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WO2025240536A1 - Composés bifonctionnels contenant des dérivés de pyrimidine 2,5-substitués pour dégrader la kinase 2 dépendante d'une cycline et/ou la kinase 4 dépendante d'une cycline par l'intermédiaire de la voie ubiquitine-protéasome - Google Patents

Composés bifonctionnels contenant des dérivés de pyrimidine 2,5-substitués pour dégrader la kinase 2 dépendante d'une cycline et/ou la kinase 4 dépendante d'une cycline par l'intermédiaire de la voie ubiquitine-protéasome

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Publication number
WO2025240536A1
WO2025240536A1 PCT/US2025/029225 US2025029225W WO2025240536A1 WO 2025240536 A1 WO2025240536 A1 WO 2025240536A1 US 2025029225 W US2025029225 W US 2025029225W WO 2025240536 A1 WO2025240536 A1 WO 2025240536A1
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compound
pharmaceutically acceptable
acceptable salt
mmol
hydrogen
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Zhiyong Yu
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Nikang Therapeutics Inc
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Nikang Therapeutics Inc
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure provides certain bifunctional compounds containing 2, 5 -substituted pyrimidine derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and/or Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2 and/or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • CDKs Cyclin-dependent kinases
  • CDKs are essential cellular serine/threonine kinases that play an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation.
  • the regulation of CDK activity is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them.
  • CDKl/Cyclin B, CDK2/Cyclin E, CDK2/Cyclin A, CDK4/Cyclin D, CDK6/Cyclin D complexes are well known to be vital regulators of cell cycle progression.
  • Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291).
  • CDK 1 -Cyclin A and CDK 1 -Cyclin B complexes are activated in late S and G2 phases to drive the transition into and completion of mitosis, respectively (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988).
  • CDK-cyclin complexes Due to their crucial roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to promote tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108). Genetic changes in CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes.
  • Common alterations include amplifications/overexpression of cyclin D, cyclin E, CDK4 and CDK6; loss of Rb; deficiency in CDK inhibitory regulators such as pl 6, p21, p27, and loss-of-function mutations in FBXW7, a component of SCF Fbw7 ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52).
  • CDK inhibitors for therapeutic purposes.
  • selective reversible inhibitors of CDK4 and CDK6 e.g., palbociclib, riboci clib, and abemaciclib have revolutionized the therapeutic management for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
  • HR+ hormone receptor-positive metastatic breast cancer
  • CDK4/6 inhibitors are also investigating these CDK4/6 inhibitors as single agents or in combination with other therapeutics for various cancers.
  • CDK4/6 inhibitors Despite their significant clinical efficacy in ER-positive metastatic breast cancer, CDK4/6 inhibitors have some limitations.
  • One major drawback is the development of primary or acquired resistance over time.
  • An important mechanism of resistance involves the abnormal activation of CDK2. This can occur due to an overactivated CDK2/Cyclin E complex caused by elevated Cyclin E expression (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561) or formation of the noncanonical CDK2/cyclin DI complex in response to CDK4/6 inhibition (Herrera- Abreu MT et al, Cancer Res. (2006) 15: 2301), which bypasses the need for CDK4/6 for cell cycle reentry.
  • CDK4/6 inhibitors palbociclib and ribociclib exhibit relatively high hematological toxicity, primarily neutropenia.
  • CDK6 is highly expressed in the blood system and plays a role in regulating the growth of hematopoietic cells. Therefore, it is generally believed that the inhibition of CDK6 leads to neutropenia, while breast cancer cells mainly depend on CDK4 for proliferation.
  • Abemaciclib exhibits weaker inhibition of CDK6 than CDK4, resulting in lower hematological toxicity.
  • CDK2 inhibitors are under clinical development in solid tumors, including PF-07104091 (NCT04553133), BLU-222 (NCT05252416), INCB123667 (NCT05238922), INX-315 (NCT05735080), ARTS-021 (NCT05867251), AZD8421
  • PF-07104091 and BLU-222 have demonstrated single agent activities in CDK4/6 inhibitor refractory breast cancer patients.
  • PF-07220060 in combination with endocrine therapy, has demonstrated clinical responses and lower neutropenia adverse events in CDK4/6 inhibitor refractory breast cancer patients.
  • a molecule blocking both CDK2 and CDK4 as single agent or in combination with endocrine therapy may address the primary and acquired resistance to CDK4/6 inhibitors, leading to enhanced antitumor activities and reduced adverse effects to achieve greater therapeutic efficacy in HR+ HER2- breast cancer.
  • PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker. PROTACs bring the protein of interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome.
  • PROTACs Compared to small molecule drugs that typically bind disease-relevant proteins and inhibit their function, PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their inhibitor counterparts, potentially reducing off-target toxicity. Moreover, PROTACs can perform multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies.
  • the E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis protein (LAP), and mouse double minute 2 (MDM2).
  • PROTACs that could recruit CDK2 and/or CDK4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of CDK2 and/or CDK4 are desirable.
  • the present disclosure fulfills this and related needs. Summary
  • R 2 and R 2a are independently hydrogen or deuterium
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;
  • M is -O- or -NR 6 -;
  • R 6 is hydrogen or alkyl
  • ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein in each heteroarylene one to three ring atoms are heteroatoms independently selected from nitrogen, oxygen, and sulfur and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with R ee and R ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and
  • Z is -O-, -NR 3 - (where R 3 is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each of the aforementioned rings is substituted with R d and R e independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; alk is C3 to Ce alkenylene substituted with R f selected from hydrogen, fluoro, and cyano; C3 to Ce alkylene or C3 to Ce heteroalkylene (wherein the C3 to Ce alkylene and C3 to Ce heteroalkylene are substituted with R g , R h , and R 1 where R g is hydrogen, deuterium or halo, R h is hydrogen, deuterium, cycloalkyl, cycloalkyloxy
  • a pharmaceutical composition comprising a compound of Formula (I) of the first aspect (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • a method of treating a disease mediated by CDK2 and/or CDK4 in a patient comprises administering to the patient a therapeutically effective amount of a compound of Formula (I) of the first aspect (and any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed in the second aspect (or any embodiments thereof described herein).
  • the disease is cancer.
  • the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, and/or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi sarcoma, and/or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and/or mouth), liver cancer (e.g., hepatocellular carcinoma and/or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine
  • lung cancer e.g
  • the cancers are those that are resistant to CDK4/6 inhibitors through CDK2-mediated mechanisms e.g., breast cancer.
  • the disease is an autoimmune disease or a condition associated with an autoimmune disease.
  • the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren’s syndrome
  • MS multiple sclerosis
  • Crohn’s disease CD
  • uveitis pemphigus vulgaris
  • sepsis sepsis.
  • the disease is gout.
  • a method of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss comprises administering to a patient, (in one embodiment a patient in need of such treatment), a therapeutically effective amount of a compound of Formula (I) of the first aspect (and any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof as disclosed in the second aspect (or any embodiments thereof described herein).
  • the amount of hearing loss is reduced when compared to an age-matched control.
  • the hearing loss is prevented when compared to an age-matched control.
  • a compound of Formula (I) of the first aspect or any of the embodiments thereof described herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the second aspect (or any embodiments thereof described herein) for use in therapy.
  • the compound of Formula (I) of the first aspect (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is for use in the treatment of one or more of diseases disclosed in the third and fourth aspects above.
  • a compound of Formula (I) of the first aspect and any of the embodiments thereof described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 and/or CDK4 contributes to the pathology and/or symptoms of the disease.
  • the disease is one or more diseases disclosed in the third and fourth aspects above.
  • a method of degrading CDK2 and/or CDK4 in a cell via ubiquitin proteasome pathway comprises contacting the cell with a compound of Formula (I) of the first aspect (or embodiments thereof as disclosed herein).
  • the CDK2 and/or CDK4 are degraded in vitro.
  • the CDK2 and/or CDK4 are degraded in vivo.
  • the CDK2 and/or CDK4 are degraded in a cell of a patient.
  • CDK2 is selectively degraded over CDK1.
  • CDK2 is selectively degraded over CDK1 and CDK4 or CDK4 is selectively degraded over CDK1 and CDK2.
  • both CDK2 and CDK4 are degraded by a compound of Formula (I), including CDK2 and CDK4 are selectively degraded over CDK1.
  • the ability of compounds of Formula (I) to degrade CDK2 and CDK4 selectively over CDK1 was measured by determining potency of the compounds in inhibiting retinoblastoma protein (Rb) phosphorylation in 0VCAR3 (CDK2 dependent cell line), T47D (CDK4 dependent cell line) and KYSE520 (CDK1 dependent cell line) as described in Biological Example 1 below, and then determining the ratio of Rb IC50 from 0VCAR3 and KYSE520 and T47D and KYSE520, respectively.
  • Rb retinoblastoma protein
  • the compounds of Formula (I) degrade both CDK2 and CDK4, they can, however, cause degradation of CDK2 to a greater extent than CDK4 or visa-versa.
  • the degree of degradation of CDK2 and CDK4 can be determined by determining the ratio of phosphorylation of Rb IC50 from 0VCAR3 and T47D.
  • Alkyl means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
  • Alkenyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.
  • Alkynyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.
  • Alkylene means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated. When alkylene contains three to six carbon atoms it is also referred to herein as C3 to C6 alkylene. Examples include, but are not limited to, methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenylene means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a double bond. When alkenylene contains three to six carbon atoms it is also referred to herein as C3 to C6 alkenylene. Examples include, but are not limited to, ethen-diyl, propen-diyl, 2-propen-diyl, buten-diyl, penten-diyl, and the like.
  • Alkynylene means a linear or branched divalent unsaturated hydrocarbon radical of two to six carbon atoms containing a triple bond. When alkynylene contains three to six carbon atoms it is also referred to herein as C3 to C6 alkynylene. Examples include, but are not limited to, the like.
  • Alkoxy means a -OR P radical where R p is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or /c/V-butoxy, and the like.
  • Alkoxycarbonyl or “alkyloxycarbonyl” means a -C(O)OR P radical where R p is alkyl as defined above, e.g., methoxy carbonyl, ethoxy carbonyl, and the like.
  • Alkylcarbonyl means a -C(O)R P radical where R p is as defined herein, e.g., methylcarbonyl, ethylcarbonyland the like.
  • Amino means -NH2.
  • Aminocarbonyl means -C(0)NH2.
  • Alkylaminocarbonyl means -C(O)NHR P radical where R p is alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.
  • Alkylcarbonylamino means -NHC(O)R P radical where R p is alkyl as defined above e.g., methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, and the like.
  • Alkyl sulfonyl means -S(O)2R P radical where R p is alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Dialkylaminocarbonyl means -C(O)NR pl R p radical where R p and R pl are independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.
  • Alkylamino means -NHR P radical where R p is alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.
  • Aryloxy means a -O-R E radical where R p is aryl as defined above e.g., phenyloxy (or phenoxy), or naphthyl oxy.
  • Bicyclic heterocyclylene means a saturated divalent fused bicyclic group of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a -CO- group.
  • bicyclic heterocyclylene includes, but is not limited to, isoindolin-diyl, decahydro-2, 6- naphthyridin-diyl, octahydrocyclopenta[c]pyrrol-diyl, octahydro-lH-pyrrolo[3,4-c]pyridin-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like.
  • “Bridged cycloalkyl” means a saturated monovalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR p R p ’) n group where n is an integer selected from 1 to 3 and R p and R p ’ are independently H or methyl (also may be referred to herein as “bridging” group). Examples include, but are not limited to, bicyclo[l. l.l]pent-l-yl, bicyclo[2.2.1]heptyl, (in one subembodiment bicy clo[2.2. l]hept-2-yl), and the like.
  • “Bridged heterocyclyl” means a saturated monovalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR p R p ’) n group where n is an integer selected from 1 to 3 and R p and R p ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH, O, and S(O) n , where n is an integer selected from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl,
  • “Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR p R p ’) n group where n is an integer selected from 1 to 3 and R p and R p ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH, O, and S(O) n , where n is an integer selected from 0 to 2.
  • Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise.
  • Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octa-3,8- diyl, 7-oxabicyclo[2.2.1]heptan-diyl, 2,5-diazabicyclo[2.2.1]heptan-diyl, 3,6-diazabicyclo- [3.1.1]heptan-diyl, 2,5-diazabicyclo[2.2.2]octan-diyl, 3,8-diazabicyclo[3.2.1]octan-diyl, 6-azabicyclo[3.1.1]heptan-diyl, 8-azabicyclo[3.2.1]octan-diyl, and the like.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Cycloalkyloxy and “cycloalkoxy” mean an -OR P radical where R p is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cycloalkylene means a divalent monocyclic saturated hydrocarbon radical of three to six carbon atoms, unless stated otherwise e.g., 1,1 -cyclopropylene, 1,1 -cyclobutylene, 1,4- cyclohexylene, 1,2-cyclobutylene, and the like.
  • Carboxy means -COOH.
  • Cyclylaminylene means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen, the remaining ring atoms being carbon. More specifically, the term cyclylaminylene includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like.
  • Cyanoalkyl means alkyl as defined above that is substituted with a cyano e.g., cyanomethyl, cyanoethyl, and the like.
  • Cyanoalkyloxy means an -OR P radical where R p is cyanoalkyl as defined above, e.g., cyanomethyloxy, cyanoethyloxy, and the like.
  • “Deuterium” means refers to 2 H or D.
  • Dialkylamino means a -NR P R P radical where each R p is alkyl as defined above and are independently selected, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or /c/V-butylmethylamino, and the like.
  • “Fused heterocyclylene” means a divalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, NH, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the fused heterocyclylene can be attached at any two atoms of the ring.
  • Representative examples include, but are not limited to, l,2,3,4-tetrahydroquinolin-l,4-diyl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-5,8-diyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-diyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-diyl, and the like.
  • Halo means fluoro, chloro, bromo, or iodo, in one embodiment, fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH 3 ) 2 , and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH 3 ) 2 , and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.
  • Haloalkoxy means an -OR P radical where R p is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like.
  • R p is haloalkyl where the alkyl is substituted with only fluoro (in some examples, one or more fluoro), it is referred to in this Application as fluoroalkoxy.
  • Heteroaryl means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, NH, O, and S, the remaining ring atoms being carbon, unless otherwise stated.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • heteroaryl and “aryl” are mutually exclusive.
  • the heteroaryl ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as 5- or 6- membered monocyclic heteroaryl.
  • the heteroaryl ring contains 9- or 10-ring atoms, it is also referred to herein as 9- or 10-membered fused bicyclic heteroaryl.
  • Heteroarylene means a divalent heteroaryl radical as defined above, unless stated otherwise. Representative examples include, but are not limited to, benzimidazoldiyl e.g., benzimidazole-l,5-diyl, and the like.
  • heteroarylene ring contains 5- or 6 ring atoms and is a monocyclic ring
  • it is also referred to herein as monocyclic heteroarylene or as 5-or 6-membered monocyclic heteroarylene e.g., pyrazolyl-diyl (pyrazolyl-1.3-diyl, pyrazolyl-1.4- diyl, pyrazolyl-1.5-diyl and the like) and imidazol-diyl (imidazol-l,2-diyl, imidazol-l,4-diyl, imidazol-l,5-diyl).
  • pyrazolyl-diyl pyrazolyl-1.3-diyl, pyrazolyl-1.4- diyl, pyrazolyl-1.5-diyl and the like
  • imidazol-diyl imidazol-l,2-diyl, imidazol-l,4-diyl, imida
  • Heterocyclylcarbonyl means a -C(O)R group where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinyl carbonyl, and the like.
  • Heterocyclyloxy means an -OR group where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinyloxy, piperazinyloxy, pyrrolidinyloxy, azetidinyloxy, and the like.
  • C3 to Ce heteroalkylene means is a linear or branched saturated divalent hydrocarbon radical of three to six carbon atoms where (a) one carbon atom of the linear portion of the divalent hydrocarbon radical is replaced by X a where X a is -O-, -CO-, or -NR q - or (b) two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by X al where X al is -NR q CO-, -CONR q -, -NR q SO-, -SONR q -, -NR q SO 2 -, or -SO 2 NR q - (where each R q is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl), provided that the linear portion of C3 to Ce heteroalkylene attaching Z and the -SO 2 - depicted in the structure of Formula (I) contains at least three atoms.
  • the linear portion of the C3 to Ce heteroalkylene means the consecutive atoms of the C3 to Ce heteroalkylene connecting Z and the -SO 2 - depicted in the structure of Formula (I) e.g., in the structure , the atoms with * form the linear portion of C5 heteroalkylene.
  • Phenylene means divalent phenyl
  • “Spiro heterocyclylene” means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from NH, N, O, and S(O) n , where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise.
  • Representative examples include, but are not limited to, 2-azaspiro[3.3]heptan-diyl, 2,6-diazaspiro[3.3]heptan-diyl, l,7-diazaspiro[3.5]nonan-diyl, 2,7-diazaspiro[3.5]nonan-diyl, 3,9-diazaspiro[5.5]undecan-diyl, and the like.
  • the present disclosure also includes protected derivatives of compounds of Formula (I) of the first aspect (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups.
  • suitable protecting groups A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) of the first aspect and (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.
  • Certain compounds of the present disclosure can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.
  • a compound of Formula (I) having a hydroxy substituted pyridyl ring can exist as a tautomer as shown below:
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenes
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.
  • alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth.
  • the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth.
  • all hydrates of a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) are within the scope of this disclosure.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 1, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with (or isotopically enriched for) heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, n C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipienf as used in the specification and claims includes both one and more than one such excipient.
  • the term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ⁇ 10%, (in one subembodiment, the range for “about” encompasses ⁇ 5%), the recited value and the range is included.
  • the substituent is not attached to a specific atom of the structure.
  • the substituent(s) may be present on any atom of the ring to which it is attached, where chemically feasible and valency rules permitting.
  • the R aa substituent, and similarly the R bb substituent is a floating substituent, and can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with R bb (in the case of R aa ), and similarly with R aa (in the case ofR bb ).
  • the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule
  • the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule.
  • the bond on the left of (a) and (b) is attached to the following ring: and the on the right side of (a) and (b) is attached to Z of the Formula (I) structure:
  • the bond on left side i.e., Z
  • the bond on right side is attached to -SO2- that is attached to an atom of Hy.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. In one embodiment, the patient is a human.
  • Treating” or “treatment” of a disease includes:
  • treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of the present disclosure and/or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • a “condition associated with an autoimmune disease” means a condition that a patient with an autoimmune disease is susceptible to, e.g., sepsis, or a condition that is caused by the autoimmune disease, e.g., uveitis.
  • the compounds of Formula (I) can also inhibit CDK2 and/or CDK4.
  • the compound of Formula (I) may independently decrease about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, of CDK2 and/or CDK4 activities, compared to their/its normal activity.
  • the CDK2 and/or CDK4 activity is reduced by at least 40% in the presence of a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 and/or CDK4, respectively, in the absence of said compound.
  • the inhibitory activity of a compound of Formula (I) can be measure using Biological Example 1, by converting a compound of Formula (I) to a corresponding compound of Formula (I) that cannot be degraded by the ubiquitin proteosome pathway e.g., by H O ⁇ N ⁇ O methylating the nitrogen atom in ' group of ligase ligand (i) or (ii) present in the compound of Formula (I).
  • degradation and “degrade,” or any variation of these terms in relation to CDK2, CDK4, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, and CDK1, respectively, over time in a sample containing a compound of Formula (I).
  • CDK2 and/or CDK4 concentration in a sample containing CDK2 and/or CDK4, respectively and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 or CDK4, in the absence of said compound.
  • the % degradation can be determined as described in Biological Example 2 below.
  • the decrease in the concentration of CDK2 and/or CDK4 is > 20%.
  • the decrease in the concentration of CDK2 and/or CDK4 is > 40%. In another embodiment, the decrease in the concentration of CDK2 and/or CDK4 is > 50%. In another embodiment, the decrease in the concentration of CDK2 and/or CDK4 is > 60%. In another embodiment, the decrease in the concentration of CDK2 and/or CDK4 > 70%. In another embodiment, the decrease in the concentration of CDK2 and/or CDK4 is > 80%.
  • the present disclosure includes:
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is halo.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is haloalkyl or haloalkoxy.
  • embodiment A4 the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R 1 is haloalkyl.
  • embodiment A5 the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R 1 is haloalkoxy.
  • the compound of any one of embodiments Al to A5, or a pharmaceutically acceptable salt thereof is wherein R 1 is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A6, or a pharmaceutically acceptable salt thereof is wherein R 1 is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy unless stated otherwise.
  • the compound of any one of embodiments Al, A2, and A6 and A7, or a pharmaceutically acceptable salt thereof, is wherein R 1 is chloro.
  • the compound of any one of embodiments Al, A3, A4, A6, and A7, or a pharmaceutically acceptable salt thereof is wherein R 1 is difluoromethyl or trifluoromethyl.
  • the compound of any one of embodiments Al, A3, A4, A6, A7, and A9, or a pharmaceutically acceptable salt thereof, is wherein R 1 is trifluoromethyl.
  • Al l the compound of any one of embodiments Al, A3, and A5 to A7, or a pharmaceutically acceptable salt thereof, is wherein R 1 is trifluoromethoxy.
  • the compound of any one of embodiments Al, A3, and A5 to A7, or a pharmaceutically acceptable salt thereof is wherein R 1 is difluoromethoxy.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is alkyl, alkenyl, or alkynyl.
  • the compound of embodiment Al or A13, or a pharmaceutically acceptable salt thereof is wherein R 1 is methyl, ethyl, propyl, vinyl, propenyl, ethynyl, or propynyl.
  • the compound of embodiment Al, A13, or A14, or a pharmaceutically acceptable salt thereof is wherein R 1 is methyl, ethyl, or propyl.
  • the compound of embodiment Al, A13, or A14, or a pharmaceutically acceptable salt thereof is wherein R 1 is vinyl, propenyl, ethynyl, or propynyl.
  • the compound of embodiment Al or A17, or a pharmaceutically acceptable salt thereof is wherein R 1 is methoxy, ethoxy, or propoxy.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is aryloxy, In one subembodiment R 1 is phenoxy.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is cyano.
  • R 1 is cycloalkyl. In one subembodiment, R 1 is cyclopropyl.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyl substituted with one to three halo. In one sub embodiment, R 1 is fluorocyclopropyl or difluorocyclopropyl.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyloxy. In one subembodiment, R 1 is cyclopropyloxy.
  • the compound of embodiment Al, or a pharmaceutically acceptable salt thereof is wherein R 1 is cycloalkyloxy substituted with one to three halo. In one sub embodiment, R 1 is fluorocyclopropyloxy or difluorocyclopropyloxy.
  • the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof, is wherein R 2 and R 2a are hydrogen.
  • the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof is wherein one of R 2 and R 2a is deuterium and the other of R 2 and R 2a is hydrogen or both R 2 and R 2a are deuterium.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene, arylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A26, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is pyrrolidin-1,3- diyl or piperidin-l,4-diyl, where each ring of Hy is substituted with R a , R b , and R c where R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, and R c is hydrogen; and -SO2- is attached to the nitrogen atom of the piperidin-l,4-diyl or pyrrolidin-1,3- diyl ring of Hy.
  • the compound of any one of embodiments Al to K 1 or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2- A29.
  • the compound of any one of embodiments Al to A28, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2-.
  • the compound of any one of embodiments Al to A29, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene of Hy is: where the N atom of the piperidin-l,4-diyl ring is attached to -SO2-.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is bridged heterocyclylene substituted with R a , R b , and R c where R c is hydrogen.
  • the compound of any one of embodiments Al to A25 and A30, or a pharmaceutically acceptable salt thereof is wherein the bridged heterocyclylene of Hy is a ring of formula: where each ring is substituted with R a , R b , and R c where R c is hydrogen, and the nitrogen atom of each ring is attached to -SO2-.
  • the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof is wherein R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.
  • A33 In embodiment A33, the compound of embodiment A30, A31, or A32, or a pharmaceutically acceptable salt thereof, is wherein R b is hydrogen.
  • A34 the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is cycloalkylene substituted with R a , R b , and R c where R a is deuterium, methyl, fluoro, methoxy, or hydroxy and R b and R c are hydrogen.
  • the compound of any one of embodiments Al to A25 and A34, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is cyclohexylene.
  • the compound of any one of embodiments Al to A25, A34, and A35, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Hy is 9 . where denotes bond to NH and denotes bond of -SO2-.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is arylene wherein the arylene is phenylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.
  • the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof is wherein Hy is spiro heterocyclylene (in one subembodiment 2-azaspiro[3.3]heptan-2-yl) substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano and R c is hydrogen.
  • the compound of embodiment A37, or a pharmaceutically acceptable salt thereof is wherein the phenylene of Hy is 1,4-phenylene according to structure denotes the bond to -SO2- where R a is hydrogen, fluoro, methyl or methoxy and where R b is hydrogen.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is fused heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano and R c is hydrogen.
  • the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof is wherein Hy is bicyclic heterocyclylene substituted with R a , R b , and R c where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano and R c is hydrogen.
  • the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i):
  • the compound of any one of embodiments Al to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a):
  • the compound of any one of embodiments Al to A41, or a pharmaceutically acceptable salt thereof is wherein R 4 and R 5 are independently hydrogen or alkyl.
  • the compound of any one of embodiments Al to A42, or a pharmaceutically acceptable salt thereof, is wherein R 4 and R 5 are hydrogen.
  • the compound of any one of embodiments Al to A42, or a pharmaceutically acceptable salt thereof is wherein R 4 is hydrogen and R 5 is methyl.
  • the compound of any one of embodiments Al to A40, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b):
  • the compound of any one of embodiments Al to A40 and A42 to A46, or a pharmaceutically acceptable salt thereof, is wherein R 6 is hydrogen.
  • the compound of any one of embodiments Al to A48, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments Al to A49, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: A51.
  • the compound of any one of embodiments Al to A50, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments Al to A51, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R aa is hydrogen (when R aa is not drawn out in above rings) and R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A41, A45, and A49 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments Al to A41, A45, and A49 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A43, and A49 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A43, A49 to A52, and A54, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R aa , R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A40, A42 to A46, and A48 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R aa , R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A40, A42 to A46, and A48 to A52, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R aa , R bb , R cc , and R dd are hydrogen.
  • ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where R aa , R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A54, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, unless stated otherwise i.e., in embodiments A52 to A54, where R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments Al to A54, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, A58, and A59, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and methoxy, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and fluoro, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, A58, and A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy, unless stated otherwise.
  • the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl, unless stated otherwise.
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl, unless stated otherwise.
  • the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):
  • the compound of any one of embodiments Al to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Y a is CH.
  • the compound of any one of embodiments Al to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Y a is N.
  • the compound of any one of embodiments Al to A39b and A41 to A69, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, -O-, or -NHC(O)-.
  • the compound of any one of embodiments Al to A39b and A41 to A70, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond, -NH-, or -NHC(O)-.
  • the compound of any one of embodiments Al to A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond.
  • the compound of any one of embodiments Al to A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NH-, or -NHC(O)-.
  • the compound of any one of embodiments Al to A39b, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NH-.
  • the compound of any one of embodiments Al to A39b, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NHC(O)-.
  • the compound of any one of embodiments Al to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, and A41 to A74a, or a pharmaceutically acceptable salt thereof is wherein ring B is cyclylaminylene substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b and A41 to A74a, or a pharmaceutically acceptable salt thereof is wherein ring B is a 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms (and not containing any additional heteroatoms) and substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b, A41 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with R ee and R ff .
  • the compound of any one of embodiments Al to A39b and A41 to A80, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula (ii) is: where ring B is as defined therein.
  • the compound of any one of embodiments Al to A39b and A41 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • R ee and/or R ff are/is hydrogen when they are/is not drawn out in a structure.
  • the compound of any one of embodiments Al to A39b and A41 to A82-1, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: where is cyclylaminylene and R is hydrogen when not drawn out in the above structures.
  • the compound of any one of embodiments Al to A39b and R is hydrogen when not drawn out in the above structures.
  • A41 to A68, A70 to A72, A77, and A79 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula
  • A41 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • A83A the compound of any one of embodiments Al to A39b and A41 to A67, A69 to A72, A77, A79 to A82, and A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula A84.
  • the compound of any one of embodiments Al to A39b and A41 to A67, A69 to A72, A77, A79 to A82, and A83, or a pharmaceutically acceptable salt thereof is wherein the E3 ubiquitin ligase ligand of formula A84.
  • A41 to A83 A is wherein each R ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A83A, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A85, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen and methoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein one of R ee and R ff is hydrogen or fluoro and the other of R ee and R ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A92, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are hydrogen.
  • the compound of any one of embodiments Al to A39b and A41 to A86, A89 and A92, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are chloro unless stated otherwise.
  • A95 the compound of any one of embodiments Al to A39b and A41 to A86, A89, and A92, or a pharmaceutically acceptable salt thereof, is wherein R ee and R ff are fluoro unless stated otherwise.
  • the compound of any one of embodiments Al to A39b and A41 to A86 and A90, or a pharmaceutically acceptable salt thereof is wherein R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof is wherein Z is phenylene, monocyclic heteroarylene, bridged heterocyclylene, heterocyclylene, or unsaturated heterocyclylene, where each ring is substituted with R d and R e as defined therein.
  • the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof is wherein Z is cycloalkylene selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene and where each ring is substituted as defined therein.
  • the compound of any one of embodiments Al to A96 and A98, or a pharmaceutically acceptable salt thereof is wherein the cycloalkylene of Z is independently selected from 1,3 -cyclopentylene, 1,3 -cyclohexylene, and 1,4-cyclohexylene.
  • Al 00 the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof, is wherein Z is phenylene or monocyclic heteroarylene (such as imidazoldiyl, pyridindiyl, or pyrimidindiyl) and where each ring is substituted with R d and R e as defined therein.
  • Z is phenylene or monocyclic heteroarylene (such as imidazoldiyl, pyridindiyl, or pyrimidindiyl) and where each ring is substituted with R d and R e as defined therein.
  • the compound of any one of embodiments Al to A97, and Al 00, or a pharmaceutically acceptable salt thereof is wherein Z is monocyclic heteroarylene selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyri din-3, 5 -diyl.
  • Al 02 the compound of any one of embodiments Al to A97 and A100, or a pharmaceutically acceptable salt thereof, is wherein Z is 1,3-phenylene or 1,4-phenylene.
  • the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof is wherein Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene (unless stated otherwise), where each ring is substituted with R d and R e as defined therein.
  • the compound of any one of embodiments Al to A97, and A103, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are selected from:
  • each ring is substituted with R d and R e independently selected from hydrogen, deuterium, alkyl, and halo.
  • the compound of any one of embodiments Al to A97, A103, and Al 04, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are independently selected from: respectively.
  • the compound of any one of embodiments Al to A97 and A103 to A105, or a pharmaceutically acceptable salt thereof, is wherein Z is heterocyclylene or bridged heterocyclylene selected from:
  • Al 07 the compound of any one of embodiments Al to A97 and
  • the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof is wherein Z is -O-, -NH-, or -NCH3-.
  • Al 09 the compound of any one of embodiments Al to Al 08, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to Ce alkenylene substituted with R f where R f is hydrogen.
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkenylene substituted with R f where R f is fluoro or cyano.
  • Al l i the compound of any one of embodiments Al to Al 08, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen.
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen or halo, provided at least one of R g , R h , and R 1 is halo.
  • the compound of embodiment Al 12, or a pharmaceutically acceptable salt thereof is wherein the halo of the at least one of R g , R h , and R 1 is fluoro.
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen or when R h and R 1 are attached to the same carbon atom or to adjacent carbon atoms of the linear portion of the C3 to Ce alkylene, R h and R 1 together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R h and R 1 are substituted with R 9 and R 10 .
  • Al 15 the compound of embodiment Al 14, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen.
  • the compound of any one of embodiments Al to Al 15, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce alkenylene and C3 to Ce alkylene of alk are linear alkenylene and alkylene, respectively, and substituted as defined therein.
  • Al 18 the compound of any one of embodiments Al to A108 and Al 12 to Al 17, or a pharmaceutically acceptable salt thereof, is wherein the linear C3 to Ce alkylene of alk is -CH2CH(R h )CH2- where R h is as defined therein and R g and R 1 are hydrogen.
  • the compound of any one of embodiments Al to Al 08 and Al 14 to Al 18, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is, unless stated otherwise, hydrogen, deuterium, or halo and R h of linear C3 to Ce alkylene of alk is, unless stated otherwise, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring is substituted as defined therein and R 1 is as defined therein.
  • the compound of any one of embodiments Al to A108 and Al 14 to Al 19, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen and R h of linear C3 to Ce alkylene of alk is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring is substituted as defined therein, and R 1 is as defined therein.
  • the compound of any one of embodiments Al to A108 and Al 14 to A120, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce alkylene of alk is hydrogen and R h of linear C3 to Ce alkylene of alk is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, where each ring is substituted as defined therein and R 1 is as defined therein.
  • the compound of any one of embodiments Al to A108 and Al 14 to A121, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl (unless stated otherwise), when present, of R h of linear C3 to Ce alkylene of alk are five or six membered rings and each ring is substituted as defined therein.
  • R g of linear C3 to Ce alkylene of alk is hydrogen, deuterium, or fluoro unless stated otherwise, R h of linear C3 to Ce alkylene of alk is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl,
  • R g of linear C3 to Ce alkylene of alk is hydrogen, deuterium, or fluoro, unless stated otherwise, R h of linear C3 to Ce alkylene of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-l-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-l-yl, 2-oxopyrrolidin-l-yl, where each ring of R h is substituted with R 7 and R 8 independently selected from hydrogen, deuterium, methyl, or fluoro
  • the compound of any one of embodiments Al to Al 15, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce alkenylene and C3 to Ce alkylene of alk are branched C4 to Ce alkenylene and C4 to Ce alkylene, respectively, substituted as defined therein.
  • the compound of any one of embodiments Al to A108, Al l i to Al 15, and A125, or a pharmaceutically acceptable salt thereof, is wherein the C3 to Ce alkylene of alk is branched C4 to Ce alkylene substituted as defined therein.
  • the compound of any one of embodiments Al to A108, Al l i to Al 15, and A125 to A128, or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce alkylene of alk are independently hydrogen or halo (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise) and each ring of R h is substituted as defined therein.
  • the compound of any one of embodiments Al to A108, Al l i to Al 15, and A125 to A129, or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce alkylene of alk are hydrogen or fluoro (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise) and each ring of R h is substituted as defined therein.
  • the compound of any one of embodiments Al to Al 08, Al l i to Al 15, and A125 to A130, or a pharmaceutically acceptable salt thereof is wherein R g and R 1 of branched C4 to Ce alkylene of alk are hydrogen or fluoro (unless stated otherwise) and R h of branched C4 to Ce alkylene of alk is (unless stated otherwise) hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • Al 32 the compound of any one of embodiments Al to Al 08, Al l i to Al 15, and A125 to A131, or a pharmaceutically acceptable salt thereof, is wherein alk is branched C4 to Ce alkylene substituted as defined therein and the heteroaryl, heterocyclyl, by itself or as part of heterocyclyloxy or heterocyclylcarbonyl, and bridged heterocyclyl of branched C4 to Ce alkylene of alk, when present, are five or six membered rings and each ring of R h is substituted as defined therein.
  • the compound of any one of embodiments Al to A108, Al l i to Al 15, and A125 to A132, or a pharmaceutically acceptable salt thereof is wherein the R g of branched C4 to Ce alkylene of alk is hydrogen, deuterium, or fluoro (unless stated otherwise), R 1 of branched C4 to Ce alkylene of alk is hydrogen or fluoro (unless stated otherwise), and R h of branched C4 to Ce alkylene of alk, when present and unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbony
  • the compound of any one of embodiments Al to Al 08, Al l i to Al 15, and A125 to 133, or a pharmaceutically acceptable salt thereof is wherein R g and R 1 of branched C4 to Ce alkylene of alk, unless stated otherwise, are hydrogen or fluoro and R h of branched C4 to Ce alkylene of alk, unless stated otherwise, is hydrogen, fluoro, hydroxy, methoxy, cyano, pyrazolyl- 1-yl, or methylaminocarbonyl.
  • the compound of any one of embodiments Al to Al 08 and Al 14, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h and R 1 are attached to the same carbon atom or to adjacent carbon atoms of the linear portion of the C3 to Ce alkylene and R h and R 1 together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R h and R 1 are substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, Al 14, and A135, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h and R 1 are attached to the same carbon atom of the linear portion of C3 to Ce alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, Al 14, and A135, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h and R 1 are attached to the same carbon atom of the linear portion of the C3 to Ce alkylene and together with the carbon atom to which they are attached can form heterocyclylene substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, Al 14 and A135, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h and R 1 are attached to adjacent carbon atoms of the linear portion of the C3 to Ce alkylene and together with the carbon atoms to which they are attached can form cycloalkylene substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, Al 14, and A135, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce alkylene substituted with R g , R h , and R 1 where R h and R 1 are attached to adjacent same carbon atoms of the linear portion of the C3 to Ce alkylene and together with the carbon atoms to which they are attached can form heterocyclylene substituted with R 9 and R 10 .
  • R h and R 1 are attached to adjacent same carbon atoms of the linear portion of the C3 to Ce alkylene and together with the carbon atoms to which they are attached form heterocyclylene substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, Al 14, and A135 to A137, or a pharmaceutically acceptable salt thereof is wherein R h and R 1 are attached to the same carbon atom of the linear portion C3 to Ce alkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 9 and R 10 , in one embodiment R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • R h and R 1 form cycloalkylene or heterocycloalkylene as provided above.
  • the compound of any one of embodiments Al to A108, Al 14, A135, A138, and A139, or a pharmaceutically acceptable salt thereof is wherein R h and R 1 are attached to adjacent carbon atoms of the linear portion of the C3 to Ce alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 9 and R 10 , (in one subembodiment R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen).
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein the alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 .
  • the compound of any one of embodiments Al to A108 and A142, or a pharmaceutically acceptable salt thereof is wherein the alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen.
  • the compound of any one of embodiments Al to A108 and A142, or a pharmaceutically acceptable salt thereof is wherein the alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R g , R h , and R 1 are hydrogen or halo, provided at least one of R g , R h , and R 1 is halo.
  • the compound of any one of embodiments Al to A108 and A142, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen, or when R h and R 1 are attached to the same carbon atom or to adjacent carbon atoms of the linear portion of the C3 to Ce heteroalkylene, R h and R 1 together with the carbon atom to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R 9 and R 10 .
  • R h and R 1 together with the carbon atom to which they are attached form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R 9 and R 10 .
  • the compound of any one of embodiments Al to A108, A142, and A145, or a pharmaceutically acceptable salt thereof is wherein R h and R 1 are attached to the same carbon atom of the linear portion of the C3 to Ce heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 9 and R 10 , preferably R 9 is hydrogen, halo, methyl or ethyl and R 10 is hydrogen.
  • R h and R 1 form cycloalkylene or heterocycloalkylene as provided above.
  • the compound of any one of embodiments Al to A108, A142, and A145, or a pharmaceutically acceptable salt thereof is wherein R h and R 1 are attached to adjacent carbon atoms of the linear portion of the C3 to Ce heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R 11 and R 12 , preferably R 11 is hydrogen, halo, methyl or ethyl and R 12 is hydrogen.
  • R h and R 1 form cycloalkylene or heterocycloalkylene as provided above.
  • A148 the compound of any one of embodiments Al to A108, A142, and A145, or a pharmaceutically acceptable salt thereof, is wherein R h and R 1 are attached to adjacent carbon atoms of the linear portion of the C3 to Ce heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where
  • the compound of any one of embodiments Al to A108, and A145, or a pharmaceutically acceptable salt thereof is wherein alk is C3 to Ce heteroalkylene substituted with R g , R h , and R 1 where R h is other than hydrogen and R 1 is hydrogen unless otherwise stated.
  • the compound of any one of embodiments Al to A108 and A142 to A148, or a pharmaceutically acceptable salt thereof is wherein the C3 to Ce heteroalkylene of alk is linear C3 to Ce heteroalkylene substituted with R g , R h , and R 1 .
  • the compound of any one of embodiments Al to Al 08 and A142 to A149, or a pharmaceutically acceptable salt thereof is wherein the linear heteroalkylene of alk is -CH2CH 2 X a CH2-, -CH2X a CH 2 CH2-, -CH 2 CH 2 CH 2 X a -, -X a CH2CH 2 CH2-, -X a CH 2 CH2-, -CH2X a CH2-, or -CH2CH2X a -, where R g , R h , and R 1 are hydrogen and X a is -NR q -, -O-, or -CO-.
  • the compound of any one of embodiments Al to Al 08 and A142 to Al 50, or a pharmaceutically acceptable salt thereof is wherein R q is hydrogen, methyl, ethyl, methylcarbonyl, or methyl sulfonyl.
  • the compound of any one of embodiments Al to Al 08 and A142, A143, and A149 to A151, or a pharmaceutically acceptable salt thereof is wherein the linear C3 to Ce heteroalkylene of alk is -CH 2 CH 2 CH 2 X a - or -CJbCJbX 3 where R g , R h , and R 1 are hydrogen.
  • the compound of any one of embodiments Al to A108 and A142, A145, A148, A149, and A151, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen or halo (unless stated otherwise) and R h of linear heteroalkylene of alk is (unless stated otherwise) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring is substituted as defined therein, and R 1 is hydrogen.
  • Al 54 the compound of any one of embodiments Al to Al 08 and A142, A145, A148, A149, A151, and A153, or a pharmaceutically acceptable salt thereof, is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen or fluoro (unless stated otherwise) and R h of linear heteroalkylene of alk (unless stated otherwise) is hydrogen, halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.
  • the compound of any one of embodiments Al to A108 and A142, A145, A148, A149, A151, A153, and A154, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of R h of linear C3 to Ce heteroalkylene of alk, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments Al to Al 08 and A142, A145, A148, A149, A151, and A153 to A155, or a pharmaceutically acceptable salt thereof is wherein R g of linear heteroalkylene of alk, unless stated otherwise, is hydrogen, deuterium, or fluoro, and R h of linear heteroalkylene of alk, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl,
  • the compound of any one of embodiments Al to Al 08 and A142, A145, A148, A149, A151, and A153 to A156, or a pharmaceutically acceptable salt thereof is wherein R g of linear C3 to Ce heteroalkylene of alk is hydrogen and R h of linear C3 to Ce heteroalkylene of alk, unless stated otherwise, is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-l-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-l-yl, 2-oxopyrrolidin-l-yl, where each ring is substituted with R 7 and R 8 independently selected from hydrogen, deuterium,
  • the compound of any one of embodiments Al to A108 and A142 to Al 57, or a pharmaceutically acceptable salt thereof is wherein X a is -NR q - where R q is hydrogen or methyl.
  • the compound of any one of embodiments Al to 108 and A142 to A148, or a pharmaceutically acceptable salt thereof, is wherein the C3 to Ce heteroalkylene of alk is branched C4 to Ce heteroalkylene.
  • the compound of any one of embodiments Al to Al 08 and A142 to A148, and Al 50 to Al 59, or a pharmaceutically acceptable salt thereof is wherein the branched C3 to Ce heteroalkylene of alk is -CH2X a CH(CH3)CH2-, -X a CH(CH3)CH2CH2-, -CH(CH3)CH 2 X a -, -X a CH(CH 3 )CH 2 -, -X a CH(CH 2 R h )CH2-, -X a CH(CH2CH 2 R h )CH2-, -X a C(CH 3 )(CH 3 )CH2-, -CH(CH2R h )CH 2 X a -, -CH(CH2CH2R h )CH 2 X a -, -C(CH 3 )(CH 3 )CH2X a -, -CH2CH(CH 2 R h )X
  • the compound of any one of embodiments Al to Al 08, A142 to A145, A148, Al 59, and A160, or a pharmaceutically acceptable salt thereof is wherein the branched C4 to Ce heteroalkylene of alk is -X a CH(CH2CH2R h )CH2-, or -X a CH(CH2R h )CH2.
  • each of R g and R 1 is hydrogen).
  • the compound of any one of embodiments Al to Al 08, A142 to A145, A148, and A159 to A161, or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce heteroalkylene of alk are hydrogen or halo (unless stated otherwise) and R h of branched C4 to Ce heteroalkylene of alk is (unless stated otherwise) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl substituted as defined therein.
  • the compound of any one of embodiments Al to A108, A142 to A145, A148, and A159 to A162,or a pharmaceutically acceptable salt thereof is wherein the R g and R 1 of branched C4 to Ce heteroalkylene of alk are hydrogen or fluoro (unless stated otherwise) and R h (unless stated otherwise) is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl, substituted as defined therein.
  • Al 64 the compound of any one of embodiments Al to Al 08, A142 to A145, A148, and A159 to A163, or a pharmaceutically acceptable salt thereof, is wherein R g and R 1 are hydrogen and R h is (unless stated otherwise) hydrogen, heteroaryl, alkylaminocarbonyl, or cyano.
  • Al 65 the compound of any one of embodiments Al to Al 08, A142 to A145, A148, and A159 to A164, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl of branched C4 to Ce heteroalkylene of alk, by itself or as part of heterocyclyloxy or heterocyclylcarbonyl, and bridged heterocyclyl, when present, are five or six membered ring and each ring is substituted as defined therein.
  • the compound of any one of embodiments Al to Al 08, A142 to A145, A148, and A159 to A165, or a pharmaceutically acceptable salt thereof is wherein R h of branched C4 to Ce heteroalkylene of alk, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolidinyl, pyridinyl, piperidinyl, piperazinyl, or tetrahydrofurany
  • A167 the compound of any one of embodiments A108, A142 to A148, and A159 to A166, or a pharmaceutically acceptable salt thereof, is wherein X a is -NR q - where R q is hydrogen or methyl.
  • A168 the compound of any one of embodiments A108, A142 to
  • A148, and A159 to A166, or a pharmaceutically acceptable salt thereof, is wherein X a is -O-.
  • Al 69 the compound of any one of embodiments Al to Al 68, or a pharmaceutically acceptable salt thereof, is wherein alk is:
  • Al 70 the compound of any one of embodiments Al to Al 69, or a pharmaceutically acceptable salt thereof, is wherein alk is:
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein alk is alkynylene substituted with R 1 and R k independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.
  • R 1 and R k independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.
  • R k independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.
  • A171 or a pharmaceutically acceptable salt thereof, is wherein alk is alkynylene substituted with R> and R k where R 1 is hydrogen and R k is selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano. A173.
  • the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof is wherein alk is alkynylene substituted with R> and R k which are attached to the same carbon atom of the alkynylene and are combined with the carbon to which they are attached to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R 11 and R 12 independently selected from hydrogen, alkyl, and halo.
  • A171 to A173, or a pharmaceutically acceptable salt thereof, is wherein the alkynylene of alk is:
  • the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A72, A75, A77 to A82, A83 to A93, and A96 to A174, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from:
  • R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A72, A75, A77 to A82, A83 to A93, and A96 to A175, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand selected from: where R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl unless stated otherwise.
  • the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A67 to A72, A77, A79 to A82, A83 to A87, A89, and A97 to A176, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ligase ligand selected from: unless stated otherwise.
  • the compound of any one of embodiments Al to A39b, A67, A69 to A72, A77, A79 to A82, A83 to A87, A89 to A93, and A97 to A176, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand i (i.e. R ff is hydrogen) where each R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, preferably methyl.
  • the compound of any one of embodiments Al to A39b, A41 to A68, A70 to A72, A77, and A79 to A82A, A84 to A93, and A96 to A174, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.
  • Degron is the E3 ubiquitin ligase ligand is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluorometh
  • the compound of embodiment A179, or a pharmaceutically acceptable salt thereof is wherein Degron is the E3 ubiquitin ligase ligand is Regardless of whether the phrase “unless stated otherwise” is used in the above embodiments, when an embodiment refers to more than one preceding embodiment of varying scopes, only those groups that fall within the scope of group(s) recited in a preceding embodiment s) should be selected from the embodiment referring thereto.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.
  • a compound of Formula (I) such as where R 2a is hydrogen, Hy is 1,4-piperidindiyl, Degron is a group of formula (i), alk is as defined in the Summary and Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene containing at least one nitrogen ring atom, can be synthesized as illustrated and described in Scheme 2.
  • An amine compound of formula 2-4 prepared by removal of the Boc protecting group of 2-3 in the presence of an acid, such as TFA, is converted to a sulfonamide compound of formula 2-6 by treating it with a sulfonyl halide of formula 2-5 where A 2 is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl and alk is as defined in the Summary or an embodiment thereof hereinabove.
  • Treatment of a compound of formula 2-6 with an amine compound of formula 2-7 where is heterocyclyl, bridged heterocyclyl or spiro heterocyclyl containing at least one nitrogen atom and ring A is defined as in the Summary or an embodiment thereof hereinabove, under basic conditions such as in the presence of DIPEA, provides a compound of Formula (I).
  • a compound of Formula (I) such as where R 2a is hydrogen, Degron is a group of formula (i) and alk is attached to Degron of formula (i) via heterocyclylene such as 4-piperidin-l-yl, can be synthesized as illustrated and described in Scheme 3.
  • the compound of Formula (I) could cause degradation of CDK2 and/or CDK4 proteins and hence are useful in the treatment of diseases mediated by CDK2 and/or CDK4.
  • CDK2/4 mutations are rarely found, the kinase activity of CDK4/Cyclin D, CDK2/Cyclin E or CDK2/Cyclin A complexes is elevated via several mechanisms in human cancers.
  • Aberrations of CDK4/cyclin D regulation have been identified in many human cancers.
  • amplification or overexpression of cyclin DI has been found in many cancers, including breast invasive ductal carcinoma, invasive breast carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung adenocarcinoma.
  • Translocation of cyclin DI Amplification of CDK4 is common in liposarcoma.
  • CDK4 amplification has also been observed at lower frequency in other solid tumors and hematologic malignancies.
  • Loss of the CDK4 inhibitor pl6 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell carcinoma, bladder urothelial carcinoma, skin cutaneous melanoma, diffuse large B-cell lymphoma, cholangiocarcinoma, lung adenocarcinoma, and stomach adenocarcinoma.
  • Cyclin E has been found to be frequently amplified in cancers, for example, in uterine cancer, ovarian cancer, stomach cancer, and breast cancer.
  • loss-of-function mutations in FBXW7 or overexpression of USP28 which control the turnover of cyclin E, leads to cyclin E overexpression and CDK2 activation.
  • certain cancer cells express a hyperactive, truncated form of cyclin E or cyclin A.
  • cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers.
  • catalytic activity of CDK2 is increased following loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21, or overexpression of SKP2, a negative regulator of p27.
  • SKP2 a negative regulator of p27.
  • CDC25A and CDC25B protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using cancer cells or mouse cancer models.
  • CDK2/cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc/ras-induced tumorigenesis.
  • CDK2 inhibition resulted in anaphase catastrophe and apoptosis.
  • inhibiting CDK2 effectively induced granulocytic differentiation in AML cell lines and arrested tumor growth in AML mice models.
  • CDK2 activation as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to HR+ or HER2+ breast cancers treated by CDK4/6 inhibitors or trastuzumab. Accordingly, compounds of Formula (I) can be used in combination with CDK4/6 inhibitors or anti-HER2 therapies for the treatment of cancers that become refractory to CDK4/6 inhibitors or anti-HER2 therapies.
  • a compound of this disclosure may be useful for treating tumors characterized by 1) overexpression of CDK2 and/or CDK4; 2) amplification /overexpression of cyclin D, cyclin E or cyclin A; 3) hyperphosphorylation of CDK2 (Thrl60) or CDK4 (Thrl72); 4) loss-of-function of mutation in FBXW7, depletion of AMBRA1, overexpression of USP28, or amplification/overexpression of CDC25A or/and CDC25B; 5) expression of truncated cyclin E or cyclin A, 6) dysregulation of pl 6, p21 or p27, or overexpression of SKP2;and 7) hyperactive MYC/RAS; 8) Aneuploid cancers, and 9) CDK4 and/or CDK6 inhibitor refractory cancers.
  • the cancer is ovarian cancer (e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas), uterine cancer (e.g. endometrial cancer and uterine sarcoma), stomach cancer (i.e. gastric cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), renal cancer (e.g.
  • ovarian cancer e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas
  • uterine cancer e.g. endometrial cancer and uterine sarcoma
  • stomach cancer i.e. gastric cancer
  • lung cancer e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-par
  • kidney cancer including astrocytoma, meningioma and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumors, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal cancers, hereditary leiomyomatosis, renal cell cancer, astrocytoma, skin cancer (e.g.
  • bladder cancer including bladder urothelial carcinoma
  • cervical cancer colorectal cancer (e.g., cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, tongue and mouth), liver cancer (e.g., hepatocellular carcinoma and cholangiocellular carcinoma), prostate cancer, testicular cancer, gall bladder cancer, pancreatic cancer (e.g.
  • exocrine pancreatic carcinoma and neuroendocrine pancreatic cancer thyroid cancer, and parathyroid cancer
  • fallopian tube cancer peritoneal cancer
  • vaginal cancer vaginal cancer
  • biliary tract cancer esophageal cancer
  • sarcoma e.g. liposarcoma and osteosarcoma
  • bone cancer chondrosarcoma
  • leukemia including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia
  • lymphoma e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma
  • multiple myeloma multiple myeloma.
  • the cancer is breast cancer, including, e.g., ER-positive/HR-positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2- positive breast cancer; ER-negative/HR-negative, HER2-positive breast cancer, triple negative breast cancer (TNBC); or inflammatory breast cancer.
  • the breast cancer is endocrine resistant breast cancer, anti-HER2 therapy (e.g. trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4/CDK6 inhibition.
  • the breast cancer is advanced or metastatic breast cancer.
  • the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
  • compounds of Formula (I) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss.
  • autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as
  • CDK2/4 potency and CDK2/4 degradation activities of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples below.
  • the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds), i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred.
  • compositions are comprised of in general, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
  • compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
  • the level of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt. %.
  • the compounds of Formula (I) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or the other drugs may have utility.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is preferred.
  • the combination therapy may also include therapies in which the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • the above combinations include combinations of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) not only with one other drug, but also with two or more other active drugs.
  • a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject can be treated with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in any combination with one or more other anti -cancer agents including but not limited to: MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL-518 (CAS No.
  • RAS/RAF/MEK/ERK MAP kinase pathway
  • CSF1R inhibitors PLX3397, LY3022855, etc.
  • CSF1R antibodies IMC-054, RG7155
  • TGF beta receptor kinase inhibitor such as LY2157299;
  • BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2-[(lS,4R)-6-[[4-cyclobutylarmno)-5-(trifluoromethyl)-2- pyrimidinyl]amino]-l, 2,3,4-tetrahydronaphthalen-l,4-imin-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3);
  • ALK inhibitors PF-2341066 (XALKOPJ ®; crizotinib); 5-chloro-N4-(2- (isopropyl- sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-l-yl)piperi din-1- yl)phenyl)pyrimidine- 2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]- pyrimidin-4-yl]morholine (also known as GDC 0941 and described in PCT Publication Nos.
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No.
  • Brivanib Alaninate ((S)-((R)-l-(4-(4-fluoro-2-methyl-lH-indol- 5-yloxy)-5-methylpyrrolo[2,l-f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4- pyridinyl- methyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No.
  • pasireotide also known as SOM230, and described in PCT Publication No. WO 02/010192
  • sorafenib sold under the tradename Nexavar®
  • AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib
  • FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib;
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the tradename Vectibix® by Amgen);
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No.
  • lapatinib or lapatinib ditosylate sold under the trademark Tykerb® by GlaxoSmithKline
  • Trastuzumab emtansine in the United States, ado- trastuzumab emtansine, trade name Kadcyla
  • an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1)
  • DM1 cytotoxic agent mertansine
  • Trastuzumab deruxtecan trade name Enhertu
  • HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by Genentech);
  • CD20 antibodies Rituximab (sold under the trademarks Riuxan® and Mab Thera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.
  • dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);
  • DNA Synthesis inhibitors Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);
  • Antineoplastic agents oxaliplatin (sold under the tradename Eloxatin® ay Sanofi -Aventis and described in US Patent No. 4,169,846);
  • G-CSF modulators Filgrastim (sold under the tradename Neupogen® by Amgen); Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®);
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);
  • Hedgehog antagonists 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958);
  • Phospholipase A2 inhibitors Anagrelide (sold under the tradename Agrylin®);
  • BCL-2 inhibitors 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l- piperazinyl]-N-[[4-[[(lR)-3-(4-morpholinyl)-l-[(phenylthio)m ethyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386);
  • MC1-1 inhibitors MIK665, S64315, AMG 397, and AZD5991;
  • Aromatase inhibitors Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);
  • Topoisomerase II inhibitors etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2[(lR,9S,12S,15R,16E, 18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-l,18-dihydroxy-19,30- dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-2,3, 10, 14,20-pentaoxo-l 1, 36-dioxa-4- azatri cyclo[30.3.1.0 4 ' 9
  • Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;
  • BET inhibitors such as INCB054329, OTX015, and CPI-0610;
  • LSD1 inhibitors such as GSK2979552, and INCB059872;
  • KAT6 inhibitors such as PF-07248144
  • HIF-2a inhibitors such as PT2977, PT2385, imdatifan, and casdatifan; Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (sold under the tradename Zevalin®);
  • octreotide also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Sandostatin® also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • IL-11 Synthetic Interleukin- 11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);
  • RANK Nuclear Factor K B
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename Nplate® by Amgen);
  • IGF-1R Anti-Insulin-like Growth Factor-1 receptor antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6);
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3);
  • CD52 antibodies Alemtuzumab (sold under the tradename Campath®);
  • Histone deacetylase inhibitors Voninostat (sold under the tradename Zolinza® by Merck);
  • Alkylating agents Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexal en®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platino
  • Anti-tumor antibiotics doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);
  • Anti -microtubule agents Estramustine (sold under the tradename Emcyl®);
  • Cathepsin K inhibitors Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4- fluoro-N-2- ⁇ (lS)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl ⁇ -L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836); Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol-Myers Squibb);
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);
  • Anti-mitotic agents Docetaxel (sold under the tradename Taxotere® by Sanofi -Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);
  • Nilutamide sold under the tradenames Nilandron® and Anandron®
  • bicalutamide sold under tradename Casodex®
  • flutamide sold under the tradename FulexinTM
  • CDK Fluoxymesterone (sold under the tradename Halotestin®); CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11/12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No. 5,621,002);
  • CDK4/6 inhibitors palbociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, TP-1287; CDK2/4/6 inhibitor such as PF-06873600;
  • SHP-2 inhibitor such as TNO155
  • GnRH Gonadotropin-releasing hormone receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi -Aventis and Lupron® by Abbott Lab);
  • Taxane anti -neoplastic agents Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5,20- epoxytax-1 l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ -2-hydroxy-3-phenylpropanoate), larotaxel ((2a,3 ⁇ ,4a,5p,7a,10p,13a)- 4, 10-bis(acetyloxy)-13-( ⁇ (2R,3 S)-3-[(tert-butoxy carbonyl) amino] -2-hydroxy-3- phenylpropanoyl ⁇ oxy)-l-hydroxy-9-oxo-5,20-epoxy-7, 19-cyclotax-l l-en-2-yl benzoate);
  • 5HTla receptor agonists Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]-4- [3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No. 5,266,573); HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);
  • Anti-metabolites Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5 -fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and MylocelTM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyaden
  • Bisphosphonates Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®); Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®); Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and OnxalTM);
  • Retinoids Ali tretinoin (sold under the tradename Panretin®), tretinoin (all -trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S,l lS,13S,14S,16R,17R)-9-fhroro-l l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-6,7,8,9,10,1 l,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradename
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin- 11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®); and elacestrant and ARV-471 (vepdegestrant);
  • Anti-estrogens tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®);
  • SERMs selective estrogen receptor modulators: Raloxifene (sold under the tradename Evista®);
  • Estrogen receptor PROTACs Vepdegestrant (ARV-471);
  • Leutinizing hormone releasing hormone (LHRH) agonists Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®); Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);
  • One or more immune checkpoint inhibitors CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2.
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti-PDl antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody.
  • the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti -CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti- LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562 or, INCAGNO 1949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MED 16383
  • Compounds of Formula (I) can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocytemacrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can also be used in combination with the following adjunct therapies: antinausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and
  • Cytoprotective agents Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • Step 2 tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidine-l-carboxylate
  • Step 3 3-(5-(Azetidin-3-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate
  • Step 1 tert-Butyl 3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]- imidazol-4-yl)azetidine- 1 -carboxylate
  • Step 2 3-(4-(Azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-
  • Step 2 tert-Butyl 4-(3-formyl-4-(m ethoxy carbonyl)phenyl)piperazine-l -carboxylate
  • Step 3 tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l-carboxylate
  • Step 3 Methyl 3-(l-(6-bromo-l-methyl-lH-indazol-3-yl)ureido)propanoate
  • Step 4 l-(6-Bromo-l -methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one
  • Step 6 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)piperidine- 1 -carboxylate
  • Step 7 l-(l-Methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2, 2, 2-2, 2, 2-tri fluoroacetate
  • Step 2 tert-Butyl 4-(4-aminophenyl)piperidine-l -carboxylate
  • Step 4 3 -((4-(Piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione 2,2,2-trifluoroacetate
  • Step 1 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
  • Step 5 tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate
  • Step 6 tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l -carboxylate
  • 1,4-dioxane (5.0 mL) was stirred at rt for 20 h under H2. The mixture was filtered and the filtrate was concentrated to give the title compound as yellow oil.
  • Step 7 3-(4-(Piperazin-l-yl)phenyl)piperidine-2, 6-dione 2,2,2-trifluoroacetate
  • Step 1 6-Bromo-l-(2,2,2-trifluoroethyl)-lH-indazol-3-amine
  • Step 2 l-(6-(Piperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate
  • Step 1 Benzyl 4-(4-cyano-3-fluorophenyl)piperazine-l -carboxylate
  • Step 2 Benzyl 4-(3-amino-lH-indazol-6-yl)piperazine-l-carboxylate
  • Step 3 Benzyl 4-(3-amino-l-methyl-lH-indazol-6-yl)piperazine-l-carboxylate
  • Step 4 Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)- piperazine- 1 -carboxylate
  • Step 5 l-(l-Methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
  • Step 1 l-(l-Methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione
  • Step 2 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3- difluoro-3,6-dihydropyridine-l(2H)-carboxylate
  • Step 3 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3- difluoropiperidine-1 -carboxylate
  • Step 4 l-(6-(3,3-Difluoropiperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate
  • Step 1 tert-Butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-2,6- di azaspiro [3.3 ]heptane-2 -carb oxy 1 ate
  • a mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 300 mg, 0.93 mmol, 1.00 eq.
  • tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate 570 mg, 2.32 mmol, 2.50 eq.
  • t-BuBrettphos Pd G3 (81mg, 0.093 mmol, 0.10
  • Step 2 l-(l-Methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate
  • Step 3 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)benzo[b]thiophen-6-yl)-3,6-dihydro- py ri dine- 1 (2H)-carb oxy 1 ate
  • Step 5 3 -(6-(Piperidin-4-yl)benzo[b]thi ophen-3 -yl)piperidine-2, 6-dione hydrochloride
  • Step 2 tert-Butyl 4-(l-methyl-lH-indol-6-yl)piperidine-l-carboxylate
  • Step 3 tert-Butyl 4-(3-iodo-l-methyl-lH-indol-6-yl)piperidine-l-carboxylate
  • Step 4 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indol-6-yl)piperidine-l- carboxylate
  • the resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere.
  • the reaction mixture was diluted with water and extracted with EtOAc.
  • the combined organic layers were washed with water and brine, dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0-40%), to afford the crude product.
  • the crude product was purified by prep-HPLC to afford the title compound as a light yellow solid.
  • Step 5 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-6-yl) piperidine-1- carboxylate
  • Step 1 tert-Butyl 4-((5-chloropyrimidin-2-yl)amino)piperidine-l -carboxylate
  • Step 1 tert-Butyl 4-(4-bromo-3,5-difluorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate
  • Step 2 tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridine-
  • Step 3 tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-l-carboxylate
  • Step 2 tert-Butyl 4-(l-cyclopropyl-3-iodo-lH-indazol-6-yl)piperidine-l-carboxylate
  • Step 3 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-cyclopropyl-lH-indazol-6-yl)- piperidine-1 -carboxylate
  • Step 4 tert-Butyl 4-(l-cyclopropyl-3-(2,6-dioxopiperidin-3-yl)-lH-indazol-6-yl)piperidine-l- carboxylate
  • Step 5 3-(l-Cyclopropyl-6-(piperidin-4-yl)-lH-indazol-3-yl)piperidine-2, 6-dione 2,2,2- tri fluoroacetate
  • tert-butyl 4-(l-cyclopropyl-3-(2,6-dioxopiperidin-3-yl)-lH-indazol-6- yl)piperidine-l -carboxylate 90 mg, 0.2 mmol
  • TFA 0.5 mL
  • Step 1 tert-Butyl 4-hydroxy-2-propyl-piperidine-l -carboxylate
  • Step 2 tert-Butyl 4-iodo-2-propyl-piperidine-l -carboxylate
  • Step 3 tert-Butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2-propyl-piperidine-l- carboxylate
  • the mixture was diluted with water and ethyl acetate, then filtered through celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.
  • Step 4 tert-Butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-propyl-piperidine-l- carboxylate
  • Step 1 tert-Butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate
  • Step 2 3-((3-(Piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride
  • Step 3 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromo-l,5-dimethyl-lH-indazole
  • Step 1 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l,5-dimethyl-lH-indazol-6-yl) piperazine- 1 -carboxylate
  • Step 2 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l,5-dimethyl-lH-indazol-6-yl) piperazine-1-
  • Step 3 3-(l,5-Dimethyl-6-(piperazin-l-yl)-lH-indazol-3-yl)piperidine-2, 6-dione hydrochloride
  • Step 1 l-(6-Bromo-l,5-dimethyl-indazol-3-yl)hexahydropyrimidine-2, 4-dione
  • Step 2 l-[l,5-Dimethyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2, 4-dione hydrochloride
  • the title compound was synthesized by proceeding analogously as described in Reference
  • Step 1 tert-Butyl 4-(3-methoxy-4-nitrophenyl)-3,6-dihydropyridine-l(2H)-carboxylate
  • Step 2 tert-Butyl 4-(4-amino-3-methoxyphenyl)piperidine-l -carboxylate
  • Step 4 3-((2 -Methoxy -4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione hydrochloride
  • Step 2 3-[4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-methoxy-5-methyl-anilino] piperidine-2,6- dione hydrochloride
  • Step 1 6-Chloro-N-(2,6-dibenzyloxy-3-pyridyl)-5-methyl-pyridazin-3-amine
  • Step 2 tert-Butyl 4-[6-[(2,6-dibenzyloxy-3-pyridyl)amino]-4-methyl-pyridazin-3-yl]piperazine-l- carboxylate
  • Step 2 tert-Butyl 4-(6-methoxy-3-methyl-5-nitro-2-pyridyl)piperazine-l -carboxylate
  • Step 1 tert-Butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate
  • Step 2 l-(l-Methyl-6-(2-azaspiro[3.3]heptan-6-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione hydrochloride
  • Step 1 6-Bromo-3-iodopyrazolo[l,5-a]pyridine
  • Step 2 3-(6-(Piperidin-4-yl)pyrazolo[l,5-a]pyridin-3-yl)piperidine-2, 6-dione hydrochloride
  • Step 3 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromo-l,7-dimethyl-lH-indazole
  • Step 4 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l,7-dimethyl-lH-indazol-6-yl)piperazine- 1 -carboxylate
  • Step 5 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l,7-dimethyl-lH-indazol-6-yl)piperazine-l-
  • Step 6 3-(l,7-Dimethyl-6-(piperazin-l-yl)-lH-indazol-3-yl)piperidine-2, 6-dione hydrochloride
  • Step 1 tert-Butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate oc
  • Step 2 tert-Butyl 3-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-6-yl)-8- azabicyclo[3.2.1 ]oct-2-ene-8-carboxylate
  • 3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole 300 mg, 0.55 mmol
  • Step 3 tert-Butyl 3-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-8- azabicyclo[3.2.1 ]octane-8-carboxylate
  • Step 1 5-Bromo-3-(difhioromethyl)-lH-indazole
  • Step 2 3 -(5-Bromo-3 -(difluoromethyl)- IH-indazol- 1 -yl)piperidine-2, 6-dione
  • Step 3 tert-Butyl 4-(3-(difluoromethyl)-l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5-yl)piperidine-l- carboxylate
  • Step 4 3-(3-(Difluoromethyl)-5-(piperidin-4-yl)-lH-indazol-l-yl)piperidine-2, 6-dione hydrochloride
  • Step 1 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl-lH-indazole
  • Step 3 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-6-yl)-3,3- dimethylpiperazine-1 -carboxylate
  • Step 4 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-3,3- dimethylpiperazine-1 -carboxylate
  • Step 5 3 -(6-(2,2-Dimethylpiperazin- 1 -yl)- 1 -methyl- lH-indazol-3 -yl)piperidine-2, 6-dione hydrochloride
  • Step 2 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-indazole
  • Step 3 tert-Butyl (R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-6-yl)-6-methyl-
  • Step 5 3-(l-Methyl-6-((2R)-2-methylpiperidin-4-yl)-lH-indazol-3-yl)piperidine-2, 6-dione 2,2,2- tri fluoroacetate
  • tert-butyl (2R)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)- 2-methylpiperidine-l -carboxylate 70 mg, 0.16 mmol
  • DCM 2.0 mL
  • TFA 0.5 mL
  • the solution was then concentrated to give the title compound as a yellow oil.
  • the following Reference compounds were synthesized by proceeding analogously as described in Reference 42.
  • Step 4 5-Bromo-3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole-6-carbaldehyde
  • Step 5 5-Bromo-3-chloro-6-(difluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole
  • Step 6 tert-Butyl 4-(3-chloro-6-(difluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- indazol-5-yl)piperazine-l -carboxylate
  • Step 7 tert-Butyl 4-(3-chloro-6-(difluoromethyl)-lH-indazol-5-yl)piperazine-l-carboxylate
  • Step 8 tert-Butyl 4-(3-chloro-6-(difluoromethyl)-l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5- yl)piperazine-l -carboxylate
  • reaction mixture was cooled in an ice water bath and quenched with sat. NH4CI aq. solution at 0 °C, then extracted with ethyl acetate.
  • the combined organic layers were washed with water and brine, dried over anhydrous ISfeSCU and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with ethyl acetate/PE (0-60%) to afford the title compound as a light yellow solid.
  • Step 9 3 -(3 -Chloro-6-(difluoromethyl)-5-(piperazin- 1 -yl)- IH-indazol- 1 -yl)piperidine-2, 6-dione hydrochloride
  • Step 1 3-(5-Bromo-6-methyl-lH-pyrazolo[3,4-b]pyridin-l-yl)piperidine-2, 6-dione
  • Step 2 tert-Butyl 4-(l-(2,6-dioxopiperidin-3-yl)-6-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)- piperazine- 1 -carboxylate
  • Step 3 3-(6-Methyl-5-(piperazin-l-yl)-lH-pyrazolo[3,4-b]pyridin-l-yl)piperidine-2, 6-dione hydrochloride
  • Step 2 tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)piperidine- 1 -carboxylate
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • the combined organic layers were washed with water, brine, dried over anhydrous ISfeSCU, and concentrated under reduced pressure.
  • Step 3 3-(5-Methyl-2-oxo-6-(piperidin-4-yl)benzo[d]oxazol-3(2H)-yl)piperidine-2, 6-dione hydrochloride
  • Step 2 6-Bromo-5-chloro-3-iodo-l-methyl-indazole To a mixture of 6-bromo-5-chl oro-3 -iodo- IH-indazole (3.2 g, 8.95 mmol) and CS2CO3 (5.83 g, 17.91 mmol) in MeCN (128 mL) at 0 °C was added Mel (1.11 mL, 17.91 mmol) dropwise. The mixture was warmed to rt and stirred for 4 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/PE (0-5%) to afford the title compound as a yellow solid.
  • Step 3 l-(6-Bromo-5-chloro-l-methyl-indazol-3-yl)hexahydropyrimidine-2, 4-dione
  • Step 4 l-[5-Chloro-l-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2, 4-dione hydrochloride
  • Step 2 3-(5-Bromo-6-fluoro-3-methyl-2-oxo-benzimidazol-l-yl)-l-[(4-methoxyphenyl)methyl]- piperidine-2, 6-dione
  • Step 3 tert-Butyl 4-[6-fluoro-l-[l-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl- 2-oxo-benzimidazol-5-yl]piperidine-l -carboxylate
  • Step 4 3-[6-Fluoro-3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-l-yl]piperidine-2, 6-dione
  • Step 1 tert-Butyl 4-(8-nitro-5-quinolyl)-3,6-dihydro-2H-pyridine-l-carboxylate
  • reaction mixture was quenched with water and extracted with ethyl acetate.
  • the combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the residue was purified with silica gel column chromatography, eluted with PE/ethyl acetate (0-50%) to afford the title compound as a brown solid.
  • Step 2 tert-Butyl 4-(8-amino-5-quinolyl)piperidine-l -carboxylate
  • Step 2 l-(6-Bromopyrazolo[l,5-a]pyridin-3-yl)hexahydropyrimidine-2, 4-dione
  • Methanesulfonic acid (0.6 mL) was added to the solution of l-(6-bromopyrazolo[l,5- a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (260 mg, 0.61 mmol) in toluene (2.5 mL) and the the mixture was stirred at 110 °C for 3 h. The mixture was concentrated, and the residue was purified with silica gel column chromatography, eluted with ethyl acetate/petroleum ester (0-50%) to afford the title compound.
  • Step 3 l-[6-(4-Piperidyl)pyrazolo[l,5-a]pyridin-3-yl]hexahydropyrimidine-2, 4-dione
  • Step 2 tert-Butyl 4-(3-methyl-6-(methylamino)-5-nitropyridin-2-yl)piperazine-l -carboxylate
  • Step 3 tert-Butyl 4-(5-amino-3-methyl-6-(methylamino)pyridin-2-yl)piperazine-l-carboxylate
  • a mixture of tert-butyl 4-(3-methyl-6-(methylamino)-5-nitropyridin-2-yl)piperazine-l- carboxylate (400 mg, 1.14 mmol) in MeOH (10.0 mL) was added Raney -Ni (400 mg), and the resulting mixture was stirred at rt under 1 atm H2 for 2 h.
  • the reaction mixture was filtered, and the organic layer was concentrated to afford the title compound as a pale yellow solid.
  • Step 4 tert-butyl 4-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3,6-dimethyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-b]pyridin-5-yl)piperazine-l-carboxylate
  • Step 5 3-(3,6-Dimethyl-2-oxo-5-(piperazin-l-yl)-2,3-dihydro-lH-imidazo[4,5-b]pyridin-l- yl)piperidine-2, 6-dione
  • Step 1 tert-Butyl 4-(4-bromo-lH-indol-l-yl)piperidine-l-carboxylate
  • 4-bromo-lH-indole (2.00 g, 10.28 mmol) in toluene (20.0 mL)
  • tert-butyl 4-hydroxypiperidine-l -carboxylate (3.10 g, 15.42 mmol) and (cyanomethylene)- tributylphosphorane (3.72 g, 15.42 mmol).
  • the resulting mixture was stirred at 100 °C for 16 h.
  • the mixture was diluted with water and extracted with ethyl acetate.
  • Step 2 tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-lH-indol-l-yl)piperidine-l- carboxylate
  • Step 3 l-(l-(Piperidin-4-yl)-lH-indol-4-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2- tri fluoroacetate
  • Step 1 2,6-Bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine
  • Step 2 tert-Butyl 4-(3-methyl-2-oxo-l-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-lH- benzo[d]imidazol-5-yl)-3-oxopiperazine-l-carboxylate
  • Step 3 tert-Butyl 4-(3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3-oxopiperazine-l- carboxylate
  • Step 4 tert-Butyl 4-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-5-yl)-3-oxopiperazine-l-carboxylate
  • Step 5 3-(3-Methyl-2-oxo-5-(2-oxopiperazin-l-yl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione
  • Step 1 S-(( 1 -(brom omethyl)cy cl opropyl)methyl) benzothioate
  • Benzothioic S-acid (0.36 g, 2.63 mmol) was added to a mixture of K2CO3 (0.18 g, 1.32 mmol) in MeOH (15.0 mL), and the resulting mixture was stirred under nitrogen for 1 h. The reaction mixture was then concentrated, and the residue was dissolved in DMF (4.0 mL). A solution of l,l-bis(bromomethyl)cyclopropane (1.00 g, 4.39 mmol) in DMF (8.0 mL) was then added to the above solution at - 40 °C slowly, and the resulting mixture was stirred at rt under nitrogen for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step 1 Methyl 3-[[4-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl] propanoate
  • 5-(difluoromethoxy)-N-(4-piperidyl)pyrimidin-2-amine hydrochloride 5.61g, 20 mmol
  • TEA 6.07 g, 60 mmol
  • Step 2 3-[[4-[[5-(Difluoromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl] propan-l-ol
  • Step 3 3-[[4-[[5-(Difluoromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl] propanal
  • Step 1 N-(l-((3-chloropropyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
  • Step 2 l-(l-Methyl-6-(l-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperi din-1- yl)sulfonyl)propyl)piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione
  • Step 2 4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)-N-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)piperidine-l-sulfonamide
  • Step 1 tert-Butyl (l-(N-(2-hydroxyethyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate
  • Step 2 tert-Butyl (l-(N-methyl-N-(2-oxoethyl)sulfamoyl)piperidin-4-yl)carbamate
  • Step 3 tert-Butyl (l-(N-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)piperidin-l-yl)ethyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate
  • Step 4 4-Amino-N-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)piperidin- 1 -yl)ethyl)-N-methylpiperidine- 1 -sulfonamide hydrochloride
  • tert-butyl l-(N-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate (90 mg, 0.14 mmol) in ethyl acetate (2.0 mL) was added 4 M HC1 solution in ethyl acetate (2.0 mL), and
  • Step 5 4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)-N-(2-(4-(3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)-N-methylpiperidine-l-sulfonamide
  • Step 2 3-(6-(l-(2-((4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)ethyl)- piperidin-4-yl)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione
  • Step 2 tert-Butyl (2-((3-(4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-l- yl)propyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)carbamate
  • Step 3 3-(6-(l-(3-((6-Amino-2-azaspiro[3.3]heptan-2-yl)sulfonyl)propyl)piperidin-4-yl)-l- methyl-lH-indazol-3-yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate
  • Step 4 tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-pyrazolo[4,3-c]pyridin-6- yl)-3 ,6-dihydropyridine- 1 (2H)-carboxylate
  • Step 1 4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)piperidine-l-sulfonyl chloride
  • Step 3 4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)-N-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)propyl)-N-methylpiperidine- 1 -sulfonamide
  • Step 1 3 -Hydroxybutyl carbamimidothioate A mixture of 4-bromobutan-2-ol (500 mg, 3.27 mmol) in EtOH (5.0 mL) was added thiourea (274 mg, 3.60 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was concentrated to afford the title compound.
  • Step 2 3 -Chlorobutane- 1 -sulfonyl chloride
  • Step 3 N-(l-((3-Chlorobutyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine
  • Step 4 1 -(1 -Methyl-6-( 1 -(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin- 1 - yl)sulfonyl)butan-2-yl)piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

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Abstract

La présente invention concerne certains composés bifonctionnels qui provoquent la dégradation de la kinase 2 dépendante d'une cycline (CDK2) et/ou de la kinase 4 dépendante d'une cycline (CDK4) par l'intermédiaire de la voie ubiquitine-protéasome et sont donc utiles pour le traitement de maladies médiées par CDK2 et/ou CDK4. L'invention concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/US2025/029225 2024-05-15 2025-05-13 Composés bifonctionnels contenant des dérivés de pyrimidine 2,5-substitués pour dégrader la kinase 2 dépendante d'une cycline et/ou la kinase 4 dépendante d'une cycline par l'intermédiaire de la voie ubiquitine-protéasome Pending WO2025240536A1 (fr)

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