548.3.
Step 3: Synthesis of 3-(6-(2-benzyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione (100c)
A stirred solution of tert-butyl 2-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-quinolin- 6-yl)-4-hydroxypiperidine-l -carboxylate (100b, 30 mg, 1 eq., 0.055 mmol) in DCM (2 mL)and TFA (0.5 mL) was allowed to stir for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure and used in the next step without purification. LCMS: m/z HESI, positive [M+H]+ = 448.2.
Step 4: Synthesis of 3-(6-(2-benzyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione (1-987)
To a stirred solution of 3-(6-(2-benzyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (100c, 0.055 mmol), triethylamine (33 mg, 46 pL, 0.33 mmol) and 4- (trifluoromethyl)benzaldehyde (17e 13 mg 0 077 mmol) in DMF (1 mL) was added sodium triacetoxyborohydride (16 mg, 77 pmol). The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was purified via General Procedure 1, Step D Purification Method (b) to give 3-(6-(2-benzyl-4- hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione, formic acid (1-987, 21 mg, 0.035 mmol, 63% yield). LCMS: m/z HESI, positive [M+H]+ = 606.5; *H NMR (500 MHz, DMSO-d6) 5 ppm 11.02-10.95 (m, 1H), 8.86-8.82 (m, 1H), 8.33-8.30 (m, 1H), 7.99-7.94 (m, 1H), 7.88-7.84 (m, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 7.7 Hz, 2H), 7.29-7.22 (m, 5H), 7.19-7.14 (m,
1H), 5.46-5.41 (m, 1H), 4.25-4.18 (m, 1H), 4.03-3.98 (m, 1H), 3.88-3.83 (m, 1H), 3.21-3.11 (m, 3H),
2.95-2.89 (m, 1H), 2.80-2.72 (m, 1H), 2.47-2.39 (m, 3H), 2.29-2.24 (m, 1H), 2.16-2.10 (m, 1H), 1.74-
1.64 (m, 2H).
Example 234: Synthesis of 3-(6-(2-benzyl-4-hydroxy-l-methylpiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (1-1319)
H .0
H
HNx> F OXNAO Formic acid, DMF, 100 °C 100c H F CAN HA)
To a stirred solution of 3-(6-(2-benzyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (Example 233, 1-987 Step 3, 0.055 mmol) in DMF (0.67 mL) was added water (3 mL), aqueous formaldehyde solution (0.56 g, 36%, 6.7 mmol) and formic acid (62 mg, 1.3 mmol). The solution was stirred at 100 °C for 16 h. Purification via General Procedure 1, Step D, Purification Method (b) gave 3-(6-(2-benzyl-4-hydroxy- 1 -methylpiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione, formic acid (1-1319, 6 mg, 0.01 mmol, 20% yield). LCMS: m/z HESI, positive [M+H]+ = 462.3; 'H NMR (500 MHz, DMSO-d6) 5 ppm 10.97 (s, 1H), 8.83 (s, 1H), 8.31-8.24 (m, 1H), 8.22-8.18 (m, 1H), 7.83-7.78 (m, 1H), 7.75-7.69 (m, 1H), 7.29 (d, J = 7.1 Hz, 2H), 7.28-7.25 (m, 2H), 7.19 (s, 1H), 4.25-4.19
(m, 1H), 3.04-3.00 (m, 1H), 2.98-2.93 (m, 1H), 2.85-2.72 (m, 2H), 2.65-2.60 (m, 1H), 2.59-2.55 (m, 1H), 2.52 (br s, 1H), 2.48-2.43 ((m, 1H), 2.35 (s, 3H), 2.32-2.24 (m, 1H), 2.23-2.16 (m, 1H), 2.16-2.09 (m, 1H), 1.84-1.76 (m, 1H), 1.59-1.51 (m, 1H).
Example 235: Synthesis of 3-(8-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1320)
Figure imgf000770_0001
Step 1: Synthesis of tert-butyl 4-(8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (101a)
Tert-butyl 4-(8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (101a, 150 mg, 0.40 mmol, 5% yield) was synthesized according to General Procedure 1, Step A starting from 6- bromo-8-fluoroquinoline (1.92 g, 8.5 mmol) and tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (2.32 g, 10.2 mmol). LCMS: m/z HESI, positive [M+H]+ = 375.2.
Step 2: Synthesis of tert-butyl 4-(3-bromo-8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1-carboxylate (101b)
A solution of tert-butyl 4-(8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (101a, 150 mg, 401 pmol) in pyridine (222 mg, 2.80 mmol) and acetonitrile (2 mL) was heated at 70 °C and then treated with bromine (320 mg, 2.00 mmol). The reaction mixture was stirred at 70 °C for 80 min. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with 20-80% EtOAc in heptane to afford tertbutyl 4-(3-bromo-8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (101b, 161 mg, 355 pmol, 89%). LCMS: m/z HESI, positive [M+H]+ = 453.3.
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-fluoroquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine- 1-carboxylate (101c)
In a microwave vial equipped with a stir bar was added tert-butyl 4-(3-bromo-8-fluoro-quinolin- 6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (101b, 151 mg, 333 pmol), PdC12(dppf)-DCM adduct (27.2 mg, 33.3 pmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (201 mg, 600 pmol), potassium carbonate (92.1 mg, 666 pmol), 1,4-dioxane (3 mL), and water (0.3 mL). The reaction mixture was sparged with argon, then the vial was sealed and heated at 110 °C for 1 h in a microwave reactor. The cooled reaction mixture was filtered through a pad of celite and silica and the filtrate was concentrated The crude residue was purified by silica gel flash chromatography, eluting with 0-100% EtOAc in heptane to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-fhioroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (101c, 188 mg, 283 pmol, 85%). LCMS: m/z HESI, positive [M+H]+ = 664.5.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-8-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (lOld)
Tert-butyl 2-benzyl-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-4-hydroxy-piperidine- 1 -carboxylate (lOld) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (101c, 148 mg, 223 pmol). The crude material was used in the next step without purification. LCMS: m/z HESI, positive [M+H]+ = 486.3.
Step 5: Synthesis of 3-(8-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (lOle)
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-8-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (directly from the previous step, lOld) in DCM (2 mL) and TEA (0.5 mL) was stirred at 45 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the entire crude product was used in the next step without purification. LCMS: m/z HESI, positive [M+H]+ = 386.2.
Step 6: Synthesis of 3-(8-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1320)
To a stirred solution of 3-(8-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (directly from the previous step, lOle), triethylamine (135 mg, 186 pL, 1.34 mmol) and 4-(trifluoromethyl)benzaldehyde (17e, 54.4 mg, 0.312 mmol) in DMF (1 mL) was added sodium triacetoxyborohydride (113 mg, 535 pmol). The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was purified via General Procedure 1, Step D Purification Method (b) to give 3- (8-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-1320, 40 mg, 0.074 mmol, 33% yield over 3 steps). LCMS: m/z HESI, positive [M+H]+ = 544.35; *H NMR (500 MHz, DMSO-d6) 5 ppm 10.99 (s, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 1.1 Hz, 1H), 7.83 (s, 1H), 7.70 (d, J = 8.2 Hz, 3H), 7.59 (d, J = 8.2 Hz, 2H), 5.04-4.91 (m, 1H), 4.22-4.12 (m, 1H), 3.67-3.63 (m, 1H), 3.58-3.54 (m, 1H), 2.88-2.70 (m, 3H), 2.52 (s, 3H), 2.48-2.38 (m, 1H), 2.18-2.12 (m, 2H), 1.58-1.51 (m, 1H), 0.93 (s, 3H), 0.68 (s, 3H).
Example 236: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-piperidin-4- yl)-7-methylquinolin-3-yl)piperidine-2, 6-dione (1-1321)
Figure imgf000772_0001
Step 1: Synthesis of tert-butyl 4-hydroxy-3,3-dimethyL4-(7-methylquinolin-6-yl)piperidine-l- carboxylate (102a) tert-butyl 4-hydroxy-3,3-dimethyl-4-(7-methylquinolin-6-yl)piperidine-l-carboxylate (102a, 240 mg, 0.65 mmol, 8% yield) was synthesized according to General Procedure 1, Step A starting from 6- bromo-7-methylquinoline (1.89 g, 8.50 mmol) and tert-butyl 3,3-dimethyl-4-oxopiperidine-l-carboxylate (2.32 g, 10.2 mmol). LCMS: m/z HESI, positive [M+H]+ = 371.2.
Step 2; Synthesis of tert-butyl 4-(3-bromo-7-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate (102b)
A solution of tert-butyl 4-hydroxy-3,3-dimethyl-4-(7-methylquinolin-6-yl)piperidine-l- carboxylate (102a, 200 mg, 540 pmol) in pyridine (299 mg, 3.78 mmol) and acetonitrile (2 mL) was heated at 70 °C, and then was treated with bromine (431 mg, 2.70 mmol). The reaction mixture was stirred at 70 °C for 80 min. The reaction mixture was concentrated, and the residue was purified via silica gel flash chromatography, eluting with 20 to 80% EtOAc in heptane to afford tert-butyl 4-(3-bromo-7- methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (102b, 230 mg, 540 iimol. 95%) LCMS: m/z HESI, positive [M+H]+ = 449.4.
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-methylquinolin-6-yl)-4- hydroxy-3,3-dimethylpiperidine- 1-carboxylate (102c)
Tert-butyl 4-(3-bromo-7-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (102b, 220 mg, 490 pmol) and (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (295 mg, 881 pmol) were subjected to Suzuki coupling using the procedure of Ex 235, (1-1320) Step 3 to afford tert-butyl 4-(3- (2,6-bis(benzyloxy)pyridin-3-yl)-7-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (102c, 250 mg, 379 pmol, 77%). LCMS: m/z HESI, positive [M+H]+ = 660.4.
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-7-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (102d)
Tert-butyl 2-benzyl-4-(3-(2,6-dioxopiperidin-3-yl)-7-methylquinolin-6-yl)-4-hydroxy-piperidine- 1 -carboxylate (102d) was synthesized according to General Procedure 1, Step B starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-methylquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (102c, 202 mg, 306 pmol). The entire crude product was used in the next step without purification. LCMS: m/z HESI, positive [M+H]+ = 482.4.
Step 5: Synthesis of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-7-methylquinolin-3-yl)piperidine- 2, 6-dione (102e)
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-7-methylquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (directly from the previous step, 102d) in DCM (2 mL) and TEA (0.5 mL) was stirred at 45 °C for 1 h. The reaction mixture was concentrated under reduced pressure and used in the next step without purification. LCMS: m/z HESI, positive [M+H]+ = 382.3.
Step 6: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-7- methylquinolin-3-yl)piperidine-2, 6-dione (1-1321)
To a stirred solution of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-7-methylquinolin-3- yl)piperidine-2, 6-dione (102e, direct from the previous step), triethylamine (186 mg, 256 pL, 1.84 mmol) and 4-(trifhmromethyl)benzaldehyde (17e, 75 mg, 0.43 mmol) in DMF (1.5 mL) was added sodium triacetoxyborohydride (156 mg, 735 pmol). The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was purified via General Procedure 1, Step D, Purification Method (b) to give 3-(6-(4- hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-7-methylquinolin-3-yl)piperidine-2,6- dione, formic acid (1-1321, 40 mg, 0.074 mmol, 24% yield over 3 steps). LCMS: m/z HESI, positive [M+H]+ = 540.3; *H NMR (500 MHz, DMSO-d6) 5 ppm 10.95 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.14 (br s, 1H), 7.93-7.87 (m, 1H), 7.76-7.69 (m, 3H), 7.66-7.58 (m, 2H), 5.03-4.72 (m, 1H), 4.13-4.06 (m, 1H), 3.79-3.59 (m, 2H), 3.04-2.96 (m, 1H), 2.81 (s, 3H), 2.80-2.56 (m, 5H), 2.43-2.33 (m, IH), 2.26-2.09 (m, 2H), 1.69-1.59 (m, IH), 0.96 (s, 3H), 0.74 (s, 3H).
Example 237: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)azepan-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-878)
Figure imgf000774_0001
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-2, 3,6,7- tetrahydro-lH-azepine-l-carboxylate
To a stirred solution of l-(6-bromoquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-1, 500 mg, 1.56 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-lH-azepine-l-carboxylate (757 mg, 2.34 mmol) and DIPEA (404 mg, 3.12 mmol). The reaction mixture was sparged with N2 for 10 minutes. Bis(tri-tert- butylphosphine)palladium(O) (80 mg, 0.156 mmol) was then added. The resulting reaction mixture was heated at 85 °C for 1 h. The cooled reaction mixture was filtered through a celite pad, then the pad was rinsed with EtOAc and the combined filtrate was concentrated. The residue was purified by silica gel flash chromatography, eluting with 5% IPA in DCM to afford tert-butyl 4-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)-2,3,6,7-tetrahydro-lH-azepine-l-carboxylate (0.53 g, 1.20 mmol, 77% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 437.3; >H NMR (400 MHz, DMSO-t/s): 3 10.58 (s, 1H), 8.88 (d, J= 4.0 Hz, 1H), 8.21 (d, J= 4.0 Hz, IH), 7.94 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, IH), 7.79-7.76 (m, IH), 6.52 (s, IH), 6.24 (d, J= 8.0 Hz, IH), 4.06-4.00 (m, 2H),
3.98-3.94 (m, 2H), 3.63-3.60 (m, 2H), 2.81-2.78 (m, 4H), 2.49-2.46 (m, IH), 1.47 (s, 9H).
Step 2: Synthesis of l-(6-(2,3,6,7-tetrahydro-lH-azepin-4-yl)quinolin-3-yl)dihydropyrimidine-
2,4(lH,3H)-dione
To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)quinolin-6-yl)- 2,3,6,7-tetrahydro-lH-azepine-l-carboxylate (1.1 g, 2.52 mmol) in DCM (10 mL) was added HCI (4.0 M in 14-dioxane) (4 mL, 16.0 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with MTBE (100 mL), filtered and dried under reduced pressure to obtain l-(6-(2,3,6,7-tetrahydro-lH-azepin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (0.9 g, 1.933 mmol, 77% yield). MM- ES+APCI, Positive [M+H]+ 337.3; *H NMR (400 MHz, DMSOYe): § 10.68 (s, 1H), 9.45 (bs, 1H), 9.06
(s, IH), 8.48 (s, IH), 8.14-8.05 (m, 2H), 8.93 (d, J= 8.0 Hz, IH), 6.40 (t, J= 8.0 Hz, IH), 4.02-3.98 (m,
2H), 3.32-3.28 (m, 2H), 3.22-3.18 (m, 2H), 3.11-3.07 (m, 2H), 3.06-3.04 (m, 2H), 3.03-3.00 (m, 2H). Step 3: Synthesis of l-(6-(l-(4-(trifluoromethyl)benzyl)-2,5,6,7-tetrahydro-lH-azepin-4-yl)quinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of l-(6-(2,5,6,7-tetrahydro-lH-azepin-4-yl)quinolin-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione, HC1 (500 mg, 1.34 mmol) in DMF (10 mL) was added 4- (trifluoromethyl)benzaldehyde (350 mg, 2.012 mmol) and the mixture was stirred at room temperature for Ih. Sodium triacetoxyborohydride (568 mg, 2.68 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 5% IP A in DCM to afford l-(6-(l-(4- (trifluoromethyl)benzyl)-2,5,6,7-tetrahydro-lH-azepin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (500 mg, 0.90 mmol, 67% yield), m/z MM-ES+APCI, Positive [M+H]+ 495.3; *H NMR (400 MHz, DMSO-rL): 3 10.58 (s, IH), 8.87 (d, J = 4.0 Hz, IH), 8.19 (s, IH), 7.93 (d, J= 8.0 Hz, 2H), 7.88-7.70 (m,
3H), 7.61 (d, J = 8.0 Hz, 2H), 6.36 (t, J = 8.0 Hz, IH), 3.97-3.94 (m, 2H), 3.80-3.75 (m, 2H), 2.89-2.73
(m, 4H), 2.67-2.58 (m, 2H), 2.49-2.46 (m, 2H), 1.99-1.03 (m, 2H).
Step 4: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)azepan-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1-878)
To a stirred solution of l-(6-(l-(4-(trifluoromethyl)benzyl)-2,5,6,7-tetrahydro-lH-azepin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (200 mg, 0.404 mmol) in DCM (5 mL) and 2- propanol (5 mL) were added phenylsilane (87 mg, 0.81 mmol) and Mn(dpmp (74.0 mg, 0.121 mmol). The mixture was stirred under an O2 bladder at 0 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative-HPLC [(Column: X select Cl 8 (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% HC1 in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)] to obtain l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)azepan-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (39 mg, 0.070 mmol, 16% yield), m/z MM-ES+APCI, Positive [M+H]+ 513.4; >H NMR (400 MHz, DMSO-r/s): 3 11.20-11.05 (m, 1H), 10.63 (s, 1H), 8.99 (d, J= 2.4 Hz, IH), 8.37 (d, J = 6.4 Hz, 1H), 8.14-7.86 (m, 7H), 5.01 (s, 2H), 4.53 (s, 2H), 3.80-3.27 (m, 5H), 2.84- 2.79 (m, 3H), 2.34-2.25 (m, 2H), 2.03-1.97 (m, IH), 1.91-1.83 (m, 2H).
Example 238: Synthesis of 3-(6-((3R,4R)-3-fluoro-4-hydroxy-3-methyl-l-(4-(trifluoroniethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-186) and 3-(6-((3R,4S)-3-fluoro-4- hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (I- 187)
Figure imgf000776_0001
Stepl: Synthesis of tert-butyl 5-methyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-l(2H)- carboxylate
To a stirred solution of tert-butyl 3-methyl-4-oxopiperidine-l -carboxylate (3 g, 14.07 mmol) in toluene (20 mL) was added TEA (5.69 g, 56.3 mmol) at 0 °C followed by TMS-OTf (3.75 g, 16.9 mmol) at 0 °C drop wise and the reaction mixture was allowed to stir at 0 °C for 4 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution and then extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude tert-butyl 5-methyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-l(2H)- carboxylate (3.6 g, 5.0 mmol, 36% yield). LCMS: m/z MM-ES+APCI, No ionization; *H-NMR (400 MHz, DMSO-d6): 8 3.67 (s, 2H), 3.43 (t, J = 6.00 Hz, 2H), 2.05 (s, 2H), 1.50 (s, 3H), 1.42 (s, 9H), 0.18
(s, 9H).
Step 2: Synthesis of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-l-carboxylate
To a stirred solution of tert-butyl 5-methyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-l(2H)- carboxylate (3.8 g, 13.31 mmol) in ACN (12 mL) was added Selectfluor (5.19 g, 14.6 mmol) at 0 °C and the reaction mixture was allowed to stir at 0 °C for Ih. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2X 100 mL) and the combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure The crude residue was purified by silica gel flash chromatography eluting with 0-100% EtOAc in hexane to afford tert-butyl 3- fluoro-3-methyl-4-oxopiperidine-l -carboxylate (1.3 g, 4.27 mmol, 32% yield). LCMS: No ionization; *H- NMR (400 MHz, DMSO-d6): 8 3.67-3.32 (m, 4H), 2.57-2.54 (m, 2H), 1.44 (s, 9H), 1.42-1.35 (m, 3H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-fluoro-4- hydroxy-3-methylpiperidine-l-carboxylate Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxy-3- methylpiperidine-1 -carboxylate (240 mg, 0.358 mmol, 71% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-quinoline (INT-1, 250 mg, 0.503 mmol) and tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-l-carboxylate (174 mg, 0.754 mmol). The crude product was purified by silica gel flash chromatography, eluting with 0-50% EtOAc in hexane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 650.5; 'H-NMR (400 MHz, DMSO-d6): 59.17 (s, 1H),
8.14 (s, IH), 8.14-8.10 (m, 2H), 7.94-7.92 (m, IH), 7.86-7.76 (m, IH), 7.75-7.73 (m, IH), 7.48-7.43 (m,
2H), 7.43-7.39 (m, 4H), 7.39-7.36 (m, 4H), 6.60 (d, J = 1.60 Hz, 2H), 5.46 (m, 4H), 4.15 (q, J = 7.20 Hz, 3H), 3.32 (s, 1H), 2.00 (m, 1H), 1.45 (s, 9H), 1.08-0.97 (m, 3H).
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxy-3- methylpiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxy-3- methylpiperidine- 1-carboxylate (240 mg, 0.369 mmol) Was treated according to General Procedure 1, Step B, The crude compound was washed with n-hexane (2 x 20 mL) and the resulting solid was dried under reduced pressure to provide tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4- hydroxy-3-methylpiperidine-l-carboxylate (170 mg, 0.33 mmol, 89% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 472.4; 1H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.79 (s, 1H), 8.26 (d, J = 2.00 Hz, IH), 8.19-8.13 (m, 1H), 7.99-7.97 (m, 2H), 5.86 (s, 1H), 4.18-4.17 (m, 1H), 3.28-3.24 (m, 2H), 2.75- 2.67 (m, 2H), 2.50-2.41 (m, 2H), 2.16-2.14 (m, IH), 1.62-1.59 (m, IH), 1.44-1.41 (m, 9H), 0.89 (t, J = 2.40 Hz, 3H).
Step 5: Synthesis of 3-(6-(3-fluoro-4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-3-fluoro-4-hydroxy-3- methylpiperidine- 1-carboxylate (150 mg, 0.318 mmol) in DCM (5 mL) and HC1 (4M in 1,4-dioxane, 120 mg, 0.32 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with n-hexane, and the resulting solid was dried under reduced pressure to provide 3-(6-(3-fluoro-4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (130 mg, 0.29 mmol, 92% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ 372.2. 1H-NMR (400 MHz, DMSO-d6): 5 11.04 (s, IH), 9.75-9.56 (m, IH), 9.22-8.89 (m, 2H), 8.63 (s, IH), 8.25-8.19 (m, 2H), 8.09-
8.00 (m, IH), 6.45 (s, 1H), 4.28-4.24 (m, 1H), 3.46-3.39 (s, 3H), 3.39-3.29 (m, 3H), 2.90-2.81 (m, 1H),
2.76-2.50 (m, 1H), 2.21-2.17 (m, 1H), 1.91-1.86 (m, IH), 1.29-1.03 (m, 3H).
Step 6: Synthesis of 3-(6-((3R,4R)-3-fluoro-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)- piperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (1-186) and 3-(6-((3R,4S)-3-fluoro-4-hydroxy-3- methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-187) 3-(6-(3-fluoro-4-hydroxy-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (130 mg, 0.319 mmol) was treated with 4-(trifluoromethyl)benzaldehyde (83 mg, 0.48 mmol) and sodium triacetoxyborohydride according to General Procedure 1, Step D Method (b). The crude residue was purified by preparative-HPLC [Method info: (SUNFIRE Cl 8 column 150 x 21.2 mm; 5 um; eluting with 0.1% NH4OAc in H2O: acetonitrile. Flow rate: 15 mL/min)] Two fractions were collected separately.
Fraction 1 : 3-(6-((3R,4R)-3-fluoro-4-hydroxy-3-methyl-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-186). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 530.3; 1H- NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.77 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.96 (s, 2H), 7.73
(d, J = 8.00 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 5.57 (s, 1H), 5.57 (d, J = 3.20 Hz, 1H), 3.38 (s, 2H), 2.78-
2.76 (m, 4H), 2.68-2.67 (m, 4H), 2.51-2.50 (m, 1H), 1.84-1.76 (m, 1H), 0.97-9.93 (m, 3H).
Fraction 2: 3-(6-((3R,4S)-3-fluoro-4-hydroxy-3-methyl- 1 -(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-187) LCMS: m/z MM-ES+APCI, Positive [M+H]+ 530.3. 1H- NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.03-8.01 (m, 3H), 7.73 (d, J =
8.00 Hz, 2H), 7.60 (d, J = 8.00 Hz, 2H), 5.48 (s, 1H), 4.18-4.15 (m, 1H), 3.77-3.70 (m, 2H), 2.89-2.84 (m,
4H), 2.79-2.75 (m, 3H), 2.50-2.45 (m, 1H), 2.18-2.16 (m, 1H), 1.83-1.81 (m, 1H), 1.20-1.14 (m, 3H).
Each fraction is a mixture of diastereomers; stereochemistry is arbitrarily assigned.
Example 239: Synthesis of 3-(6-((3R,4R)-4-hydroxy-3-(methoxymethyl)-3-methyl-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-805) and 3-(6-((3R,4S)-
4-hydroxy-3-(methoxymethyl)-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-807)
Figure imgf000778_0001
Step 1: Synthesis of tert-butyl 3-formyl-4-oxopiperidine-l-carboxylate
To a stirred solution of sodium methoxide (4.67 mL, 25.1 mmol) in methanol (5 mL) under a nitrogen atmosphere at 0 °C was added ethyl formate (3 04 mL 37 6 mmol) dropwise and the resulting mixture was stirred at 0 °C for 5 min. Tert-butyl 4-oxopiperidine-l -carboxylate (5 g, 25.1 mmol) was then added at 0 °C, and the mixture was allowed to warm and was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to yield crude tert-butyl 3-formyl-4-oxopiperidine-l- carboxylate (5 g, 22 mmol, 88% yield). LCMS: not ionized by LCMS; 1H-NMR (400 MHz, DMSO-d6): 59.14 (s, 1H), 3.91 (s, 2H), 3.64-3.59 (m, 1H), 3.38-3.35 (m, 2H), 2.37-2.33 (m, 1H), 1.95-1.91 (m, 2H),
1.40 (s, 9H).
Step 2: Synthesis of tert-butyl-3-(methoxymethylene)-4-oxopiperidine-l-carboxylate
A stirred mixture of tert-butyl 3-formyl-4-oxopiperidine-l-carboxylate (5 g, 22 mmol), acetone (50 mL), potassium carbonate (6.08 g, 44.0 mmol) and dimethyl sulfate (2.77 g, 22.0 mmol) was heated at 65 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was taken up in water (100 mL) and extracted with EtOAc (2 x 350 mL). The combined organic layers were dried over NazSO4 and concentrated. The residue was purified by silica gel flash chromatography, eluting with 50-60% EtOAc in n-hexane to afford tert-butyl-3-(methoxymethylene)-4-oxopiperidine-l- carboxylate (2.5 g, 4.77 mmol, 22% yield). LCMS: not ionized by LCMS; ’H-NMR (400 MHz, DMSO- d6): 5 7.33 (s, 1H), 4.16 (s, 2H), 3.91-3.81 (m, 3H), 3.59-3.57 (m, 2H), 2.35 (t, J = 6.40 Hz, 2H), 1.43- 1.37 (m, 9H).
Step 3: Synthesis of tert-butyl 3-(methoxymethyl)-4-oxopiperidine-l-carboxylate
A mixture of tert-butyl-3-(methoxymethylene)-4-oxopiperidine-l -carboxylate (2.5 g, 10.4 mmol), methanol (15 mL), and Pd/C (2.2 g, 2.07 mmol) was stirred under 1 atmosphere of hydrogen for 8 h. The reaction mixture was sparged with nitrogen and was then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to provide tert-butyl 3-(methoxymethyl)-4-oxopiperidine-l- carboxylate (2.4 g, 96% yield) LCMS: m/z MM-ES+APCI, Positive [M-Boc]+ 188.3; ’H-NMR (400 MHz, DMSO-d6): 54.03-3.97 (m, 1H), 3.88-3.82 (m, 1H), 3.59-3.55 (m, 1H), 3.47-3.40 (m, 2H), 3.23 (s,
3H), 2.74-2.72 (m, 1H), 2.42-2.34 (m, 3H), 1.43 (s, 9H).
Step 4: Synthesis of tert-butyl 3-(methoxymethyl)-3-methyl-4-oxopiperidine-l-carboxylate
To a stirred solution of tert-butyl 3-(methoxymethyl)-4-oxopiperidine-l-carboxylate (500 mg, 2.1 mmol) in THE (20 mL) under a nitrogen atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (2.466 mL, 2.466 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 10 min. The reaction mixture was cooled to -78 °C, then iodomethane (438 mg, 3.08 mmol) was added dropwise. The mixture was allowed to warm to rt and stirred at rt for 3h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with EtOAc (2 x 350 mL). The combined organic layers were dried over Na?SO4 and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 5-20% EtOAc in n-hexane to afford tert-butyl 3- (methoxymethyl)-3-methyl-4-oxopiperidine-l -carboxylate (120 mg, 0.47 mmol, 23% yield). LCMS Not ionized; ’H-NMR (400 MHz, DMSO-d6): 5 3.81-3.70 (m, 2H), 3.52-3.42 (m, 4H), 3.31 (m, 3H), 2.53- 2.49 (m, 2H), 1.52-1.47 (s, 9H), 1.13-1.06 (m, 3H).
Step 5: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl) quinolin-6-yl)-4-hydroxy-3- (methoxymethyl) -3-methylpiperidine- 1 -carboxylate
3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (200 mg, 0.40 mmol) was reacted with tertbutyl 3-(methoxymethyl)-3-methyl-4-oxopiperidine-l -carboxylate (INT-13A, 114 mg, 0.44 mmol) according to General Procedure 1, Step A, to provide tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3- yl)quinolin-6-yl)-4-hydroxy-3-(methoxymethyl)-3-methylpiperidine-l -carboxylate (60 mg, 0.051 mmol, 13% yield), following purification via silica gel flash chromatography (40-50% EtOAc in hexane as eluant). LCMS: m/z MM-ES+APCI, [M+H]+676. 1H-NMR (400 MHz, DMSO-d6): 59.07 (s, 1H), 8.51
(s, 1H), 8.00-7.89 (m, 4H), 7.30-7.44 (m, 11H), 6.67 (d, J = 8.40 Hz, 1H), 5.46-5.44 (m, 4H), 4.35-3.89
(m, 2H), 3.77-3.56 (m, 2H), 3.13-2.88 (m, 3H), 2.71 (m, 2H), 1.43 (m, 9H), 0.79 (m, 3H).
Step 6: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl) quinolin-6-yl)-4-hydroxy-3- (methoxymethyl) -3-methylpiperidine- 1 -carboxylate
Tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl) quinolin-6-yl)-4-hydroxy-3-(methoxymethyl)-3- methylpiperidine-1 -carboxylate (65 mg, 0.098 mmol, 55% yield) was synthesized according to General Procedure 1, Step B, starting from tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl) quinolin-6-yl)-4- hydroxy-3-(methoxymethyl)-3-methylpiperidine-l -carboxylate (120 mg, 0.178 mmol). The crude product was purified by trituration with MTBE/pentane. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 484.4; *H- NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.76 (s, 1H), 8.22-8.19 (m, 1H), 7.96-7.87 (m, 3H), 5.35- 5.22 (m, 1H), 4.34 (d, J = 4.40 Hz, 1H), 4.17-4.13 (m, 2H), 3.79-3.76 (m, 1H), 3.23 (s, 3H), 2.87-2.68 (m, 5H), 2.55-2.33 (m, 1H), 2.33-2.16 (m, 1H), 1.47 (s, 9H), 1.05-1.03 (m, 4H), 0.79-0.74 (m, 3H).
Step 7: Synthesis of 3-(6-(4-hydroxy-3-(methoxymethyl)-3-methylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl) quinolin-6-yl)-4-hydroxy-3- (methoxymethyl)-3-methylpiperidine-l-carboxylate (398 mg, 0.800 mmol) in dichloromethane (5 mL) and 4.0 M HC1 in dioxane (0.2 mL, 0.80 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(6-(4-hydroxy-3-(methoxymethyl)-3-methylpiperidin-4- yl) quinolin-3-yl) piperidine-2, 6-dione (50 mg, 0.078 mmol, 10% yield), which was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 398.3.
Step 8: Synthesis of 3-(6-((3R,4R)-4-hydroxy-3-(methoxymethyl)-3-methyl-l-(4-(trifluoromethyl) benzyl) piperidin-4-yl) quinolin-3-yl) piperidine-2, 6-dione (1-805, Fraction 1) and 3-(6-((3R,4S)-4- hydroxy-3-(methoxymethyl)-3-methyl-l-(4-(trifluoromethyl) benzyl) piperidin-4-yl) quinolin-3-yl) piperidine-2, 6-dione (1-807, Fraction 2) 3-(6-(4-Hydroxy-3-(methoxymethyl)-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine -2, 6-dione hydrochloride (50 mg, 0.115 mmol) was treated with 4-(trifluoromethyl)benzaldehyde (40.1 mg, 0.230 mmol) and sodium triacetoxyborohydride according to General Procedure 1, Step D. The crude product was purified by reverse phase chromatography on a C 18 column, eluting with Mobile phase A: 0.1% NH4OAC in H2O, Mobile phase B: Acetonitrile, eluted with 50% ACN in Water (0.1%HCOOH)]. And.
Two fractions were collected separately.
Fraction 1 : 3-(6-((3R,4R)-4-hydroxy-3-(methoxymethyl)-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-805) (4.5 mg, 8.0 pmol, 7% yield);
LCMS: m/z MM-ES+APCI, Postive [M+H]+ 556.4; ’H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H),
8.77 (s, 1H), 8.22 (s, 1H), 7.99-7.88 (m, 3H), 7.69 (d, J = 8.00 Hz, 2H), 7.59 (d, J = 8.00 Hz, 2H), 4.98 (s,
1H), 4.15 (d, J = 4.80 Hz, 1H), 3.97 (d, J = 8.00 Hz, 1H), 3.71 (d, J = 14.40 Hz, 1H), 3.52 (d, J = 14.40
Hz, 1H), 3.12 (s, 3H), 2.90-2.89 (m, 1H), 2.87-2.81 (m, 2H), 2.75-2.51 (m, 4H), 2.27 (d, J = 10.40 Hz,
1H), 2.17-2.13 (m, 1H), 1.75 (s, 1H), 1.61 (d, J = 13.20 Hz, 1H), 0.71 (s, 3H)
Fraction 2: 3-(6-((3R,4S)-4-hydroxy-3-(methoxymethyl)-3-methyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-807) (2.0 mg, 3.6 pmol, 3% yield);
LCMS: m/z MM-ES+APCI, Postive [M+H]+ 556.4 ’H-NMR (400 MHz, DMSO-d6): 8 10.98 (s, 1H),
8.76 (s, 1H), 8.22 (s, 1H), 7.99-7.96 (m, 2H), 7.93-7.91 (m, 1H), 7.72 (d, J = 8.00 Hz, 2H), 7.60 (d, J =
8.00 Hz, 2H), 5.10 (s, 1H), 4.28-4.12 (m, 2H), 3.70 (d, J = 14.00 Hz, 1H), 3.54-3.52 (m, 2H), 3.07 (s, 3H),
2.86 (d. J = 9.20 Hz, 2H), 2.75-2.74 (m, 2H), 2.68-2.49 (m, 4H), 2.17-2.14 (m, 1H), 1.52 (d, J = 13.20 Hz,
1H), 1.00 (s, 3H).
Example 240: Synthesis of 3-(6-(3-cyclopropyl-4-hydroxy-l-(4-(trifluoromethyl) benzyl) piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-208)
Figure imgf000781_0001
Step 1: Synthesis of 4- (benzyloxy) -3-bromopyridine
To a stirred solution of 3-bromopyridin-4-ol (5.0 g, 28.7 mmol) in DMF (40 mL) at 0 °C was added NaH (1.72 g, 43.1 mmol), and the reaction mixture was stirred for 15 min at 0 °C. Benzyl bromide (5.90 g, 34.5 mmol) was added and the rection mixture was allowed to warm to rt and stirred. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 filtered and concentrated under reduced pressure. The crude residue was triturated with hexane, and the resulting solid was collected via filtration and dried to afford 4-(benzyloxy)-3- bromopyridine (7.5 g, 19 mmol, 66% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 265; 'H-NMR (400 MHz, DMSO-d6): 5 8.44 (d, J = 2.40 Hz, 1H), 7.86 (d, J = 5.20 Hz, 1H), 7.41-7.35 (m, 5H), 6.25 (s, lH), 5.13 (s, 2H).
Step 2: Synthesis of 4- (benzyloxy) -3-cyclopropylpyridine
A stirred mixture of cyclopropylboronic acid (244 mg, 2.84 mmol). 4-(benzyloxy)-3- bromopyridine (500 mg, 1.893 mmol), dioxane (5 mL), CS2CO3 (1850 mg, 5.68 mmol), and water (0.75 mL) was sparged with nitrogen for 5 minutes. PdC12(dppf)-CH2C12 adduct (155 mg, 0.189 mmol) was added and the reaction mixture was sparged with nitrogen for another 5 minutes. The reaction mixture was stirred at 100°C for 16 h, then the cooled mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with DCM/methanol to afford 4- (benzyloxy)-3-cyclopropylpyridine (0.38 g, 1.5 mmol, 79% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 226.3; ’H-NMR (400 MHz, DMSO-d6): 57.42-7.40 (m, 3H), 7.39 (d, J = 4.00 Hz, 1H), 7.27 (d, J = 2.40 Hz, 2H), 7.01 (s, 1H), 6.39 (d, J = 7.60 Hz, 1H), 4.93 (s, 2H), 2.05-2.02 (m, 1H), 0.92 (q, J = 1.60 Hz, 2H), 0.51 (q, J = 4.00 Hz, 2H).
Step 3: Synthesis of 4-(benzyloxy)-3-cyclopropyl-l-(4-(trifluoromethyl)benzyl)pyridin-l-ium bromide
A solution of 4-(benzyloxy)-3-cyclopropylpyridine (3.8 g, 16.87 mmol) and 4-
( trifluoromethyl) benzyl bromide (4.03 g, 16.87 mmol) in acetonitrile (40 mL) was stirred at 100 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the crude residue was triturated with acetone, collected via filtration, and dried to afford 4-(benzyloxy)-3-cyclopropyl-l-(4- (trifluoromethyl)benzyl)pyridin-l-ium bromide (5.2g, 9.8 mmol, 58% yield. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 384.5; ’H-NMR (400 MHz, DMSO-d6): 5 8.96-8.93 (m, 1H), 8.75 (s, 1H), 7.84 (d, J = 8.40 Hz, 2H), 7.77-7.67 (m, 3H), 7.51 (d, J = 2.00 Hz, 2H), 7.49-7.40 (m, 3H), 5.64 (m, 4H), 2.13-2.10 (m, 3H), 0.93 (q, J = 2.00 Hz, 2H).
Step 4: Synthesis of 4-(benzyloxy)-5-cyclopropyl-l-(4-(trifluoromethyl) benzyl) -1,2, 3,6- tetrahydropyridine To a stirred solution of 4-(benzyloxy)-3-cyclopropyl-l-(4-(trifluoromethyl)benzyl)-pyridin-l-ium bromide (5.0g, 10.8 mmol) in MeOH (40 mL) at 0 °C was added NaBH4 (2.04 g, 53.8 mmol), and the reaction mixture was stirred for 2 h at rt. Ice cold water was added, and the mixture was extracted with
EtOAc (4 x 50 mL). The combined organic layers were dried over anhydrous NaiSCL. filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 0-40% EtOAc in hexane to afford 4-(benzyloxy)-5-cyclopropyl-l-(4-(trifluoromethyl) benzyl)- 1,2, 3, 6-tetrahydropyridine (2.6 g, 5.33 mmol, 49% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 388.8; ’H-NMR (400 MHz, DMSO-d6): 57.64 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.00 Hz, 2H), 7.33-7.27 (m, 5H), 4.91 (s, 2H), 3.58 (s, 2H), 2.71 (s, 2H), 2.63 (t, J = 5.60 Hz, 2H), 2.33-2.30 (m, 2H), 1.91-1.87 (m, 1H), 0.59 (q, J = 2.40 Hz, 2H), 0.46 (q, J = 1.20 Hz, 2H).
Step 5: Synthesis of l-benzyl-3-cyclopropylpiperidin-4-one
To a stirred solution of 4-(benzyloxy)-5-cyclopropyl-l-(4-(trifluoromethyl) benzyl)-!, 2,3,6- tetrahydropyridine (500 mg, 1.07 mmol) in DCM (5 mL) at 0 °C was added TEA (0.33 mL, 4.3 mmol), then the reaction mixture was allowed to warm to rt and was stirred for 3 h. The mixture was concentrated under reduced pressure, then was taken up in EtOAc (20 mL) and washed with saturated NaHCO3 (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-20% ethyl acetate in hexane to afford l-benzyl-3-cyclopropylpiperidin-4-one (153 mg, 0.515 mmol, 48% yield). LCMS: m/z MM-ES+APCI, Positive [M+H] + 230.6; ’H-NMR (400 MHz, DMSO-d6): 57.35-7.29 (m, 5H), 3.66 (d, J = 13.20 Hz, 1H), 3.57 (d, J = 13.20 Hz, 1H), 2.93-2.90 (m, 2H), 2.51-2.45 (m, 4H), 1.78 (t, J = 5.20 Hz, 1H), 0.90 (t, J = 4.40 Hz, 1H), 0.48 (t, J = 4.40 Hz, 1H), 0.34 (t, J = 3.60 Hz, 1H), 0.10-0.07 (m, 2H). (Under the acidic conditions of the reaction, the benzyl and 4- trifluoromethylbenzyl groups were scrambled, and the isolated product was l-benzyl-3- cyclopropylpiperidin-4-one.)
Step 6: Synthesis of l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl) quinolin-6-yl)-3- cyclopropylpiperidin-4-ol l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-cyclopropylpiperidin-4-ol (250 mg, 0.324 mmol, 32% yield) was synthesized according to General Procedure 1, Step A starting from 3- (2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 500 mg, 1.00 mmol) and 3 -cyclopropyl- 1- (4-(trifluoromethyl) benzyl) piperidin-4-one (359 mg, 1.21 mmol). The crude product was purified by silica gel flash column chromatography, eluting with 0-50% EtOAc in hexane to afford the title compound. LCMS m/z MM-ES+APCI, Positive [M+H]+ 649.4; ’H-NMR (400 MHz, DMSO-d6): 5 9.06 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.98 (s, 2H), 7.48 (s, IH), 7.40-7.33 (m, 15H), 6.66 (d, J = 8.00 Hz, IH), 5.43 (s, 2H), 5.47 (s, 2H), 5.10 (s, 1H), 4.50 (s, 1H), 3.72 (m, 2H), 3.14 (m, 2H), 1.92 (s, 2H), 0.70- 0.68 (m, 2H), 0.16 (s, 1H), -0.27 (s, 2H), -0.88 (s, 2H).
Step 7: Synthesis of tert-butyl-3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate
To a stirred solution of l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3- cyclopropylpiperidin-4-ol (220 mg, 0.340 mmol) in DMF (4 mL) was added di-tert-butyl dicarbonate (148 mg, 0.68 mmol) and 10% Pd/C (150 mg, 0.340 mmol) at rt, and the reaction mixture was stirred under 1 atmosphere of hydrogen for 10 h. The reaction mixture was filtered through Celite, rinsing with DMF followed by EtOAc. The combined filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with EtOAc/Hexane to provide tert-butyl 3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxypiperidine- 1 -carboxylate (75 mg, 0.16 mmol, 39% yield), m/z MM-ES+APCI, Positive [M+H]+ 480.5; 1H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.75 (d, J = 2.00 Hz, 1H), 8.18 (d, J = 2.00 Hz, 1H), 8.12 (s, 1H), 7.94 (m, 2H), 7.83 (d, J =
8.80 Hz, 1H), 5.31 (s, 1H), 4.13 (d, J = 4.80 Hz, 1H), 3.89-3.86 (m, 2H), 3.34-3.30 (m, 1H), 2.90 (s, 2H),
2.77-2.68 (m, 3H), 2.17-2.15 (m, 1H), 1.44 (s, 9H), 1.29-1.27 (m, 1H), 0.88-0.84 (m, IH), 0.23-0.19 (m, 2H), -0.22-0.30 (m, 2H).
Step 8: Synthesis of 3-(6-(3-cyclopropyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
A solution of tert-butyl 3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (75 mg, 0.16 mmol) in DCM (5 mL) and 4M HC1 in dioxane (0.3 mL, 1.20 mmol) was stirred at 0 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was washed with pentane to afford 3-(6-(3-cyclopropyl-4-hydroxypiperidin-4-yl) quinolin-3-yl) piperidine-2, 6-dione (65 mg, 0.14 mmol, 90% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 380.3; ’H-NMR (400 MHz, DMSO-d6): 5 11.04 (s, IH), 8.98 (s, IH), 8.93 (s, IH), 8.56 (s, IH),
8.15-8.09 (m, 2H), 7.88 (d, J = 8.80 Hz, 1H), 4.27 (d, J = 4.40 Hz, 1H), 3.29-3.22 (m, 4H), 2.77-2.70 (m, 1H), 2.68-2.67 (m, 1H), 2.33 (t, J = 2.00 Hz, 1H), 1.83-1.78 (m, 1H), 1.63-1.52 (m, 3H), 0.73-0.64 (m, 1H), 0.28-0.22 (m, 1H), -0.12-0.25 (m, 2H), -8.82-0.86 (m, 1H).
Step 9: Synthesis of 3-(6-(3-cyclopropyl-4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-208)
3-(6-(3-cyclopropyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (60 mg, 0.14 mmol) was treated with 4-(trifluoromethyl)benzaldehyde (38 mg, 0.22 mmol) and sodium triacetoxyborohydride according to General Procedure 1 , Step 4. The crude product was triturated with MTBE/pentane, then the resulting crude solid was further purified by reverse phase chromatography using a C-18 column, eluting with 0.1% HC1 in H2O: Acetonitrile as eluant to afford 3-(6-(3-cyclopropyl- 4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-208, 15 mg, 0.026 mmol, 18% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 538.4; ’H-NMR (400 MHz, DMSO-d6): 5 11.07 (s, 1H), 11.02 (s, 1H), 8.94 (s, 1H), 8.49 (s, 1H), 8.10 (d, J = 8.40 Hz, 2H), 7.97-7.89
(m, 4H), 7.85 (d, J = 8.80 Hz, 1H), 5.80 (s, 1H), 4.62 (d, J = 9.20 Hz, 1H), 4.52 (d, J = 5.60 Hz, 1H), 4.23
(d, J = 4.40 Hz, 1H), 3.39-3.27 (m, 4H), 2.79-2.76 (m, 1H), 2.68-2.66 (m, 2H), 2.46 (s, 1H), 2.18 (d, J =
3.20 Hz, 1H), 1.85-1.82 (m, 2H), 0.69 (d, J = 3.60 Hz, 1H), 0.25 (d, J = 5.60 Hz, 1H), -0.12-0.28 (m,
2H), -8.82-0.86 (m, 1H).
Example 241: Synthesis of 3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methyl-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-198)
Figure imgf000785_0001
Step 1: Synthesis of l-(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-l,3-dicarboxylate
To a stirred mixture of 1 -(tert-butyl) 3-methyl 4-oxopiperidine-l,3-dicarboxylate (5 g, 19.43 mmol) and potassium carbonate (4.12 g, 68.0 mmol) in acetone (50 mL) at rt was added iodomethane
(4.97 g, 35.0 mmol). The reaction mixture was stirred at 40 °C for 12 h. The cooled reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in EtOAc, and the organic layer was washed with water followed by brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by trituration with n-pentane to yield 1 -(tert-butyl) 3-methyl 3 -me thyl-4-oxopiperidine- 1,3 -dicarboxylate. (7.5 g, 20.4 mmol, 53% yield). LCMS: MM-ES+APCI, Positive [M-56+H]+ 216.06; ’H-NMR (400 MHz, DMSO-d6): 54.28 (dd, J = 2.00, 13.60 Hz, 1H), 3.95 (d, J = 8.00 Hz, 1H), 3.65 (s, 3H), 3.35-3.22 (m,
2H), 2.61-2.58 (m, 1H), 2.48-2.41 (m, 1H), 1.42 (s, 9H), 1.19 (s, 3H).
Step 2: Synthesis of tert-butyl 4-hydroxy-3-(hydroxymethyl)-3-methylpiperidine-l-carboxylate
To a stirred solution of 1 -(tert-butyl) 3-methyl 3-methyl-4-oxopiperidine-l,3-dicarboxylate (4 g, 14.7 mmol) in THF (60 mL) and methanol (15 mL) at 0 °C was added sodium borohydride (1.39 g, 36.9 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure, then crude residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 20% EtOAc in hexane to afford tert-butyl 4-hydroxy-3-(hydroxymethyl)-3-methylpiperidine-l- carboxylate (2.5 g, 9.3 mmol, 63% yield). LCMS: m/z MM-ES+APCI, Negative [M-H-BOC] 144.1; ’H- NMR (400 MHz, DMSO-d6): 5 4.49-4.44 (m, 2H), 3.83-3.77 (m, 1H), 3.56-3.46 (m, 2H), 3.31-3.22 (m, 2H), 2.76-2.63 (m, 2H), 1.56-1.51 (m, 1H), 1.42 (m, 1H), 1.38 (s, 9H), 0.70 (s, 3H).
Step 3: Synthesis of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-3- methylpiperidine- 1-carboxylate
To a stirred solution of tert-butyl 4-hydroxy-3-(hydroxymethyl)-3-methylpiperidine-l- carboxylate (0.5 g, 2.038 mmol), triethylamine (0.390 mL, 2.85 mmol) and DMAP (0.025 g, 0.204 mmol) in THE at 0 °C was added TBDMS-C1 (0.40 g, 2.65 mmol). The reaction mixture was allowed to warm to rt and was stirred for 16 h. The mixture was concentrated under reduced pressure. The crude residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous NazSCh, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with EtOAc in hexane to afford tert-butyl 3-(((tert- butyldimethylsilyl)-oxy)methyl)-4-hydroxy-3-methylpiperidine-l-carboxylate (0.28 g, 0.58 mmol, 28% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 360.2; ’H-NMR (400 MHz, DMSO-d6): 54.30 (d, J = 4.80 Hz, 1H), 3.82 (d, J = 13.60 Hz, 1H), 3.64-3.61 (m, 1H), 3.50-3.42 (m, 3H), 2.82-2.78 (m, 1H), 2.69 (d, J = 10.00 Hz, 1H), 1.60-1.44 (m, 2H), 1.42 (s, 9H), 0.91 (s, 9H), 0.78 (s, 3H), 0.05 (s, 6H).
Step 4: Synthesis of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-4-oxopiperidine-l- carboxylate
To a stirred solution of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-3- methylpiperidine- 1-carboxylate (1.7 g, 4.73 mmol) in dichloromethane (30 mL) at 0 °C was added Dess- Martin periodinane (3.01 g, 7.09 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was poured into ice water and extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 0-5% EtOAc in hexane to afford tert-butyl 3-(((tert- butyldimethylsilyl)oxy)methyl)-3-methyl-4-oxopiperidine-l-carboxylate (1 g, 2.8 mmol, 59% yield). LCMS: MM-ES+APCI, Positive [M-BOC+H]+ 258.1; ’H-NMR (400 MHz, CDCh): 5 3.86-3.53 (m, 6H), 2.49 (br s, 2H), 1.51 (s, 9H), 1.09 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H).
Step 5: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(((tert- butyldimethylsilyl)oxy)methyl) -4-hydroxy-3-methylpiperidine- 1 -carboxylate Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(((tert-butyldimethyl- silyl)oxy)methyl)-4-hydroxy-3-methylpiperidine-l -carboxylate (350 mg, 0.45 mmol, 45% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyl-oxy)pyridin-3- yl)-6-bromoquinoline (INT-13A, 500 mg, 1.00 mmol) and tert-butyl 3-(((tert- butyldimethylsilyl)oxy)methyl)-3-methyl-4-oxopiperidine-l-carboxylate (431 mg, 1.21 mmol). The crude product was purified by silica gel flash chromatography eluting with 0-50% EtOAc in hexane to afford the title compound. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 777.5; *H NMR (400 MHz, DMSO-T,): <59.07 (d, J = 4.0 Hz, 1H), 8.49 (s, 1H), 8.03-7.87 (m, 4H), 7.48-7.29 (m, 11H), 6.66 (d, J = 8.0 Hz, 1H), 5.47-5.20 (m, 5H), 4.10-3.90 (m, 3H), 3.15-2.60 (m, 4H), 1.42 (s, 9H), 0.82 (s, 9H), 0.74 (s, 3H), -0.02 (s, 3H), -0.20 (s, 3H).
Step 6: Synthesis of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3-(2,6-dioxopiperidin-3- yl)quinolin-6-yl)-4-hydroxy-3-methylpiperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(((tert-butyldimethyl- silyl)oxy)methyl)-4-hydroxy-3-methylpiperidine-l -carboxylate (500 mg, 0.644 mmol) was treated according to General Procedure 1, Step B. The crude product was purified by silica gel flash chromatography, eluting with 10% IP A in DCM to afford tert-butyl 3-(((tert- butyldimethylsilyl)oxy)methyl)-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3- methylpiperidine- 1 -carboxylate (180 mg, 0.28 mmol, 44% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 598.5; >H NMR (400 MHz, DMS(M): 3 10.97 (s, 1H), 8.77 (s, 1H), 8.20 (d, J= 8.0 Hz, 2H), 8.00-7.86 (m, 1H), 5.76 (bs, 1H), 4.16-4.12 (m, 1H), 3.89-3.85 (m, 4H), 2.77-2.71 (m, 3H), 2.68-2.59 (m, 2H), 2.57-2.53 (m, 2H), 2.48-2.43 (m, 1H), 2.20-2.16 (m, 1H), 1.47 (s, 9H), 1.41 (s, 3H), 0.80 (s, 9H), - 0.02 (s, 3H), -0.18 (s, 3H).
Step 7: Synthesis of 3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione
A solution of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3-(2,6-dioxopiperidin-3- yl)quinolin-6-yl)-4-hydroxy-3-methylpiperidine-l -carboxylate (160 mg, 0.27 mmol) in DCM (5 mL) and HC1 (4 M in dioxane, 0.34 mL, 1.34 mmol) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was washed with MTBE/pentane and dried to afford 3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine- 2,6-dione (120 mg, 0.27 mmol, 100% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 384.0; *H NMR (400 MHz, DMSO-de): <5 11.00 (s, 1H), 8.87 (bs, 1H), 8.84 (s, 1H), 8.39 (s, 1H), 8.07-8.02 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H), 5.99 (bs, 1H), 4.21-4.17 (m, 2H), 3.68-3.65 (s, 1H), 3.57-3.19 (m, 1H), 3.09-3.00 (m, 1H), 2.98-2.74 (m, 1H), 2.67-2.60 (m, 2H), 2.33-2.18 (m, 2H), 1.91-1.60 (m, 2H), 1.35-1.24 (m, 2H), 0.93 (s, 3H). Step 8: Synthesis of 3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-198)
3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (70 mg, 0.167 mmol) was treated with 4-(trifluoromethyl) benzaldehyde (44 mg, 0.25 mmol) and sodium triacetoxyborohydride according to General Procedure 1, Step D. The crude product was purified by reverse phase chromatography using a C-18 column, eluting with 0.1% HC1 in H2O and acetonitrile to afford 3-(6-(4-hydroxy-3-(hydroxymethyl)-3-methyl- 1 -(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-198, 20 mg, 0.034 mmol, 21% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 542.7; *H NMR (400 MHz, DMSO-t/e): S 11.01 (s, 1H), 8.90 (bs, 1H), 8.47
(s, 1H), 8.06 (d, J= 8.0 Hz, 1H), 8.01-7.89 (m, 6H), 5.99 (bs, 1H), 4.60-4.56 (m, 2H), 4.22-4.17 (m, 1H),
3.68-3.43 (m, 3H), 3.08-2.95 (m, 3H), 2.79-2.68 (m, 2H), 2.67-2.55 (m, 1H), 2.43-2.33 (m, 2H), 2.18-
2.16 (m, 2H), 0.97 (s, 3H).
Example 242: Synthesis of 3-(6-(l,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3- yl)piperidine-2, 6-dione (1-329) o
BnO. N .OBn
F ey N BnO.
Br Boc n-Buli, -78 °C, 1 h rt, 1 h N N
INT-6B Step-1
O,
4M HCI in Dioxane N
DCM, 0 °C-rt 2 h
Step-3 N N
Step-4 1-329
Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4- hydroxypiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4-hydroxy- piperidine- 1-carboxylate (250 mg, 0.372 mmol, 55% yield) was synthesized according to General Procedure 1, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoroquinoline (INT- 6B, 0.35 g, 0.679 mmol) and tert-butyl 3-ethyl-4-oxopiperidine- 1-carboxylate (28a, 0.232 g, 1.019 mmol). The crude product was purified by silica gel flash chromatography, eluting with 15-20% EtOAc in hexane to afford the title compound. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 664.5; *H NMR (400 MHz, DMSO-rT): <59.13 (s, 1H), 8.61 (d, / = 4.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 8.02 (d, J= 8.0 Hz, 1H), 7.50-7.30 (m, 10H), 6.67 (d, J= 8.0 Hz, 1H), 5.49-5.45 (m, 5H), 4.00-3.96 (m, 2H), 2.49-2.33 (m, 2H), 1.99-1.94 (m, 1H), 1.46 (s, 9H), 1.26-1.18 (m, 2H), 1.07-0.83 (m, 2H), 0.67 (t, J= 8.0 Hz, 3H). Step 2: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4- hydroxypiperidine- 1-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4-hydroxy- piperidine- 1-carboxylate (250 mg, 0.377 mmol) was treated according to General Procedure 1, Step B. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 5 to 100% acetonitrile to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4- hydroxypiperidine- 1-carboxylate (140 mg, 0.28 mmol, 75% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 486.2; *H NMR (400 MHz, DMSO-T,): 3 10.98 (s, IH), 8.85 (d, 7 = 4.0 Hz, IH), 8.33 (d, 7 = 4.0
Hz, IH), 8.03 (d, 7= 8.0 Hz, 1H), 7.89 (d, 7 = 8.0 Hz, 1H), 5.49 (s, IH), 4.24-4.20 (m, 1H), 3.90-3.87 (m,
2H), 2.77-2.72 (m, 2H), 2.63-2.60 (m, 2H), 2.59-2.55 (m, IH), 2.27-2.22 (m, IH), 2.14-2.11 (m, IH),
2.08-2.05 (m, 2H), 1.69-1.65 (m, IH), 1.45 (m, 9H), 0.95-0.93 (m, IH), 0.66 (t, 7= 8.0 Hz, 3H).
Step 3: Synthesis of 3-(6-(3-ethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoroquinolin-6-yl)-3-ethyl-4-hydroxy- piperidine-1 -carboxylate (120 mg, 0.25 mmol) in DCM (5 mL) and HC1 (4M in 1,4-dioxane, 0.7 ml, 2.80 mmol) was stirred at 0 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was washed with pentane to obtain 3-(6-(3-ethyl-4-hydroxypiperidin-4-yl)-5- fluoroquinolin-3-yl)piperidine-2, 6-dione (100 mg, 0.23 mmol, 93% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 386.2; >H NMR (400 MHz, DMSO-r/6): 3 11.00 (s, 1H), 8.92 (s, 1H), 8.43-8.40 (m, 2H), 8.05 (d, 7 = 8.0 Hz, IH), 7.97-7.94 (m, 2H), 6.00 (bs, IH), 4.29-4.24 (m, 1H), 3.57-3.25 (m, 2H), 2.78- 2.61 (m, 2H), 2.56-2.53 (m, 1H), 2.45-2.16 (m, IH), 1.99-1.85 (m, 1H), 1.28-1.25 (m, 3H), 1.10-1.08 (m, 2H), 0.66 (t, 7 = 8.0 Hz, 3H).
Step 4: Synthesis of 3-(6-(l,3-diethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2,6- dione (1-329)
3-(6-(3-ethyl-4-hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione (120 mg, 0.284 mmol) was treated with acetaldehyde (12.5 mg, 0.284 mmol) and sodium triacetoxyborohydride (151 mg, 0.711 mmol) according to General Procedure 1, Step D. The crude product was purified by prep-HPLC [Method info: (Column: X Select C18 (250 xl9 mm), 5 pm, eluting with Mobile phase A: 0.05%HCl in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min] to afford 3-(6-( 1 ,3-diethyl-4- hydroxypiperidin-4-yl)-5-fluoroquinolin-3-yl)piperidine-2, 6-dione (1-329) (30 mg, 0.066 mmol, 23% yield) solid. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 414.4; >H NMR (400 MHz, DMSO-t/e): 3 11.04 (s, 1H), 9.96 (bs, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 6.00 (bs, 1H), 4.27-4.23 (m, 1H), 3.49-3.20 (m, 4H), 3.05-3.02 (m, 1H), 2.78-2.56 (m, 4H), 2.33-2.08 (m, 2H), 1.95-1.91 (m, 1H), 1.31 (t, 7 = 8.0 Hz, 3H), 1.13-1.11 (m, 2H), 0.66 (t, 7= 8.0 Hz, 3H). Example 243: Synthesis of 3-(6-(4-hydroxy-3-(2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-212)
Figure imgf000790_0001
Step 1: Synthesis of 3-(2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one
To a stirred solution of l-(4-(trifluoromethyl)benzyl)piperidin-4-one (5 g, 19 mmol) in toluene (100 mL) under nitrogen atmosphere at 0°C was added potassium tert-butoxide (4.32 g, 23.3 mmol). After 40 min, at the same temperature, l,l,l-trifluoro-2-iodoe thane (4.90 g, 23.3 mmol) was added. The reaction mixture was stirred at 50°C for 16 h. The cooled reaction mixture was diluted with saturated aqueous NH4CI solution (100 mL) and then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SC)4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-10% EtOAc in hexane to afford 3- (2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)benzyl)piperidin-4-one (1.3 g, 3.7 mmol, 19% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 340.2; ’H-NMR (400 MHz, DMSO-d6): 57.72 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 3.77 (AB, J = 13.60 Hz, 2H), 3.18-3.13 (m, 1H), 3.05-3.01 (m, 1H), 2.94- 2.91 (m, 1H), 2.72-2.80 (m, 2H), 2.50-2.47 (m, 1H), 2.48-2.30 (m, 2H), 2.28-2.16 (m, 1H).
Step 2: Synthesis of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2,2-trifluoroethyl)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol
4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2,2-trifhroroethyl)-l-(4- (trifluoromethyl)benzyl)piperidin-4-ol (210 mg, 0.211 mmol, 42% yield) was synthesized according to General Procedure 2, Step A starting from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (250 mg, 0.503 mmol) and 3-(2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)-benzyl)piperidin-4-one (205 mg, 0.603 mmol). The crude product was purified by silica gel flash chromatography, eluting with 0-60% EtOAc in hexane to afford the title compound. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 759.2; *H- NMR (400 MHz, DMSO-d6): 5 9.08 (s, 1H), 8.49 (d, J = 1.60 Hz, 1H), 8.10 (s, 1H), 7.93-7.99 (m, 4H), 7.74-7.70 (m, 2H), 7.64-7.59 (m, 2H), 7.32-7.42 (m, 9H), 6.67 (d, J = 8.00 Hz, 1H), 5.47 (s, 2H), 5.44 (s, 2H), 3.71 (AB, J = 13.60 Hz, 2H), 2.89-2.75 (m, 2H), 2.68-2.59 (m, 2H), 2.51-2.50 (m, 1H), 2.34-2.28
(m, 1H), 2.25-2.07 (m, 1H), 1.77-1.68 (m, 2H).
Step 3: Synthesis of 3-(6-(4-hydroxy-3-(2,2,2-trifluoroethyl)-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin- 3- yl)piperidine-2, 6-dione (1-212)
4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-(2,2,2-trifluoroethyl)-l-(4-
( trifluoromethyl) benzyl)piperidin-4-ol (100 mg, 0.132 mmol) was treated according to General Procedure 2, Step B. The crude product was purified by Preparative-HPLC [Method info: Column: X Select (150 mm x 19 mm) Sum, eluting with Mobile phase A: 0.1%AA H2O, Mobile phase B: ACN, Flow rate: 15 mL/min] to afford 3-(6-(4-hydroxy-3-(2,2,2-trifluoroethyl)- 1 -(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)piperidine-2, 6-dione (1-212, 12.9 mg, 0.022 mmol, 17% yield). LCMS: m/z MM-
ES+APCI, Positive [M+H]+ 580.1; ’H-NMR (400 MHz, DMSO-d6): 5 11.03 (s, 1H), 8.78 (d, J = 2.00 Hz,
1H), 8.22 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.80 Hz, 1H), 7.88 (d, J = 1.60 Hz, 1H), 7.86 (d, J = 1.60 Hz,
1H), 7.73 (d, J = 8.40 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 5.40 (s, 1H), 4.15 (dd, J = 4.80, 12.40 Hz, 1H),
3.71 (q, J = 14.00 Hz, 2H), 2.88-2.79 (m, 1H), 2.78-2.74 (m, 1H), 2.68-2.60 (m, 2H), 2.46-2.39 (m, 3H), 2.34-2.16 (m, 2H), 2.15-2.13 (m, 1H), 1.91 (s, 1H), 1.76-1.67 (m, 2H).
Example 244: Synthesis of 3-(6-(4-hydroxy-3,3-bis(methoxymethyl)-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-184)
Figure imgf000791_0001
Step 1: Synthesis of tert-butyl 3,3-bis(hydroxymethyl)-4-oxopiperidine-l-carboxylate
A stirred mixture of tert-butyl 4-oxopiperidine-l -carboxylate (10.0 g, 50.2 mmol), water (30 mL), potassium carbonate (0.104 g, 0.753 mmol) and formaldehyde (7.10 mL, 95 mmol) heated at 40 °C for 16 h. Water was added to the cooled reaction mixture, and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 0-50% EtOAc in n-hexane to afford tert-butyl 3,3-bis(hydroxymethyl)-4-oxopiperidine-l-carboxylate (2.30 g, 7.46 mmol, 15% yield). LCMS: m/z MM-ES+APCI, Positive [M-Boc]+ 160.1. 1H-NMR (400 MHz, DMSO-d6): 56.62 (t, J =
5.60 Hz, 2H), 3.61-3.52 (m, 8H), 2.37 (t, J = 6.40 Hz, 2H), 1.41 (s, 9H).
Step 2: Synthesis of tert-butyl 3,3-bis(methoxymethyl)-4-oxopiperidine-l-carboxylate
To a stirred solution of tert-butyl 3,3-bis(hydroxymethyl)-4-oxopiperidine-l-carboxylate (4.5 g, 17.35 mmol) and Nl,Nl,N8,N8-tetramethylnaphthalene-l,8-diamine (22.32 g, 104 mmol) in chloroform (80 mL) at rt was added trimethyl oxonium tetrafluoroborate (12.8 g, 87 mmol), and the resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered through a Celite pad and washed with dichloromethane (100 mL). The combined filtrate was washed with IN aqueous hydrochloric acid (2 x 100 mL) followed by saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was dried over anhydrous Na2SC>4 filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-10% EtOAc in n-hexane to afford tert-butyl 3,3-bis(methoxymethyl)-4-oxopiperidine-l-carboxylate (2.5 g, 6.63 mmol, 38% yield). LCMS: m/z MM- ES+APCI, Positive [M-Boc]+ 188.0; ’H-NMR (400 MHz, DMSO-d6): 53.63-3.58 (m, 4H), 3.43 (s, 4H), 3.22 (s, 6H), 2.41 (t, J = 6.40 Hz, 2H), 1.44 (s, 9H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- bis(methoxymethyl)piperidine-l-carboxylate n-Butyllithium (1.6 M in hexane) (0.75 mL, 1.2 mmol) was added dropwise at -78 °C to a stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 500 mg, 1.005 mmol) and tert-butyl 3,3-bis(methoxymethyl)-4-oxopiperidine-l-carboxylate (433 mg, 1.508 mmol) in THE (5 mL) under a nitrogen atmosphere. The reaction mixture was allowed to warm to rt and was stirred for 3 h. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 0-25% EtOAc in n- hexane to afford tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- bis(methoxymethyl)piperidine-l -carboxylate (180 mg, 0.253 mmol, 25% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ 706.5; ’H-NMR (400 MHz, DMSO-d6): 59.06 (s, 1H), 8.47 (s, 1H), 7.97-
7.85 (m, 4H), 7.30-7.43 (m, 10H), 6.67 (d, J = 8.00 Hz, 1H), 5.44 (d, J = 12.00 Hz, 5H), 4.06-4.01 (m,
2H), 3.33-3.22 (m, 5H), 3.07 (s, 6H), 1.82-1.73 (m, 1H), 1.49-1.38 (m, 11H).
Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- bis(methoxymethyl)piperidine-l-carboxylate
Tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- bis(methoxymethyl)piperidine-l -carboxylate (160 mg, 0.227 mmol) was treated according to General Procedure 1, Step B. The crude product was purified by trituration with DCM/hexane, and the resulting solid was collected by filtration and dried to afford tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6- yl)-4-hydroxy-3,3-bis(methoxymethyl)piperidine-l-carboxylate (105 mg, 0.17 mmol, 75% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 528.4; 'H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.76 (s,
1H), 8.20 (s, 1H), 7.94-7.86 (m, 3H), 5.40 (s, 1H), 4.17-4.02 (m, 3H), 3.23-3.08 (m, 12H), 2.82-2.79 (m,
2H), 2.77-2.63 (m, 2H), 2.59-2.50 (m, 1H), 2.05-2.01 (m, 1H), 1.44 (s, 9H).
Step 5: Synthesis of 3-(6-(4-hydroxy-3,3-bis(methoxymethyl)piperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione
A solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxy-3,3- bis(methoxymethyl)piperidine-l -carboxylate (100 mg, 0.190 mmol) in dichloromethane (5 mL) and 4M HC1 in dioxane (0.47 mL, 1.9 mmol) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to afford 3-(6-(4-hydroxy-3,3-bis(methoxymethyl)-piperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (82 mg, 0.16 mmol, 84% yield), which was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 428.4; 'H-NMR (400 MHz, DMSO-d6): 5 11.00 (s, 1H), 9.06-9.02 (m, 1H), 8.87 (s, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.80 Hz, 1H), 8.00 (s, 1H), 7.87 (d, J = 7.60 Hz, 1H), 7.55-7.42 (m, 1H), 5.84 (s, 1H), 4.21-4.16 (m, 1H), 3.57-3.54 (m, 2H), 3.39-3.09 (m, 12H), 2.99-2.95 (m, 1H), 2.68-2.66 (m, 2H), 2.20-2.13 (m, 1H), 1.81-1.76 (m, 1H).
Step 6: Synthesis of 3-(6-(4-hydroxy-3,3-bis(methoxymethyl)-l-(4-
(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-184)
3-(6-(4-hydroxy-3,3-bis(methoxymethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (70 mg, 0.151 mmol) was treated with 4-(trifhroromethyl)benzaldehyde (0.027 mL, 0.196 mmol) and sodium triacetoxyborohydride according to General Procedure 1, Step D. The crude product was purified by preparative HPLC [Method: X Select Cl 8 (250 x 19 mm), 5 pm; eluting with Mobile phase A: 0.1% FA in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min] to afford 3-(6-(4-hydroxy-3,3- bis(methoxymethyl)-l-(4-(trifluoromethyl)benzyl)-piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (I- 184, 28.5 mg, 0.048 mmol, 32% yield. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 587.0; 'H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.75 (s, 1H), 8.20 (s, 1H), 7.94-7.85 (m, 3H), 7.71 (d, J = 8.00 Hz, 2H), 7.59 (d, J = 8.00 Hz, 2H), 5.27 (s, 1H), 4.14 (d, J = 4.80 Hz, 1H), 3.78-3.69 (m, 2H), 3.52 (d, J =
14.00 Hz, 1H), 3.38-3.33 (m, 2H), 3.16-3.13 (m, 2H), 3.05 (s, 6H), 2.90-2.75 (m, 1H), 2.67-2.62 (m, 2H),
2.51-2.50 (m, 3H), 2.43 (d, J = 3.60 Hz, 2H), 2.07-2.02 (m, 1H), 1.53 (d, J = 13.60 Hz, 1H).
Example 245: Synthesis of l-(5-fhioro-6-(5-hydroxy-2-((l-methyl-lH-pyrazol-5-yl)methyl)-9-oxa-2- azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-788)
Figure imgf000794_0001
Step 1: Synthesis of 6-chloro-5-fluoro-2-methylquinolin-3-amine l-chloropropan-2-one (2.78 mL, 34.6 mmol) was added to a stirred solution of pyridine (2.80 mL,
34.6 mmol) in ethanol (20 mL) under continuous nitrogen sparging at rt, then the mixture heated at 80°C for 2 h. The reaction mixture was cooled to rt and subjected to three cycles of vacuum followed by nitrogen backfill. Pyridine (3.49 mL, 43.2 mmol) and 6-amino-3-chloro-2-fluorobenzaldehyde (5 g, 28.8 mmol) in ethanol (20 mL) were added, and the resulting mixture was heated at 80°C for 16 h. The reaction mixture was cooled to 70°C, pyrrolidine (5.96 mL, 72.0 mmol) was added, and the mixture was heated to 80°C for 2 h. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the crude residue, and the mixture was extracted with DCM.
The combined organic layers were concentrated under reduced pressure to obtain 6-chloro-5-fluoro-2- methylquinolin-3-amine (2.5 g, 11.9 mmol, 41% yield) LCMS: m/z MM-ES+APCI, Positive [M+H,
M+2+H]+ 211.0, 212.8; ’H-NMR (400 MHz, DMSO-d6): 5 7.59 (d, J = 9.20 Hz, 1H), 7.35 (d, J = 8.80
Hz, 1H), 7.25 (s, 1H), 5.88 (s, 2H), 1.92 (s, 3H).
Step 2: Synthesis of 6-chloro-5-fluoro-3-iodo-2-methylquinoline
To a stirred solution of 6-chloro-5-fhioro-2-methylquinolin-3-amine (2.5 g, 11.87 mmol) in concentrated HC1 (15 mL) was added a solution of sodium nitrite (1.56 g, 22.6 mmol) dissolved in water (8 mL) at 0°C, and the reaction was stirred at 0°C for 1 h. To this resulting mixture was added KI (4.93 g, 29.7 mmol) dissolved in water (8 mL) dropwise, and the reaction mixture was allowed to warm to rt over 2h. The reaction mixture was poured into 10% NaHCOs solution and the mixture was extracted with EtOAc (2 x 180 mL). The organic layer was washed with aqueous sodium hypochlorite solution (200 mL). The organic layer was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 0-6% EtOAc in hexane to afford 6-chloro-5-fluoro-3-iodo-2- methylquinoline (1.4 g, 4.35 mmol, 37% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 321.9, 323.7; 'H-NMR (400 MHz, DMSO-d6): 5 8.90 (s, 1H), 7.89 (d, J = 9.20 Hz, 1H), 7.81 (d, J = 9.20 Hz, 1H), 2.85 (s, 3H).
Step 3: Synthesis of l-(6-chloro-5-fluoro-7-methylquinolin-3-yl)-3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione
A stirred mixture of 6-chloro-5-fluoro-3-iodo-7-methylquinoline (1.4 g, 4.35 mmol), 3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (1.726 g, 6.53 mmol), CS2CO3 (3.55 g, 10.89 mmol), and 2-methyl-THF (15 mL) was sparged with argon for 15 minutes. Anhydrous copper(II) acetate (0.395 g, 2.177 mmol) and (1R,2R)-N,N’ -dimethyl- 1,2-cyclohexanediamine (0.433 g, 3.05 mmol) were then added at ambient temperature, and the reaction mixture was sparged with argon for another 15 minutes. The reaction mixture was stirred at 100°C for 16 h. The cooled reaction mixture was filtered through Celite, washing with EtOAc (200 mL), and the combined filtrates were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-99% EtOAc in hexane to afford 1- (6-chloro-5-fluoro-7-methylquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (850 mg, 1.71 mmol, 39% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 458.4, 460.1; >H- NMR (400 MHz, DMSO-d6): 5 8.53 (s, 1H), 7.89-7.87 (m, 2H), 6.95 (d, J = 8.00 Hz, 1H), 6.56 (s, 1H), 6.49 (d, J = 2.40 Hz, 1H), 4.83 (m, 2H), 4.09-4.06 (m, 1H), 3.80 (s, 6H), 3.33 (m, 1H), 3.09-3.05 (m, 2H), 2.68 (s, 3H).
Step 4: Synthesis of tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoro-2-methylquinolin-6-yl)-9-oxa-2-azaspiro[5.5]undec-4-ene-2-carboxylate
To a stirred solution of l-(6-chloro-5-fluoro-2-methylquinolin-3-yl)-3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (400 mg, 0.87 mmol) and tert-butyl 5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-9-oxa-2-azaspiro[5.5]undec-4-ene-2-carboxylate (530 mg, 1.40 mmol) in 1,4-dioxane (5 mL) and water (0.25 mL) at rt was added tri-potassium phosphate (167 mg, 0.79 mmol). The resulting reaction mixture was sparged with argon, then cataCXium A Pd G3 (32 mg, 0.044 mmol) was added. The reaction mixture was sparged with argon for 5 minutes and then stirred at 100 °C for 16 h. The cooled reaction mixture was filtered through a Celite, rinsing with EtOAc (2 x 50 mL). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 50-80% EtOAc in n-hexane to afford tert-butyl 5-(3-(3-(2,4- dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2-methylquinolin-6-yl)-9-oxa-2- azaspiro[5.5]undec-4-ene-2-carboxylate (250 mg, 0.21 mmol, 24% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 675.5; ’H-NMR (400 MHz, DMSO-d6): 8 8.46 (s, IH), 7.85 (s, IH), 7.80 (d, J = 8.80
Hz, IH), 7.49 (t, J = 8.40 Hz, 1H), 6.96 (d, J = 8.40 Hz, 1H), 6.75 (s, 1H), 6.55 (d, J = 2.40 Hz, 1H), 6.46 (dd, J = 10.40 Hz, 1H), 5.76 (s, 1H), 4.80 (d, J = 11.20 Hz, 1H), 4.68 (s, 2H), 4.06-4.01 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75-3.73 (m, 1H), 3.56-3.53 (m, 2H), 3.28 (t, J = 2.80 Hz, IH), 3.08 (q, J = 6.00 Hz, 2H), 2.68 (t, J = 6.80 Hz, 2H), 2.60 (s, 3H), 1.60-1.58 (m, 2H), 1.57 (s, 9H).
Step 5: Synthesis of tert-butyl 5-(3-(3-(3,5-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoro-2-methylquinolin-6-yl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate
Tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)-5-fluoro-2- methylquinolin-6-yl)-9-oxa-2-azaspiro[5.5]undec-4-ene-2-carboxylate (300 mg, 0.445 mmol) was treated according to General Procedure 3, Step C. The crude product was purified by reverse phase chromatography using a Cl 8 column, eluting with 0.1% FA in water and acetonitrile to afford tert-butyl 5-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-2-methylquinolin-6-yl)- 4-hydroxy-9-oxa-2-azaspiro[5.5]undec-4-ene-2-carboxylate (80 mg, 0.083 mmol, 19% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 693.8; ’H-NMR (400 MHz, DMSO-d6): 8 8.47 (s, IH), 8.07 (d, J = 8.40 Hz, IH). 7.84 (d, J = 8.80 Hz, IH), 6.95 (d, J = 8.40 Hz, IH), 6.56 (d, J = 2.40 Hz, IH), 6.48 (dd, J = 2.00, 8.40 Hz, IH), 5.78 (s, IH), 5.57 (d, J = 9.60 Hz, IH), 4.77 (d, J = 15.20 Hz, 2H), 4.40 (m, IH), 4.07- 4.02 (m, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 3.59-3.56 (m, 3H), 3.07-3.06 (m, 4H), 2.68-2.55 (m, 4H), 1.68- 1.65 (m, IH), 1.51 (s, 9H), 1.19-1.08 (m, 3H).
Step 6: Synthesis of l-(5-fluoro-6-(5-hydroxy-9-oxa-2-azaspiro [5.5] undecan-5-yl)-2- methylquinolin-3-yl) dihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of tert-butyl 5-(3-(3-(3,5-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin- l(2H)-yl)-5-fluoro-2-methylquinolin-6-yl)-5-hydroxy-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate (20 mg, 0.029 mmol) in DCM (1 mL) at 0 °C under nitrogen atmosphere were added TEA (5.56 pl, 0.072 mmol) and trifluoromethanesulfonic acid (5.13 pl, 0.058 mmol), and the reaction mixture was stirred at 0 °C for 2 h. The mixture was concentrated under reduced pressure, and the crude residue was triturated with MTBE. The resulting solid was collected and dried to provide l-(5-fluoro-6-(5-hydroxy-9-oxa-2- azaspiro [5.5] undecan-5-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, TEA (10 mg, 0.012 mmol, 41% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 443.4; 1H-NMR (400 MHz, DMSO-d6): 10.5 (s, IH), 8.48 (s, IH), 8.13-8.05 (m, IH), 6.55 (s, IH), 5.99 (s, IH), 4.36-4.25 (m, 2H), 4.00-3.96 (m, 2H), 3.80-3.71 (m, IH), 3.38-3.16 (m, 2H), 2.90-2.89 (m, 2H), 2.80-2.75 (m, 2H), 2.68- 2.62 (m, IH), 2.10 (d, J = 14.80 Hz, 2H), 1.90 (d, J = 13.60 Hz, 2H), 1.59 (d, J = 14.40 Hz, 2H), 1.30-1.24 (m, 2H), 1.11 (s, 2H).
Step 7: Synthesis of l-(5-fluoro-6-(5-hydroxy-2-((l-methyl-lH-pyrazol-5-yl)methyl)-9-oxa-2- azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-788) l-(5-fhioro-6-(5-hydroxy-9-oxa-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, TEA (50 mg, 0.090 mmol) was reacted with 1-methyl-lH- pyrazole-5-carbaldehyde (11 mg, 0.099 mmol) and sodium triacetoxyborohydride according to General Procedure 1, Step D. The crude product was purified by preparative-HPLC [Method info: Column: X SELECTCI 8 (150 x 19 mm) 5 pm, eluting with Mobile phase A: 0.05% FA in H2O, Mobile phase B: acetonitrile, flow rate: 15 mL/min)] to afford l-(5-fhioro-6-(5-hydroxy-2-((l-methyl-lH-pyrazol-5- yl)methyl)-9-oxa-2-azaspiro[5.5]undecan-5-yl)-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (1-788) (2.4 mg, 4.44 pmol, 5% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ 537.5; *H- NMR (400 MHz, DMSO-d6): 5 10.55 (s, IH), 8.41 (d, J = 5.20 Hz, IH), 8.10-8.03 (m, IH), 7.81 (d, J =
6.40 Hz, IH), 7.50 (d, J = 2.00 Hz, IH), 6.19 (s, IH), 5.27 (d, J = 12.80 Hz, IH), 4.07-3.97 (m, IH), 3.76
(s, 3H), 3.68-3.63 (m, 2H), 3.59-3.53 (m, 4H), 3.49 (s, 3H), 3.25-3.14 (m, 2H), 2.88-2.79 (m, 1H), 2.75- 2.74 (m, 2H), 2.59 (s, 3H), 2.12 (d, J = 12.80 Hz, 1H), 1.69 (d, J = 8.00 Hz, 1H), 1.47 (d, J = 13.20 Hz, 1H), 1.23 (t, J = 6.00 Hz, 1H), 1.09 (m, 1H).
Step 8: Synthesis of tert-butyl 5-oxo-9-oxa-2-azaspiro [5.5] undecane-2-carboxylate
To a stirred solution of tert-butyl 4-oxopiperidine-l -carboxylate (5 g, 25.09 mmol) in toluene (50 mL) under a nitrogen atmosphere was added potassium tert-butoxide (7.04 g, 62.7 mmol) portion-wise at rt, and the mixture was stirred for Ih. l-Bromo-2-(2-bromoethoxy)ethane (6.40 g, 27.6 mmol) was then added dropwise and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was allowed to cool to rt, then aqueous ammonium chloride solution (50 mL) was added, and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 18-30% EtOAc in n-hexane to afford tert-butyl 5-oxo-9-oxa-2-azaspiro[5.5]undecane-2-carboxylate (650 mg, 2.15 mmol, 9% yield). LCMS m/z MM-ES+APCI, Positive [M-56+H]+ 214.0; 'H-NMR (400 MHz, CDCh): 54.15- 4.01 (m, 6H), 3.60 (s, 2H), 2.54-2.51 (m, 2H), 2.07-1.94 (m, 2H), 1.52 (s, 9H).
Step 9: Synthesis of tert-butyl 5-(((trifluoromethyl)sulfonyl) oxy)-9-oxa-2-azaspiro[5.5]-undec-4-ene- 2-carboxylate
To a stirred solution of tert-butyl 5-oxo-9-oxa-2-azaspiro [5.5] undecane-2-carboxylate (300 mg, 1.11 mmol) in THE (5 mL) at -78 °C under a nitrogen atmosphere was added potassium tert-butoxide (IM in THE, 2.90 mL, 2.90 mmol), and the mixture was stirred at -50 °C for 1 h. The reaction mixture was again cooled to -78 °C, and a solution of N-(5-chloropyridin-2-yl)-l,l,l-trifluoro-N- ((trifluoromethyl)sulfonyl) methane sulfonamide (787 mg, 2.01 mmol) in THF (2 mL) was then added. The reaction mixture was warmed to 0 °C and stirred for Ih. Aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, eluting with 15- 20% EtOAc in hexane to afford tert-butyl 5-(((trifluoromethyl)sulfonyl) oxy)-9-oxa-2-azaspiro [5.5] undec-4-ene-2-carboxylate (290 mg, 0.71 mmol, 64% yield). LCMS m/z MM-ES+APCI, Positive [M- 56+H]+ 346.3; ’H-NMR (400 MHz, CDCh): 55.83-5.77 (m, IH), 4.14 (d, J = 12.80 Hz, 2H), 4.09 (s, 2H), 3.74-3.60 (m, 4H), 2.06 (t, J = 9.20 Hz, 2H), 1.50 (s, 9H), 1.38 (d, J = 13.60 Hz, 2H).
Step 10: Synthesis of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-9-oxa-2- azaspiro[5.5]undec-4-ene-2-carboxylate
PdCh(dppf)-DCM adduct (0.224 g, 0.274 mmol) was added to a stirred mixture of tert-butyl 5- (((trifluoromethyl)sulfonyl)oxy)-9-oxa-2-azaspiro[5.5]undec-4-ene-2-carboxylate (1.1 g, 2.74 mmol), 1,4- dioxane (15 mL), bispinacolato diboron (1.39 g, 5.48 mmol), and potassium acetate (0.807 g, 8.22 mmol). The reaction mixture was sparged with nitrogen for 5 min, then stirred at 100 °C for 4 h. The cooled reaction mixture was filtered through Celite, rinsing with EtOAc (2 x 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0-30% EtOAc in hexane to afford tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-9-oxa- 2-azaspiro[5.5]undec-4-ene-2-carboxylate (800 mg, 1.75 mmol, 64% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ 380.4. ’H-NMR (400 MHz, CDCh): 5 6.49-6.42 (m, IH), 3.97 (d. J = 10.80 Hz, 2H), 3.90-3.82 (m, 2H), 3.74-3.57 (m, 5H), 2.25 (t, J = 4.80 Hz, 2H), 1.50 (s, 9H), 1.27 (s, 12H), 1.20 (d, J = 14.00 Hz, IH).
Example 246: Synthesis of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethyl- piperidin-4-yl)-2-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-529)
Figure imgf000799_0001
Step 1: Synthesis of 6-bromo-5-fluoro-3-iodoquinoline 1-oxide
To a stirred solution of 6-bromo-5-fluoro-3-iodoquinoline (12 g, 34.1 mmol) in DCM (50 mL) was added m-CPBA (9.17 g, 40.9 mmol) at 0°C. The reaction mixture was allowed to stir at rt for 3 h. The reaction mixture was diluted with DCM (100 mL) and saturated aq NaHCXL (150 mL) was added. The separated organic layer was washed with brine (200 mL), dried with Na2SCL, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-20% EtOAc in hexane to afford 6-bromo-5-fluoro-3-iodoquinoline 1-oxide (5 g, 10.8 mmol, 32% yield. LCMS m/z MM-ES+APCI, Positive [M+H]+ 367.9; ’H-NMR (400 MHz, DMSO-d6): 59.09 (d, J = 2.00 Hz, 1H), 8.78 (d, J = 1.60 Hz, 1H), 7.85-7.79 (m, 2H).
Step 2: Synthesis of 6-bromo-2-chloro-5-fluoro-3-iodoquinoline
To a stirred solution of 6-bromo-5-fluoro-3-iodoquinoline 1-oxide (7.5 g, 20.38 mmol) in toluene (75 mL) at 0°C was added POCL (9.50 mL, 102 mmol), and the reaction mixture was heated at 80°C for 2 h. The cooled reaction mixture was diluted with EtOAc (100 mL) and the pH was adjusted to 8 using saturated aq NaHCOs (50 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-4% EtOAc in hexane to afford 6-bromo-2-chloro-5-fluoro-3- iodoquinoline (4.7 g, 9.73 mmol, 48% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 386.0, 388.0; ’H-NMR (400 MHz, DMSO-d6): 59.07 (s, IH), 8.11-8.05 (m, 1H), 7.78 (d, J = 9.20 Hz, 1H).
Step 3: Synthesis of l-(6-bromo-2-chloro-5-fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione
A stirred mixture of 6-bromo-2-chloro-5-fluoro-3-iodoquinoline (300 mg, 0.776 mmol), and 3- (2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 205 mg, 0.776 mmol), 1,4-dioxane (6 mL), and CS2CO3 (506 mg, 1.553 mmol) was sparged for 15 min with argon. Copper(I) iodide (74 mg, 0.39 mmol) and (lR,2R)-N,N’-dimethyl-l,2-cyclohexanediamine (55 mg, 0.39 mmol) were then added at rt and the reaction mixture was stirred at 60°C for 18 h. The cooled reaction mixture was filtered through Celite, rinsing with EtOAc (250 mL). The filtrate was washed with water (2 x 250 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-45% EtOAc in hexane to afford l-(6-bromo-2-chloro-5- fluoroquinolin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (130 mg, 0.236 mmol, 30% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 522.0, 524.0; ’H-NMR (400 MHz, DMSO-d6): 5 8.81 (s, IH), 8.13 (d, J = 1.20 Hz, IH), 7.94 (d, J = 9.20 Hz, IH), 6.95 (d, J = 8.40
Hz, IH), 6.56 (s, 1H), 6.48 (d, J = 2.40 Hz, 1H), 4.81 (s, 2H), 3.99-3.96 (m, 1H), 3.90-3.80 (m, 1H), 3.75
(s, 3H), 3.32 (s, 3H), 3.05 (t, J = 7.60 Hz, 2H).
Step 4: Synthesis of l-(6-bromo-2-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione
To a stirred solution of l-(6-bromo-2-chloro-5-fluoroquinolin-3-yl)-3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (1.0 g, 1.91 mmol) in DCM (10 mL) at 0°C were added, TFA (2.06 mL, 26.8 mmol) and triflic acid (0.34 mL, 3.8 mmol) and the resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, and saturated aq NaHCOs solution was added to the residue. The resulting solid was collected via filtration and dried to afford the crude product, which was purified by silica gel flash chromatography, eluting with 0- 55% EtOAc in hexane to afford l-(6-bromo-2-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (0.5 g, 1.16 mmol, 61% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 372.0, 374.0; ’H-NMR (400 MHz, DMSO-d6): 5 10.43 (s, 1H), 8.71 (s, 1H), 8.07 (d, J = 7.60 Hz, 1H), 7.83 (d, J = 9.20 Hz, 1H), 3.85 (t, J = Hz, 2H), 2.84 (t, J = 6.80 Hz, 2H).
Step 5: Synthesis of tert-butyl 4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
To a stirred solution of l-(6-bromo-2-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione (300 mg, 0.81 mmol) and tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (INT-40, 407 mg, 1.21 mmol) in 1,4-dioxane (12 mL), PdC12(dppf)-CH2C12 adduct (66 mg, 0.081 mmol) was added, and the reaction mixture was sparged with nitrogen for 5 min. The reaction mixture was stirred at 80°C for 16 h. The cooled reaction mixture was filtered through a pad of celite, and the pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography on a Cl 8 column, eluting with 50% acetonitrile in 0.1% FA in H2O to afford tert-butyl 4- (2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine- l(2H)-carboxylate (100 mg, 0.19 mmol, 23% yield). LCMS m/z MM-ES+APCI,
Positive [M+H, M+2+H? 503.2, 505.2; ’H-NMR (400 MHz, DMSO-d6): 5 10.66 (s, IH), 8.72 (s, IH),
7.84 (d, J = 8.80 Hz, IH), 7.65 (t, J = 8.00 Hz, IH), 5.64 (s, IH), 4.04 (s, 2H), 3.89 (t, J = 6.00 Hz, IH),
3.77 (t, J = 5.60 Hz, IH), 3.39 (s, 2H), 2.85-2.80 (m, 2H), 1.46 (s, 9H), 1.00 (s, 6H).
Step 6: Synthesis of tert-butyl 4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate
Tert-butyl 4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin-6-yl)-3,3- dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (200 mg, 0.40 mmol) was treated according to General Procedure 3, Step C. The crude product was purified by silica gel flash chromatography, eluting with 5% IP A in DCM to afford tert-butyl 4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (100 mg, 0.130 mmol, 33% yield. LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 521.2, 523.2.
Step 7: Synthesis of l-(2-chloro-5-fhioro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione
A solution of tert-butyl 4-(2-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoroquinolin- 6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (80 mg, 0.154 mmol) in DCM (3 mL) and HC1 (4 M in dioxane, 0.1 mL, 0.400 mmol) was stirred at 0 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with pentane, collected and dried under vacuum to afford l-(2-chloro-5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione, HC1 (80 mg, 0.19 mmol, 84% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ 421.1, 423.2; ’H-NMR (400 MHz, DMSO-d6): 5 10.67 (s, 1H), 8.75 (s, 1H), 8.22 (d, J = 8.00 Hz, IH), 7.89 (d, J = 4.00 Hz, 1H), 5.97 (s, 1H), 3.91 (t, J = 2.40 Hz, 2H), 3.80-3.74 (m, 2H), 3.44-3.15 (m, 3H), 2.94-2.81 (m, 3H), 1.92 (s, IH), 1.07 (s, 9H).
Step 8: Synthesis of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-
2-chloro-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-529)
To a stirred solution of l-(2-chloro-5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl) quinolin-
3-yl) dihydropyrimidine-2,4(lH,3H)-dione, HC1 (70 mg, 0.15 mmol) in 2-propanol (2 mL) was added 4- (l,2,4-oxadiazol-3-yl)benzaldehyde (ALD-107, 27 mg, 0.15 mmol) and potassium acetate (45.1 mg, 0.46 mmol) and the mixture was stirred at rt for 20 min. Sodium cyanoborohydride (29 mg, 0.46 mmol) was added and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was poured into cooled water (100 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative-HPLC [(Column: X select C18 (150 x l9 mm) 5 pm, eluting with Mobile phase A: 0.1% acetic acid in H2O, Mobile phase B: Acetonitrile, flow rate: 15 mL/min)]. The resulting product was dissolved in acetonitrile (5 mL) and 0.1M HC1 (aq) and lyophilized to afford l-(6-(l-(4-
(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-chloro-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (1-529) (18.0 mg, 0.029 mmol, 19% yield). LCMS m/z
MM-ES+APCI, Positive [M+H, M+2+H]+ 579.2, 581.2; ’H-NMR (400 MHz, DMSO-d6): 5 10.67 (s,
1H), 10.10 (s, 1H), 9.78 (s, 1H), 8.76 (s, 1H), 8.16 (d, J = 8.00 Hz, 3H), 7.90 (t, J = 9.20 Hz, 3H), 6.01 (d,
J = 8.80 Hz, 1H), 4.54 (q, J = 3.20 Hz, 2H), 3.91 (t, J = 7.20 Hz, 1H), 3.87-3.86 (m, 2H), 3.40-3.27 (m,
2H), 2.95-2.85 (m, 3H), 2.08-2.03 (m, 2H), 1.09 (s, 3H), 0.77 (s, 3H).
Example 247: Synthesis of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethyl- piperidin-4-yl)-4-amino-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-879)
Figure imgf000802_0001
Step 1: Synthesis of 6-amino-3-bromo-2-fluorobenzoic acid
To a stirred a solution of 2-amino-6-fluorobenzoic acid (30 g, 193 mmol) in DMF (300 mL) at 0
°C was added NBS (34.4 g, 193 mmol). The reaction was stirred at 25 °C for 2 h. Water (500 mL) was added to the reaction mixture, and the resultant solid was collected by filtration and dried under vacuum to afford 6-amino-3-bromo-2-fluorobenzoic acid (40 g, 171 mmol, 88% yield). LCMS: m/z MM- ES+APCI, Positive [M+2+H]+ = 235.8; ’H-NMR (400 MHz, DMSO-d6): 57.38 (d, J = 8.80 Hz, 1H), 6.56 (d, J = 8.80 Hz, 1H). (Note: NHo and COOH protons were not observed in ’H-NMR).
Step 2: Synthesis of (E)-3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid
In a 500 mL multi-neck round-bottom flask under a nitrogen atmosphere, NaOH (51.3 g, 1282 mmol) was dissolved in water (180 mL) and the solution cooled to 0 °C. To this solution, nitromethane
(31.3 g, 513 mmol) was added dropwise resulting in an exothermic reaction. The mixture was then stirred at 45 °C for approximately 10 minutes. The reaction mixture was allowed to reach ambient temperature and was carefully poured into an ice (92 g, 5128 mmol) and HC1 (395 mL, 4743 mmol) solution. This mixture was then added dropwise to a suspension of 6-amino-3-bromo-2-fluorobenzoic acid (30 g, 128 mmol) in water (750 mL) and HC1 (660 mL, 7948 mmol). The resulting mixture was stirred at room temperature for 16 h. The obtained solids were collected via flitration and washed with water (300 mL) and methanol (300 mL) to yield (E)-3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid (17.5 g, 51.1 mmol, 40% yield). LCMS: m/z MM-ES+APCI, Positive [M+2+H]+ = 306.9; ’H-NMR (400 MHz, DMSO-d6): 5 14.1 (bs, 1H), 12.33 (d, J = 8.20 Hz, 1H), 7.93-8.03 (m, 2H), 7.53 (d, J = 9.60 Hz, 1H),
6.80 (d, J = 6.40 Hz, 1H).
Step 3: Synthesis of 6-bromo-5-fluoro-3-nitroquinolin-4-ol
To a stirred solution of (E)-3-bromo-2-fluoro-6-((2-nitrovinyl)amino)benzoic acid (15 g, 49.2 mmol) in DMF (150 mL) were added at rt n-hydroxysuccinimide (9.05 g, 79 mmol) and EDC (13.2 g, 68.8 mmol). The reaction was stirred for 1 h, after which DMAP (7.21 g, 59.0 mmol) was added. The reaction was stirred at rt for an additional 2 h, then the reaction mixture was added to water (1 L). The obtained solid was collected via filtration and dried under vacuum, and was then washed with
MTBE/acetonitrile (1:1 ratio) and dried under vacuum to yield 6-bromo-5-fluoro-3-nitroquinolin-4-ol (4.4 g, 11 mmol, 22% yield). 'H-NMR (400 MHz, DMSO-d6): 59.10 (s, 1H), 7.95 (d, J = 9.20 Hz, 1H), 7.45 (d, J = 8.80 Hz, 1H). (Note: OH proton was not observed in ’H-NMR).
Step 4: Synthesis of 6-bromo-4-chloro-5-fluoro-3-nitroquinoline
A mixture of 6-bromo-5-fluoro-3-nitroquinolin-4-ol (10 g, 35 mmol) and thionyl chloride (166 g, 1394 mmol) was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain crude 6-bromo-4-chloro-5-fluoro-3-nitroquinoline (10 g), which was used in the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 305.2; ’H-NMR (400 MHz, DMSO-d6): 59.12 (s, 1H), 8.06 (d, J = 9.20 Hz, 1H), 7.98 (d, J = 9.20 Hz, 1H).
Step 5: Synthesis of 6-bromo-5-fluoro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine
To a stirred solution of 6-bromo-4-chloro-5-fluoro-3-nitroquinoline (10 g, 32.7 mmol) in DMF (100 mL), at 0 °C was added 4-methoxybenzylamine (8.98 g, 65.5 mmol). The mixture was stirred and allowed to warm to rt over 10 minutes. Water (100 mL) was added, and the mixture was extracted with EtOAc (500 mL). The combined organic layers were washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with 30% EtOAc in petroleum ether to afford 6-bromo-5- fluoro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine (6 g, 13.7 mmol, 42% yield). LCMS m/z MM- ES+APCI, Positive [M+2+H? = 408.2’; ’H-NMR (400 MHz, DMSO-d6): 8 8.92 (s, 1H), 8.62 (hr s, 1H),
8.07 (t, J = 7.80 Hz, 1H), 7.69 (d, J = 8.80 Hz, 1H), 7.17 (d, J = 8.80 Hz, 2H), 6.85 (d, J = 8.80 Hz, 2H), 4.47 (s, 2H), 3.72 (s, 3H).
Step 6: Synthesis of 6-bromo-5-fluoro-N4-(4-methoxybenzyl)quinoline-3,4-diamine
A stirred mixture of 6-bromo-5-fluoro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine (5 g, 12.3 mmol), THF (25 mL), ethanol (25 mL), water (5 mL), iron powder (4.12 g, 73.9 mmol), and ammonium chloride (3.95 g, 73.9 mmol) was stirred at 80 °C for 2 h. The cooled reaction mixture was filtered through celite, rinsing with ethanol (150 mL) and THF (150 mL), then the combined filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, eluting with 0-60% EtOAc in petroleum ether to afford 6-bromo-5-fluoro-N4-(4- methoxybenzyl)quinoline-3,4-diamine (3.4 g, 8.22 mmol, 67% yield). LCMS: m/z MM-ES+APCI, Positive [M+2+H]+ = 377.8; ’H-NMR (400 MHz, DMSO-d6): 8 8.45 (s, 1H), 7.49 (d, J = 4.00 Hz, 1H), 7.26 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 8.40 Hz, 2H), 5.41 (s, 2H), 5.09-5.10 (m, 2H), 4.20 (d, J = 6.80 Hz, 2H), 3.71 (s, 3H).
Step 7: Synthesis of 3-((6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3-yl)amino)- propanenitrile
A mixture of 6-bromo-5-fluoro-N4-(4-methoxybenzyl)quinoline-3,4-diamine (10 g, 26.6 mmol), cesium carbonate (10.4 g, 31.9 mmol), acrylonitrile (2.12 g, 39.9 mmol), and acetonitrile (100 ml) was stirred at rt for 2 h and then at 80 °C for 16 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (300 mL). The combined organic layers were washed with water (300 mL) followed by brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography on a C 18 column, eluting with 5 to 100% acetonitrile in 0.1% FA in water to afford 3-((6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3- yl)amino)propanenitrile (7 g, 16.3 mmol, 61% yield). LCMS: m/z MM-ES+APCI, Positive [M+2+H]+ = 431.3; ’H-NMR (400 MHz, DMSO-d6): 8 8.58 (s, 1H), 7.47-7.58 (m, 2H), 7.26 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 8.40 Hz, 2H), 5.65-5.68 (m, 1H), 5.27-5.30 (m, 1H), 4.22 (t, J = 6.80 Hz, 2H), 3.71 (s, 3H), 3.59- 3.64 (m, 2H), 2.85 (t, J = 6.40 Hz, 2H).
Step 8: Synthesis of 3-((6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3-yl)amino)- propanamide To a solution of 3-((6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3-yl)amino)- propanenitrile (6.8 g, 15.84 mmol) in EtOH (68 mL) and water (102 mL) at rt was added urea hydrogen peroxide (17.9 g, 190 mmol) and NaOH (4.43 g, 111 mmol). The reaction mixture was stirred at rt for 16h, then water was added, and the resultant solid precipitate was collected by filtration. The crude product was purified by reverse phase column chromatography on a Cl 8 column, eluting with 5 to 100% acetonitrile in 0.1% FA in water to yield 3-((6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3- yl)amino)propenamide (2 g, 4.47 mmol, 30% yield). LCMS m/z MM-ES+APCI, Positive [M+2+H]+ = 449.2; ’H-NMR (400 MHz, DMSO-d6): 5 8.57 (s, 1H), 7.45-7.62 (m, 3H), 7.27 (d, J = 8.80 Hz, 2H), 6.95 (d, J = 1.20 Hz, 1H), 6.83 (d, J = 4.80 Hz, 2H), 5.46 (t, J = 6.00 Hz, 1H), 5.11 (q, J = 7.20 Hz, 1H), 4.15 (d, J = 6.40 Hz, 2H), 3.71 (s, 3H), 3.52 (q, J = 6.40 Hz, 2H), 2.45 (t, J = 6.80 Hz, 2H).
Step 9: Synthesis of l-(6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione
NaH (214 mg, 5.36 mmol) was added at 0 °C to a stirred solution of 3-((6-bromo-5-fluoro-4-((4- methoxybenzyl)amino)quinolin-3-yl)amino)propanamide (0.8 g, 1.79 mmol) in THE (20 mL) and the mixture was stirred for 15 min at 0 °C. CDI (870 mg, 5.36 mmol) was then added, and the reaction mixture was allowed to warm to rt over 2 h. The pH of the reaction mixture was adjusted with 4M HC1 (aq) to approximately pH 6-7. The resultant solid precipitate was collected by filtration and triturated with MTBE (20 mL) to afford l-(6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (1.0 g, 2.1 mmol). LCMS m/z MM-ES+APCI, Positive [M+2+H]+ = 475.1; ’H-NMR (400 MHz, DMSO-d6): 5 10.95 (s, 1H), 8.45 (s, 1H), 7.87 (d, J = 8.80 Hz, 1H), 7.65 (d, J = 8.80 Hz, 1H), 7.26 (d, J = 8.80 Hz, 2H), 6.90 (d, J = 8.80 Hz, 2H), 6.58-6.62 (m, 1H), 4.44-4.55 (m, 2H), 3.68-3.37 (m, 4H), 3.27-3.33 (m, 1H), 2.68-2.68 (m, 2H).
Step 10: Synthesis of (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-((4- methoxybenzyl)amino)quinolin-6-yl)boronic acid
To a stirred solution of l-(6-bromo-5-fluoro-4-((4-methoxybenzyl)amino)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (200 mg, 0.423 mmol) and 5,5,5’,5’-tetramethyl-2,2’-bi(l,3,2- dioxaborinane) (191 mg, 0.845 mmol) in 1,4-dioxane (4 mL) was added potassium acetate (124 mg, 1.268 mmol), and the mixture was sparged with nitrogen for 10 minutes. TerLbutyldiphenylphosphine (20.5 mg, 0.085 mmol) and palladium(II) acetate (9.5 mg, 0.042 mmol) were added, and the reaction mixture was stirred at 100 °C for 2 h. The cooled reaction mixture was filtered through celite, washing with EtOAc, and the combined filtrate was concentrated under reduced pressure. The crude residue was triturated with hexane, collected by filtration and dried to afford (3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)-5-fluoro-4-((4-methoxybenzyl)-amino)quinolin-6-yl)boronic acid (0.21 g, 0.28 mmol, 66% yield). LCMS, m/z MM-ES+APCI, Positive [M+H]+ = 438.9. Step 11: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-((4- methoxybenzyl)amino)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
A stirred mixture of (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-((4-methoxy- benzyl)amino)quinolin-6-yl)boronic acid (175 mg, 0.399 mmol), tert-butyl 3,3-dimethyl-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (40b, 172 mg, 0.479 mmol), 1,4- dioxane (4 mL), water (0.4 mL), and potassium carbonate (110 mg, 0.799 mmol) was sparged with nitrogen for 10 min at rt. PdC12(dppf)-CH2Ch adduct (33 mg, 0.040 mmol) was added, and the reaction mixture was stirred at 80 °C for 1 h. Water was added to the cooled reaction mixture, and the mixture was extracted with DCM. The combined organic layers were concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a C18 column, eluting with acetonitrile in 0.01% FA in water to provide tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-((4- methoxybenzyl)amino)-quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (130 mg, 0.17 mmol, 44% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 604.3; ’H-NMR (400 MHz, DMSO-d6): 5 10.48 (s, 1H), 8.41 (s, 1H), 7.65 (d, J = 8.00 Hz, 1H), 7.41 (t, J = 8.00 Hz, 1H), 7.23 (d, J =
4.00 Hz, 2H), 6.85 (d, J = 6.00 Hz, 2H), 6.55 (d, J = 4.00 Hz, 1H), 5.55 (s, 1H), 4.46-4.56 (m, 1H), 4.36- 4.44 (m, 1H), 4.04 (d, J = 4.00 Hz, 2H), 3.68-3.78 (m, 3H), 3.35-3.40 (m, 1H), 3.22-3.29 (m, 2H), 2.50- 2.60 (m, 1H), 2.35-2.45 (m, 1H), 2.08-2.09 (m, 1H), 1.44 (s, 9H), 0.98 (s, 6H).
Step 12: Synthesis of l-(4-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-((4- methoxybenzyl)amino)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (50 mg, 0.083 mmol) in CH2Q2 (4 mL) were added TFA (0.064 mL, 0.828 mmol) followed by trifluoromethanesulfonic acid (0.022 mL, 0.248 mmol) at 0 °C and stirred at this temperature for 1 h. After completion of the reaction as confirmed by TLC and LCMS, the reaction mixture was evaporated and triturated with hexane to afford a crude l-(4-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoroquinolin-3- yl)dihydro pyrimidine-2,4(lH,3H)-dione (21 mg, 55 mmol). The erode taken forward to the next step without further purification. LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 384.1; ’H-NMR (400 MHz, DMSO-d6): 5 10.37 (s, 1H), 8.32 (s, 1H), 7.55 (d, J = 8.40 Hz, 1H), 7.33 (t, J = 8.40 Hz, 1H), 6.72 (s,
2H), 5.55 (t, J = 2.80 Hz, 1H), 3.78-3.68 (m, 3H), 3.56-3.51 (m, 1H), 2.95-2.85 (m, 1H), 2.69-2.60 (m,
4H), 1.00 (s, 6H).
Step 13: Synthesis of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-3,3-dimethyl-l,2,3,6- tetrahydropyridin-4-yl)-4-amino-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
A mixture of l-(4-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (35 mg, 0.091 mmol), 4-(l,2,4-oxadiazol-3-yl)benzaldehyde (74a, 16 mg, 0.091 mmol), potassium acetate (26.9 mg, 0.274 mmol) and 2-propanol (1.5 mL) was stirred at rt for 1 h. Sodium cyanoborohydride (17.2 mg, 0.274 mmol) was then added and the reaction mixture was stirred at 60 °C for 1 h. The cooled reaction mixture was partitioned between water and 10% IPA/DCM, and the organic layer was collected and concentrated under reduced pressure. The crude residue was triturated with hexane and collected via filtration to afford l-(6-(l-(4-(l,2,4-oxadiazol-3- yl)benzyl)-3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-4-amino-5-fluoroquinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (40 mg, 0.039 mmol). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 542.3.
Step 14: Synthesis of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)- 4-amino-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-879)
To a stirred solution of l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-3,3-dimethyl-l,2,3,6- tetrahydropyridin-4-yl)-4-amino-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (40 mg, 0.074 mmol) in DCM (2 mL) and 2-propanol (1 mL) at 0 °C was added phenylsilane (0.028 mL, 0.22 mmol) followed by Mn(dpm)s (22.3 mg, 0.037 mmol) and the reaction mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM. The combined extracts were concentrated under reduced pressure, and the residue was purified by preparative-HPLC [Method info: (Column: X SELECT Cl 8 (19 x 250 mm), 5 pm), eluting with Mobile phase A: 0.05% ammonium acetate in water, Mobile phase B: Acetonitrile, flow rate: 15 mL/min] to afford l-(6-(l-(4-(l,2,4-oxadiazol-3-yl)benzyl)-4- hydroxy-3,3-dimethylpiperidin-4-yl)-4-amino-5-fluoroquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (1-879) (0.81 mg, 1.4 pmol, 2% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ = 560.3; >H- NMR (400 MHz, DMSO-d6): 5 10.37 (s, 1H), 9.70 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.00 Hz, 2H), 7.94 (t, J = 6.20 Hz, 1H), 7.55-7.59 (m, 3H), 6.71 (s, 2H), 5.06 (s, 1H), 3.50-3.76 (m, 4H), 2.65-2.70 (m, 2H), 1.56-1.75 (m, 6H), 1.04 (s, 3H), 0.68 (s, 3H).
Example 248: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-863)
Figure imgf000808_0001
Step 1: Synthesis of 6-amino-3-bromo-2-fluorobenzoic acid
6-Amino-3-bromo-2-fluorobenzoic acid was prepared in Example 247, 1-879, Step 1.
Step 2: Synthesis of 6-amino-3-bromo-2-fluoro-N-methoxy-N-methylbenzamide
To a stirred solution of 6-amino-3-bromo-2-fluorobenzoic acid (100 g, 427 mmol) in N,N- dimethylformamide (500 mL) 0°C were added DIPEA (166 g, 1282 mmol) and HATU (325 g, 855 mmol). After 30 min, N,O-dimethylhydroxylamine hydrochloride (62.5 g, 641 mmol) was added and the mixture was stirred at rt for 16 h. The reaction mixture was concentrated, then ice-cold water (3 L) was added and the mixture was extracted with 10% MeOH in DCM (2 x 1000 mL). The combined organic layers were dried over anhydrous NazSCh, filtered and concentrated. The crude residue was purified by silica gel column chromatography, eluting with 40% EtOAc in hexanes to afford 6-amino-3-bromo-2- fluoro-N-methoxy-N-methylbenzamide (65 g, 167 mmol, 39% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H? = 277.0, 278.9; ’H-NMR (400 MHz, DMSO-d6): 5 7.30 (d, I = 8.40 Hz, IH),
6.50 (d, J = 8.80 Hz, IH), 5.55 (s, 2H), 3.52 (s, 3H), 3.26 (s, 3H).
Step 3: Synthesis of l-(6-amino-3-bromo-2-fluorophenyl)ethan-l-one
To a stirred solution of 6-amino-3-bromo-2-fluoro-N-methoxy-N-methylbenzamide (60 g, 217 mmol) in THE (600 mL) at rt was added methylmagnesium bromide (1.4 M in THE) (619 mL, 866 mmol) and the mixture was stirred at rt for 1 h. Ammonium chloride was added and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 0-10% EtOAc in hexane to afford l-(6- amino-3-bromo-2-fluorophenyl)ethan-l-one (14.8 g, 63.8 mmol, 30% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ = 232.1, 234.3; ‘H-NMR (400 MHz, DMSO-d6): 5 7.45-7.40 (m, 3H), 6.60 (d, J = 8.80 Hz, IH), 2.51 (s, 3H).
Step 4: Synthesis of N-(2-acetyl-4-bromo-3-fluorophenyl)pivalamide
To a stirred solution of l-(6-amino-3-bromo-2-fluorophenyl)ethan-l-one (2 g, 8.62 mmol) and triethylamine (1.80 mL, 12.9 mmol) in dichloromethane (30 mL) at 0°C was added pivaloyl chloride (1.161 mL, 9.48 mmol) and the mixture was stirred at 30°C for 1 h. Aqueous NaHCCh solution (50 mL) was added and the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous NaaSCL filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with 30% EtOAc in hexanes to afford N-(2-acetyl-4-bromo-3-fluorophenyl)- pivalamide (2 g, 5.95 mmol, 69% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ = 315.9, 318.0; ’H-NMR (400 MHz, DMSO-d6): 5 8.10 (s, 1H), 7.81 (m, 1H), 7.61 (d, J = 8.80 Hz, 1H), 2.53 (s, 3H), 1.18 (s, 9H).
Step 5: Synthesis of methyl 6-bromo-5-fluoro-4-methylquinoline-3-carboxylate
A mixture of N-(2-acetyl-4-bromo-3-fluorophenyl)pivalamide (2 g, 6.33 mmol), methyl (£)-3- methoxyacrylate (1.10 g, 9.49 mmol), MeOH (20 mL), and 3M HC1 (aq) (10.5 mL, 31.6 mmol) was stirred at 70°C for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 0.1% FA in H2O and MeCN to afford methyl 6-bromo-5-fluoro-4-methylquinoline-3-carboxylate (0.8 g, 1.89 mmol, 30% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ = 297.9, 299.9; ’H-NMR (400 MHz, DMSO-d6): 59.07 (s, 1H), 8.12 (d, J = 9.20 Hz, 1H), 7.37 (d, J = 4.40 Hz, 1H), 3.98 (s, 3H), 2.95 (s, 3H).
Step 6: Synthesis of 6-bromo-5-fluoro-4-methylquinoline-3-carboxylic acid
A mixture of methyl 6-bromo-5-fluoro-4-methylquinoline-3-carboxylate (800 mg, 2.68 mmol), NaOH (215 mg, 5.37 mmol), THE (10 mL), MeOH (2 mL) and H2O (2 mL) was stirred at 60 °C for 16 h. The cooled reaction mixture was concentrated, diluted with water (50 mL), amd extracted with MTBE (2 x 25 mL). The aqueous layer was acidified with 1 N HC1 resulting in a solid precipitate, which was collected via filtration to afford 6-bromo-5-fluoro-4-methylquinoline-3-carboxylic acid (0.65 g, 2.3 mmol, 85% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ = 283.9, 285.9; ’H-NMR (400 MHz, DMSO-d6): 8 13.54 (s, IH), 9.05 (s, IH), 8.05 (d, J = 8.40 Hz, IH), 7.82 (d, J = 8.80 Hz, IH), 2.95 (s,
3H).
Step 7: Synthesis of 6-bromo-5-fluoro-4-methylquinolin-3-amine
A mixture of 6-bromo-5-fluoro-4-methylquinoline-3-carboxylic acid (3 g, 10.6 mmol), tert-BuOH (50 mL), triethylamine (2.97 mL, 21.1 mmol), and diphenylphosphoryl azide (4.36 g, 15.8 mmol) was stirred at 100°C for 12 h. The cooled reaction mixture was concentrated under reduced pressure. The resulting crude residue was taken up in DCM (25 mL), then concentrated HC1 (10 mL) was added and the mixture was stirred for 1 h. The pH of the mixture was adjusted to 8 with NaHCCL, and then the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 1% MeOH in DCM to afford 6-bromo-5-fhioro-4-methylquinolin-3-amine (0.95 g, 2.87 mmol, 27% yield). LCMS m/z MM-ES+APCI, Positive [M+H, M+2+H]+ = 255.0, 257.1; ’H-NMR (400 MHz, DMSO-d6): 8 8.48 (s, IH), 7.58 (d, J = 0.80 Hz, 1H), 7.50 (d, J = 7.60 Hz, 1H), 5.84 (s, 2H), 2.45 (s, 3H).
Step 8: Synthesis of tert-butyl 4-(3-amino-5-fluoro-4-methylquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine- 1 (2H)-carboxylate
A stirred mixture of 6-bromo-5-fhroro-4-methylquinolin-3-amine (850 mg, 3.33 mmol), tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (INT-40, 1120 mg, 3.33 mmol, potassium phosphate tribasic (707 mg, 3.33 mmol), 1,4-dioxane (15 mL) and water (1.5 mL) was sparged with nitrogen for 10 min, then PdCh(dppf)-CH2C12 adduct (272 mg, 0.333 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 3 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated. The crude residue was purified by silica gel flash column chromatography, eluting with 4% MeOH in DCM to afford tert-butyl 4-(3-amino-5-fluoro-4-methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (0.95 g, 1.85 mmol, 56% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 386.3; ’H-NMR (400 MHz, DMSO-d6): 8 8.45 (s, IH), 7.53 (d, J = 12.80 Hz, IH), 7.02 (d, J = 8.00 Hz, IH), 5.63 (s, 2H), 4.04-4.01 (m, 3H), 3.93 (s, 2H), 2.44 (s, 3H), 1.42 (s, 9H), 0.98 (s, 6H).
Step 9: Synthesis of tert-butyl 4-(5-fluoro-3-iodo-4-methylquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine- 1 (2H)-carboxylate To a stirred solution of tert-butyl nitrite (428 mg, 4.15 mmol) in acetonitrile (10 mL) was added copper(I) iodide (790 mg, 4.15 mmol) at rt and the mixture was stirred for 10 min. Tert-butyl 4-(3-amino- 5-fluoro-4-methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (800 mg, 2.08 mmol) was added and the mixture was stirred at 60 °C for 1 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 filtered and concentrated to dryness. The crude residue was purified by silica gel flash chromatography, eluting with 0-20% EtOAc in hexane to afford tert-butyl 4-(5-fluoro-3-iodo-4- methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (290 mg, 0.51 mmol, 24% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 497.3; ’H-NMR (400 MHz, DMSO-d6): 5 9.14 (s, 1H), 7.82 (d, J = 8.80 Hz, 1H), 7.41 (d, J = 8.00 Hz, 1H), 5.58 (t, J = 0.80 Hz, 1H), 4.12-4.10 (m, 2H),
3.46 (s, 2H), 3.03 (s, 3H), 1.52 (s, 9H), 1.07 (s, 6H).
Step 10: Synthesis of tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydro-pyrimidin-l(2H)- yl)-5-fluoro-4-methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
A stirred mixture of tert-butyl 4-(5-fluoro-3-iodo-4-methylquinolin-6-yl)-3,3-dimethyl-3,6- dihydropyridine-l(2H)-carboxylate (180 mg, 0.363 mmol), 3-(2,4-dimethoxybenzyl) dihydropyrimidine- 2,4(1 H,3H)-dione ((lb, 144 mg, 0.544 mmol) and K2CO3 (150 mg, 1.088 mmol) in DMSO (12 mL) was sparged with nitrogen for 2 min. Then copper(I) iodide (34.5 mg, 0.181 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 3 h. The cooled reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. This crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 50% acetonitrile in 0.1% FA in water to yield tertbutyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-fluoro-4-methylquinolin- 6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (85 mg, 0.120 mmol, 33% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 633.6; ’H-NMR (400 MHz, DMSO-d6): 5 8.83 (s, 1H), 7.84 (d, J = 8.40 Hz, 1H), 7.53 (t, J = 8.00 Hz, 1H), 7.18 (d, J = 5.8 Hz, 1H), 6.97 (d, J = 9.60 Hz, 1H), 6.48 (d, J = 8.00 Hz, 1H), 5.59 (s, 1H), 4.80 (s, 2H), 4.02-3.91 (m, 3H), 3.80 (s, 6H), 3.11-3.06 (m, 4H), 2.65-2.64 (m, 4H), 1.46 (s, 9H), 1.00 (s, 6H).
Step 11: Synthesis of 3-(2,4-dimethoxybenzyl)-l-(6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5- fluoro-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
A solution of tert-butyl 4-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydro pyrimidin-l(2H)-yl)- 5-fluoro-4-methylquinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate (60 mg, 0.084 mmol) in dichloromethane (1 mL) and HC1 (4 M in 1,4-dioxane, 0.063 mL, 0.25 mmol) was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(2,4- dimethoxybenzyl)-l-(6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-4-methyl quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (50 mg, 0.075 mmol, 88% yield). LCMS m/z MM- ES+APCI, Positive [M+H]+ = 532.8; ’H-NMR (400 MHz, DMSO-d6): 5 8.99 (s, 2H), 8.86 (s, 1H), 7.89
(d, J = 8.40 Hz, 1H), 7.51 (t, J = 8.00 Hz, 1H), 6.97 (d, J = 6.80 Hz, 1H), 6.56 (d, J = 2.40 Hz, 1H), 6.47
(d, J = 2.00 Hz, 1H), 5.65 (s, 1H), 4.80 (s, 2H), 3.98-3.90 (m, 2H), 3.78-3.70 (m, 6H), 3.59 (s, 6H), 2.10
(s, 3H), 1.13 (s, 6H).
Step 12: Synthesis of 3-(2,4-dimethoxybenzyl)-l-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)-benzyl)- l,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione
A mixture of 3-(2,4-dimethoxybenzyl)-l-(6-(3,3-dimethyl-l,2,3,6-tetrahydro pyridin-4-yl)-5- fluoro-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (50 mg, 0.080 mmol), 4- (trifluoromethyl)benzaldehyde (20.8 mg, 0.120 mmol), potassium acetate (23 mg, 0.24 mmol), 2- propanol (1 mL), and NaCNBH4 (15.0 mg, 0.24 mmol) was stirred at 80 °C for 1 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with 10% IP A in CH2Q2 (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated. The crude residue was purified by silica gel flash chromatography, eluting with 5% IP A in DCM to afford 3-(2,4- dimethoxybenzyl)-l-(6-(3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)-5- fluoro-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (50 mg, 0.047 mmol, 59% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 691.6; ’H-NMR (400 MHz, DMSO-d6): 5 8.82 (s, 1H), 8.13 (d. J = 1.20 Hz, 1H), 8.00 (d, J = 7.60 Hz, 1H), 7.86-7.83 (m, 1H), 7.61-7.79 (m, 3H), 7.59 (d, J = 2.40 Hz, 1H). 7.29 (d, J = 6.40 Hz, 1H), 6.98 (d, J = 8.40 Hz, 1H), 5.40 (t, J = 5.60 Hz, 1H), 4.62 (s, 2H), 3.73 (s, 6H), 3.10-3.06 (m, 2H), 2.23 (s, 3H), 1.03 (s, 6H).
Step 13: Synthesis of 3-(2,4-dimethoxybenzyl)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4 (1H,3H)- dione
3-(2,4-Dimethoxybenzyl)- 1 -(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl) benzyl)- 1 ,2,3,6- tetrahydropyridin-4-yl)-5-fluoro-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (40 mg, 0.038 mmol) was treated according to General Procedure 3, Step C. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with 50% acetonitrile in 0.1% FA in water. The partially purified product was further purified by silica gel flash chromatography, eluting with 10% IP A in DCM to afford 3-(2,4-dimethoxybenzyl)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (18 mg, 0.011 mmol, 30% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 709.6.
Step 14: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-863) To a stirred solution of 3-(2,4-dimethoxybenzyl)-l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydropyrimidine-2,4-(lH,3H)-dione (18 mg, 0.011 mmol) and TEA (1.761 pl, 0.023 mmol) in DCM (2 mL) was added dropwise trifluoromethanesulfonic acid (2.0 pl, 0.023 mmol), and the resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative-HPLC [Method info: (Column: X-Select C18 (19 x 250 mm), 5pm), eluting with Mobile phase A: 5 mM ammonium acetate in water, Mobile phase B: acetonitrile, flow rate=15 mL/min] to afford l-(5-fluoro-6-(4-hydroxy- 3,3-dimethyl-l-(4-(trifluoromethyl)-benzyl)piperidin-4-yl)-4-methylquinolin-3-yl)dihydro pyrimidine - 2,4(1 H,3H)-dione (1-863) (0.8 mg, 1.4 pmol, 12% yield). LCMS m/z MM-ES+APCI, Positive [M+H]+ = 559.2; 'H-NMR (400 MHz, DMSO-d6): 5 10.55 (s, 1H), 8.78 (s, 1H), 8.12 (t, J = 8.00 Hz, 1H), 7.83 (d, J
= 9.20 Hz, 1H), 7.71 (d, J = 8.00 Hz, 2H), 7.61 (d, J = 8.00 Hz, 2H), 5.12 (s, 1H), 3.85-3.91 (m, 2H),
3.55-3.70 (m, 4H), 3.19 (s, 2H), 2.61-2.70 (m, 4H), 2.34 (s, 3H), 1.24 (s, 6H).
Example 249: Synthesis of 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-173)
Figure imgf000813_0001
Step 1: Synthesis of tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-2- azaspiro [5.5]undec-4-ene-2-carboxylate
A mixture of (3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)boronic acid (65a, 250 mg, 0.79 mmol), tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (37c, 316 mg, 0.79 mmol), potassium phosphate, tribasic (165 mg, 0.95 mmol) and dioxane (5 mL) was sparged with nitrogen for 10 min at rt. TPdC^dppQ-CHaCL adduct (65 mg, 0.079 mmol) was added and the mixture was again sparged with nitrogen for 10 min. the mixture was sealed and stirred at 80 °C under microwave irradiation for 1 h. The cooled reaction mixture was diluted with water and extracted with
EtOAc. The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 0-80% EtOAc in hexane to afford tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylquinolin-6-yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (400 mg, 0.54 mmol, 68%). LCMS m/z MM-ES+APCI, Positive [M+H]+ 522.5; ’H-NMR (400 MHz, DMSO-d6): 5 10.96 (s, 1H), 8.30 (s, 1H), 7.74 (d, J = 3.60 Hz, 1H), 7.59-7.58 (m, 1H), 7.57-7.46 (m, 1H), 5.60-5.57 (m, 1H), 3.99 (s, 2H), 3.62 (s, 2H), 3.54 (s, 2H), 2.82 (t, J = 8.00 Hz, 1H), 2.68 (s, 3H), 2.12-2.11 (m, 1H), 1.56-1.46 (m, 10H), 0.75 (s, 9H).
Step 2: Synthesis of 3-(5-fluoro-2-methyl-6-(2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine- 2, 6-dione
To a stirred solution of tert-butyl 5-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methyl-quinolin-6- yl)-2-azaspiro[5.5]undec-4-ene-2-carboxylate (600 mg, 1.15 mmol) in DCM (10 mL) at 0 °C was added HC1 (4.0 M in 1,4-dioxane, 2.88 mL, 11.5 mmol) and the mixture was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was triturated with MTBE (20 mL) and dried under vacuum to yield 3-(5-fluoro-2-methyl-6-(2- azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (500 mg, 0.34 mmol, 29%). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 422.1; ’H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, 1H), 8.48 (s, 1H), 7.96-7.93 (m, 1H), 7.57-7.53 (m, 1H), 5.67 (s, 1H), 5.67 (s, 1H), 4.46-4.42 (m, 1H), 3.41- 3.39 (m, 2H), 3.14 (s, 2H), 2.80 (s, 3H), 1.52-1.44 (m, 4H), 0.82-0.75 (m, 10H).
Step 3: Synthesis of 3-(6-(2-ethyl-2-azaspiro[5.5]undec-4-en-5-yl)-5-fluoro-2-methylquinolin-3- yl)piperidine-2, 6-dione
3-(5-Fluoro-2-methyl-6-(2-azaspiro[5.5]undec-4-en-5-yl)quinolin-3-yl)piperidine -2, 6-dione (200 mg, 0.47 mmol) and acetaldehyde (0.027 mL, 0.47 mmol) were reacted with sodium triacetoxyborohydride according to General Procedure 1, Step D. The crude product was purified by reverse phase chromatography on a Cl 8 column, eluting with acetonitrile and 0.1% FA in water to afford 3-(6-(2-ethyl-2-azaspiro[5.5]undec-4-en-5-yl)-5-fhioro-2-methylquinolin-3-yl)piperidine-2, 6-dione (80 mg, 0.10 mmol, 21%). LCMS m/z MM-ES+APCI, Positive [M+H]+ 450.5.
Step 4: Synthesis of 3-(6-(2-ethyl-5-hydroxy-2-azaspiro[5.5]undecan-5-yl)-5-fluoro-2- methylquinolin-3-yl)piperidine-2, 6-dione (1-173)
3-(6-(2-ethyl-2-azaspiro[5.5]undec-4-en-5-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine-2,6- dione (51 mg, 0.113 mmol) was treated according to General Procedure 3, Step C. The reaction mixture was directly concentrated under reduced pressure, and the crude product was triturated with n-hexane and dried under vacuum. The crude product was further purified by preparative-HPLC [Method info: (Column: X Select C18 (150 mm x 19 mm), 5 pm, eluting with Mobile phase A: 0.1% HC1 in water, and Mobile phase B: acetonitrile, flow rate: 10 mL/min] to afford 3-(6-(2-ethyl-5-hydroxy-2- azaspiro[5.5]undecan-5-yl)-5-fluoro-2-methylquinolin-3-yl)piperidine -2, 6-dione, HC1 (36 mg, 0.071 mmol, 29%). LCMS m/z MM-ES+APCI, Positive [M+H]+ 468.4; ’H-NMR (400 MHz, DMSO-d6): 5 10.97 (s, 1H), 8.94 (br s, 1H). 8.28 (d, J = 5.60 Hz, 1H), 8.02 (t, J = 8.40 Hz, 1H), 7.82 (d, J = 8.80 Hz, 1H), 5.87 (s, 1H), 4.40-4.36 (m, 1H), 3.66 (d, J = 12.40 Hz, 1H), 3.29-3.20 (m, 4H), 2.85 (m, 1H), 2.68 (s,
4H), 2.68-2.60 (m, 1H), 2.34-2.33 (m, 1H), 2.12 (m, 1H), 1.96-1.93 (m, 2H), 1.46-1.32 (m, 10H), 0.96
(m, 3H).
Example 250: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5- methylquinolin-3-yl)dihydropyrimidine-2,4(lZ7,3H)-dione (1-307)
Figure imgf000815_0001
Step 1: Synthesis of 3-bromo-6-chloro-5-methylquinoline
A stirred solution of 4-chloro-3-methylaniline (2 g, 14.12 mmol) and 2,2,3-tribromopropanal (9.16 g, 31.1 mmol) in acetic acid (30 mL) was stirred at rt for 3 h, and then at 115 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the crude residue was diluted with EtOAc and washed with water (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with 3% EtOAc in hexanes to afford 3-bromo-6-chloro-5- methylquinoline (0.8 g, 14.1 mmol, 22% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 257.8. ’H-NMR (400 MHz, DMSO-d6): 39.04-8.65 (m, 1H), 8.65-8.41 (m, 1H), 8.23 (d, J = 7.60 Hz, 1H), 7.65-
7.62 (m, 1H), 2.52 (s, 3H).
Step 2: Synthesis of l-(6-chloro-5-methylquinolin-3-yl)-3-(2,4-dimethoxybenzyl)-dihydropyrimidine-
2,4i l//,3//i-dione
To a stirred solution of 3 -bromo-6-chloro-5 -methylquinoline (0.3 g, 1.17 mmol) in DMF (3 mL) under argon sparging was added 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 0.309 g, 1.17 mmol), potassium carbonate (0.194 g, 1.40 mmol), and potassium iodide (0.233 g, 1.40 mmol), with sparging continued for 15 min. Copper (I) iodide (0.044 g, 0.23 mmol) and (lR,2R)-(-)- N,N’ -dimethylcyclohexane- 1,2-diamine (0.033 g, 0.23 mmol) were added, and the reaction mixture was heated at 120 °C for 16 h. The cooled reaction mixture was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 0-35% EtOAc in hexane to afford l-(6-chloro-5-methylquinolin-3-yl)-3- (2,4-dimethoxybenzyl)-dihydropyrimidine-2,4(lH,3H)-dione (0.3 g, 1.17 mmol, 58% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 441.3. ’H-NMR (400 MHz, DMSO-d6): <59.00 (dd, J = 1.60, 4.20
Hz, IH), 8.64 (dd, J = 1.60, 8.80 Hz, 1H), 7.90 (s, 1H), 7.69 (d, J = 4.00 Hz, 1H), 7.11 (d, J = 9.20 Hz,
1H), 6.56-6.53 (m, 2H), 4.79 (s, 2H), 3.90 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.02 (t, 1= 6.40 Hz, 2H),
2.74 (s, 3H).
Step 3: Synthesis of L(6-chh)ro-5-methylquinolin-3-yl)dihydropyrimidine-2,4( 1//.3II )-dione
To a stirred solution of l-(6-chloro-5-methylquinolin-3-yl)-3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (0.3 g, 0.682 mmol) in DCM (3 mL) were added 2,2,2-trifluoroacetic acid (0.74 mL, 0.68 mmol) and trifluoromethanesulfonic acid (0.12 mL, 0.68 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was neutralized with sodium bicarbonate solution and extracted with EtOAc (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4 filtered, and concentrated under reduced pressure to afford l-(6-chloro-5-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (0.16 g, 0.50 mmol, 74% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 290.0. 'H-NMR (400 MHz, DMSO-de): 8 10.43 (s, 1H), 8.97 (dd, J= 1.60, 4.00 Hz, 1H), 8.64 (d, J = 7.20 Hz, 1H), 7.86 (s, 1H), 7.70-7.67 (m, 1H), 3.77 (t, J = 6.40 Hz, 2H), 2.80 (t, J= 6.40 Hz, 2H), 2.74 (s, 3H).
Step 4: Synthesis of tert-butyl 4-(3-(2,4-dioxotetraliydropyriinidin-l(2//)-yl)-5-niethylquinolin-6-yl )- 3,6-dihydropyridine-l(2//)-carhoxylate
A stirred solution of l-(6-chloro-5-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (120 mg, 0.41 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1(2H) -carboxylate (35b, 128 mg, 0.414 mmol), and DIPEA (0.217 mL, 1.24 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was sparged with nitrogen for 5 min. Pdit-BmPh (21.2 mg, 0.041 mmol) was added and reaction mixture was stirred at 80 °C for 4 h. The cooled reaction mixture was concentrated under reduced pressure. The crude was purified by silica gel flash chromatography eluting with 0- 70% EtOAc in hexane to afford tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5-methyl- quinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (40 mg, 0.089 mmol, 39% yield). LCMS: MM- ES+APCI, POSITIVE [M+H]+m/z 437.4. 'H-NMR (400 MHz, DMSO-d6): <5 10.36 (s, IH), 8.91 (d, J = 2.80 Hz, IH), 8.57 (d, 7= 1.60 Hz, IH), 7.62 (dd, J = 4.00, 8.60 Hz, IH), 7.55 (s, IH), 5.69 (s, IH), 4.03 (s, 2H), 3.80-3.60 (m, 4H), 2.79 (t, J= 6.40 Hz, 2H), 2.61 (s, 3H), 2.38 (t, J= 5.20 Hz, 2H), 1.31 (s, 9H). Step 5: Synthesis of l-(5-methyl-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine- 2,4i l//,3//i-dione
To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (40 mg, 0.092 mmol) in 1,4-dioxane (2 mL) was added 4M HC1 in 1,4-dioxane (0.18 mL, 0.73 mmol) at 0 °C. The mixture was stirred and allowed to warm to rt for 3 h. The reaction mixture was concentrated under reduced pressure to provide l-(5-methyl- 6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 337.4. ’H-NMR (400 MHz, DMSO-d6): 5 10.44 (s, 1H), 9.25 (s, 2H), 9.00 (d, J = 3.20 Hz, 1H), 8.73 (d, J = 7.60 Hz, 1H), 7.75-7.60 (m, 2H), 5.71 (s, 1H), 3.77-3.57 (m, 4H), 3.39 (t, J= 5.60 Hz, 2H), 2.82 (t, 7= 6.40 Hz, 2H), 2.67 (s, 3H), 2.58-2.51 (m, 2H).
Step 6: Synthesis of l-(5-methyl-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihvdropyrimidine-2,4( l//,3//)-dione
To a stirred solution of l-(5-methyl-6-(l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, HC1 (0.032 g, 0.086 mmol) in DMF (2 mL) was added 4- (trifluoromethyl)benzaldehyde (0.014 mL, 0.103 mmol) and the mixture was stirred for 1 h at rt. Sodium triacetoxyborohydride (0.045 g, 0.215 mmol) was added in portions and the reaction mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 0-10% IP A in DCM to afford l-(5-methyl-6-(l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(17/,37/)- dione (25 mg, 0.045 mmol, 53% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 495.6.
Step 7: Synthesis of l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-5-methylquinolin- 3-yl )dihydropyrimidine-2,4( l//,3//)-dione (1-307)
To a stirred solution of l-(5-methyl-6-(l-(4-(trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (0.025 g, 0.051 mmol) in 2-propanol (5 mL) and DCM (1 mL) were added Mn(dpmh (0.015 g, 0.025 mmol) and phenylsilane (0.012 mL, 0.101 mmol) at 0 °C and the reaction mixture was stirred at rt under 1 atmosphere O2 for 16 h. The reaction mixture was quenched with saturated aqueous sodium thiosulphate (10 mL) and was then extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SOr, filtered and concentrated under reduced pressure. The crude residue was purified by preparative-HPLC [Method info: (Column: ZORBAX C18 150 x 21.2), 7pm, eluting with Mobile phase A: 0.1 FA in H2O:ACN, Mobile phase B: Acetonitrile, flow rate: 15 mL/min] to obtain l-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)-5-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1.5 mg, 2.7 pmol, 5% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 513.3. ’H-NMR (400 MHz, DMSO-dg): d 10.32 (s, 1H), 8.89 (d, 7= 1.60 Hz, 1H), 8.62 (d, 7= 7.20 Hz, 1H), 8.48 (s, 1H), 7.91 (s, IH), 7.70 (d, 7= 8.00 Hz, 2H), 7.58 (d, 7 = 4.40 Hz, 2H), 6.69 (s, 1H), 5.11 (s, 1H), 3.79-3.32 (m, 4H), 2.95 (s, 3H), 2.66-2.50 (m, 5H), 2.19-2.17 (m, 2H), 1.90 (d, 2H).
Example 251: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-8- methylquinolin-3-yl)piperidine-2, 6-dione (1-902)
Figure imgf000818_0001
Step 1: Synthesis of 3-bromo-6-iodo-8-methylquinoline
A stirred solution of 4-iodo-2-methylaniline (5 g, 21.5 mmol) and 2,2,3-tribromopropanal (6.32 g, 21.5 mmol) in acetic acid (30 mL) was heated at 115 °C for 2 h. Saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was extracted with EtOAc (2 x 75 mL). The combined organic layers were concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 0-100% EtOAc in hexane to afford 3-bromo-6-iodo-8-methylquinoline (2.5 g, 5.3 mmol, 25% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+ 347.7, 349.6; >H- NMR (400 MHz, DMSO-d6): 89.00 (dd, J= 2.40, 7.60 Hz, 1H), 8.67 (dd, 7 = 2.00, 17.40 Hz, 1H), 8.29 (d, J = 1.60 Hz, 1H), 7.97 (d, J = 1.20 Hz, 1H), 2.68 (s, 3H).
Step 2: Synthesis of tert-butyl 4-(3-bromo-8-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate
To a stirred solution of 3 -bromo-6-iodo- 8 -methylquinoline (1 g, 2.87 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(27f)-carboxylate (35b, 0.355 g, 1.15 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at rt was added tripotassium phosphate (1.22 g, 5.75 mmol) and the mixture was sparged with nitrogen for 10 min. Then was added PdC12(dppf)-CH2Ch adduct (0.117 g, 0.144 mmol) and the mixture was again sparged with nitrogen for 10 min. The reaction vessel was sealed and the mixture heated with stirring under microwave irradiation at 70 °C for 1 h. The cooled mixture was filtered through a pad of Celite, rinsing with EtOAc (2 x 50 mL). The combined organic layers were concentrated under reduced pressure and the crude residue was purified by silica gel flash chromatography, eluting with 0-6% EtOAc in hexane to afford tert-butyl 4-(3-bromo-8- methylquinolin-6-yl)-3,6-dihydro-pyridine-l(2H)-carboxylate (340 mg, 0.79 mmol, 28% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+2+H]+ 404.7; ’H-NMR (400 MHz, DMSO-d6): 3 8.91 (d, I = 2.40 Hz, 1H), 8.65 (d, J = 2.40 Hz, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 6.41 (s, 1H), 4.08 (m, 2H), 3.61-3.58 (m, 2H), 2.61 (s, 3H), 2.56 (m, 2H), 1.45 (s, 9H).
Step 3: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)-3,6- dihydropyridine- 1 ( 2// )-ca rboxy lat e
To a stirred solution of tert-butyl 4-(3-bromo-8-methylquinolin-6-yl)-3,6-dihydro-pyridine- 1(2H) -carboxylate (340 mg, 0.84 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (INT-4B, 352 mg, 0.843 mmol) in 1,4-dioxane (10.0 mL) and water (2.0 mL) was added DIPEA (0.294 mL, 1.686 mmol) at rt and the mixture was sparged with nitrogen for 10 min. Bis(tri-tert-butylphosphine)palladium(0) (21.5 mg, 0.042 mmol) was added and the mixture sparged again with nitrogen for 10 min. The reaction mixture was irradiated in a microwave at 80 °C for 1 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc (2 x 50 mL). The organic layer was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 25-30% EtOAc in hexanes as the eluent to provide tert-butyl 4-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (320 mg, 0.508 mmol, 60% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 614.5. ’H-NMR (400 MHz, DMSO-d6): 59.07 (d, J = 2.00 Hz, 1H), 8.43 (d, J = 2.40 Hz, 1H), 7.97 (d, J = 8.00 Hz, 1H). 7.79 (dd, J = 13.20, Hz, 2H), 7.48-7.34 (m, 10H), 6.66 (d, J = 8.40 Hz, 1H), 6.39 (s, 1H), 5.45 (dd, J= 18.80, Hz, 4H), 4.08-4.01 (m, 4H), 3.61 (m, 2H), 2.68 (s, 3H), 1.45 (s, 9H).
Step 4: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate
To a stirred solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)- 3,6-dihydropyridine-l(2H)-carboxylate (320 mg, 0.52 mmol) in DCM (20 mL)/IPA (10 mL) was added Mn(dpm)s (94 mg, 0.16 mmol), at 25 °C and the mixture was sparged with O2 for 5 min. followed by addition of phenyl silane (0.162 mL, 1.30 mmol). The reaction mixture was stirred at rt under 1 atmosphere of oxygen for 16 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc (2 x 50 mL). The combined filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography eluting with 30-35% EtOAc in hexanes to provide tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)-4-hydroxypiperidine-l- carboxylate (170 mg, 0.25 mmol, 47% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 632.7. ’H- NMR (400 MHz, DMSO-dg): 39.08 (d, J= 2.40 Hz, 1H), 8.45 (d, J = 2.40 Hz, 1H), 7.97 (d, J= 8.00 Hz, IH), 7.85 (s, IH), 7.77 (s, 1H), 7.48-7.36 (m, 10H), 6.66 (d. J = 8.40 Hz, 1H), 5.76 (s, 1H), 5.45 (m, 4H), 3.93 (s, 2H), 2.74-2.73 (m, 4H), 1.94-1.91 (m, 2H), 1.44 (s, 9H), 1.08 (s, 3H).
Step 5: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-8-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate
To a solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (300 mg, 0.475 mmol) in DMF (5.0 mL) was added Pd/C (250 mg, 2.349 mmol), and the mixture was stirred under 1 atmosphere hydrogen pressure at rt for 16 h. The reaction mixture was filtered through celite, rinsing with EtOAc (2 x 25 mL). The combined filtrate was concentrated under reduced pressure to provide terf-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-8-methyl- quinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (200 mg, 0.410 mmol, 86% yield). LCMS: m/z MM- ES+APCI, POSITIVE [M+H]+ 454.5. 'H-NMR (400 MHz, DMSO-d6): <5 10.97 (s, 1H), 8.77 (d, J= 2.00
Hz, IH), 8.15 (d, J= 2.00 Hz, 1H), 7.96-7.93 (m, 1H), 5.25 (s, 1H), 4.12 (m, 2H), 3.93 (m, 4H), 3.32-3.29
(m, IH), 2.48-2.43 (m, 2H), 2.34-2.33 (m, 2H), 1.67 (d, J = 12.40 Hz, 2H), 1.43 (s, 9H), 1.41 (s, 3H).
Step 6: Synthesis of 3-(6-(4-hydroxypiperidin-4-yl)-8-methylquinolin-3-yl)piperidine-2, 6-dione
To a stirred solution of terf-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-8-methylquinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate (200 mg, 0.44 mmol) in DCM (10 mL) was added 4 M HC1 in 1,4- dioxane (0.8 mL, 3.20 mmol) at 0 °C. The mixture was stirred and allowed to warm to rt over 2h. The reaction mixture was concentrated under reduced pressure to provide 3-(6-(4-hydroxypiperidin-4-yl)-8- methylquinolin-3-yl)piperidine-2, 6-dione, HC1 (150 mg, 0.32 mmol, 72% yield). LCMS: m/z MM- ES+APCI, POSITIVE [M+H]+ 354.0. ’H-NMR (400 MHz, DMSO-d6): 8 11.00 (s, IH), 8.86 (d, J = 2.00 Hz, IH), 8.79 (br s, 2H), 8.33 (s, IH), 7.86 (s, IH), 7.76 (s, IH), 6.00 (s, IH), 4.22-4.18 (m, IH), 3.39- 3.26 (m, 5H), 2.90-2.80 (m, 3H), 2.79 (s, 3H), 2.17-2.10 (m, 2H), 1.91-1.85 (m, 2H).
Step 7: Synthesis of 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-8-methylquinolin- 3-yl)piperidine-2, 6-dione (1-902)
To a stirred solution of 3-(6-(4-hydroxypiperidin-4-yl)-8-methylquinolin-3-yl)piperidine-2,6- dione, HC1 (150 mg, 0.39 mmol) in DMF (2.0 mL) was added 4-(trifluoromethyl)-benzaldehyde (80 mg, 0.46 mmol) and the mixture was stirred at rt for 1 h. Sodium triacetoxyborohydride (163 mg, 0.769 mmol) was added and the reaction mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure, and the crude residue was purified by preparative-HPLC [Method info: (Column: X select (150 xl9 mm), Sum, eluting with Mobile phase A: 0.1% HC1 in FLO. Mobile phase B: Acetonitrile, flow rate: 15 mL/min] to provide 3-(6-(4-hydroxy-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-8- methylquinolin-3-yl)piperidine-2, 6-dione, HC1 (1-902) (44.1 mg, 0.080 mmol, 21% yield) LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 512.5. ’H-NMR (400 MHz, DMSO-d6): 5 11.01 (s, IH), 10.54 (br s,
IH), 8.83 (s, IH), 8.26 (s, 1H), 7.88 (br s, 4H), 7.83 (s, 1H), 7.72 (s, 1H), 5.69 (br s, 1H), 4.54 (d, J= 5.20 Hz, 2H), 4.20-4.16 (m, 1H), 3.36 (br s, 4H), 2.77 (s, 3H), 2.64-2.61 (m, 2H), 2.60-2.59 (m, 1H), 2.46-2.41 (m, 1H), 2.46-2.41 (m, 1H), 1.93-1.89 (m, 2H).
Example 252: Synthesis of 3-(6-(3-cyclopropyl-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione (1-330)
Figure imgf000821_0001
Step 1: Synthesis of l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3- cyclopropylpiperidin-4-ol l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3-cyclopropylpiperidin-4-ol (290 mg, 0.421 mmol, 42% yield) was prepared from 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromoquinoline (INT-13A, 500 mg, 1.005 mmol) and l-benzyl-3-cyclopropylpiperidin-4-one (prepared in Ex 240 Step 1, 300 mg, 1.307 mmol) according to General Procedure 2, Step A. The crude product was purified by silica gel flash chromatography, eluting with 0-50% EtOAc in hexanes. LCMS: ES+APCI, POSITIVE [M+H]+ 648.9. ’H-NMR (400 MHz, DMSO-d6): 89.04 (d, J= 2.40 Hz, 1H), 8.46 (d, 7 = 2.00 Hz, 1H),
8.07 (s, 1H), 7.98 (d, 7 = 8.40 Hz, 1H), 7.90-7.85 (m, 2H), 7.47-7.35 (m, 15H), 6.66 (d, J = 8.00 Hz, 1H),
5.45 (s, 4H), 5.01 (s, 1H), 3.60-3.55 (m, 1H), 3.37-3.32 (m, 1H), 2.68-2.65 (m, 2H), 2.51-2.49 (m, 1H),
2.37-2.33 (m, 1H), 1.46-1.30 (m, 1H), 1.20-1.16 (m, 1H), 0.98 (bs, 1H), 0.66-0.65 (m, 1H), 0.14-0.10 (m,
1H), -0.13-0.24 (m, 2H), -0.83-0.94 (m, 1H).
Step 2: Synthesis of tert-butyl 3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine- 1-carboxylate
To a stirred solution of l-benzyl-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)quinolin-6-yl)-3- cyclopropylpiperidin-4-ol (280 mg, 0.432 mmol) in DMF (5 mL) was added Boc-anhydride (283 mg, 1.30 mmol) and Pd/C 10% (250 mg, 0.432 mmol), and the reaction mixture was stirred for 10 h at rt under 1 atmosphere hydrogen pressure. The reaction mixture was filtered through celite, rinsing with DMF and EtOAc. The combined filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with IP A in DCM to afford tert-butyl 3- cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4-hydroxypiperidine-l-carboxylate (90 mg, 0.19 mmol, 40% yield). LCMS: ES+APCI, POSITIVE [M+H]+ 480.4. ’H-NMR (400 MHz, DMSO-dg): 8 10.97 (s, 1H), 8.75 (d, J= 2.00 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 9.20 Hz, 1H), 7.83 (d, J = 9.60 Hz, IH), 5.31 (s, IH), 4.17-4.12 (m, IH), 3.89 (s, IH), 3.20-3.15 (m, 2H), 2.90-2.81 (m, IH), 2.78-
2.74 (m, IH), 2.67-2.62 (m, IH), 2.16-2.03 (m, IH), 1.63-1.59 (m, IH), 1.44 (s, 1 IH), 1.11-0.84 (m, 2H),
0.65-0.63 (m, 1H), 0.12-0.10 (m, 1H), -0.13-0.24 (m, 2H), -0.83-0.94 (m, 1H).
Step 3: Synthesis of 3-(6-(3-cyclopropyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione
To a stirred solution of tert-butyl 3-cyclopropyl-4-(3-(2,6-dioxopiperidin-3-yl)quinolin-6-yl)-4- hydroxypiperidine-1 -carboxylate (80 mg, 0.17 mmol) in DCM (5 mL) was added 4M HC1 in 1,4-dioxane (0.3 mL, 1.2 mmol) at 0 °C and reaction mixture was stirred for 2 h at 0 °C. The mixture was concentrated under reduced pressure, and the crude was washed with pentane to afford 3-(6-(3- cyclopropyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (70 mg, 0.16 mmol, 97% yield). LCMS: ES+APCI, POSITIVE [M+H]+ 380.3. 'H-NMR (400 MHz, DMSO-d6): 8 11.04 (s, IH), 9.01-8.95 (m, 3H), 8.61 (s, IH), 8.16 (d, 7= 8.40 Hz, 2H), 7.91 (d, 7= 8.00 Hz, IH), 5.76 (s, IH), 4.28 (d,
7 = 4.40 Hz, IH), 3.26-3.13 (m, 5H), 2.90-2.86 (m, IH), 2.77-2.74 (m, IH), 2.34-2.20 (m, IH), 1.82-1.79
(m, IH), 1.60-1.57 (m, 1H), 1.11-1.08 (m, 1H), 0.87-0.68 (m, 1H), 0.25-0.23 (m, 2H), -0.12-0.24 (m,
2H), -0.83-0.86 (m, 1H).
Step 4: Synthesis of 3-(6-(3-cyclopropyl-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine- 2, 6-dione (1-330)
A mixture of 3-(6-(3-cyclopropyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, HC1 (60 mg, 0.14 mmol) DMF (2 mL) and acetaldehyde (12.7 mg, 0.29 mmol) was stirred at rt for 1 h. To this mixture was added sodium triacetoxyborohydride (92 mg, 0.433 mmol) and the reaction mixture was stirred at rt for 6 h. The mixture was concentrated under reduced pressure, and the crude residue was triturated with MTBE/pentane to give a crude solid. The crude solid was further purified by reverse phase chromatography using a C-18 column, eluting with acetonitrile in 0.1% FA in H2O to afford 3-(6-(3- cyclopropyl-l-ethyl-4-hydroxypiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1-330, 5.8 mg, 0.013 mmol, 9% yield). LCMS: ES+APCI, POSITIVE [M+H]+ 408.5. 'H-NMR (400 MHz, DMSO- d6): 8 10.97 (s, 1H), 8.74 (d, J= 2.00 Hz, 1H), 8.18 (s, 2H), 8.03 (s, 1H), 7.93 (d, J = 8.80 Hz, 1H), 7.81 (d, J = 8.80 Hz, 1H), 5.07 (s, 1H), 4.17-4.12 (m, 1H), 2.81-2.75 (m, 3H), 2.68-2.64 (m, IH), 2.63-2.59 (m, 2H), 2.19-2.16 (m, 2H), 1.66-1.63 (m, IH), 1.28-1.24 (m, IH), 1.13 (t, 7 = 7.20 Hz, 3H), 0.87-0.68 (m, IH), 0.25-0.23 (m, 2H), -0.12-0.24 (m, 2H), -0.83-0.86 (m, H).
Example 253: Synthesis of l-(5-amino-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)- benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-914)
Figure imgf000823_0001
Step 1: Synthesis of 6-bromo-3-iodo-5-nitroquinoline
To a stirred solution of 6-bromo-5 -nitroquinoline (2.5 g, 9.88 mmol) in acetic acid (20 mL) was added N-iodosuccinimide (6.67 g, 29.6 mmol) at rt. The resulting reaction mixture was stirred at 80 °C for 16 h. The cooled reaction mixture was filtered through a Celite bed, rinsing with EtOAc (60 mL), and the combined filtrate was washed with water (30 mL). The organic layer was dried over anhydrous NasSOx. filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography, eluting with 30-40% EtOAc in hexanes to afford 6-bromo-3-iodo-5-nitroquinoline (1.8 g, 4.32 mmol, 44% yield). LCMS: m/z MM-ES+APCI, Positive [M+H, M+2+HJ+ = 378.9, 380.8. ’H-NMR (400 MHz, DMSO-d6): 39.18 (d, J= 1.60 Hz, 1H), 8.43 (d, J= 1.20 Hz, 1H), 8.12 (d, J= 9.20
Hz, IH), 7.95 (d, J= 9.20 Hz, 1H).
Step 2: Synthesis of 6-bromo-3-iodoquinolin-5-amine
A stirred mixture of 6-bromo-3-iodo-5-nitroquinoline (3.5 g, 9.24 mmol), acetic acid (30 mL), water (3 mL), iron powder (3.09 g, 55.4 mmol), and ammonium chloride (0.99 g, 18.5 mmol) was stirred at 80 °C for Ih. The cooled reaction mixture was concentrated under reduced pressure. The crude residue was taken up in 10% IP A in DCM (40 mL) then washed with water (10 mL). The organic layer was concentrated under reduced pressure, and the crude residue was purified by silica gel flash chromatography, eluting with 0-100% EtOAc in hexane to afford 6-bromo-3-iodoquinolin-5-amine (1.7 g, 4.7 mmol, 51% yield). LCMS m/z MM-ES+APCI, POSITIVE [M+H, M+2+H? = 349.7, 351.7; ’H-NMR (400 MHz, DMSO-de): <59.15 (d, J= 1.20 Hz, IH), 8.96 (d, J= 2.00 Hz, IH), 7.71 (d, J= 8.80 Hz, IH),
7.12 (d, J = 8.80 Hz, IH), 6.24 (s, 2H),
Step 3: Synthesis of l-(5-amino-6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)-dihydropyrimidine- 2,4i l//,3//l-di<me To a stirred solution of 6-bromo-3-iodoquinolin-5-amine (500 mg, 1.43 mmol) in 2-methyl tetrahydrofuran (10 mL) at rt was added 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (lb, 379 mg, 1.433 mmol) and potassium carbonate (K2CO3, 297 mg, 2.149 mmol) and the mixture was sparged with nitrogen for 10 min. To the reaction mixture were added copper(I) iodide (27.3 mg, 0.143 mmol) and (R,R)-(-)-N,N-dimethyl-l,2-cyclohexane-diamine (20.4 mg, 0.143 mmol), then the mixture was again sparged with nitrogen for 5 min. The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was filtered through Celite, rinsing with EtOAc (80 mL). The combined filtrate was washed with water (30 mL), dried over anhydrous Na?SO4 filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on alumina, eluting with 70-80% EtOAc in hexane to afford l-(5-amino-6-bromoquinolin-3-yl)-3-(2,4- dimethoxybenzyl)dihydropyrimidine-2,4(lH,3H)-dione (0.5 g, 2.81 mmol, 69% yield). LCMS: m/z MM- ES+APCI, POSITIVE [M+H, M+2+H]+ = 485.1, 487.0. *H-NMR (400 MHz, DMSO-d6): 8 8.87 (d, 7 =
2.40 Hz, 1H), 8.59 (d, 7= 2.00 Hz, 1H), 7.67 (d, J = 8.80 Hz, 1H), 7.17 (d, 7= 8.80 Hz, 1H), 6.94 (d, 7 =
8.40 Hz, 1H), 6.56 (d, 7= 2.00 Hz, 1H), 6.46 (d, 7= 2.40 Hz, 1H), 6.16 (s, 2H), 4.82 (s, 2H), 4.03 (t, 7 =
6.40 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.03 (t, 7 = 6.40 Hz, 2H).
Step 4: Synthesis of tert-butyl 4-(5-amino-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydro- pyrimidin-l(2H)-yl)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(2H)-carboxylate
To a stirred solution of l-(5-amino-6-bromoquinolin-3-yl)-3-(2,4-dimethoxybenzyl)- dihydropyrimidine-2,4(lH,3H)-dione (0.5 g, 1.03 mmol) and tert-butyl 3,3-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2//)-carboxylate (INT-40, 0.347 g, 1.03 mmol) in 1,4-dioxane (5 mL) was added a solution of K2CO3 (0.142 g, 1.03 mmol) in water 2 (0.5 mL), followed by cataCXium A PdG3 (0.075 g, 0.103 mmol). The mixture was sparged with nitrogen, then was stirred at 100 °C for 1 h. The cooled reaction mixture was filtered through Celite, rinsing with 10% IP A in DCM. The combined filtrate was washed with water (100 mL), dried over Na^SOr and concentrated. The crude residue was purified by reverse phase chromatography on a Cl 8 column, eluting with 70% ACN in 0.05% FA in water to provide tert-butyl 4-(5-amino-3-(3-(2,4-dimethoxybenzyl)-2,4- dioxotetrahydropyrimidin-l(27/)-yl)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(27/)-carboxylate (0.2 g, 0.32 mmol, 24% yield). LCMS: m/z MM-ES+APCI, Positive [M+l]+ = 616.9.
Step 5: Synthesis of l-(5-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of tert-butyl 4-(5-amino-3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetra- hydropyrimidin-l(270-yl)quinolin-6-yl)-3,3-dimethyl-3,6-dihydropyridine-l(27f)-carboxylate (200 mg, 0.32 mmol) in DCM (4 mL) was added TEA (0.2 mL, 2.60 mmol) and triflic acid (0.2 mL, 2.3 mmol) under a nitrogen atmosphere at rt. The reaction mixture was stirred at 80°C for 1 h. The mixture was concentrated under reduced pressure to provide l-(5-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, TFA (0.15 g, 0.31 mmol). LCMS: m/z MM- ES+APCI, Positive [M+H]+ = 366.2.
Step 6: Synthesis of l-(5-amino-6-(3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6- tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(XH,3H)-dione
To a stirred solution of l-(5-amino-6-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, TFA (0.15 g, 0.313 mmol) in DCM (2 mL) were added 1- (bromomethyl)-4-(trifluoromethyl)benzene (0.090 g, 0.38 mmol) and TEA (0.16 g, 1.56 mmol) and the mixture was stirred at 60 °C for 1 h in a pressure vessel. The cooled reaction mixture was diluted with water (25 mL) and extracted with 10% IP A in DCM. The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The crude residue was purified by silica gel column chromatography, eluting with 10% IP A in DCM to provide l-(5-amino-6-(3,3-dimethyl-l-(4- (trifluoromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3/7)- dione (100 mg, 0.13 mmol, 43% yield). LCMS: m/z MM-ES+APCI, Positive [M+l]+ = 524.3.
Step 7: Synthesis of l-(5-amino-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)-piperidin- 4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (1-914) l-(5-amino-6-(3,3-dimethyl-l-(4-(trifhioromethyl)benzyl)-l,2,3,6-tetrahydropyridin-4- yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (100 mg, 0.134 mmol) was treated according to General Procedure 3, Step C. The crude product was purified by preparative-HPLC [Method info: (Column: Zorbax C18 (150 x21.2mm), 5pm, eluting with Mobile phase B: 0.1% acetic acid in water, Mobile phase B: acetonitrile, flow rate: 15.0 mL/min] to afford l-(5-amino-6-(4-hydroxy-3,3-dimethyl-l- (4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)dihydropyrimidine-2,4(lH,3F?)-dione (0.98 mg, 1.7 pmol, 1% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+l]+ = 542.3. ’H-NMR (400 MHz, DMSO-ds): d 10.54 (s, 1H), 8.77 (d, J= 2.00 Hz, 1H), 8.41 (d, 7= 2.00 Hz, 1H), 7.71 (d, J= 8.00 Hz, 2H), 7.60 (d, J= 8.00 Hz, 2H), 7.44 (d, 7= 9.20 Hz, 1H), 7.15 (d, 7= 8.80 Hz, 1H), 6.62 (s, 1H), 5.46 (s, 1H), 5.33 (s, 1H), 3.94 (t, 7 = 6.80 Hz, 2H), 3.63-3.61 (m, 3H), 3.41-3.39 (m, 2H), 2.09-1.98 (m, 3H), 1.77-1.72 (m, 1H), 1.54-1.49 (m, 1H), 1.00 (s, 3H), 0.85 (s, 3H).
Example 254: Synthesis of l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy- 3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (I- 1079), R)-l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3- dimethylpiperidin-4-yl )-5-fhioro-2-methylquinolin-3-yl )dihydropyriniidine-2,4( l//,3//)-dione (I- 1079-peakl) and (S) l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3- dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lfl,3H)-dione (I- 1079-peak2)
Figure imgf000826_0001
Step 1: Synthesis of l-(6-(l-((2-amino-6-(trifhioromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3- dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3fD-dione
To a stirred solution of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)-2-methylquinolin- 3-yl)dihydropyrimidine-2,4(lH,3H)-dione (INT-S6, 100 mg, 0.25 mmol) and 2-amino-6- (trifluoromethyl)nicotinaldehyde (48 mg, 0.25 mmol) in DMF (0.5 mL) was added MP-cyanoborohydride (100 mg, 0.25 mmol), and the reaction mixture was stirred for 1 h at 80 °C. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by preparative-HPLC [Method info: (Column: Shim-pack C18 (20 x 250 mm), 5pm, eluting with Mobile phase A: 5 mM ammonium acetate in water, Mobile phase B: acetonitrile, flow rate: 15 mL/min] to afford l-(6-(l-((2-amino-6- (trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin- 3-yl)dihydropyrimidine-2,4(lH,3fl)-dione (21.6 mg, 0.037 mmol, 15% yield). LCMS: ES+APCI, POSITIVE [M+H]+ 575.4, ‘H-NMR (400 MHz, DMSO-d6): ‘H-NMR (400 MHz, DMSO-d6): 5 10.55 (s, 1H), 8.42 (s, 1H), 8.09 (t, 7 = 8.80 Hz, 1H), 7.79 (d, J = 9.20 Hz, 1H), 7.57 (d, J = 7.20 Hz, 1H), 6.96 (d, 7 = 7.20 Hz, 1H), 6.80 (s, 2H), 5.22 (d, 7= 9.20 Hz, 2H), 3.99-3.97 (m, 1H), 3.71-3.68 (m, 1H), 3.48 (s, 2H), 3.33-3.11 (m, 1H), 2.88-2.80 (m, 1H), 2.79-2.67 (m, 1H), 2.65 (s, 3H), 2.54-2.51 (m, 1H), 2.35-2.33 (m, 1H), 1.76-1.71 (m, 1H), 1.24 (s, 1H), 0.98 (s, 3H), 0.97 (s, 3H).
Step 2: Chiral SEC Separation of (R)-l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4- hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine- 2,4i l//,3//i-dione and (S) l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3- dimethylpiperidin-4-yl )-5-fhioro-2-melhyl(piinolin-3-yl )dihydropyriinidine-2,4( l//,3//)-dione l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-hydroxy-3,3-dimethylpiperidin-4- yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3//)-dione was subjected to chiral SEC chromatography using methods similar those disclosed for other examples. Two fractions obtained after chiral SEC chromatography were collected separately and lyophilized. Each fraction was separately further purified by preparative-HPLC [Method info: (Column: Shim-pack C18 (20 x 250 mm)), 5pm, eluting with Mobile phase A: 0.1% FA in Water, Mobile phase B: Acetonitrile, flow rate: 15 mL/min]. Fraction 1 (1-1079, Peak-1): (R)-l-(6-(l-((2-amino-6-(trifluoromethyl)pyridin-3-yl)methyl)-4- hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,377)- dione (4.1 mg, 7.1 pmol, 20 % yield). LCMS: ES+APCI, POSITIVE [M+H] + 575.2, ’H-NMR (400 MHz, DMSO-ds): ’H-NMR (400 MHz, DMSO-d6): 8 10.55 (s, 1H), 8.42 (s, 1H), 8.09 (t. J = 8.80 Hz, 1H), 7.79 (d, J = 9.20 Hz, 1H), 7.57 (d, J = 7.20 Hz, 1H), 6.96 (d, J = 7.60 Hz, 1H), 6.80 (s, 2H), 5.22 (d, J = 8.80
Hz, IH), 4.01-3.98 (m, 1H), 3.71-3.68 (m, 1H), 3.48 (s, 2H), 3.48-3.12 (m, 1H), 2.88-2.85 (m, 1H), 2.85- 2.75 (m, IH), 2.69-2.65 (m, IH), 2.63 (s, 3H), 2.54-2.51 (m, IH), 2.34 (d, J = 2.00 Hz, IH), 1.74-1.71 (m, IH), 1.24 (s, IH), 0.98 (s, 3H), 0.70 (s, 3H)
Fraction 2 (1-1079, Peak-2): (S)-l-(6-(l-((2-amino-6-(trifhioromethyl)pyridin-3-yl)methyl)-4- hydroxy-3,3-dimethylpiperidin-4-yl)-5-fluoro-2-methylquinolin-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (4.1 mg, 7.1 pmol, 20 % yield). LCMS: ES+APCI, POSITIVE [M+H] + 575.4, ’H-NMR (400 MHz, DMSO-d6): 8 10.55 (s, IH), 8.38 (s, 2H), 8.09 (t, J= 8.80 Hz, IH), 7.79 (d, J = 8.80 Hz, IH), 7.57 (d, J = 7.20 Hz, IH), 6.96 (d, J = 7.20 Hz, IH), 6.80 (s, 2H), 6.60 (s, IH), 5.22 (d, J = 9.20 Hz, IH), 3.99 (m, IH), 3.70-3.47 (m, 2H), 3.32-3.21 (m, IH), 2.88-2.80 (m, 2H), 2.79-2.75 (m, IH), 2.68 (s, 3H), 2.34-2.33 (m, IH), 1.74-1.71 (m, IH), 1.24 (s, IH), 0.97 (s, 3H), 0.70 (s, 3H).
Note: Absolute stereochemistry was assigned arbitrarily.
Example 255: Synthesis of 3-(5-fluoro-6-(4-hydroxy-l-(2-hydroxy-2-methylpropyl)-3,3- dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-217)
Figure imgf000827_0001
51d 40°C, 10 h
To a stirred solution of 3-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3- yl)piperidine-2, 6-dione, HC1 (51d, 50 mg, 0.119 mmol) in tetrahydrofuran (2 mL) and 2-propanol (2 mL) was added triethylamine (TEA, 36.0 mg, 0.36 mmol) at 25 °C and the mixture was stirred for 10 min. 2,2- dimethyloxirane (10.3 mg, 0.14 mmol) was added portion-wise over a period of 10 h. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with MTBE/pentane and then was further purified by reverse phase chromatography using a Cl 8 column, eluting with acetonitrile in 0.1% formic acid in water to afford 3-(5-fluoro-6-(4-hydroxy-l-(2-hydroxy-2- methylpropyl)-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione, formic acid (1-217, 20 mg, 0.040 mmol, 33% yield). LCMS: m/z MM-ES+APCI, Positive [M+H]+ 458.5; ’H-NMR (400 MHz, DMSO-d6): 5 10.98 (s, IH), 8.84 (d, J = 2.00 Hz, IH), 8.32 (s, IH), 8.16 (s, IH), 8.09 (t, J = 8.40 Hz, IH), 7.83 (d, J = 9.20 Hz, IH), 6.55 (bs, IH), 5.04 (s, IH), 4.23 (q, J = 4.40 Hz, IH), 3.17 (t, J = 13.60 Hz, IH), 2.76-2.60 (m, 5H), 2.48-2.44 (m, 1H), 2.25-2.14 (m, 3H), 1.64 (d, J = 13.20 Hz, 1H), 1.13 (m, 6H), 1.02 (s, 3H), 0.68 (s, 3H).
Example 256: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-((S)-l-(4-(trifluoromethyl)- phenyl)ethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1015)
Figure imgf000828_0001
Step 1: Synthesis of (R)-l-(4-(trifluoromethyl)phenyl)ethyl methanesulfonate
To a stirred solution of (R)-l-(4-(trifluoromethyl)phenyl)ethan-l-ol (0.162 mL, 1.05 mmol) in dichloromethane (DCM, 3 mL) at 0 °C were added triethylamine (0.43 mL, 3.16 mmol) and methane sulfonyl chloride (0.122 mL, 1.58 mmol), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography using neutral alumina, eluting with 0-5% EtOAc in hexane obtain (R)-l-(4- (trifhioromethyl)phenyl)ethyl methane sulfonate (200 mg, 0.653 mmol, 62% yield). LCMS: m/z MM- ES+APCI, Positive [M+H]+ Not ionized; ’H-NMR (400 MHz, CDC13): 57.69 (d, J = 8.40 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 5.81 (q, J = 6.40 Hz, 1H), 2.87 (s, 3H), 1.75 (d, J = 6.40 Hz. 3H).
Step 2: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-((S)-l-(4-(trifluoromethyl)phenyl)- ethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1015)
To a stirred solution of 3-(6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)piperidine-2,6- dione (INT-S20, 50 mg, 0.136 mmol) in acetonitrile (3 mL) at rt were added DIPEA (0.073 mL, 0.408 mmol) and (R)-l-(4-(trifluoromethyl)phenyl)ethyl methane sulfonate (73.0 mg, 0.272 mmol), and the reaction mixture was stirred at 60 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative-HPLC [Method info: (Column: Prudent C18, 20 x 250 mm), 5 pm, Mobile phase A: 0.1% FA in water, Mobile phase B: acetonitrile, flow rate = 15 mL/min] to afford 3-(6-(4-hydroxy-3,3-dimethyl-l-((S)-l-(4-(trifluoromethyl)phenyl)ethyl)piperidin- 4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1015) (19 mg, 0.034 mmol, 25% yield. LCMS: m/z MM- ES+APCI, Positive [M+H]+ 540.5; ’H-NMR (400 MHz, DMSO-d6): 5 10.96 (s, 1H), 8.75 (d, J = 1.60 Hz,
1H), 8.20 (s, 1H), 7.98-7.89 (m, 3H), 7.73-7.70 (m, 2H), 7.64-7.59 (m, 2H), 4.77 (d, J = 6.80 Hz, 1H),
4.16-4.12 (m, 1H), 2.82-2.73 (m, 3H), 2.60-2.59 (m, 2H), 2.51-2.50 (m, 2H), 2.34-2.29 (m, 1H), 2.17-
2.10 (m, 2H), 1.36 (m, 1H), 1.35 (m, 3H), 0.92-0.87 (m, 3H), 0.71-0.63 (m, 3H).
Example 257: Synthesis of 3-(6-(4-hydroxy-3,3-dimethyl-l-((R)-l-(4-(trifhioromethyl)- phenyl)ethyl)piperidin-4-yl)quinolin-3-yl)piperidine-2, 6-dione (1-1014)
Figure imgf000829_0001
3-(6-(4-hydroxy-3,3-dimethyl-l-((R)-l-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)quinolin-
3-yl)piperidine-2, 6-dione (1-1014) was prepared in two steps similarly to Example 256, 1-1015, starting from (S)-l-(4-(trifluoromethyl)phenyl)ethan-l-ol. LCMS: m/z MM-ES+APCI, Positive [M+H]+ 540.3; ’H-NMR (400 MHz, DMSO-d6): 8 10.97 (s, 1H), 8.75 (s, 1H), 8.21-8.16 (m, 1H), 7.98-7.91 (m, 3H),
7.73-7.70 (m, 2H), 7.64-7.58 (m, 2H), 4.77 (d, J = 7.20 Hz, 1H), 4.16-4.12 (m, 1H), 3.65-3.33 (m, 1H),
2.89-2.73 (m, 3H), 2.68-2.59 (m, 2H), 2.44-2.41 (m, 2H), 2.17-2.07 (m, 2H), 1.57-1.43 (m, 1H), 1.35 (d, J
= 6.40 Hz, 3H), 0.92-0.87 (m, 3H), 0.71-0.63 (m, 3H).
Example 258: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)- piperidin-4-yl)quinolin-3-yl)-5,5-dimethyldihydropyrimidine-2,4(lH,3H)-dione (1-724)
Figure imgf000829_0002
Step-1: Synthesis of 6-amino-3-bromo-2-fluorobenzoic acid
To a stirred solution of 2-amino-6-fluorobenzoic acid (50 g, 322 mmol) in DMF (500 mL) at 0 C was added NBS (57.4 g, 322 mmol) and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was added to water (500 mL), and the resulting solid precipitate was collected via filtration and dried under vacuum to afford 6-amino-3-bromo-2-fluorobenzoic acid (60 g, 227 mmol, 71% yield). LCMS m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+ 233.9, 235.6; ’H-NMR (400 MHz, DMSO-d6): 8 8.78 (br s, 2H), 7.41-7.37 (m, 1H), 6.58-6.55 (m, 1H).
Step-2: Synthesis of (6-amino-3-bromo-2-fluorophenyl)methanol
To a stirred solution of 6-amino-3-bromo-2-fluorobenzoic acid (50 g, 214 mmol) in tetrahydrofuran (750 mL) was added BHs-DMS (534 mL, 1068 mmol) dropwise at 0 °C and the reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched with methanol (1000 mL) at 0 °C and stirred for 30 min at 25 °C. The reaction mixture was concentrated under reduced pressure, and the crude residue was taken up in ethyl acetate (500 mL) and washed with water (2 x 200 mL). The aqueous layer was further extracted with ethyl acetate (2 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-amino-3-bromo- 2-fluorophenyl)methanol (45 g, 182 mmol, 85% yield). LCMS m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+ 220, 222; ’H-NMR (400 MHz, DMSO-d6): 87.31-7.17 (m, 1H), 6.45 (s, 1H), 5.48 (s, 2H), 5.06-5.04 (m, 1H), 4.55-4.46 (m, 2H).
Step-3: Synthesis of 6-amino-3-bromo-2-fluorobenzaldehyde
To a stirred solution of (6-amino-3-bromo-2-fluorophenyl)methanol (46 g, 209 mmol) in DCM (2800 mL) was added manganese dioxide (109 g, 1254 mmol) at 25 °C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through a Celite bed and was washed with DCM (2000 mL). The combined filtrate was concentrated under reduced pressure. The crude residue (40 g) was triturated with hexanes (120 mL) and dried under vacuum to afford 6-amino-3-bromo-2- fluorobenzaldehyde (37 g, 161 mmol, 77% yield). LCMS m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+ 220.0, 218.0; ’H-NMR (400 MHz, DMSO-d6): 8 10.14 (s, 1H), 7.63 (s, 2H), 7.52 (t, J = 8.00 Hz, 1H), 6.59 (d, J = 9.20 Hz, 1H).
Step-4: Synthesis of 6-bromo-5-fluoroquinoline
To a stirred solution of 6-amino-3-bromo-2-fluorobenzaldehyde (23 g, 105 mmol) in THE (350 mL) under nitrogen was added sodium tert-butoxide (2.028 g, 21.10 mmol) in portions at 0 °C. To this mixture was added acetaldehyde (31.6 mL, 158 mmol) dropwise at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with Aq. NaCl solution (100 mL) and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under vacuum. The crude residue was purified by silica gel column chromatography eluting with 8 % ethyl acetate in hexane to afford 6-bromo-5 -fluoroquinoline (24 g, 67% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+ 225.9, 227.9; ’H-NMR (400 MHz, DMSO-de): 8 9.03 (q, 7 = 1 .60 Hz, 1H), 8.50 (d. 7 = 8.40 Hz, 1H), 7.99 (t. 7 = 7.60 Hz, 1H), 7.85 (d, 7 = 8.80 Hz, 1H), 7.71-7.68 (m, 1H).
Step-5: Synthesis of tert-butyl 4-(5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate
To a stirred solution of 6-bromo-5 -fluoroquinoline (10 g, 44.2 mmol) in 2-methyl tetrahydrofuran (100 mL) was added dropwise n-butyllithium (2.5 M in hexane, 17.3 mL, 43.4 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then tert-butyl 3,3-dimethyl-4-oxopiperidine-l- carboxylate (11.06 g, 48.7 mmol) in 2-methyl THE (50 mL) was added dropwise at -78 °C. The resulting reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with aqueous ammonium chloride solution (50 mL) and diluted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL). The aqueous layer was further extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 0 to 60% ethyl acetate in hexane afford tert-butyl 4-(5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (10 g, 57% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H]+ 375; ’H-NMR (400 MHz, DMSO-de): 8 8.97-8.96 (m, 1H), 8.50 (d, 7= 8.80 Hz, 1H), 8.11 (t, 7 = 8.80 Hz, 1H), 7.87 (d, 7= 8.80 Hz, 1H), 7.64-7.60 (m, 1H), 5.43 (s, 1H), 4.06-3.98 (m, 1H), 3.53-3.43 (m. 1H), 3.33-3.16 (m, 2H), 2.99-2.96 (m, 1H), 1.64 (d, 7 = 4.80 Hz. 1H), 1.43 (s, 9H), 0.89 (s, 3H), 0.73 (s, 3H). Step-6: Synthesis of tert-butyl 4-(3-bromo-5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine- 1 -carboxylate
To a stirred solution of tert-butyl 4-(5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l- carboxylate (5 g, 13.35 mmol) in ACN (50 mL) was added pyridine (7.39 g, 93 mmol) at 25 °C and the mixture was then stirred at 70 °C for 30 min. Bromine (10.7 g, 66.8 mmol) was added dropwise over 30 minutes at 70 °C and the mixture was stirred at 70 °C for 5 min following completion of the addition. The reaction mixture was cooled to 0 °C, aqueous NaHCO; solution was added, and the mixture was extracted with EtOAc (2x 50 mL). The combined organic layer was washed with sodium thiosulphate solution and dried over Na2SOr, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with 20-30% ethyl acetate in hexanes to obtain tert-butyl 4-(3-bromo-5-fhioroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (3.1 g, 51% yield). LCMS m/z MM-ES+APCI, POSITIVE [M+H, M+2+H]+_ 453, 455. ’H-NMR (400 MHz, DMSO-de): 8 9.01 (d, 7 = 2.00 Hz, 1H), 8.74 (d, 7 = 1.60 Hz, 1H), 8.15 (t, 7 = 8.80 Hz, 1H), 7.88 (d, 7= 9.20 Hz, 1H), 5.49 (s, 1H), 4.04-3.98 (m, 1H), 4.04-3.98 (m, 1H), 3.33-3.22 (m, 2H), 2.95 (d, 2 = 11.60 Hz, 1H), 1.67 (d, /= 13.60 Hz, 1H), 1.43 (s, 9H), 0.95 (s, 3H), 0.83 (s, 3H).
Step-7: Synthesis of tert-butyl 4-(3-(5,5-dimethyl-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fhioroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate
A stirred mixture of tert-butyl 4-(3-bromo-5-fluoroquinolin-6-yl)-4-hydroxy-3,3- dimethylpiperidine-1 -carboxylate (100 mg, 0.221 mmol), 1,4-dioxane (1 mL), 5,5- dimethyldihydropyrimidine-2,4(lH,3/7)-dione (31.4 mg, 0.221 mmol) and K2CO3 (45.7 mg, 0.331 mmol) was sparged with nitrogen at rt for 10 min, then thereto were added Brettphos (11.84 mg, 0.022 mmol) followed by Brettphos PdGs (6.52 mg, 0.018 mmol). The resulting reaction mixture was stirred at 100 °C for 12 h. The crude reaction mixture was purified by silica gel flash chromatography eluting with 0-70 % ethyl acetate in hexane to afford tert-butyl 4-(3-(5,5-dimethyl-2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 5-fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (35 mg, 30% yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H.]+ 515.4. ’H-NMR (400 MHz, DMSO-d6): 8 10.59 (s, 1H), 9.03 (s,
1H), 8.31 (s, 1H), 8.09 (t, J= 8.80 Hz, 1H), 7.88 (d, J = 9.20 Hz, 1H), 5.76 (s, 1H), 3.98 (s, 1H), 3.18-
2.96 (m, 4H), 1.69-1.67 (m, 1H), 1.43 (s, 9H), 1.28 (s, 6H), 1.27 (s, 3H), 0.87 (s, 3H), 0.79 (m, 2H).
Step-8: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)-5,5- dimethyldihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of tert-butyl 4-(3-(5,5-dimethyl-2,4-dioxotetrahydropyrimidin-l(2H)-yl)-5- fluoroquinolin-6-yl)-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (60 mg, 0.117 mmol) in DCM (1 mL) under a nitrogen atmosphere was added HC1 (4M in dioxane, 0.833 mL, 1.17 mmol) at 0 °C. The resulting reaction mixture was stirred at rt for 2 h, then was concentrated under reduced pressure. The crude residue was washed with MTBE, and then was dried under vacuum to provide l-(5-fluoro-6-(4- hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)-5,5-dimethyldihydropyrimidine-2,4(lH,3H)-di°ne, HC1 (50 mg, 0.094 mmol, 81% yield) LCMS m/z MM-ES+APCI, POSITIVE [M+H]+ 515.4. ’H-NMR (400 MHz, DMSO-de): 8 10.61 (s, 1H), 9.06 (d, J = 2.40 Hz, 1H), 9.06 (s, 1H), 8.67 (d, J= 2.80 Hz, 1H), 8.34 (d, J = 2.00 Hz, 1H), 7.91 (d. J = 9.20 Hz, 1H), 5.76 (s, 1H), 3.39-3.17 (m, 4H), 3.01 (s, 1H), 2.92 (d, J = 11.60 Hz, 1H), 1.99-1.91 (m, 1H), 1.40 (s, 1H), 1.27 (s, 6H), 1.08 (s, 6H).
Step-9: Synthesis of l-(5-fluoro-6-(4-hydroxy-3,3-dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4- yl)quinolin-3-yl)-5,5-dimethyldihydropyrimidine-2,4(lH,3H)-dione
To a stirred solution of l-(5-fluoro-6-(4-hydroxy-3,3-dimethylpiperidin-4-yl)quinolin-3-yl)-5,5- dimethyldihydropyrimidine-2,4(lH,3/7)-dione, HC1 (50 mg, 0.111 mmol) in IPA (1 mL) was added 4- (trifhioromethyl)benzaldehyde (23.17 mg, 0.133 mmol) followed by potassium acetate (32.6 mg, 0.333 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 30 min. Then NaCNBH> (20.9 mg, 0.333 mmol) was added and the reaction mixture was stirred at 80 °C for 1 h. The cooled reaction mixture was diluted with water (5 mL) and extracted with IPA: DCM (2 x 20 mL). The combined organic extract was dried over anhydrous NajSCL, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography on a C 18 column, eluting with 5 to 100 % ACN in 0.1% acetic acid in water to afford a partially purified product (20 mg). This was further purified by preparative-HPLC [Method info: Column: X Select C18 (250 x 19mm), Mobile phase A: 0.1%HCl in water, Mobile phase B: acetonitrile, flow rate: 15 mL/min] to afford l-(5-fluoro-6-(4-hydroxy-3,3- dimethyl-l-(4-(trifluoromethyl)benzyl)piperidin-4-yl)quinolin-3-yl)-5 ,5 -dimethyldihydropyrimidine - 2,4( 1 W.3H)-dionc, HC1 (1-724, 2.9 mg, 4.57 pmol, 4.1 % yield). LCMS: m/z MM-ES+APCI, POSITIVE [M+H.]+ 573.3; ’H-NMR (400 MHz, DMSO-d6): 5 10.61 (s, 1H), 9.33 (s, 1H), 9.05 (d, 7= 2.40 Hz, 1H), 8.33 (d, J = 2.00 Hz, 1H), 8.05 (t, J = 8.80 Hz, 1H), 7.93-7.84 (m, 5H), 5.96 (s, 1H), 4.96 (m, 2H), 3.86 (s, 2H), 3.423-3.40 (m, 4H), 2.68 (t, 7= 2.00 Hz, 1H), 2.33 (t, J= 1.60 Hz, 1H), 1.28 (m, 6H), 1.05 (s, 3H), 0.80 (s, 3H).
Example 259: General Method for Separation of Isomers of 3-(Quinolin-3-yl)-piperidine-2,6-dione- Containing Compounds
To obtain single enantiomers or diastereomers with defined stereochemistry at the 3-position of the piperidine-2, 6-dione contained in certain compounds of the invention, chiral SEC purification can be applied using a method similar to the following:
Column: ChiralPak IH, 250 x 30mm, lOum; mobile phase: [CO2-EtOH], isocratic elution mode, with 0.1 % HC1 (aq) added to each fraction after SEC separation before concentrating by freeze drying. Biological Assays and Data
The activity of a compound according to the present disclosure can be assessed by the following in vitro methods.
Example 260: Quantification of endogenous ARNT levels in 786-0 cells
The HiBiT Protein Tagging System (Promega) was used to develop a high-throughput and quantitative assay to measure changes in endogenous ARNT protein levels following treatment with compounds. The endogenous ARNT gene was tagged by knocking in the HiBiT sequence immediately preceding the ARNT termination codon using CRISPR. Briefly, ARNT -targeting CRISPR ribonucleoprotein complexes (RNP) and a donor template including the 33 nucleotide HiBiT sequence were delivered to 786-0 cells using the Nucleofector 4D system (Lonza). Subsequently, single cell clones were isolated and screened for successful knock-in by genomic DNA sequencing and for HiBiT signal using the Nano-Gio® HiBiT Lytic Detection System (Promega).
The level of ARNT degradation following compound treatment was measured as follows:
Day 1. Triplicate 10-point dose-response curves of all compounds were generated by pre-spotting compounds into solid white 384 well plates using a D300e Digital Dispenser (Tecan). All compounds were run in half-log dilution starting from 10 pM final concentration and all wells were normalized to 0.21% DMSO per well. Cells were then lifted from flasks using 0.25% Trypsin EDTA (Gibco) and quenched with normal growth medium containing 10% fetal bovine serum before viable cells were counted using a Countess II instrument (Thermo Fisher). Cells were then diluted to 2.0 x 105 cells/mL in normal growth medium and 25 pL of cells were plated in each well of pre-spotted 384 well plates using a Multidrop Combi Reagent Dispenser (Thermo Fisher). Plates were then incubated in humidified 37°C incubators maintaining 5% CO2 for 24 h.
Day 2. Plates were removed from incubators and allowed to equilibrate to room temperature for 30 minutes before adding 15 pL of Nano-Gio® HiBiT Lytic Detection System reagent to each well using a Multidrop Combi Reagent Dispenser. Plates were incubated for an additional 10 minutes at room temperature and luminescence was read using a PHERAstar Microplate Reader (BMG Labtech). Data was analyzed and visualized using GraphPad Prism 9 software (Dotmatics).
Table 3 shows ARNT (HIF-lb) degradation activity of compounds of the disclosure in Pro-label assays in 7860-0. In Table 3 below, Dmax is defined as A = >60%; B = 30-60%; C = <30% and DC50 is defined as A = <0.20 pM; B = 1 pM-0.20 pM; C = >1 pM
Table 3: ARNT degradation activity of exemplary compounds of Formula (I)
Cmpd ARNT ARNT Cmpd ARNT ARNT Cmpd ARNT ARNT No. DCso Dmax No. DCso Dmax No. DCso Dmax
1-1 A A 1-23 B A 1-40 A A
1-5 A A 1-24 B A 1-43 A A
1-8 A A 1-25 A A 1-44 A A
1-9 C B 1-26 A A 1-45 A A
1-10 B £ 1-27 A A 1-46 A A
1-11 C B 1-28 A A 1-47 C £
1-12 B A 1-29 A A 1-48 A A
1-13 B A 1-30 A A 1-49 A A
1-14 B A 1-31 A A 1-50 A A
1-16 B A 1-33 A A 1-51 B B
1-17 B A 1-34 A B 1-52 A A
1-18 B A 1-35 A A 1-55 A A
1-19 B A 1-36 A A 1-56 A A
1-20 B A 1-37 A A 1-57 A A
1-21 B B 1-38 A A 1-58 A A
1-22 B B 1-39 C C 1-59 A A Cmpd ARNT ARNT Cmpd ARNT ARNT Cmpd ARNT ARNT No. DCso Dmax No. DCso Dmax No. DCso Dmax
1-62 A A 1-149 A A 1-235 A A
1-63 A A 1-155 A A 1-238 A A
1-64 A A 1-158 A A 1-242 A A
1-67 A A 1-164 A A 1-243 A A
1-68 A A 1-167 C C 1-244 A A
1-69 A A 1-168 B B 1-247 A A
1-74 A A 1-169 B A 1-250 A A
1-75 A A 1-170 A A 1-255 A A
1-76 A A 1-173 A A 1-256 A A
1-79 A A 1-176 B A 1-258 A A
1-82 A A 1-177 B A 1-259 C B
1-83 B B 1-178 A A 1-260 B A
1-84 A A 1-179 A A 1-261 A A
1-85 C C 1-181 B A 1-262 B B
1-86 A A 1-184 B A 1-265 A A
1-87 A A 1-187 A A 1-268 A A
1-88 C C 1-189 C B 1-271 A A
1-89 A A 1-198 A A 1-272 A A
1-92 A A 1-199 A B 1-273 A A
1-95 A A 1-200 B A 1-274 A A
1-98 A A 1-201 A B 1-291 A A
1-101 A A 1-202 C C 1-293 A A
1-104 A A 1-203 A A 1-294 A A
1-107 A A 1-206 A B 1-295 A A
1-110 A A 1-207 A B 1-297 A A
1-113 A A 1-208 A A 1-299 A A
1-116 A A 1-210 A A 1-306 C B
1-119 A A 1-212 C A 1-307 C C
1-122 A A 1-213 A A 1-308 B B
1-124 A A 1-217 A C 1-311 A B
1-129 A A 1-218 A A 1-313 B B
1-132 A A 1-221 A A 1-314 C C
1-133 A A 1-222 A A 1-316 C B
1-139 A A 1-225 A A 1-317 A A
1-142 A A 1-228 A A 1-318 C C
1-145 A A 1-231 A A 1-319 A A
1-146 A A 1-234 B A 1-324 A A Cmpd ARNT ARNT Cmpd ARNT ARNT Cmpd ARNT ARNT No. DCso Dmax No. DCso Dmax No. DCso Dmax
1-327 B A 1-419 A A 1-569 C A
1-329 A A 1-422 C C 1-572 A A
1-330 C B 1-424 A A 1-575 A A
1-334 C C 1-428 A A 1-578 A A
1-335 A A 1-431 C C 1-579 A A
1-336 B A 1-432 A A 1-581 A A
1-337 A A 1-433 A A 1-584 A A
1-338 B B 1-438 A A 1-591 A A
1-339 A A 1-441 A A 1-594 A A
1-342 A A 1-454 A A 1-597 A A
1-345 A A 1-455 A A 1-598 B A
1-348 A A 1-458 A A 1-599 C B
1-351 A A 1-459 A A 1-600 A A
1-354 A A 1-460 A A 1-603 A A
1-357 A A 1-465 A A 1-606 A A
1-360 A A 1-471 A A 1-613 A A
1-364 A A 1-473 A A 1-616 A A
1-365 A A 1-475 A A 1-619 A A
1-366 A A 1-479 A A 1-622 A A
1-369 A A 1-484 A A 1-625 A A
1-372 A A 1-519 A A 1-628 A A
1-375 A A 1-526 A A 1-631 A A
1-378 A A 1-529 A A 1-632 A A
1-381 A A 1-532 A A 1-635 A A
1-384 A A 1-535 A A 1-640 A A
1-387 A A 1-538 A A 1-643 A A
1-389 A A 1-541 A A 1-650 A A
1-394 A A 1-542 A A 1-651 A A
1-397 A A 1-543 A A 1-656 A A
1-400 A A 1-545 B A 1-659 A A
1-403 A A 1-546 A A 1-662 A A
1-406 A A 1-549 A A 1-665 A A
1-408 A A 1-556 A A 1-668 A A
1-409 A A 1-559 A A 1-669 A A
1-412 A A 1-560 A A 1-674 A A
1-415 A A 1-561 A A 1-675 A A
1-418 A A 1-566 A A 1-678 A A Cmpd ARNT ARNT Cmpd ARNT ARNT Cmpd ARNT ARNT No. DCso Dmax No. DCso Dmax No. DCso Dmax
1-679 A A 1-760 A A 1-816 B A
1-680 A A 1-763 A A 1-817 A A
1-687 A A 1-766 A A 1-818 B A
1-688 A A 1-769 A A 1-819 A A
1-689 B A 1-770 B A 1-820 A A
1-692 A A 1-771 A A 1-821 A A
1-697 A A 1-774 A A 1-822 A A
1-698 A A 1-775 A A 1-823 A A
1-701 A A 1-776 A A 1-824 A A
1-702 A A 1-777 A A 1-825 A A
1-705 A A 1-778 A A 1-829 C C
1-708 A A 1-779 A A 1-830 A A
1-709 A A 1-780 A A 1-831 A A
1-712 A A 1-781 A A 1-832 A A
1-713 A A 1-782 A A 1-833 B A
1-716 A A 1-783 A A 1-834 A A
1-717 A A 1-784 A A 1-835 A A
1-720 A A 1-785 A A 1-836 B A
1-723 A A 1-786 A A 1-837 A A
1-726 A A 1-787 A A 1-838 A A
1-729 A A 1-788 B A 1-839 A A
1-730 A A 1-789 B A 1-840 A A
1-731 A A 1-790 A A 1-841 A A
1-732 A A 1-791 A A 1-842 B A
1-733 A A 1-792 A A 1-843 A A
1-734 A A 1-793 A A 1-844 B A
1-737 A A 1-794 A A 1-845 A A
1-740 A A 1-795 A A 1-846 B A
1-743 A A 1-796 A A 1-847 A A
1-746 A A 1-797 A A 1-848 A A
1-747 B A 1-798 B A 1-849 A A
1-748 A A 1-799 A A 1-850 B A
1-749 A A 1-800 A A 1-851 A A
1-752 A A 1-802 C A 1-852 A A
1-755 A A 1-804 B A 1-853 B A
1-758 A A 1-814 A A 1-854 A A
1-759 A A 1-815 B A 1-855 A A Cmpd ARNT ARNT Cmpd ARNT ARNT Cmpd ARNT ARNT No. DCso Dmax No. DCso Dmax No. DCso Dmax
1-856 B A 1-886 C C 1-920 C C
1-857 A A 1-887 C C 1-921 C C
1-858 A B 1-888 C c 1-922 C c
1-859 A B 1-889 C c 1-923 c c
1-860 A B 1-890 B c 1-928 A A
1-861 B B 1-891 C c 1-931 A A
1-862 B B 1-892 C c 1-938 A A
1-863 B B 1-893 C c 1-941 A A
1-864 B B 1-894 C c 1-944 A A
1-865 B B 1-895 C c 1-947 A A
1-866 B B 1-896 C c 1-950 A A
1-867 A B 1-897 B c 1-953 A A
1-868 A B 1-898 C c 1-956 A A
1-869 B B 1-899 C c 1-959 A A
1-870 B B 1-900 C c 1-962 A A
1-871 B B 1-901 C c 1-965 A A
1-872 B B 1-902 C c 1-968 A A
1-873 B B 1-903 C c 1-975 A A
1-874 B B 1-908 C c 1-978 A A
1-875 B B 1-909 C c 1-981 A A
1-876 B B 1-910 C c 1-984 A A
1-877 B B 1-911 C c 1-985 A A
1-878 B B 1-912 C c 1-986 C B
1-879 C A 1-913 C c 1-987 C C
1-880 C A 1-914 C c 1-1190 A A
1-881 C B 1-915 C c 1-1193 A A
1-882 C B 1-916 C c 1-1196 A A
1-883 C B 1-917 c c 1-1197 A A
1-884 C B 1-918 C c 1-1200 A A
1-885 C C 1-919 C c
Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS What is claimed is:
1. A compound of Formula (I’):
Figure imgf000839_0001
pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
Xi is N or CR3;
X2 is N, N(0), or CR5;
X7 is N and N(0);
Ri is H, D, -C(0)Rn, -CH20C(0)RH, -CH2OC(O)NHRI2, -CH2OC(O)OR12, -P(O)(ORI2)2, - CH2OP(O)(OR12)2, -CH2OP(O)(OH)OR12, -CH2OP(O)(R12)2, -CH2OC(O)CH2NHC(O)CH2NH2, - CH2OC(O)CH(RI2')NHRI2', -CH2OC(O)(CH2)q-C(O)ORi2', or -CH2OC(O)-(5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S);
R2a, RM, RM, and RM are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, halogen, or -OH, wherein two of R2a, RM, RM, and RM may be taken together with the carbon atom to which they are attached form a (Cs-C7)carbocyclyl or (Cs-C7)spirocarbocyclyl optionally substituted with one or more R40;
Rs is H, D, (C1-C6)alkyl, (Ci-Cb)deuteroalkyl, or halogen, wherein Rs may be taken together with one of Rsa, RM, RM, and RM with the carbon atom to which they are attached to form a (Cs-CsXarbocyclyl or (Cs-C7)spirocarbocyclyl optionally substituted with one or more R40;
R4s D (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6) alkoxy, (Ci- C6)deuteroalkoxy, (C1-C6)haloalkoxy, (C3-C7)carbocyclyl, -O(Cs-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10; wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;
R5 is D, (C,-C6)alkyl, (C1-C6)deuteroalkyl, (C,-C6)haloalkyl, (C,-C6)alkoxy, (C,- C6)deuteroalkoxy, (C1-C6)haloalkoxy, (Cs-C7)carbocyclyl, O(Cs-C7)carbocyclyl, (Cs-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; halogen, -OH, or -NR9R10, wherein each alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteoalkoxy, haloalkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more R40;
Re is H, D, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, (C1-C6)aminoalkyl, (C1-C6)alkyl-O- (C1-C6)hydroxyalkyl, -C(O)Rn, -CH2OC(O)Rn, -CH2OC(O)NHR12, -CH2OC(O)OR12, -P(O)(OR12)2, - CH2OP(O)(OH)OR12, or -CH2OP(O)(Ri2)2;
R?a, R?b, R?c, and R?d are each independently H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (Ci-C2)haloalkyl; or two of R?a, R?b, R?c, and R?d are taken together with the carbon atoms to which they are attached form (C3-C7)carbocyclyl, (C3-C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6ldeuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halogen, -C(O)ORB', -C(0)Ri3, and -C(O)NRi3'Ri3-; each R7e is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C1-C6)hydroxyalkyl, -CN, -OH, -O-(Ci- C6)hydroxyalkyl, (C6-C10) aryl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the alkyl is optionally substituted with one or more R19, the aryl and heteroaryl are optionally substituted with one or more R2I , and the carbocyclyl and heterocyclyl are optionally substituted with one or more R22; or two R?e together with the carbon atom to which they are attached form a (C3-C7)carbocyclyl, (C3- C7)spirocarbocyclyl, or a 4- to 7-membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl, spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one or more substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (Ci-Cb)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0Ri3-, -C(0)Ri3, and -C(O)NRi3’Ri3’; one R?e is taken together with any one of R?a, R?b, R?c, and R?d and the atoms to which they are attached form a (C3-C7)carbocyclyl or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R22;
Rs is (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)halohydroxy alkyl, or (C3- C7)carbocyclyl, wherein alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, and carbocyclyl are optionally substituted with one or more substituents independently selected from R21, D, (C1-C6)alkoxy, -SF5, -SRua, -NR14R14', -C(O)NR32R33, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 and the carbocyclyl and heterocyclyl are optionally substituted with one or more R 15' ;
R9 and Rio are each independently at each occurrence H, D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, or (C1-C6)haloalkyl;
Rn is independently at each occurrence H, (C1-C6)alkoxy, -NH2, -N(H)(C1-C6)alkyl, -N((Ci-Cft)alkyl)2, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10jaryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (Ci-Gjhydroxyalkyl, (C1-C6)haloalkyl, halogen, -OH, -NH2, and -CN;
R12 is independently at each occurrence H, (C1-C6)alkyl optionally substituted with one or more substituents independently selected from (C6-C10)aryl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci- C6)haloalkyl, halogen, -OH, -NH2, and -CN, or (C6-C10)aryl optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (Ci-
Gjhaloalkyl, halogen, -OH, -NH2, and -CN;
R12' is independently at each occurrence H or (C1-C6)alkyl; R13 is independently at each occurrence (C,-C6)alkyl or (C1-C6)haloalkyl;
R13' is independently at each occurrence H, (C1-C6)alkyl or (C1-C6)haloalkyl;
R14 and G are each independently at each occurrence H or (C1-C6)alkyl;
Ri4a is H, (C1-C6)alkyl or (Ci-Gjhaloalkyl;
R15 and R15’ are each independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (G-Gjalkoxy, (Ci-Gjhaloalkoxy. (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SF5, - SRie, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -0(C3-C7)carbocyclyl, phenyl, -O-phenyl, monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, -0-(monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S or -O-(4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S), wherein alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroalkyl, phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, - OH, -NR35R36, -C(O)NR37R38, -C(O)R37, -C(O)OR37, -SF5, -SR29, SO2NR30R31, -CN, and Rig; or two R15, when on adjacent atoms, together with the atoms to which they are attached form a phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3- C7)carbocyclyl, or 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the phenyl, heteroaryl, carbocyclyl, and heterocyclyl are optionally substituted with one or more Rn; two R15-, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more Rn; or two Rn- together with the atoms to which they are attached form a (CnC-Jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; or two Rn- when on the same carbon atom form C=(0);
Rie is H, (C1-C6)alkyl or (C1-C6)haloalkyl;
Rn is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NH2, -SF5, -SRis, or -CN;
Ris is H, (C1-C6)alkyl, or (C1-C6)haloalkyl; each R19 is independently at each occurrence (C1-C6)alkoxy, (C1-C6)haloalkoxy, -NR20R20', -CN, (Ca-Cvjcarbocyclyl, 4- to 7 -membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (Cg-Cio) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more R23 and the aryl and heteroaryl are optionally substituted with one or more R24; or two R19 when on the same carbon atom form C=(0); or two R19 together with the atoms to which they are attached form a (C3-C7jcarbocyclyl or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more Rn; R20 and R20’ are each independently at each occurrence H or (C1-C6)alkyl; each R21 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR25, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R21, when on adjacent atoms, together with the atoms to which they are attached form a phenyl or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl are optionally substituted with one or more R15 ; each R22 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR26, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7jcarbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R22 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R23 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR27, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; or two R23 together with the atoms to which they are attached form a (C3-C7)carbocyclyl or a 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S; each R24 is independently at each occurrence D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -OH, -NH2, -SF5, -SR28, -CN, phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, (C3-C7)carbocyclyl, or 4- to 7- membered heterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S;
R25, R26, R27, R28, and R29 are each independently at each occurrence H, (C1-C6)alkyl, or (Ci- C6)haloalkyl; R30 and Rsi are each independently at each occurrence H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C?)carbocyclyl, -C(O)R34, phenyl, or 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl or heteroaryl can be substituted with one or more R17;
R32, R33, and R34 are each independently at each occurrence H or (C1-C6) alkyl;
R35 and R36 are each independently at each occurrence H, (C1-C6)alkyl, or -C(O)R39;
R37, R38, and R39 are each independently at each occurrence H or (C1-C6)alkyl;
R40 is D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -OH, -NR30R31, -SRis, -CN, -C(O)NR32R33, -C(O)OR32, (C3-C7)carbocyclyl, -O(C3-C7)carbocyclyl, phenyl; m and n are each independently 0, 1 or 2; o is 0, 1 or 2; p is 0, 1, 2, 3 or 4; q is 1, 2, or 3; and r is 0 or 1.
2. The compound according to claim 1, wherein Ri is H.
3. The compound according to claim 1 , wherein R2a is H.
4. The compound according to claim 1 , wherein R2b is H.
5. The compound according to claim 1 , wherein R2C is H.
6. The compound according to claim 1 , wherein R2d is H.
7. The compound according to claim 1, wherein one to four members of R2a, R2b, R2c, and R2d is CH3.
8. The compound according to claim 1, wherein Xi is CR3.
9. The compound according to claim 1, wherein Xi is N.
10. The compound according to claim 1 , wherein X2 is N.
11. The compound according to claim 1 , wherein X2 is CR5.
12. The compound according to claim 1 , wherein R3 is H.
13. The compound according to claim 1 , wherein R3 is D.
14. The compound according to claim 1 , wherein R3 is CH3.
15. The compound according to claim 1, wherein R4 is independently in each instance (C1-C6)alkyl, (C1-C6)haloalkyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.
16. The compound according to claim 1, wherein R4 is independently in each instance -CH3, -C2H5, - CF3, -OH, -OCH3, -NH2, -NHCH3, or -Cl.
17. The compound according to claim 1, wherein R5 is independently in each instance (C1-C6)alkyl or halogen.
18. The compound according to claim 1, wherein R5 is independently in each instance -CH3, -F.
19. The compound according to claim 1, wherein R5 is independently in each instance (C1-C6)alkyl, (C3-C7)carbocyclyl, -OH, -O-(C1-C6)alkyl, -NR9R10, or halogen.
20. The compound according to claim 1, wherein R5 is independently in each instance -CH3, cyclopropyl, -OH, -OCH3, -NH2, -F, -Cl.
21. The compound according to claim 1, wherein n is 0.
22. The compound according to claim 1, wherein n is 1.
23. The compound according to claim 1, wherein m is 0.
24. The compound according to claim 1, wherein m is 1.
25. The compound according to claim 1, wherein m is 2.
26. The compound according to claim 1 wherein R is H
27. The compound according to claim 1, wherein R?a is H, or (C1-C6)alkyl.
28. The compound according to claim 1 , wherein R?a is -H, -CH3, or -CH(CH3h.
29. The compound according to claim 1 , wherein R?b is H.
30. The compound according to claim 1 , wherein R?c is H.
31. The compound according to claim 1 , wherein R?d is H.
32. The compound according to claim 1, wherein each R?e is independently at each occurrence (Ci- Cs)alkyl, (C1-C6)deuteroalkyl, halogen, -OH, -O-(C1-C6)alkyl, (C3-C7)carbocyclyl, or phenyl wherein the alkyl is optionally substituted with one to six R19 and the carbocyclyl is optionally substituted with one to five R22 and the phenyl is optionally substituted with one to five R22; or two R?e, when on the same carbon atom, together with the carbon atom to which they are attached form a (C3-C7)spirocarbocyclyl or 4- to 7- membered spiroheterocyclyl comprising 1 to 4 heteroatoms selected from 0, N, NH, and S, wherein the spirocarbocyclyl and spiroheterocyclyl are optionally substituted with one to four substituents independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (Ci- C6)haloalkoxy, (C1-C6)hydroxyalkyl, halogen, -C(0)0RB’, -C(0)RB, and -C(0)NRB’RB’.
33. The compound according to claim 1, wherein each R?e is independently at each occurrence
Figure imgf000845_0001
two R?e, when on the same carbon atom, together with the carbon atom to which they are attached, form
Figure imgf000845_0002
, wherein
R in each instance is independently selected from D, (C1-C6)alkyl, (C1-C6)deuteroalkyl, (Ci- C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)hydroxy alkyl, halogen, -C(0)0RB , -C(0)RB, and -C(0)NRB’RI3S and
R21, R22, and R24 are defined as in claim 1.
34. The compound according to claim 1, wherein each R?e is independently at each occurrence / ,
_ D
Figure imgf000846_0001
two R?e, when on the same carbon atom, together with the carbon atom to which they are attached,
Figure imgf000846_0002
35. The compound according to claim 1 , wherein o is 2.
36. The compound according to claim 1 , wherein o is 1.
37. The compound according to claim 1 , wherein p is 0.
38. The compound according to claim 1 , wherein p is 1.
39. The compound according to claim 1 , wherein p is 2.
40. The compound according to claim 1 , wherein p is 4.
41. The compound according to claim 1, having a Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (le), Formula (If), Formula (Ig), Formula (Ih), Formula (li), Formula (Ij), Formula (Ik), or Formula (II):
Figure imgf000846_0003
Figure imgf000847_0001
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
42. The compound according to claim 1, having a Formula (Im), Formula (Io), Formula (Ip), Formula (Iq), Formula (Ir), Formula (lu), Formula (Iv), Formula (Iw), Formula (lx), Formula (ly), Formula (Iz), Formula (laa), Formula (Ibb), or Formula (Icc):
Figure imgf000848_0001
Figure imgf000849_0001
43. The compound according to claim 1, wherein Rs is (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (Ci- C6)alkyl optionally substituted with one to three substituents independently selected from D, (C1-C6)alkoxy, -SRi4a, -NR14R14', phenyl, 5- or 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, (C3-C7)carbocyclyl, and 4- to 7-membered heterocyclyl comprising 1 to 4 heteroatoms selected from O, N, NH, and S, wherein the phenyl and heteroaryl optionally substituted with one to three R15 and the carbocyclyl and heterocyclyl are optionally substituted with one to three R15'.
44. The compound according to claim 1 , wherein Rs is selected from:
Figure imgf000849_0002
Figure imgf000850_0001
each of X t, and X si-> is independently selected from 0, S, NH, and NR15;
X4 is 0, S, NH, and NRLV;
R is selected from (Ci-C5)alkyl and (C3-C7)cycloalkyl, and is optionally substituted with one or more of D, hydroxy, halogen, alkoxy, imidazol-2-yl, and -ClOjNR^R^; and
R15, Ri5', R32, and R33 are as defined in claim 1.
45. The compound according to claim 1 , wherein Rg is selected from:
Figure imgf000850_0002
Figure imgf000851_0001
Figure imgf000852_0001
0
NI H2N
0
N UXA
Figure imgf000852_0002
Figure imgf000853_0001
Figure imgf000854_0001
Figure imgf000855_0001
Figure imgf000856_0001
Figure imgf000857_0001
Figure imgf000858_0001
46. The compound according to claim 1, wherein each R19 is independently at each occurrence (Ci- C6)alkoxy, -NR20R20', or (C3-C7)carbocyclyl wherein carbocyclyl is optionally substituted with two to four R23.
47. The compound according to claim 1, wherein the compound is selected from any compound provided in Table 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
48. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
49. The pharmaceutical composition according to claim 48, further comprising at least one additional pharmaceutical agent.
50. The pharmaceutical composition according to claim 48 for use in the treatment of a disease or disorder that is affected by the reduction of HIF-1 P levels.
51. A method of degrading HIF-ip, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
52. A method of modulating HIF- 1 [3 levels comprising administering to a patient in need thereof an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
53. An in vitro method of reducing the proliferation of a cell, comprising contacting the cell with an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
54. A method of treating a disease or disorder that is affected by the modulation of HIF-ip levels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
55. The method according to claim 54, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary diseases, autoimmune and inflammatory -related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, neovascular diseases, retinal vascular diseases, fibrosis, endometriosis, preeclampsia, and allergic and genetic diseases.
56. The method according to claim 54, wherein the disease or disorder is selected from renal cell carcinoma (RCC), von Hippel-Lindau disease (VHL), advanced pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), pulmonary arterial hypertension (PAH), glioblastoma, colitis, Crohn’s disease, ulcerative colitis, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’ s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), myeloid leukemia, and coronary heart disease.
57. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
58. The method according to claim 57, wherein the cancer is VHL-deficient cancer.
59. The method according to claim 57, wherein the cancer is selected from renal cell carcinoma (RCC), glioblastoma, T cell leukemia or T cell lymphoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, gastrointestinal stromal tumor (GIST), and myeloid leukemia.
60. A method for reducing HIF-ip levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
61. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
62. A method of treating a neoplastic condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
63. A method of treating renal cell carcinoma (RCC), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
64. The method of claim 63, wherein the renal cell carcinoma is clear cell renal cell carcinoma
(ccRCC).
65. The method according to claim 54, wherein the administration is oral, parenteral, subcutaneous, by injection, or by infusion.
66. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder that is affected by the reduction of HIF- I |3 levels.
67. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder associated with the reduction of HIF-1 P levels.
68. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder that is affected by the reduction of HIF-1 P levels.
69. Use of a compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder associated with the reduction of HIF- 1 P levels.
70. The compound for use according to claim 68 or 69 or the use according to claim 52 or 53, wherein the disease or disorder is selected from cancer, von Hippel-Lindau (VHL) disease, iron overload disorders, cardiovascular diseases, pulmonary arterial hypertension (PAH), autoimmune and inflammatory-related diseases and conditions, neurodegenerative diseases, viral diseases, metabolic diseases, and allergic and genetic diseases.
PCT/US2024/054315 2023-11-02 2024-11-02 Substituted (piperidin-4-yl)-1,5-naphthyridine and (piperidin-4-yl)quinoline derivatives and uses thereof Pending WO2025097090A1 (en)

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