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WO2025072637A1 - Oxygenated heterocyclic lsd-1 inhibitors and related methods of use - Google Patents

Oxygenated heterocyclic lsd-1 inhibitors and related methods of use Download PDF

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Publication number
WO2025072637A1
WO2025072637A1 PCT/US2024/048808 US2024048808W WO2025072637A1 WO 2025072637 A1 WO2025072637 A1 WO 2025072637A1 US 2024048808 W US2024048808 W US 2024048808W WO 2025072637 A1 WO2025072637 A1 WO 2025072637A1
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compound
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amino
ethyl
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Mathivanan Packiarajan
Yu Wang
Andrew D. White
James Douglas ENGEL
Lei Yu
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University of Michigan System
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University of Michigan System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • IUR m(TY ⁇ OV[ ⁇ ]NaUVR ⁇ N_R aUR d ⁇ _YQi ⁇ Z ⁇ a P ⁇ ZZ ⁇ [ UR_RQVaN_f Z ⁇ [ ⁇ TR[VP QV ⁇ RN ⁇ R ⁇ N[Q are designated as a major global health burden by the World Health Organization.
  • Sickle cell disease results from the inheritance of a mutant m-globin gene conferring a single amino NPVQ PUN[TR V[ aUR UbZN[ m(TY ⁇ OV[ ]_ ⁇ aRV[ YRNQV[T a ⁇ N aRa_NZR_VP URZ ⁇ TY ⁇ OV[ Z ⁇ YRPbYR composed of two alpha globin subunits and two beta S subunits, termed HbS.
  • HbS polymerizes in hypoxic red blood cells (RBCs) causing their deformation, increased fragility, and hemolysis, leading to pathological organ damage, acute episodic pain, strokes, and early death[1,2].
  • SCD pathophysiology and severity of SCD are reduced by reciprocally increased levels of fetal k- globin in the blood [forming HbF (e2k2)] to replace m S .
  • SCD patients with higher levels of HbF have an increased life expectancy indicating that elevation of HbF levels in RBCs promotes Y ⁇ [TR_ G9: ⁇ b_cVcNY N[Q aUb ⁇ QVZV[V ⁇ URQ ]NaU ⁇ ]Uf ⁇ V ⁇ Y ⁇ Tf) m(aUNYN ⁇ RZVN ZNW ⁇ _ $IC' NXN : ⁇ YRf# ⁇ N[RZVN% N_V ⁇ R ⁇ S_ ⁇ Z ZbaNaV ⁇ [ ⁇ V[ aUR m(TY ⁇ OV[ Y ⁇ Pb ⁇ aUNa _RQbPR Re]_R ⁇ V ⁇ [ ⁇ S aUR NQbYa m(TY ⁇ OV[ TR[e[3].
  • Allogenic bone marrow transplantation requires cells harvested from an HLA-matched donor and are available to > 10% of SCD patients. Toxic ablation of transplant recipient’s bone marrow is required prior to the procedure, and in the presence of SCD-related organ damage, leading already compromised patients to possible bone marrow failure and death[10].
  • BCL11A transcription factor B-cell lymphoma/leukemia 11A
  • CRISPR-Cas9 modifications have off- target effects and can generate double-stranded DNA breaks in the targeted HSC, conferring potentially greater risk for selection of a proliferative population of precancerous cells through clonal expansion during hematopoiesis.
  • the duration of benefits with gene therapy for treating m- globinopathies is unknown.
  • a further, often prohibitive, disadvantage of bone marrow transplantation and gene therapy interventions is that access to these technologies requires skilled personnel and specialized facilities that are simply unavailable to the vast majority (many millions) of patients suffering from SCD and TM.
  • the US Food and Drug Administration (FDA) has approved 3 small molecules to manage SCD i.e., hydroxyurea, L-glutamine and voxeletor.
  • Hydroxyurea is effective in approximately 50% of SCD patients, and confers benefits that diminish over time, while the two newer medications confer marginally advantageous benefit [9]. Accordingly, there is a need for ⁇ ZNYY Z ⁇ YRPbYR(ON ⁇ RQ' ]UN_ZNP ⁇ Y ⁇ TVP Z ⁇ QVSVPNaV ⁇ [ ⁇ S aUR m(TY ⁇ OV[ QRcRY ⁇ ]ZR[aNY ⁇ dVaPU aUNa favors k-globin Re]_R ⁇ V ⁇ [' N[Q aUNa ⁇ b]]_R ⁇ R ⁇ Re]_R ⁇ V ⁇ [ ⁇ S ZbaN[a m S in SCD.
  • TF transcription factors
  • transcription factors including BCL11A
  • BCL11A While transcription factors, including BCL11A, have served as the targets for modification by gene editing, small molecules that pharmacologically target epigenetic enzymes would be more cost-effective; perhaps most important, drug therapy would be accessible to the millions of ]NaVR[a ⁇ ⁇ bSSR_V[T S_ ⁇ Z m(TY ⁇ OV[ ⁇ ]NaUVR ⁇ V[ RP ⁇ [ ⁇ ZVPNYYf ⁇ _ aRPU[ ⁇ Y ⁇ TVPNYYf PUNYYR[TRQ N_RN ⁇ around the globe.
  • TR2/TR4 and BCL11A both recruit corepressor enzymes, including the epigenetic modifying enzymes DNMT1 and LSD1, to chromatin-bound TF binding sites [19-21].
  • LSD1 genetic or pharmacological loss-of-function induces k-globin transcription in erythroid cells derived from human primary hematopoietic stem and progenitor cells (HSPCs)[22].
  • the cofactor flavin adenine dinucleotide FAD
  • FADH2 cofactor flavin adenine dinucleotide
  • H2O2 oxygen with the generation of H2O2 [25].
  • the oxidase domain of LSD1 consists of two functional domains, one that binds FAD and another that recognizes and binds the substrate[29].
  • Irreversible LSD1 inhibitors, including TCP, share a cyclopropane ring structure which can fuse to the flavin of LSD1, forming an FAD–inhibitor covalent adduct that inhibits LSD1 activity[30,31].
  • Reversible LSD1 inhibitors form non-covalent interactions in the active site cavity of the oxidase domain of LSD1, blocking the catalytic lysine residue (K661) which is critical for demethylation activity[32]. Since H3K4me1/2 is primarily chromatin marks coincident with transcriptional activation, inhibition of LSD1 is typically associated with activation of formerly repressed genes. LSD1 has been found to play an important role in numerous physiological and pathological processes. The specificity of LSD1 is almost certainly determined by the transcription factors to which it binds as a required co-effector protein.
  • LSD1 is also a critical regulator of both long-term HSC self- renewal as well as differentiation towards the myeloid and erythroid lineages[33-36].
  • One small- molecule compound (UM171) that targets the LSD1-CoREST complex robustly promotes HSC expansion[37] and is now in clinical trials.
  • a wild-type form of LSD1 is frequently overexpressed in acute myeloid leukemia (AML)[38].
  • LSD1 Reduction of LSD1 impaired proliferation and self-renewal of AML cells, and increased differentiation and apoptosis in AML models, particularly in AMLs bearing MLL- and AML1-rearrangements [39,40].
  • LSD1 inhibitors have been developed and tested in AML models and are a promising approach for treating AML, with some already in phase I/II clinical trials[38,41,42].
  • Overexpression of LSD1 has also been reported in various solid tumors and correlated with poor overall prognosis in patients[43].
  • LSD1 utilizes different binding partners in different cancer types to regulate genes associated with cancer development, progression, metastasis, and recurrence after therapy[44].
  • LSD1 is associated with TF FOXA1 in prostate cancer cells, and LSD1 inhibition dramatically decreased prostate cancer cell growth in vivo [45].
  • High expression of LSD1 has also been found in cell lines or specimens of lung cancer, breast cancer, cervical cancer, bladder cancer, gastric cancer, colorectal cancer and melanoma; hence LSD1 inhibitors have been tested in these cancer models and shown to inhibit cancer development, progression and metastasis[47-53].
  • LSD1 has been implicated in the regulation of the pool of cancer stem cells as well as in epithelial-mesenchymal transition (EMT) which has been implicated in cancer initiation/relapse or cancer metastasis, respectively, in most types of tumors, it has been suggested that pharmacological inhibition of LSD might be incorporated into novel therapeutic treatments for additional cancers that are yet to be revealed[54,55]. Furthermore, LSD1 has been recently identified as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy, highlighting another potential novel cancer treatment strategy using LSD1 inhibitors in combination with anti-PD-1 treatment[56,57].
  • X is selected from O and CH 2 ;
  • Z is selected from CHR y and NR z , wherein R y is selected from H, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, and C 1 -C 4 haloalkyl, and R z is selected from H and -C(O)O-C 1 -C 6 -alkyl;
  • R 1 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, and C 1 -C 4 haloalkyl;
  • R 2 is -(CH2)nNR a R b or hydrogen, wherein n is 0 or 1, R a is H, and R b is selected
  • X is O and Z is CHR y , and R y is hydrogen. In some embodiments, X is CH2 and Z is NR z . In some embodiments, R 1 is selected from hydrogen and -CH2OH. In some embodiments, R 2 is -NR a R b , wherein R a is H and R b is selected from H, - C(O)CF3, and -COO(tert-butyl), or wherein R a and R b are taken together with the nitrogen atom to which they are attached to form a phthalimido group.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form a 4-, 5-, or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O, wherein the heterocyclic ring is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, C1-C4 haloalkyl, -C(O)OR c , and a 4- or 5-membered monocyclic heterocyclyl having one oxygen atom, wherein R c is C1-C4 alkyl.
  • the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein: R q is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)OR c , and monocyclic heterocyclyl, wherein R c is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In some embodiments, R q is hydrogen.
  • L 1 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -
  • R 3 is phenyl, pyridyl, thiazolyl, or pyridizinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from cyano, fluoro, and -SO2CH3.
  • L 2 is -CH2-.
  • L 2 is -C(O)-.
  • R 4 is phenyl, pyridyl, thiazolyl, cyclohexyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkoxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl.
  • the compound of formula (I) is selected from compounds shown in Table A, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating a disorder related to LSD1 activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the disorder related to LSD-1 activity is a hematological disorder, cancer, a neurological disorder, or a metabolic disorder.
  • the disorder is a URZ ⁇ a ⁇ Y ⁇ TVPNY QV ⁇ _QR_ ⁇ RYRPaRQ S_ ⁇ Z ⁇ VPXYR PRYY QV ⁇ RN ⁇ R N[Q m(aUNYN ⁇ RZVN) @[ ⁇ ZR embodiments, the disorder is a cancer selected from acute myeloid leukemia, multiple myeloma, biliary tract cancer, non-small cell lung cancer, and chronic lymphocytic leukemia. In some embodiments, the disorder is a neurological disorder selected from Alzheimer’s disease, Parkinson disease, and Huntington disease. In some embodiments, the disorder is a metabolic disorder selected from type-2 diabetes and obesity.
  • the disorder related to LSD-1 activity is selected from myocardial fibrosis and autism.
  • the subject is a human.
  • the method further comprises administering a second therapeutic agent to the subject.
  • FIG. 1 shows activities of compounds assessed in vitro by an LSD1 enzymatic assay
  • FIG. 2 shows results of Erythroid Differentiation Blockage of Selected Compounds CD71+GPA levels from an in vitro study
  • FIG. 3 shows results of an HPLC analysis of %F Cells and %HbF induction levels from an in vitro study
  • FIG. 4 shows dose-dependent HbF induction by CCG-385349 analogs one week after IP dosing
  • FIG. 1 shows activities of compounds assessed in vitro by an LSD1 enzymatic assay
  • FIG. 2 shows results of Erythroid Differentiation Blockage of Selected Compounds CD71+GPA levels from an in vitro study
  • FIG. 3 shows results of an HPLC analysis of %F Cells and %HbF in
  • FIG. 5 shows blood smear data for selected compounds.
  • FIG. 6 shows changes in reticulocyte percentage and reticulocyte count one week after IP dosing.
  • FIG. 7 shows data demonstrating changes in body weight one week after IP dosing
  • FIG. 8 shows quantification of %F Cells by HPLC two weeks after po dosing.
  • FIG. 9 shows blood smear with fresh blood data and %Sickle cells (two weeks after po dosing).
  • FIG. 10 shows changes in reticulocyte% in PB one to two weeks of po dosing.
  • FIG. 11 shows reduction of splenomegaly two weeks after PO dosing.
  • FIG. 12 and 13 show results of IP dosing of compounds disclosed herein for six days in C57bl6/j mice (body weights are changes in (grams) and in (%)).
  • FIG. 14 shows docking of compound 52 in LSD1 Inhibitor CC90011 bound 6wk_crystal structure (MOE) and (surface plot, MOE).
  • MOE LSD1 Inhibitor CC90011 bound 6wk_crystal structure
  • any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art.
  • the meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition.
  • singular terms shall include pluralities and plural terms shall include the singular.
  • the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.
  • the term “and/or” includes any and all combinations of listed items, including any of the listed items individually.
  • “A, B, and/or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and/or C.”
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • alkyl refers to a radical of a straight or branched saturated hydrocarbon chain.
  • the alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1- C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C 1 -C 6 alkyl), 1 to 4 carbon atoms (C 1 -C 4 alkyl), 1 to 3 carbon atoms (C 1 -C 3 alkyl), or 1 to 2 carbon atoms (C 1 -C 2 alkyl).
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • aryl refers to a radical of a monocyclic, bicyclic, or tricyclic /[&- N_ ⁇ ZNaVP _V[T ⁇ f ⁇ aRZ $R)T)' UNcV[T 1' ,+' ⁇ _ ,/ p RYRPa_ ⁇ [ ⁇ ⁇ UN_RQ V[ N PfPYVP N__Nf% UNcV[T 6-14 ring carbon atoms and zero heteroatoms (“C 6 -C 14 aryl”).
  • an aryl group has six ring carbon atoms (“C6 aryl,” i.e., phenyl).
  • an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).
  • C10 aryl e.g., naphthyl such as 1-naphthyl and 2-naphthyl
  • an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).
  • the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic.
  • halogen refers to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”).
  • heteroaryl refers to a radical of a 5-10 membered monocyclic ⁇ _ OVPfPYVP /[&- N_ ⁇ ZNaVP _V[T ⁇ f ⁇ aRZ $R)T)' UNcV[T 1 ⁇ _ ,+ p RYRPa_ ⁇ [ ⁇ ⁇ UN_RQ V[ N PfPYVP N__Nf% having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5- membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7- membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • heterocyclyl refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety.
  • exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5- membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6- tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin- 2-onyl), and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl).
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl).
  • Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).
  • azabicyclononanyl e.g., 9-azabicyclo[3.3.1]nonanyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced with a hydroxy group.
  • hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3-dihydroxypentyl, 4-hydroxybutyl, 2-ethyl-4-hydroxyheptyl, 3,4- dihydroxybutyl, and 5-hydroxypentyl.
  • substituted indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded.
  • Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.
  • the indication represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left.
  • a bivalent group is shown as -CH 2 O-, such indication also encompasses -OCH 2 -; similarly, -OC(O)NH- also encompasses -NHC(O)O-.
  • linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction.
  • the terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition.
  • the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • an “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition).
  • the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.
  • a “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • a human i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof.
  • “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • X is selected from O and CH 2 ;
  • Z is selected from CHR y and NR z , wherein R y is selected from H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl, and R z is selected from H and -C(O)O-C1-C6-alkyl;
  • R 1 is selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl;
  • R 2 is -(CH2)nNR a R b , wherein n is 0 or 1, R a is H, and R b is selected from H, C1-C4 alkyl, - C(O)-C 1 -C 6 -haloalkyl, and -C(O)O-C 1 -C 6 -al
  • X is O and Z is CHR y
  • R y is hydrogen (i.e., Z is CH2).
  • X is CH2 and Z is NR z .
  • R 1 is selected from hydrogen and C 1 -C 4 hydroxyalkyl.
  • R 1 is hydrogen.
  • R 1 is -CH 2 OH.
  • the group L 1 is selected from -(CH2)p-, -X-, and -CH2X-.
  • L 1 is - (CH2)p-, wherein p is 1, 2, or 3.
  • p is 1.
  • p is 2.
  • p is 3.
  • L 1 is -X-, wherein -X- is cycloalkylene.
  • L 1 is -CH2X-, wherein X is -CR d R e -, and R d and R e are taken together with the carbon atom to which they are attached to form monocyclic heterocyclyl containing one heteroatom selected from O, N, and S (e.g., O).
  • L 1 is selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - .
  • R 4 is selected from phenyl, pyridyl, thiazolyl, cyclohexyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C 1 -C 4 alkoxy, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 3 -C 6 cycloalkyl.
  • R 4 is selected from phenyl, pyridyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, methoxy, ethoxy, cyano, methyl, isopropyl, tert-butyl, trifluoromethyl, and cyclopropyl.
  • the group -L 2 -R 4 has a structure selected from:
  • the invention further provides processes for preparing any of the compounds of the present invention.
  • Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use.
  • “Pharmaceutically acceptable acid addition salt” refers to those pharmaceutically acceptable salts which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • prodrug refers to a precursor of an active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, or amino group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, or free amino group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • Isomers are different compounds that have the same molecular formula.
  • Stepoisomers are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereo isomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Certain compounds described herein contain one or two adjacent carbon-carbon bonds with a stereo center and thus give rise to exist in Z- or E- form (or cis- or trans- form) or syn- or anti- form.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or nonstoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • the absolute stereochemistry of a compound may be determined by using X-ray crystallography to determine the crystal structure of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diastereomeric derivatives may then be converted to pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), fluorine-18 ( 18 F) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), fluorine-18 ( 18 F) or carbon-14 ( 14 C).
  • the compounds disclosed herein have one, some, or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; GeorgeW.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • the compounds disclosed herein have one, some, or all of the 19 F atoms replaced with 18 F atoms.
  • the methods of synthesis for fluorine-containing compounds are known in the art. See, e.g., Molecular Imaging (Second Edition) Principles and Practice, Henry F. VanBrocklin, Chapter-25, 2021, 445-478.
  • the compounds disclosed herein can be prepared by a variety of methods, including those shown in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis.
  • Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography.
  • the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure.
  • Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006).
  • an optically active form of a disclosed compound When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).
  • compositions and Formulations The present disclosure further provides pharmaceutical compositions (e.g., comprising the compounds described above and elsewhere herein).
  • compositions of the present disclosure may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), oral, intravenous, intravascular, gastrointestinal, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal, or intraventricular, administration.
  • topical including ophthalmic and to mucous membranes including vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epi
  • Administration may be achieved by single shot, a series of single shots, and/or by continuous administration.
  • continuous administration is provided by a programmable external pump.
  • continuous administration is provided by a programmable implantable pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets.
  • compositions and formulations for parenteral administration may include sterile aqueous solutions that may also contain buffers, diluents, and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.
  • Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids.
  • compositions of the present disclosure may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the compositions of the present disclosure may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present disclosure may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
  • Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions.
  • the compositions may contain additional, compatible, pharmaceutically active materials such as materials useful in physically formulating various dosage forms of the compositions of the present disclosure, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional, compatible, pharmaceutically active materials such as materials useful in physically formulating various dosage forms of the compositions of the present disclosure, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present disclosure.
  • the compounds may be administered to mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis.
  • about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders.
  • the dose is generally about one-half of the oral dose.
  • a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg.
  • the unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound.
  • compositions particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • the pharmaceutical compositions of the invention may be administered to any patient which may experience the beneficial effects of the compounds of the invention.
  • mammals e.g., humans, although the invention is not intended to be so limited.
  • Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).
  • the compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee- making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Compounds of formula (VIIIc) can be converted into diols of formula (XXI) by one skilled in the art by following dihydroxylation ZRaU ⁇ Q ⁇ $RVaUR_ 8;(CVe(m' ⁇ _ 8;(CVe(e, t-BuOH, rt or OsO4-NMO, t-BuOH:H2O, rt).
  • the alcohols of formula (XXI) can be transformed into an azidoalcohols of formula (X) in a two-step process by converting it into its monomesylate or monotosylate followed by displacement with NaN3 under heating condition.
  • Compounds of formula (XIIb) can be synthesized by treatment of compounds of formula (XIb) with R 4 ’CHO in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH 3 in MeOH.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • an acid such as acetic acid or a Lewis acid, such as zinc chloride
  • a suitable solvent such as dichloroethane or methanol
  • Compounds of formula (VIIId) can be prepared by nucleophilic substitution using fluoro or bromo compounds of formula (I) with compounds of formula (XIIb) in the presence of base such as DIEA or Et3N in DMSO or NMP at 80 – 110 o C or palladium or copper catalyzed arylation or heteroarylation.
  • compounds of formula (VIIIa) and (VIIId) can be prepared via the process outlined in Scheme - IX using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (II) and compounds of formula (XXVI) where R 3 and R’ are as previously defined herein.
  • Compounds of formula (Ia3) can be synthesized by treatment of compounds of formula (Ia2) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3) with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol.
  • a reducing agent such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3)
  • an acid such as acetic acid or a Lewis acid, such as zinc chloride
  • a suitable solvent such as dichloroethane or methanol.
  • Compounds of formula (XXX) can be synthesized by treatment of alcohol of formula (XXIX) with DAST in DCM at room temperature which upon deprotection using TFA in DCM to afford the compounds of invention of formula (Ia
  • Compounds of Invention of formula (Ia5) can be synthesized by treatment of compounds of formula (Ia5) with RCHO or RCOR with NaBH(OAc) 3 in DCE or with NaCNBH 3 in MeOH
  • Compounds of invention of formula (Ib2 to Ib6) can be synthesized via the process outlined in Scheme - XI using customary coupling procedures or may be synthesized by one skilled in the art, where R, R 3 and R 4 are as previously defined herein.
  • Compounds of invention of formula (Ib5) can be synthesized by treatment of compounds of formula (Ib4) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids (RCO 2 H), that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane.
  • acid chlorides RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids (RCO 2 H), that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/
  • Compounds of formula (Ib5) can be synthesized by treatment of compounds of formula (Ib4) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH 3 in MeOH.
  • a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride
  • an acid such as acetic acid or a Lewis acid, such as zinc chloride
  • a suitable solvent such as dichloroethane or methanol
  • optically active, or racemic compounds of formula (XXXI) can be synthesized via the process outlined in Scheme - XII using customary coupling procedures or may be synthesized by one skilled in the art, where R 3 and R 4 are as previously defined herein.
  • Commercially available optically active or racemic aminodiol of formula (XXXIV) can be converted it its N-Cbz derivative under standard condition to afford N-protected amino diol of formula (XXXV) which upon mild oxidation using N-Cloroisocyanuric acid in the presence of TEMPO to afford the hydroxy aldehyde of formula (XXXVI).
  • Compounds of formula (Ia'D xx ) can be synthesized by treatment of compounds of formula (Ia'D) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH.
  • a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride
  • an acid such as acetic or a Lewis acid, such as zinc chloride
  • a suitable solvent such as dichloroethane or methanol
  • Compounds of invention of formula (Ic and Ic1) can be synthesized via the process outlined in Scheme - XVI using customary coupling procedures or may be synthesized by one skilled in the art, where R, R 1 , R 2 , R 3 and R 4 are as previously defined herein.
  • Compounds of invention of formula (Ic and Ic1) may be from starting compound alcohol of formula (THP-I) by converting into the nitrile derivatives of formula (THP-II) in a two-step process via treatment with mesyl chloride in the presence of a base followed by treatment of KCN in DMSO at 80 o C or n- Bu 4 NCN in THF under refluxing condition.
  • Compounds of invention of formula (Ic1) can be synthesized by treatment of compounds of formula (Ic) with RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (RCO 2 H), using customary coupling procedures such as EDC/HOBt or HATU or HBTU in the presence of base.
  • compounds of invention of formula (Ic1) can be synthesized by treatment of compounds of formula (Ic) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH.
  • Compounds of invention of formula (Id1) can be synthesized by treatment of compounds of formula (Id) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (RCOOH), that are commercially available or synthesized by methods known in the art, or treatment of (Id) with in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T 3 P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane.
  • compounds of invention of formula (Id1) can be synthesized by treatment of compounds of formula (Id) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH.
  • compounds of invention of formula (Ie1) can be synthesized by treatment of compounds of formula (Ie) with RCHO or RCOR with NaBH(OAc) 3 in DCE or with NaCNBH 3 in MeOH.
  • Compounds of invention of formula of deuterated analogs of formula (Ib7) can be synthesized via the process outlined in Scheme – XVIII using customary coupling procedures or may be synthesized by one skilled in the art, where R, R 3 and R 4 are as previously defined herein.
  • Step a Intermediate of Formula - 17a: Formation of 4-((2,2- dimethoxyethyl)amino)benzonitrile
  • 2,2-dimethoxyethan-1-amine 0.87 g, 8.30 mmol
  • 4- fluorobenzonitrile I, 1.00 g, 8.30 mmol
  • anhydrous DMSO 10.0 mL
  • DIEA 2.60 mL, 1.90 g, 17.0 mmol
  • Step c Compound of Invention (19a) (Compound-1): Formation of Trans-4-((((2r,5r)-5- (1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile
  • 2-(1,3- dihydroxypropan-2-yl)isoindoline-1,3-dione (4, 0.106 g, 0.479 mmol)
  • Toluene (10 mL) was added catalytic amount of 4- methylbenzenesulfonic acid ( 0.023 g, 0.131 mmol).
  • Step a Intermediate of formula 2: Formation of 2-(1,3-dihydroxypropan-2-yl)isoindoline- 1,3-dione
  • Phthalic anhydride 9.0 g, 61.0 mmol
  • 2-aminopropane-1,3-diol Am-Diol1, 5.50 g, 61.0 mmol
  • anhydrous toluene 75 mL
  • the white suspension becomes a clear solution, and the solution was continued heated at 115 o C for 24 h.
  • Step b Intermediate of formula - 4: Formation of N-(1,3-dihydroxypropan-2-yl)-2,2,2- trifluoroacetamide
  • Step a Intermediates of formula - 15a and 15b: tert-butyl (2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)ethyl)-1,3dioxan-5-yl)carbamate
  • tert-butyl (2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)ethyl)-1,3dioxan-5-yl)carbamate To a stirred solution of (9H-Fluoren-9-yl)methyl (3-oxopropyl)carbamate (3.40 g, 11.5 mmol, following literature method (Crawford, Lee, and Rudolph; US 2014/0323477) in a mixture of toluene (35 mL) and chloroform (12 mL) was added tert-butyl (1,3-dihydroxypropan- 2yl)carbamate
  • Step b Intermediate of formula-16a: tert-butyl ((2r,5r)-2-(2-aminoethyl)-1,3-dioxan-5- yl)carbamate
  • Step b Intermediate of formula-16b: tert-butyl ((2s,5s)-2-(2-aminoethyl)-1,3-dioxan-5- yl)carbamate
  • the cis isomer was synthesized in a similar manner using cis-isomer of tert-butyl ((2r,5r)-2-(2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-1,3-dioxan-5yl)carbamate (0.35 g, 0.75 mmol ) in dichloromethane (5 mL) with Et2NH (1.1 g, 1.6 mL, 15 mmol).
  • Step d Compound of Invention of formula-29a (Example-21): Formation of 4-(((S)-2- ((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)amino)benzonitrile (28a, 0.280 g, 0.712 mmol) and compound 4-(bromomethyl)-2- fluoro-1-methoxybenzene (4a, 0.187 gm, 0.854 mmol) in acetonitrile (10 mL) was added DIEA (0.33
  • Step e Compound of Invention of formula- 30a (Compound-22) and 31a (Compound-23): Formation of 4-((2-((2r,5R)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile and 4-((2-((2r,5S)-5-amino-1,3-dioxan-2-yl)-2- hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile To a stirred solution of compound 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,
  • Step b Compound of Invention of formula-29b (Compound-24): Formation of 4-((4- chloro-3-fluorobenzyl)((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)amino)benzonitrile
  • Compound of Invention of formula-29b was synthesized in a similar manner to the compound of Invention of formula-– 29a.
  • Step c Compound of Invention of formula- 30b (Compound-25): Formation of 4-(((S)-2- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(4-chloro-3- fluorobenzyl)amino)benzonitrile
  • Compound of Invention of formula-30b was synthesized in a similar manner to the compound of Invention of formula-– 30a.
  • Step-a Intermediate of formula-28c: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile
  • the intermediate 28c was synthesized in an analogous manner to the intermediate – 28a.
  • Step-a Intermediate of formula-28c: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile
  • the intermediate 28c was synthesized in an analogous manner to the intermediate – 28a.
  • the intermediate compound (28c) (((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3- dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile (28c, 1.30 g, 58%) was obtained as a pale brown color solid.
  • Step b Compound of Invention of formula-29c (Compound-26): Formation of 4-(((S)-2- ((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)-2-fluorobenzonitrile
  • Compound of Invention of formula-29c was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step c Compound of Invention of formula- 30c (Compound-27): Formation of 4-(((S)-2- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile
  • Compound of Invention of formula-30c was synthesized in a similar manner to the compound of Invention of formula -30a.
  • Step-a Intermediate of formula-28d: Formation of 2-((2r,5S)-2-((S)-1-hydroxy-2-((4- (methylsulfonyl)phenyl)amino)ethyl)-1,3-dioxan-5-yl)isoindoline-1,3-
  • the intermediate 28d was synthesized in an analogous manner to the intermediate – 28a.
  • Step b Compound of Invention of formula- 29d (Compound-28): Formation of 2-((2r,5S)- 2-((S)-2-((3-fluoro-4-methoxybenzyl)(4-(methylsulfonyl)phenyl)amino)-1-hydroxyethyl)- 1,3-dioxan-5-yl)isoindoline-1,3-dione Compound of Invention of formula-29d was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-d Compound of Invention of formula- 32 (Compound-30): Formation of Racemic 4- (((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile
  • Step-c Compound of Invention of formula- 33 (Compound-31): Formation of 4-(((R)-2- ((2r,5R)-5-amino-1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile and 4-(((S)-2-((2r,5S)-5-amino-1,3-dioxan-2-yl)-2- fluoroethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile
  • Compound of Invention of formula-32 was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-a Intermediate of formula-DEOxir: Formation of 2-(diethoxymethyl)oxirane A mixture of acrolein diethyl acetal (ADEA, 4.00, 30.70 mmol) and KHCO3 (0.615 g, 30 mmol) in methanol (16 mL) was added acetonitrile (3.8 mL) followed by addition of 30% hydrogen peroxide (3.90 mL, 180 mmol) at room temperature. The resulting mixture is heated at 40 °C. After 24h hours of initial addition, 1 equ. of hydrogen peroxide (3.9 mL) and acetonitrile (2 mL) were added continued heating for 48 hours at 40 °C.
  • Step-b Intermediate of formula-34a: Formation of 4-((3,3-diethoxy-2- hydroxypropyl)amino)benzonitrile To a mixture of 2-(diethoxymethyl)oxirane (DEOxir, 0.640 g, 4.40 mmol) in 5 M LiClO4 (8 mL) was added 4-amino-2-fluorobenzonitrile (1, 0.50 g, 3.70 mmol) at rt.
  • 2-(diethoxymethyl)oxirane DEOxir, 0.640 g, 4.40 mmol
  • 5 M LiClO4 8 mL
  • Step-b Intermediate of formula-35a: Formation of 4-((3,3-diethoxy-2-hydroxypropyl)(3- fluoro-4-methoxybenzyl)amino)benzonitrile
  • the intermediate 35a was synthesized in an analogous manner to the intermediate – 29a.
  • the intermediate compound (35a) 4-((3,3-diethoxy-2-hydroxypropyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile (35a, 1.80 g, 79%) was obtained as a gummy material.
  • TLC Rf 0.25 in 30%EA/Hex.
  • HPLC RT 6.696 min.
  • Step-b Intermediate of formula-34b: Formation of 4-((3,3-diethoxy-2- hydroxypropyl)amino)-2-fluorobenzonitrile
  • the intermediate 34b was synthesized in an analogous manner to the intermediate – 34a.
  • the intermediate compound (34b) 4-((3,3-diethoxy-2-hydroxypropyl)amino)-2-fluorobenzonitrile (34b, 0.700 g, 68%) was obtained as a gummy material.
  • Step-b Intermediate of formula-35b: Formation of 4-((3,3-diethoxy-2-hydroxypropyl)(3- fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile
  • the intermediate 35b was synthesized in an analogous manner to the intermediate – 29a.
  • TLC Rf 0.25 in 30%EA/Hex.
  • Step-a Compound of Invention of formula- 36a (Compound-32): Formation of tert-butyl (S)-3-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate
  • Compound of Invention of formula-36a was synthesized in a similar manner to the compound of Invention of formula—19a.
  • Step-b Compound of Invention of formula- 37a (Compound-33): Formation of (S)-4-((3- fluoro-4-methoxybenzyl)(2-hydroxy-2-(2,4-dioxa-9-azaspiro[5.5]undecan-3- yl)ethyl)amino)benzonitrile
  • Compound of Invention of formula-37a was synthesized in a similar manner to the compound of Invention of formula-– 25a.
  • Step-a Compound of Invention of formula-36b (Compound-34): Formation of tert-butyl (S)-7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-36b was synthesized in a similar manner to the compound of Invention of formula—19a.
  • Step-b Compound of Invention of formula- 37b (Compound-35): Formation of (S)-4-((3- fluoro-4-methoxybenzyl)(2-hydroxy-2-(6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile
  • Compound of Invention of formula-37b was synthesized in a similar manner to the compound of Invention of formula-– 25a.
  • Step-a Compound of Invention of formula- 38a (Compound-36): Formation of Trans tert- butyl 3-(3-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate
  • Compound of Invention of formula-38a was synthesized in an analogous manner to the compound of Invention of formula-– 15.
  • Step-b Compound of Invention of formula- 39a (Compound-37): Formation of 3-(3-((4- cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9-azaspiro[5.5]undecan- 9-ium trifluoroacetate
  • Compound of Invention of formula-38a was synthesized in an analogous manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 38b (Compound-38): Formation of tert-butyl 3-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-38b was synthesized in an analogous manner to the compound of Invention of formula-15.
  • Step-b Compound of Invention of formula- 39b (Compound-39): Formation of 4-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile
  • Compound of Invention of formula-39b was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 38c (Compound-40): Formation of tert-butyl 7-(3-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)propyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-38c was synthesized in a similar manner to the compound of Invention of formula-15.
  • Step-b Compound of Invention of formula- 39c (Compound-41): Formation of 4-((3-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)propyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile
  • Compound of Invention of formula-39c was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 38d (Compound-42): Formation of tert-butyl 3-(3-(((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)methyl)oxetan-3-yl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate
  • Compound of Invention of formula-38c was synthesized in an analogous manner to the compound of Invention of formula-– 15.
  • Step-b Compound of Invention of formula- 39d (Compound-43): Formation of 4-(((3-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)oxetan-3-yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile, Compound of Invention of formula-39d was synthesized in a similar manner to the compound of Invention of formula-25a.
  • reaction becomes cloudy and stirred for three days at rt and refluxed for 8h. Cool the reaction mixture was cool to room temperature and quenched with aqueous sodium bicarbonate solution. The product was extracted u with DCM and washed with water and brine.
  • Step-b Intermediate of formula (41a): Formation of tert-butyl 3-(2-aminoethyl)-2,4-dioxa- 9-azaspiro[5.5]undecane-9-carboxylate To a stirred solution of compound tert-butyl 3-(2-(((benzyloxy)carbonyl)amino)ethyl)-2,4-dioxa- 9-azaspiro[5.5]undecane-9-carboxylate (40a, 1.70 g, 3.91 mmol) in methanol (20 mL) and ethyl acetate (10 mL) was added 10% Pd-C (200 mg) was hydrogenated at room temperature for 12h.
  • Step-a Intermediate of formula (40b): Formation of tert-butyl 7-(2- (((benzyloxy)carbonyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate
  • the intermediate (40b) was synthesized in an analogous manner to the intermediate – 40a.
  • the intermediate compound (40b) tert-butyl 7-(2-(((benzyloxy)carbonyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (40b, 4.60 g, 98%) was obtained as a colorless solid.
  • Step-b Intermediate of formula (41b): Formation of tert-butyl 7-(2-aminoethyl)-6,8-dioxa- 2-azaspiro[3.5]nonane-2-carboxylate
  • the intermediate (41b) was synthesized in an analogous manner to the intermediate – 40b.
  • the intermediate compound (41b) tert-butyl 7-(2-aminoethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (XIb2, 900 mg,) was obtained as a colorless solid.
  • HPLC RT 6.148 min.
  • Step-a Intermediate of formula (42a): Formation of tert-butyl 3-(2-((6-cyanopyridin-3- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate
  • NMP NMP
  • the resulting solution was heated at 80 o C for 16 h. After heating 18h, the reaction was cool to room temperature and quenched with water. The product was extracted with ethyl acetate and washed wither water and brine. The organic portion was dried over anhydrous sodium sulfate, filtered followed by removal of solvent afforded the crude product.
  • Step-b Compound of Invention of formula-43a (Compound-44): Formation of tert-butyl 3-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43a was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-c Compound of Invention of formula- 44a (Compound-45): Formation of 5-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile
  • Compound of Invention of formula-44a was synthesized in a similar manner to the compound of Invention of formula—25a.
  • Step-a Intermediate of formula (42a): Formation of tert-butyl 3-(2-((5-cyanopyridin-2- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate
  • the intermediate (42b) was synthesized in an analogous manner to the intermediate – 42a.
  • the intermediate compound (42b) tert-butyl 3-(2-((5-cyanopyridin-2-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (42b, 120 mg, 90%) was obtained as a pale brown color foam.
  • Step-b Compound of Invention of formula- 43b (Compound-46): Formation of tert-butyl 3-(2-((5-cyanopyridin-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43b was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-a Intermediate of formula (42c): Formation of tert-butyl 3-(2-((4-cyano-3- fluorophenyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate
  • the intermediate (42c) was synthesized in an analogous manner to the intermediate – 42a.
  • Step-c Compound of Invention of formula- 44c (Compound-48): Formation of 4-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile
  • Compound of Invention of formula-44c was synthesized in a similar manner to the compound of Invention of formula—25a.
  • Step-a Intermediate of formula (42d): Formation of tert-butyl 3-(2-((5-cyanothiazol-2- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate
  • the intermediate (42d) was synthesized in an analogous manner to the intermediate – 42a.
  • the intermediate compound (42d) tert-butyl 3-(2-((5-cyanothiazol-2-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (42d, 120 mg, 88%) was obtained as a pale brown color foam.
  • Step-b Compound of Invention of formula- 43d (Compound-49): Formation of tert-butyl 3-(2-((5-cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43d was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-c Compound of Invention of formula- 44d (Compound-50): Formation of tert-butyl 3-(2-((5-cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-44d was synthesized in a similar manner to the compound of Invention of formula—25a.
  • Step-b Compound of Invention of formula- 46a (Compound-51): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46a was synthesized in a similar manner to the compound of Invention of formula—29a.
  • Step-c Compound of Invention of formula-47a (Compound-52): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile
  • Compound of Invention of formula-47a was synthesized in a similar manner to the compound of Invention of formula - 25a.
  • Step-a Intermediates of formula (45b1 and 45b2): Formation of tert-butyl 7-(2-((4-cyano-3- fluorophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate
  • the intermediates 45b1 and 45b2 were synthesized in an analogous manner to the intermediate – 21a.
  • Step-b Compound of Invention of formula- 46b1 (Compound-53): Formation of tert-butyl 7-(2-((4-cyano-3-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • a stirred suspension of NaH 36 mg, 0.89 mmol
  • THF THF solution
  • THF solution 2 mL
  • compound tert-butyl 7-(2-((4-cyano-3-fluorophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate 45b1, 70 mg, 0.18 mmol
  • Step-c Compound of Invention of formula- 47b1 (Compound-54): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile
  • Compound of Invention of formula-47b1 was synthesized in a similar manner to the compound of Invention of formula - 25a.
  • Step-b Compound of Invention of formula- 46c (Compound-55): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-c Compound of Invention of formula- 47c (Compound-56): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (3,5-difluoro-4-methoxybenzyl)amino)benzonitrile
  • Compound of Invention of formula-47c was synthesized in a similar manner to the compound of Invention of formula - 25a.
  • Step-b Compound of Invention of formula- 46b2 (Compound-57): Formation of tert-butyl 7- (2-((2-cyano-4-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46b2 was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula- 47b1 (Compound-58): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile
  • Compound of Invention of formula-47b1 was synthesized in a similar manner to the compound of Invention of formula - 25a.
  • Step-b Compound of Invention of formula- 47d (Compound-60): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-3-fluorobenzyl)amino)benzonitrile
  • Compound of Invention of formula-47d was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 46e (Compound-61): Formation of tert-butyl 7-(2-((4-cyano-3-fluorobenzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46e was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-b Compound of Invention of formula- 47e (Compound-62): Formation of 4-(((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-cyanophenyl)amino)methyl)-2-fluorobenzonitrile TFA Salt
  • Compound of Invention of formula-47e was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 46f (Compound-63): Formation of tert-butyl 7- (2-((4-cyanophenyl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46f was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-b Compound of Invention of formula- 47f (Compound-64): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)benzonitrile
  • Compound of Invention of formula-47f was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 46g (Compound-65): tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-(trifluoromethyl)benzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46g was synthesized in an analogous manner to the compound of Invention of formula-46b.
  • Step-a Compound of Invention of formula- 46h (Compound-66): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3,4- dichlorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate
  • Compound of Invention of formula-46h was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-b Compound of Invention of formula- 47h (Compound-67): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (3,4-dichlorobenzyl)amino)benzonitrile
  • Compound of Invention of formula-47h was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 46i (Compound-68): Formation of tert-butyl 7- (2-((4-cyanophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46i1 was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-b Compound of Invention of formula- 47i (Compound-69): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((6- methylpyridin-3-yl)methyl)amino)benzonitrile
  • Compound of Invention of formula-47i was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula- 46i2 (Compound-70): Formation of tert-butyl 7-(2-((4-cyano-3-fluorophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46i2 was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-a Compound of Invention of formula- 46j (Compound-71): Formation of tert-butyl 7- (2-((4-cyanophenyl)((2-methylthiazol-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-46j was synthesized in a similar manner to the compound of Invention of formula-46b.
  • Step-a Intermediate of formula (CyhAlk-OH4): Formation of Trans-((1r,4r)-4- methoxycyclohexyl)methanol
  • the intermediate of formula (CyhAlk-OH4) was synthesized in an analogous manner to the intermediate – (CyhAlk-OH2).
  • the intermediate trans-((1r,4r)-4-methoxycyclohexyl)methanol was obtained as a colorless solid.
  • Step-b Compound of Invention of formula- 47s (Compound-89): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((4- methyl cyclohexyl)methyl)amino)benzonitrile
  • Compound of Invention of formula-47s was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50c (Compound-106): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50c was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-a Compound of Invention of formula-50d (Compound-108): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50b was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51d (Compound-109): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)picolinonitrile
  • Compound of Invention of formula-51d was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50e (Compound-110): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50e was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-a Compound of Invention of formula-50f (Compound-111): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50f was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51f (Compound-112): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5- yl)methyl)amino)picolinonitrile
  • Compound of Invention of formula-51f was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50g (Compound-113): Formation of tert-butyl 7-(2-((4-chloro-3-fluorobenzyl)(6- cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50g was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51g (Compound-114): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4- chloro-3-fluorobenzyl)amino)picolinonitrile
  • Compound of Invention of formula-51g was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50e (Compound-115): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50h was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51h (Compound-116): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)picolinonitrile, Compound of Invention of formula-51h was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50i (Compound-117): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-cyclopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of Invention of formula-50i was synthesized in an analogous manner to the compound of formula-46b1.
  • Step-b Compound of Invention of formula-51i (Compound-118): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-cyclopropylbenzyl)amino)picolinonitrile
  • Compound of Invention of formula-51i was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50j (Compound-119): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-50j was synthesized in an analogous manner to the compound of Invention of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51j (Compound-120): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (4-isopropylbenzyl)amino)picolinonitrile
  • Compound of Invention of formula-51j was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50k (Compound-121): Formation of tert-butyl 7-(2-((4-(tert-butyl)benzyl)(6-cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of Invention of formula-50k was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-b Compound of Invention of formula-51k (Compound-122): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-(tert-butyl)benzyl)amino)picolinonitrile
  • Compound of Invention of formula-51k was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50k (Compound-123): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(((1s,4s)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of Invention of formula-50l was synthesized in an analogous manner to the compound of formula-46b1.
  • Step-b Compound of Invention of formula-51l (Compound-124): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((4-methylcyclohexyl)methyl)amino)picolinonitrile
  • Compound of Invention of formula-51l was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-a Compound of Invention of formula-50m (Compound-125): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of Invention of formula-50m was synthesized in an analogous manner to the compound of formula-46b1.
  • Step-b Compound of Invention of formula-51m (Compound-126): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((tetrahydro-2H-pyran-4- yl)methyl)amino)picolinonitrile
  • Compound of Invention of formula-51m was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52a (Compound-127): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52a was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula-53a (Compound-128): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)nicotinonitrile, Compound of Invention of formula-53a was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52b (Compound-129): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylatem
  • Compound of Invention of formula-52b was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula-53b (Compound-130): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)nicotinonitrile
  • Compound of Invention of formula-53b was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52c (Compound-131): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(4-ethoxy-2,3-difluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, Compound of Invention of formula-52c was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula-53c (Compound-132): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-ethoxy-2,3-difluorobenzyl)amino)nicotinonitrile
  • Compound of Invention of formula-53c was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52d (Compound-133): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-52d was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula-53d (Compound-134): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)nicotinonitrile
  • Compound of Invention of formula-53d was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52e (Compound-135): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate
  • Compound of Invention of formula-52e was synthesized in an analogous manner to the compound of Invention of formula-46b1.
  • Step-c Compound of Invention of formula-53e (Compound-136): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3,5-difluoro-4-methoxybenzyl)amino)nicotinonitrile
  • Compound of Invention of formula-53e was synthesized in a similar manner to the compound of Invention of formula-25a.
  • Step-b Compound of Invention of formula-52f (Compound-137): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,4-dimethoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52f was synthesized in an analogous manner to the compound of Invention of formula-46b1.

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Abstract

Disclosed herein is a class of small-molecules having oxygenated heterocyclic ring structure. Compounds disclosed herein are lysine demthylase-1 (LSD-1) inhibitors, and accordingly, also disclosed herein is the use the compounds as therapeutics for the treatment of hematological disorders (e.g., sickle cell disease (SCD), β-thalassemia), cancer (e.g., acute myeloid leukemia (AML), multiple myeloma, biliary tract cancer, non-small cell lung cancer (NSCLC), chronic lymphocytic leukemia, advanced solid tumor, advanced malignancies), and/or a neurological disorder (e.g., Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson disease (PD), Schizophrenia, Huntington disease (HD)), a metabolic disorder (e.g., type-2 diabetes (T2D), obesity) and other conditions related to LSD-1 activity (e.g., mild to moderate Alzheimer's disease, myocardial fibrosis, autism, complex neurodevelopmental diseases).

Description

OXYGENATED HETEROCYCLIC LSD-1 INHIBITORS AND RELATED METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/541,161, filed on September 28, 2023, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under HL146372 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION The present invention addresses the synthesis and use of oxygenated heterocyclic derivatives, as well as pharmaceutical compositions and methods of treatment using same. BACKGROUND OF THE INVENTION IUR m(TY\OV[\]NaUVR` N_R aUR d\_YQi` Z\`a P\ZZ\[ UR_RQVaN_f Z\[\TR[VP QV`RN`R` N[Q are designated as a major global health burden by the World Health Organization. Sickle cell disease (SCD) results from the inheritance of a mutant m-globin gene conferring a single amino NPVQ PUN[TR V[ aUR UbZN[ m(TY\OV[ ]_\aRV[ YRNQV[T a\ N aRa_NZR_VP URZ\TY\OV[ Z\YRPbYR composed of two alpha globin subunits and two beta S subunits, termed HbS. HbS polymerizes in hypoxic red blood cells (RBCs) causing their deformation, increased fragility, and hemolysis, leading to pathological organ damage, acute episodic pain, strokes, and early death[1,2]. The pathophysiology and severity of SCD are reduced by reciprocally increased levels of fetal k- globin in the blood [forming HbF (e2k2)] to replace mS. SCD patients with higher levels of HbF have an increased life expectancy indicating that elevation of HbF levels in RBCs promotes Y\[TR_ G9: `b_cVcNY N[Q aUb` QVZV[V`URQ ]NaU\]Uf`V\Y\Tf) m(aUNYN``RZVN ZNW\_ $IC' NXN :\\YRf#` N[RZVN% N_V`R` S_\Z ZbaNaV\[` V[ aUR m(TY\OV[ Y\Pb` aUNa _RQbPR Re]_R``V\[ \S aUR NQbYa m(TY\OV[ TR[e[3]. Coinheritance of inherited persistent expression of k-globin alleles (termed HPFH) into adulthood leads to a benign elevation in HbF levels that significantly mitigate SCD and TM disease phenotypes, thereby supporting reactivation of k-globin expression as a strategy S\_ a_RNaV[T aUR m(TY\OV[\]NaUVR`' H:; N[Q ICL/(4M) :b__R[a ZN[NTRZR[a \S m(TY\OV[\]NaUVR` V[PYbQR` ]UN_ZNP\Y\TVP V[aR_cR[aV\[`' O\[R marrow transplantation and, most recently, gene therapy. Allogenic bone marrow transplantation requires cells harvested from an HLA-matched donor and are available to > 10% of SCD patients. Toxic ablation of transplant recipient’s bone marrow is required prior to the procedure, and in the presence of SCD-related organ damage, leading already compromised patients to possible bone marrow failure and death[10]. Evidence that transcription factor B-cell lymphoma/leukemia 11A (BCL11A) is required for m-globin “switching” from production of HbF to HbS spurred advances in gene therapy modifications of hematopoietic stem cells to reestablish k-globin expression in order to compensate for a defective or inactive m- or mS-globin gene[11]. Gene therapy trials aimed at BCL11A inactivation report increased expression of HbF, and clinical benefits using lentiviral gene transfer[12] or using CRISPR-Cas9 BCL11A inactivation[13]. Both approaches are limited by the required chemical or radiologic ablation of SCD patients’ bone marrow before transplantation of the genetically modified HSC cells, which increases the risks of both infection and chemotherapy-induced leukemia[14]. Moreover, lentiviral integration generates thousands of insertional mutations, with subsequent possible oncogenic transformations that may arise decades later. CRISPR-Cas9 modifications have off- target effects and can generate double-stranded DNA breaks in the targeted HSC, conferring potentially greater risk for selection of a proliferative population of precancerous cells through clonal expansion during hematopoiesis. The duration of benefits with gene therapy for treating m- globinopathies is unknown. A further, often prohibitive, disadvantage of bone marrow transplantation and gene therapy interventions is that access to these technologies requires skilled personnel and specialized facilities that are simply unavailable to the vast majority (many millions) of patients suffering from SCD and TM. The US Food and Drug Administration (FDA) has approved 3 small molecules to manage SCD i.e., hydroxyurea, L-glutamine and voxeletor. Hydroxyurea is effective in approximately 50% of SCD patients, and confers benefits that diminish over time, while the two newer medications confer marginally advantageous benefit [9]. Accordingly, there is a need for `ZNYY Z\YRPbYR(ON`RQ' ]UN_ZNP\Y\TVP Z\QVSVPNaV\[ \S aUR m(TY\OV[ QRcRY\]ZR[aNY `dVaPU aUNa favors k-globin Re]_R``V\[' N[Q aUNa `b]]_R``R` Re]_R``V\[ \S ZbaN[a mS in SCD. Increased levels of HbF in the blood of greater than 20% are widely considered to be `bSSVPVR[a S\_ aUR_N]RbaVP `VT[VSVPN[PR a\ VZ]_\cR `fZ]a\Z` \S aUR m(TY\OV[\]NaUVR`) =RaNY TY\OV[ gene transcription is under repression by multiple transcription factors (TF) including TR2/TR4, BCL11A and LRF[15-17], as well as multiple epigenetic enzymes [9,18] in adult erythroid cells. While transcription factors, including BCL11A, have served as the targets for modification by gene editing, small molecules that pharmacologically target epigenetic enzymes would be more cost-effective; perhaps most important, drug therapy would be accessible to the millions of ]NaVR[a` `bSSR_V[T S_\Z m(TY\OV[\]NaUVR` V[ RP\[\ZVPNYYf \_ aRPU[\Y\TVPNYYf PUNYYR[TRQ N_RN` around the globe. TR2/TR4 and BCL11A both recruit corepressor enzymes, including the epigenetic modifying enzymes DNMT1 and LSD1, to chromatin-bound TF binding sites [19-21]. LSD1 genetic or pharmacological loss-of-function induces k-globin transcription in erythroid cells derived from human primary hematopoietic stem and progenitor cells (HSPCs)[22]. Pharmacologic inhibition of LSD1 by the small-molecule compound tranylcypromine (TCP) TR[R_NaR` Q\`R(QR]R[QR[a V[P_RN`R` V[ n(TY\OV[ `f[aUR`V` \S b] a\ .+" ?O= V[ UbZN[ ?HF:( derived erythroid differentiation cultures [22]. In vivo administration of LSD1 inhibitors to SCD mice or baboons showed that its inhibition efficiently induced k-globin synthesis and alleviated many pathological features associated with SCD [23,24]. Robust HbF induction by LSD1 V[UVOVa\_` `b]]\_a` aURV_ ]\aR[aVNY b`R N` N a_RNaZR[a S\_ aUR m(TY\OV[\]NaUVR`) LSD1 was the first histone lysine demethylase to be discovered [25]. It is a flavin- dependent monoamine oxidase that catalyzes removal of mono-methyl and di-methyl groups on histone H3 lysine 4 (H3K4) and H3K9, with much higher specificity for H3K4 [26]. LSD1 is bound by a transcriptional co-repressor protein (CoREST) to form a complex. Non-covalent binding of the cofactor FAD with the LSD1/CoREST complex results in a conformational change, permitting interaction with the N-terminal histone H3 tail leading to demethylation of methylated lysine 4 and lysine 9[27,28]. The major reaction product of this amine oxidase- mediated demethylation reaction is H2O2. In this oxidation reaction, the cofactor flavin adenine dinucleotide (FAD) is reduced to FADH2 and then reoxidized to FAD by oxygen with the generation of H2O2 [25]. The oxidase domain of LSD1 consists of two functional domains, one that binds FAD and another that recognizes and binds the substrate[29]. Irreversible LSD1 inhibitors, including TCP, share a cyclopropane ring structure which can fuse to the flavin of LSD1, forming an FAD–inhibitor covalent adduct that inhibits LSD1 activity[30,31]. Reversible LSD1 inhibitors, on the other hand, form non-covalent interactions in the active site cavity of the oxidase domain of LSD1, blocking the catalytic lysine residue (K661) which is critical for demethylation activity[32]. Since H3K4me1/2 is primarily chromatin marks coincident with transcriptional activation, inhibition of LSD1 is typically associated with activation of formerly repressed genes. LSD1 has been found to play an important role in numerous physiological and pathological processes. The specificity of LSD1 is almost certainly determined by the transcription factors to which it binds as a required co-effector protein. The complex that has been exclusively defined in erythropoiesis is DRED, in which co-repressors recruited by the TR2/TR4 TF complex bind to direct repeat (DR) elements in the k-globin gene promotors[20]. Within the hematopoietic system, LSD1 is also a critical regulator of both long-term HSC self- renewal as well as differentiation towards the myeloid and erythroid lineages[33-36]. One small- molecule compound (UM171) that targets the LSD1-CoREST complex robustly promotes HSC expansion[37] and is now in clinical trials. A wild-type form of LSD1 is frequently overexpressed in acute myeloid leukemia (AML)[38]. Reduction of LSD1 impaired proliferation and self-renewal of AML cells, and increased differentiation and apoptosis in AML models, particularly in AMLs bearing MLL- and AML1-rearrangements [39,40]. Several LSD1 inhibitors have been developed and tested in AML models and are a promising approach for treating AML, with some already in phase I/II clinical trials[38,41,42]. Overexpression of LSD1 has also been reported in various solid tumors and correlated with poor overall prognosis in patients[43]. LSD1 utilizes different binding partners in different cancer types to regulate genes associated with cancer development, progression, metastasis, and recurrence after therapy[44]. LSD1 is associated with TF FOXA1 in prostate cancer cells, and LSD1 inhibition dramatically decreased prostate cancer cell growth in vivo [45]. Down-regulation of LSD1 in renal cancer cells attenuated tumor growth in vitro and in vivo[46]. High expression of LSD1 has also been found in cell lines or specimens of lung cancer, breast cancer, cervical cancer, bladder cancer, gastric cancer, colorectal cancer and melanoma; hence LSD1 inhibitors have been tested in these cancer models and shown to inhibit cancer development, progression and metastasis[47-53]. Since an increasing number of studies have implicated LSD1 in the regulation of the pool of cancer stem cells as well as in epithelial-mesenchymal transition (EMT) which has been implicated in cancer initiation/relapse or cancer metastasis, respectively, in most types of tumors, it has been suggested that pharmacological inhibition of LSD might be incorporated into novel therapeutic treatments for additional cancers that are yet to be revealed[54,55]. Furthermore, LSD1 has been recently identified as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy, highlighting another potential novel cancer treatment strategy using LSD1 inhibitors in combination with anti-PD-1 treatment[56,57]. Several recent studies have demonstrated that LSD1 plays a vital role in energy metabolism, suggesting a potential role for LSD1 inhibitors in treating obesity[58]. SUMMARY OF THE INVENTION Disclosed herein is a compound of formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O and CH2; Z is selected from CHRy and NRz, wherein Ry is selected from H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl, and Rz is selected from H and -C(O)O-C1-C6-alkyl; R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl; R2 is -(CH2)nNRaRb or hydrogen, wherein n is 0 or 1, Ra is H, and Rb is selected from H, C1-C4 alkyl, -C(O)-C1-C6-haloalkyl, and -C(O)O-C1-C6-alkyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached to form a heteroaryl or heterocyclyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a heterocyclic ring that is optionally substituted with one or two substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L1 is -(CH2)p-, -X-, or -CH2X-, wherein: X is selected from -CRdRe-, -C(O)-, and cycloalkylene; Rd and Re are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and halo, or Rd and Re are taken together with the carbon atom to which they are attached to form a cycloalkyl or heterocyclyl; and p is 1, 2, or 3; R3 is aryl or monocyclic heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from cyano, halo, C1-C4-alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C3-C6 cycloalkyl; L2 is -CH2- or -C(O)-; and R4 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl, halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C4-alkylsulfonyl. In some embodiments, X is O and Z is CHRy, and Ry is hydrogen. In some embodiments, X is CH2 and Z is NRz. In some embodiments, R1 is selected from hydrogen and -CH2OH. In some embodiments, R2 is -NRaRb, wherein Ra is H and Rb is selected from H, - C(O)CF3, and -COO(tert-butyl), or wherein Ra and Rb are taken together with the nitrogen atom to which they are attached to form a phthalimido group. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form a 4-, 5-, or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O, wherein the heterocyclic ring is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, C1-C4 haloalkyl, -C(O)ORc, and a 4- or 5-membered monocyclic heterocyclyl having one oxygen atom, wherein Rc is C1-C4 alkyl. In some embodiments, the compound of formula (I) is a compound of formula (IA):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein: Rq is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In some embodiments, Rq is hydrogen. In some embodiments, L1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -
Figure imgf000007_0002
In some embodiments, R3 is phenyl, pyridyl, thiazolyl, or pyridizinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from cyano, fluoro, and -SO2CH3. In some embodiments, L2 is -CH2-. In some embodiments, L2 is -C(O)-. In some embodiments, R4 is phenyl, pyridyl, thiazolyl, cyclohexyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkoxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, the compound of formula (I) is selected from compounds shown in Table A, and pharmaceutically acceptable salts thereof. Also disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also disclosed herein is a method of treating a disorder related to LSD1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder related to LSD-1 activity is a hematological disorder, cancer, a neurological disorder, or a metabolic disorder. In some embodiments, the disorder is a URZ\a\Y\TVPNY QV`\_QR_ `RYRPaRQ S_\Z `VPXYR PRYY QV`RN`R N[Q m(aUNYN``RZVN) @[ `\ZR embodiments, the disorder is a cancer selected from acute myeloid leukemia, multiple myeloma, biliary tract cancer, non-small cell lung cancer, and chronic lymphocytic leukemia. In some embodiments, the disorder is a neurological disorder selected from Alzheimer’s disease, Parkinson disease, and Huntington disease. In some embodiments, the disorder is a metabolic disorder selected from type-2 diabetes and obesity. In some embodiments, the disorder related to LSD-1 activity is selected from myocardial fibrosis and autism. In some embodiments, the subject is a human. In some embodiments, the method further comprises administering a second therapeutic agent to the subject. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows activities of compounds assessed in vitro by an LSD1 enzymatic assay FIG. 2 shows results of Erythroid Differentiation Blockage of Selected Compounds CD71+GPA levels from an in vitro study FIG. 3 shows results of an HPLC analysis of %F Cells and %HbF induction levels from an in vitro study FIG. 4 shows dose-dependent HbF induction by CCG-385349 analogs one week after IP dosing FIG. 5 shows blood smear data for selected compounds. FIG. 6 shows changes in reticulocyte percentage and reticulocyte count one week after IP dosing. FIG. 7 shows data demonstrating changes in body weight one week after IP dosing FIG. 8 shows quantification of %F Cells by HPLC two weeks after po dosing. FIG. 9 shows blood smear with fresh blood data and %Sickle cells (two weeks after po dosing). FIG. 10 shows changes in reticulocyte% in PB one to two weeks of po dosing. FIG. 11 shows reduction of splenomegaly two weeks after PO dosing. FIGS. 12 and 13 show results of IP dosing of compounds disclosed herein for six days in C57bl6/j mice (body weights are changes in (grams) and in (%)). FIG. 14 shows docking of compound 52 in LSD1 Inhibitor CC90011 bound 6wk_crystal structure (MOE) and (surface plot, MOE). DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. As used herein, the term “and/or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and/or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and/or C.” For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2nd edition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rd Edition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (C1- C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl. As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. As used herein, the term “alkylsulfonyl” refers to a group -SO2R, wherein R is an alkyl group (as defined herein). As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic /[&- N_\ZNaVP _V[T `f`aRZ $R)T)' UNcV[T 1' ,+' \_ ,/ p RYRPa_\[` `UN_RQ V[ N PfPYVP N__Nf% UNcV[T 6-14 ring carbon atoms and zero heteroatoms (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl). As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. As used herein, the term “cycloalkylene” refers to a divalent cycloalkyl. As used herein, the term “cyano” refers to a -CN group. As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I. As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl. As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic \_ OVPfPYVP /[&- N_\ZNaVP _V[T `f`aRZ $R)T)' UNcV[T 1 \_ ,+ p RYRPa_\[` `UN_RQ V[ N PfPYVP N__Nf% having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5- membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6- tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin- 2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5- bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl). As used herein, the term “hydroxy” refers to an -OH group. As used herein, the term “hydroxyalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom is replaced with a hydroxy group. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3-dihydroxypentyl, 4-hydroxybutyl, 2-ethyl-4-hydroxyheptyl, 3,4- dihydroxybutyl, and 5-hydroxypentyl. As used herein, the term “oxo” refers to a group =O. When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof. As used herein, in chemical structures the indication:
Figure imgf000015_0001
represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound). For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH2-; similarly, -OC(O)NH- also encompasses -NHC(O)O-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction. The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor. A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys). As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Compounds Disclosed herein is a compound of formula (I):
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O and CH2; Z is selected from CHRy and NRz, wherein Ry is selected from H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl, and Rz is selected from H and -C(O)O-C1-C6-alkyl; R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl; R2 is -(CH2)nNRaRb, wherein n is 0 or 1, Ra is H, and Rb is selected from H, C1-C4 alkyl, - C(O)-C1-C6-haloalkyl, and -C(O)O-C1-C6-alkyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached to form a heteroaryl or heterocyclyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a heterocyclic ring that is optionally substituted with one or two substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L1 is -(CH2)p-, -X-, or -CH2X-, wherein: X is selected from -CRdRe-, -C(O)-, and cycloalkylene; Rd and Re are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and halo, or Rd and Re are taken together with the carbon atom to which they are attached to form a cycloalkyl or heterocyclyl; and p is 1, 2, or 3; R3 is aryl or monocyclic heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from cyano, halo, C1-C4-alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C3-C6 cycloalkyl; L2 is -CH2- or -C(O)-; and R4 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl, halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C4-alkylsulfonyl. In some embodiments, X is O and Z is CHRy, and Ry is hydrogen (i.e., Z is CH2). In some embodiments, X is CH2 and Z is NRz. In some embodiments, R1 is selected from hydrogen and C1-C4 hydroxyalkyl. In some embodiments, hydrogen and -CH2OH. In some embodiments, R1 is hydrogen. In some embodiments, R1 is -CH2OH. In some embodiments, R2 is -(CH2)nNRaRb, wherein n is 0 or 1, Ra is H, and Rb is selected from H, C1-C4 alkyl, -C(O)-C1-C6-haloalkyl, and -C(O)O-C1-C6-alkyl. In some embodiments, R2 is -NRaRb, wherein Ra is H and Rb is selected from H, C1-C4 alkyl, -C(O)-C1- C6-haloalkyl, and -C(O)O-C1-C6-alkyl. In some embodiments, R2 is -NRaRb, wherein Ra is H and Rb is selected from H, -C(O)CF3, and -COO(tert-butyl). In some embodiments, R2 is -NRaRb, wherein Ra and Rb are taken together with the nitrogen atom to which they are attached to form a heteroaryl or a heterocyclyl, such as a substituted bicyclic heteroaryl, such as a phthalimido group. In some embodiments, R2 has a structure selected from:
Figure imgf000018_0001
. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form a 4-, 5-, or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O, wherein the heterocyclic ring is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, C1-C4 haloalkyl, -C(O)ORc, and a 4- or 5-membered monocyclic heterocyclyl having one oxygen atom, wherein Rc is C1-C4 alkyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form a 4-membered heterocyclic ring having one nitrogen atom, wherein the ring is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, C1-C4 haloalkyl, - C(O)ORc, and a 4- or 5-membered monocyclic heterocyclyl having one oxygen atom, wherein Rc is C1-C4 alkyl. In some embodiments, the ring is unsubstituted. In some embodiments, the group
Figure imgf000018_0002
in formula (I) has a formula selected from:
Figure imgf000018_0003
Figure imgf000019_0001
. The group L1 is selected from -(CH2)p-, -X-, and -CH2X-. In some embodiments, L1 is - (CH2)p-, wherein p is 1, 2, or 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, L1 is -X-, wherein -X- is cycloalkylene. In some embodiments, L1 is -CH2X-, wherein X is selected from -CRdRe-, -C(O)-, and cycloalkylene, and Rd and Re are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and halo, or Rd and Re are taken together with the carbon atom to which they are attached to form a cycloalkyl or heterocyclyl. In some embodiments, L1 is -CH2X-, wherein X is -CRdRe-, Rd is hydrogen, and Re is selected from hydroxy and halo (e.g., fluoro). In some embodiments, L1 is -CH2X-, wherein X is -CRdRe-, and Rd and Re are taken together with the carbon atom to which they are attached to form monocyclic heterocyclyl containing one heteroatom selected from O, N, and S (e.g., O). In some embodiments, L1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -
Figure imgf000019_0002
. In some embodiments, R3 is phenyl or a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N and S, each of which is optionally substituted with 1 or 2 substituents independently selected from cyano, halo, and C1-C4-alkylsulfonyl. In some embodiments, R3 is phenyl, pyridyl, thiazolyl, or pyridizinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from cyano, fluoro, and -SO2CH3. In some embodiments, R3 has a structure selected from:
Figure imgf000020_0001
In some embodiments, L2 is -CH2-. In some embodiments, L2 is -C(O)-. R4 is selected from: phenyl; a 5- or 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, and O; a bicyclic heteroaryl having 1 or 2 heteroatoms independently selected from N, S, and O; C5-C6 cycloalkyl; and a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from O, S, and N; each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl, halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C4- alkylsulfonyl. In some embodiments, R4 is selected from phenyl, pyridyl, thiazolyl, cyclohexyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkoxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, R4 is selected from phenyl, pyridyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, methoxy, ethoxy, cyano, methyl, isopropyl, tert-butyl, trifluoromethyl, and cyclopropyl. In some embodiments, the group -L2-R4 has a structure selected from:
Figure imgf000020_0002
Figure imgf000021_0001
. In some embodiments, the group -L2-R4 has a structure:
Figure imgf000021_0002
In some embodiments, the compound is a compound of formula (IA):
Figure imgf000021_0003
or a pharmaceutically acceptable salt thereof, wherein L1, L2, R3, and R4 are as defined and described herein, and Rq is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In some embodiments, Rq is hydrogen. In some embodiments, the compound of formula (I) is selected from compounds shown in Table A, and pharmaceutically acceptable salts thereof. Table A. Compounds of Formula (I)
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
and pharmaceutically acceptable salts thereof. The invention further provides processes for preparing any of the compounds of the present invention. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. “Pharmaceutically acceptable acid addition salt” refers to those pharmaceutically acceptable salts which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). “Prodrug” indicates a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein. Thus, the term prodrug refers to a precursor of an active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, or amino group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, or free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like. Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereo isomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Certain compounds described herein contain one or two adjacent carbon-carbon bonds with a stereo center and thus give rise to exist in Z- or E- form (or cis- or trans- form) or syn- or anti- form. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or nonstoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms. Compounds of the present disclosure have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituent groups. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this disclosure. The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. The absolute stereochemistry of a compound may be determined by using X-ray crystallography to determine the crystal structure of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), fluorine-18 (18F) or carbon-14 (14C). Isotopic substitution with 2H, 3H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 17O, 18O, 14F, 15F, 16F, 17F, 18F, 35Cl, 37Cl, are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In certain embodiments, the compounds disclosed herein have one, some, or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art. In some embodiments deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; GeorgeW.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. In certain embodiments, the compounds disclosed herein have one, some, or all of the 19F atoms replaced with 18F atoms. The methods of synthesis for fluorine-containing compounds are known in the art. See, e.g., Molecular Imaging (Second Edition) Principles and Practice, Henry F. VanBrocklin, Chapter-25, 2021, 445-478. The compounds disclosed herein can be prepared by a variety of methods, including those shown in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution). Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. Pharmaceutical Compositions and Formulations The present disclosure further provides pharmaceutical compositions (e.g., comprising the compounds described above and elsewhere herein). The pharmaceutical compositions of the present disclosure may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), oral, intravenous, intravascular, gastrointestinal, or parenteral. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal, or intraventricular, administration. Administration may be achieved by single shot, a series of single shots, and/or by continuous administration. In certain embodiments, continuous administration is provided by a programmable external pump. In other embodiments, continuous administration is provided by a programmable implantable pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, or binders may be desirable. Compositions and formulations for parenteral administration may include sterile aqueous solutions that may also contain buffers, diluents, and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids. The pharmaceutical formulations of the present disclosure, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present disclosure may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. The compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions. Thus, for example, the compositions may contain additional, compatible, pharmaceutically active materials such as materials useful in physically formulating various dosage forms of the compositions of the present disclosure, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present disclosure. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g., humans, orally at a dose of 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg/kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose. For example, a suitable intramuscular dose would be about 0.0025 to about 25 mg/kg, or from about 0.01 to about 5 mg/kg. The unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or it solvates. In a topical formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In one embodiment, the compound is present at a concentration of about 0.07-1.0 mg/ml, for example, about 0.1-0.5 mg/ml, and in one embodiment, about 0.4 mg/ml. In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient. The pharmaceutical compositions of the invention may be administered to any patient which may experience the beneficial effects of the compounds of the invention. Foremost among such patients are mammals, e.g., humans, although the invention is not intended to be so limited. Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like). The compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee- making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above- mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents, and lubricants, for example, silica, talc, stearic acid, or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropyl methyl- cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses. Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added. Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension includes, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. The topical compositions of this invention are formulated in one embodiment as oils, creams, lotions, ointments, and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). The carriers may be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety. Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol. One of ordinary skills in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the present invention. Various modifications and alterations of the compositions and methods described above can readily be achieved using expertise available in the art and are within the scope of the invention. Methods of Use The present disclosure provides methods of using the compounds and compositions described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof), or pharmaceutical compositions comprising such compounds. For example, disclosed herein are methods of treating disorders related to LSD1 activity in a subject in need thereof (e.g., a human subject in need thereof), comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). The disorders related to LSD-1 activity include hematological disorders, cancers, neurological disorders, metabolic disorders, and other disorders. For example, in some embodiments, the disorder is a hemotological disorder, such as a disorder selected from sickle PRYY QV`RN`R N[Q m(aUNYN``RZVN) @[ `\ZR RZO\QVZR[a`' aUR QV`\_QR_ V` N PN[PR_' `bPU N` N PN[PR_ selected from acute myeloid leukemia, multiple myeloma, biliary tract cancer, non-small cell lung cancer, and chronic lymphocytic leukemia. In some embodiments, the disorder is a neurological disorder, such as a disorder selected from Alzheimer’s disease, Parkinson disease, and Huntington disease. In some embodiments, the disorder is a metabolic disorder, such as a disorder selected from type-2 diabetes and obesity. In some embodiments, the disorder related to LSD-1 activity is selected from myocardial fibrosis and autism. Appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. A compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. EXAMPLES Example 1: Compound Syntheses Experimental The compounds of the present invention may be prepared, without limitation, according to one of the general methods outlined below. For example, Schemes 1-12 that follow are intended as an illustration of some embodiments of the invention and no limitation of the present invention is implied because of them. The following defines acronyms as used herein unless specified otherwise in a particular instance: ; ACN = Acetonitrile; ABq = AB quartet; t-BuOH = t-Butanol; br. = broad; 1,2-DCE = 1,2-Dichloroethane; DCM = Dichloromethane or Methylene chloride; ddd = doublet of doublet doublet; ddt = doublet of doublet triplet; DIEA = Diisopropyl ethyl amine ; DMF = Dimethyl formamide; DMSO = Dimethyl sulfoxide; EtOAc or EA = Ethyl acetate; EDC = N-Ethyl-N'-(3- dimethylaminopropyl)carbodiimide ; Et3N = Triethyl amine; EtOH = Ethanol; Et2O = Diethyl ether or Ether; HBTU = 2-(1H-Benzotriazol-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate, ; Hex = Hexanes; HOBT = 1-Hydroxybenzotriazole; m-cPBA = m- Chloroperbenzoic acid or meta Chloroperbenzoic; MeNH2 = Methyl amine; MeOH = Methanol ; MTBE = Methyl t-butyl ether; NaBH(OAc)3 = Sodium triacetoxyborohydride; NMP = N-Methyl Pyrrolidinone; NMO = N-Methyl Morpoline N-Oxide; 10% Pd/C = 10% Palladium on charcoal; PPh3 = Triphenyl phosphine; RT =room temperature; TFA = Trifluoroacetic acid; TFA salt = Trifluoroacetate salt; THF = Tetrahydrofuran; tt = triplet of triplet; p-TsOH or TsOH = p- Toluene sulfonic acid.
Figure imgf000043_0001
Compounds of formula (Ia1) of invention can be prepared via the process outlined in Scheme - I using customary coupling procedures from starting compound (II) and compound (III) where R, R2, R3 and R4 are as previously defined herein. Nucleophilic substitution of amino alcohol of formula (III) in the presence of base in DMSO or NMP at 80 – 110oC to afford the amino alcohol of formula (IV) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to result the compounds of formula (V). Oxidation of disubstituted amino alcohols of formula (V) using Dess-Martin reagent to afford the compounds of formula (VI) which upon cyclization with N-protected amino diols of formula (VIIa) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (VIIIa). Deprotection of N-protecting group using either TFA in DCM or MeNH2 in MeOH or Hydrazine in Ethyl acetate under refluxing conditions to afford the compounds of invention (Ia). Compounds of formula (Ia1) can be synthesized by treatment of compounds of formula (Ia) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids, that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base (Carpenter, R. D. J. Comb. Chem.2006, 8, 907; Dunetz, J. R. Org. Proc. Res. Dev. 2016, 20, 140) or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane (Millbanks, C. and Bonnekessel, M. (2009). Propylphosphonic Anhydride. In Encyclopedia of Reagents for Organic Synthesis, (Ed.)). Compounds of formula (Ia1) can be synthesized by treatment of compounds of formula (Ia) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic acid (Abdel-Magid, A. F. et.al., J. Org. Chem.1996, 61, 3849) or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH.
Figure imgf000044_0001
Compounds of formula (VIIIa) can be prepared can be prepared via the process outlined in Scheme - II using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (VIIa) and compound of formula (IX) and where R2, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of N-protected amino diols of formula (VIIa) with N-Protected aminoaldehyde of formula (IX) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition to afford compounds of formula (Xa). Deprotection of N-protecting group under hydrogenolysis condition using hydrogen and 10% Pd/C in EtOH, 45psi at room temperature to afford the amines of formula (XIa). Nucleophilic substitution using fluoro or bromo compounds of formula (I) with in the presence of in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XIIa) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (VIIIa).
Figure imgf000045_0001
Compounds of formula (VIIIb) can be prepared can be prepared via the process outlined in Scheme - III using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (IX) and (XIII) where R2, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of N-protected triols of formula (XIII) with N- Protected aminoaldehyde of formula (IX) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition afford compounds of formula (XIV). Alcohol of formula can be converted into azide of formula (XV) by converting it into its mesylate derivatives followed by treatment with NaN3 in DMF under heating condition. Reduction of azides of formula (XV) using PPh3/H2O at room temperature or other reducing agent followed by protection of amino group using Boc2O to afford compounds of formula (Xb). Deprotection of N-protecting group under hydrogenolysis condition 10% Pd/C in EtOH, hydrogen under 45 psi conditions at room temperature to afford the amines of formula (XIb). Nucleophilic substitution using fluoro or bromo compounds of formula (I) with in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XIIb) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (VIIIb).
Figure imgf000046_0001
Compounds of formula (VIIIc) can be prepared can be prepared via the process outlined in Scheme – IV using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (IX) and compound of formula (XVI) where R2, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of methylene diols of formula (XVI) with N-Protected aminoaldehyde of formula (VI) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition afford compounds of formula (XVII) (Brenneman, J, B. et.al. WO 2019/094552 PCT/US2018/059763). Treatment of alkene of formula (XVII) with N-iodo succinimide or N-Bromosuccininimde in DCM followed by treatment with Et3N. HF or Pyridine.HF to afford the compounds of formula (XVIII). Base catalyzed treatment of potassium phthalide with compounds of formula (XVIII) to afford phthalides of formula (XIX) by converting it into its mesylate derivatives followed by treatment with NaN3 in DMF under heating condition. Reduction of azides of formula (XV) using PPh3/H2O at room temperature or other reducing agent followed by protection of amino group using Boc2O to afford compounds of formula (Xb). Deprotection of N-protecting group under hydrogenolysis condition 10% Pd/C in EtOH, hydrogen under 45 psi conditions at room temperature to afford the amines of formula (XIb). Nucleophilic substitution using fluoro or bromo compounds of formula (I) with in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XIIb) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (VIIIx).
Figure imgf000047_0001
Compounds of formula (Iaax) and (Iaay) of invention can be synthesized via the process outlined in Scheme - V using customary coupling procedures from starting compound of formula (VI) where R3 and R4 are as previously defined herein. Acid catalyzed cyclization of N-protected amino aldehyde of formula (VI) with diol of formula (XVI) in the presence of catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford alkenes of formula (XX) (Brenneman, J, B. et.al. WO 2019/094552 PCT/US2018/059763). Compounds of formula (VIIIc) can be converted into diols of formula (XXI) by one skilled in the art by following dihydroxylation ZRaU\Q` $RVaUR_ 8;(CVe(m' \_ 8;(CVe(e, t-BuOH, rt or OsO4-NMO, t-BuOH:H2O, rt). The alcohols of formula (XXI) can be transformed into an azidoalcohols of formula (X) in a two-step process by converting it into its monomesylate or monotosylate followed by displacement with NaN3 under heating condition. Alternatively, the azidoalcohols of formula (XXII) can be synthesized from alkene of formula (XX) via epoxidation followed by opening of epoxides of formula (XXIV) with NaN3 by following standard literature conditions. Compounds of formula (Iaax) of invention may be synthesized by reduction of azidoalcohols of formula (XXV) using PPh3/H2O at room temperature. Compounds of formula (Iaay) of invention can be synthesized by treatment of azidoalcohols of formula (XXII) using fluorinating agent such as DAST to afford compounds of formula (XXIII) and subsequent reduction using PPh3/H2O at room temperature condition.
Figure imgf000048_0001
Compounds of formula (Ib1) of invention can be prepared via the process outlined in Scheme - VI using customary coupling procedures from starting compound of formula (VI) where R, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of N-protected amino diols of formula (VIIb) with aldehyde of formula (VI) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (VIIId). Deprotection of N- protecting group using TFA in DCM at room temperature to afford the compounds of invention (Ib). Compounds of formula (Ib1) can be synthesized by treatment of compounds of formula (Ib) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids, that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base (Carpenter, R. D. J. Comb. Chem. 2006, 8, 907; Dunetz, J. R. Org. Proc. Res. Dev.2016, 20, 140) or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane (Millbanks, C. and Bonnekessel, M. (2009). Propylphosphonic Anhydride. In Encyclopedia of Reagents for Organic Synthesis, (Ed.).). Compounds of formula (Ib1) can be synthesized by treatment of compounds of formula (Ib) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic acid (Abdel-Magid, A. F. et.al., J. Org. Chem.1996, 61, 3849) or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH.
Figure imgf000049_0002
Compounds of formula (VIIId) can be prepared via the process outlined in Scheme - VII using customary coupling procedures or may be synthesized by one skilled in the art where R3 and R4 are as previously defined herein. Acid catalyzed cyclization of N-protected amino diols of formula (VIIb) with N-protected aminoaldehyde of formula (IX) in the presence of a catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition to afford compounds of formula (Xb). Deprotection of N-protecting group under hydrogenolysis condition using hydrogen and 10% Pd/C in EtOH, 45psi at room temperature to afford the amines of formula (XIb). Nucleophilic substitution using fluoro or bromo compounds of formula (I) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XIIb) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (VIIId).
Figure imgf000049_0001
Alternatively, compounds of formula (VIIId) can be prepared via the process outlined in Scheme – VIII using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (XIb) where R3 and R’ are as previously defined herein. Treatment of compounds of formula (XIb) with acid chlorides, R4’COCl or R4’SO2Cl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (R4’CO2H), that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (to afford compounds of formula (XIIb). Compounds of formula (XIIb) can be synthesized by treatment of compounds of formula (XIb) with R4’CHO in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH. Compounds of formula (VIIId) can be prepared by nucleophilic substitution using fluoro or bromo compounds of formula (I) with compounds of formula (XIIb) in the presence of base such as DIEA or Et3N in DMSO or NMP at 80 – 110oC or palladium or copper catalyzed arylation or heteroarylation.
Figure imgf000050_0001
Alternatively, compounds of formula (VIIIa) and (VIIId) can be prepared via the process outlined in Scheme - IX using customary coupling procedures or may be synthesized by one skilled in the art from starting compound of formula (II) and compounds of formula (XXVI) where R3 and R’ are as previously defined herein. Nucleophilic substitution using fluoro or bromo compounds of formula (I) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XXVII) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (XXVIII). Acid catalyzed cyclization of N-protected amino diols of formula (VIIa) with compounds of formula (XXVIII) in the presence of a catalytic amount of p-TsOH in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (VIIIa). Similarly, cyclization of N-protected amino diols of formula (VIIb) with compounds of formula (XXVIII) in the presence of a catalytic amount of p-TsOH in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (VIIId).
Figure imgf000051_0001
Compounds of formula (Ia2 to Ia5) of invention can be prepared via the process outlined in Scheme - X using customary coupling procedures or may be synthesized by one skilled in the art, where R, R1, R2, R3 and R4 are as previously defined herein. Epoxidation of alkenes of formula (VA) with H2O2 in the presence of base in a mixture of CH3CN/MeOH at 40oC to afford the epoxides of formula (EpAc) which upon treatment with amines of formula (R3NH2) in the presence of base under refluxing conditions in EtOH or with 5M LiClO4 in Et2O at rt to afford the amino alcohols of formula (XXVII). Benzylation of amino alcohols of formula (XXVII) in the presence of base such as DIEA or K2CO3 or CS2CO3 to afford compounds of formula (XXVIII). Cyclization with N-protected amino diols of formula (VIIa) in the presence of a catalytic amount of p-TsOH in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (XXIX). Alternatively, compounds of formula can be synthesized from N-protected amino diol of formula (VIIa) in four steps. Acid catalyzed cyclization of acrolein diethyl acetal with (VIIa) in DCM at room temperature to afford compounds of formula (VA-I). Epoxidation of vinyl acetate of formula (ViDiox-I) using m-cPBA in DCM at room temperature to afford epoxy dioxane of formula (EpDiox-I) which upon treatment with amines of formula (R3NH2) in the presence of base under refluxing conditions in EtOH or with 5M LiClO4 in Et2O at rt to afford the amino alcohols of formula (AA-I). Benzylation of amino alcohols of formula (AA-I) in the presence of base such as DIEA or K2CO3 or CS2CO3 to afford compounds of formula (XXVIII). Deprotection of N-protecting group using either TFA in DCM or MeNH2 in MeOH or Hydrazine or ethanolamine in Ethyl acetate under refluxing conditions to afford the compounds of invention (Ia2). Compounds of formula (Ia3) can be synthesized by treatment of compounds of formula (Ia2) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3) with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol. Compounds of formula (XXX) can be synthesized by treatment of alcohol of formula (XXIX) with DAST in DCM at room temperature which upon deprotection using TFA in DCM to afford the compounds of invention of formula (Ia4). Similarly, Compounds of Invention of formula (Ia5) can be synthesized by treatment of compounds of formula (Ia5) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH
Figure imgf000052_0001
Compounds of invention of formula (Ib2 to Ib6) can be synthesized via the process outlined in Scheme - XI using customary coupling procedures or may be synthesized by one skilled in the art, where R, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of compounds of formula (XXVIII) with N-protected amino diols of formula (VIIb) in the presence of p-TsOH in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (XXXI). Alternatively, compounds of formula (XXXI) can be synthesized from N-protected amino diol of formula (VIIb) in four steps. Acid catalyzed cyclization of acrolein diethyl acetal with (VIIb) in DCM at room temperature to afford compounds of formula (ViDioX-II). Epoxidation of vinyl acetate of formula (ViDioX-II) using m-cPBA in DCM at room temperature to afford epoxy dioxane of formula (EpDiox-II) which upon treatment with amines of formula (R3NH2) in the presence of base under refluxing conditions in EtOH or with 5M LiClO4 in Et2O at rt to afford the amino alcohols of formula (AADioX-II). Benzylation of amino alcohols of formula (AADiox-II) in the presence of base such as DIEA or K2CO3 or CS2CO3 to afford compounds of formula (XXXI). Deprotection of N- protecting group using TFA in DCM to afford the compounds of invention (Ib2). Compounds of formula (Ib3) can be synthesized by treatment of compounds of formula (Ib2) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH. Compounds of formula (XXII) can be synthesized by treatment of alcohol of formula (XXXI) with DAST in DCM at room temperature which upon deprotection using TFA in DCM to afford the compounds of invention of formula (Ib4). Compounds of invention of formula (Ib5) can be synthesized by treatment of compounds of formula (Ib4) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids (RCO2H), that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane. Compounds of formula (Ib5) can be synthesized by treatment of compounds of formula (Ib4) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic acid or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH. Compounds of invention of formula (Ib5) can be synthesized by oxidation of compounds of formula (XXXI) using Dess-Martin reagent in DCM to afford compounds of formula (XXIII), which upon deprotection using TFA in DCM to afford compounds of formula of invention (Ib6).
Figure imgf000054_0001
Alternatively, optically active, or racemic compounds of formula (XXXI) can be synthesized via the process outlined in Scheme - XII using customary coupling procedures or may be synthesized by one skilled in the art, where R3 and R4 are as previously defined herein. Commercially available optically active or racemic aminodiol of formula (XXXIV) can be converted it its N-Cbz derivative under standard condition to afford N-protected amino diol of formula (XXXV) which upon mild oxidation using N-Cloroisocyanuric acid in the presence of TEMPO to afford the hydroxy aldehyde of formula (XXXVI). (Concia, Alda Lisa et.al., Chemistry - A European Journal, 15(15), 3808-3816; 2009; De Luca, Lidia, et.al., Organic Letters, 3(19), 3041-3043; 2001 and Journal of the American Chemical Society, 129(47), 14811- 14817; 2007). Acid catalyzed cyclization of N-protected amino aldehyde of formula (XXXVI) with diol of formula (VIIb) in the presence of catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (XXXVII) which upon deprotection under hydrogenolysis condition to afford aminoalcohol of formula (XXXVIII). Nucleophilic substitution using fluoro or bromo compounds of formula (I) with N-protected amino alcohol of formula (XXXVIII) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XXIX) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 O to afford the compounds of formula (XXXI).
Figure imgf000055_0001
Compounds of invention of formula (Ia'D) can be synthesized via the process outlined in Scheme - XIII using customary coupling procedures or may be synthesized by one skilled in the art, where R, R3 and R4 are as previously defined herein. Acid catalyzed cyclization of compounds of diols of formula (XXXX) with N-protected amino aldehydes of formula (IX) in the presence of catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (XXXXI). Deprotection of N-protecting group (PG') under hydrogenolysis condition (10%Pd/C, EtOH, H2, 45psi) to afford compounds of formula (XXXXII). Nucleophilic substitution using fluoro or bromo compounds of formula (I) with compounds of formula (XXXXII) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (XXXXIII) which upon benzylation in the presence of base such as DIEA or K2CO3 or Cs2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (XXXXIV). Deprotection of N-protecting group in compounds of formula (XXXXIV) using TFA in DCM or 4M HCl in dioxane or 1M HCl in Ether to afford the compounds of invention (Ia'D). Compounds of invention of formula (Ia'Dxx) can be synthesized by treatment of compounds of formula (Ia'D) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with or carboxylic acids, that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane. Compounds of formula (Ia'Dxx) can be synthesized by treatment of compounds of formula (Ia'D) with RCHO or RCOR in the presence of a reducing agent such as sodium triacetoxy borohydride or sodium cyanoborohydride with an acid, such as acetic or a Lewis acid, such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, with NaCNBH3 in MeOH.
Figure imgf000056_0001
Compounds of diols of formula (XXXX) can be synthesized via the process outlined in Scheme – XIV using customary procedures or may be synthesized by one skilled in the art. Base catalyzed alkylation of commercially available esters of formula (A1) with LDA or LHMDS followed by addition of chloromethyl benzyl ether (BOM-Cl) to afford compounds of formula (A2), which upon reduction using reducing agents such as LiAlH4 or LiBH4 to afford compounds of formula (A3). Deprotection of compounds of formula (A3) under hydrogenolysis condition to afford diols of formula (XXXX). Alternatively, diols of formula (XXXX) can be synthesized from commercially available N-protected amino alcohol of formula (A4) as shown in the above- mentioned method. Dess-Martin Oxidation of commercially available optically active or racemic N-protected amino alcohol of formula (A4) to afford N-protected aminoaldehyde of formula (A5), which upon treatment with formaldehyde (CH2O) in the presence of base followed by reduction with sodium borohydride (NaBH4) to afford diols of formula (XXXX).
Figure imgf000057_0001
The intermediate of compounds of formula (XXXXIIIa) can be synthesized via the process outlined in Scheme – XV using customary procedures or may be synthesized by one skilled in the art. Acid catalyzed cyclization of compounds of N-protected aminotriol of formula (AT) with N-protected amino aldehydes of formula (IX) in the presence of catalytic amount of p-TsOH in DCM at room temperature followed by refluxing condition or in Toluene or Toluene/CHCl3 mixture under heating conditions to afford compounds of formula (XXXXVa) which upon deprotection using TFA in DCM to afford the compounds of invention of formula (XXXXVI). Treatment of chloroacetyl chloride in the presence of base followed treatment with NaH or t- BuOK to afford compound of (XXXXVII). Reduction of the amide group using reducing agent such as LAH or LiBH4 to afford the spiromorpoline of formula (XXXXVIII) which upon protection using Boc2O under standard condition to afford N-Boc protected spiromorpoline of formula (XXXXIa). Deprotection of N-protecting group (PG') under hydrogenolysis condition (10%Pd/C, EtOH, H2, 45psi) to afford compounds of formula (XXXXIIa).
Figure imgf000058_0001
Compounds of invention of formula (Ic and Ic1) can be synthesized via the process outlined in Scheme - XVI using customary coupling procedures or may be synthesized by one skilled in the art, where R, R1, R2, R3 and R4 are as previously defined herein. Compounds of invention of formula (Ic and Ic1) may be from starting compound alcohol of formula (THP-I) by converting into the nitrile derivatives of formula (THP-II) in a two-step process via treatment with mesyl chloride in the presence of a base followed by treatment of KCN in DMSO at 80oC or n- Bu4NCN in THF under refluxing condition. Reduction of nitrile derivative of formula (THP-II) under Raney nickel or NiCl2-6H2O/NaBH4 (Bunker, K. et.al., WO 2016/044331) or DIBAL- H/NaBH4 (Wu et al. Chem. Commun., 2021, 57, 6066) condition to afford the amines of compound of formula (THP-III). Nucleophilic substitution using fluoro or bromo compounds of formula (I) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (THP-IV) which upon benzylation in the presence of base such as DIEA or K2CO3 or CS2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (XXVII). Deprotection of N-protecting group using TFA in DCM or 4M HCl in dioxane to afford compounds of invention of formula (Ic). Compounds of invention of formula (Ic1) can be synthesized by treatment of compounds of formula (Ic) with RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (RCO2H), using customary coupling procedures such as EDC/HOBt or HATU or HBTU in the presence of base. Similarly, compounds of invention of formula (Ic1) can be synthesized by treatment of compounds of formula (Ic) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH.
Figure imgf000059_0001
Compounds of invention of formula (Id and Id1) can be synthesized via the process outlined in Scheme - XVI using customary coupling procedures or may be synthesized by one skilled in the art, where R, R3 and R4 are as previously defined herein. Nucleophilic substitution using fluoro or bromo compounds of formula (I) with N-protected amine of formula (AM-I) in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (AM-II) which upon benzylation in the presence of base such as DIEA or K2CO3 or Cs2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (AM-III). Deprotection of N-protecting group using TFA in DCM condition to afford compounds of invention of formula (Id). Compounds of invention of formula (Id1) can be synthesized by treatment of compounds of formula (Id) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (RCOOH), that are commercially available or synthesized by methods known in the art, or treatment of (Id) with in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane. Similarly, compounds of invention of formula (Id1) can be synthesized by treatment of compounds of formula (Id) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH.
Figure imgf000060_0001
Compounds of invention of formula (Ie and Ie1) can be synthesized via the process outlined in Scheme - XVII using customary coupling procedures or may be synthesized by one skilled in the art, where R, R3 and R4 are as previously defined herein. Compounds of invention of formula (Ie and Ie1) may be synthesized from starting commercially available ketone of formula (Az-I). Acid catalyzed cyclization of N-protected ketone of formula (Az-I) with triol of formula (T-OH) in the presence of a catalytic amount of p-TsOH in Toluene under heating condition followed by deprotection/protection with Boc under hydrogenolysis condition to afford compounds of formula (Az-II). The alcohol of formula (Az-II) can be converted into the nitrile derivative of formula (Az-III) in a two-step process via treatment with mesyl chloride in the presence of a base followed by treatment with KCN in DMSO at 80oC or n-Bu4NCN in THF under refluxing condition. Reduction of nitrile derivative of formula (Az-III) under Raney nickel condition to afford the amines of compound of formula (Az-IV). Nucleophilic substitution using fluoro or bromo compounds of formula (Az-VI) with in the presence of base in DMSO or NMP at 80 – 110oC to afford the substituted amines of formula (Az-V) which upon benzylation in the presence of base such as DIEA or K2CO3 or Cs2CO3 or NaH in acetonitrile or THF or DMF or DMSO to afford the compounds of formula (Az-VI). Deprotection of N-protecting group using TFA in DCM condition to afford compounds of invention of formula (Ie). Compounds of invention of formula (Ie1) can be synthesized by treatment of compounds of formula (Ie) with acid chlorides, RCOCl that are commercially available or synthesized by methods known in the art, in the presence of base or it can be mixed with carboxylic acids (RCOOH), that are commercially available or synthesized by methods known in the art, or in the presence of a customary coupling procedures coupling reagent such as EDC/HOBt or HATU or HBTU in the presence of base or propylphosphonic anhydride (T3P) solution in a suitable solvent such as acetonitrile, dimethyl formamide, and dichloroethane. Similarly, compounds of invention of formula (Ie1) can be synthesized by treatment of compounds of formula (Ie) with RCHO or RCOR with NaBH(OAc)3 in DCE or with NaCNBH3 in MeOH.
Figure imgf000061_0001
Compounds of invention of formula of deuterated analogs of formula (Ib7) can be synthesized via the process outlined in Scheme – XVIII using customary coupling procedures or may be synthesized by one skilled in the art, where R, R3 and R4 are as previously defined herein. Treatment of aldehyde of formula (1, wherein R is monofluoro or difluoro or trifluoro substituted or R is Cl or CN or Methyl substituted) with CD3I in the presence of base such as K2CO3 or NaH in THF to afford the compound of formula (2) which upon reduction using NaBH4 in MeOH to the corresponding alcohol of formula (3). Treatment of alcohol of formula (3) under refluxing condition with SOCl2 in DCM or PBr3 in DCM to afford the compounds of formula (4, wherein X = Cl or Br). Similarly, reduction of aldehyde of formula (5) using NaBD4 or LiAlD4 under standard condition to afford the alcohol of formula of (6) which upon treatment with SOCl2 in DCM or PBr3 in DCM to afford the compounds of formula (7, wherein X = Cl or Br). Benzylation of compounds of formula of (VIIb) with halides of formula of (4 or 7) using NaH in THF or DMF to afford the compounds of formula (VIIId). Deprotection of compounds of formula (VIIId) using TFA in DCM at room temperature to afford the compounds of invention (Ib7). Dioxane ring precursors are nitrogen substituted 1, 1 bis-methanols and cyclic 1,3-diols are synthesized by following literature methods or modified synthetic schemes mentioned here.
Figure imgf000062_0001
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room temperature (about 18oC to about 25oC) under nitrogen atmosphere. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure. The course of the reaction was followed by thin layer chromatography (TLC) or liquid chromatography (LC), and reaction times are given for illustration only. Silica gel chromatography was carried out on a CombiFlash® system (Teledyne Isco, Inc., Lincoln, NE, USA) with pre-packed silica gel cartridge or performed on Merck silica gel 60 (230-400 mesh) (Merck KGaA, Darmstadt, Germany). The structure and purity of all final products was assured by at least one of the following analytical methods: nuclear magnetic resonance (NMR) and LC-MS. a) NMR NMR data was acquired at the Biochemical NMR Core Laboratory, College of Pharmacy, University of Michigan, on an Agilent 400MHz MR spectrometer with a 5mm ONE probe and operated by host software VNMRJ 3.4 Data was analyzed using MestreNova 14.1.0 (Mestrelab GR`RN_PU H)B)%) :URZVPNY `UVSa $l% V` TVcR[ V[ ]N_a` ]R_ ZVYYV\[ $]]Z% _RYNaVcR a\ aRa_NZRaUfY silane (TMS) as an internal standard. Coupling constants (J) are expressed in hertz (Hz), and conventional abbreviations used for signal shape are s = singlet; d = doublet; t = triplet; m = multiplet; br = broad; etc. b) ESI-MS Unless specifically stated otherwise, the electrospray ioniozation - mass spectrometric (ESI-MS) procedures were performed using electrospray ionization (ESI) operating in positive mode via a Waters LCT time-of-flight (TOF) mass spectrometer (Waters Corp., Milford, MA, USA). The solvent carrier used is a gradient of 100% to 85% of solvent (A) Water with 0.1% Trifluoroacetic acid and 0% to 15% of Solvent (B) Acetonitile with 0.1% Trifluoroacetic acid MeOH (with 0.1% TFA). From mass spectra obtained, (M+H)+ and in some cases (M+H - 56)+ are reported. From chromatographic spectra obtained, RT = (RT) and Rt is reported retention time in minutes. c) Q-TOF LC/MS Unless specifically stated otherwise, the Quadrupole Time of Flight - mass spectrometric (Q- TOF LC/MS) procedures were performed using Quadrupole Time of Flight - mass spectrometer (Q-TOF) operating in positive mode via Agilent Technologies, 6520 Accurate Mass Q-TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA). The solvent carrier used is a gradient of Water with 0.1% Formic acid and 95% Acetonitrile/0.5% Water with 0.1% Formic acid. From mass spectra obtained, (M+H)+ and in some cases (M+H - 56)+ are reported. c) HPLC Unless specifically stated otherwise, the liquid chromatographic analysis was performed using Agilent LAB CDS Chemstation Edition for LC and LC/MS system. The chromatograms were analyzed using Agilent Open LAB Intelligent Reporting A.01.06.111 software. The samples dR_R ]_R]N_RQ b`V[T , ZT*ZB' N[Q aUR `NZ]YR V[WRPaV\[ c\YbZR V` 0(,+ oB) =\_ RYbaV\[' N gradient of a mobile phase with water: acetonitrile (90:10) to acetonitrile:water (90:10) over 13 minutes, with 0.1% TFA added to both water and acetonitrile (Method-1) using Agilent Eclipse C-18 column. The compounds are assayed at 250 nm UV wavelength and RT =(RT) is reported in min. 2) Intermediate of Formulas of the Invention Unless specified otherwise, the reagents used in the preparation of compounds, including intermediates, of the present invention were purchased from Fisher Scientific, TCI Chemicals, Ambeed Inc., Enamine LLC, Matrix Inc., and Sigma-Aldrich Corporation. Compound of Invention – 1: Formation of trans 4-(((5-amino-1,3-dioxan-2-yl)methyl)(3- fluoro-4-methoxybenzyl)amino)benzonitrile Compounds of Invention – 1 and 19a were prepared via the process of Scheme XIX, supra, as follows. Step a: Intermediate of Formula - 17a: Formation of 4-((2,2- dimethoxyethyl)amino)benzonitrile To a stirred solution of 2,2-dimethoxyethan-1-amine ( 0.87 g, 8.30 mmol) and 4- fluorobenzonitrile (I, 1.00 g, 8.30 mmol) in anhydrous DMSO (10.0 mL) was added DIEA (2.60 mL, 1.90 g, 17.0 mmol) at room temperature and the resulting clear solution is heated to 110 oC overnight (16 h).The reaction was cool to room temperature and the product was extracted using DCM. The organic portion was washed with aqueous citric acid solution, water, brine successively and dried over anhydrous sodium sulfate. Filtered followed by removal of solvent gave the desired product 4-((2,2-dimethoxyethyl)amino)benzonitrile (17a, 1.80 g, 94%) as a pale yellow color solid which was used as such for the next step. HPLC RT: 5.343 Min., 1H-NMR (400 MHz, CDCl3% l 2).3 $QQQ' J = 8.8, 4.4, 1.8 Hz, 1H), 6.63 – 6.44 (m, 1H), 4.52 (tdd, J = 5.3, 2.8, 1.3 Hz, 1H), 3.42 – 3.35 (m, 3H), 3.25 (tdd, J = 5.5, 2.7, 1.2 Hz, 1H). Step b: Intermediate of formula 18a: Formation of 4-((2,2-dimethoxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-((2,2-dimethoxyethyl)amino)benzonitrile ( 1.80 g, 8.73 mmol) and 4- (bromomethyl)-2-fluoro-1-methoxybenzene ( 1.91 g, 8.73 mmol) in Acetonitrile (25.0 mL) was added DIEA (2.71 mL, 2.01 g, 17.5 mmol) was added and the resulting clear solution is heated to reflux for 18 h. Then solvent was removed using rotovap and the crude product was dissolved in DCM and washed the organic portion with aqueous citric acid solution, water, and brine. The organic phase is dried over anhydrous sodium sulfate then Filtered followed by removal of solvent gave the crude product as a viscous material (18a, 1.60 g, 68%). TLC Rf: 0.32 (30% EA/Hex). (400 MHz, CDCl3) l 2)/3 h 2)./ $Z' -?%' 1)41 h 1)23 $Z' .?%' 1)2/ h 1)1. (m, 2H), 4.61 (s, 2H), 4.55 (dt, J = 8.2, 5.2 Hz, 1H), 3.94 – 3.78 (m, 1H), 3.57 (d, J = 5.1 Hz, 2H), 3.40 (dd, J = 3.2, 0.7 Hz, 6H), 3.27 (t, J = 5.4 Hz, 0H). Step c: Compound of Invention (19a) (Compound-1): Formation of Trans-4-((((2r,5r)-5- (1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-((2,2-dimethoxyethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (I, 0.150 g, 0.436 mmol), and 2-(1,3- dihydroxypropan-2-yl)isoindoline-1,3-dione (4, 0.106 g, 0.479 mmol) in Toluene (10 mL) was added catalytic amount of 4- methylbenzenesulfonic acid ( 0.023 g, 0.131 mmol). After heating 6h at 90oC, the reaction mixture was cooled to room temperature and quenched with aqueous sodium bicarbonate solution. The product was extracted using DCM and washed with water, brine, and dried over anhydrous sodium sulfate. Filter and removal of solvent yielded the crude product. Purification on a silica gel Prep TLC plate using 30% EA/Hex. The product from the polar bottom band was extracted using DCM followed by removal of solvent afforded the titled compound (19a, 80 mg, 26%) as a white color foam. TLC Rf: 0.21 (30% EA/Hex). HPLC Rf: 7.343 min. MS-ESI (m/z): Calculated [M+H]+ = 502.1734; Observed [M+H]+ = 502.1810. Compound of Invention – 1 (Compound-2): Step 4: Formation of Trans 4-(((5-amino-1,3- dioxan-2-yl)methyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile To a stirred solution of compound 4-((((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2- yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile (19a, 0.070 g, 0.14 mmol) in ethyl acetate (10 mL) was added 2-aminoethan-1-ol (0.32 mL, 0.26 g, 4.2 mmol, 30 equ.) at room temperature under nitrogen atmosphere. The resulting mixture is allowed to reflux for 3h and stirred at rt overnight. The solvent was removed using rotovap and the resulting crude product is purified directly using 50%EA/Hex as an eluent. The desired product is found in the more polar spot and the product is isolated as a white solid (1, 0.040 g, 70%). HPLC RT: 5.356 min.; MS- ESI (m/z): Calculated [M+H]+ =372.1679; Observed [M+H]+ = 372.1746.
Figure imgf000065_0001
Intermediates of formula 2 and 3 are prepared via the process of Scheme XX, supra, as follows. Step a: Intermediate of formula 2: Formation of 2-(1,3-dihydroxypropan-2-yl)isoindoline- 1,3-dione To a mixture of Phthalic anhydride (9.0 g, 61.0 mmol) and 2-aminopropane-1,3-diol (Am-Diol1, 5.50 g, 61.0 mmol) was added anhydrous toluene (75 mL) and the resulting mixture was heated to reflux under a static nitrogen atmosphere. Within 30 minutes the white suspension becomes a clear solution, and the solution was continued heated at 115 oC for 24 h. After 24 h, the heat was removed gradually and around 83oC, a white precipitate formed and around 62 oC, MTBE (30 mL) was added with constant stirring for an additional 1h. Filtered the precipitate and washed with MTBE (10 mL) and air dried. The precipitate was grounded and stirred with an additional 30 mL of MTBE for 2h. Filtered the white precipitate and dried it under high vacuum afforded the titled compound (2, 12.30 g, 83%) as a white solid. HPLC RT: 2.65Min., 1H NMR (400 MHz, DMSO-d6% l 2)4, h 2).- $Z' /?%' /)32 $a' J = 6.0 Hz, 1H), 4.22 (tt, J = 8.7, 5.6 Hz, 1H), 3.78 (ddd, J = 11.0, 8.8, 5.4 Hz, 2H), 3.64 (dt, J = 11.4, 6.0 Hz, 2H), 3.33 (d, J = 9.1 Hz, 0H), 2.48 (p, J = 1.8 Hz, 0H). Ref: WO 2018/195098 Step b: Intermediate of formula - 4: Formation of N-(1,3-dihydroxypropan-2-yl)-2,2,2- trifluoroacetamide A mixture of 2-aminopropane-1,3-diol (Am-Diol1, 2.00 g, 22.0 mmol) and ethyl 2,2,2- trifluoroacetate (6.86 g, 48.3 mmol) in anhydrous THF (50 mL) was added and continued stirring at room temperature. After stirring 24 h, solid sodium bicarbonate (1.0 g) was added and continued the stirring for an additional 1h. Filtered followed by concentrated solvent using rotovap. Redissolve the crude product in DCM (100 mL) and wash with water (20 mL) and dried the organic portion with anhydrous sodium sulfate. Filtered followed by removal of solvent resulted colorless viscous semi-solid (3, 2.05 g, 50%) Ref: Keli Gu,b Lanrong Bi, Ming Zhao, Chao Wang,b Cheryl Dolan, Michael C. Kao, Jeffrey B.-H. Tokc, and Shiqi Peng and K. Gu et al. / Bioorg. Med. Chem.14 (2006) 1339–1347 Compound of Invention - 21a and 21b (Compounds-3 and 4):: Formation of N-(-2-(((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)methyl)-1,3- dioxan-5-yl)-2,2,2- trifluoroacetamide, and N-(-2-(((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)methyl)- 1,3-dioxan-5-yl)-2,2,2-trifluoroacetamide
Figure imgf000067_0001
To a stirred solution of 4-((2,2-dimethoxyethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (18a, 0.150 g, 0.436 mmol), N-(1,3-dihydroxypropan-2-yl)-2,2,2-trifluoroacetamide (3, 0.090 g, 0.480 mmol) in Toluene (10 mL) was added catalytic amount of 4-methylbenzenesulfonic acid (0.023 g, 0.43 mmol). After heating 6h at 90 C, the reaction mixture was cooled to room temperature and quenched with aqueous sodium bicarbonate solution. The product was extracted using DCM and washed the organic portion with water and brine. Removal of solvent resulted the crude product and purification on a silica gel prep TLC eluted with 30%EA/Hex afforded a mixture of cis and trans isomers. Rf: 0.28 and 0.31 (30% EA/Hex). The more polar band was extracted using DCM followed by removal of solvent afforded the titled product (Trans-isomer, 21a, 60 mg) as yellow color solid. Similarly, extraction of the product from less polar band results in the minor isomer (Cis-isomer, 21b, 20 mg, 10%,) as a pale yellow color solid. (Trans- isomer, 21a, 60 mg). TLC Rf: 0.28 (30% EA/Hex). HPLC RT: 6.753 min. MS-ESI (m/z): Calculated [M+H]+ = 468.1502; Observed [M+H]+ = 468.1574. (Cis-isomer, 21b, Pale yellow color solid): TLC Rf: 0.31 (30% EA/Hex). HPLC RT: 6.819 min. MS-ESI (m/z): Calculated [M+H]+ = 468.1502; Observed [M+H]+ = 468.1566.
Figure imgf000067_0002
Intermediates of formula 16a and 16b are prepared via the process of Scheme XXI, supra, as follows. Step a: Intermediates of formula - 15a and 15b: tert-butyl (2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)ethyl)-1,3dioxan-5-yl)carbamate To a stirred solution of (9H-Fluoren-9-yl)methyl (3-oxopropyl)carbamate (3.40 g, 11.5 mmol, following literature method (Crawford, Lee, and Rudolph; US 2014/0323477) in a mixture of toluene (35 mL) and chloroform (12 mL) was added tert-butyl (1,3-dihydroxypropan- 2yl)carbamate (2.64 g, 13.8 mmol), followed by addition of p-TsOH (198 mg, 1.15 mmol) and anhydrous sodium sulfate (16.4 g, 115 mmol) at room temperature. After stirring overnight, the suspension was then treated with anhydrous sodium carbonate until a pH of ~7 was reached. Stirring was halted, and the solids were filtered away. The precipitate was washed well with toluene and then with dichloromethane (20 mL). The solids were partitioned between ethyl acetate and water, and the aqueous phase was separated and re-extracted with ethyl acetate. The combined organic extracts were washed with water and brine and were dried over magnesium sulfate. Removal of solvent afforded (15a, 1.34 g, ~50%) as a bright white solid.1H-NMR (400 MHz, CDCl3) l 2)3+ h 2)2/ $Z' -?%' 2)1/ h 2)03 $Z' -?%' 2)/+ h 2)-4 $Z' /?%' 0)-, $`' -?%' /)0. (s, 1H),4.37 (d, J = 7.2 Hz, 2H), 4.28 – 4.13 (m, 3H), 3.81 (d, J = 11.8 Hz, 4H), 3.43 – 3.26 (m, 3H), 2.42 (s, 2H), 1.86 (d, J = 6.0 Hz, 1H), 1.45 (s, 24H). The filtrate and washings from the work-up above were combined and partitioned between water and dichloromethane. The aqueous phase was separated and re-extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to give yellow oil. Purification on a silica gel column chromatography with a gradient of 15% to 40% EtOAc/Hex, resulted the syn-isomer (15b, 1.3 g, 48%) as a colorless solid 1H NMR (400 MHz, CDCl3% l 2)22 $Q' J = 7.5 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.38 – 7.32 (m, 2H), 5.56 (d, J = 9.2 Hz, 1H), 5.09 (s, 1H), 4.40 (d, J = 7.0 Hz, 2H), 4.23 (t, J = 7.0 Hz, 1H), 4.03 – 3.84 (m, 5H), 3.59 (d, J = 9.2 Hz, 1H), 3.40 – 3.15 (m, 2H), 1.85 (d, J = 6.0 Hz, 2H), 1.46 (s, 9H). Step b: Intermediate of formula-16a: tert-butyl ((2r,5r)-2-(2-aminoethyl)-1,3-dioxan-5- yl)carbamate To a stirred cold suspension of tert-butyl ((2r,5r)-2-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)ethyl)-1,3dioxan-5-yl)carbamate (trans isomer, 0.92 g, 2.0 mmol) in acetonitrile (12 mL) was added Et2NH (2.3 g, 3.3 mL, 31 mmol). The suspension was warmed to room temperature and added DCM (15 mL) and the resulting clear colorless solution was stirred at room temperature for another 2 hours. The solvents were concentrated, and the crude product was suspended in ethyl acetate. Filtered followed by washed the solid with ether and upon drying at air to afford the desired trans isomer (16a, 180 mg, 38%) as a white powder. MS shows a {M+H} peak for 247.16.1H NMR (400 MHz, Methanol-d4% l /)12 $Q' J = 4.2 Hz, 1H), 4.10 (dd, J = 10.9, 5.0 Hz, 2H), 3.74 (s, 1H), 3.40 (t, J = 10.8 Hz, 2H), 3.07 (t, J = 6.5 Hz, 2H), 1.95 (q, J = 6.1 Hz, 2H), 1.42 (s, 9H). Step b: Intermediate of formula-16b: tert-butyl ((2s,5s)-2-(2-aminoethyl)-1,3-dioxan-5- yl)carbamate The cis isomer was synthesized in a similar manner using cis-isomer of tert-butyl ((2r,5r)-2-(2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-1,3-dioxan-5yl)carbamate (0.35 g, 0.75 mmol ) in dichloromethane (5 mL) with Et2NH (1.1 g, 1.6 mL, 15 mmol). Purification on a silica gel column chromatography, eluting with DCM/MeOH (4/1) followed by removal of solvent afforded the desired cis isomer (16b, 100 mg, 59%) as a brown color oil.1H-NMR (400 MHz, CDCl3) l 0)01 $Q' J = 8.7 Hz, 1H), 4.66 (td, J = 5.2, 1.4 Hz, 1H), 3.99 – 3.82 (m, 4H), 3.54 (d, J = 8.7 Hz, 1H), 2.82 (t, J = 6.7 Hz, 2H), 1.81 – 1.71 (m, 2H), 1.43 (d, J = 1.6 Hz, 9H).
Figure imgf000069_0001
Compound of Invention – 18a, 19a, 18b and 19b were prepared via the process of Scheme XXII, supra, as follows. Step a: Intermediate of formula-17a: tert-butyl ((2s,5s)-2-(2-((4-cyanophenyl)amino)ethyl)- 1,3-dioxan-5yl)carbamate (7-syn isomer) To a stirred solution of tert-butyl ((2s,5s)-2-(2-aminoethyl)-1,3-dioxan-5-yl)carbamate (Compound 16a; 0.10 g, 0.41 mmol) in DMSO (3 mL) were added 4-fluorobenzonitrile (0.059 g, 0.49 mmol) and DIEA (0.16 g, 0.21 mL, 1.2 mmol). The resulting solution was stirred at 110oC for 24 h. The reaction was cool to room temperature and quenched with water and extracted with DCM. The organic portion was washed successively with water, brine and dried over magnesium sulfate. Purification on a silica gel column chromatography, eluting with 50% EA/Hex afforded the desired compound (17a, 61 mg, 44%) as a clear colorless oil.1H-NMR (400 MHz, CDCl3) l 2)/2 h 2).4 $Z' -?%' 1)03 h 1)0, $Z' -?%' 0)/. $Q' J = 9.0 Hz, 1H), 4.76 – 4.62 (m, 2H), 3.99 (dd, J = 11.8, 1.6 Hz, 2H), 3.90 (d, J = 11.0 Hz, 2H), 3.59 (d, J = 9.1 Hz, 1H), 3.29 (d, J = 5.9 Hz, 2H), 1.96 (td, J = 6.4, 4.7 Hz, 2H), 1.45 (s, 9H). Step b: Compound of Invention – 18a (Compound-5): tert-butyl ((2s,5s)-2-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-1,3-dioxan-5yl)carbamate (syn isomer) To a stirred solution of tert-butyl ((2s,5s)-2-(2-((4-cyanophenyl)amino)ethyl)-1,3-dioxan-5- yl)carbamate (0.055 g, 0.16 mmol), and 4-methoxy-3-fluorobenzyl bromide (0.069 g, 0.32 mmol) in acetontirile (5 mL) was added DIEA (0.041 g, 0.055 mL, 0.31 mmol) at room temperature. The resulting solution was refluxed for 48 h. After 48 h, the solution concentrated and extracted the product using dichloromethane. The organic portion was washed successively with water, brine and dried over magnesium sulfate. Purification on a silica gel prep TLC, eluting with 50% EA/Hex afforded the title compound (18a, 47 mg, 61%) as a clear colorless gummy material. Step c: Compound of Invention – 19a (Compound-6): Step 3: 4-((2-((2s,5s)-5-amino-1,3- dioxan-2-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile To a cold stirred solution of tert-butyl ((2s,5s)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-1,3-dioxan-5-yl)carbamate (0.046 g, 0.095 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.11 g, 0.073 mL, 0.95 mmol) at 0oC under nitrogen atmosphere and stirred at room temperature for 6h. After stirring 6h at rt, the excess solvents were removed under vacuum. The desired product was isolated as a white solid after standing overnight in the freezer, washed the precipitate with cold ether followed by drying under high vacuum afforded the title compound (19a, 33 mg). HPLC RT:5.53 min. MS-ESI (m/z): Calculated [M+H]+= 386.1876; Observed [M+H]+ = 386.1914. Step a: Intermediate of formula-17b: tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)amino)ethyl)- 1,3-dioxan-5-yl)carbamate (7-anti isomer) The intermediate –17b: tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)amino)ethyl)-1,3-dioxan-5- yl)carbamate (7-anti isomer) was synthesized in an analogous manner to the intermediate 17a. The compound tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)amino)ethyl)-1,3-dioxan-5-yl)carbamate (17b, 27 mg) was obtained as a white solid
Figure imgf000071_0001
(400 MHz, CDCl3) l 2)/, $Q' J = 8.7 Hz, 2H), 6.54 (d, J = 8.7 Hz, 2H), 4.63 (s, 1H), 4.57 (t, J = 4.6 Hz, 1H), 4.22 (dd, J = 10.9, 5.0 Hz, 2H), 4.15 (s, 1H), 3.90 (s, 1H), 3.37 – 3.23 (m, 4H), 1.96 (td, J = 6.4, 4.6 Hz, 2H), 1.44 (s, 9H). Step b: Compound of Invention -18 (Compound-7): tert-butyl ((2r,5r)-2-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-1,3-dioxan-5-yl)carbamate (8-anti isomer) The intermediate –18b: tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-1,3-dioxan-5-yl)carbamate (8-anti) was synthesized in a similar manner to the intermediate 18b. Compound tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-1,3-dioxan-5-yl)carbamate (18b, 32 mg, 48%) was obtained as a white solid. Step c: Compound of Invention – 19b (Compound-8): 4-((2-((2r,5r)-5-amino-1,3-dioxan-2- yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention – 19b (Compound-8): 4-((2-((2r,5r)-5-amino-1,3-dioxan-2- yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile was synthesized in a similar manner to the intermediate 19a. Compound of Invention – 19b (4-((2-((2r,5r)-5-amino-1,3-dioxan-2- yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile was obtained as a brittle foam. HPLC RT=5.60 min. MS-ESI (m/z): Calculated [M+H]+ = 386.1876; Observed [M+H]+ = 386.1874.
Figure imgf000071_0002
Intermediate – 6 was prepared via the process of Scheme XXIII, supra, as follows. Step a: Intermediate of formula-3a: Formation of 4-((3-hydroxypropyl)amino)benzonitrile To a stirred solution of 4-fluorobenzonitrile (1, 4.00 g, 33.0 mmol) and 3-aminopropan-1-ol (2a, 2.48 g, 33.0 mmol) in anhydrous DMSO (25.0 mL) was added DIEA (10.30 mL, 7.61 g, 66.1 mmol) at room temperature and the resulting clear solution is heated to 110oC overnight. After heating 16 h, the reaction was cooled to room temperature and extracted the product using DCM. Washed the organic portion with aqueous citric acid solution, water, brine, and dried over anhydrous sodium sulfate. Filtered followed by removal of solvent resulted the titled product 4- ((3-hydroxypropyl)amino)benzonitrile (3, 5.76 g) as a pale yellow color solid. HPLC RT: 4.455 min., 1H-NMR (400 MHz, CDCl3% l 2).0 $QQQ' J = 9.7, 7.6, 5.8 Hz, 1H), 6.61 – 6.48 (m, 1H), 3.75 (qd, J = 8.2, 5.8 Hz, 1H), 3.71 – 3.56 (m, 1H), 3.33 – 3.08 (m, 3H), 1.96 – 1.83 (m, 1H). Step-b: Intermediate of formula-5a: Formation of 4-((3-fluoro-4-methoxybenzyl)(3- hydroxypropyl)amino)benzonitrile To a stirred solution of 4-((3-hydroxypropyl)amino)benzonitrile (3, 2.20 g, 12.50 mmol) and 4- (bromomethyl)-2-fluoro-1-methoxybenzene (4, 3.42 g, 15.60 mmol) in acetonitrile (20.0 mL) was added DIEA (4.85 mL, 3.60 g, 31.2 mmol) and the resulting clear solution was refluxed for 18 h. After 18 h, the solvents were removed and extracted using DCM. The organic portion was washed with aqueous citric acid solution, water, brine, and dried over anhydrous sodium sulfate. Filtered followed by removal of solvent gave the crude product as a viscous material. Purification on a silica gel column chromatography using a gradient of 15% EA/Hex to 30% EA/Hex followed by removal of solvent resulted the titled compound (5a, 2.90 g, 74%) as a pale yellow color viscous material. HPLC RT: 5.98 min. 1H-NMR (400 MHz, CDCl3) l 2)-. h 1)4/ (m, 2H), 6.62 (dt, J = 27.9, 9.1 Hz, 3H), 6.53 – 6.14 (m, 3H), 4.29 (d, J = 30.2 Hz, 2H), 3.78 – 3.46 (m, 4H), 3.46 – 3.09 (m, 4H), 2.30 (d, J = 29.7 Hz, 1H), 1.83 – 1.37 (m, 3H Step-c: Intermediate of formula-6a: Formation of 4-((3-fluoro-4-methoxybenzyl)(3- oxopropyl)amino)benzonitrile To a stirred solution of 4-((3-fluoro-4-methoxybenzyl)(4-hydroxybutyl)amino)benzonitrile (5a, 1.25 g, 0.76 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane reagent (1.855 g, 4.374 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium bicarbonate (10 mL) were added, and the mixture was stirred for 30 min. The reaction mixture was filtered through celite, and the phases separated. The organic layer was washed twice with brine and dried over anhydrous K2CO3. Filtered followed by removal of solvent resulted the tilted compound as a (6a, 1.250 g, >99%) as a pale brown color solid. TLC Rf: 0.27 (30% EA/Hex). HPLC RT: 6.161 min.; 1H-NMR (400 MHz, CDCl3) l 4)3/ $a' J = 0.9 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.02 – 6.79 (m, 3H), 6.66 – 6.50 (m, 2H), 5.29 (s, 1H), 4.55 (s, 2H), 3.86 (s, 3H), 3.80 (t, J = 6.7 Hz, 2H), 2.86 (td, J = 6.7, 0.9 Hz, 2H). Step a: Intermediate of formula-3b: Formation of 4-((4-hydroxybutyl)amino)benzonitrile The intermediate 3b was synthesized in an analogous manner to the intermediate – 3a. The intermediate 4-((4-hydroxybutyl)amino)benzonitrile (3b, 1.92 g, 98%) was obtained as a pale yellow color solid. HPLC RT: 4.825 min., 1H-NMR (400 MHz, CDCl3% l 2).4 h 2)-4 $Z' ,?%' 6.62 – 6.35 (m, 1H), 3.63 (t, J = 6.1 Hz, 1H), 3.13 (t, J = 6.8 Hz, 1H), 2.58 (s, 1H), 1.75 – 1.39 (m, 2H). Step b: Intermediate of formula-5b: Formation of 4-((3-fluoro-4-methoxybenzyl)(4- hydroxybutyl)amino)benzonitrile The intermediate 5b was synthesized in an analogous manner to the intermediate – 5a. The intermediate (5b) 4-((3-fluoro-4-methoxybenzyl)(4-hydroxybutyl)amino)benzonitrile (5b, 2.80 g, 90%) was obtained as a pale yellow color solid. TLC Rf: 0.13 (30% EA/Hex). HPLC RT: 6.192 min., 1H-NMR (400 MHz, CDCl3% l 2)/. h 2).- $Z' ,?%' 1)41 h 1)23 $Z' -?%' 1)11 h 1)00 (m, 1H), 4.49 (s, 1H), 3.82 (s, 1H), 3.65 (t, J = 6.3 Hz, 1H), 3.52 – 3.38 (m, 1H), 2.20 (s, 1H), 1.73 (tt, J = 8.2, 6.0 Hz, 1H), 1.64 – 1.48 (m, 1H). Step c: Intermediate of formula-6b: Formation of 4-((3-fluoro-4-methoxybenzyl)(4- oxobutyl)amino)benzonitrile The intermediate 6b was synthesized in an analogous manner to the intermediate – 6a. The intermediate (6b) 4-((3-fluoro-4-methoxybenzyl)(4-oxobutyl)amino)benzonitrile (6b, 250 mg, >99%) was obtained as a pale brown color solid. TLC Rf: 0.27 (30% EA/Hex). HPLC RT: 5.18 min., 1H-NMR (400 MHz, CDCl3%% l 4)21 $`' ,?%' 2)4. $QQ' J = 27.4, 7.8 Hz, 2H), 7.44 – 7.29 (m, 3H), 7.12 (td, J = 7.7, 6.8, 2.8 Hz, 1H), 6.95 – 6.75 (m, 4H), 6.74 – 6.61 (m, 2H), 6.59 (dd, J = 9.2, 2.6 Hz, 1H), 5.27 (s, 1H), 4.49 (s, 3H), 3.82 (s, 5H), 3.52 – 3.23 (m, 3H), 2.53 (t, J = 6.7 Hz, 2H), 2.01 – 1.79 (m, 2H).
Figure imgf000074_0001
Intermediate – 6c was prepared via the process of Scheme XXIV, supra, as follows Step-a: Intermediate of formula-3c: Formation of4-(((3-(hydroxymethyl)oxetan-3- yl)methyl)amino)benzonitrile The intermediate 3c was synthesized in an analogous manner to the intermediate – 3a. The intermediate compound (3c) 4-(((3-(hydroxymethyl)oxetan-3-yl)methyl)amino)benzonitrile (3c, 0.80 g, 85%) was obtained as a pale yellow color solid. TLC Rf: 0.21 in 50% EA/Hex. HPLC RT: 4.22 min. Step-b: Intermediate of formula-5c: Formation of 4-((3-fluoro-4-methoxybenzyl)((3- (hydroxymethyl)oxetan-3-yl)methyl)amino)benzonitrile The intermediate 5c was synthesized in an analogous manner to the intermediate – 5a. The intermediate 4-((3-fluoro-4-methoxybenzyl)((3-(hydroxymethyl)oxetan-3- yl)methyl)amino)benzonitrile (5c, 0.620 g, 48%) was obtained as a pale color foam. TLC Rf:12 in 50% EA/Hex. HPLC RT: 7.29 min.1H-NMR (400 MHz, CDCl3) l 3),/ h 3)+. $Z' +?%' 2).2 (dd, J = 9.4, 2.5 Hz, 2H), 7.07 – 6.98 (m, 2H), 6.93 (dd, J = 9.8, 6.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.80 – 6.65 (m, 2H), 4.66 (s, 2H), 4.53 (d, J = 6.4 Hz, 0H), 4.38 (s, 2H), 3.91 (d, J = 1.6 Hz, 3H), 3.84 (s, 3H), 3.66 (s, 3H), 3.52 (d, J = 5.7 Hz, 2H), 3.39 (d, J = 3.4 Hz, 2H), 3.09 (s, 1H), 1.93 (t, J = 5.3 Hz, 1H). Step-c: Intermediate of formula-6c: Formation of 4-((3-fluoro-4-methoxybenzyl)((3- formyloxetan-3-yl)methyl)amino)benzonitrile The intermediate 6c was synthesized in an analogous manner to the intermediate – 6a. The intermediate compound 4-((3-fluoro-4-methoxybenzyl)((3-formyloxetan-3- yl)methyl)amino)benzonitrile (6c, 0.180 g, 91%) was obtained as a pale brown color solid. TLC Rf: 0.34 in 30% EA/Hex and 0.51 in 50% EA/Hex.1H-NMR (400 MHz, CDCl3) l 4)31 $Q' J = 2.2 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.44 – 7.39 (m, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.93 (td, J = 8.2, 3.9 Hz, 2H), 6.85 – 6.80 (m, 1H), 6.76 – 6.65 (m, 1H), 6.61 – 6.55 (m, 1H), 4.57 (s, 1H), 4.36 (s, 1H), 4.30 (d, J = 4.1 Hz, 1H), 3.98 (s, 3H), 3.88 (s, 2H), 3.84 (d, J = 2.6 Hz, 2H), 3.65 (d, J = 2.7 Hz, 1H), 3.56 (s, 1H), 3.35 (q, J = 9.3 Hz, 2H).
Figure imgf000075_0001
Compounds of invention of formula (15 and 16) were synthesized via the process of Scheme XXV, supra, as follows Step a: Compound of Invention of formula-15 (Compound-9): Formation of trans 4-((3- ((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)propyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-((3-fluoro-4-methoxybenzyl)(4-oxobutyl)amino)benzonitrile (5, 1.40 g, 4.29 mmol), 2-(1,3-dihydroxypropan-2- yl)isoindoline-1,3-dione (3, 0.949 g, 4.29 mmol) in toluene (50 mL) was added catalytic amount of 4-methylbenzenesulfonic acid (0.074 mg, 0.429 mmol). After heating 6h at 90 C, the reaction mixture was cooled to room temperature and quenched with aqueous sodium bicarbonate solution. The product is extracted using DCM and washed the organic portion with water and brine. Removal of solvent gave the crude product which was dissolved in DCM and triturated with minimum amount of methanol. The desired product of trans 4-((3-((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)propyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile crashed out (15, 1.727 g, 77%) as a pale yellow color solid. TLC Rf: 0.36 (30% EA/Hex). HPLC RT: 7.54 min. Step b: Compound of Invention of formula-16 (Compound-10): Formation of 4-((3-((2r,5r)- 5-amino-1,3-dioxan-2-yl)propyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile To a stirred solution of compound (15, 0.580 g, 1.10 mmol) in ethyl acetate (25 mL) was added 2-aminoethan-1-ol (2.00 mL, 2.01 g, 32.90 mmol, 30 equ.) at room temperature under nitrogen atmosphere. The resulting mixture was refluxed for 3h and stirred at rt overnight. The excess solvent was removed, and the resulting crude product was purified on a silica gel column chromatography using 50%EA/Hex as an eluent. Removal of solvent afforded the titled product 4-((3-((2r,5r)-5-amino-1,3-dioxan-2-yl)propyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (16, 0.200 g, 31%) as a white solid. HPLC RT: 5.482 min..
Figure imgf000076_0001
Compounds of invention of formula (17 and 18) were synthesized via the process of Scheme XXVI, supra, as follows Step a: Compound of Invention of formula-17 (Compound-11): Formation of 4-(((3- ((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3- dioxan-2-yl)oxetan-3-yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-((3-fluoro-4-methoxybenzyl)((3-formyloxetan-3- yl)methyl)amino)benzonitrile (6c, 0.180 g, 0.508 mmol), 2-(1,3-dihydroxypropan-2- yl)isoindoline-1,3-dione (3, 0.140 g, 0.635 mmol) in Chloroform/Toluene (1:1, 10 mL) was added a catalytic amount of p-TsOH (0.018 g, 0.107 mmol). After heating 6h at 70oC, the reaction mixture was cooled to room temperature and quenched with aqueous sodium bicarbonate solution. The product is extracted using DCM and washed the organic portion with water and brine and concentrated. Purification on a silica gel column chromatography using a gradient of 20%EA/Hex to 60%EA/Hex as an eluent followed by removal of solvent afforded the titled compound 4-(((3-((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3- dioxan-2-yl)oxetan-3- yl)methyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (17, 0.100 g, 35%) as a colorless foam. Step b: Compound of Invention of formula-18 (Compound-12): Formation of 4-(((1- ((2r,5r)-5-amino-1,3-dioxan-2-yl)cyclobutyl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of compound 4-(((3-((2r,5r)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2- yl)oxetan-3-yl)methyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (17, 0.100 g, 0.179 mmol) in Ethyl acetate (5 mL) was added 2-aminoethanol (329 mg, 5.38 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was refluxed for 6 h and stirred rt for an additional 2h. The excess solvent was removed extracted the product using DCM. Washed the organic portion with water, brine and dried it over anhydrous sodium sulfate. Filter followed by removal of solvent resulted in the crude product. Purification on a prep silica gel TLC plate using 6% 7N Ammonia in methanol in DCM. The product was extracted using DCM/MeOH followed by removal of solvent afforded the titled product 4-(((1-((2r,5r)-5-amino-1,3-dioxan-2- yl)cyclobutyl)methyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (18, 15 mg, 20%) as a white color foam. HPLC RT: 6.09 min. MS-ESI (m/z): Calculated [M+Na]+ = 451.1833; Observed [M+Na]+ = 451.2044.
Figure imgf000077_0001
Compounds of invention of formula (22a, 22a, 23a, 23b, 24a, 24b, 25a and 25b) were synthesized via the process of Scheme XXVII, supra, as follows Step-a: Intermediate of formula-19: Formation of benzyl (2-((2r,5r)-5-((tert- butoxycarbonyl)amino)-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)carbamate To a stirred clear solution of tert-butyl (1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamate (18, 2.00 g, 9.00 mmol), benzyl (3-oxopropyl)carbamate (17, 2.00 g, 9.50 mmol) in DCM (20 mL) was added catalytic amount of p-TsOH (0.160 g,0.90 mmol) at room temperature under nitrogen atmosphere for three days and refluxed for 6h. Cool the reaction to room temperature and quenched with aqueous sodium bicarbonate solution. The product was extracted using DCM and washed the organic portion with water and brine. Removal of solvent followed by purification on a silica gel column chromatography using a gradient of 20%EA/Hex to 50%EA/Hex as an eluent afforded the titled compound benzyl (2-((2r,5r)-5-((tert- butoxycarbonyl)amino)-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)carbamate (19, 3.60 g, 97%) as a colorless solid as mixture of its diastereomers. TLC Rf: 0.38 and 0.56 in 4%MeOH in DCM. 1H-NMR (400 MHz, CDCl3% l 2)00 h 2)-4 $Z' 0?%' 0)/, $a' J = 21.0 Hz, 0H), 5.27 – 5.12 (m, 1H), 5.08 (d, J = 4.2 Hz,1H), 4.78 – 4.62 (m, 1H), 4.62 (dt, J = 9.7, 4.0 Hz, 1H), 4.57 (t, J = 4.9 Hz, 0H), 4.17 – 3.86 (m, 3H), 3.69 – 3.48 (m, 2H), 3.37 (ddq, J = 23.7, 11.9, 6.1 Hz, 2H), 1.88 (ddq, J = 24.7, 19.2, 5.9 Hz, 2H), 1.55 – 1.45 (m, 3H), 1.44 (d, J = 2.9 Hz, 3H), 1.41 (s, 2H). Step-b: Intermediate of formula-20: Formation of tert-butyl ((2r,5r)-2-(2-aminoethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate To a solution of compound benzyl (2-((2r,5r)-5-((tert-butoxycarbonyl)amino)-5- (hydroxymethyl)-1,3-dioxan-2-yl)ethyl)carbamate (19, 2.40 g, 5.85 mmol) in MeOH/EtOAc (2:1, 20 mL: 10 mL) was added 10%Pd-C (173 mg, 1.46 mmol, 0.25 equ.). The resulting mixture was degassed under a water aspirator vacuum and purged with hydrogen. The process was repeated three times and stirred under a static pressure of hydrogen at 45 psi for 24 h at rt. Filtered through a pad of celite and washed with methanol. Combined the organic portions and concentration resulted the titled compound tert-butyl ((2r,5r)-2-(2-aminoethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate (20, 1.55 g, 96%) as a colorless solid. 1H-NMR (400 MHz, CDCl3% l 0)0. $`' ,?%' 0),2 $`' ,?%' /)1. $Q' J = 4.4 Hz, 1H), 4.56 (t, J = 4.9 Hz, 1H), 4.12 – 3.88 (m, 10H), 3.79 (s, 2H), 3.56 (t, J = 5.8 Hz, 4H), 2.91 – 2.74 (m, 3H), 1.78 (q, J = 6.0 Hz, 3H), 1.39 (s, 9H), 1.34 (s, 8H). Step-c: Intermediate of formula-21a: Formation of tert-butyl ((2r,5r)-2-(2-((4- cyanophenyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate To a stirred solution of tert-butyl ((2r,5r)-2-(2-aminoethyl)-5-(hydroxymethyl)-1,3-dioxan-5- yl)carbamate (20, 0.760 g, 2.80 mmol) in DMSO (10 mL) was added 4-fluorobenzonitrile (330 mg, 2.80 mmol) followed by DIEA (1.40 mL, 1.10 g, 8.30mmol) at room temperature under nitrogen atmosphere. After heating 18 h 110oC, the reaction was cooled to room temperature and quenched with water. The product was extracted using ethyl acetate and washed wither water and brine. The organic portion was dried over anhydrous sodium sulfate, filtered followed by removal of solvent gave the crude product. Purification on a glass silica gel prep TLC plate using 60%EA/Hex followed by removal of solvent afforded the titled compound (21a) tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate (21a, 580 mg, 56%) as a colorless foam. 1H-NMR (400 MHz, CDCl3% l 2)0, h 2).0 $Z' -?%' 1)04 h 6.33 (m, 2H), 5.38 (s, 1H), 4.67 (p, J = 5.0 Hz, 2H), 4.09 (dd, J = 19.9, 11.3 Hz, 2H), 3.99 (s, 1H), 3.81 (d, J = 10.9 Hz, 1H), 3.63 (d, J = 3.5 Hz, 2H), 3.29 (dq, J = 12.0, 6.1 Hz, 2H), 2.01 (td, J = 6.5, 4.6 Hz, 1H), 1.95 (dd, J = 6.5, 4.6 Hz, 1H), 1.46 (d, J = 3.9 Hz, 1H), 1.43 (s, 5H), 1.42 (s, 6H). Step d: Compound of Invention of formula-22a (Compound-13) and 23a (Compound-14): Formation of tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate and tertbutyl ((2s,5s)-2-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5- (hydroxymethyl)- 1,3-dioxan-5-yl)carbamate To a stirred solution of compound tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)amino)ethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate (21a, 0.270 g, 0.715 mmol) in acetonitrile (15 mL) was added 4-(bromomethyl)-2-fluoro-1-methoxybenzene (0.313 g, 1.430 mmol) followed by DIEA (0.462 g, 0.623 mL, 1.34 mmol) at room temperature under nitrogen atmosphere. After refluxing 48h, the excess solvent was removed under vacuum and the crude product was extracted using DCM. The organic portion was washed with aqueous citric acid solution, water, brine, and dried over anhydrous sodium sulfate. Filter followed by removal of solvent resulted in the crude product. TLC Rf: 0.21 in 50% EA/Hex. Purification of the crude product on a silica gel preparatory glass TLC plate using 50%EA/Hex as an eluent resulted two products. Removal of solvent from the bottom band followed by drying under high vacuum afforded the titled compound (22a, Trans-isomer) tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate (22a, 140 mg, 38%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 516.2465; Observed [M+H]+ = 516.2518. Similarly, removal of solvent from the top band followed by drying under high vacuum afforded the titled compound (22b, Cis-isomer) tert-butyl ((2s,5s)-2-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5- yl)carbamate (22b, 100 mg, 27%) as a viscous oily material. MS-ESI (m/z): Calculated [M+H]+ = 516.2465; Observed [M+H]+ = 516.2524. Step e: Compound of Invention of formula-24a (Compound-15): Trans Isomer Formation of 4-((2-((2r,5r)-5-amino-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of compound tert-butyl ((2r,5r)-2-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate (22a, 0.080 g, 0.16 mmol) in DCM (5 mL) was added TFA (0.24 mL, 0.35 g, 3.10 mmol) at rt under nitrogen atmosphere. After stirring 4 h at rt, the solvents were removed, and the resulting crude product was purified on a silica gel prep TLC using 6% 7M Ammonia in MeOH in DCM. Isolation of the product followed by removal of solvent under high vacuum afforded the titled compound (24a) Trans-Isomer4-((2-((2r,5r)-5-amino-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile (24a, 0.050 g, 78%) as a colorless foam. HPLC RT: 5.251 min.; MS-ESI (m/z): Calculated [M+H]+ = 416.1941; Observed [M+H]+ = 416.2032. Step e: Compound of Invention of formula-25a (Compound-16): Cis Isomer Formation of 4-((2-((2r,5r)-5-amino-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile Compound of Invention of formula-25a was synthesized in an analogous manner to the intermediate – 24a. The Compound of Invention of formula-25a Cis-Isomer 4-((2-((2s,5s)-5- amino-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (25a, 0.045 g, 60%) was obtained as a colorless foam. HPLC RT: 5.305 min.; MS-ESI (m/z): Calculated [M+H]+ = 416.1941; Observed [M+H]+ = 416.2049. Step-c: Intermediate of formula-21b: Formation of tert-butyl ((2r,5r)-2-(2-((6- cyanopyridin-3-yl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate The intermediate 21b was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (21b) tert-butyl ((2r,5r)-2-(2-((6-cyanopyridin-3-yl)amino)ethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate (21b, 780 mg, 81%) was obtained as a pale brown color foam. 1H-NMR (400 MHz, CDCl3% l 3)+, $QQ' J = 5.3, 2.9 Hz, 1H), 7.45 (dd, J = 8.6, 5.8 Hz, 1H), 6.79 (ddd, J = 8.7, 5.9, 2.8 Hz, 1H), 4.92 (dt, J = 17.9, 5.2 Hz, 1H), 4.70 (dt, J = 6.8, 4.4 Hz, 1H), 4.18 – 4.04 (m, 2H), 3.97 (s, 1H), 3.83 (d, J = 11.2 Hz, 1H), 3.67 – 3.58 (m, 2H), 3.32 (dq, J = 11.8, 6.0 Hz, 2H), 2.04 (td, J = 6.4, 4.4 Hz, 1H), 1.98 (td, J = 6.3, 4.3 Hz, 1H), 1.71 (s, 1H), 1.42 (d, J = 5.4 Hz, 9H). Step d: Compound of Invention of formula-22b (Compound-17) and 23b (Compound-18): Formation of tert-butyl ((2r,5r)-2-(2-((6-cyanopyridin-3-yl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate and tert-butyl ((2s,5s)-2-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate, Compound of Invention of formula-22b and 23b was synthesized in an analogous manner to the Compound of Invention of formula – 22a and 23a. Compound of Invention of formula-22b tert- butyl ((2r,5r)-2-(2- ((6-cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5- (hydroxymethyl)-1,3-dioxan-5-yl)carbamate tTrans-Isomer, 22b, 140 mg, 35%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 516.2465; Observed [M+H]+ = 51.2564. Compound of Invention of formula-23b tert-butyl ((2s,5s)-2-(2-((6-cyanopyridin-3-yl)(3-fluoro- 4-methoxybenzyl)amino)ethyl)-5-(hydroxymethyl)-1,3-dioxan-5-yl)carbamate (Cis-Isomer, 23b, 110 mg, 28%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 516.2465; Observed [M+H]+ = 516.2524. Step e: Compound of Invention of formula-24b (Compound-19): Formation of trans isomer, 5-((2-((2r,5r)-5-amino-5-(hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-24b was synthesized in a similar manner to the compound of Invention of formula-– 24a. Compound of Invention of formula-(24b) 5-((2-((2r,5r)-5-amino-5- (hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile (24b,trans-isomer, 0.040 g, 83%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 417.1893; Observed [M+H]+ = 417.1975. Step e: Compound of Invention of formula-25b (Compound-20): Formation of cis isomer, 5-((2-((2s,5s)-5-amino-5- (hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-25b was synthesized in a similar manner to the compound of Invention of formula-– 25a. Compound of Invention of formula-(25b) 5-((2-((2s,5s)-5-amino-5- (hydroxymethyl)-1,3-dioxan-2-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile (25b, 0.040 g, 83%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 417.1893; Observed [M+H]+ = 417.2003.
Figure imgf000082_0001
Compounds of invention of formula (29a, 30a and 31a) were synthesized via the process of Scheme XXIII, supra, as follows. Step-a: Intermediate of formula-26: Formation of Trans-2-((2r,5r)-2-vinyl-1,3-dioxan-5- yl)isoindoline-1,3-dione To a stirred solution of 2-(1,3-dihydroxypropan-2-yl)isoindoline-1,3-dione (3, 2.00 g, 9.04 mmol) and acrolein dimethyl acetal (AA, 2.77 g, 27.1 mmol, 3.0 eq.) in DCM (75 mL) was added p-toluene sulfonic acid monohydrate (156 mg, 0.904 mmol) at room temperature under nitrogen atmosphere. The resulting suspension was stirred at room temperature for 2h and quenched with water. The crude product was extracted using DCM and washed the organic portion with aqueous NaHCO3 Solution, water, and brine. Filter and removal of solvent gave the crude product as an oily material. It was redissolved in DCM (~3 mL) and triturated with hexane; the product precipitated. Filtered followed by washed with hexane gave the desired product as a white solid (26, 2.10 g, 81%).1H-NMR (400 MHz, CDCl3% l 2)4+ h 2)3+ $Z' ,?%' 7.74 (dd, J = 5.5, 3.0 Hz, 1H), 5.96 – 5.82 (m, 1H), 5.53 (dq, J = 17.5, 1.2 Hz, 1H), 5.35 (dt, J = 10.7, 1.2 Hz, 1H), 5.09 (dd, J = 4.6, 1.2 Hz, 1H), 4.66 (tdd, J = 9.8, 5.0, 1.5 Hz, 0H), 4.50 (ddd, J = 2.1, 10.4, 1.7 Hz, 1H), 4.08 (ddd, J = 10.8, 4.8, 1.2 Hz, 1H). HPLC RT: 5.962 Min., 90% Pure Step-b: Intermediate of formula-27: Formation of Trans-2-((2r,5S)-2-((S)-oxiran-2-yl)-1,3- dioxan-5-yl)isoindoline-1,3-dione To a stirred mixture of 2-(1,3-dihydroxypropan-2-yl)isoindoline-1,3-dione (26, 2.50 g, 1.62 mmol) in DCM (50.0 mL) was added m-CPBA (4.75 g, 70%, 19.3 mmol) at room temperature under nitrogen atmosphere. The resulting suspension was stirred at room temperature over the weekend (92h). The reaction was diluted with DCM and quenched with 1M NaOH solution (25 mL). The product was isolated in DCM, washed the organic portion with brine and dried over anhy sodium sulfate. Filtered followed by removal of solvent yield the product as a white solid (27, 2.400 g, 90%). HPLC RT: 5.317 min.1H-NMR (400 MHz, CDCl3) l 2)3/ $QQQ' J = 5.5, 3.2, 0.5 Hz, 1H), 7.74 (ddd, J = 5.7, 3.0, 0.5 Hz, 1H), 4.79 – 4.58 (m, 1H), 4.45 (td, J = 10.9, 7.2 Hz, 1H), 4.14 – 3.98 (m, 1H), 3.15 (td, J = 3.9, 2.6 Hz, 1H), 2.93 – 2.71 (m, 1H). Ref: WO 2018/195098 Step-c: Intermediate of formula-28a: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)benzonitrile To a stirred solution of 2-((2r,5S)-2-((S)-oxiran-2-yl)-1,3-dioxan-5-yl)isoindoline-1,3-dione (27, 0.700 g, 2.54 mmol) in acetonitrile (10 mL) was added DIEA (1.33 mL, 0.986 g,4.68 mmol) followed by addition of 4-aminobenzonitrile (1a, 0.600 g, 5.09 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated to reflux for 24 h and removed the volatiles. The resulting crude product was dissolved in DCM and washed with aqueous solution of NaHCO3 solution, water, and brine. Purification on a silica gel column chromatography with a gradient of Hex to 40%EA/Hex followed by removal of solvent afforded the titled compound (28a, 0.300 g) as a white color foam. TLC rf: 0.24 (40%EA/Hex). HPLC RT: 5.869 min.; 1H- NMR (400 MHz, CDCl3) l 2)30 $QQ' J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.0 Hz, 2H), 7.49 – 7.38 (m, 2H), 6.73 – 6.43 (m, 2H), 4.71 (d, J = 5.0 Hz, 1H), 4.46 (q, J = 11.2 Hz, 2H), 4.17 – 4.05 (m, 2H), 3.88 (dq, J = 8.6, 4.4 Hz, 1H), 3.48 (d, J = 13.3 Hz, 1H), 3.36 – 3.22 (m, 1H), 2.36 (d, J = 4.6 Hz, 1H). Step-c: Intermediate of formula-28a: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)benzonitrile To a stirred solution of 2-((2r,5S)-2-((S)-oxiran-2-yl)-1,3-dioxan-5-yl)isoindoline-1,3-dione (27, 0.400 g, 1.45 mmol) was added 5M LiClO4 in Et2O (5 mL, 1.55 g, 14.5 mmol) followed by addition of 4-aminobenzonitrile (1a, 172 mg, 1.45 mmol) at room temperature under nitrogen atmosphere and stirred 4 h. Purification on a silica gel column chromatography with a gradient of Hex to 40%EA/Hex followed by removal of solvent afforded the titled compound (28a, 150 mg) as a white color foam. HPLC RT: 5.883 min.; 1H-NMR (400 MHz, CDCl3) l 2)3. $aQ' J = 5.2, 2.1 Hz, 3H), 7.73 (ddd, J = 8.5, 5.5, 3.1 Hz, 2H), 7.49 – 7.38 (m, 2H), 6.71 – 6.48 (m, 2H), 4.70 (d, J = 4.9 Hz, 1H), 4.63 – 4.54 (m, 1H), 4.44 (q, J = 10.9 Hz, 2H), 4.16 – 4.00 (m, 2H), 3.92 – 3.78 (m, 1H), 3.48 (d, J = 3.9 Hz, 0H), 3.32 – 3.20 (m, 3H). Step d: Compound of Invention of formula-29a (Example-21): Formation of 4-(((S)-2- ((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)amino)benzonitrile (28a, 0.280 g, 0.712 mmol) and compound 4-(bromomethyl)-2- fluoro-1-methoxybenzene (4a, 0.187 gm, 0.854 mmol) in acetonitrile (10 mL) was added DIEA (0.33 mL, 0.246 g, 2.14 mmol) at room temperature under nitrogen atmosphere. The resulting solution was refluxed for 72h. Cool the reaction mixture, quench the reaction with water, and extract the product using DCM. The organic portion was washed with citric acid solution, water, and brine. Filtered followed by removal of solvent resulted in the crude product. Purification on a silica gel column chromatography with a gradient of 10%EA/Hex to 50%EA/Hex followed by removal of solvent afforded the titled compound (29a, 310 mg, 67%) as a pale yellow color foam. TLC Rf: 0.45 in 50% EA/Hex and 0.13 in 30% EA/Hex. HPLC RT: 6.834 min.; MS-ESI (m/z): Calculated [M+H]+ = 532.1839; Observed [M+H]+ = 532.1912. Step e: Compound of Invention of formula- 30a (Compound-22) and 31a (Compound-23): Formation of 4-((2-((2r,5R)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile and 4-((2-((2r,5S)-5-amino-1,3-dioxan-2-yl)-2- hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile To a stirred solution of compound 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2- yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile (29a, 0.130 g, 0.15 mmol) in Ethyl acetate (10 mL) was added 2-aminoethan-1-ol (0.32 mL, 0.448 g, 4.5 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was refluxed for 4h and removed the solvent. The crude product was extracted using DCM and washed with water, brine, and dried over anhydrous sodium sulfate. Filtered followed by removal of solvent resulted in the crude product. TLC Rf: 0.33 and 0.39 in 6%7N ammonia in methanol in DCM. Purification on a silica gel prep TLC plate eluting with 6%7N ammonia in methanol in DCM, two bands were isolated. Removal of solvent from the upper band fraction resulted the titled compound (30a, 50 mg, 47%) as a colorless foam and removal of solvent from the lower band fraction resulted the titled compound (31a, 30 mg, 28%) as a white color foam. The stereochemistry of both compounds is tentatively assigned. Compound 30a, (Compound-22) HPLC RT: 5.060 min.; MS-ESI (m/z): Calculated [M+H]+ = 402.1784; Observed [M+H]+ = 402.1919. Compound 31a, (Compound-23) HPLC RT: 5.076 min.; MS-ESI (m/z): Calculated [M+H]+ = 402.1784; Observed [M+H]+ = 402.1911.
Figure imgf000085_0001
Compounds of invention of formula (29b-d, 30b-d, 32 and 33) were synthesized via the process of Scheme XXIV, supra, as follows Step b: Compound of Invention of formula-29b (Compound-24): Formation of 4-((4- chloro-3-fluorobenzyl)((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)amino)benzonitrile Compound of Invention of formula-29b was synthesized in a similar manner to the compound of Invention of formula-– 29a. Compound of Invention of formula-(29b) 4-(((S)-2-((2r,5S)-5-(1,3- dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3- fluoro-4- (methylsulfonyl)benzyl)amino)-2-fluorobenzonitrile (29b, 130 mg, 48%) was obtained as a pale yellow color foam. TLC Rf:0.45 in 50% EA/Hex and 0.13 in 30% EA/Hex. HPLC RT: 7.221 min. MS-ESI (m/z): Calculated [M+H]+ = 536.1344; Observed [M+H]+ = 536.1432. Step c: Compound of Invention of formula- 30b (Compound-25): Formation of 4-(((S)-2- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(4-chloro-3- fluorobenzyl)amino)benzonitrile Compound of Invention of formula-30b was synthesized in a similar manner to the compound of Invention of formula-– 30a. Compound of Invention of formula-(30b) 4-(((S)-2-((2r,5S)-5- amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(4-chloro-3-fluorobenzyl)amino)benzonitrile (30b, 15 mg, 47%) as a white color foam. TLC Rf: 0.33 in 6% 7N Ammonia in methanol in DCM. HPLC RT: 5.298 min.; MS-ESI (m/z): Calculated [M+H]+ = 406.1289; Observed [M+H]+ = 406.1329. Step-a: Intermediate of formula-28c: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile The intermediate 28c was synthesized in an analogous manner to the intermediate – 28a. The intermediate compound (28c) (((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)amino)-2-fluorobenzonitrile (28c, 430 mg, 52%) was obtained as a pale brown color foam. TLC rf: 0.24 (50%EA/Hex). HPLC RT: 6.084 min.; 1H-NMR (400 MHz, CD3E;% l 7.76 (ddd, J = 32.6, 5.9, 3.2 Hz, 4H), 7.49 (t, J = 11.2 Hz, 0H), 7.36 – 7.13 (m, 1H), 6.44 – 6.24 (m, 2H), 4.71 – 4.49 (m, 1H), 4.39 (q, J = 10.4 Hz, 1H), 4.05 (t, J = 6.8 Hz, 2H), 3.73 (d, J = 18.4 Hz, 8H), 3.51 – 3.01 (m, 2H).1H-NMR (400 MHz, CDCl3) l 2)30 $QQ' J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.5, 3.0 Hz, 2H), 7.33 (dd, J = 8.6, 7.4 Hz, 1H), 6.48 – 6.28 (m, 2H), 4.84 (s, 1H), 4.70 (d, J = 5.0 Hz, 1H), 4.64 (dq, J = 10.8, 5.4, 4.9 Hz, 1H), 4.52 – 4.37 (m, 2H), 4.11 (qt, J = 6.9, 3.7 Hz, 2H), 3.88 (d, J = 10.6 Hz, 1H), 3.45 (ddd, J = 13.2, 6.5, 3.9 Hz, 1H), 3.35 – 3.22 (m, 1H), 2.42 (s, 1H), 1.59 (s, 2H), 1.41 – 1.11 (m, 1H), 0.91 (q, J = 7.8, 7.0 Hz, 1H). Step-a: Intermediate of formula-28c: Formation of 4-(((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin- 2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile Alternatively, the intermediate 28c was synthesized in an analogous manner to the intermediate – 28a. The intermediate compound (28c) (((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3- dioxan-2-yl)-2-hydroxyethyl)amino)-2-fluorobenzonitrile (28c, 1.30 g, 58%) was obtained as a pale brown color solid.
Figure imgf000086_0001
(400 MHz, CDCl3) l 2)3, $QQ' J = 5.5, 3.1 Hz, 2H), 7.73 (ddd, J = 8.6, 5.3, 3.1 Hz, 2H), 7.33 – 7.21 (m, 2H), 6.45 – 6.23 (m, 2H), 4.65 (d, J = 4.7 Hz, 1H), 4.58 (dq, J = 10.6, 5.4, 4.9 Hz, 1H), 4.40 (q, J = 10.8 Hz, 2H), 4.14 – 3.96 (m, 2H), 3.79 (dt, J = 8.3, 4.2 Hz, 1H), 3.40 (dd, J = 13.4, 3.8 Hz, 1H), 3.22 (dd, J = 13.4, 7.4 Hz, 1H), 2.65 (s, 3H). Step b: Compound of Invention of formula-29c (Compound-26): Formation of 4-(((S)-2- ((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4- methoxybenzyl)amino)-2-fluorobenzonitrile Compound of Invention of formula-29c was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(29c) 4-(((S)-2-((2r,5S)-5-(1,3- dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile (29c, 60 mg, 19%) was obtained as a pale yellow color foam. TLC Rf:0.45 in 50% EA/Hex and 0.13 in 30% EA/Hex. HPLC RT: 6.962 min.; MS-ESI (m/z): Calculated [M+H]+ = 550.1745; Observed [M+H]+ = 550.1782. Step c: Compound of Invention of formula- 30c (Compound-27): Formation of 4-(((S)-2- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile Compound of Invention of formula-30c was synthesized in a similar manner to the compound of Invention of formula -30a. Compound of Invention of formula-(30c) 4-(((S)-2-((2r,5S)-5-amino- 1,3-dioxan-2-yl)-2-hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile (30c, 20 mg, 47%) was obtained as a white color foam. TLC Rf: 0.336% 7N Ammonia in methanol in DCM. HPLC RT: 5.146 min. MS-ESI (m/z): Calculated [M+H]+ = 420.1690; Observed [M+H]+ = 420.1732. Step-a: Intermediate of formula-28d: Formation of 2-((2r,5S)-2-((S)-1-hydroxy-2-((4- (methylsulfonyl)phenyl)amino)ethyl)-1,3-dioxan-5-yl)isoindoline-1,3- The intermediate 28d was synthesized in an analogous manner to the intermediate – 28a. The intermediate compound (28d) 2-((2r,5S)-2-((S)-1-hydroxy-2-((4- (methylsulfonyl)phenyl)amino)ethyl)-1,3-dioxan-5-yl)isoindoline-1,3-dione (28d, 0.630 g, 0.630 g, 78%) was obtained as a pale yellow color solid. HPLC RT: 5.338min.; 1H-NMR (400 MHz, CDCl3) l 2)3/ $QQ' J = 5.4, 3.1 Hz, 1H), 7.75 (dd, J = 5.5, 3.0 Hz, 1H), 7.72 – 7.67 (m, 1H), 6.69 (d, J = 1.7 Hz, 1H), 4.72 (d, J = 4.9 Hz, 0H), 4.64 (dq, J = 11.0, 5.4, 4.8 Hz, 0H), 4.49 – 4.35 (m, 1H), 4.17 – 4.06 (m, 2H), 3.89 (d, J = 7.0 Hz, 1H), 3.50 (dd, J = 13.1, 3.8 Hz, 0H), 3.37 – 3.28 (m, 1H), 3.00 (s, 2H), 2.50 (d, J = 4.6 Hz, 1H). Step b: Compound of Invention of formula- 29d (Compound-28): Formation of 2-((2r,5S)- 2-((S)-2-((3-fluoro-4-methoxybenzyl)(4-(methylsulfonyl)phenyl)amino)-1-hydroxyethyl)- 1,3-dioxan-5-yl)isoindoline-1,3-dione Compound of Invention of formula-29d was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(29d) 2-((2r,5S)-2-((S)-2-((3- fluoro-4-methoxybenzyl)(4- (methylsulfonyl)phenyl)amino)-1-hydroxyethyl)-1,3-dioxan-5- yl)isoindoline-1,3-dione (29d, 220 mg, 60%) was obtained as a white color foam. TLC Rf:0.45 in 50% EA/Hex and 0.13 in 30% EA/Hex. HPLC RT: 5.802 min.; MS-ESI (m/z): Calculated [M+H]+ = 585.1662; Observed [M+H]+ = 585.1701. Step c: Compound of Invention of formula- 30d (Compound-29): Formation of (S)-1- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-((3-fluoro-4-methoxybenzyl)(4- (methylsulfonyl)phenyl)amino)ethan-1-ol Compound of Invention of formula-30d was synthesized in a similar manner to the compound of Invention of formula—30a. Compound of Invention of formula-(30d) (S)-1-((2r,5S)-5-amino- 1,3-dioxan-2-yl)-2-((3-fluoro-4-methoxybenzyl)(4-(methylsulfonyl)phenyl)amino)ethan-1-ol (30d , 70 mg, 90%) was obtained as a white color foam. TLC Rf: 0.0.42 in 10% 7N Ammonia in methanol in DCM. HPLC RT: 4.66 min. MS-ESI (m/z): Calculated [M+H]+ = 455.1607; Observed [M+H]+ = 455.1969. Step-d: Compound of Invention of formula- 32 (Compound-30): Formation of Racemic 4- (((S)-2-((2r,5S)-5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of a racemic 4-(((S)-2-(5-(1,3-dioxoisoindolin-2-yl)-1,3-dioxan-2-yl)-2- hydroxyethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (29a, 0.165 g, 0.31 mmol) in DCM (10 mL) was cool to 0oC and DAST (0.090 mL, 0.110 g, 0.682 mmol) was added under nitrogen atmosphere. After stirring 3h at 0oC, the resulting solution is quenched with aq. NaHCO3 solution, and the product is extracted using DCM. Washed the organic portions with water and brine. Purification on a silica gel column chromatography with a gradient of Hex to 30% EA/Hex followed by removal solvent afforded the titled compound (32, 0.140 g, 84%) as a colorless foam. TLC Rf: 0.29 in 30% EA/Hex. HPLC RT: 7.311 min.; MS-ESI (m/z): Calculated [M+H]+ = 534.1796; Observed [M+H]+ = 534.1836. Step-c: Compound of Invention of formula- 33 (Compound-31): Formation of 4-(((R)-2- ((2r,5R)-5-amino-1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile and 4-(((S)-2-((2r,5S)-5-amino-1,3-dioxan-2-yl)-2- fluoroethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-32 was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(32) 4-(((R)-2-((2r,5R)-5-amino- 1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile and 4-(((S)-2- ((2r,5S)-5-amino-1,3-dioxan-2-yl)-2-fluoroethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (32, 80 mg, 72%) was obtained as a white color foam. TLC Rf: 0.39 in 6% 7N Ammonia in methanol in DCM. HPLC RT: 5.574 min.; MS-ESI (m/z): Calculated [M+H]+ = 404.1741; Observed [M+H]+ = 404.1798.
Figure imgf000089_0001
Compounds of invention of formula (34 and 35) were synthesized via the process of Scheme XXV, supra, as follows. Step-a: Intermediate of formula-DEOxir: Formation of 2-(diethoxymethyl)oxirane A mixture of acrolein diethyl acetal (ADEA, 4.00, 30.70 mmol) and KHCO3 (0.615 g, 30 mmol) in methanol (16 mL) was added acetonitrile (3.8 mL) followed by addition of 30% hydrogen peroxide (3.90 mL, 180 mmol) at room temperature. The resulting mixture is heated at 40 °C. After 24h hours of initial addition, 1 equ. of hydrogen peroxide (3.9 mL) and acetonitrile (2 mL) were added continued heating for 48 hours at 40 °C. At the end of the reaction, it was quenched with water (5 mL) and the crude product is extracted using DCM. The titled compound (DEOxir, 2.65 g, 59%) was obtained as a colorless liquid. 1H-NMR (400 MHz, CDCl3) l /).0 h 4.30 (m, 1H), 3.82 – 3.68 (m, 3H), 3.66 – 3.54 (m, 3H), 3.14 – 3.05 (m, 1H), 2.86 – 2.65 (m, 2H), 2.15 – 2.03 (m, 1H), 2.03 – 1.93 (m, 6H), 1.28 – 1.12 (m, 9H). Ref: F. Camps Bres et al. / Tetrahedron: Asymmetry 24 (2013) 1075–1081; Flora Camps Bres, Christine Guérard-Hélaine, Carlos Fernandes, José A. Castillo, Marielle Lemaire. Ref: WO2018/195098 Step-b: Intermediate of formula-34a: Formation of 4-((3,3-diethoxy-2- hydroxypropyl)amino)benzonitrile To a mixture of 2-(diethoxymethyl)oxirane (DEOxir, 0.640 g, 4.40 mmol) in 5 M LiClO4 (8 mL) was added 4-amino-2-fluorobenzonitrile (1, 0.50 g, 3.70 mmol) at rt. After stirring 14h, the reaction was quenched with water and extracted with CH2Cl2. The organic portion was washed with water, brine, and dried over anhydrous sodium sulfate. Filtered followed by removal of solvent resulted in the crude product. Purification on a silica gel column chromatography using 30%EA/Hex afforded the titled compound (34a, 0.470 g, 84%) as a colorless viscous material. Rf: 0.46 in 50%EA/Hex. HPLC RT: 5.469 min.; 1H-NMR (400 MHz, CDCl3% l 2).- $Q' J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 4.87 (t, J = 5.8 Hz, 1H), 4.39 (t, J = 5.5 Hz, 2H), 3.82 – 3.67 (m, 4H), 3.61 – 3.45 (m, 3H), 3.39 – 3.28 (m, 1H), 3.17 (ddd, J = 12.6, 6.9, 5.0 Hz, 1H), 2.82 (d, J = 4.1 Hz, 1H), 1.19 (td, J = 7.1, 4.7 Hz, 9H). Step-b: Intermediate of formula-35a: Formation of 4-((3,3-diethoxy-2-hydroxypropyl)(3- fluoro-4-methoxybenzyl)amino)benzonitrile The intermediate 35a was synthesized in an analogous manner to the intermediate – 29a. The intermediate compound (35a) 4-((3,3-diethoxy-2-hydroxypropyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile (35a, 1.80 g, 79%) was obtained as a gummy material. TLC Rf: 0.25 in 30%EA/Hex. HPLC RT: 6.696 min.1H-NMR (400 MHz, CDCl3) l 2)/0 h 2)., $Z' 2H), 6.93 – 6.81 (m, 3H), 6.77 – 6.61 (m, 2H), 4.67 (d, J = 3.4 Hz, 2H), 4.36 (d, J = 5.9 Hz, 1H), 4.11 (q, J = 7.1 Hz, 1H), 3.91 (tdd, J = 8.5, 4.4, 2.3 Hz, 1H), 3.86 (s, 4H), 3.83 – 3.74 (m, 3H), 3.59 (ddq, J = 18.2, 9.3, 7.0 Hz, 2H), 3.49 – 3.37 (m, 1H), 2.30 (dd, J = 3.9, 1.0 Hz, 1H), 1.25 (td, J = 7.2, 2.2 Hz, 7H). Step-b: Intermediate of formula-34b: Formation of 4-((3,3-diethoxy-2- hydroxypropyl)amino)-2-fluorobenzonitrile The intermediate 34b was synthesized in an analogous manner to the intermediate – 34a. The intermediate compound (34b) 4-((3,3-diethoxy-2-hydroxypropyl)amino)-2-fluorobenzonitrile (34b, 0.700 g, 68%) was obtained as a gummy material. HPLC RT: 5.469 min.; 1H-NMR (400 MHz, CDCl3) l 2).- $Q' J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 4.87 (t, J = 5.8 Hz, 1H), 4.39 (t, J = 5.5 Hz, 2H), 3.82 – 3.67 (m, 4H), 3.61 – 3.45 (m, 3H), 3.39 – 3.28 (m, 1H), 3.17 (ddd, J = 12.6, 6.9, 5.0 Hz, 1H), 2.82 (d, J = 4.1 Hz, 1H), 1.19 (td, J = 7.1, 4.7 Hz, 9H). Step-b: Intermediate of formula-35b: Formation of 4-((3,3-diethoxy-2-hydroxypropyl)(3- fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile The intermediate 35b was synthesized in an analogous manner to the intermediate – 29a. The intermediate compound (35b) of 4-((3,3-diethoxy-2-hydroxypropyl)(3-fluoro-4- methoxybenzyl)amino)-2-fluorobenzonitrile (35b, 0.600 g, 58%) %) was obtained as brown color gummy material. TLC Rf: 0.25 in 30%EA/Hex. HPLC RT: 6.884 min.; 1H-NMR (400 MHz, CDCl3) l 2).. h 2)-. $Z' -?%' 1)40 h 1)3- $Z' /?%' 1)0. h 1)/0 $Z' -?%' /)10 $Q' A 71)/ Hz, 2H), 4.44 (dd, J = 6.2, 1.0 Hz, 1H), 4.36 (dd, J = 6.0, 1.0 Hz, 1H), 3.85 (d, J = 1.1 Hz, 3H), 3.84 – 3.75 (m, 3H), 3.64 – 3.53 (m, 3H), 3.47 – 3.37 (m, 1H), 2.41 (dd, J = 22.8, 4.2 Hz, 2H), 1.33 – 1.13 (m, 12H). Synthesis of Intermediate of formula (VIIb-Pip-DiOH1): Formation of tert-butyl 4,4- bis(hydroxymethyl)piperidine-1-carboxylate
Figure imgf000091_0001
Potassium carbonate (1.620 g, 11.70 mol) was added to a stirred solution of commercially available tert-butyl 4-formylpiperidine-1-carboxylate (36, 5.00 g, 23.40 mmol), water (12.50 mL), methanol (17.50 mL), and formaldehyde (2.57 mL, 1.90 g of 37%, 23.40 mmol) at OoC. After stirring 18 h at O oC the solvent was concentrated to 1/3 of its volume, and the product was extracted with ethyl acetate. The organic portion was washed with water, brine, and dried over Na2CO3. Filtered followed by removal of solvent afforded compound (PiPOHAl)) as a colorless viscous liquid which was used as such for the next step. To a stirred solution of (PiPOHAl) in methanol (10 mL), was added NaBH4 (1.97 g, 51.60 mmol) at OoC and stirred for 30 min and warm into room temperature overnight. The reaction was quenched with concentrated NH4Cl solution and concentrated to minimum volume of solvent. This crude product was extracted with ethyl acetate and washed with water, brine and dried over Na2SO4. Filtered followed by removal of solvent under vacuum afforded colorless viscous material. The product was re-dissolved in ethyl acetate and triturated with hexane to afford the titled product diol (VIIb-Pip-DiOH1, 5.00 g, 87%) as a white solid.1H-NMR (400 MHz, CDCl3% l /),, $`' ,?%' .)24 $Q' J = 1.4 Hz, 0H), 3.71 – 3.59 (m, 1H), 3.55 – 3.44 (m, 1H), 3.44 – 3.30 (m, 1H), 2.77 – 2.57 (m, 1H), 1.66 (dddd, J = 24.2, 14.3, 7.5, 2.9 Hz, 2H), 1.45 (d, J = 1.0 Hz, 7H), 1.13 (qd, J = 12.4, 4.5 Hz, 1H). Ref: WO 2018/013999 PCT/US2017/042259
Figure imgf000092_0001
Compounds of invention of formula (36a, 36b, 37a and 37b) were synthesized via the process of Scheme XXVI, supra, as follows. Step-a: Compound of Invention of formula- 36a (Compound-32): Formation of tert-butyl (S)-3-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-36a was synthesized in a similar manner to the compound of Invention of formula—19a. Compound of Invention of formula-(36a) tert-butyl (S)-3-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (36a, 0.056 g, 18%) was obtained as a white color foam. TLC Rf 0.21, in 50% EA/Hex. HPLC RT:7.072 min., MS-ESI (m/z): Calculated [M+H]+ = 556.2778; Observed [M+H]+ = 556.2993. Step-b: Compound of Invention of formula- 37a (Compound-33): Formation of (S)-4-((3- fluoro-4-methoxybenzyl)(2-hydroxy-2-(2,4-dioxa-9-azaspiro[5.5]undecan-3- yl)ethyl)amino)benzonitrile Compound of Invention of formula-37a was synthesized in a similar manner to the compound of Invention of formula-– 25a. Compound of Invention of formula-(37a) (S)-4-((3-fluoro-4- methoxybenzyl)(2-hydroxy-2-(2,4-dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)amino)benzonitrile (37a, 24 mg, 57%) was obtained as a white color foam. HPLC RT: 5.24 min. MS-ESI (m/z): Calculated [M+H]+ = 456.2254; Observed [M+H]+ = 456.2294. Step-a: Compound of Invention of formula-36b (Compound-34): Formation of tert-butyl (S)-7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-36b was synthesized in a similar manner to the compound of Invention of formula—19a. Compound of Invention of formula-(36b) tert-butyl (S)-7-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)-1-hydroxyethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (36b, 0.080 g, 28%). HPLC RT:6.76 min.; MS-ESI (m/z): Calculated [M+H]+ = 528.2465; Observed [M+H]+ = 528.2910. Step-b: Compound of Invention of formula- 37b (Compound-35): Formation of (S)-4-((3- fluoro-4-methoxybenzyl)(2-hydroxy-2-(6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile Compound of Invention of formula-37b was synthesized in a similar manner to the compound of Invention of formula-– 25a. Compound of Invention of formula-(37b) (S)-4-((3-fluoro-4- methoxybenzyl)(2-hydroxy-2-(6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)amino)benzonitrile ((37b, 15 mg) was obtained as a white color foam. HPLC RT: 5.12 min.; MS-ESI (m/z): Calculated [M+H]+ = 428.1941; Observed [M+H]+ = 428.1974.
Figure imgf000093_0001
Compounds of invention of formula (38a, 38b, 39a and 39b) were synthesized via the process of Scheme XXVII, supra, as follows. Step-a: Compound of Invention of formula- 38a (Compound-36): Formation of Trans tert- butyl 3-(3-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-38a was synthesized in an analogous manner to the compound of Invention of formula-– 15. Compound of Invention of formula-(38a) tert-butyl 3- (3-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (38a, 0.051 g, 15%) was obtained as a gummy material. HPLC RT:7.846 min.; MS-ESI (m/z): Calculated [M+H]+ = 554.2986; Observed [M+H]+ = 554.2994. Step-b: Compound of Invention of formula- 39a (Compound-37): Formation of 3-(3-((4- cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9-azaspiro[5.5]undecan- 9-ium trifluoroacetate Compound of Invention of formula-38a was synthesized in an analogous manner to the compound of Invention of formula-25a. Compound of Invention of formula-(39a) 3-(3-((4- cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)propyl)-2,4-dioxa-9-azaspiro[5.5]undecan-9- ium trifluoroacetates (39a, TFA salt, 0.056 g, >99% and free base, 0.021 g, 47%) was obtained as a white color foam. HPLC RT: 5.745 min.; MS-ESI (m/z): Calculated [M+H]+ = 454.2461; Observed[M+H]+ = 454.2492. Step-a: Compound of Invention of formula- 38b (Compound-38): Formation of tert-butyl 3-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-38b was synthesized in an analogous manner to the compound of Invention of formula-15. Compound of Invention of formula-(38b) of tert-butyl 3- (2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (38b, 0.080 g, 52%) was obtained as a white color foam. TLC Rf 0.26 (30% EA/Hex). MS-ESI (m/z): Calculated [M+H]+ = 540.2829; Observed [M+H]+ = 540.2872. Step-b: Compound of Invention of formula- 39b (Compound-39): Formation of 4-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-39b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(39b) 4-((2-(2,4-dioxa-9- azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (39b, 0.050 g, 82%) was obtained as a white color foam. TLC Rf: 0.28 in 6% MeOH in DCM HPLC RT: 5.621 min.; MS-ESI (m/z): Calculated [M+H]+ = 440.2305; Observed [M+H]+ = 440.3124.
Figure imgf000094_0001
Compounds of invention of formula (38c, and 39c) were synthesized via the process of Scheme XXVIII, supra, as follows. Step-a: Compound of Invention of formula- 38c (Compound-40): Formation of tert-butyl 7-(3-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)propyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-38c was synthesized in a similar manner to the compound of Invention of formula-15. Compound of Invention of formula-(38c) tert-butyl 7-(3-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)propyl)-6,8- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (38c, 0.125 g, 51%) was obtained as a white color foam. TLC Rf 0.62 (50% EA/Hex). HPLC RT: 7.466 min.; MS-ESI (m/z): Calculated [M+H]+ = 526.2673; Observed [M+H]+ = 526.2727. Step-b: Compound of Invention of formula- 39c (Compound-41): Formation of 4-((3-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)propyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-39c was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(39c) 4-((3-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)propyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile base (39b, 61 mg, 90%) was obtained as a colorless foam. TLC Rf: 0.32 in 6% MeOH in DCM. HPLC RT: 5.587 min.; MS-ESI (m/z): Calculated [M+H]+ = 426.2148; Observed [M+H]+ = 426.2237.
Figure imgf000095_0001
Compounds of invention of formula (38d, and 39d) were synthesized via the process of Scheme XXIX, supra, as follows. Step-a: Compound of Invention of formula- 38d (Compound-42): Formation of tert-butyl 3-(3-(((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)methyl)oxetan-3-yl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-38c was synthesized in an analogous manner to the compound of Invention of formula-– 15. Compound of Invention of formula-(38d) of tert-butyl 3-(3-(((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)methyl)oxetan-3-yl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (38d, 0.045 g, 46%) was obtained as a colorless foam. TLC R: 0.63 (30% EA/Hex). MS-ESI (m/z): Calculated [M+H]+ = 582.2935; Observed [M+H]+ = 582.3668. Step-b: Compound of Invention of formula- 39d (Compound-43): Formation of 4-(((3-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)oxetan-3-yl)methyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile, Compound of Invention of formula-39d was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(39d) product 4-(((3-(2,4-dioxa-9- azaspiro[5.5]undecan-3-yl)oxetan-3-yl)methyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (39d, 30 mg, 91%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 482.2410; Observed [M+H]+ = 482.2484.
Figure imgf000096_0001
Compounds of invention of formula (40a, 40b, 41a and 41b) were synthesized via the process of Scheme XXX, supra, as follows Step-a: Intermediate of formula (40a): Formation of tert-butyl 3-(2- (((benzyloxy)carbonyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate To a stirred clear solution of tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (VIIb1, 2.00 g, 8.15 mmol), benzyl (3-oxopropyl)carbamate (IX, 1.86 g, 8.97 mmol) in DCM (50 mL) was added catalytic amount of 4-methylbenzenesulfonic acid ( 0.140 g, 0.815 mmol) at rt. Within 5 minutes, the reaction becomes cloudy and stirred for three days at rt and refluxed for 8h. Cool the reaction mixture was cool to room temperature and quenched with aqueous sodium bicarbonate solution. The product was extracted u with DCM and washed with water and brine. Removal of solvent followed by purification on a silica gel column chromatography using a gradient of 20%EA/Hex to 50%EA/Hex as an eluent afforded the titled compound tert-butyl 3- (2-(((benzyloxy)carbonyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate (40a, 3.20 g, 90%) as a colorless foamy material. TLC Rf 0.60 (50% EA/Hex), Starting material aldehyde Rf 0.76
Figure imgf000097_0001
(400 MHz, CDCl3) l 2).4 h 2)., $Z' 0?%' 0)-+ $`' 1H), 5.09 (s, 2H), 4.57 (t, J = 4.6 Hz, 1H), 3.94 – 3.82 (m, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.41 (s, 1H), 3.36 (dd, J = 11.9, 5.5 Hz, 3H), 3.31 – 3.26 (m, 2H), 1.82 (ddd, J = 21.0, 9.1, 5.4 Hz, 4H), 1.45 (s, 9H), 1.15 (t, J = 6.0 Hz, 2H). Step-b: Intermediate of formula (41a): Formation of tert-butyl 3-(2-aminoethyl)-2,4-dioxa- 9-azaspiro[5.5]undecane-9-carboxylate To a stirred solution of compound tert-butyl 3-(2-(((benzyloxy)carbonyl)amino)ethyl)-2,4-dioxa- 9-azaspiro[5.5]undecane-9-carboxylate (40a, 1.70 g, 3.91 mmol) in methanol (20 mL) and ethyl acetate (10 mL) was added 10% Pd-C (200 mg) was hydrogenated at room temperature for 12h. After 12 h, filtered through a pad of celite and washed with methanol/ethyl acetate (1:1, 30 mL) followed by removal of solvent afforded the t titled compound tert-butyl 3-(2-aminoethyl)-2,4- dioxa-9-azaspiro[5.5]undecane-9-carboxylate (41a, 1.10 g) was obtained as a colorless solid. 1H-NMR (400 MHz, CDCl3) l /)04 $a' J = 4.9 Hz, 1H), 3.98 – 3.81 (m, 2H), 3.49 – 3.42 (m, 3H), 3.40 (d, J = 1.6 Hz, 1H), 3.34 – 3.19 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 1.79 (ddd, J = 11.6, 8.9, 5.4 Hz, 4H), 1.66 – 1.54 (m, 3H), 1.45 (s, 9H), 1.16 (t, J = 6.0 Hz, 2H). Step-a: Intermediate of formula (40b): Formation of tert-butyl 7-(2- (((benzyloxy)carbonyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate (40b) was synthesized in an analogous manner to the intermediate – 40a. The intermediate compound (40b) tert-butyl 7-(2-(((benzyloxy)carbonyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (40b, 4.60 g, 98%) was obtained as a colorless solid. TLC Rf 0.66 (50% EA/Hex). 1H-NMR (400 MHz, CDCl3) l 2)0+ h 2)-4 $Z' 1?%' 0),/ $`' ,?%' 0)+4 $`' 2H), 4.57 (t, J = 4.7 Hz, 1H), 4.11 (d, J = 11.2 Hz, 2H), 3.90 (s, 2H), 3.64 (d, J = 11.2 Hz, 2H), 3.42 (s, 2H), 3.33 (q, J = 6.0 Hz, 2H), 1.81 (q, J = 5.8 Hz, 2H), 1.43 (d, J = 1.0 Hz, 9H). Step-b: Intermediate of formula (41b): Formation of tert-butyl 7-(2-aminoethyl)-6,8-dioxa- 2-azaspiro[3.5]nonane-2-carboxylate The intermediate (41b) was synthesized in an analogous manner to the intermediate – 40b. The intermediate compound (41b) tert-butyl 7-(2-aminoethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (XIb2, 900 mg,) was obtained as a colorless solid. HPLC RT: 6.148 min.1H-NMR (400 MHz, CDCl3) l 2).4 h 2)-2 $Z' -?%' 0)0, $`' ,?%' /)2- $a' J = 4.3 Hz, 1H), 4.52 (s, 1H), 4.16 (d, J = 11.2 Hz, 2H), 3.94 (d, J = 5.3 Hz, 2H), 3.78 (t, J = 5.7 Hz, 1H), 3.74 – 3.65 (m, 3H), 3.42 (s, 2H), 3.09 (t, J = 6.2 Hz, 2H), 1.47 (d, J = 1.1 Hz, 1H), 1.43 (s, 9H).
Figure imgf000098_0001
Compounds of invention of formula (43a, 43b, 44a and 44b) were synthesized via the process of Scheme XXXI, supra, as follows. Step-a: Intermediate of formula (42a): Formation of tert-butyl 3-(2-((6-cyanopyridin-3- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate To a stirred solution of compound tert-butyl 3-(2-aminoethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate(41a, 0.125 g, 0.416 mmol) in NMP (5 mL) was added 5- fluoropicolinonitrile (50.8mg, 0.416 mmol) followed by DIEA (0.217 mL, 0.161 g, 1.25 mmol) at room temperature. The resulting solution was heated at 80oC for 16 h. After heating 18h, the reaction was cool to room temperature and quenched with water. The product was extracted with ethyl acetate and washed wither water and brine. The organic portion was dried over anhydrous sodium sulfate, filtered followed by removal of solvent afforded the crude product. Purification on a silica gel prep TLC plate using 50%EA/Hex followed by isolation of the product afforded the titled compound tert-butyl 3-(2-((6-cyanopyridin-3-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (42a, 120 mg, 72%) as a pale brown color foam. TLC Rf: 0.39 in 50% EA/Hex. HPLC RT: 6.22 min.1H-NMR (400 MHz, CDCl3) l 2)44 $Q' J = 2.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.6, 2.9 Hz, 1H), 5.03 (s, 1H), 4.65 (t, J = 4.4 Hz, 1H), 3.93 (d, J = 11.2 Hz, 2H), 1.98 (td, J = 6.3, 4.2 Hz, 3H), 1.79 (t, J = 5.9 Hz, 2H), 1.44 (s, 11H), 1.17 (t, J = 6.1 Hz, 2H). Step-b: Compound of Invention of formula-43a (Compound-44): Formation of tert-butyl 3-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43a was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(43a) tert-butyl 3-(2-((6- cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane- 9-carboxylate (40a, 82 mg, 51%) was obtained as a pale yellow color foam. TLC Rf: 0.21 in 50% EA/Hex. HPLC RT: 7.08 min.; MS-ESI (m/z): Calculated [M+H]+ = 541.2782; Observed [M+H]+ = 541.2795. Step-c: Compound of Invention of formula- 44a (Compound-45): Formation of 5-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-44a was synthesized in a similar manner to the compound of Invention of formula—25a. Compound of Invention of formula-(44a) 5-((2-(2,4-dioxa-9- azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile (43a, 48 mg, 91%) was obtained as a colorless foam. HPLC RT: 5.132 min.; MS-ESI (m/z): Calculated [M+H]+ = 441.2257; Observed[M+H]+ = 441.2567. Step-a: Intermediate of formula (42a): Formation of tert-butyl 3-(2-((5-cyanopyridin-2- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate The intermediate (42b) was synthesized in an analogous manner to the intermediate – 42a. The intermediate compound (42b) tert-butyl 3-(2-((5-cyanopyridin-2-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (42b, 120 mg, 90%) was obtained as a pale brown color foam. TLC Rf: 0.39 in 60% EA/Hex. 1H NMR (499 MHz, CDCl3% l 3)0+ $Q' J = 2.4 Hz, 0H), 8.30 (dt, J = 2.4, 1.0 Hz, 0H), 8.25 (d, J = 2.4 Hz, 1H), 7.47 – 7.40 (m, 1H), 7.05 (ddd, J = 8.6, 3.1, 0.7 Hz, 0H), 6.35 – 6.25 (m, 1H), 4.55 (t, J = 4.6 Hz, 1H), 3.88 – 3.79 (m, 2H), 3.41 (q, J = 6.0 Hz, 2H), 3.36 (td, J = 8.7, 3.6 Hz, 5H), 3.30 (s, 1H), 3.30 (d, J = 14.2 Hz, 3H), 3.27 – 3.15 (m, 2H), 2.75 (d, J = 0.9 Hz, 4H), 2.28 (t, J = 8.1 Hz, 3H), 1.99 – 1.91 (m, 3H), 1.87 (td, J = 6.6, 4.6 Hz, 2H), 1.76 – 1.68 (m, 2H), 1.37 (s, 9H), 1.11 – 1.00 (m, 2H). Step-b: Compound of Invention of formula- 43b (Compound-46): Formation of tert-butyl 3-(2-((5-cyanopyridin-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43b was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(43b) tert-butyl 3-(2-((5- cyanopyridin-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane- 9-carboxylate (43b, 40 mg, 25%) was obtained as a pale yellow color foam. Rf: 0.21 in 50% EA/Hex. HPLC RT.7.08 min; MS-ESI (m/z): Calculated [M+H]+ = 541.2782; Observed [M+H]+ = 541.2791.
Figure imgf000100_0001
Compounds of invention of formula (43c, and 44c) were synthesized via the process of Scheme XXXII, supra, as follows. Step-a: Intermediate of formula (42c): Formation of tert-butyl 3-(2-((4-cyano-3- fluorophenyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate The intermediate (42c) was synthesized in an analogous manner to the intermediate – 42a. The intermediate compound (42c) tert-butyl 3-(2-((4-cyano-3-fluorophenyl)amino)ethyl)-2,4-dioxa- 9-azaspiro[5.5]undecane-9-carboxylate (42c, 125 mg, 90%) as a pale brown color foam. TLC Rf: 0.39 in 50% EA/Hex. 1H-NMR (400 MHz, CDCl3) l 2).+ $QQ' A 73)0' 1)- ?g' ,?%' 2)-1 h 2),3 (m, 1H), 6.34 – 6.26 (m, 2H), 6.26 – 6.16 (m, 1H), 5.65 (s, 1H), 5.20 (d, J = 5.6 Hz, 1H), 4.65 (t, J = 4.1 Hz, 1H), 4.58 (t, J = 4.5 Hz, 1H), 3.44 – 3.36 (m, 8H), 3.33 (s, 3H), 3.33 (d, J = 14.1 Hz, 8H), 3.28 – 3.19 (m, 7H), 2.79 (d, J = 0.9 Hz, 11H), 2.31 (t, J = 8.1 Hz, 7H), 1.75 (dt, J = 5.6, 3.1 Hz, 5H), 1.40 (d, J = 2.2 Hz, 19H), 1.13 (d, J = 6.0 Hz, 3H). Step-b: Compound of Invention of formula-43c (Compound-47):Formation of tert-butyl 3- (2-((4-cyano-3-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43c was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(43c) tert-butyl 3-(2-((4-cyano- 3-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9- carboxylate (43c, 60 mg, 38%) was obtained as a pale yellow color foam. TLC Rf: 0.21 in 50% EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 558.2735; Observed [M+H]+ = 558.2792. Step-c: Compound of Invention of formula- 44c (Compound-48): Formation of 4-((2-(2,4- dioxa-9-azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile Compound of Invention of formula-44c was synthesized in a similar manner to the compound of Invention of formula—25a. Compound of Invention of formula-(44c) 4-((2-(2,4-dioxa-9- azaspiro[5.5]undecan-3-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile (44c, 42 mg, 85%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 458.2211; Observed [M+H]+ = 458.2278.
Figure imgf000101_0001
Compounds of invention of formula (43d, and 44d) were synthesized via the process of Scheme XXXIII, supra, as follows. Step-a: Intermediate of formula (42d): Formation of tert-butyl 3-(2-((5-cyanothiazol-2- yl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane-9-carboxylate The intermediate (42d) was synthesized in an analogous manner to the intermediate – 42a. The intermediate compound (42d) tert-butyl 3-(2-((5-cyanothiazol-2-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (42d, 120 mg, 88%) was obtained as a pale brown color foam. TLC Rf: 0.39 in 50% EA/Hex. 1H-NMR (400 MHz, CDCl3) l 1)34 $`' ,?%' /)1- $a' J = 4.4 Hz, 1H), 3.94 – 3.84 (m, 2H), 3.39 (tdd, J = 9.7, 8.1, 7.1, 3.9 Hz, 7H), 3.30 – 3.22 (m, 2H), 2.80 (s, 2H), 2.33 (t, J = 8.1 Hz, 1H), 2.11 – 1.88 (m, 3H), 1.76 (t, J = 5.8 Hz, 3H), 1.41 (s, 9H), 1.18 – 1.03 (m, 3H). Step-b: Compound of Invention of formula- 43d (Compound-49): Formation of tert-butyl 3-(2-((5-cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-43d was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(43d) tert-butyl 3-(2-((5- cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane- 9-carboxylate (43d, 100 mg, 62%) was obtained as a pale yellow color foam. TLC Rf: 0.21 in 50% EA/Hex. HPLC RT:7.08 min.; MS-ESI (m/z): Calculated [M+H]+ = 547.2346; Observed [M+H]+ = 547.2509. Step-c: Compound of Invention of formula- 44d (Compound-50): Formation of tert-butyl 3-(2-((5-cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate Compound of Invention of formula-44d was synthesized in a similar manner to the compound of Invention of formula—25a. Compound of Invention of formula-(44d) tert-butyl 3-(2-((5- cyanothiazol-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-2,4-dioxa-9-azaspiro[5.5]undecane- 9-carboxylate (44d, 65 mg, 65%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 447.1821; Observed [M+H]+ = 447.1862.
Figure imgf000102_0001
Compounds of invention of formula (46a, 46b, 4bc, 47a, 47b, and 47c) were synthesized via the process of Scheme XXXIV, supra, as follows Step-a: Intermediate of formula (45a): tert-butyl 7-(2-((4-cyanophenyl)amino)ethyl)-6,8- dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 45a was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (45a) tert-butyl 3-(2-((6-cyanopyridin-3-yl)amino)ethyl)-2,4-dioxa-9- azaspiro[5.5]undecane-9-carboxylate (45a, 310 mg, 65%) was obtained as a pale brown color foam. TLC Rf: 0.65 in 50%EA/Hex, HPLC RT: 6.33 min.1H-NMR (400 MHz, CDCl3% l 2)/, (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 4.61 (d, J = 7.3 Hz, 1H), 4.18 – 4.09 (m, 2H), 3.72 – 3.64 (m, 2H), 3.27 (q, J = 6.1 Hz, 2H), 1.93 (td, J = 6.4, 4.5 Hz, 2H), 1.44 (s, 9H). Step-b: Compound of Invention of formula- 46a (Compound-51): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46a was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(46a) tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (46a, 1.03 g, 90%) was obtained as a colorless foam. TLC Rf: 0.36 in 30% EA/Hex and 0.46 in 50% EA/Hex. HPLC RT: 7.15 min. MS-ESI (m/z): Calculated [M+H]+ = 512.2516; Observed [M+H]+ = 512.2568. Step-c: Compound of Invention of formula-47a (Compound-52): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile Compound of Invention of formula-47a was synthesized in a similar manner to the compound of Invention of formula - 25a. Compound of Invention of formula-(47a) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (47a, 620 mg, 77%) was obtained as a colorless foam. HPLC RT: 6.783 min.; MS-ESI (m/z): Calculated [M+H]+ = 412.1992; Observed [M+H]+ = 412.2067. Step-a: Intermediates of formula (45b1 and 45b2): Formation of tert-butyl 7-(2-((4-cyano-3- fluorophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediates 45b1 and 45b2 were synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (45b1 and 45b2). The desired intermediate compound (45b1) tert-butyl 7-(2-((4-cyano-3-fluorophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2- carboxylate (45b1, 190 mg, 59%) was obtained as a colorless solid. TLC Rf: 0.54 in 60% EA/Hex. HPLC RT: 6.418 min. 19F- NMR (376 MHz, CDCl3% l (,+1),, 1H-NMR (400 MHz, CDCl3% l 2)./ h 2)-2 $Z' ,?%' 1).- $QQQ' J = 8.7, 2.3, 0.9 Hz, 1H), 6.26 (dd, J = 12.0, 2.2 Hz, 1H), 4.83 (s, 1H), 4.64 (t, J = 4.5 Hz, 1H), 4.24 – 4.02 (m, 2H), 3.90 (s, 2H), 3.68 (d, J = 11.2 Hz, 2H), 3.44 (s, 2H), 3.26 (q, J = 6.0 Hz, 2H), 1.93 (td, J = 6.4, 4.4 Hz, 2H), 1.58 (s, 2H), 1.44 (d, J = 0.9 Hz, 9H). The undesired intermediate compound (45b2) tert-butyl 7-(2-((2-cyano-4- fluorophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (45b2, 120 mg, 37%) was obtained as a colorless foam. TLC Rf: 0.78 in 60% EA/Hex. HPLC RT: 6.67 min. 19F- NMR (376 MHz, CDCl3%% l (,+,)01 $Q' J = 11.7 Hz%) ,? DCG $/++ C?g' :;:Y.% l 2)./ $QQ' J = 8.6, 6.2 Hz, 1H), 6.46 – 6.20 (m, 2H), 5.48 (s, 1H), 4.67 (t, J = 4.3 Hz, 1H), 4.25 – 4.11 (m, 2H), 3.92 (s, 2H), 3.68 (d, J = 11.2 Hz, 2H), 3.42 (s, 2H), 3.37 – 3.13 (m, 2H), 1.96 (td, J = 6.2, 4.2 Hz, 2H), 1.42 (s, 9H). Step-b: Compound of Invention of formula- 46b1 (Compound-53): Formation of tert-butyl 7-(2-((4-cyano-3-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate To a stirred suspension of NaH (36 mg, 0.89 mmol) in THF (1 mL) was added a THF solution (2 mL) of compound tert-butyl 7-(2-((4-cyano-3-fluorophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (45b1, 70 mg, 0.18 mmol) at 0oC under nitrogen atmosphere. After stirring 30 min at 0oC, a THF solution of 4-(bromomethyl)-2-fluoro-1-methoxybenzene (59 mg, 0.27 mmol, 2 mL) was added quickly at 0oC and stirred for 30 min followed by warming to room temperature over a period of 16 h. The reaction was quenched with water and extracted the product using ethyl acetate (50 mL). Washed the organic portion with water, brine, dried over anhyd. sodium sulfate. Filtered followed by removal of solvent resulted the crude product which was purified by a silica gel glass prep TLC using 50%EA/Hex as an eluent. TLC: Rf: 0.68 in 50%EA/Hex. Removal of solvent from the middle band followed by drying under high vacuum afforded the titled compound tert-butyl 7-(2-((4-cyano-3-fluorophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46b1, 70 mg, 74%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 530.2422; Observed [M+H]+ = 530.2451. Step-c: Compound of Invention of formula- 47b1 (Compound-54): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile Compound of Invention of formula-47b1 was synthesized in a similar manner to the compound of Invention of formula - 25a. Compound of Invention of formula-(47b1) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile (47b1, 45 mg, 79%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 430.1898; Observed [M+H]+ = 430.1925. Step-b: Compound of Invention of formula- 46c (Compound-55): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46c) tert-butyl 7-(2-((4- cyanophenyl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (46c, 80 mg, 47%) as a colorless foam. HPLC RT: 7.137 min.; MS-ESI (m/z): Calculated [M+H]+ = 530.2422; Observed [M+H]+ = 530.2499. Step-c: Compound of Invention of formula- 47c (Compound-56): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (3,5-difluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-47c was synthesized in a similar manner to the compound of Invention of formula - 25a. Compound of Invention of formula-(47c) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,5-difluoro-4-methoxybenzyl)amino)benzonitrile (47c, 55 mg, 69%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 430.1898; Observed [M+H]+ = 430.1982. Step-b: Compound of Invention of formula- 46b2 (Compound-57): Formation of tert-butyl 7- (2-((2-cyano-4-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46b2 was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(46b2) product tert-butyl 7-(2-((2-cyano-4-fluorophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46b2, 120 mg, 74%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 530.2422; Observed [M+H]+ = 530.2458. Step-c: Compound of Invention of formula- 47b1 (Compound-58): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2- fluorobenzonitrile Compound of Invention of formula-47b1 was synthesized in a similar manner to the compound of Invention of formula - 25a. Compound of Invention of formula-(47b1) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)-2-fluorobenzonitrile (47b1, 45 mg, 79%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 430.1898; Observed [M+H]+ = 430.1898.
Figure imgf000106_0001
Compounds of invention of formula (46d 46e, 46f, 46 g, 47e, 47d, 47f and 47g) were synthesized via the process of Scheme XXXV, supra, as follows Step-a: Compound of Invention of formula- 46d (Compound-59): Formation of tert-butyl 7-(2-((4-chloro-3-fluorobenzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46d was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46d) tert-butyl 7-(2-((4- chloro- 3-fluorobenzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46d, 80 mg, 58%) was obtained as a colorless foam. TLC: Rf: 0.68 in 50%EA/Hex; HPLC RT: 7.192 min.; MS-ESI (m/z): Calculated [M+H]+ = 516.2021; Observed [M+H]+ = 516.2066 and [M+H-Boc]+ = 416.1635. Step-b: Compound of Invention of formula- 47d (Compound-60): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-3-fluorobenzyl)amino)benzonitrile Compound of Invention of formula-47d was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47d) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-3-fluorobenzyl)amino)benzonitrile (47d, 0.037 g, 92%) was obtained as a colorless foam. HPLC RT: 5.467min.; MS-ESI (m/z): Calculated [M+H]+ = 416.1496 ; Observed [M+H]+ = 416.1569. Step-a: Compound of Invention of formula- 46e (Compound-61): Formation of tert-butyl 7-(2-((4-cyano-3-fluorobenzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46e was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46e) tert-butyl 7-(2-((4-cyano-3- fluorobenzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46e, 30 mg, 40%) was obtained as a colorless foam. TLC: Rf: 0.68 in 50%EA/Hex.; MS-ESI (m/z): Calculated [M+H]+ = 506.5784; Observed [M+H]+ =506.5864. Step-b: Compound of Invention of formula- 47e (Compound-62): Formation of 4-(((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-cyanophenyl)amino)methyl)-2-fluorobenzonitrile TFA Salt Compound of Invention of formula-47e was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47e) 4-(((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-cyanophenyl)amino)methyl)-2-fluorobenzonitrile TFA salt (47e, 0.015 g, 73%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 520.1734 (TFA Salt); Observed [M+H]+ = 520.2102. Step-a: Compound of Invention of formula- 46f (Compound-63): Formation of tert-butyl 7- (2-((4-cyanophenyl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46f was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46f) tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (46f, 100 mg, 75%) as a colorless foam. TLC: Rf: 0.50 in 50%EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 496.2567; Observed [M+H]+ = 496.2638. Step-b: Compound of Invention of formula- 47f (Compound-64): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)benzonitrile Compound of Invention of formula-47f was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47f) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)benzonitrile (47f, 35 mg, 63%,) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 396.2043; Observed [M+H]+ = 396.2168. Step-a: Compound of Invention of formula- 46g (Compound-65): tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-(trifluoromethyl)benzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46g was synthesized in an analogous manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46g) tert-butyl 7- (2-((4-cyanophenyl)(3-fluoro-4-(trifluoromethyl)benzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (46g, 110 mg, 85%) as a colorless foam. HPLC RT: 7.051min.; MS-ESI (m/z): Calculated [M+H]+ = 550.2284; Observed [M+H]+ = 550.2298. Step-a: Compound of Invention of formula- 46h (Compound-66): Formation of tert-butyl 7-(2-((4-cyanophenyl)(3,4- dichlorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate Compound of Invention of formula-46h was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46h) tert-butyl 7-(2-((4- cyanophenyl)(3,4-dichlorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46h, 100 mg, 88%) as a colorless foam. HPLC RT: 6.027 min.; MS-ESI (m/z): Calculated [M+H]+ = 532.1725; Observed [M+H]+ = 532.1782. Step-b: Compound of Invention of formula- 47h (Compound-67): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (3,4-dichlorobenzyl)amino)benzonitrile Compound of Invention of formula-47h was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47h) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,4-dichlorobenzyl)amino)benzonitrile (47h, 40 mg, 90%,) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 432.1201; Observed [M+H]+ = 432.2043.
Figure imgf000108_0001
Compounds of invention of formula (46i1, 46i2, 46j, 47i and 47j) were synthesized via the process of Scheme XXXVI, supra, as follows Step-a: Compound of Invention of formula- 46i (Compound-68): Formation of tert-butyl 7- (2-((4-cyanophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46i1 was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46i1) tert-butyl 7-(2-((4- cyanophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (180 mg, 77%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 479.2614; Observed [M+H]+ = 479.2684. Step-b: Compound of Invention of formula- 47i (Compound-69): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((6- methylpyridin-3-yl)methyl)amino)benzonitrile Compound of Invention of formula-47i was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47i) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((6-methylpyridin-3-yl)methyl)amino)benzonitrile (47i, 50 mg, 79%) was obtained as a colorless foam. HPLC RT: 3.261 min.; MS-ESI (m/z): Calculated [M+H]+ = 378.4760; Observed [M+H]+ = 378.4814. Step-a: Compound of Invention of formula- 46i2 (Compound-70): Formation of tert-butyl 7-(2-((4-cyano-3-fluorophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46i2 was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46i2) tert-butyl 7-(2-((4-cyano-3- fluorophenyl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (100 mg, 64%) as a colorless foam. HPLC RT: 5.210min.; MS-ESI (m/z): Calculated [M+H]+ = 497.2519; Observed [M+H]+ = 497.2547. Step-a: Compound of Invention of formula- 46j (Compound-71): Formation of tert-butyl 7- (2-((4-cyanophenyl)((2-methylthiazol-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46j was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46j) tert-butyl 7-(2-((4- cyanophenyl)((2-methylthiazol-5-yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (46j, 90 mg, 60%) as a colorless foam. HPLC Rt: 5.961 min.; MS-ESI (m/z): Calculated [M+H]+ = 485.2178; Observed [M+H]+ = 485.2234. Step-b: Compound of Invention of formula- 47j (Compound-72): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) ((2-methylthiazol-5-yl)methyl)amino)benzonitrile, Compound of Invention of formula-47j was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47j) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((2-methylthiazol-5-yl)methyl)amino)benzonitrile (47j, 35 mg, 55%) was obtained as a colorless foam. HPLC Rt: 4.208 min.; MS-ESI (m/z): Calculated [M+H]+ = 385.1654; Observed [M+H]+ = 385.1692.
Figure imgf000110_0001
Compounds of invention of formula (46k, 46l, 46m, 47k, 47l and 47m) were synthesized via the process of Scheme XXXVII, supra, as follows Step-a: Compound of Invention of formula- 46k (Compound-73): Formation of tert-butyl 7-(2-((4-cyanophenyl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate Compound of Invention of formula-46k was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46k) tert-butyl 7-(2-((4- cyanophenyl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46k, 60 mg, 44%) as a colorless foam. MS-ESI (m/z):Calculated [M+H]+ = 506.2974; Observed [M+H]+ = 506.3047. Step-b: Compound of Invention of formula- 47k (Compound-74): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-isopropylbenzyl)amino)benzonitrile Compound of Invention of formula-47k was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47k) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-isopropylbenzyl)amino)benzonitrile (40 mg, 83%) was obtained as a colorless foam. HPLC RT: 6.056 min.; MS-ESI (m/z): Calculated [M+H]+ = 406.2450; Observed [M+H]+ = 406.8514. Step-a: Compound of Invention of formula- 46l (Compound-75): Formation tert-butyl 7-(2- ((4-(tert-butyl)benzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate Compound of Invention of formula-46l was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46l) tert-butyl 7-(2-((4-(tert- butyl)benzyl)(4-cyanophenyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46l, 110 mg, 50%) as a colorless gummy material. TLC: Rf: 0.68 in 40%EA/Hex. HPLC RT: 6.767 min.; MS-ESI (m/z): Calculated [M+H]+ = 520.3131; Observed [M+H]+ = 520.3182. Step-b: Compound of Invention of formula- 47l (Compound-76): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-(tert-butyl)benzyl)amino)benzonitrile Compound of Invention of formula-47l was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47l) product 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-(tert-butyl)benzyl)amino)benzonitrile (47l, 65mg, 73%) was obtained as a colorless foam. HPLC RT: 6.262 min.; MS-ESI (m/z): Calculated [M+H]+ = 420.2606; Observed [M+H]+ = 420.2664. Step-a: Compound of Invention of formula- 46m (Compound-77): Formation of tert-butyl 7-(2-((4-cyanophenyl)(4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate Compound of Invention of formula-46m was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46m) tert-butyl 7-(2-((4- cyanophenyl)(4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (46m, 150 mg, 68%) as a colorless foam. HPLC RT: 6.986 min.; MS-ESI (m/z): Calculated [M+H]+ = 494.2610; Observed [M+H]+ = 494.2694. Formation of 5-(chloromethyl)-2,3-dihydrobenzofuran
Figure imgf000111_0001
To a stirred solution of (2,3-dihydrobenzofuran-5-yl)methanol (0.500 g, 3.30 mmol) in DCM (10 mL) was added thionyl chloride (1.21 mL, 1.98 g, 16.60 mmol) at room temperature under nitrogen atmosphere for 1h. After stirring 1h at rt, the excess solvents and volatiles were removed under rotovap. Drying under high vacuum resulted the desired product 5- (chloromethyl)-2,3-dihydrobenzofuran (0.560 g, >99%) as a colorless oil. 1H-NMR (499 MHz, PQPY.% l 2)-/ $Q' A 7 -)+ ?g' ,?%' 2),. $QQ' A 73)-' -)+ ?g' ,?%' 1)20 $Q' A 73)- ?g' ,?%' /)04 $Q' J = 8.7 Hz, 2H), 4.57 (d, J = 2.1 Hz, 3H), 3.21 (t, J = 8.7 Hz, 2H). Formation of (6-isopropoxypyridin-3-yl)methanol and 5-(chloromethyl)-2- isopropoxypyridine
Figure imgf000112_0001
Step-1. To a stirred solution of 6-isopropoxynicotinaldehyde (0.500 g, 3.03 mmol) in Methanol (10 mL) was added sodium borohydride (115 mg, 3.03 mmol) at 0oC under nitrogen atmosphere and stirred for 1h. The reaction was then quenched by the addition of NH4Cl (aq.), and the resulting solution was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain (6- isopropoxypyridin-3-yl)methanol (0.500 mg, >99%). 1H-NMR (400 MHz, CDCl3% l 3)+1 $QQ' A = 2.4, 0.8 Hz, 1H), 7.71 – 7.51 (m, 1H), 6.66 (dd, J = 8.5, 0.8 Hz, 1H), 5.25 (h, J = 6.2 Hz, 1H), 4.58 (s, 2H), 1.32 (d, J = 6.2 Hz, 6H). Step-2. To a stirred solution of (6-isopropoxypyridin-3-yl)methanol (0.500 g, 3.00 mmol) in CHCl3 (10 mL) was added thionyl chloride (1.080 mL, 1.78 g,15.00 mmol) at room temperature under nitrogen atmosphere for 1h. After stirring 2h at rt, the excess solvents and volatiles were removed under rotovap. Drying under high vacuum resulted the desired product 5- (chloromethyl)-2-isopropoxypyridine (0.560 g, >99%) as a colorless oil.1H-NMR (400 MHz, CDCl3) l 3)+1 $QQ' A 7 -)/' +)3 ?g' ,?%' 2)2, h 2)0, $Z' ,?%' 1)11 $QQ' A 73)0' +)3 ?g' ,?%' 0)-0 (h, J = 6.2 Hz, 1H), 4.58 (s, 2H), 1.32 (d, J = 6.2 Hz, 6H). Formation of 5-(chloromethyl)-2-methylpyrimidine
Figure imgf000112_0002
To a stirred solution of (2,3-dihydrobenzofuran-5-yl)methanol (0.500 g, 3.30 mmol) in DCM (10 mL) was added thionyl chloride 1.21 mL, 1.98 g at room temperature under nitrogen atmosphere for 2h. As soon as the addition of thionyl chloride, the reaction mixture turns into a milky and white precipitate appeared. After stirring 2h at rt, the excess solvents and volatiles were removed under rotovap. Drying under high vacuum resulted the desired product 5-(chloromethyl)-2- methylpyrimidine (0.560 g, >99%) as a white color solid as its HCl salt. 1H-NMR (400 MHz, CD3E;% l 1)4/ $Q' A 7 -)- ?g' ,?%' 0)2, $`' ,?%' /).. $`' -?%' .).+ $]' A 7 ,)1 ?g' -?%' -)// $QQ' J = 3.4, 1.5 Hz, 3H). Ref: 5-(chloromethyl)-2-methyl- Pyrimidine, WO2019028309
Figure imgf000113_0001
Compounds of invention of formula (46n, 46o, 47n and 47o) were synthesized via the process of Scheme XXXVIII, supra, as follows. Step-a: Compound of Invention of formula- 46n (Compound-78): Formation tert-butyl 7- (2-((4-cyanophenyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, Compound of Invention of formula-46n was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46n) tert-butyl 7-(2-((4- cyanophenyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (46n, 100 mg, 57%) as a colorless foam. HPLC RT: 6.695 min.; MS-ESI (m/z): Calculated [M+H]+ = 506.2610; Observed [M+H]+ = 506.2590. Step-b: Compound of Invention of formula- 47n (Compound-79): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)benzonitrile, CCG-385448, VMCC-MP-012-023-001 Compound of Invention of formula-47n was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47n) product tert-butyl 7-(2-((4- cyanophenyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (47n, 90 mg, 44%) as a colorless foam. HPLC RT: 5.917 min.; MS-ESI (m/z): Calculated [M+H]+ = 406.2086; Observed [M+H]+ = 406.2135. Step-a: Compound of Invention of formula- 46o (Compound-80): Formation tert-butyl 7- (2-((4-cyanophenyl)((6-isopropoxypyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46o was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46o) tert-butyl 7-(2-((4- cyanophenyl)((6-isopropoxypyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane- 2-carboxylate, (46o, 70 mg, 38%) as a colorless foam. HPLC RT: 6.392 min.; MS-ESI (m/z): Calculated [M+H]+ = 523.2876; Observed [M+H]+ =523.2905. Step-b: Compound of Invention of formula- 47o (Compound-81): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((6-isopropoxypyridin-3- yl)methyl)amino)benzonitrile Compound of Invention of formula-47o was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47o) product 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((6-isopropoxypyridin-3-yl)methyl)amino)benzonitrile (47o, 35 mg, 72%) was obtained as a colorless foam. HPLC RT: 4.766 min.; MS-ESI (m/z): Calculated [M+H]+ = 423.2351; Observed [M+H]+ = 423.2420.
Figure imgf000114_0001
Compounds of invention of formula (46p, 46q, 46r, 47p 47 and 47r) were synthesized via the process of Scheme XXXIX, supra, as follows. Step-a: Compound of Invention of formula- 46p (Compound-82): Formation tert-butyl 7- (2-((4-cyanophenyl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46p was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46p) tert-butyl 7-(2-((4- cyanophenyl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (46p, 100 mg, 64%) as a colorless foam. HPLC RT: 6.986 min.; MS-ESI (m/z): Calculated [M+H]+ = 530.2422; Observed [M+H]+ = 530.2478. Step-b: Compound of Invention of formula- 47p (Compound-83): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-47p was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47p) product 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)benzonitrile, (47p, 45 mg, 69%) was obtained as a colorless foam. HPLC Rt: 5.379 min; MS-ESI (m/z): Calculated [M+H]+ = 430.1898; Observed [M+H]+ = 430.1959. Step-a: Compound of Invention of formula- 46q (Compound-84): Formation tert-butyl 7- (2-((4-cyanophenyl)(4-ethoxy-2,3-difluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46q was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46q) tert-butyl 7-(2-((4- cyanophenyl)(4-ethoxy-2,3-difluorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (46q, 110 mg, 68%) as a colorless foam. HPLC RT: 7.208 min.; MS-ESI (m/z): Calculated [M+H]+ = 544.2578; Observed [M+H]+ = 544.2625. Step-b: Compound of Invention of formula- 47q (Compound-85): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-ethoxy-2,3-difluorobenzyl)amino)benzonitrile Compound of Invention of formula-47o was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47q) product 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-ethoxy-2,3-difluorobenzyl)amino)benzonitrile, (47q, 30 mg, 74%) was obtained as a colorless foam. HPLC Rt: 5.379 min.; MS-ESI (m/z): Calculated [M+H]+ = 444.2054; Observed [M+H]+ = 444.2093. Step-a: Compound of Invention of formula- 46o (Compound-86): Formation tert-butyl 7- (2-((4-cyanophenyl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46r was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46r) tert-butyl 7-(2-((4- cyanophenyl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (46r, 280 mg, 40%) as a colorless foam., HPLC RT: 7.019 min.; MS-ESI (m/z): Calculated [M+H]+ = 530.2422; Observed [M+H]+ = 530.2431. Step-b: Compound of Invention of formula- 47r (Compound-87): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)benzonitrile Compound of Invention of formula-47r was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47r) product 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)benzonitrile (47r, 200 mg, 84%) was obtained as a colorless foam., HPLC RT: 5.502 min.; MS-ESI (m/z): Calculated [M+H]+ = 430.1898; Observed [M+H]+ = 430.2102.
Figure imgf000116_0001
Step-a: Intermediate of formula (CyhAlk-OH2): Formation of ((1r,4r)-4- isopropylcyclohexyl)methanol To a cold stirred suspension of LAH (0.267 g, 7.05 mmol) in THF (15 mL) was added solid trans-(1r,4r)-4-isopropylcyclohexane-1-carboxylic acid (1.00 g, 5.87 mmol) quickly at 0 C. After stirring 15 minutes at 0oC, the resulting slurry was stirred at rt for 2h. Then the reaction was quenched carefully by adding water (0.3 mL), 15% NaOH solution (0.30 mL) and water (0.8 mL). The resulting mixture was filtered through a pad of celite and washed with THF (5 mL). Combined the filtrate and upon concentration under vacuum afforded the desired product ((1r,4r)-4-isopropylcyclohexyl)methanol (CyhAlk-OH2, 0.75 g, 82%) as a colorless solid. Step-a: Intermediate of formula (CyhAlk-OH3): Formation of trans ((1r,4r)-4-(tert- butyl)cyclohexyl)methanol The intermediate of formula (CyhAlk-OH3) was synthesized in an analogous manner to the intermediate – (CyhAlk-OH2). The intermediate ((1r,4r)-4-(tert-butyl)cyclohexyl)methanol (CyhAlk-OH3, 0.530 g, 46%) was obtained as a colorless solid. Step-a: Intermediate of formula (CyhAlk-OH4): Formation of Trans-((1r,4r)-4- methoxycyclohexyl)methanol The intermediate of formula (CyhAlk-OH4) was synthesized in an analogous manner to the intermediate – (CyhAlk-OH2). The intermediate trans-((1r,4r)-4-methoxycyclohexyl)methanol (CyhAlk-OH4, 0.75 g, 82%) was obtained as a colorless solid. Step-b: Intermediate of formula (CyhAlkBr1): Formation of 1-(bromomethyl)-4- methylcyclohexane To a stirred solution of (4-methylcyclohexyl)methanol (1.0 g, 7.80 mmol) in DCM (20 mL) was added CBr4 (3.23 g, 9.75 mmol) at room temperature under nitrogen atmosphere followed by triphenyl phosphine (2.66 g, 10.1 mmol). The resulting reaction mixture was stirred for 18 h at room temperature. After stirring 18 h, the solvents were concentrated, and the resulting residue was diluted with Hexane/Ethyl acetate (4/1, 15 mL). Washed the residue using 25% EA/Hex and combined the organic portion and concentrated to afford the desired product 1-(bromomethyl)-4- methylcyclohexane (CyhAlkBr1, 1.25 g, 84%) as a colorless oil. HPLC RT: 7.144 min.; 1H - DCG $/++ C?g' PQPY.% l .).3 $QQ' J = 7.1, 1.0 Hz, 2H), 3.28 (dd, J = 6.5, 1.0 Hz, 1H), 1.91 – 1.75 (m, 1H), 1.61 – 1.44 (m, 5H), 1.31 – 1.20 (m, 3H), 0.91 (dd, J = 6.9, 0.8 Hz, 3H), 0.88 (d, J = 6.5 Hz, 1H). Ref: Reutershan, M. H., et. al. 1-(bromomethyl)-4-methylcyclohexane, Page - 16227 Step-b: Intermediate of formula (trans-CyhAlkBr1): Formation of trans 1-(bromomethyl)- 4-methylcyclohexane The intermediate of formula trans-CyhAlkBr1 was synthesized in an analogous manner to the intermediate – CyhAlkBr1. The intermediate trans-1-(bromomethyl)-4-methylcyclohexane (trans-CyhAlkBr1, 1.35 g, 91%) was obtained as a colorless oil.1H-NMR (400 MHz, CDCl3% l 3.27 (d, J = 6.4 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.75 – 1.67 (m, 1H), 1.56 (dddt, J = 14.4, 7.9, 6.3, 3.1 Hz, 0H), 1.07 – 0.90 (m, 2H), 0.88 (d, J = 6.6 Hz, 1H). Step-b: Intermediate of formula (CyhAlkBr2): Formation of 1-(bromomethyl)-4- isopropylcyclohexane The intermediate of formula CyhAlkBr2 was synthesized in an analogous manner to the intermediate – CyhAlkBr1. The intermediate (1-(bromomethyl)-4-isopropylcyclohexane (CyhAlkBr2, 1.35 g, 96%) was obtained as a mixture of cis and trans as a colorless oil. 1H-NMR (400 MHz, CDCl3% l .)/, $Q' J = 7.3 Hz, 2H), 3.27 (d, J = 6.3 Hz, 1H), 1.99 – 1.86 (m, 2H), 1.74 (dt, J = 7.5, 4.3 Hz, 1H), 1.64 – 1.26 (m, 5H), 1.10 (tt, J = 8.0, 4.0 Hz, 1H), 1.02 – 0.96 (m, 2H), 0.86 (dd, J = 6.8, 2.5 Hz, 9H Step-b: Intermediate of formula (trans-CyhAlkBr3): Formation of (1r,4r)-1- (bromomethyl)-4-(tert-butyl)cyclohexane The intermediate of formula CyhAlkBr2 was synthesized in an analogous manner to the intermediate – CyhAlkBr1. The intermediate trans-(1r,4r)-1-(bromomethyl)-4-(tert- butyl)cyclohexane (trans-CyhAlkBr3, 0.480 g, 88%) was obtained as a colorless oil. Step-b: Intermediate of formula (trans-CyhAlkBr4): Formation of (1r,4r)-1-(bromomethyl)- 4-methoxycyclohexane The intermediate of formula CyhAlkBr4 was synthesized in an analogous manner to the intermediate – CyhAlkBr1. The intermediate trans-(1r,4r)-1-(bromomethyl)-4- methoxycyclohexane (trans-CyhAlkBr4, 0.530 g, 74%) was obtained as a colorless oil. Step-b: Intermediate of formula (spiro-CyhAlkBr): Formation of 6- (bromomethyl)spiro[2.5]octane The intermediate of formula spiro-CyhAlkBr was synthesized in an analogous manner to the intermediate – CyhAlkBr1. The intermediate spiro-CyhAlkBr 6- (bromomethyl)spiro[2.5]octane (spiro-CyhAlkBr, 0.34 g, 94%) was obtained as a colorless oil. 1H-NMR (400 MHz, CDCl3% l .).- $Q' J = 6.4 Hz, 2H), 1.91 – 1.79 (m, 2H), 1.75 – 1.53 (m, 3H), 1.18 (tdd, J = 12.5, 11.4, 3.8 Hz, 3H), 0.96 – 0.74 (m, 2H), 0.34 – 0.23 (m, 2H), 0.22 – 0.14 (m, 2H). Formation of trans -1-(bromomethyl)-4-isopropylcyclohexane
Figure imgf000118_0001
To a stirred solution of ((1r,4r)-4-isopropylcyclohexyl)methanol (I, 1.00 g, 6.40 mmol) in DCM (20 mL) was added CBr (2.33 g, 7.04 mmol) at room temperature under nitrogen atmosphere followed by triphenyl phosphine (1.68 g, 6.40 mmol). The resulting reaction mixture was stirred for 18 h at room temperature. After stirring 18 h, the solvents were concentrated, and the resulting residue was diluted with Hexane/Ethylacetate (4/1, 15 mL) then filtered. Washed the residue using 25% EA/Hex and combined the organic portion and concentrated to afford the product (1r,4r)-1-(bromomethyl)-4-isopropylcyclohexane (1.15 g, 82%) as a colorless oil.1H- NMR (400 MHz, CDCl3% l .)-2 $Q' A 71)/ ?g' ,?%' ,)40 h ,)32 $Z' ,?%' ,)3, h ,)12 $Z' ,?%' 1.60 – 1.50 (m, 0H), 1.45 – 1.32 (m, H), 1.06 – 0.93 (m, 3H), 0.85 (d, J = 6.8 Hz, 4H).
Figure imgf000119_0001
Compounds of invention of formula (46s, 46t, 46u, 46w, 47s, 47t, 47u and 47w) were synthesized via the process of Scheme XXXX, supra, as follows Step-a: Compound of Invention of formula- 46s (Compound-88): tert-butyl 7-(2-((4- cyanophenyl)((4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate Compound of Invention of formula-46s was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46s) tert-butyl 7-(2-((4- cyanophenyl)(((1s,4s)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (46s, 180 mg, 63%) as a colorless foam. TLC: Rf: 0.68 in 50%EA/Hex, MS-ESI (m/z): Calculated [M+H]+ = 483.6530; Observed [M+H]+ = 484.3182. Step-b: Compound of Invention of formula- 47s (Compound-89): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((4- methyl cyclohexyl)methyl)amino)benzonitrile Compound of Invention of formula-47s was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47s) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((4-methylcyclohexyl)methyl)amino)benzonitrile (47s , 60 mg, 63%) was obtained as a colorless foam, MS-ESI (m/z): Calculated [M+H]+ = 384.2606; Observed [M+H]+ = 384.2620. Step-a: Compound of Invention of formula- 46s (Compound-90): Formation of tert-butyl 7- (2-((4-cyanophenyl)(((1r,4r)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46s was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46s) trans-tert-butyl 7-(2-((4- cyanophenyl)(((1r,4r)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (46s, 135 mg, 69%) as a colorless foam. TLC: Rf: 0.68 in 50%EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 484.3131; Observed [M+H]+ = 484.3178. Step-b: Compound of Invention of formula- 47s (Compound-91): Formation of trans 4-((2- (6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(((1r,4r)-4- methylcyclohexyl)methyl)amino)benzonitrile Compound of Invention of formula-47sn was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47s) product trans - 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(((1r,4r)-4-methylcyclohexyl)methyl)amino)benzonitrile (47s, 40 mg, 56%) was obtained as a colorless foam. HPLC RT: 6.185 min.; MS-ESI (m/z): Calculated [M+H]+ = 384.2606: Observed [M+H]+ = 384.2716. Step-a: Compound of Invention of formula- 46t (Compound-92): Formation of tert-butyl 7- (2-((4-cyanophenyl)(((1s,4s)-4-isopropylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46t was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46t) tert-butyl 7-(2-((4- cyanophenyl)(((1s,4s)-4-isopropylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (46t, 135 mg, 66%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 512.3444l; Observed [M+H]+ = 512.3479. Step-b: Compound of Invention of formula- 47t (Compound-93): Formation of 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) ((4-isopropylcyclohexyl)methyl)amino)benzonitrile Compound of Invention of formula-47t was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47t) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((4-isopropylcyclohexyl)methyl)amino)benzonitrile (47t, 40 mg, 83%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 412.2919; Observed [M+H]+ = 412.3015. Step-a: Compound of Invention of formula- 46t (Compound-94): Formation of trans- isomer, tert-butyl 7-(2-((4-cyanophenyl)(((1r,4r)-4- isopropylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-46t was synthesized in a similar manner to the compound of Invention of formula-46b. Compound of Invention of formula-(46t) Trans-isomer, tert-butyl 7- (2-((4-cyanophenyl)(((1r,4r)-4-isopropylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (46t, 100 mg, 61%) as a colorless foam. HPLC RT: 8.509 min.; MS-ESI (m/z): Calculated [M+H]+ = 512.3444; Observed [M+H]+ = 512.3451. Step-b: Compound of Invention of formula- 47t (Compound-95): Formation 4-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (((1r,4r)-4- isopropylcyclohexyl)methyl)amino)benzonitrile Compound of Invention of formula-47t was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(47t) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((4-isopropylcyclohexyl)methyl)amino)benzonitrile (47t, 20 mg, 63%) was obtained as a colorless foam. HPLC RT: 6.855 min.; MS-ESI (m/z): Calculated [M+H]+ = 412.2919; Observed [M+H]+ = 412.2920.
Figure imgf000121_0001
Compounds of invention of formula (46Am and 48a) were synthesized via the process as outlined in Scheme XXXXXI, supra, as follows Step-a: Compound of Invention of formula-46Am (Compound-96): Formation of tert-butyl 7-(2-(N-(4-cyanophenyl)-3-fluoro-4-methoxybenzamido)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate To a stirred solution of compound tert-butyl 7-(2-((4-cyanophenyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (45a, 0.060 g, 0.16 mmol) in DCM (5 mL) was added DIEA (III, 011 mL, 0.64 mmol) followed by addition of 3-fluoro-4-methoxybenzoyl chloride (0.039 mg, 0.21 mmol) at rt under nitrogen atmosphere. After stirring 24h, at rt the reaction was quenched with water and extracted the product using DCM. Purification on a silica gel prep TLC using 50%EA/Hex followed by isolation afforded the titled compound tert-butyl 7-(2-(N-(4- cyanophenyl)-3-fluoro-4-methoxybenzamido)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (46Am, 0.075 g, 89%) as a colorless solid. MS-ESI (m/z): Calculated [M+H]+ = 526.2309; Observed [M+H]+ = 526.2345. Step-b: Compound of Invention of formula- 48a (Compound-97): Formation of N-(2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)-N-(4-cyanophenyl)-3-fluoro-4-methoxybenzamide Compound of Invention of formula-48a was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(48a) N-(2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)-N-(4-cyanophenyl)-3-fluoro-4-methoxybenzamide (48a, 0.028 g, 69%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 426.1784; Observed [M+H]+ = 426.1868.
Figure imgf000122_0001
Compounds of invention of formula (48b, 48c, 48d, and 48e) were synthesized via the process of Scheme XXXXII, supra, as follows Step-a: Compound of Invention of formula-48b (Compound-98): Formation of 4-((3-fluoro- 4-methoxybenzyl)(2-(2-(oxetan-3-yl)-6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile To a stirred solution of compound 7-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonan-2-ium 2,2,2-trifluoroacetate (47a, 0.060 g, 0.11 mmol) in 1,2-DCE (5 mL) was added DIEA (0.053 mL, 39 ,g, 0.34 mL) followed by addition of oxetan-3-one (16 mg, 0.23 mL) at room temperature under nitrogen atmosphere. After stirring 5 min at rt, sodium triacetoxyborohydride (36 mg, 0.17 mL) was at rt for 8h. After stirring 8h at rt, the reaction was quenched with water and extracted the product with DCM. Washed the organic portion with water and brine. Purification on a silica gel prep TLC using % 7M Ammonia in MeOH and 95% DCM followed by isolation afforded the titled compound 4- ((3-fluoro-4-methoxybenzyl)(2-(2-(oxetan-3-yl)-6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile (48b, 0.030 mg, 56%) as a colorless foam. TLC rf: 0.32 in 5% 7M Ammonia in MeOH and 95% DCM. HPLC RT: 5.047 min.; MS-ESI (m/z): Calculated [M+H]+ = 468.2254; Observed [M+H]+ = 468.2576. Step-a: Compound of Invention of formula-48c (Compound-99): Formation of 4-((3-fluoro- 4-methoxybenzyl)(2-(2-(tetrahydrofuran-3-yl)-6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile Compound of Invention of formula-48b was synthesized in a similar manner to the compound of Invention of formula-48a. Compound of Invention of formula-(48c) 4-((3-fluoro-4- methoxybenzyl)(2-(2-(tetrahydrofuran-3-yl)-6,8-dioxa-2-azaspiro[3.5]nonan-7- yl)ethyl)amino)benzonitrile (48c, 0.045 mg, 82%) was obtained as a colorless foam. TLC rf: 0.36 in 5% 7M Ammonia in MeOH and 95% DCM. HPLC RT: 5.223min.; MS-ESI (m/z): Calculated [M+H]+ = 482.2410; Observed [M+H]+ = 482.2627. Step-b: Compound of Invention of formula-48d (Compound-100): 4-((3-fluoro-4- methoxybenzyl)(2-(2-methyl-6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)amino)benzonitrile Compound of Invention of formula-48d was synthesized in a similar manner to the compound of Invention of formula-48a. Compound of Invention of formula-(48d) 4-((3-fluoro-4- methoxybenzyl)(2-(2-methyl-6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)amino)benzonitrile (48d, 40 mg, 83%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 426.2148; Observed [M+H]+ = 426.2324. Step-c: Compound of Invention of formula-48e (Compound-101): 4-((2-(2-(2,2- difluoroethyl)-6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile To a stirred solution of compound 7-(2-((4-cyanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonan-2-ium 2,2,2-trifluoroacetate (47a, 0.060 g, 0.11 mmol) in THF (3 mL) was added DIEA (0.053 mL, 39 mg, 0.34 mmol) followed by addition of 2,2-Difluoroethyl trifluoromethanesulfonate (37 mg, 0.17 mmol) at room temperature under nitrogen atmosphere. Purification on a silica gel prep TLC using 5%7M NH3 in MeOH/DCM, followed by isolation afforded the titled compound 4-((2-(2-(2,2-difluoroethyl)- 6,8-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (48e, 45 mg, 83%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 476.2116; Observed [M+H]+ = 476.2164. Ref: WO 2021/105474 PCT/EP2020/083796 and Wang, X., et.al., WO2013010453, P-197
Figure imgf000124_0001
Compounds of invention of formula (50a, 50b, 50c, 50d, 50e, 51a, 51b, 51c and 51d) were synthesized via the process of Scheme XXXXII, supra, as follows Step-a: Intermediates of formula (49a): Formation of tert-butyl 7-(2-((6-cyanopyridin-3- yl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 49a was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (49a) tert-butyl 7-(2-((6-cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (49a, 260 mg, 84%) was obtained as a colorless foam. TLC Rf: 0.34 in 50% EA/Hex. HPLC RT: 5.73 min.1H-NMR (400 MHz, CDCl3% l 3)++ $QQ' J = 2.9, 0.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.6, 2.9 Hz, 1H), 4.78 (s, 1H), 4.66 (t, J = 4.5 Hz, 1H), 4.28 – 4.08 (m, 2H), 3.90 (s, 2H), 3.69 (d, J = 11.3 Hz, 2H), 3.44 (s, 2H), 3.30 (q, J = 6.0 Hz, 2H), 1.96 (td, J = 6.4, 4.4 Hz, 2H), 1.66 – 1.54 (m, 3H), 1.44 (s, 9H). Step-b: Compound of Invention of formula-50a (Compound-102): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50a was synthesized in a similar manner to the compound of Invention of formula - 29a. Compound of Invention of formula-(50a) tert-butyl 7-(2-((6- cyanopyridin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (50a, 80 mg, 68%) was obtained as a colorless foam. TLC Rf: 0.21 in 50% EA/Hex. HPLC RT: 6.72 min.; MS-ESI (m/z): Calculated [M+H]+ = 513.2469; Observed [M+H]+ = 513.2517. Step-c: Compound of Invention of formula-51a (Compound-103): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-51a was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51a) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile (51a, 50 mg, 44%) was obtained as a colorless foam. HPLC RT: 4.910 min.; MS-ESI (m/z): Calculated [M+H]+ = 413.1944; Observed [M+H]+ = 413.1960. Step-a: Compound of Invention of formula-50b (Compound-104): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(3,5-difluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50b was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50b) tert-butyl 7- (2-((6- cyanopyridin-3-yl)(3,5-difluoro-4- ethoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50b, 80 mg, 56%) as a colorless foam. TLC: Rf: 0.39 in 60%EA/Hex. HPLC RT: 6.756 min.; MS-ESI (m/z): Calculated [M+H]+ = 531.2374: Observed [M+H]+ = 531.2426. Step-b: Compound of Invention of formula-51b (Compound-105): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (3,5-difluoro-4-methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-51b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51b) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,5-difluoro-4-methoxybenzyl)amino)picolinonitrile (51b, 50 mg, 88%) was obtained as a colorless foam. HPLC RT: 5.157 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850; Observed [M+H]+ = 431.1883. Step-a: Compound of Invention of formula-50c (Compound-106): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50c was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50c) tert-butyl 7- (2-((6- cyanopyridin-3-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50c, 90 mg, 58%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 531.2374: Observed [M+H]+ = 531.2423. Step-b: Compound of Invention of formula-51c (Compound-107): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)picolinonitrile, Compound of Invention of formula-51c was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51c) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)picolinonitrile (51c, 55 mg, 75%) was obtained as a colorless foam. HPLC Rt: 5.188 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850, Observed [M+H]+ = 431.1977. Step-a: Compound of Invention of formula-50d (Compound-108): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50b was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50d) of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50d, 70 mg, 45%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 531.2374; Observed [M+H]+ = 531.2435. Step-b: Compound of Invention of formula-51d (Compound-109): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-51d was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51d) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)picolinonitrile (51d, 45 mg, 79%) was obtained as a colorless foam. HPLC Rt: 5.423 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850, Observed [M+H]+ = 431.1927. Step-a: Compound of Invention of formula-50e (Compound-110): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50e was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50e) tert-butyl 7- (2-((6-cyanopyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (50e, 150 mg, 68%) as a colorless foam. Rf: 0.68 in 50%EA/Hex , HPLC RT: 2.516 min.; MS-ESI (m/z): Calculated [M+H]+ = 495.2563; Observed [M+H]+ = 495.2632.
Figure imgf000127_0001
Compounds of invention of formula (50f and 51f) were synthesized via the process of Scheme XXXXIII, supra, as follows Step-a: Compound of Invention of formula-50f (Compound-111): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50f was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50f) of tert-butyl 7-(2-((6-cyanopyridin-3-yl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (50f, 120 mg, 59%) as a colorless foam. HPLC RT: 6.494 min.; MS-ESI (m/z): Calculated [M+H]+ = 507.2563; Observed [M+H]+ = 507.2584. Step-b: Compound of Invention of formula-51f (Compound-112): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5- yl)methyl)amino)picolinonitrile Compound of Invention of formula-51f was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51f) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)picolinonitrile, (51f) as a colorless foam. HPLC Rt: 5.379 min,; MS-ESI (m/z): Calculated [M+H]+ = 407.2038; Observed [M+H]+ = 407.2132.
Figure imgf000128_0001
Compounds of invention of formula (50g, 50h, 51g, and 51h) were synthesized via the process of Scheme XXXXIV, supra, as follows Step-a: Compound of Invention of formula-50g (Compound-113): Formation of tert-butyl 7-(2-((4-chloro-3-fluorobenzyl)(6- cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50g was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50g) tert-butyl 7- (2-((4-chloro-3-fluorobenzyl)(6-cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50g, 140 mg, 68%) was obtained as a colorless foam. TLC: Rf: 0.44 in 50%EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 51517.1973; Observed [M+H- 56]+ = 517.2024. Step-b: Compound of Invention of formula-51g (Compound-114): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4- chloro-3-fluorobenzyl)amino)picolinonitrile Compound of Invention of formula-51g was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51g) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-3-fluorobenzyl)amino)picolinonitrile (51g, 0.045 g, 51%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 417.1449; Observed [M+H]+ = 417.1549. Step-a: Compound of Invention of formula-50e (Compound-115): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50h was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50h) tert-butyl 7- (2-((6-cyanopyridin-3-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50h, 100 mg, 75%) as a colorless foam. TLC: Rf: 0.50 in 50%EA/Hex. HPLC RT: 6.903 min.; MS-ESI (m/z): Calculated [M+H]+ = 496.2486; Observed [M+H]+ = 497.2567. Step-b: Compound of Invention of formula-51h (Compound-116): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)picolinonitrile, Compound of Invention of formula-51h was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51h) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)picolinonitrile(51h, 65 mg, 81%) was obtained as a colorless foam. HPLC RT: 5.294 min.; MS-ESI (m/z): Calculated [M+H]+ = 397.1995; Observed [M+H]+ = 397.2039.
Figure imgf000129_0001
Compounds of invention of formula (50i, 50j, 50k, 51i, 51j, and 51k) were synthesized via the process of Scheme XXXXV, supra, as follows Step-a: Compound of Invention of formula-50i (Compound-117): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-cyclopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of Invention of formula-50i was synthesized in an analogous manner to the compound of formula-46b1. Compound of Invention of formula-(50i) tert-butyl 7-(2-((6- cyanopyridin-3-yl)(4-cyclopropylbenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (50i, 80 mg, 59%) as a colorless foam. TLC: Rf: 0.59 in 60%EA/Hex. HPLC RT: 7.144 min.; HPLC RT: 7.14 min.; MS-ESI (m/z): Calculated [M]+ = 504.2737; Observed [M+H]+ = 505.2823 MS-ESI (m/z): Calculated [M+H]+ = 505.2770; Observed [M+H]+ = 505.2823. Step-b: Compound of Invention of formula-51i (Compound-118): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-cyclopropylbenzyl)amino)picolinonitrile Compound of Invention of formula-51i was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51i) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-cyclopropylbenzyl)amino)picolinonitrile (51i , 50 mg, 90%) was obtained as a colorless foam. HPLC RT: 5.521 min.; MS-ESI (m/z): Calculated [M+H]+ = 405.2285; Observed [M+H]+ = 405.2297. Step-a: Compound of Invention of formula-50j (Compound-119): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-50j was synthesized in an analogous manner to the compound of Invention of Invention of formula-46b1. Compound of Invention of formula-(50j) tert-butyl 7-(2-((6-cyanopyridin-3-yl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50j, 90 mg, 67%) as a colorless foam. TLC: Rf: 0.59 in 60%EA/Hex. HPLC RT: 7.420 min.; MS-ESI (m/z): Calculated [M+H]+ = 507.2966; Observed [M+H]+ = 507.2974. Step-b: Compound of Invention of formula-51j (Compound-120): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl) (4-isopropylbenzyl)amino)picolinonitrile Compound of Invention of formula-51j was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51j) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-isopropylbenzyl)amino)picolinonitrile (51j , 65 mg, 81%) was obtained as a colorless foam. HPLC RT: 5.733 min.; MS-ESI (m/z): Calculated [M+H]+ = 407.2402; Observed [M+H]+ = 407.2449. Step-a: Compound of Invention of formula-50k (Compound-121): Formation of tert-butyl 7-(2-((4-(tert-butyl)benzyl)(6-cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of Invention of formula-50k was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(50k) tert-butyl 7-(2-((4-(tertbutyl) benzyl)(6-cyanopyridin-3-yl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane- 2-carboxylate (50k, 150 mg, 68%) as a colorless foam. TLC: Rf: 0.68 in 50%EA/Hex. HPLC RT: 7.473 min.; MS-ESI (m/z): Calculated [M+H]+ = 521.3083; Observed [M+H]+ = 521.3124. Step-b: Compound of Invention of formula-51k (Compound-122): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-(tert-butyl)benzyl)amino)picolinonitrile Compound of Invention of formula-51k was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51k) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-(tert-butyl)benzyl)amino)picolinonitrile (51k, 55 mg, 49%) was obtained as a colorless foam. HPLC RT: 5.900 min.; MS-ESI (m/z): Calculated [M+H]+ = 421.2559; Observed [M+H]+ = 421.2594.
Figure imgf000131_0001
Compounds of invention of formula (50l, 50m, 51l and 51,)) were synthesized via the process of Scheme XXXXVI, supra, as follows Step-a: Compound of Invention of formula-50k (Compound-123): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)(((1s,4s)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of Invention of formula-50l was synthesized in an analogous manner to the compound of formula-46b1. Compound of Invention of formula-(50l) tert-butyl 7-(2-((6- cyanopyridin-3-yl)(((1s,4s)-4-methylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50l, 80 mg,48%) as a colorless foam. TLC: Rf: 0.67 in 50%EA/Hex. HPLC RT: 7.670 min.; HPLC RT: 7.670 min.; MS-ESI (m/z): Calculated [M+H]+ = 485.3083; Observed [M+H]+ = 485.3128. Step-b: Compound of Invention of formula-51l (Compound-124): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((4-methylcyclohexyl)methyl)amino)picolinonitrile Compound of Invention of formula-51l was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51l) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((4-methylcyclohexyl)methyl)amino)picolinonitrile (51l , I35 mg, 55%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 385.2559; Observed [M+H]+ = 385.2582. Step-a: Compound of Invention of formula-50m (Compound-125): Formation of tert-butyl 7-(2-((6-cyanopyridin-3-yl)((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of Invention of formula-50m was synthesized in an analogous manner to the compound of formula-46b1. Compound of Invention of formula-(50m tert-butyl 7-(2-((6- cyanopyridin-3-yl)((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (50m, 50 mg, 40%) as a colorless foam. TLC: Rf: 0.42 in 70%EA/Hex. HPLC RT: 6.101 min.; MS-ESI (m/z): Calculated [M+H]+ = 473.2719; Observed [M+H]+ =473.2774. Step-b: Compound of Invention of formula-51m (Compound-126): Formation of 5-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((tetrahydro-2H-pyran-4- yl)methyl)amino)picolinonitrile Compound of Invention of formula-51m was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(51m) 5-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)picolinonitrile (51m , 35 mg, 90%) was obtained as a colorless foam. HPLC RT: 4.225 min.; MS-ESI (m/z): Calculated [M+H]+ = 373.2195; Observed [M+H]+ = 373.2239.
Figure imgf000133_0001
Compounds of invention of formula (52a, 52b, 52c, 52d, 52e, 52f, 53a, 53b, 53c, 53d, 53e and 53f) were synthesized via the process of Scheme XXXXVII, supra, as follows Step-a: Intermediates of formula (49b): Formation of tert-butyl 7-(2-((5-cyanopyridin-2- yl)amino)ethyl)- 6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 49b was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (49b) tert-butyl 7-(2-((5-cyanopyridin-2-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (49b, 160 mg, 90%) was obtained as a pale brown color foam. TLC Rf: 0.32 in 60% EA/Hex. 1H-NMR (499 MHz, CDCl3% l 3)-2 $QQ' A 7 -).' +)3 ?g' 1H), 7.47 (dd, J = 8.7, 2.1 Hz, 1H), 6.32 (dd, J = 8.9, 0.8 Hz, 1H), 5.73 (t, J = 5.6 Hz, 1H), 4.58 (t, J = 4.6 Hz, 1H), 4.08 (d, J = 11.6 Hz, 1H), 3.84 (s, 2H), 3.62 (d, J = 11.2 Hz, 2H), 3.41 (q, J = 6.3 Hz, 2H), 3.37 (s, 2H), 2.93 (s, 1H), 1.86 (td, J = 6.5, 4.6 Hz, 2H), 1.37 (s, 9H). Step-b: Compound of Invention of formula-52a (Compound-127): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52a was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52a) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (52a, 150 mg, 73%) was obtained as a colorless foam. TLC: Rf: 0.44 in 50%EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 513.2469; Observed [M+H]+ = 513.2517. Step-c: Compound of Invention of formula-53a (Compound-128): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)nicotinonitrile, Compound of Invention of formula-53a was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53a) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)nicotinonitrile (53a, 0.100 g, 89%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 4413.1944; Observed [M+H]+ = 413.2029. Step-b: Compound of Invention of formula-52b (Compound-129): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylatem Compound of Invention of formula-52b was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52a) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,3-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (52b, 130 mg, 58%) as a colorless foam. HPLC RT: 6.969 min.; MS-ESI (m/z): Calculated [M+H]+ = 531.2374; Observed [M+H]+ = 531.2476. Step-c: Compound of Invention of formula-53b (Compound-130): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)nicotinonitrile Compound of Invention of formula-53b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53b) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,3-difluoro-4-methoxybenzyl)amino)nicotinonitrile (53a, 70 mg, 78%) was obtained as a colorless foam. HPLC Rt: 5.395 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850; Observed [M+H]+ = 431.1918. Step-b: Compound of Invention of formula-52c (Compound-131): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(4-ethoxy-2,3-difluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, Compound of Invention of formula-52c was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52c) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(4-ethoxy-2,3-difluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (52c, 400 mg, 81%) as a colorless foam. HPLC RT: 7.111 min.; MS-ESI (m/z): Calculated [M+H]+ = 545.2531; Observed [M+H]+ = 545.2650. Step-c: Compound of Invention of formula-53c (Compound-132): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-ethoxy-2,3-difluorobenzyl)amino)nicotinonitrile Compound of Invention of formula-53c was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53c) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-ethoxy-2,3-difluorobenzyl)amino)nicotinonitrile, (53c, 220 mg, 80%) was obtained as a colorless foam. HPLC Rt: 5.3631 min, MS-ESI (m/z): Calculated [M+H]+ = 445.2007; Observed [M+H]+ = 445.2044. Step-b: Compound of Invention of formula-52d (Compound-133): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52d was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52d tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,6-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (52d, 100 mg, 64%) as a colorless foam. HPLC RT: 6.940 min.; MS-ESI (m/z): Calculated [M+H]+ = 531.2374; Observed [M+H]+ = 531.2466. Step-c: Compound of Invention of formula-53d (Compound-134): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)nicotinonitrile Compound of Invention of formula-53d was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53d) product 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,6-difluoro-4-methoxybenzyl)amino)nicotinonitrile,(53d, 400 mg, 80%) was obtained as a colorless foam. HPLC RT: 5.323 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850; Observed [M+H]+ = 431.1924. Step-b: Compound of Invention of formula-52e (Compound-135): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52e was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52e tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,5-difluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (52e, 50 mg, 35%) as a colorless foam. HPLC RT: 4.949 min.; MS-ESI (m/z): Calculated [M+H]+ = 531.2374; Observed [M+H]+ = 531.2384. Step-c: Compound of Invention of formula-53e (Compound-136): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3,5-difluoro-4-methoxybenzyl)amino)nicotinonitrile Compound of Invention of formula-53e was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53e) product 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,5-difluoro-4-methoxybenzyl)amino)nicotinonitrile, (53e, , 20 mg, 49%) was obtained as a colorless foam. HPLC RT: 1.377 min.; MS-ESI (m/z): Calculated [M+H]+ = 431.1850; Observed [M+H]+ = 431.2866. Step-b: Compound of Invention of formula-52f (Compound-137): Formation tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,4-dimethoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52f was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52f tert-butyl 7-(2- ((5-cyanopyridin-2-yl)(3,4-dimethoxybenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (52f, 100 mg, 71%) as a colorless foam. HPLC RT: 6.443 min.; MS-ESI (m/z): Calculated [M+H]+ = 525.2668; Observed [M+H]+ = 525.2760. Step-c: Compound of Invention of formula-53f (Compound-138): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3,4-dimethoxybenzyl)amino)nicotinonitrile Compound of Invention of formula-5f was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53f) product 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,4-dimethoxybenzyl)amino)nicotinonitrile (53f, 60 mg, 74%) was obtained as a colorless foam. HPLC Rt: 4.845 min,; MS-ESI (m/z): Calculated [M+H]+ = 425.2144; Observed [M+H]+ = 425.2191.
Figure imgf000136_0001
Compounds of invention of formula (52g and 53g) were synthesized via the process of Scheme XXXXVIII, supra, as follows Step-a: Compound of Invention of formula-52f (Compound-139): tert-butyl 7-(2-((5- cyanopyridin-2-yl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52g was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52g) tert-butyl 7- (2-((5-cyanopyridin-2-yl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (52g , 90 mg, 74%) as a colorless foam. HPLC Rt: 6.660 min,; MS-ESI (m/z): Calculated [M+H]+ = 507.2563; Observed [M+H]+ = 507.2590. Step-b: Compound of Invention of formula- 53g (Compound-140): Formation -((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5- yl)methyl)amino)nicotinonitrile Compound of Invention of formula- 53g was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-( 53g) product 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((2,3-dihydrobenzofuran-5-yl)methyl)amino)nicotinonitrile, CCG- 385450, (53f, VMCC-MP-012-025-001, 60 mg, 75%) was obtained as a colorless foam. HPLC Rt: 6.660 min,; MS-ESI (m/z): Calculated [M+H]+ = 507.2563; Observed [M+H]+ = 507.2590.
Figure imgf000137_0001
Compounds of invention of formula (52h, 52i, 52j, 53h, 53i, and 53j) were synthesized via the process of Scheme XXXXIX, supra, as follows Step-a: Compound of Invention of formula-52h (Compound-141): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52h was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52h) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (52h, 40 mg, 30%) as a colorless foam, HPLC RT: 7.093 min.; MS-ESI (m/z): Calculated [M+H]+ = 497.2519; Observed [M+H]+ = 497.2564. Step-b: Compound of Invention of formula-53h (Compound-142): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)nicotinonitrile Compound of Invention of formula-53h was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53h) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methylbenzyl)amino)nicotinonitrile (53h, 25 mg, 78%) was obtained as a colorless foam. HPLC RT: 5.536 min.; MS-ESI (m/z): Calculated [M+H]+ = 397.1995; Observed [M+H]+ = 397.2145. Step-a: Compound of Invention of formula-52i (Compound-143): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)((2-methylthiazol-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52i was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52i) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3-fluoro-4-methylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, (52i, 30 mg, 23%) as a colorless foam. HPLC RT: 5.708 min.; MS-ESI (m/z): Calculated [M+H]+ = 485.2097; Observed [M+H]+ = 486.2129. Step-a: Compound of Invention of formula-52j (Compound-144): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52j was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52j tert-butyl 7-(2- ((5-cyanopyridin-2-yl)((6-methylpyridin-3-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate, CCG-385664 , (52j, 50 mg, 35%) as a colorless foam. HPLC RT: 5.314 min.; MS-ESI (m/z): Calculated [M+H]+ = 480.2566; Observed [M+H]+ = 480.2592. Step-b: Compound of Invention of formula-53j (Compound-145): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)((6-methylpyridin-3-yl)methyl)amino)nicotinonitrile Compound of Invention of formula-53j was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53j) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((6-methylpyridin-3-yl)methyl)amino)nicotinonitrile, (53j, 20 mg, 49%) was obtained as a colorless foam. HPLC RT: 2.622 min.; MS-ESI (m/z): Calculated [M+H]+ = 380.2042; Observed [M+H]+ = 380.2078; Observed [M+H]+ = 380.2078.
Figure imgf000139_0001
Compounds of invention of formula (52k, 52l, 53k and 53l) were synthesized via the process of Scheme XXXX, supra, as follows Step-a: Compound of Invention of formula-52k (Compound-146): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(3,4-dimethylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52k was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52k) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(3,4-dimethylbenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate, (52k, 90 mg, 74%) as a colorless foam. HPLC RT: 7.166 min.; MS-ESI (m/z): Calculated [M+H]+ = 493.2770; Observed [M+H]+ = 493.2854 Step-b: Compound of Invention of formula-53k (Compound-147): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3,4-dimethylbenzyl)amino)nicotinonitrile Compound of Invention of formula-53k was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53k) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3,4-dimethylbenzyl)amino)nicotinonitrile (53k, 30 mg, 54%) was obtained as a colorless foam. HPLC RT: 7.166 min.; MS-ESI (m/z): Calculated [M+H]+ = 493.2770; Observed [M+H]+ = 493.2854. Step-a: Compound of Invention of formula-52l (Compound-148): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52l was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52l) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(4-isopropylbenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2- carboxylate (52l, 100 mg, 74%) as a colorless foam. HPLC RT: 7.419 min.; MS-ESI (m/z): Calculated [M+H]+ = 507.2927; Observed [M+H]+ = 507.2974. Step-b: Compound of Invention of formula-53l; (Compound-149): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4-isopropylbenzyl)amino)nicotinonitrile Compound of Invention of formula-53l was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53l) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-isopropylbenzyl)amino)nicotinonitrile (53l, 40 mg, 71%) was obtained as a colorless foam. HPLC RT: 5.828 min.; MS-ESI (m/z): Calculated [M+H]+ = 407.2402; Observed [M+H]+ = 407.2471.
Figure imgf000140_0001
Compounds of invention of formula (52m, 52n, 52o, 53m, 53n and 53o) were synthesized via the process of Scheme XXXXXI, supra, as follows Step-a: Compound of Invention of formula-52m (Compound-150): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(2,4,6-trifluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52m was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52m) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,4,6-trifluorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (52m, 90 mg, 74%) as a colorless foam. HPLC RT: 6.890 min.; MS-ESI (m/z): Calculated [M+H]+ = 519.2174; Observed [M+H]+ = 519.2223. Step-b: Compound of Invention of formula-53m (Compound-151): Formation 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,4,6-trifluorobenzyl)amino)nicotinonitrile Compound of Invention of formula-53 m was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53m) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,4,6-trifluorobenzyl)amino)nicotinonitrile (53m, 20 mg, 72%) was obtained as a colorless foam. HPLC RT: 5.208 min.; MS-ESI (m/z): Calculated [M+H]+ = 419.1650; Observed [M+H]+ = 419.1746. Step-a: Compound of Invention of formula-52n (Compound-152): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(2,3,4-trifluorobenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52n was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52n) tert-butyl 7- (2-((5-cyanopyridin-2-yl)(2,3,4-trifluorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (52n, 60 mg, 43%) as a colorless foam. HPLC RT: 6.673 min.; MS-ESI (m/z): Calculated [M+H]+ = 519.2174; Observed [M+H]+ = 519.2354. Step-b: Compound of Invention of formula-53n; (Compound-153): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(2,3,4-trifluorobenzyl)amino)nicotinonitrile Compound of Invention of formula-53n was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53n) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(2,3,4-trifluorobenzyl)amino)nicotinonitrile (53n, 20 mg, 50%) was obtained as a colorless foam. HPLC RT: 5.208 min.; MS-ESI (m/z): Calculated [M+H]+ = 419.1650; Observed [M+H]+ = 419.1771. Step-a: Compound of Invention of formula-52o (Compound-154): Formation of tert-butyl 7-(2-((4-chloro-2,6-difluorobenzyl)(5-cyanopyridin-2-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52o was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52o) tert-butyl 7- (2-((4-chloro-2,6-difluorobenzyl)(5-cyanopyridin-2-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (52o, 50 mg, 35%) as a colorless foam. HPLC RT: 7.166 min.; MS-ESI (m/z): Calculated [M+H]+ = 535.1879; Observed [M+H]+ = 535.1924. Step-b: Compound of Invention of formula-53o; (Compound-155): 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-2,6-difluorobenzyl)amino)nicotinonitrile Compound of Invention of formula-53o was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53o) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-2,6-difluorobenzyl)amino)nicotinonitrile (53o, 20 mg, 49%) was obtained as a colorless foam. HPLC RT: 5.650 min.; MS-ESI (m/z): Calculated [M+H]+ = 435.1355; Observed [M+H]+ = 435.1403. Compounds of invention of formula (52p and 53p) were synthesized via the process of Scheme XXXX, supra, as follows Step-a: Compound of Invention of formula-52p (Compound-156): Formation of tert-butyl 7-(2-((5-cyanopyridin-2-yl)(((1r,4r)-4-isopropylcyclohexyl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-52p was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(52p) product tert- butyl 7-(2-((5-cyanopyridin-2-yl)(((1r,4r)-4-isopropylcyclohexyl)methyl)amino)ethyl)-6,8- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (52p, 40 mg, 32%) as a colorless foam. HPLC RT: 8.146 min.; MS-ESI (m/z): Calculated [M+H]+ = 513.3396; Observed [M+H]+ = 513.3415. Step-b: Compound of Invention of formula-53p; (Compound-157): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(((1r,4r)-4- isopropylcyclohexyl)methyl)amino)nicotinonitrile Compound of Invention of formula-53[ was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(53p) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(((1r,4r)-4-isopropylcyclohexyl)methyl)amino)nicotinonitrile (53p, 22 mg, 70%) was obtained as a colorless foam. HPLC RT: 6.498 min.; MS-ESI (m/z): Calculated [M+H]+ = 413.2872; Observed [M+H]+ = 413.2975.
Figure imgf000142_0001
Compounds of invention of formula (54a and 55a) were synthesized via the process of Scheme XXXXXII, supra, as follows Step-a: Intermediates of formula (49c): Formation of tert-butyl 7-(2-((6-cyanopyridazin-3- yl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 49c was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (49c) tert-butyl 7-(2-((6-cyanopyridazin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (49c, 160 mg, 89%) was obtained as a pale brown color foam. TLC Rf: 0.36 in 5% 7M NH3 in MeOH in DCM. 1?(DCG $/44 C?g' :;:Y.% l 2).1 $Q' J = 9.3 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 4.64 (t, J = 4.6 Hz, 1H), 4.11 (d, J = 11.7 Hz, 2H), 3.86 (s, 2H), 3.65 (d, J = 11.2 Hz, 2H), 3.56 (s, 2H), 3.40 (s, 2H), 1.94 (td, J = 6.5, 4.6 Hz, 2H), 1.39 (s, 9H). Step-b: Compound of Invention of formula-54a (Compound-158): Formation of tert-butyl 7-(2-((6-cyanopyridazin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-54a was synthesized in an analogous manner to the compound of Invention of formula-46b1. Compound of Invention of formula-(54a) tert-butyl 7- (2-((6-cyanopyridazin-3-yl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (54a, 25 mg, 12%) was obtained as a colorless foam. TLC: Rf: 0.44 in 50%EA/Hex. MS-ESI (m/z): Calculated [M+H]+ = 514.2421; Observed [M+H]+ = 514.2436. Step-c: Compound of Invention of formula-55a (Compound-159): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)pyridazine-3- carbonitrile Compound of Invention of formula-55a was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(55a) 6-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)pyridazine-3-carbonitrile TFA Salt (55a, 20m g, >99%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 414.1897; Observed [M+H]+ = 414.1965.
Figure imgf000144_0001
Compounds of invention of formula (53a, and 54a) were synthesized via the process of Scheme XXXXXIII, supra, as follows Step-a: Intermediate of formula-56a: Formation of tert-butyl 7-(2-((4-chloro-3- fluorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate To a stirred solution of compound tert-butyl 7-(2-aminoethyl)-6,8-dioxa-2-azaspiro[3.5]nonane- 2-carboxylate (41a, 0.125 g, 0.459 mmol) and 4-chloro-3-fluorobenzaldehyde (69 mg, 0.459 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride (136 mg,0.643 mmol) at room temperature under nitrogen atmosphere. After stirring 3h at rt, the excess reagent was quenched with water and extracted the product using DCM and washed the organic portion with water, brine, and dried over anhydrous sodium sulfate. Purification on a silica gel prep TLC plate using 5%MeOH in DCM afforded the titled compound tert-butyl 7-(2-((4-chloro-3- fluorobenzyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (52a, 120 mg, 63%) as a colorless solid. TLC Rf: 0.62 in 6%MeOH in DCM. 19F-NMR (470 MHz, CDCl3% l (,,0)+0) 1H-NMR (499 MHz, CDCl3% l 2).1 $a' J = 7.8 Hz, 1H), 7.18 (dd, J = 9.8, 2.0 Hz, 1H), 7.08 (dd, J = 8.2, 1.9 Hz, 1H), 5.57 (s, 3H), 4.61 (t, J = 4.5 Hz, 1H), 4.22 – 4.06 (m, 2H), 3.89 (s, 2H), 3.83 (s, 2H), 3.66 (d, J = 11.2 Hz, 2H), 3.43 (s, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.07 (s, 2H), 1.88 (q, J = 6.1 Hz, 2H), 1.46 (d, J = 1.8 Hz, 9H). Step-b: Compound of Invention of formula-54b (Compound-160): Formation of tert-butyl 7-(2-((4-chloro-3-fluorobenzyl)(6- cyanopyridazin-3-yl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of 54b was synthesized in an analogous manner to the intermediate – 21a. Compound of Invention of 54b tert-butyl 7-(2-((4-chloro-3-fluorobenzyl)(6- cyanopyridazin-3-yl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (54b, 20 mg, 16%) was obtained as a white solid. MS-ESI (m/z): Calculated [M+H]+ = 517.9864; Observed [M+H]+ = 517.9924. Ref: WO 2007/015162, PCT/IB2006/002151, Page 92 and WO 2007/096763 PCT/IB2007/000456, Page 53 Step-c: Compound of Invention of formula-55b (Compound-161): Formation of 6-((2-(6,8- dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(4- chloro-3-fluorobenzyl)amino)pyridazine-3- carbonitrile TFA Salt Compound of Invention of formula-55b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(55b) 6-((2-(6,8- dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(4-chloro-3-fluorobenzyl)amino)pyridazine-3-carbonitrile TFA Salt (55b, 0.027 g, 88%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 419.1338; Observed [M+2]+ = 419.1756.
Figure imgf000145_0001
Compounds of invention of formula (57, and 58) were synthesized via the process of Scheme XXXXXIV, supra, as follows Step-a: Intermediate of formula-56b: Formation of tert-butyl 7-(2-(((1-methyl-1H-indazol- 5-yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 52b was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (56b) tert-butyl 7-(2-(((1-methyl-1H-indazol-5-yl)methyl)amino)ethyl)- 6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (56b, 120 mg, 52%, polar bottom) was obtained as a white solid. TLC Rf: 0.18 and 0.56 in 6% MeOH in DCM. 1H-NMR (499 MHz, CDCl3% l 7.91 (d, J = 0.9 Hz, 1H), 7.66 (s, 1H), 7.41 – 7.36 (m, 4H), 7.32 (d, J = 8.6 Hz, 1H), 4.52 (t, J = 4.5 Hz, 1H), 4.05 – 3.99 (m, 2H), 3.98 (s, 3H), 3.93 (s, 2H), 3.78 (s, 2H), 3.57 (d, J = 11.2 Hz, 2H), 3.35 (s, 2H), 2.81 (t, J = 6.9 Hz, 2H), 1.94 (s, 2H), 1.91 – 1.85 (m, 2H), 1.39 (s, 8H). Less polar product, Bis adduct (56b, 60 mg, 19%). TLC Rf: 0.18 and 0.56 in 6% MeOH in DCM. 1H- NMR (499 MHz, CDCl3% l 2)43 h 2)31 $Z' -?%' 2)1- $`' -?%' 2)/2 h 2).1 $Z' -?%' 2).. $Q' J = 8.6 Hz, 2H), 4.47 (t, J = 5.1 Hz, 1H), 4.06 (s, 6H), 4.01 – 3.93 (m, 2H), 3.84 (s, 2H), 3.65 (s, 4H), 3.52 (d, J = 11.1 Hz, 2H), 3.37 (s, 2H), 2.56 (t, J = 7.1 Hz, 2H), 1.81 (q, J = 6.5 Hz, 2H), 1.42 (s, 9H). Step-b: Compound of Invention of formula-57 (Compound-162): Formation of tert-butyl 7- (2-((4-cyanophenyl)((1-methyl-1H-indazol-5-yl)methyl)amino)ethyl)-6,8-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of 57 was synthesized in an analogous manner to the intermediate – 21a. Compound of Invention of 57 tert-butyl 7-(2-((4-cyanophenyl)((1-methyl-1H-indazol-5- yl)methyl)amino)ethyl)-6,8-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (57, 25 mg, 17%) was obtained as a brown color foam. MS-ESI (m/z): Calculated [M+H]+ = 517.6300; Observed [M+H]+ = 517.6421. Step-c: Compound of Invention of formula-58 (Compound-163): 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((1-methyl-1H-indazol-5-yl)methyl)amino)benzonitrile, Compound of Invention of formula-58 was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(58) 4-((2-(6,8-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)((1-methyl-1H-indazol-5-yl)methyl)amino)benzonitrile (58, 0.016 g, 79%) was obtained as a colorless foam. MS-ESI (m/z): Calculated [M+2H]+ = 419.2232; Observed [M+2H]+ = 419.2250. Table – I: Compounds of invention of formula of Ia’ and Ib’ - Examples 1- 163
Figure imgf000146_0001
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Figure imgf000187_0002
Figure imgf000187_0001
Compounds of invention of formula (61a, 61b, 62a and 62b) were synthesized via the process of Scheme XXXXXV supra, as follows Step-a: Intermediates of formula (60a): tert-butyl 2-(3-((4- cyanophenyl)amino)propyl)morpholine-4-carboxylate The intermediate 60a was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (56a) tert-butyl 2-(3-((4-cyanophenyl)amino)propyl)morpholine- 4carboxylate (60a, 130 mg, 45%) was obtained as a pale yellow oil.1H-NMR (400 MHz, CDCl3) l 2)// h 2).1 $Z' -?%' 1)02 h 1)/3 $Z' -?%' /).0 $`' ,?%' .)4+ h .)3- $Z' .?%' .)/4 $aQ' J = 11.5, 2.8 Hz, 1H), 3.35 (s, 1H), 3.26 – 3.01 (m, 2H), 2.92 (s, 1H), 2.58 (s, 1H), 1.75 (dq, J = 14.1, 7.1 Hz, 2H), 1.65 – 1.49 (m, 2H), 1.45 (d, J = 0.6 Hz, 9H). Step-b: Compounds of Invention of formula (61a) (Compound-164): tert-butyl 2-(3-((4- cyanophenyl)(4-fluoro-3-methoxybenzyl)amino)propyl)morpholine-4-carboxylate Compound of Invention of formula-61a was synthesized in a similar manner to the compound of Invention of formula -29a. Compound of Invention of formula-(61a) tert-butyl 2-(3-((4- cyanophenyl)(4-fluoro-3-methoxybenzyl)amino)propyl)morpholine-4-carboxylate-(61a, 136 mg, 50%) was obtained as a pale yellow color oily material. HPLC RT:6.55 min.; MS-ESI (m/z): Calculated [M+H]+ = 484.2567; Observed [M+H]+ = 484.2624. Step-c: Compounds of Invention of formula (62a) (Compound-165): 4-((3-fluoro-4- methoxybenzyl)(3-morpholin-2-yl)propyl)amino)benzonitrile Compound of Invention of formula-62awas synthesized in an analogous manner to the compound of Invention of formula-25a. Compound of Invention of formula-(62a) 4-((3-fluoro- 4-methoxybenzyl)(3-morpholin-2-yl)propyl)amino)benzonitrile (62a, 0.105 g) was obtained as a white foam. HPLC RT:5.57 min.; MS-ESI (m/z): Calculated [M+H]+ = 383.4674; Observed [M+H]+ = 383.4752. Step-a: Intermediates of formula (60b): Formation of tert-butyl 2-(2-((4- cyanophenyl)amino)ethyl)morpholine-4-carboxylate The intermediate 60b was synthesized in an analogous manner to the intermediate – 21a. The intermediate compound (60b) tert-butyl 2-(2-((4-cyanophenyl)amino)ethyl)morpholine-4- carboxylate (60b, 230 mg, 74 %) was obtained as a pale brown color foam TLC Rf: 0.52 in 6%DCM in MeOH.1H-NMR (400 MHz, CDCl3% l 2)/, h 2).+ $Z' -?%' ' 1)0. $aa' A 74)/' -). Hz, 2H), 4.69 (d, J = 38.6 Hz, 1H), 3.94 – 3.76 (m, 2H), 3.59 – 3.39 (m, 3H), 3.29 (ddt, J = 19.1, 12.7, 6.3 Hz, 2H), 3.03 – 2.85 (m, 2H), 2.77 – 2.57 (m, 2H), 1.92 – 1.62 (m, 3H), 1.44 (d, J = 1.1 Hz, 9H). Step-b: Compounds of Invention of formula (61b) (Compound-166): Formation of tert- butyl 2-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)morpholine-4- carboxylate Compound of Invention of formula-61b was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula (61b) tert-butyl 2-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)morpholine-4-carboxylate (61b, mg, 35%) was obtained as a colorless foam. TLC Rf: 0.46 in 50% EA/Hex. HPLC RT:7.25 min; MS- ESI (m/z): Calculated [M+H]+ = 470.2410; Observed [M+H]+ = 470.2461. Step-c: Compounds of Invention of formula (62b) (Compound-167): Formation of 4-((3- fluoro-4-methoxybenzyl)(2-(morpholin-2-yl)ethyl)amino)benzonitrile Compound of Invention of formula-58b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(58b) 4-((3-fluoro-4- methoxybenzyl)(2-(morpholin-2-yl)ethyl)amino)benzonitrile (58b, 35 mg, 80%) was obtained as a colorless foam. HPLC RT: 5.29 min.; MS-ESI (m/z): Calculated [M+H]+ = 370.1886; Observed [M+H]+ = 370.1973.
Figure imgf000189_0001
Compounds of invention of formula (70a, 70b, 71a and 72b) were synthesized via the process of Scheme XXXXXVI, supra, as follows. Step-a: Intermediates of formula (60): Formation of tert-butyl (S)-2-formylmorpholine-4- carboxylate To a solution of tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (63, 2.00 g, 9.21 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane reagent (4.290 g, 10.10 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium bicarbonate (10 mL) were added, and the mixture was stirred for 30 min. The reaction mixture was filtered through celite, and the phases separated. The organic layer was washed twice with brine, then concentrated to give compound tert-butyl (S)-2-formylmorpholine-4-carboxylate as a pale brown color solid (64, 1.750 g, 88%) used without further purification. TLC Rf: 0.36 in 50% EA/Hex.1H-NMR (400 MHz, CDCl3) l 4)1. $`' ,?%' .)44 $a' J = 3.1 Hz, 1H), 3.96 (t, J = 3.1 Hz, 1H), 3.91 (d, J = 9.9 Hz, 2H), 3.78 (d, J = 13.4 Hz, 1H), 3.62 (td, J = 11.1, 3.0 Hz, 2H), 3.53 (s, 1H), 3.13 – 3.01 (m, 1H), 2.97 (t, J = 11.6 Hz, 1H), 1.46 (s, 9H). Step-b and c: Intermediates of formula (66): Formation of tert-butyl 2,2- bis(hydroxymethyl)morpholine-4-carboxylate The intermediate 66 was synthesized in a similar manner to the intermediate – VIIb-Pip- DiOH1. The intermediate compound (66) tert-butyl 2,2-bis(hydroxymethyl)morpholine-4- carboxylate (66, 0.760 g, 33%) was obtained as a white solid.1H-NMR (400 MHz, CDCl3) l 3.95 (t, J = 10.7 Hz, 0H), 3.84 – 3.70 (m, 1H), 3.67 – 3.53 (m, 4H), 3.52 – 3.39 (m, 1H), 3.34 (t, J = 5.0 Hz, 1H), 3.30 (s, 1H), 1.37 (s, 9H). Ref: WO 2018/013999 PCT/US2017/042259 Step-d: Intermediates of formula (67): Formation of tert-butyl 9-(2- (((benzyloxy)carbonyl)amino)ethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane-4-carboxylate The intermediate 67 was synthesized in a similar manner to the intermediate – 40a. The intermediate compound (67) tert-butyl 9-(2-(((benzyloxy)carbonyl)amino)ethyl)-1,8,10-trioxa-4- azaspiro[5.5]undecane-4-carboxylate (67, 1.20 g, 92%) as a colorless solid. TLC Rf 0.66 (50%
Figure imgf000190_0001
l 2).4 $Q' J = 8.8 Hz, 1H), 7.37 – 7.32 (m, 3H), 7.33 – 7.29 (m, 1H), 6.55 (d, J = 8.3 Hz, 1H), 5.25 (s, 1H), 5.08 (s, 2H), 4.56 (t, J = 4.6 Hz, 1H), 4.08 – 4.05 (m, 1H), 4.03 (d, J = 10.9 Hz, 2H), 3.64 (s, 1H), 3.61 (s, 3H), 3.60 (d, J = 5.8 Hz, 2H), 3.44 (dt, J = 11.2, 8.4 Hz, 6H), 3.36 (q, J = 6.1 Hz, 2H), 3.31 (t, J = 6.5 Hz, 1H), 1.96 (td, J = 6.5, 4.3 Hz, 1H), 1.85 (q, J = 5.6 Hz, 2H), 1.44 (s, 9H). Step-e: Intermediates of formula (68): Formation of tert-butyl 9-(2-aminoethyl)-1,8,10- trioxa-4-azaspiro[5.5]undecane-4-carboxylate The intermediate 68 was synthesized in a similar manner to the intermediate –41a. The intermediate compound (68) tert-butyl 9-(2-aminoethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane- 4-carboxylate (68, 850 mg, 94%) 1H-NMR (499 MHz, CDCl3% l /),, $Q' J = 12.0 Hz, 1H), 4.01 (d, J = 10.8 Hz, 1H), 3.87 (d, J = 10.9 Hz, 1H), 3.79 (t, J = 5.1 Hz, 1H), 3.60 (td, J = 12.0, 7.6 Hz, 2H), 3.56 – 3.50 (m, 1H), 3.41 (dt, J = 9.2, 4.7 Hz, 3H), 3.10 (s, 1H), 2.96 (d, J = 58.7 Hz, 2H), 1.94 (dt, J = 40.1, 9.6 Hz, 2H), 1.44 (t, J = 3.7 Hz, 14H). Step-f: Intermediates of formula (69): Formation of tert-butyl 9-(2-((4- cyanophenyl)amino)ethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane-4-carboxylate The intermediate 69 was synthesized in a similar manner to the intermediate – 21a. The intermediate compound (69) tert-butyl 9-(2-((4-cyanophenyl)amino)ethyl)-1,8,10-trioxa-4- azaspiro[5.5]undecane-4-carboxylate (69, 180 mg, 31%) as a colorless viscous material.1H- NMR (499 MHz, CDCl3) l 1)40 $Q' J = 8.1 Hz, 2H), 6.54 – 6.44 (m, 2H), 4.69 (t, J = 4.6 Hz, 2H), 4.63 (t, J = 5.1 Hz, 1H), 3.92 – 3.84 (m, 7H), 3.80 (t, J = 5.3 Hz, 8H), 3.64 (dd, J = 11.6, 3.7 Hz, 4H), 3.57 (t, J = 5.8 Hz, 3H), 3.54 (s, 3H), 3.45 – 3.34 (m, 8H), 3.21 (t, J = 6.5 Hz, 2H), 3.13 – 3.07 (m, 6H), 3.01 – 2.85 (m, 8H), 2.74 (d, J = 12.2 Hz, 4H), 2.21 (s, 3H), 1.98 (q, J = 6.3 Hz, 2H), 1.92 (q, J = 5.9 Hz, 3H), 1.44 (d, J = 4.2 Hz, 64H). Step-g: Compounds of Invention of formula (70a and 70b) (Compound-168 and Compound-169): Formation of tert-butyl (6r,9r)-9-(2-((4-yanophenyl)(3-fluoro-4- methoxybenzyl)amino)ethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane-4-carboxylate Compound of Invention of formula-70a (trans), and 70b (cis) were synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-
Figure imgf000191_0001
tert-butyl (6r,9r)-9-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane-4- carboxylate (70a, trans, 85 mg, 26%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 542.2622; Observed [M+H]+ = 542.2894. Cis Isomer, 70b, tert-butyl 9-(2-((4-cyanophenyl)(3- fluoro-4-methoxybenzyl)amino)ethyl)-1,8,10-trioxa-4-azaspiro[5.5]undecane-4-carboxylate (70b, cis-isomer, 80 mg, 25%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 542.2622; Observed [M+H]+ = 542.2881. Step-h: Compounds of Invention of formula (71a) (Compound-170): 4-((2-((6r,9r)-1,8,10- trioxa-4-azaspiro[5.5]undecan-9-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile, Compound of Invention of formula-71a was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(71a) 4-((2-((6r,9r)-1,8,10-trioxa- 4-azaspiro[5.5]undecan-9-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (71a, 0.020 g, 41%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 442.2097; Observed [M+H]+ = 442.2190. Step-h: Compounds of Invention of formula (71b) (Compound-171): Cis-Isomer Formation of Cis 4-((2-(1,8,10-trioxa-4-azaspiro[5.5]undecan-9-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)benzonitrile Compound of Invention of formula-71b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(71b) Cis-Isomer 4-((2-((6r,9r)- 1,8,10-trioxa-4-azaspiro[5.5]undecan-9-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)benzonitrile (71b, 0.030 g, 61%) as a colorless foam. MS-ESI (m/z): Calculated [M+H]+ = 442.2097; Observed [M+H]+ = 442.2157.
Figure imgf000192_0001
Compounds of invention of formula (79a, 79b, 80a and 80b) were synthesized via the process of Scheme XXXXXVII, supra, as follows Step-a: Intermediates of formula (74): Formation of benzyl 7-(hydroxymethyl)-5,9-dioxa- 2- azaspiro[3.5]nonane-2-carboxylate To a stirred solution of benzyl 3-oxoazetidine-1-carboxylate (3.00 g, 14.60 mmol) and 2- (hydroxymethyl)propane-1,3-diol (1.630 g, 15.40 mmol, 1.05 equ.) in Toluene (60 mL) was added p-TsOH (0.20 equi. 503 mg, 2.92 mmol) at rt under nitrogen atmosphere. The resulting mixture was heated to reflux with azeotropic removal of water. benzyl 7-(hydroxymethyl)-5,9- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (74, 3.65 g, 85%). 1H-NMR (400 MHz, CDCl3) l 7.44 – 7.26 (m, 7H), 5.09 (d, J = 1.5 Hz, 2H), 4.49 (d, J = 2.7 Hz, 1H), 4.04 (dd, J = 2.0, 0.8 Hz, 2H), 4.00 (d, J = 1.0 Hz, 2H), 3.93 (d, J = 3.8 Hz, 1H), 3.91 (t, J = 3.6 Hz, 1H), 3.76 (t, J = 5.3 Hz, 1H), 3.73 – 3.65 (m, 2H), 3.61 (q, J = 7.8 Hz, 2H), 1.90 (s, 1H). Ref: ACS Med. Chem. Lett. -+,0' 1' ,-/,j,-/1' Hb]] FNTR(-4 Step-b: Intermediates of formula (75): Formation of tert-butyl 7-(hydroxymethyl)-5,9- dioxa-2-azaspiro[3.5]nonane-2-carboxylate To a stirred solution of benzyl 7-(hydroxymethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (3.60 g, 12.30 mmol) and di-tert-butyl dicarbonate (3.48 g, 16.0 mmol) in EtOH (40 mL) was added 3-methylcyclohexa-1,4-diene (5.78 g, 61.4 mmol) followed by addition of 20% Pd(OH)2 (3.45 g, 24.5 mmol). The resulting slurry was heated to reflux for 12 h. Cool the reaction and filtered it though a pad of celite, washed with ethyl acetate and the solvents were removed from the combined filtrate. TLC Rf: in 50%EA/Hex. The crude product was purified by column chromatography on a silica gel column using a gradient of Hex to 50%EA/Hex. Removal of solvent from fractions 5-8, afforded the desired compound tert-butyl 7-(hydroxymethyl)-5,9- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (75, 3.00 g, 94%) as a brown color gummy material 1H-NMR (400 MHz, CDCl3% l .)40 $^' J = 5.0, 3.8 Hz, 4H), 3.92 (d, J = 0.9 Hz, 2H), 3.78 – 3.72 (m, 2H), 3.72 – 3.67 (m, 3H), 2.32 – 1.99 (m, 1H), 1.92 (s, 1H), 1.50 (d, J = 1.0 Hz, 25H), 1.42 (s, 9H). Step-c: Intermediates of formula (76): Formation of tert-butyl 7-(cyanomethyl)-5,9-dioxa- 2-azaspiro[3.5]nonane-2-carboxylate To a cold stirred solution of tert-butyl 7-(hydroxymethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (1.00 g, 3.86 mmol) in DCM (25 mL) was Et3N (1.161 mL, 1.17 g, 11.6 mmol) at 0oC followed by addition of methane sulfonyl chloride (II, 0.39 mL, 0.574 g, 5.01 mmol) under nitrogen atmosphere. After stirring 2h at 0oC, the solution was warm into rt and stirred for an additional 1h, then quenched with water (5 mL). The crude product was extracted using DCM and washed the organic portion using aqueous citric acid solution, water, aqueous NaHCO3 solution, water, and brine. The organic portion was dried over anhydrous Na2SO4, filtered and removal of solvent resulted the crude product tert-butyl 7-(((methylsulfonyl)oxy)methyl)-5,9- dioxa-2-azaspiro[3.5]nonane-2-carboxylate (1.30 g, >99%). 1H-NMR (499 MHz, CDCl3) l /)/- (d, J = 7.3 Hz, 1H), 4.01 (s, 1H), 4.00 – 3.96 (m, 1H), 3.92 (s, 1H), 3.84 (dd, J = 11.8, 3.7 Hz, 1H), 3.68 (d, J = 1.2 Hz, 1H), 3.05 (d, J = 1.2 Hz, 2H), 2.08 (d, J = 10.9 Hz, 1H), 1.53 (s, 4H), 1.45 (s, 4H). To a stirred solution of mesylate tert-butyl 7-(cyanomethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate tert-butyl 7-(((methylsulfonyl)oxy)methyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (1.30 g) in DMSO (10 mL) was added sodium cyanide (473 mg, 9.64 mmol) at room temperature under nitrogen atmosphere and the resulting solution was heated at 110oC for 16h. After heating 16h, the reaction was cooled to room temperature and extracted the product using ethyl acetate. The organic portion was washed with water and brine and dried over anhydrous sodium sulfate. Filter and removal of solvent resulted the desired product tert-butyl 7-(cyanomethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (76, VMCC- MP-08-065-002, 0.90 g, 87%) as a brown color solid.1H-NMR (499 MHz, CDCl3% l /),- $QQ' J = 12.1, 6.4 Hz, 0H), 3.96 (d, J = 3.1 Hz, 1H), 3.95 (d, J = 0.9 Hz, 2H), 3.94 – 3.90 (m, 1H), 3.90 – 3.86 (m, 3H), 3.72 (dd, J = 12.3, 4.5 Hz, 2H), 2.61 (d, J = 7.5 Hz, 2H), 2.02 (pd, J = 8.1, 2.7 Hz, 1H), 1.44 (d, J = 2.1 Hz, 1H), 1.40 (s, 8H), 1.14 (d, J = 15.3 Hz, 1H). Step-d: Intermediates of formula (77): Formation of tert-butyl 7-(2-aminoethyl)-5,9-dioxa- 2- azaspiro[3.5]nonane-2-carboxylate To a solution of tert-butyl 7-(cyanomethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (0.85 g, 3.2 mmol) in EtOH (20 mL)/THF (10 mL) was added a slurry of 50% aqueous Raney-Ni (5.40 g, 9.50 mmol) and 2N NaOH solution (10.0 ml, 0.80 g, 20.0 mmol) at room temperature. The resulting solution was hydrogenated at 45 psi pressure under hydrogen atmosphere at rt for 18h. After 18h, the reaction mixture was filtered through a pad of celite and concentrated the solvent. The crude product was dissolved in water (10 mL) and extracted using DCM (50 mLX2), washed the organic portion with water and brine and dried over anhydrous Na2SO4. Filtered and removal of solvent afforded the desired product tert-butyl 7-(2-aminoethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (77, 0.80 g, 93%).1H-NMR (499 MHz, CDCl3) l 0)1/ h 0)/4 (m, 2H), 4.03 – 3.93 (m, 2H), 3.91 (s, 2H), 3.74 (td, J = 11.6, 5.5 Hz, 1H), 3.42 (s, 6H), 2.63 (d, J = 7.5 Hz, 1H), 1.42 (s, 9H). Ref: Burkhard Klenke and Ian H. Gilbert, J. Org. Chem., Vol. 66, No. 7, 20012481. Step-e: Intermediates of formula (78a): Formation of tert-butyl 7-(2-((4- cyanophenyl)amino)ethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 78a was synthesized in an analogous manner to the intermediate – 21a. The intermediate 78a tert-butyl 7-(2-((4-cyanophenyl)amino)ethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (78a, 0.250 g, 73%) was obtained as a pale brown color foam. 1H-NMR (400 MHz, CDCl3) l 2)1. $QQaQ' J = 11.5, 8.6, 5.3, 2.7 Hz, 2H), 7.13 (dtdd, J = 11.6, 8.6, 5.6, 2.8 Hz, 2H), 4.09 – 3.74 (m, 5H), 3.68 – 3.46 (m, 1H), 2.57 (ddt, J = 11.5, 5.8, 2.5 Hz, 13H), 2.33 – 2.13 (m, 1H), 1.37 (ddt, J = 11.6, 5.9, 2.6 Hz, 7H), 1.14 (dddt, J = 34.3, 11.7, 6.0, 2.9 Hz, 1H) Step-e: Intermediates of formula (78b): Formation of tert-butyl 7-(2-((4- cyanophenyl)amino)ethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate The intermediate 78b was synthesized in an analogous manner to the intermediate – 21a. The intermediate 78b tert-butyl 7-(2-((6-cyanopyridin-3-yl)amino)ethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate (78b, 0.250 g, 73%) was obtained as a pale brown color foam. 1H-NMR (400 MHz, CDCl3) l 3).0 h 3)-/ $Z' ,?%' 2)1, h 2)// $Z' ,?%' 2).2 h2)-4 h 2)-- (m, 1H), 7.16 (dtt, J = 8.6, 5.5, 3.2 Hz, 0H), 3.78 – 3.55 (m, 8H), 3.54 – 3.41 (m, 1H), 3.41 – 3.15 (m, 1H), 2.78 – 2.62 (m, 1H), 2.48 – 2.29 (m, 3H), 2.12 – 1.87 (m, 1H), 1.84 – 1.64 (m, 1H), 1.25 – 1.05 (m, 12H), 1.01 – 0.76 (m, 2H). Step-f: Compounds of Invention of formula (79a) (Compound--172): Formation of tert- butyl 7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-78a was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(78a) tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (78a, 60 mg, 24%) as a colorless foam. TLC Rf: 0.45 in 30% EA/Hex. HPLC RT: 6.377 min.; MS-ESI (m/z): Calculated [M+H]+ = 512.2516; Observed [M+H-Boc]+ = 412.2510. Step-f: Compounds of Invention of formula (79b) (Compound--173): Formation of tert- butyl 7-(2-((4-cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5,9-dioxa-2- azaspiro[3.5]nonane-2-carboxylate Compound of Invention of formula-79b was synthesized in a similar manner to the compound of Invention of formula—29a. Compound of Invention of formula-(79b) tert-butyl 7-(2-((4- cyanophenyl)(3-fluoro-4-methoxybenzyl)amino)ethyl)-5,9-dioxa-2-azaspiro[3.5]nonane-2- carboxylate (79b, 60 mg, 20%) as a colorless foam. TLC Rf: 0.45 in 30% EA. HPLC RT: 5.940 min.; MS-ESI (m/z): Calculated [M+H]+ = 513.2469; Observed [M+H]+ = 513.2534. Step-h: Compounds of Invention of formula (80b) (Compound-174): Formation of 5-((2- (5,9-dioxa-2-azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4- methoxybenzyl)amino)picolinonitrile Compound of Invention of formula-80b was synthesized in a similar manner to the compound of Invention of formula-25a. Compound of Invention of formula-(80b) 5-((2-(5,9-dioxa-2- azaspiro[3.5]nonan-7-yl)ethyl)(3-fluoro-4-methoxybenzyl)amino)picolinonitrile (80b, 40 mg, 83%) was obtained as a colorless foam. HPLC RT: 4.606 min.; MS-ESI (m/z): Calculated [M+H]+ = 413.1944; Observed [M+H]+ = 413.2340. Table – II: Compounds of invention of formula of type Ia’-D22 and Id’ - Compounds 164 – 174
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Selected compounds DMPK data are listed in Table-III and the data were generated from external CRO vendors to advance the compounds for in vivo studies. Table-III: Selected compounds DMPK Data
Figure imgf000199_0002
Figure imgf000200_0001
For in vitro clearance study, diclofenac was used as a control with Hepatic Extraction Ratio (E) 0f 0.64. For protein binding study, ketoconazole was used as control substance which is 99.30% bound in Mouse Plasma. Example 2 – Compound Activities The following examples are provided to demonstrate and further illustrate certain embodiments and aspects of the present disclosure and are not to be construed as limiting the scope thereof. Experimental Methods LSD1 enzymatic assay. The assay was performed utilizing an LSD1 Inhibitor Screening Assay Kit (Cayman, cat#700120) following manufacturer’s instructions. The assay is based on the enzymatic reaction that LSD1 produces H2O2 during H3K4 demethylation. In the assay, recombinant human hLSD1 was incubated with or without each test compound in an 8-point, 3- fold dilution series, the first 21 amino acids of the N-terminal tail of histone H3 peptide substrate, horseradish peroxidase (HRP) and fluorometric substrate. After incubation for 30 min at 37°C, the fluorometric signal was read on a plate reader (SpectraMax M5e) with excitation at 530-540 nm and emission at 585-595nm and analyzed with SoftMax Pro software. Erythroid differentiation of human CD34+ cells. Human CD34+ HSPCs from mobilized peripheral blood of healthy donors were purchased from Fred Hutchinson Cancer Research Center, supported by a Center of Excellence in Hematology award from the NIDDK (U54 DK106829). The erythroid differentiation of CD34+ cells was performed following a standard three-phase culture model[22] . The basic erythroid cell expansion/differentiation media (EDM) was prepared using IMDM supplemented with human AB plasma (5%, Octaplas, Rhode Island Blood Center), penicillin-streptomycin (1%, Gibco), L-glutamine (1%, Gibco), holo- transferrin (330 µg/ml, Sigma cat#T4132), heparin (2 IU/ml, Sigma, cat#H3149), and human insulin (10 µg/ml, Sigma, cat#91077C). From days (d) 0-7, EDM-2 was prepared with EDM supplemented with hydrocortisone (1 µM, Stem Cell Technologies, cat#07904), human IL-3 (5 ng/ml, R&D, cat#203-IL), human SCF (100 ng/ml, R&D, cat#255-SC-050), and EPO (3 IU/ml, Epoetin Alfa, Amgen). Hydrocortisone and IL-3 were removed from the media at d7 while SCF was removed from d11 onward. Test compounds were added to the media at d7 and continued throughout cell culture differentiation. Evaluation of erythroid differentiation was carried out by flow cytometry at d11. At d18 of culture, cell pellets were collected, and their lysates were subjected to HPLC analysis to detect the % of HbF. HPLC. On the day erythroid differentiation terminated, cells were washed with PBS and the cell pellets were hemolyzed. The hemolysate was then subjected to HPLC analyses according to the manufacturer’s instructions using a BioRad CDM System CDM5.1 VII Instrument. Sickle cell disease (SCD) model mice. SCD mice [59]were purchased from the Jackson Laboratory (stock# 013071) and bred following the breeding strategy from the Jackson Laboratory using standard genotyping primers 11841, 11842,11843. Mice of both genders within 8-12 weeks of age were used in all experiments. Compound solutions were prepared in 30% (2- UfQ_\ef]_\]fY%(m(PfPY\QRea_V[ V[ `NYV[R P\[aNV[V[T ,+" ;CHE) CVPR dR_R NQZV[V`aR_RQ adVPR a day (b.i.d.) at 5mL/kg body weight by either intraperitoneal (IP) injection or oral gavage (PO) for up to 2 weeks. Blood was collected from saphenous veins into EDTA K2-treated capillary blood collection tubes every week. Red blood cells that express fetal hemoglobin (F cells) were analyzed by flow cytometry. Basically, whole blood was fixed with 0.05% glutaraldehyde solution followed by permeabilization with 0.1% Triton X-100. Cells were subsequently stained with APC conjugated anti-HbF antibody for flow cytometry analysis. Blood smear was prepared from fresh blood immediately after blood collection and stained using Fisher Healthcare Hema 3 Manual Staining System and Stat Pack. Images were captured from blood smear slides, followed by cell detection using Cellpose [60], extraction of cell shape using RedTell [61], and classification of sickle cells by training a LightGBM model. Results 1. In vitro IC50. The activities of compounds of invention were assessed in vitro by LSD1 enzymatic assay (FIG.1, Table-IV). In FIG.1: GSK-690 (145 nM), CC-90011 (26 nM, 0.03 nM, lit), CCG-369416 (26 nM), CCG-377222 (93 nM), CCG-385349 (14 nM), CCG-385352 (42 nM), CCG-385446 (32 nM), CCG-385450 (56 nM) and CCG-385669 (42 nM). Both irreversible and reversible LSD-1 inhibitors such as RN-1, CC-90011 and GSK-690 were included as a positive control. The tested compounds were shown to have IC50 values are varied from 16 nm to 10000 nM, under the same assay condition IC50s of RN-1, CC-90011 and GSK-690 were 22 nM, 26 nM, and 145 nm, respectively. Table-IV: Tool compounds and selected compounds IC50 Data
Figure imgf000202_0001
A++: <100 nM; A+: 100 - 250 nM; A: 250 - 500 nM; B: 500 - 1000 nM; C: 1000 - 5000 nM, and D: >5000 nM. Selected compounds DMPK data are shown in Table-V. Microsomal stability, protein binding and Caco-2 permeability studies were performed and generated data from external CRO vendors to advance the compounds for in vivo studies. For in vitro clearance study, diclofenac was used as a control with Hepatic Extraction Ratio (E) 0f 0.64. For protein binding study, ketoconazole was used as control substance which is 99.30% bound in Mouse Plasma. Table-V: Selected compounds DMPK Data
Figure imgf000203_0001
Table VI. Selected compounds plasma exposure data in CD1 and SCD mice
Figure imgf000203_0002
Figure imgf000204_0001
In vivo exposure analyses were performed in treated and untreated (control) CD1 mice. The * data obtained from the plasma concentration (nM) after 30mg/kg dose in treated and untreated (control) SCD mice. IR`a P\Z]\b[Q` dR_R ]_R]N_RQ V[ .+" $-(UfQ_\ef]_\]fY%(m( cyclodextrin (Sigma cat#332607) in saline containing 10% DMSO. Mice were administered test compounds by either IP or PO at 30mg/kg. Blood was collected from submandibular veins into K2 EDTA-treated capillary blood collection tubes after 0.5hr, 2hr, 4hr and 7hr of administration. Cells were removed from plasma by centrifugation for 15 minutes at 2,000 x g. The plasma concentration of test compounds was quantified by LC-MS/MS. Plasma concentration was determined from the area under the curve of HPLC chromatogram using Waters ACQUITY UPLC BEH C18, 2.1X50 mm, 1.7 µm and 5 cm x 2.1 mm I.D., packed with 3.5 µm Waters C18 columns were used. A mobile phase A:0.1% formic acid in purified deionized water and mobile phase B:0.1% formic acid in acetonitrile with a flow Rate:0.6 mL/min and injection volume of 5 µL, run times are 2.5 min and 4.0 min. The analytical curve was constructed using eleven non- zero standards with CCG-compounds concentration ranging from 1 to 5000 or 1 to 10000 ng/mL in the blank plasma samples. A blank sample (matrix sample processed without internal standard) was used to exclude contamination. The linear regression analysis of CCG-compounds was performed by plotting the peak area ratio (y) against the CCG-compounds concentration (x) in ng/mL. The linearity of the relationship between peak area ratio and concentration was demonstrated by the correlation coefficients (R) obtained for the linear regression of CCG- compounds (r = >0.990 in all samples) 2. In vitro induction of fetal hemoglobin Compounds were tested in a human erythroid cell differentiation model in vitro for effects on erythroid differentiation and fetal globin induction. Compounds were added at day7 of culture and present until day18. The new LSD1 inhibitors showed delayed erythroid differentiation in a dose-dependent manner, as indicated by the decrease in CD71+CD235a+ cell (maturing intermediate erythroid progenitor cell) percentage at day 11 of differentiation (FIG. 2). This is in keeping with our previous findings that LSD1 inhibition converts hematopoietic differentiation potential from an erythroid to a myeloid fate (Yu et al. Blood 2021, 138(18):1691- 1704). At day18 of culture, cells were collected for HPLC analysis of hemoglobin. HbF level was elevated over the baseline of vehicle (DMSO)-treated control and induced in a dose- dependent manner by the new LSD1 inhibitors as shown by the representative HPLC profiles of HbF% in the example (FIG. 3). GSK690 was included as a positive control, which induced HbF level to above 10% when used at 300 nM. Some of the new compounds, for example CCG- 369416, induced HbF level to over 20% at 100 nM, demonstrating a significant improvement in terms of HbF induction. Selective compounds were also shown in a bar graph presenting dose- dependent induction of F cell% examined by flow cytometry as well as induction of HbF% examined by HPLC (FIG.4). 3. In vivo induction of fetal hemoglobin and reduction of sickle cells in Townes sickle cell mouse model SCD mice were tested with three different dosing regimens, either twice a day (b.i.d.) by intraperitoneal (IP) injection, twice a day (b.i.d.) by oral gavage (PO), or once daily (q.d.) by PO for up to 2 weeks. Selective compounds tested by IP dose study shows elevated F cells in peripheral blood of sickle cell mice (FIG.5). Compounds CCG-385450, 385446, 385352 and 369416 also showed moderate increase of F cells by IP injection. Compounds CCG-385349 and CCG-385669 showed very potent and dose-dependent increase of F cells by IP injection (FIG.5). In addition, IP injection of CCG-385349 and CCG-385669 at 30mg/kg b.i.d were sufficient to significantly reduce the sickle cell numbers in peripheral blood of SCD mice compared to vehicle (DMSO)- treated mice (FIG.6). However, it is also noteworthy that IP injection of CCG-385349 and CCG- 385669 at higher doses (i.e.30mg/kg b.i.d) reduced the body weight of SCD mice after 1 week of administration (FIG.7). Selective compounds were tested for oral administration. PO administration of CCG- 385349 and CCG-385669 at 50mg/kg b.i.d for two weeks resulted in elevated F cells potently, and similar level of HbF induction was observed by PO administration of CCG-385349 and CCG-385669 at 100mg/kg q.d for two weeks (FIG.8). PO administration of CCG-385349 and CCG-385669 at 50mg/kg b.i.d significantly reduces the sickle cell numbers in peripheral blood of SCD mice compared to vehicle (DMSO)-treated mice (quantification was performed by machine learning based cell detection) (FIG.9). SCD mice have high reticulocyte numbers, a hallmark disease predictor for the disease. The reticulocyte numbers in PB of SCD mice after PO administration of CCG-385349 and CCG-385669 at 50mg/kg b.i.d was measured by thiazole orange staining followed by flow cytometry. The percentage of reticulocytes were significantly lowered by CCG-385349 and CCG-385669 after 2 weeks of oral administration, although after 1 week of treatment the mice exhibited only minimal reticulocyte reduction (FIG.10). Splenomegaly is usually observed with SCD. SCD mice were sacrificed after PO administration of CCG-385349 and CCG-385669 at 50mg/kg b.i.d for 2 weeks and their spleens were examined. While vehicle-treated SCD mice displayed enlarged spleens, either CCG-385349 or CCG-385669 treatment reduced spleen size and weight (FIG.11). 4. In vivo Body weight reduction in DIO Mice Compounds CCG-385349, and CCG-369416 were first dissolved in DMSO for stock solution, aliquoted for single use and stored in -20oC. Stock solution is diluted tenfold freshly RNPU aVZR ORS\_R V[WRPaV\[) IUR QVYbaV[T cRUVPYR V` -+" ?F(ORaN(:; $$-(?fQ_\ef]_\]fY%(m( cyclodextrin, Sigma cat# 332607) in physiological saline. To make high concentration solutions of our compounds CCG-385349, and CCG-369416, HP-beta-CD was added as a co-solvent to a final solution contains 10% DMSO. All animals were previously acclimated to handling, mice were caged by 4 and maintained on a 12h/12h light-dark cycle. Diet induced obese (DIO) mice were treated daily for 4 consecutive days with a 10, 30 mg/kg dose of the referred compounds, intraperinetional (IP) delivered, and animals' body weight was monitored daily. Changes in the mice's body weights after treatment are presented as a percentage of their initial body weights. For the study, C57bl6/j mice were purchased from Charles River at four weeks of age and kept on an HFD for 12 wks. Results are shown in FIGS.12 and 13. As shown in FIG.14, Compound 52 (CCG-369416, blue) was docked into CC90011 bound LSD1 crystal structure 6wk in MOE. Compound 52 (CCG-369416, blue) fit well into the binding pocket of CC90011 (magenta), in which the nitrile group (CN) interacting with Lys661 and the basic amino group (N- H) exhibits strong interaction with Asp555 amino acid residues. The benzylic moiety occupies the hydrophobic cleft of Phe538, Ile356 and Trp695 residues. EQUIVALENTS The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. INCORPORATION BY REFERENCE All publications, published patent documents, and patent applications cited herein are hereby incorporated by reference to the same extent as though each individual publication, published patent document, or patent application was specifically and individually indicated as being incorporated by reference. REFERENCES 1. Murayama M. Molecular mechanism of red cell "sickling". Science.1966 Jul 8;153(3732):145-9. 2. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44. 3. E_VTN G) m(IUNYN``RZVN) >R[Ra CRQ) -+,2 Ab[6,4$1%51+4(1,4) 4. Dedoussis GV, Sinopoulou K, Gyparaki M, et al. 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Claims

CLAIMS 1. A compound of formula (I):
Figure imgf000212_0001
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O and CH2; Z is selected from CHRy and NRz, wherein Ry is selected from H, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl, and Rz is selected from H and -C(O)O-C1-C6-alkyl; R1 is selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 haloalkyl; R2 is -(CH2)nNRaRb or hydrogen, wherein n is 0 or 1, Ra is H, and Rb is selected from H, C1-C4 alkyl, -C(O)-C1-C6-haloalkyl, and -C(O)O-C1-C6-alkyl, or Ra and Rb are taken together with the nitrogen atom to which they are attached to form a heteroaryl or heterocyclyl; or R1 and R2 are taken together with the carbon atom to which they are attached to form a heterocyclic ring that is optionally substituted with one or two substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; L1 is -(CH2)p-, -X-, or -CH2X-, wherein: X is selected from -CRdRe-, -C(O)-, and cycloalkylene; Rd and Re are each independently selected from hydrogen, C1-C4 alkyl, hydroxy, and halo, or Rd and Re are taken together with the carbon atom to which they are attached to form a cycloalkyl or heterocyclyl; and p is 1, 2, or 3; R3 is aryl or monocyclic heteroaryl, each of which is optionally substituted with 1 or 2 substituents independently selected from cyano, halo, C1-C4-alkylsulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C3-C6 cycloalkyl; L2 is -CH2- or -C(O)-; and R4 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C6 alkyl, halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C4-alkylsulfonyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O and Z is CHRy, and Ry is hydrogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH2 and Z is NRz.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen and -CH2OH.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R2 is -NRaRb, wherein Ra is H and Rb is selected from H, -C(O)CF3, and -COO(tert- butyl), or wherein Ra and Rb are taken together with the nitrogen atom to which they are attached to form a phthalimido group.
6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are taken together with the carbon atom to which they are attached to form a 4-, 5-, or 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N and O, wherein the heterocyclic ring is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, C1-C4 haloalkyl, -C(O)ORc, and a 4- or 5-membered monocyclic heterocyclyl having one oxygen atom, wherein Rc is C1-C4 alkyl.
7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IA):
Figure imgf000213_0001
or a pharmaceutically acceptable salt thereof, wherein: Rq is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, halo, hydroxy, oxo, -C(O)ORc, and monocyclic heterocyclyl, wherein Rc is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Rq is hydrogen.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CHOH-, -CH2CHF-, and
Figure imgf000214_0001
.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl, pyridyl, thiazolyl, or pyridizinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from cyano, fluoro, and -SO2CH3.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L2 is -CH2-.
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L2 is -C(O)-.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl, pyridyl, thiazolyl, cyclohexyl, tetrahydropyranyl, and benzopyrazolyl, each of which is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, C1-C4 alkoxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl.
14. The compound of claim 1, selected from:
Figure imgf000214_0002
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
M
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
and pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method of treating a disorder related to LSD1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15.
17. The method of claim 16, wherein the disorder related to LSD-1 activity is a hematological disorder, cancer, a neurological disorder, or a metabolic disorder.
18. The method of claim 17, wherein the disorder is a hemotological disorder selected from `VPXYR PRYY QV`RN`R N[Q m(aUNYN``RZVN)
19. The method of claim 17, wherein the disorder is a cancer selected from acute myeloid leukemia, multiple myeloma, biliary tract cancer, non-small cell lung cancer, and chronic lymphocytic leukemia.
20. The method of claim 17, wherein the disorder is a neurological disorder selected from Alzheimer’s disease, Parkinson disease, and Huntington disease.
21. The method of claim 17, wherein the disorder is a metabolic disorder selected from type- 2 diabetes and obesity.
22. The method of claim 16, wherein the disorder related to LSD-1 activity is selected from myocardial fibrosis and autism.
23. The method of any one of claims 16-22, wherein the subject is a human.
24. The method of any one of claims 16-23, further comprising administering a second therapeutic agent to the subject.
PCT/US2024/048808 2023-09-28 2024-09-27 Oxygenated heterocyclic lsd-1 inhibitors and related methods of use Pending WO2025072637A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200157091A1 (en) * 2017-05-15 2020-05-21 The Regents Of The University Of Michigan Pyrrolo[2,3-c]pyridines and related analogs as lsd-1 inhibitors
WO2021058024A1 (en) * 2019-09-29 2021-04-01 南京明德新药研发有限公司 Lsd1 inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200157091A1 (en) * 2017-05-15 2020-05-21 The Regents Of The University Of Michigan Pyrrolo[2,3-c]pyridines and related analogs as lsd-1 inhibitors
WO2021058024A1 (en) * 2019-09-29 2021-04-01 南京明德新药研发有限公司 Lsd1 inhibitor

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