GCN2-modulating compounds and uses thereof

Abstract

Provided herein are compounds, compositions, and methods useful for modulating the activity of GCN2 and treating associated conditions, diseases, and disorders, such as cancer and neurodegenerative diseases. General control nonderepressible kinase 2 (GCN2) is a serine / threonine protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) in response to amino acid starvation. GCN2 expression and activation have been shown to be elevated in human and mouse tumors, and reduced expression of GCN2 has been shown to inhibit tumor growth.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 140,314, filed January 22, 2021, which is incorporated herein by reference in its entirety. [Background technology]

[0002] 2. Background of the Invention Cancer continues to be a significant health problem, despite substantial research efforts and scientific advances reported in the literature to treat this disease. Some of the most frequently diagnosed cancers include prostate cancer, breast cancer, and lung cancer. Prostate cancer is the most common form of cancer in men. Breast cancer remains the leading cause of death in women. Current treatment options for these cancers may not be effective for all patients and / or have substantial adverse side effects. New therapies are needed to address this unmet need in cancer treatment. General control nonderepressible kinase 2 (GCN2) is a serine / threonine protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) in response to amino acid starvation (see, e.g., Wek, RC et al. in Biochem. Soc. Trans. 2006, 34(Pt 1), p. 7-11). Expression and activation of GCN2 has been shown to be elevated in human and mouse tumors, and reduced expression of GCN2 has been shown to inhibit tumor growth (see, e.g., Ye, J. et al. in EMBO J. 2010, 29(12), p. 2082-2096). Tumors grow in an environment of amino acid starvation, which can be further depleted with chemotherapy, which induces a dependency on autophagy that requires GCN2 activity. In addition, GCN2 mediates the induction of anergy in T cells in response to tryptophan depletion by indoleamine 2,3-dioxygenase (IDO) in tumor microenvironment (Munn, DH et al in Immunity 2005, 22, p. 633-642), and is essential for the growth adaptability of cytotoxic T cells in amino acid-limiting environments (Van de Velde, LA., et al. in Cell Reports 2016, 17, p. 2247-2258). Inhibition of GCN2 has been reported as a therapeutic approach for cancer treatment (see, for example, Wei, C. et al. in Mol. Biol. Cell. 2015, 26(6), p. 1044-1057). Thus, there is a need for compounds that have modulating activity against GCN2, which have further applications in the treatment of neurodegenerative diseases and doxorubicin-induced cardiotoxicity, as therapeutic agents for treating cancer. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Wek, RC et al. in Biochem. Soc. Trans. 2006, 34(Pt 1), p. 7-11 [Non-Patent Document 2] Ye, J. et al. in EMBO J. 2010, 29(12), p. 2082-2096 [Non-Patent Document 3] Munn, DH et al in Immunity 2005, 22, p. 633-642 [Non-Patent Document 4] Van de Velde, LA., et al. in Cell Reports 2016, 17, p. 2247-2258 [Non-Patent Document 5] Wei, C. et al. in Mol. Biol. Cell. 2015, 26(6), p. 1044-1057 Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention Provided herein are compounds and compositions for modulating GCN2 (e.g., activating or inhibiting GCN2). In various embodiments, the compounds and compositions described herein are useful for treating GCN2-mediated conditions, diseases, or disorders (e.g., cancer and neurodegenerative diseases).

[0005] In one aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 7-10 membered bicyclic heterocyclyl, an 8 membered bicyclic heteroaryl, or [ka] and wherein the 7-10 membered bicyclic heterocyclyl, 8 membered bicyclic heteroaryl, or 9 membered bicyclic heteroaryl is selected from the group consisting of R 3 and wherein a 7-10 membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, an 8 membered bicyclic heteroaryl contains at least two nitrogen atoms, and when a 7-10 membered bicyclic heterocyclyl, an 8 membered bicyclic heteroaryl, or a 9 membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ) and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, Cyano, C 1~6 Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 4a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 5a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 6 is a halogen, C 1~6 Alkyl, Cyano, C1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6 Cycloalkyl is R 6a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 7 is selected from the group consisting of fluoro, chloro, methyl, and cyano; R 8 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 8a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from Or X is C(R 8 ), then R 8 and R 5can optionally be combined together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when the 3- to 7-membered carbocyclyl, the 3- to 7-membered heterocyclyl, or the 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be C 1~6 optionally substituted with alkyl; R A Each occurrence independently represents hydrogen or C 1~6 is alkyl, R B Each occurrence independently represents hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 5a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 6a is, independently at each occurrence, a halogen; R 8a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl, The compound of formula (I-1) is [ka] isn't it].

[0006] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 9-membered bicyclic heterocyclyl; [ka] wherein the 9-membered bicyclic heterocyclyl or the 8-9-membered bicyclic heteroaryl is selected from the group consisting of R 3 and wherein the 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when the 9-membered bicyclic heterocyclyl or the 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ) and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, Cyano, C 1~6 Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3aand when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 4a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 5 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 5a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 6 is a halogen, C 1~6 Alkyl, Cyano, C 1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6 Cycloalkyl is R 6a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 7 is selected from the group consisting of fluoro, chloro, methyl, and cyano; R 8 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 8aand optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from Or X is C(R 8 ), then R 8 and R 5 can optionally be combined together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when the 3- to 7-membered carbocyclyl, the 3- to 7-membered heterocyclyl, or the 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be C 1~6 optionally substituted with alkyl; R A Each occurrence independently represents hydrogen or C 1~6 is alkyl, R B Each occurrence independently represents hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C1~6 alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 5a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 6a is, independently at each occurrence, a halogen; R 8a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl.

[0007] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 9-membered bicyclic heterocyclyl; [ka] wherein the 9-membered bicyclic heterocyclyl or the 8-9-membered bicyclic heteroaryl is selected from the group consisting of R 3 and wherein the 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when the 9-membered bicyclic heterocyclyl or the 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ) and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6alkyl, and cyano; 1~6 Alkyl is R 4a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 5 is C 1~6 Alkyl, cyano, hydroxyl, C 1~6 Alkoxyl, and -OC 3~6 cycloalkyl, C 1~6 Alkyl and C 1~6 Alkoxy is R 5a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 8 is cyano, Or X is C(R 8 ), then R 8 and R 5 can optionally combine together with the atoms to which they are attached to form a 3- to 7-membered carbocyclyl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents; R 6 is hydrogen, halogen, C 1~6 alkyl, and cyano; 1~6 Alkyl is R 6a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 7 is a halogen, R A is hydrogen, R B Each occurrence independently represents hydrogen, C 1~6 selected from the group consisting of alkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is, independently at each occurrence, a halogen; R 5a is independently selected at each occurrence from halogen and phenyl; R 6a is a halogen, R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl.

[0008] In another aspect, provided herein is a compound selected from any of the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound of any of the embodiments and a pharma- ceutically acceptable carrier.

[0010] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of the embodiments.

[0011] In some embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, sweat gland carcinoma, sebaceous gland carcinoma, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, head cancer, neck cancer, throat cancer, oral cancer, bone cancer, chest cancer, lymph node cancer, eye cancer, mesothelioma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or any combination thereof.

[0012] In another aspect, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of the embodiments or a pharmaceutical composition of any of the embodiments. In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or spinocerebellar ataxia.

[0013] In another aspect, provided herein is a method of treating doxorubicin-induced cardiotoxicity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of the embodiments or a pharmaceutical composition of any of the embodiments.

[0014] In another aspect, provided herein is a method of modulating activity of GCN2, comprising exposing GCN2 to an effective amount of a compound of any of the embodiments, or a pharmaceutical composition of any of the embodiments, to modulate activity of said GCN2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention The present invention provides GCN2 interacting and related compounds, pharmaceutical compositions, and their use in treating conditions such as cancer, neurodegenerative diseases, and doxorubicin-induced cardiotoxicity, as well as modulating (inhibiting / activating) GCN2 activity. The practice of the present invention employs conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, unless otherwise specified. Such techniques are described in such publications as "Comprehensive Organic Synthesis" (BM Trost & I. Fleming, eds., 1991-1992), "Handbook of experimental immunology" (DM Weir & CC Blackwell, eds.), "Current protocols in molecular biology" (FM Ausubel et al., eds., 1987, and periodically updated), and "Current protocols in immunology" (JE Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0016] Various aspects of the present invention are described in the following sections, however, the aspect of the present invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of that variable takes precedence. definition

[0017] The terms used herein have their usual meanings, and the meaning of such terms is independent at each occurrence. Nevertheless, the following definitions apply throughout this specification and claims, unless otherwise stated. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a chemical compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure shall prevail. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise specified. Thus, the definition of "alkyl" applies to the "alkyl" moiety of "alkyl" and "-O-alkyl", etc.

[0018] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon, e.g., straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, and is used herein as C 1 ~C 12 Alkyl, C 1 ~C 10 Alkyl, and C 1 ~C 6Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0019] The term "alkylene" refers to a diradical of an alkyl group. Exemplary alkylene groups include -CH 2 -, -CH 2 CH 2 - and -CH 2 C(H)(CH 3 )CH 2 - is one of them. 0 The term "-(C alkylene)-" refers to a bond. 0~3 The term "alkylene)-" refers to a bond (i.e., C 0 ) and -(C 1~3 alkylene) groups.

[0020] As used herein, "carbocyclyl" or "carbocyclic" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms. In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7 carbocyclyl"). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C7-10 carbocyclyl"). Exemplary C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3-8 carbocyclyl groups include, but are not limited to, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C3-10 carbocyclyl groups include, but are not limited to, the C3-8 carbocyclyl groups mentioned above, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), etc. As the above examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic (a "monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, e.g., a bicyclic system (a "bicyclic carbocyclyl"), which may be saturated or partially unsaturated.

[0021] The term "cycloalkyl" refers to a monovalent cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) saturated hydrocarbon radical of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, and is used herein to refer to, for example, "cycloalkyl" derived from a cycloalkane. 3 ~C 6 The term "cycloalkyl" refers to a cycloalkyl group that is substituted with at least one halogen. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "halocycloalkyl" refers to a cycloalkyl group that is substituted with at least one halogen.

[0022] The term "cycloalkylene" refers to a diradical of a cycloalkyl group. Exemplary cycloalkylene groups include: [ka] Examples include:

[0023] The term "haloalkyl" refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 etc.

[0024] The term "hydroxyalkyl" refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH 2 CH 2 OH, -C(H)(OH)CH 3 , -CH 2 C(H)(OH)CH 2 CH 2 OH, etc.

[0025] The term "hydroxyfluoroalkyl" refers to a hydroxyalkyl that is substituted with at least one fluoro.

[0026] The term "aralkyl" refers to an alkyl group substituted with an aryl group. Exemplary aralkyl groups include: [ka] Examples include:

[0027] The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group.

[0028] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0029] The term "cycloalkenyl" refers to a monovalent unsaturated cyclic, bicyclic, or bridged (e.g., adamantyl) carbocyclic hydrocarbon containing at least one C-C double bond. In certain embodiments, a cycloalkenyl contains 5 to 10, 5 to 8, or 5 to 6 carbons, and is referred to herein as, for example, "C 5 ~C 6 Exemplary cycloalkenyl groups include cyclohexenyl and cyclopentenyl.

[0030] The term "aryl" is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. Unless otherwise specified, the aromatic ring may contain, at one or more ring positions, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, carboxylic acid, -C(O)alkyl, -CO 2Alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamide, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moiety, -CF 3 , -CN, etc. The term "aryl" also includes polycyclic aromatic ring systems having two or more carbocyclic rings, where two or more carbons are common to two adjacent rings (the rings are "fused rings"), and all of the fused rings are aromatic rings, such as naphthyl groups.

[0031] The term "phenylene" refers to a diradical of a phenyl group. Exemplary phenylene groups include: [ka] Examples include:

[0032] The term "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., 6n or 10n electrons are shared in the cyclic arrangement) in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring, in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described as, for example, 6- to 10-membered heteroaryl, with the term "membered" referring to the non-hydrogen ring atoms in that moiety.

[0033] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system provided with ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system provided with ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system provided with ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl group, independently in each occurrence, may be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0034] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0035] The term "heteroarylene" refers to a diradical of a heteroaryl group. Exemplary heteroarylene groups include phenylene, pyridinylene, pyridazinylene, pyrimidinylene, pyrazinylene, [ka] Examples include:

[0036] The terms ortho, meta, and para are art-recognized and refer to 1,2-, 1,3-, and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0037] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, with the point of attachment being on either the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyl, with the term "membered" referring to the non-hydrogen ring atoms in that moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Heterocyclyls, in each instance, may be independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0038] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0039] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0040] The term "heterocycloalkyl" refers to a saturated heterocyclyl group having, for example, from three to seven ring atoms selected from carbon and heteroatoms (eg, O, N, or S).

[0041] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., those of the general formula [ka] [In the formula, R 50 , R 51 , R 52 and R 53 are each independently hydrogen, alkyl, alkenyl, -(CH 2 ) m -R 61 or R 50 and R 51 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, R 61 represents an aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, and m is 0 or an integer ranging from 1 to 8. In certain embodiments, R 50 or R 51 Only one of R can be a carbonyl, e.g., R 50 , R 51 and nitrogen do not together form an imide. 50 and R 51 (and R if needed) 52 ) are each independently a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R 61 Represents.

[0042] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, substituents of an alkyl that render it an ether include, for example, -O-alkyl, -O-alkenyl, -O-alkynyl, and -O-(CH 2 ) m -R 61 (m and R 61 is or resembles an alkoxyl, as may be represented by one of the following:

[0043] The term "fluoroalkoxyl" refers to an alkoxyl group substituted with at least one fluoro group. Exemplary fluoroalkoxyl groups include -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 etc.

[0044] The term "oxo" is art-recognized to refer to a "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0045] symbol" [ka] ", * " and " ** " indicates the point of attachment.

[0046] The term "substituted" means that one or more hydrogens on an atom of the specified group are replaced with a group selected from the indicated groups, provided that the replacement does not exceed the normal valence of the atom under the present circumstances and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The term "stable compound" or "stable structure" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0047] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition at each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0048] It should also be noted that any carbon and heteroatoms with unsatisfied valences in the text, schemes, examples, and tables herein are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0049] One or more compounds of the present invention may exist in unsolvated or solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like, and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" refers to a solvate in which the solvent molecules are H 2 O.

[0050] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, certain compounds described herein may be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, to be included within the scope of the present invention. Compounds may contain one or more asymmetric centers. For example, asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof, such as racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, are intended to be included in the present invention. Depending on the nature of the various substituents on the molecule, additional asymmetric centers may exist. Each such asymmetric center independently gives rise to two optical isomers, and all possible optical isomers, diastereomers in mixtures, and pure or partially purified compounds are intended to be included within the scope of the present invention.

[0051] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., hydrolyzing). Alternatively, a specific enantiomer of a compound of the present invention can be prepared by asymmetric synthesis. Still further, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), a diastereomeric salt can be formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, followed by recovery of the pure enantiomers.

[0052] The individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may be, for example, racemic, or mixed with all or selected other stereoisomers. The chiral centers in the compounds of the present invention may have S or R configurations as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all such atropisomer forms are considered as part of the present invention.

[0053] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably include humans.

[0054] "I C 50 The term "concentration of a compound required to achieve 50% inhibition of a target" is art-recognized and refers to the concentration of a compound required to achieve 50% inhibition of a target.

[0055] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as decreasing, reducing, regulating, ameliorating or eliminating, or relieving the symptoms thereof.

[0056] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that renders the composition suitable, inter alia, for in vivo or ex vivo diagnostic or therapeutic use.

[0057] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline solution, water, emulsions (such as oil / water or water / oil emulsions), and various types of wetting agents. The composition can also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0058] As used herein, the term "pharmaceutical acceptable salt" refers to any pharmaceutical acceptable salt (e.g., acid or base) of the compound of the present invention that can provide the compound of the present invention, or its active metabolite or residue, when administered to a subject. As known to those skilled in the art, the "salt" of the compound of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, are not themselves pharmaceutical acceptable, but can be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutical acceptable acid addition salts.

[0059] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of the formula NW 3 Compound (W is C 1~4 Examples of the aryl group include, but are not limited to, alkyl.

[0060] Exemplary salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate (also known as toluenesulfonate), undecanoate, and the like. Another example of a salt is Na + , N.H. 4 + , and N.W. 4 + (W is C 1~4Examples of salts include the anion of the compound of the present invention combined with a suitable cation, such as an alkyl group. Further examples of salts include, but are not limited to, ascorbate, borate, nitrate, phosphate, salicylate, and sulfate. In addition, acids that are generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, in 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) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York, and The Orange Book (Food & Drug Administration, Washington, DC, on their website). These disclosures are incorporated herein by reference.

[0061] Further exemplary basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, t-butylamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups may be quaternized with agents such as, for example, lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl chloride, bromide, and iodide, lauryl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0062] For therapeutic use, the salts of the compounds of the invention are contemplated as pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0063] In addition, when the compound of the present invention contains both a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, carboxylic acid), zwitterions ("inner salts") can be formed. Such acid and base salts used within the scope of the present invention are pharma- ceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the present invention can be formed, for example, by reacting the compound of the present invention with an equivalent amount of an acid or base in a solvent such as one that precipitates the salt or in an aqueous solvent, followed by lyophilization.

[0064] The present invention includes the compounds of the present invention in all their isolated forms (e.g., any solvates, hydrates, stereoisomers, and tautomers thereof). In addition, the present invention includes compounds in which one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from that found predominantly in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the present invention. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enrichment of deuterium can confer certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds can be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates without undue experimentation.

[0065] Throughout this description, where compositions are described as having, including, or comprising certain components, or processes and methods are described as having, including, or comprising certain steps, it is contemplated that there are also compositions of the invention that consist essentially of or consist of the recited components, and that there are processes and methods according to the invention that consist essentially of or consist of the recited processing steps.

[0066] The terms "a" and "an" as used herein mean "one or more" and include plurals unless the context is inappropriate.

[0067] As a general matter, compositions specifying percentages are by weight unless otherwise specified. compound

[0068] In one aspect, the compound represented by formula (I) [ka] or a pharma- ceutically acceptable salt thereof is provided, A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, 7-10 membered carbocyclyl, and 5-6 membered heterocyclyl, wherein phenyl, 5-6 membered heteroaryl, 7-10 membered carbocyclyl, or 5-6 membered heterocyclyl is selected from the group consisting of R 1 and is substituted on one or more available carbons with one, two, three or more substituents each independently selected from B is phenylene or 5- to 6-membered heteroarylene, and the phenylene or 5- to 6-membered heteroarylene is R 2 may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from C is a 7-10 membered bicyclic heterocyclyl, a 5-8 membered heteroaryl, an 8 membered bicyclic heteroaryl, and [ka] and wherein the 7-10 membered bicyclic heterocyclyl, 5-8 membered heteroaryl, 8 membered bicyclic heteroaryl, or 9 membered bicyclic heteroaryl is selected from the group consisting of R 3 and when a 7- to 10-membered heterocyclyl, a 5- to 8-membered heteroaryl, or a 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6optionally substituted with alkyl; R 1 Each occurrence independently represents hydrogen, halogen, or C. 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 1a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 Each occurrence independently represents halogen, methyl, cyano, 1~6 Alkyl, Cyano, C 1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6 Cycloalkyl is R 2a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, Cyano, C 1~6 Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R A )(R B ), -N(RA )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R A Each occurrence independently represents hydrogen or C 1~6 is alkyl, R B Each occurrence independently represents hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 1a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 2a is, independently at each occurrence, a halogen; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ) and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl.

[0069] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, 7-10 membered carbocyclyl, and 5-6 membered heterocyclyl, wherein phenyl, 5-6 membered heteroaryl, 7-10 membered carbocyclyl, or 5-6 membered heterocyclyl is selected from the group consisting of R 1 and is substituted on one or more available carbons with one, two, three or more substituents each independently selected from B is phenylene or 5- to 6-membered heteroarylene, and the phenylene or 5- to 6-membered heteroarylene is R 2 and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from C is a 7- to 10-membered heterocyclyl, a 5- to 8-membered heteroaryl, a 9-membered bicyclic heterocyclyl, or [ka] and wherein the 7-10 membered heterocyclyl, 5-8 membered heteroaryl, 9 membered bicyclic heterocyclyl, or 8-9 membered bicyclic heteroaryl is selected from the group consisting of R 3 and when a 7- to 10-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 1 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, and -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl or C 1~6 Alkoxy is R 1aand optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 2 Each occurrence independently represents a halogen, C 1~6 is selected from the group consisting of alkyl, aryl, and cyano; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R A Each occurrence independently represents hydrogen or C 1~6 is alkyl, R B Each occurrence independently represents hydrogen, C 1~6 selected from the group consisting of alkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 1ais independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently 1~6 alkyl].

[0070] In some embodiments, A is phenyl, pyridyl, [ka] A is selected from the group consisting of halogen, C 1~6 Alkyl, C 3~6Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, and -OC 3~6 one or two independent R selected from the group consisting of cycloalkyl 1 Substituted with a substituent, C 1~6 Alkyl or C 1~6 The alkoxyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen or phenyl.

[0071] In some embodiments, A is phenyl, [ka] A is selected from the group consisting of halogen, C 1~6 Alkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, and -OC 3~6 Two independent R selected from the group consisting of cycloalkyl 1 Substituted with a substituent, C 1~6 Alkyl or C 1~6 The alkoxyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen or phenyl.

[0072] In some embodiments, R 1 represents independently at each occurrence chloro, fluoro, cyano, hydroxyl, oxo, CH 3 , C.F. 3 , -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 CH(CH 3 ) 2 , -O-CH 2 CF 3 , [ka] is selected from the group consisting of:

[0073] In some embodiments, A is [ka] [ka] is selected from the group consisting of:

[0074] In some embodiments, B is phenylene or pyridylene; B is halogen, C 1~6 one or two independent R selected from the group consisting of alkyl, aryl, aryloxy ... 2 It may be substituted with a substituent as necessary.

[0075] In some embodiments, B is [ka] where: * teeth, [ka] indicates the point of attachment to ** teeth, [ka] B is a halogen, C is a 1~6 one or two independent R selected from the group consisting of alkyl, aryl, aryloxy ... 2 It may be substituted with a substituent as necessary.

[0076] In some embodiments, B is [ka] B is a halogen, C 1~6 one R selected from the group consisting of alkyl, and cyano; 2 It is substituted with a substituent.

[0077] In some embodiments, R 2 is fluoro.

[0078] In some embodiments, B is [ka] It is.

[0079] In some embodiments, B is [ka] B is a halogen, C 1~6 two independent R selected from the group consisting of alkyl, 2 It is substituted with a substituent.

[0080] In some embodiments, R 2 represents independently at each occurrence chloro, fluoro, cyano, and CH 3 is selected from the group consisting of:

[0081] In some embodiments, B is [ka] is selected from the group consisting of:

[0082] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 7-10 membered bicyclic heterocyclyl, an 8 membered bicyclic heteroaryl, or [ka] and wherein the 7-10 membered bicyclic heterocyclyl, 8 membered bicyclic heteroaryl, or 9 membered bicyclic heteroaryl is selected from the group consisting of R3 and wherein a 7- to 10-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, an 8-membered bicyclic heteroaryl contains at least two nitrogen atoms, and when a 7- to 10-membered bicyclic heterocyclyl, an 8-membered bicyclic heteroaryl, or a 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ), and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, Cyano, C 1~6 Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A)-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 4a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 5a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 6 is a halogen, C 1~6 Alkyl, Cyano, C 1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6Cycloalkyl is R 6a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R 7 is selected from the group consisting of fluoro, chloro, methyl, and cyano; R 8 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 8a and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from Or X is C(R 8 ), then R 8 and R 5can optionally be combined together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when the 3- to 7-membered carbocyclyl, the 3- to 7-membered heterocyclyl, or the 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be C 1~6 optionally substituted with alkyl; R A is hydrogen or C 1~6 is alkyl, R B is hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 5a is selected from the group consisting of halogen, hydroxyl, and phenyl, R 6a is, independently at each occurrence, a halogen; R 8a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl, The compound of formula (Ib) [ka] isn't it].

[0083] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 9-membered bicyclic heterocyclyl; [ka] wherein the 9-membered bicyclic heterocyclyl or the 8-9-membered bicyclic heteroaryl is selected from the group consisting of R 3 and wherein the 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when the 9-membered bicyclic heterocyclyl or the 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ) and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, Cyano, C 1~6 Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3aand when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 4a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 5 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 5a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 6 is a halogen, C 1~6 Alkyl, Cyano, C 1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6 Cycloalkyl is R 6a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 7 is selected from the group consisting of fluoro, chloro, methyl, and cyano; R 8 is a halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 Alkyl) is R 8amay optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from Or X is C(R 8 ), then R 8 and R 5 can optionally be combined together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when the 3- to 7-membered carbocyclyl, the 3- to 7-membered heterocyclyl, or the 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can be C 1~6 optionally substituted with alkyl; R A is hydrogen or C 1~6 is alkyl, R B is hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 5a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R 6a is, independently at each occurrence, a halogen; R 8a is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl.

[0084] In another aspect, the present invention provides a compound represented by formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 9-membered bicyclic heterocyclyl; [ka] wherein the 9-membered bicyclic heterocyclyl or the 8-9-membered bicyclic heteroaryl is selected from the group consisting of R 3 and wherein the 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when the 9-membered bicyclic heterocyclyl or the 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; X is CH, C(R 8 ) and N; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 4 is a halogen, C 1~6alkyl, and cyano; 1~6 Alkyl is R 4a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 5 is C 1~6 Alkyl, cyano, hydroxyl, C 1~6 Alkoxyl, and -OC 3~6 cycloalkyl, C 1~6 Alkyl and C 1~6 Alkoxy is R 5a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 8 is cyano, Or X is C(R 8 ), then R 8 and R 5 can optionally combine together with the atoms to which they are attached to form a 3- to 7-membered carbocyclyl, which can be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents; R 6 is hydrogen, halogen, C 1~6 alkyl, and cyano; 1~6 Alkyl is R 6a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 7 is a halogen, R A is hydrogen, R B is hydrogen, C 1~6 selected from the group consisting of alkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6Alkyl or phenyl is R e and when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 4a is, independently at each occurrence, a halogen; R 5a is independently selected at each occurrence from halogen and phenyl; R 6a is a halogen, R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently hydrogen and C 1~6 alkyl.

[0085] In some embodiments, R 4 are independently chloro, fluoro, cyano, hydroxyl, oxo, CH 3 , C.F. 3 , -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 CH(CH 3 ) 2 , -O-CH 2 CF 3 , [ka] In some embodiments, R 4 are chloro, fluoro, cyano, and CF 3 is selected from the group consisting of:

[0086] In some embodiments, R 5 is chloro, fluoro, cyano, hydroxyl, oxo, CH 3 , C.F. 3 , -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 CH(CH 3 ) 2 , -O-CH 2 CF 3 , [ka] In some embodiments, R5 is CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH 2 -CF 3 , -O-CH 2 -C(H)(CH 3 ) 2 , -O-CH-(CH 3 ) 2 , [ka] is selected from the group consisting of:

[0087] In some embodiments, X is N.

[0088] In some embodiments, X is (R 8 ).

[0089] In some embodiments, R 8 and R 5 together with the atom to which they are attached form a 3- to 7-membered carbocyclyl, which is optionally substituted with hydroxyl. 8 and R 5 together with the atom to which they are attached form a 3- to 7-membered carbocyclyl, which is substituted with hydroxyl. 8 and R 5 together with the atoms to which they are attached form a 5-membered carbocyclyl, which is optionally substituted with hydroxyl. In some embodiments, R 8 and R 5 together with the atom to which they are attached form a 5-membered carbocyclyl, which is substituted with a hydroxyl.

[0090] In some embodiments, R 6 is a halogen, C 1~6In some embodiments, R 6 is hydrogen, chloro, fluoro, cyano, and CH 3 In some embodiments, R 6 is fluoro.

[0091] In some embodiments, R 7 is fluoro or chloro. In some embodiments, R 7 is fluoro.

[0092] In some embodiments, R 6 is methyl, R 7 is fluoro. In some embodiments, R 6 is fluoro and R 7 is fluoro. In some embodiments, R 6 is chloro and R 7 is fluoro. In some embodiments, R 6 is fluoro and R 7 is chloro. In some embodiments, R 6 is cyano and R 7 is fluoro. In some embodiments, R 6 is methyl, R 7 is fluoro.

[0093] In another aspect, the present invention provides a compound represented by formula (Ib) [ka] or a pharma- ceutically acceptable salt thereof is provided, C is a 7-10 membered bicyclic heterocyclyl, a 5-8 membered bicyclic heteroaryl, or [ka] and wherein the 7-10 membered bicyclic heterocyclyl, the 5-8 membered bicyclic heteroaryl, or the 9 membered bicyclic heteroaryl is selected from the group consisting of R3 and wherein a 7- to 10-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, an 8-membered bicyclic heteroaryl contains at least two nitrogen atoms, and when a 7- to 10-membered bicyclic heterocyclyl, an 8-membered bicyclic heteroaryl, or a 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C 1~6 optionally substituted with alkyl; R 3 Each occurrence independently represents a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, Cyano, C 1~6 Alkoxyl, hydroxyl, phenyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R A Each occurrence independently represents hydrogen or C 1~6 is alkyl, R B Each occurrence independently represents hydrogen, C 1~6 Alkyl, C 3~6 is selected from the group consisting of cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; 1~6 Alkyl or phenyl is R eand when a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 optionally substituted with alkyl; R 3a Each occurrence independently represents halogen, cyano, hydroxyl, C 1~6 Alkyl, Phenyl, C 3~6 Cycloalkyl, 5- to 6-membered heterocyclyl, and -CO 2 (C 1~6 alkyl), C 1~6 An alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, and phenyl, and when a 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from the group consisting of C 1~6 optionally substituted with alkyl; R e Each occurrence independently represents a halogen, a hydroxyl, or a C 1~6 Alkyl, 3-6 membered cycloalkyl, 5-6 membered heterocyclyl, -N(R C )(R D ), and -S(O) 2 C 1~6 alkyl, C 1~6 Alkyl or 5-6 membered heterocyclyl is oxo and -N(R C )(R D ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R C and R D are each independently 1~6 is alkyl, R 4 is halogen, cyano, and C 1~6alkyl, C 1~6 The alkyl may be optionally substituted on one or more available carbons with one, two, three or more independent halogen substituents; R 5 is C 1~6 Alkyl, C 1~6 Alkoxyl, -OC 3~6 Cycloalkyl, C 3~6 Cycloalkyl, cyano, hydroxyl, oxo, -N(R A )(R B ), -N(R A )-C(O)(R B ), -(C 1~6 alkylene)-N(R A )(R B ), -CO 2 H, -CO 2 (C 1~6 alkyl), and -S-(C 1~6 alkyl), C 1~6 Alkyl, C 1~6 Alkoxyl, and -S-(C 1~6 alkyl) may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from hydroxyl, halogen and phenyl; R 6 is hydrogen, halogen, cyano, C 1~6 Alkyl, C 1~6 Alkoxyl, and C 3~6 cycloalkyl, C 1~6 Alkyl and C 3~6 Cycloalkyl is R 6a may optionally be substituted on one or more available carbons by one, two, three or more substituents independently selected from R 6a is a halogen, R 7 is selected from the group consisting of fluoro, chloro, methyl, and cyano.

[0094] In some embodiments, R 4 are chloro, fluoro, cyano, and CF 3 is selected from the group consisting of:

[0095] In some embodiments, R 5 is CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH 2 -CF 3 , -O-CH 2 -C(H)(CH 3 ) 2 , -O-CH-(CH 3 ) 2 , [ka] is selected from the group consisting of:

[0096] In some embodiments, R 6 is hydrogen, chloro, fluoro, cyano, C 1~6 Alkyl, and CH 3 is selected from the group consisting of:

[0097] In some embodiments, R 7 is fluoro or chloro.

[0098] In some embodiments, C is [ka] C is selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B one, two, three or more independent R selected from the group consisting of aryl, ... 3Substituents may optionally be substituted on one or more available carbons, C 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 It may be optionally substituted with alkyl.

[0099] In some embodiments, C is [ka] C is selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B one, two, three or more independent R selected from the group consisting of aryl, ... 3 Substituents may optionally be substituted on one or more available carbons, C 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 It may be optionally substituted with alkyl.

[0100] In some embodiments, C is [ka] C is selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 3 Substituted with a substituent, C 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 It may be optionally substituted with alkyl.

[0101] In some embodiments, R 3 is C 1~6 Alkyl, -C(O)N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 1~6 Alkyl and 5-10 membered heteroaryl are chloro, cyano, hydroxyl, CH 3 , C.F. 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -C(O)OCH 3 , cyclopropyl, phenyl, [ka] and optionally substituted on one or more available carbons with one, two, three or more substituents independently selected at each occurrence from the group consisting of:

[0102] In some embodiments, R Ais hydrogen.

[0103] In some embodiments, R B is hydrogen, CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 CF 3 , C.H. 2 CH 2 OH, -CH 2 CH 2 N(CH 3 ) 2 , -(CH 2 ) 3 N(CH 3 ) 2 , -CH 2 CH 2 S(O) 2 CH 3 , [ka] It is.

[0104] In some embodiments, R 3 is -CH 2 OH, [ka] [ka] [ka] is selected from the group consisting of:

[0105] In some embodiments, C is [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0106] In some embodiments, C is [ka] C is selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Alkoxyl, oxo, -C(O)N(R A )(R B ), -N(R A )(R B ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; 3 Substituted with a substituent, C 1~6 Alkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl is R 3a and when a 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from 1~6 It may be optionally substituted with alkyl.

[0107] In some embodiments, R 3 Each occurrence independently represents halogen, oxo, C 1~6 Alkyl, C 1~6 Alkoxyl, -C(O)N(R A )(R B ), -N(RA )(R B ), and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with chloro.

[0108] In some embodiments, R A is hydrogen.

[0109] In some embodiments, R B is CH 3 It is.

[0110] In some embodiments, R 3 is fluoro, oxo, CH 3 , -O-CH 3 , -NHCH 3 , [ka] is selected from the group consisting of:

[0111] In some embodiments, C is [ka] [ka] is selected from the group consisting of:

[0112] In another embodiment, the compound is selected from any compound set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0113] In certain embodiments, the compound is 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 2-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide; 2-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-cyano-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethylimidazo[1,5-a]pyridine-1-carboxamide; 2-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide; 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxy-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide; 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-2-methoxy-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide; N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 7-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-8-fluoro-N-methylimidazo[1,5-a]pyridine-3-carboxamide; 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,1-dimethyl-2-oxoimidazo[1,5-a]pyrimidine-8-carboxamide; 6-[3-[3-cyano-5-(trifluoromethyl)benzenesulfonamido]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methyl-5-(methylamino)imidazo[1,5-a]pyridine-1-carboxamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-Chloro-N-[3,5-difluoro-4-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]pyridin-2-yl]-2-methoxypyridine-3-sulfonamide; (6R)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; (6S)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 7-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-3-carboxamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(2H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; (6R)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,7-dimethyl-5H,6H,8H-imidazo[1,5-a]pyrazine-1-carboxamide; (6S)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,7-dimethyl-5H,6H,8H-imidazo[1,5-a]pyrazine-1-carboxamide; 5-chloro-N-[2,4-difluoro-3-[1-(3H-1,2,3-triazol-4-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1-methylpyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2-cyano-4-fluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 6-cyano-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[8-fluoro-3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[8-fluoro-3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-(3-(1-(4-cyano-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; N-[3-[1-(4-cyano-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-[3-[1-(4-chloro-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1-methylpyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[8-fluoro-3-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-7-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[1-(4-methyl-3H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-(2,4-difluoro-3-[1-[4-(hydroxymethyl)-3H-imidazol-2-yl]imidazo[1,5-a]pyridin-6-yl]phenyl)-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(4-methyl-3H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-(2,4-difluoro-3-[1-[4-(hydroxymethyl)-3H-imidazol-2-yl]imidazo[1,5-a]pyridin-6-yl]phenyl)-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-[3-[1-(4-chloro-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(1-methylpyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1-methylpyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1,2,3-triazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1,2,3-triazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[1-(4-methyl-3H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(1-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-2-methylpyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1,2,3,4-tetrazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; (R)—N-(3-(3-(1H-imidazol-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; (S)—N-(3-(3-(1H-imidazol-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-5-cyano-2-methoxypyridine-3-sulfonamide; (R)-6-(2,6-difluoro-3-((5-fluoro-2-methoxypyridine)-3-sulfonamido)phenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-6-(2,6-difluoro-3-((5-fluoro-2-methoxypyridine)-3-sulfonamido)phenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (R)-6-(3-((5-cyano-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-6-(3-((5-cyano-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; 5-cyano-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-7-methyl-5H,6H,8H-imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-7-methyl-5H,6H,8H-imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1,2,3,4-tetrazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(1,2,3,4-tetrazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1,2,3,4-tetrazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1,2,3,4-tetrazol-1-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6R)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6S)-1-(1H-imidazol-2-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[5-(1H-imidazol-2-yl)imidazo[1,5-b]pyridazin-2-yl]phenyl]-2-methoxypyridine-3-sulfonamide; (R)-6-(2,6-difluoro-3-((5-fluoro-2-methylpyridine)-3-sulfonamido)phenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-6-(2,6-difluoro-3-((5-fluoro-2-methylpyridine)-3-sulfonamido)phenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; 5-chloro-N-[3-[1-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[1-(5-isopropyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; (R)-6-(3-((5-chloro-2-methylpyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; (S)-6-(3-((5-chloro-2-methylpyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 5-Chloro-N-(2,4-difluoro-3-(1-(hydroxymethyl)imidazo[1,5-a]pyridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[5-(1H-imidazol-2-yl)imidazo[1,5-b]pyridazin-2-yl]phenyl]-2-methylpyridine-3-sulfonamide; (5S,6R)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; (5R,6S)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; 5-cyano-N-[2,4-difluoro-3-[5-(1H-imidazol-2-yl)imidazo[1,5-b]pyridazin-2-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[5-(1H-imidazol-2-yl)imidazo[1,5-b]pyridazin-2-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(1-(isoxazol-5-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1-hydroxyethyl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 6-(2-chloro-3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-6-fluorophenyl)-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 5-chloro-N-(2,4-difluoro-3-[1-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]imidazo[1,5-a]pyridin-6-yl]phenyl)-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2-chloro-4-fluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[5-fluoro-1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[5-fluoro-1-(2H-pyrazol-3-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 6-[2-chloro-3-(5-chloro-2-methoxypyridine-3-sulfonamido)-6-fluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; N-[2,4-difluoro-3-[5-fluoro-1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[5-fluoro-1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[5-fluoro-1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-chloro-2-methoxypyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-cyano-2-methoxypyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-chloro-2-methylpyridine-3-sulfonamide; N-[3-[1-(1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-[3-[1-(4-chloro-1H-imidazol-2-yl)-5-fluoroimidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[3-[1-(4-chloro-1H-imidazol-2-yl)-5-fluoroimidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2-cyano-6-fluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; N-[2,4-difluoro-3-[1-(1,2-oxazol-5-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(1,2-oxazol-5-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 2-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[4,3-b][1,3]thiazole-7-carboxamide; 5-Chloro-N-[2,4-difluoro-3-[1-(1,2-oxazol-5-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-6-fluoro-2-methylphenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 5-cyano-N-[2,4-difluoro-3-[1-(4,5,6,7-tetrahydro-1H-1,3-benzodiazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-Chloro-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(1,2-oxazol-5-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-cyano-N-[3-[1-(4,5-dimethyl-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]-2,4-difluorophenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6S)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6R)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6S)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6R)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 6-(3-((5-chloro-2-oxo-1,2-dihydropyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 5-chloro-N-[2,4-difluoro-3-[1-(5-methyl-4H-1,2,4-triazol-3-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6S)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; N-[2,4-difluoro-3-[(6R)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-5-fluoro-2-methylpyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[(6S)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-cyano-N-[2,4-difluoro-3-[(6R)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6S)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 5-chloro-N-[2,4-difluoro-3-[(6R)-1-(5-methyl-4H-1,2,4-triazol-3-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methylpyridine-3-sulfonamide; 6-[6-chloro-3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2-fluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide; 2-[6-chloro-3-(5-chloro-2-methylpyridine-3-sulfonamido)-2-fluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide; 2-[2-chloro-3-(5-chloro-2-methylpyridine-3-sulfonamido)-6-fluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide; 6-(2-fluoro-5-((5-fluoro-2-methoxypyridine)-3-sulfonamido)phenyl)-N-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-1-carboxamide; 6-(6-chloro-3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2-fluorophenyl)-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; N-[4-chloro-2-fluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 5-chloro-N-(3-(1-(4,5-dimethyl-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)-2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide; N-(3-(1-(4,5-dimethyl-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methoxypyridine-3-sulfonamide; N-(3-(1-(4,5-dimethyl-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)-2,4-difluorophenyl)-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-(3-(1-(4,5-dimethyl-1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)-2,4-difluorophenyl)-2-methylpyridine-3-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(1-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-2-methoxypyridine-3-sulfonamide; N-(2,4-difluoro-3-(1-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-5-fluoro-2-methoxypyridine-3-sulfonamide; N-(2,4-difluoro-3-(1-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-5-fluoro-2-methylpyridine-3-sulfonamide; 5-chloro-N-(2,4-difluoro-3-(1-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl)phenyl)-2-methylpyridine-3-sulfonamide; N-[2-chloro-4-fluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; (6R)-6-[2-chloro-6-fluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; (6S)-6-[2-chloro-6-fluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; Methyl 2-[6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyrazin-1-yl]-3H-1,3-benzodiazole-5-carboxylate; (6S)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methyl-5H,6H,8H-imidazo[4,3-c][1,4]oxazine-1-carboxamide; (6R)-6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methyl-5H,6H,8H-imidazo[4,3-c][1,4]oxazine-1-carboxamide; (6R)-6-[6-chloro-2-fluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; (6S)-6-[6-chloro-2-fluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyridine-1-carboxamide; N-[2,4-difluoro-3-[1-(4-phenyl-1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]phenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-isopropylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(2-methylpropyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(2-hydroxyethyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(1-methylpyrazol-4-yl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(oxan-4-ylmethyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(2-methanesulfonylethyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-ethylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(cyclopropylmethyl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-ethoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-isopropoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-cyclopropoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-5-fluoro-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[3-(dimethylamino)propyl]imidazo[1,5-a]pyrazine-1-carboxamide; (R)-6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-(1-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazine-1-carboxamide; (S)-6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-N-(1-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-(1,2-oxazol-4-yl)imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[2-(morpholin-4-yl)ethyl]imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-[5-chloro-2-(2-methylpropoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; N-[3-[1-(5-cyclopropyl-3H-imidazol-4-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; N-[3-[1-(4-benzyl-1H-imidazol-2-yl)imidazo[1,5-a]pyrazin-6-yl]-2,4-difluorophenyl]-5-fluoro-2-methoxypyridine-3-sulfonamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[2-(dimethylamino)ethyl]imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[2-(2-oxopyrrolidin-1-yl)ethyl]imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-[4-[(dimethylamino)methyl]phenyl]imidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-[5-chloro-2-(2,2,2-trifluoroethoxy)pyridine-3-sulfonamido]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[3-[2-(benzyloxy)-5-chloropyridine-3-sulfonamido]-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-5-fluoro-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; N-(2,4-difluoro-3-[1-[5-(4-methylpiperazin-1-yl)-3H-1,3-benzodiazol-2-yl]imidazo[1,5-a]pyridin-6-yl]phenyl)-5-fluoro-2-methoxypyridine-3-sulfonamide; and 6-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyrazine-1-carboxamide; or a pharma- ceutically acceptable salt thereof. therapeutic application

[0114] Compounds that modulate (inhibit / activate) GCN2 It is contemplated that the compounds that modulate (inhibit / activate) GCN2 and related compounds described herein, such as the compounds of formula I, provide therapeutic benefit to subjects suffering from cancer, neurodegenerative disease, and doxorubicin-induced cardiotoxicity.Therefore, one aspect of the present invention provides a therapeutic method for treating the aforementioned diseases and conditions using the compounds that modulate (inhibit / activate) GCN2 and related compounds described herein.Various aspects and embodiments of the therapeutic method are described below. cancer

[0115] One aspect of the present invention provides a method for treating cancer in a subject.The method comprises administering a therapeutically effective amount of a compound that modulates (inhibits / activates) GCN2 or related compound as described herein, for example, a compound of formula 1, to a subject in need thereof to treat cancer.In certain embodiments, the specific compound of formula I is a compound defined by one of the above embodiments.

[0116] In certain embodiments, the cancer is a solid tumor, leukemia, or lymphoma.In certain embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, sweat gland carcinoma, sebaceous gland carcinoma, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, head cancer, neck cancer, throat cancer, oral cancer, bone cancer, breast cancer, lymph node cancer, eye cancer, mesothelioma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, leukemia, or lymphoma.In certain embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, leukemia, or lymphoma. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, or diffuse large B-cell lymphoma.In certain other embodiments, the cancer is breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, kidney cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.

[0117] Further exemplary cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, and hemangioblastoma.

[0118] In certain embodiments, the cancer is selected from the group consisting of neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumors, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous The following cancer types are considered to be present in the patient population: gynecologic carcinoma, gynecologic sarcoma, soft tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresecectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or leiomyoma.

[0119] In certain embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, sweat gland carcinoma, sebaceous gland carcinoma, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, head cancer, neck cancer, throat cancer, oral cancer, bone cancer, breast cancer, lymph node cancer, eye cancer, mesothelioma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, leukemia, or lymphoma. Neurodegenerative diseases

[0120] Another aspect of the present invention provides a method for treating neurodegenerative disease in a subject.The method comprises administering a therapeutically effective amount of the compound described herein, for example the compound of formula I, to a subject in need thereof to treat neurodegenerative disease.In certain embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or spinocerebellar ataxia.

[0121] Abnormal autophagy process contributes to neurodegenerative diseases. For example, γ-secretase activity is enhanced in autophagic vacuoles through signal transduction mediated by GCN2 phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) (see, for example, Ohta, K. et al. in Autophagy 2010, 6, 345-352). γ-secretase enhances the synthesis of amyloid-β and the progression of Alzheimer's disease. Therefore, compounds that have inhibitory activity against GCN2 will benefit patients suffering from neurodegenerative diseases.

[0122] In certain embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, leukemia, or lymphoma. Doxorubicin-induced cardiotoxicity

[0123] Another aspect of the present invention provides a method for treating doxorubicin-induced cardiotoxicity in a subject, comprising administering a therapeutically effective amount of a compound as described herein, for example a compound of formula I, to a subject suffering from doxorubicin-induced cardiotoxicity in need thereof, thereby treating doxorubicin-induced cardiotoxicity.

[0124] Another aspect of the present invention provides a method for preventing doxorubicin-induced cardiotoxicity in a subject, comprising administering a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I, to a subject who has received or will receive doxorubicin in need thereof, thereby preventing doxorubicin-induced cardiotoxicity.

[0125] It has been reported that GCN2 deficiency ameliorates doxorubicin-induced cardiotoxicity. See, for example, Wang et al. in Redox Biology (2018) vol. 17, pages 25-34. Therefore, compounds with inhibitory activity against GCN2 may benefit patients suffering from or at risk of suffering from doxorubicin-induced cardiotoxicity.

[0126] In certain embodiments, the subject is a human.

[0127] Another aspect of the present invention provides the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer.

[0128] Another aspect of the present invention provides the use of a compound described herein (e.g., a compound of Formula I) for treating a medical disorder, such as a medical disorder described herein (e.g., cancer).

[0129] It is further contemplated that the GCN2 modulators (inhibitors / activators) and related compounds described herein, such as compounds of formula I, can inhibit / activate the activity of GCN2. Accordingly, another aspect of the present invention provides a method for inhibiting / activating the activity of GCN2. The method includes exposing GCN2 to an effective amount of a GCN2 modulator (inhibitor / activator) or related compound described herein, such as compounds of formula I, to inhibit / activate GCN2 activity. In certain embodiments, the specific compound of formula I is a compound defined by one of the preceding embodiments. Combination therapy

[0130] Another aspect of the present invention provides combination therapy. GCN2 modulators (inhibitors / activators) and related compounds (e.g., compounds of formula I) or their pharma- ceutically acceptable salts can be used in combination with additional therapeutic agents to treat medical disorders, such as cancer.

[0131] Exemplary therapeutic agents that may be used as part of a combination therapy in the treatment of cancer include, for example, mitomycin, tretinoin, ribomustine, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocine, and the like. These include flucloxone, nimustine, vindesine, flutamide, drogenil, butosin, carmofur, razoxane, sizofiran, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epithiostanol, formestane, interferon-alpha, interferon-2alpha, interferon-beta, interferon-gamma, colony-stimulating factor-1, colony-stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone-releasing factor.

[0132] Radiation therapy may also be used as part of a combination therapy.

[0133] Another class of drugs that can be used as part of combination therapy in the treatment of cancer are immune checkpoint inhibitors (also called immune checkpoint blockers). Immune checkpoint inhibitors are a class of therapeutic agents that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol. 12, pages 252-264. Exemplary immune checkpoint inhibitors include agents that inhibit one or more of: (i) cytotoxic T-lymphocyte-associated antigen 4 (CTLA4); (ii) programmed cell death protein 1 (PD1); (iii) PDL1; (iv) LAB3; (v) B7-H3; (vi) B7-H4; and (vii) TIM3. Ipilumumab, a CTLA4 inhibitor, has been approved by the U.S. Food and Drug Administration for the treatment of melanoma.

[0134] Other additional agents that may be used as part of a combination therapy in the treatment of cancer are monoclonal antibody agents that target non-checkpoint targets (e.g., Herceptin) and non-cytoxic agents (e.g., tyrosine kinase inhibitors).

[0135] Other additional agents that may be used as part of a combination therapy in the treatment of cancer are agents that deplete amino acids or other nutrients, radiation, and agents that induce an integrated stress response or promote autophagy. Such agents may include argininase inhibitors of kinases such as asparaginase, b-Raf, and cytotoxic agents such as cisplatin.

[0136] Accordingly, another aspect of the present invention provides a method of treating cancer in a patient, comprising administering to a patient in need thereof (i) a therapeutically effective amount of a GCN2 modulator (activator / inhibitor) compound described herein and (ii) a second anti-cancer agent to treat the cancer, wherein the second therapeutic agent can be one of the additional therapeutic agents previously described (e.g., mitomycin, tretinoin, ribomustin, gemcitabine, immune checkpoint inhibitors, or monoclonal antibody agents targeting non-checkpoint targets) or one of the following: - an inhibitor selected from ALK inhibitors, ATR inhibitors, A2A antagonists, base excision repair inhibitors, Bcr-Abl tyrosine kinase inhibitors, Bruton's tyrosine kinase inhibitors, CDC7 inhibitors, CHK1 inhibitors, cyclin-dependent kinase inhibitors, DNA-PK inhibitors, inhibitors of both DNA-PK and mTOR, DNMT1 inhibitors, DNMT1 inhibitors with 2-chloro-deoxyadenosine, HDAC inhibitors, hedgehog signaling pathway inhibitors, IDO inhibitors, JAK inhibitors, mTOR inhibitors, MEK inhibitors, MELK inhibitors, MTH1 inhibitors, PARP inhibitors, phosphoinositide 3-kinase inhibitors, inhibitors of both PARP1 and DHODH, proteasome inhibitors, topoisomerase-II inhibitors, tyrosine kinase inhibitors, VEGFR inhibitors, and WEE1 inhibitors; - an agonist of OX40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS; - a therapeutic antibody targeting one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, mucin, TAG-72, CAIX, PSMA, folate binding protein, ganglioside, Le, VEGF, VEGFR, VEGFR2, integrin αVβ3, integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin-1 beta, B4GALNT1, interleukin-6, and interleukin-6 receptor; - a cytokine selected from IL-12, IL-15, GM-CSF, and G-CSF; - a therapeutic agent selected from sipuleucel-T, aldesleukin (human recombinant interleukin-2 product having the chemical name des-alanyl-1,serine-125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), and 2-chloro-deoxyadenosine, or - Placental growth factors, antibody-drug conjugates, oncolytic viruses, or anticancer vaccines.

[0137] In certain embodiments, the second anti-cancer agent is an ALK inhibitor. In certain embodiments, the second anti-cancer agent is an ALK inhibitor comprising ceritinib or crizotinib. In certain embodiments, the second anti-cancer agent is an ATR inhibitor. In certain embodiments, the second anti-cancer agent is an ATR inhibitor comprising AZD6738 or VX-970. In certain embodiments, the second anti-cancer agent is an A2A antagonist. In certain embodiments, the second anti-cancer agent is a base excision repair inhibitor comprising methoxyamine. In certain embodiments, the second anti-cancer agent is a base excision repair inhibitor, such as methoxyamine. In certain embodiments, the second anti-cancer agent is a Bcr-Abl tyrosine kinase inhibitor. In certain embodiments, the second anti-cancer agent is a Bcr-Abl tyrosine kinase inhibitor comprising dasatinib or nilotinib. In certain embodiments, the second anti-cancer agent is a Bruton's tyrosine kinase inhibitor. In certain embodiments, the second anticancer drug is a Bruton's tyrosine kinase inhibitor, including ibrutinib.In certain embodiments, the second anticancer drug is a CDC7 inhibitor.In certain embodiments, the second anticancer drug is a CDC7 inhibitor, including RXDX-103 or AS-141.

[0138] In certain embodiments, the second anti-cancer agent is a CHK1 inhibitor. In certain embodiments, the second anti-cancer agent is a CHK1 inhibitor comprising MK-8776, ARRY-575, or SAR-020106. In certain embodiments, the second anti-cancer agent is a cyclin-dependent kinase inhibitor. In certain embodiments, the second anti-cancer agent is a cyclin-dependent kinase inhibitor comprising palbociclib. In certain embodiments, the second anti-cancer agent is a DNA-PK inhibitor. In certain embodiments, the second anti-cancer agent is a DNA-PK inhibitor comprising MSC2490484A. In certain embodiments, the second anti-cancer agent is an inhibitor of both DNA-PK and mTOR. In certain embodiments, the second anti-cancer agent comprises CC-115.

[0139] In certain embodiments, the second anticancer agent is a DNMT1 inhibitor.In certain embodiments, the second anticancer agent is a DNMT1 inhibitor comprising decitabine, RX-3117, guadecitabine, NUC-8000, or azacitidine.In certain embodiments, the second anticancer agent comprises a DNMT1 inhibitor and 2-chloro-deoxyadenosine.In certain embodiments, the second anticancer agent comprises ASTX-727.

[0140] In certain embodiments, the second anticancer drug is HDAC inhibitor.In certain embodiments, the second anticancer drug is HDAC inhibitor, including OBP-801, CHR-3996, entinostat, resminostat, prasinostat, CG-200745, panobinostat, romidepsin, mocetinostat, belinostat, AR-42, ricorinostat, KA-3000 or ACY-241.

[0141] In certain embodiments, the second anti-cancer agent is a hedgehog signaling pathway inhibitor. In certain embodiments, the second anti-cancer agent is a hedgehog signaling pathway inhibitor comprising sonidegib or vismodegib. In certain embodiments, the second anti-cancer agent is an IDO inhibitor. In certain embodiments, the second anti-cancer agent is an IDO inhibitor comprising INCB024360. In certain embodiments, the second anti-cancer agent is a JAK inhibitor. In certain embodiments, the second anti-cancer agent is a JAK inhibitor comprising ruxolitinib or tofacitinib. In certain embodiments, the second anti-cancer agent is an mTOR inhibitor. In certain embodiments, the second anti-cancer agent is an mTOR inhibitor comprising everolimus or temsirolimus. In certain embodiments, the second anti-cancer agent is a MEK inhibitor. In certain embodiments, the second anti-cancer agent is a MEK inhibitor comprising cobimetinib or trametinib. In certain embodiments, the second anti-cancer agent is a MELK inhibitor. In certain embodiments, the second anti-cancer agent is a MELK inhibitor comprising ARN-7016, APTO-500, or OTS-167. In certain embodiments, the second anti-cancer agent is an MTH1 inhibitor. In certain embodiments, the second anti-cancer agent is an MTH1 inhibitor comprising (S)-crizotinib, TH287, or TH588.

[0142] In certain embodiments, the second anti-cancer agent is a PARP inhibitor. In certain embodiments, the second anti-cancer agent is a PARP inhibitor, including MP-124, olaparib, BGB-290, talazoparib, veliparib, niraparib, E7449, rucaparb, or ABT-767. In certain embodiments, the second anti-cancer agent is a phosphoinositide 3-kinase inhibitor. In certain embodiments, the second anti-cancer agent is a phosphoinositide 3-kinase inhibitor, including idelalisib. In certain embodiments, the second anti-cancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly ADP-ribose polymerase 1 and dihydroorotate dehydrogenase).

[0143] In certain embodiments, the second anti-cancer drug is a proteasome inhibitor.In certain embodiments, the second anti-cancer drug is a proteasome inhibitor comprising bortezomib or carfilzomib.In certain embodiments, the second anti-cancer drug is a topoisomerase-II inhibitor.In certain embodiments, the second anti-cancer drug is a topoisomerase-II inhibitor comprising vosaroxin.

[0144] In certain embodiments, the second anti-cancer agent is a tyrosine kinase inhibitor. In certain embodiments, the second anti-cancer agent is a tyrosine kinase inhibitor comprising bosutinib, cabozantinib, imatinib or ponatinib. In certain embodiments, the second anti-cancer agent is a VEGFR inhibitor. In certain embodiments, the second anti-cancer agent is a VEGFR inhibitor comprising regorafenib. In certain embodiments, the second anti-cancer agent is a WEE1 inhibitor. In certain embodiments, the second anti-cancer agent is a WEE1 inhibitor comprising AZD1775.

[0145] In certain embodiments, the second anti-cancer agent is an agonist of OX40, CD137, CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS. In certain embodiments, the second anti-cancer agent is an agonist of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregonomab. Bomab, minetumomab, cG250, J591, Mov18, farletuzumab, 3F8, ch14.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, pazopanib, sorafenib, axitinib, CDP791, lenvatinib, ramucirumab, etaracizumab, boro Ciximab, cetuximab, panitumumab, nimotuzumab, 806, afatinib, erlotinib, gefitinib, osimertinib, vandetanib, trastuzumab, pertuzumab, MM-121, AMG102, METMAB, SCH900105, AVE1642, IMC-A12, MK-0646, R1507, CP75187 and a therapeutic antibody selected from the group consisting of: 1, KB004, IIIA-4, mapatumumab, HGS-ETR2, CS-1008, denosumab, sibrotuzumab, F19, 81C6, MEDI551, lirilumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab.

[0146] In certain embodiments, the second anti-cancer drug is a placenta growth factor. In certain embodiments, the second anti-cancer drug is a placenta growth factor that comprises ziv-aflibercept. In certain embodiments, the second anti-cancer drug is an antibody-drug conjugate. In certain embodiments, the second anti-cancer drug is an antibody-drug conjugate selected from the group consisting of brentoxumab vedotin and trastuzumab emtransine.

[0147] In certain embodiments, the second anti-cancer agent is an oncolytic virus. In certain embodiments, the second anti-cancer agent is the oncolytic virus talimogene laherparepvec. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine selected from the group consisting of GM-CSF tumor vaccine, STING / GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anti-cancer agent is a cytokine selected from IL-12, IL-15, GM-CSF, and G-CSF.

[0148] In certain embodiments, the second anticancer agent is a therapeutic agent selected from sipuleucel-T, aldesleukin (human recombinant interleukin-2 product having the chemical name des-alanyl-1,serine-125 human interleukin-2), dabrafenib (kinase inhibitor having the chemical name N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide), vemurafenib (kinase inhibitor having the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), and 2-chloro-deoxyadenosine.

[0149] The dose and dosage regimen of the active ingredients used in combination therapy can be determined by the attending clinician.In certain embodiments, the GCN2 modulator (inhibitor / activator) or related compound (e.g., any one of the compounds of formula I) and additional therapeutic agent are administered at a dose that is generally used when such agents are used as monotherapy to treat disorders.In other embodiments, the GCN2 modulator (inhibitor / activator) or related compound (e.g., any one of the compounds of formula I) and additional therapeutic agent are administered at a dose that is lower than the dose that is generally used when such agents are used as monotherapy to treat disorders.In certain embodiments, the GCN2 modulator (inhibitor / activator) or related compound (e.g., any one of the compounds of formula I) and additional therapeutic agent are present in the same composition suitable for oral administration.

[0150] In certain embodiments, the GCN2 modulator (inhibitor / activator) or related compound (e.g., any one of the compounds of formula I) and the additional therapeutic agent may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce treatment toxicity without reducing the effectiveness of the treatment.

[0151] Another aspect of the invention is a kit containing a therapeutically effective amount of a GCN2 modulator (inhibitor / activator) or related compound (e.g., any one of the compounds of Formula I), a pharma- ceutically acceptable carrier, vehicle or diluent, and, optionally, at least one additional therapeutic agent as listed above. Pharmaceutical Composition and Administration Considerations

[0152] As indicated above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the aforementioned compounds formulated together with one or more pharma- ceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including those adapted for: (1) Oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., intraoral buccal, sublingual, and tablets targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained release formulation; (3) topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin; (4) vaginally or rectally, e.g., as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) transdermally; or (8) nasally.

[0153] The phrase "therapeutically effective amount," as used herein, means an amount of a compound, material, or composition, including a compound of the invention, effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / loss ratio applicable to any medical treatment.

[0154] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / disadvantage ratio.

[0155] Wetting agents, emulsifying agents and lubricating agents, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0156] The formulations of the present invention include those suitable for oral, nasal, topical (including oral buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations can conveniently be presented in unit dosage form and can be prepared by any method of compounding known in the art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of compound that produces a therapeutic effect. Generally, this amount will range from about 0.1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent, out of one hundred percent.

[0157] In certain embodiments, a formulation of the invention comprises an excipient selected from the group consisting of cyclodextrin, cellulose, liposomes, micelle forming agents, and a compound of the invention, hi certain embodiments, the formulation renders the compound of the invention orally bioavailable.

[0158] The method of preparing these formulations or compositions includes the step of combining the compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0159] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base), powders, granules, each containing a predetermined amount of a compound of the present invention as an active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert base), and / or as a mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0160] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers and / or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrants, (5) dissolution retarders, (6) absorption promoters, such as quaternary ammonium compounds and surfactants, (7) wetting agents, (8) absorbents, (9) lubricants, (10) colorants, and (11) controlled-release agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also include buffers.

[0161] Tablets may be made by compression or molding, optionally with one or more accessory ingredients.Compressed tablets may be prepared using binders, lubricants, inert diluents, preservatives, disintegrants, surface active agents or dispersants.Molded tablets may be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0162] Tablets, as well as other solid dosage forms, such as dragees, capsules, pills, and granules, of the pharmaceutical composition of the present invention can be scored as needed, or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to sustain or control release their active ingredients, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to produce the desired release profile. They can be formulated for rapid release, for example, freeze-dried. They can be sterilized, for example, by passing through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water, or some other sterile medium that can be injectable, immediately before use. These compositions can also contain opacifying agents as needed, and can be of a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, as needed, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0163] The liquid dosage form for oral administration of the compound of the present invention includes pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.The liquid dosage form may contain, in addition to the active ingredient, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers.

[0164] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservatives.

[0165] Suspensions may contain, in addition to the active compounds, a suspending agent.

[0166] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers that are solid at room temperature but liquid at body temperature and thus will melt in the rectal or vaginal cavity and release the active compound.

[0167] Formulations of the present invention which are suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0168] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0169] Transdermal patches have the added advantage of controlling the delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds through the skin. The rate of such flux can be controlled by providing a rate-limiting membrane or dispersing the compounds in a polymer matrix or gel.

[0170] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0171] Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharma- ceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which compositions may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the preparation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0172] Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0173] These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of microbial action on the subject compounds can be ensured by including various antibacterial and antifungal agents. It may also be desirable to include an isotonic agent in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0174] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injection in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility.The absorption rate of drugs then depends on their dissolution rate, which in turn depends on the size of crystals and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drugs in oil vehicles.

[0175] Injectable depot forms are made by forming a microencapsulated matrix of the subject compound in a biodegradable polymer. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the release rate of the drug can be controlled. Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0176] When the compounds of the present invention are administered as pharmaceuticals to humans and animals, they can be given as such or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0177] The preparations of the present invention can be given orally, parenterally, topically or rectally.They are naturally given in a form suitable for each administration route.For example, they are given in the form of tablets or capsules, by injections, inhalants, eye lotions, ointments, suppositories, etc., by administration by injection, infusion or inhalation, topically by lotions or ointments, and rectally by suppositories.Oral administration is preferred.

[0178] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0179] The phrases "systemic administration," "systemically administered," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and thus undergoes metabolic and other similar processes.

[0180] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., as by spray, rectally, vaginally, parenterally, intravesically, as well as topically, buccally and sublingually, as by powders, ointments or drops.

[0181] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharma- ceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0182] Actual dosage levels of the active ingredients in pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration, without toxicity to the patient.

[0183] The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention or its esters, salts or amides employed, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, overall health and past medical history of the patient receiving treatment, and similar factors well known in the medical arts.

[0184] A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start dosages of the compounds of the invention used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0185] In general, a suitable daily dose of the compound of the present invention is that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally vary depending on the factors mentioned above. Preferably, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compound described herein is administered in combination with another agent (e.g., as a sensitizer), the effective amount may be less than the amount when that agent is used alone.

[0186] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. Preferred administration is a single daily administration.

[0187] The present invention further provides unit dosage forms (e.g., tablets or capsules) containing a therapeutically effective amount of an (aza)indazolyl-arylsulfonamide or related compound described herein for the treatment of a medical disorder described herein. EXAMPLES

[0188] The following representative examples are intended to help illustrate the invention and are not intended, nor should they be construed, to limit the scope of the invention.

[0189] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Although optimal reaction conditions may vary with the particular reactants or solvents used, such conditions can be determined by those skilled in the art through routine optimization.

[0190] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for certain functional groups, and the conditions suitable for protection and deprotection are well known in the art.For example, numerous protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references listed therein.

[0191] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). It should be noted that flash chromatography can be performed manually or by an automated system. The compounds provided herein can be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectroscopy (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are obtained using methods well known to those skilled in the art. List of abbreviations: Ac Acetyl ACN Acetonitrile AcOH Acetic acid AIBN Azobisisobutyronitrile BAST Bis(2-methoxyethyl)aminosulfur trifluoride Boc tert-Butyloxycarbonyl BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1'-Bi-2-naphthol BPO Benzoyl Peroxide COD 1,5-Cyclooctadiene Cy Cyclohexyl CDI Carbonyldiimidazole DAST Diethylaminosulfur trifluoride dba Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD Diethyl azodicarboxylate DHP Dihydropyran DIEA Diisopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl dtbpf 1,1'-bis(di-tert-butylphosphino)ferrocene EA Ethyl acetate EDTA Ethylenediaminetetraacetic acid EtOAc Ethyl acetate FA Formic Acid HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HMDS Bis(trimethylsilyl)amide HPLC High Performance Liquid Chromatography IBX 2-Iodoxybenzoic acid IPA Isopropyl Alcohol LAH Lithium Aluminum Hydride LCMS Liquid Chromatography-Mass Spectrometry LDA Lithium diisopropylamide MeCN Acetonitrile MTBE Methyl tert-butyl ether NBS N-Bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMI N-Methylimidazole NMP N-Methylpyrrolidinone NMR nuclear magnetic resonance spectroscopy PE Petroleum Ether Pin Pinacolete PMB p-Methoxybenzyl Py Pyridine rt room temperature RT retention time SEM Trimethylsilylethoxymethyl SFC Supercritical Fluid Chromatography TBAB Tetrabutylammonium bromide TBAF Tetrabutylammonium fluoride TBDPS tert-Butyldiphenylsilyl TBS tert-Butyldimethylsilyl TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TEA Triethylamine Tf triflate / trifluoromethanesulfonate TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride TMAD N,N,N',N'-Tetramethylazodicarboxamide TMS Trimethylsilyl Ts Tosil General Scheme

[0192] In some embodiments, the compounds of the present disclosure can be prepared using a process that includes one or more of the following schemes 1-14. The reaction steps represented by dashed arrows should be understood as optional. Unless otherwise specified, the variables in the schemes are as defined herein. The reaction conditions should be understood as exemplary and non-limiting, and can occur in the presence of a suitable solvent.

[0193] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 1, where Z is a halide, R is alkyl, and R a is alkyl, R b is substituted or unsubstituted alkyl. [ka]

[0194] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 2, where Z is a halide, R is alkyl, and R a is alkyl, R b is substituted or unsubstituted alkyl. [ka]

[0195] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 3, where Z is a halide, R is alkyl, and R a is methyl, R b is substituted or unsubstituted alkyl. [ka]

[0196] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 4, where Z is a halide, Y is an amide or ester, and R is alkyl. [ka]

[0197] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 5, where Z is a halide, Y is an amide or ester, and R is alkyl. [ka]

[0198] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 6, where Z is a halide, R is alkyl, and R a is alkyl. [ka]

[0199] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 7, where Z is a halide, R is alkyl, and Hy is a heterocycle or heteroaryl. [ka]

[0200] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 8, where Z is a halide, R is alkyl, and Hy is a heterocycle or heteroaryl. [ka]

[0201] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 9, where Z is a halide, R is alkyl, and Hy is a heterocycle or heteroaryl. [ka]

[0202] In some embodiments, compounds of the present disclosure can be synthesized using a process including Scheme 10, where Z is a halide, R is an alkyl, FG is a functional group that can be easily converted to a heterocycle or heteroaryl, and Hy is a heterocycle or heteroaryl. In some embodiments, FG is cyano and can be reacted with, for example, an aminoaldehyde acetal with base and / or acid, or with an amidine reagent with base to form a heterocycle or heteroaryl. In some embodiments, FG is a halogen and can be reacted with a heterocyclyl or heteroaryl using an organolithium reagent and a metal catalyst. [ka]

[0203] In some embodiments, compounds of the present disclosure can be synthesized using a process comprising Scheme 11, where Z is a halide, R is alkyl, and Hy is a heterocycle or heteroaryl. [ka]

[0204] In some embodiments, compounds of the present disclosure can be synthesized using a process including Scheme 12, where FG is a functional group that can be easily converted to a heterocycle or heteroaryl, and Hy is a heterocycle or heteroaryl. In some embodiments, FG is cyano and can be reacted with, for example, an aminoaldehyde acetal with base and / or acid, or with an amidine reagent with base to form a heterocycle or heteroaryl. In some embodiments, FG is halogen and can be reacted with a heterocyclyl or heteroaryl using organolithium and metal catalysts. [ka]

[0205] In some embodiments, compounds of the present disclosure can be synthesized using a process including Scheme 13, where Hy is a heterocycle or heteroaryl. [ka]

[0206] In some embodiments, compounds of the present disclosure can be synthesized using a process including Scheme 14, where W is -NCH 3 or -OCH 3 and R c is H or methyl. [ka] Example 1 Synthesis of 5-fluoro-2-methoxypyridine-3-sulfonyl chloride (Intermediate 1) [ka] Int.1-a: Synthesis of 3-(benzylsulfanyl)-5-fluoro-2-methoxypyridine

[0207] A 2000 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3-bromo-5-fluoro-2-methoxypyridine (150 g, 728 mmol, 1 equiv.), benzyl mercaptan (109 g, 878 mmol, 1.2 equiv.), Pd 2 (dba) 3 (41.9 g, 36 mmol, 0.05 equiv), Xantphos (30 g, 52 mmol, 0.07 equiv), DIEA (189 g, 1.46 mol) and toluene (1.2 L). The resulting solution was stirred in an oil bath at 85° C. for 2 h and then concentrated under vacuum. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:10) to give 3-(benzylsulfanyl)-5-fluoro-2-methoxypyridine (172 g, 95% yield) as a colorless oil. Int.1: Synthesis of 5-fluoro-2-methoxypyridine-3-sulfonyl chloride

[0208] Into a 2000 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added 3-(benzylsulfanyl)-5-fluoro-2-methoxypyridine (172 g, 690 mmol, 1 equiv.) and CH 3 CN (1000 mL) was added. This was followed by the addition of HCl (57 mL) at 10° C. To this, NCS (368.5 g, 2760 mmol, 4 equiv.) was added in small portions at 10° C. The resulting solution was stirred in a water / ice bath at 10-20° C. for 30 min. The resulting solution was then diluted with 2000 mL of H 2 The mixture was diluted with 2000 mL of O and extracted with 2×1.5 L of dichloromethane. The combined organics were washed with 2000 mL of brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was applied to a silica gel column, which was eluted with PE. 5-Fluoro-2-methoxypyridine-3-sulfonyl chloride (50.5 g, 32% yield) was isolated as a white solid. 1 H-NMR: (300 MHz, Chloroform-d, ppm): δ 8.366 (d, J = 3.0 Hz, 1H), 8.043-8.011 (m, 1H), 4.178(s, 3H). Example 2 Synthesis of 5-chloro-2-methoxypyridine-3-sulfonyl chloride (Intermediate 2) [ka] Int.2-a: Synthesis of 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine

[0209] Into a 3000 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was added 3-bromo-5-chloro-2-methoxypyridine (150 g, 678 mmol, 1.0 equiv), toluene (1500 mL), phenylmethanethiol (92.6 g, 746 mmol, 1.1 equiv), DIEA (175.4 g, 1357 mmol, 2.0 equiv), Xantphos (3.9 g, 6 mmol, 0.01 equiv), and Pd 2 (dba) 3 -CHCl3 (5.3 g, 5 mmol 0.0075 equiv.). The resulting solution was stirred in an oil bath at 110° C. for 4 h. The solids were removed by filtration and the filtrate was concentrated. The residue was loaded onto a silica gel column eluted with PE:EA=20:1. The appropriate fractions were concentrated to give a solid which was slurried with PE (3V). The solid was removed by filtration and dried to give 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (130 g, 72% yield) as a yellow solid. Int.2: Synthesis of 5-chloro-2-methoxypyridine-3-sulfonyl chloride

[0210] In a 4000 mL round bottom flask, add 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (130 g, 490 mmol, 1 equiv.), MeCN (2600 mL, 20 V), H 2 HO (130 mL, 1V), acetic acid (294 g, 491 mmol, 10 equiv.) and NCS (196 g, 1471 mmol, 3.0 equiv.) were charged. The resulting solution was stirred at 25° C. for 30 min. The reaction was quenched by the addition of 1000 mL of water and extracted with 2×1000 mL of ethyl acetate. The combined organics were washed with H 2 The mixture was washed with 500 mL of diethyl ether and concentrated. The resulting solution was diluted with 500 mL of diethyl ether and the solids were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with PE / THF (100:1). The concentrated product was slurried with 300 mL of hexane and kept at 0° C. for 1 h. The solids were removed by filtration and dried to give 5-chloro-2-methoxypyridine-3-sulfonyl chloride (66.5 g, 56% yield) as a white solid. 1 H-NMR: (300 MHz, CDCl 3 , ppm): δ 8.45 (d, J = 2.5 Hz, 1H), 8.23 ​​(d, J = 2.6 Hz, 1H), 4.21 (s, 3H). Example 3 Synthesis of 5-cyano-2-methoxypyridine-3-sulfonyl chloride (intermediate 3) [ka] Int.3-a: Synthesis of 5-bromo-6-methoxypyridine-3-carbonitrile

[0211] In a 2 L round bottom flask, 6-methoxypyridine-3-carbonitrile (100 g, 746 mmol, 1 equiv.), HOAc (1000 mL), NaOAc (61 g, 746 mmol, 1 equiv.), and Br 2 (235 g, 1490 mmol, 2 equiv.) was added at room temperature. The resulting mixture was stirred at 80° C. for 48 h. The mixture was allowed to cool to room temperature and diluted with ice water (3 L). The precipitated solid was collected by filtration and suspended in 1 L of PE:EA=5:1, which was stirred at room temperature for 1 h. The precipitated solid was collected by filtration and dried to give 5-bromo-6-methoxypyridine-3-carbonitrile (70 g, 44% yield) as a pale yellow solid. Int.3-b: Synthesis of 5-(benzylsulfanyl)-6-methoxypyridine-3-carbonitrile

[0212] In a 3 L three-neck round bottom flask, 5-bromo-6-methoxypyridine-3-carbonitrile (70 g, 330 mmol, 1 equiv.), toluene (1400 mL) and benzyl mercaptan (43 g, 347 mmol, 1.05 equiv.) were added at room temperature. 2 (dba) 3 .CHCl 3 (17 g, 16.5 mmol, 0.05 equiv), Xantphos (19 g, 33 mmol, 0.1 equiv) and DIEA (128 g, 990 mmol, 3 equiv) were added under nitrogen atmosphere. The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 3 h, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / THF (10:1). 5-(benzylsulfanyl)-6-methoxypyridine-3-carbonitrile (65 g, 77% yield) was obtained as a light brown solid. Int.3: Synthesis of 5-cyano-2-methoxypyridine-3-sulfonyl chloride

[0213] In a 2 L three-neck round bottom flask, add 5-(benzylsulfanyl)-6-methoxypyridine-3-carbonitrile (65 g, 2540 mmol, 1 equiv.), MeCN (520 g), H 2 O (260 g) and HCl (21 mL, 254 mmol, 1 equiv.) were added at room temperature. To this, NCS (101 g, 762 mmol, 3 equiv.) was added in small portions at 0° C. The resulting mixture was stirred at room temperature for 0.5 h, then cooled to 0° C. and stirred for 1 h. The precipitated solid was collected by filtration and dried to give 5-cyano-2-methoxypyridine-3-sulfonyl chloride (25 g, 42% yield) as a white solid. H-NMR: (300 MHz, CDCl3, ppm): δ 8.78 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 4.31 (s, 3H). Example 4 Synthesis of 5-fluoro-2-methylpyridine-3-sulfonyl chloride (Intermediate 4) [ka] Int.4-a: Synthesis of tert-butyl N-(2-bromo-5-fluoropyridin-3-yl)-N-(tert-butoxycarbonyl)carbamate

[0214] A 500 mL three-neck round bottom flask was charged with 2-bromo-5-fluoropyridin-3-amine (20 g, 1 equiv.), DCM (220 mL) and TEA (44 mL, 3 equiv.). This was followed by addition of Boc 2 O (57 g, 2.5 equiv.) was added in several batches at 26° C. The resulting solution was stirred at 26° C. for 14 h. The reaction mixture was concentrated and the residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). This resulted in tert-butyl N-(2-bromo-5-fluoropyridin-3-yl)-N-(tert-butoxycarbonyl)carbamate (33 g) as a white solid. Int.4-b: Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-(5-fluoro-2-methylpyridin-3-yl)carbamate

[0215] Into a 500 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added tert-butyl N-(2-bromo-5-fluoropyridin-3-yl)-N-(tert-butoxycarbonyl)carbamate (33 g, 84 mmol, 1 equiv.), 1,4-dioxane (150 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (21.2 g, 169 mmol, 2 equiv.), K 2 CO 3 (35 g, 253 mmol, 3 equiv.) and Pd(dppf)Cl 2 (3.09 g, 4.2 mmol, 0.05 equiv.) was added. The resulting solution was then purified by N 2 The mixture was stirred overnight at 110° C. under atmospheric pressure. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with 200 mL of H 2 The mixture was diluted with 200 mL of ethyl acetate and extracted with 3×100 mL of ethyl acetate. The combined organics were concentrated and the residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:10 to 1:5). tert-Butyl N-(tert-butoxycarbonyl)-N-(5-fluoro-2-methylpyridin-3-yl)carbamate (16 g, 58% yield) was isolated as a yellow solid. Int.4-c: Synthesis of 3-bromo-5-fluoro-2-methylpyridine

[0216] A 2 L three-neck round bottom flask was charged with tert-butyl N-(tert-butoxycarbonyl)-N-(5-fluoro-2-methylpyridin-3-yl)carbamate (50 g, 153 mmol, 1 equiv.) and HBr (1 L, 48%). This was followed by addition of HBr with stirring at 0-5 °C. 2 NaNO in O (100 mL) 2(11.6 g, 169 mmol, 1.1 equiv.) was added dropwise. The resulting solution was stirred in an ice bath for 30 min. To this was added CuBr (24.2 g, 169 mmol, 1.1 equiv.) at 0° C. The resulting solution was stirred at room temperature for 1 h and then quenched by the addition of 1 L of water / ice. The pH of the solution was adjusted to 100 with Na 2 CO 3 The acid was adjusted to 8 with 50 mL of ethyl acetate and the resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:50). 3-Bromo-5-fluoro-2-methylpyridine (13 g, 45% yield) was isolated as a white solid. Int.4-d: Synthesis of 3-(benzylsulfanyl)-5-fluoro-2-methylpyridine

[0217] Into a 250 mL three-neck round bottom flask purged and maintained under an inert atmosphere of nitrogen was added 3-bromo-5-fluoro-2-methylpyridine (13 g, 68 mmol, 1 equiv.), toluene (130 mL), benzyl mercaptan (12.8 g, 103 mmol, 1.5 equiv.), DIEA (17.7 g, 137 mmol, 2 equiv.), Xantphos (3.96 g, 6.8 mmol, 0.1 equiv.) and Pd 2 (dba) 3 (3.13 g, 3.4 mmol, 0.05 equiv.). The resulting solution was stirred at 115° C. for 4 h, then cooled and concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:20) to give 3-(benzylsulfanyl)-5-fluoro-2-methylpyridine (11 g, 69% yield) as a yellow solid. Int.4: Synthesis of 5-fluoro-2-methylpyridine-3-sulfonyl chloride

[0218] In a 2000 mL three-neck round bottom flask, add 3-(benzylsulfanyl)-5-fluoro-2-methylpyridine (45 g, 193 mmol, 1 equiv.), HOAc (700 mL) and H 20 (200 mL). This was followed by the addition of NCS (103 g, 772 mmol, 4 equiv.) while maintaining the temperature below 20° C. The resulting solution was stirred at room temperature for 2 h. The reaction was quenched by the addition of 700 mL of water and the resulting solution was extracted with 3×300 mL of dichloromethane. The combined organics were concentrated and the residue was loaded onto a silica gel column eluting with ethyl acetate / petroleum ether (1:10). 5-Fluoro-2-methylpyridine-3-sulfonyl chloride (25.4 g, 63% yield) was obtained as a yellow oil. LCMS: (ES, m / z): [M+1] + =210 1 H-NMR: (300 MHz, CDCl 3 , ppm): δ 8.72-8.71 (d, J = 3.0 Hz, 1H), 8.11-8.08 (dd, J = 3.0 Hz, 1H), 3.01 (s, 3H). Example 5 Synthesis of 5-chloro-N-[3,5-difluoro-4-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]pyridin-2-yl]-2-methoxypyridine-3-sulfonamide (Intermediate 5) [ka] Intermediate 5: Synthesis of N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0219] To a solution of 3-bromo-2,4-difluoroaniline (5 g, 24 mmol, 1 equiv.) in DCM (100 mL) was added 5-chloro-2-methoxypyridine-3-sulfonyl chloride (8.73 g, 36 mmol, 1.5 equiv.) and pyridine (5.7 g, 72 mmol, 3 equiv.). The resulting solution was stirred at room temperature for 1 h. The reaction was concentrated and purified by column chromatography on silica gel (eluent: PE:EA=8:1) to give N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (7 g, 70% yield) as a white solid. LCMS (ES, m / z): [M+H] + :412 1 H NMR (300 MHz, Chloroform-d) δ 8.30 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.56 (td, J = 8.9, 5.4 Hz, 1H), 7.28 (d, J = 3.4 Hz, 1H), 6.96 (ddd, J = 9.4, 7.6, 2.1 Hz, 1H), 4.16 (s, 3H). Example 6 Synthesis of ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (intermediate 6) [ka] Int.6-a Synthesis of ethyl 2-(5-bromopyridin-2-yl)acetate

[0220] A 250 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 5-bromo-2-methylpyridine (3 g, 17 mmol, 1 equiv.) in THF (100 mL). This was followed by the dropwise addition of LiHMDS (34 mL, 34 mmol, 2 equiv.) in THF over a period of 30 min with stirring at 0° C. To this was added diethyl carbonate (3.1 g, 26 mmol, 1.5 equiv.) at 0° C. and the resulting solution was stirred at room temperature for 5 h. The reaction was diluted with 30 mL of H 2 The mixture was quenched by the addition of O and the resulting mixture was concentrated in vacuo. The residue was diluted with 100 mL of EA and the organics were washed with H 2 0 (2×100 mL) and brine (100 mL). After drying over anhydrous sodium sulfate, the solution was concentrated in vacuo to give ethyl 2-(5-bromopyridin-2-yl)acetate (3.0 g crude) as a yellow oil. LCMS (ES, m / z): [M+H] + :244 Int.6-b: Synthesis of ethyl 2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate

[0221] A 25 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of ethyl 2-(5-bromopyridin-2-yl)acetate (2.9 g, 12 mmol, 1 equiv.) in AcOH (5 mL). This was followed by stirring at 0° C. with H 2 NaNO in O (2 mL) 2 (823 mg, 12 mmol, 1 equiv.) was added dropwise. The resulting solution was stirred at room temperature for 1 h and then diluted with 20 mL of H 2 The mixture was diluted with 2×20 mL of ethyl acetate and the combined organics were washed with 30 ml of brine and then dried over anhydrous sodium sulfate. Concentration afforded ethyl 2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate (2.3 g) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :273 Int.6-c: Synthesis of ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate

[0222] A 100 mL three-neck round bottom flask was charged with a solution of ethyl 2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate (2.3 g, 8.3 mmol, 1 equiv.) in AcOH (20 mL). This was followed by the addition of Zn (1.6 g, 25 mmol, 3 equiv.) in portions over 10 min at 0° C. The resulting solution was stirred at room temperature for 60 min. The solids were removed by filtration and the filtrate was concentrated under vacuum to give crude ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate (1.8 g) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :259 Intermediate 6: Synthesis of ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate

[0223] A 5 mL microwave tube was charged with ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate (1.8 g, 7 mmol, 1 equiv.) and triethyl orthoformate (3 mL). The resulting solution was stirred at 130° C. for 10 min, then cooled and concentrated. The residue was loaded onto a silica gel column eluted with THF / PE (1:1). Ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (530 mg) was isolated as a purple solid. LCMS (ES, m / z): [M+H] + :269 Example 7 Synthesis of 6-bromo-1-iodoimidazo[1,5-a]pyridine (intermediate 7) [ka] Int.7-a Synthesis of (E)-N-[(5-bromopyridin-2-yl)methylidene]hydroxylamine

[0224] In a 500 mL three-neck round-bottom flask, add a solution of 5-bromopyridine-2-carbaldehyde (20 g, 0.11 mol, 1 equiv.) in MeOH (150 mL), followed by H 2 Na in O (100 mL) 2 CO 3 (23 g, 0.2 mol, 2 equiv.) was charged. Hydroxylamine hydrochloride (9.7 g, 0.14 mol, 1.3 equiv.) was then added at 0° C. The resulting solution was stirred at 60° C. in an oil bath for 2 h. The reaction was quenched by the addition of 500 mL of water / ice and the solid was collected by filtration. Air drying afforded (E)-N-[(5-bromopyridin-2-yl)methylidene]hydroxylamine (21 g, 87% yield) as a white solid. LCMS (ES, m / z): [M+H] + :201 Int.7-b: Synthesis of 1-(5-bromopyridin-2-yl)methanamine

[0225] A 500 mL three-neck round bottom flask was charged with (E)-N-[(5-bromopyridin-2-yl)methylidene]hydroxylamine (21 g, 0.1 mol, 1 equiv.) and AcOH (200 mL). Zn (20.5 g, 0.3 mol, 3 equiv.) was then added in small portions at 0-10 °C. The resulting solution was stirred in an ice / salt bath at 0-10 °C for 30 min. The solids were filtered off and the filtrate was concentrated under vacuum. The resulting mixture was diluted with 200 mL of H 2 The mixture was diluted with O and the pH was adjusted to 10 with ammonia. The resulting solution was extracted with 6×150 mL of DCM:MeOH (10:1) and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration afforded 1-(5-bromopyridin-2-yl)methanamine (18 g, 92% yield) as a white solid. LCMS (ES, m / z): [M+H] + :187 Int.7-c: Synthesis of N-[(5-bromopyridin-2-yl)methyl]formamide

[0226] A 500 mL three-neck round-bottom flask was charged with 1-(5-bromopyridin-2-yl)methanamine (18 g, 97 mmol, 1 equiv.) and formic acid (150 mL). The resulting solution was stirred in an oil bath at 100° C. for 3 h, then cooled and diluted with 500 mL of H 2 The mixture was diluted with 2×300 mL of ethyl acetate and the organic layers were combined. The solution was washed with 500 ml of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give N-[(5-bromopyridin-2-yl)methyl]formamide (13 g) as a crude brown solid. LCMS (ES, m / z): [M+H] + :215 Int.7-d: Synthesis of 6-bromoimidazo[1,5-a]pyridine

[0227] In a 500 mL three-neck round-bottom flask, add N-[(5-bromopyridin-2-yl)methyl]formamide (13 g, 61 mmol, 1 equiv.), toluene (150 mL) and POCl. 3(46.4 g, 305 mmol, 5 equiv.). The resulting solution was stirred at 100° C. for 2 h, then cooled and concentrated in vacuo. The residue was diluted with 150 mL of H 2 The mixture was carefully diluted with O and the pH was adjusted to 10 with ammonia. The resulting solution was extracted with 3×150 mL of dichloromethane and the organic layers were combined. The solution was washed with 300 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 6-bromoimidazo[1,5-a]pyridine (10.5 g, 79% yield) as a brown solid. LCMS (ES, m / z): [M+H] + :197 Intermediate 7: Synthesis of 6-bromo-1-iodoimidazo[1,5-a]pyridine

[0228] A 250 mL three-neck round bottom flask was charged with 6-bromoimidazo[1,5-a]pyridine (10.5 g, 53.5 mmol, 1 equiv.) in DMF (100 mL). This was followed by the addition of NIS (12 g, 53.5 mmol, 1 equiv.) at 0° C. The resulting solution was stirred in an ice / salt bath at 0° C. for 60 min, then added with 200 mL of saturated Na 2 S 2 O 3 / H 2 The reaction was quenched by the addition of O. The solid was collected by filtration and dried to give 6-bromo-1-iodoimidazo[1,5-a]pyridine (12.8 g, 67% yield) as a brown solid. LCMS (ES, m / z): [M+H] + :323 Example 8 Synthesis of 6-bromo-1-iodoimidazo[1,5-a]pyridine (intermediate 8) [ka] Int.8-a: Synthesis of ethyl 3-(4-bromo-2-fluorophenyl)propanoate

[0229] A 500 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-bromo-2-fluoro-1-iodobenzene (20 g, 67 mmol, 1 equiv.), DMF (200 mL), 3,3-diethoxy-1-propene (11.3 g, 86 mmol, 1.3 equiv.), tetrabutylammonium chloride (18.5 g, 67 mmol, 1 equiv.), DIEA (23 g, 179 mmol, 2.7 equiv.) and Pd(AcO). 2 (750 mg, 3 mmol, 0.05 equiv.) was added. The resulting solution was stirred in an oil bath at 90° C. for 2 h. The reaction mixture was cooled to 25° C. in a water / ice bath, and the solution was diluted with 600 mL of H 2 The mixture was diluted with 2×200 mL of ethyl acetate and the organic layers were combined. The organics were washed with 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column eluted with PE / EA=95 / 5. Ethyl 3-(4-bromo-2-fluorophenyl)propanoate (14.5 g, 50% yield) was isolated as a pale yellow oil. LCMS (ES, m / z): [M+H] + :275. Int.8-b: Synthesis of 3-(4-bromo-2-fluorophenyl)propanoic acid

[0230] A 1000 mL round bottom flask was charged with ethyl 3-(4-bromo-2-fluorophenyl)propanoate (16.5 g, 60 mmol, 1 equiv), THF (120 mL), MeOH (120 mL) and 4N aqueous NaOH (120 mL, 480 mmol). The resulting solution was stirred in an oil bath at 50 °C for 2 h. The reaction mixture was concentrated under vacuum and the residue was extracted with 2 x 100 mL ethyl acetate. The pH of the aqueous layer was acidified with 4N HCl. The resulting suspension was extracted with 3 x 100 mL ethyl acetate and the organic layers were combined. The organics were washed with 100 mL brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column eluting with 0-40% EA / PE. 3-(4-bromo-2-fluorophenyl)propanoic acid (11.5 g, 78% yield) was isolated as a white solid. Int.8-c: Synthesis of 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one

[0231] To a stirred mixture of 3-(4-bromo-2-fluorophenyl)propanoic acid (11.5 g, 47 mmol, 1 equiv.) in DCM (200 mL) was added oxalyl chloride (11.8 g, 93 mmol, 2 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h and then concentrated under reduced pressure. The residue was dissolved in DCM (200 mL). To the above mixture was added AlCl 3 (18.6 g, 140 mmol, 3 equiv.) was added in portions at room temperature. The resulting mixture was stirred at 40° C. for an additional 3 h. Additional AlCl 3 (18.6 g, 140 mmol, 3 equiv.) was added in small portions. The resulting mixture was stirred at 40° C. overnight. The reaction mixture was diluted with NH 4 Dilute with Cl (300 mL) and CH 2 Cl 2 (3×200 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA / PE=1 / 2 to give 6-bromo-4-fluoro-2,3-dihydroinden-1-one (6.5 g, yield 61%) as a white solid. Int.8-d: Synthesis of 7-fluoro-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile

[0232] In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 6-bromo-4-fluoro-2,3-dihydroinden-1-one (4.6 g, 20.1 mmol, 1 equiv.), NMP (50 mL) and Cu(CN) 2 (4.7 g, 40 mmol, 2 equiv.). The resulting solution was stirred at 175 °C overnight. The cooled reaction mixture was diluted with 200 mL of H 2The mixture was diluted with 20 mL of HO and extracted with 3×50 mL of ethyl acetate. The combined extracts were washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column eluted with 50-70% THF / PE. 7-Fluoro-3-oxo-1,2-dihydroindene-5-carbonitrile (1.5 g, 43% yield) was isolated as a pale yellow solid. Int.8-e: Synthesis of 7-(benzylthio)-3-oxo-2,3-dihydro-1H-indene-5-carbonitrile

[0233] In a 4 mL vial, 7-fluoro-3-oxo-1,2-dihydroindene-5-carbonitrile (450 mg, 2.6 mmol, 1 equiv.) and ACN (15 mL) were added at room temperature. 2 CO 3 (920 mg, 2.8 mmol, 1.1 equiv) and benzyl mercaptan (478 mg, 3.9 mmol, 1.5 equiv) were added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 Purification by silica gel column chromatography eluting with 5,3-dihydro-1,2-dihydroindene-5-carbonitrile (550 mg, 77% yield) gave 7-(benzylsulfanyl)-3-oxo-1,2-dihydroindene-5-carbonitrile as a white solid. Int.8-f: Synthesis of 7-(benzylsulfanyl)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile

[0234] In a 100 mL round bottom flask was added 7-(benzylsulfanyl)-3-oxo-1,2-dihydroindene-5-carbonitrile (550 mg, 2 mmol, 1 equiv.) and MeOH (15 mL). The solution was diluted with NaBH 4 (97 mg, 2.6 mmol, 1.3 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 1 h and then diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (30 mL) and anhydrous Na 2 SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was 2 Cl 2 Purification by silica gel column chromatography eluting with 5,3-dihydro-2,3-dihydro-1H-indene-5-carbonitrile (560 mg, crude) as a light grey solid. Int.8-g: Synthesis of 4-(benzylsulfanyl)-6-cyano-2,3-dihydro-1H-inden-1-yl acetate

[0235] In a 2 mL vial, 7-(benzylsulfanyl)-3-hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (400 mg, 1.4 mmol, 1 eq.) and DCM (10 mL) were added. To the stirred solution, TEA (288 mg, 2.8 mmol, 2 eq.) and acetyl chloride (167 mg, 2.1 mmol, 1.5 eq.) were added dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h and then quenched by the addition of MeOH (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give 4-(benzylsulfanyl)-6-cyano-2,3-dihydro-1H-inden-1-yl acetate (360 mg, 78% yield) as a white solid. Intermediate 8: Synthesis of 4-(chlorosulfonyl)-6-cyano-2,3-dihydro-1H-inden-1-yl acetate

[0236] In a 20 mL vial, 4-(benzylsulfanyl)-6-cyano-2,3-dihydro-1H-inden-1-yl acetate (400 mg, 1.2 mmol, 1 equiv.) and MeCN (4 mL) were added. To the stirred mixture, 1 M HCl (1.2 mL, 33 mmol, 32 equiv.) and NCS (661 mg, 4.8 mmol, 4 equiv.) were added in portions. The resulting mixture was diluted with water (10 mL), at which point the reaction was shown to be complete. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 4° C. After filtration, the filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. Example 9 Synthesis of ethyl 2-bromoimidazo[1,5-b]pyridazine-5-carboxylate (intermediate 9) [ka] Int.9: Synthesis of ethyl 2-bromoimidazo[1,5-b]pyridazine-5-carboxylate

[0237] In a 10 L three-neck round-bottom flask, add a solution of ethyl 2-chloroimidazo[1,5-b]pyridazine-5-carboxylate (500 g, 2200 mmol, 1 equiv.) in AcOH (5 L) and PBr 3 (1800 g, 6650 mmol, 3 equiv.). The resulting solution was stirred at 100° C. overnight and then quenched by the addition of water / ice. The resulting solution was extracted with ethyl acetate (3×2 L) and the combined organic layers were treated with ammonia until pH was 8. The resulting mixture was washed with brine (5 L) and then concentrated to give ethyl 2-bromoimidazo[1,5-b]pyridazine-5-carboxylate (351 g, 59% yield) as a yellow solid. LC-MS: (ES, m / z): [M+H] + :270 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.85 (s, 1H), 8.34 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 9.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). Example 10 Synthesis of 3-cyano-5-(trifluoromethyl)benzenesulfonyl chloride (intermediate 10) [ka] Int.10-a: Synthesis of 3-(benzylsulfanyl)-5-(trifluoromethyl)benzonitrile

[0238] A 250 mL round bottom flask was charged with 3-fluoro-5-(trifluoromethyl)benzonitrile (2 g, 10 mmol, 1 equiv), DMF (50 mL), LiOH (0.5 g, 21 mmol, 2 equiv) and benzyl mercaptan (1.6 g, 13 mmol, 1.2 equiv). The resulting solution was stirred at 25° C. for 1 h and then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the combined organics were washed with 3×100 mL of water. The organics were dried over anhydrous sodium sulfate and concentrated to give 3-(benzylsulfanyl)-5-(trifluoromethyl)benzonitrile (3 g, 97% yield) as a yellow oil, which was used directly in the next step without further purification. Intermediate 10: Synthesis of 3-cyano-5-(trifluoromethyl)benzenesulfonyl chloride

[0239] A 40 mL vial was charged with MeCN (7.5 mL) and HCl (aq, 6 M) (1.5 mL). This was followed by the addition of NCS (910 mg, 6.8 mmol, 4 equiv) in portions at 0° C. To this was added 3-(benzylsulfanyl)-5-(trifluoromethyl)benzonitrile (500 mg, 1.7 mmol, 1 equiv) in portions at 0° C. The resulting solution was stirred in a water / ice bath for 1 h. The reaction was quenched by the addition of 20 mL of water / ice and the resulting solution was extracted with 2×20 mL of dichloromethane. The combined organics were washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated. This resulted in 3-cyano-5-(trifluoromethyl)benzenesulfonyl chloride (300 mg) as a crude yellow oil, which was used directly in the next step without further purification. Example 11 Synthesis of 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylic acid and 2,4-difluoro-3-[1-iodoimidazo[1,5-a]pyrazin-6-yl]aniline (Intermediate 11 and Intermediate 12) [ka] Int.11-a: Synthesis of 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate

[0240] Dioxane (1L) and H 2 To a solution of ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (120 g, 444 mmol, 1 equiv.) and 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (170 g, 666 mmol, 1.5 equiv.) in 20O (200 mL), was added 100 mL of KCl. 3 PO 4 (189 g, 889 mmol, 2 equiv.) and Pd(dtbpf)Cl 2(29 g, 44 mmol, 0.1 equiv.) was added. After stirring at 90° C. under nitrogen for 3 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate (110 g, 78% yield) as an off-white solid. LCMS (ES, m / z): [M+H] + :319 Intermediate 11: Synthesis of 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylic acid

[0241] MeOH (500 mL), H 2 To a stirred solution of ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate (110 g, 345 mmol, 1 equiv.) in 2H2O (500 mL) and THF (500 mL) was added LiOH (25 g, 1040 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred for 1 h and then concentrated under vacuum. The resulting mixture was diluted with water (100 mL) and acidified to pH 3 with HCl (aq.). The precipitated solid was collected by filtration and washed with water (3×50 mL). Drying afforded 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylic acid (100 g, 99% yield) as a white solid. LCMS (ES, m / z): [M+H] + :291 Int.12-a: Synthesis of 2,4-difluoro-3-[imidazo[1,5-a]pyrazin-6-yl]aniline

[0242] In a 2 L sealed tube, 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylic acid (100 g, 344 mmol, 1 eq.) and NMP (1.5 L) were added at room temperature. The resulting mixture was stirred at 200° C. for 3 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2,4-difluoro-3-[imidazo[1,5-a]pyrazin-6-yl]aniline (50 g, 59% yield) as a white solid. LCMS (ES, m / z): [M+H] + :247 Intermediate 12: Synthesis of 2,4-difluoro-3-[1-iodoimidazo[1,5-a]pyrazin-6-yl]aniline

[0243] To a stirred solution of 2,4-difluoro-3-[imidazo[1,5-a]pyrazin-6-yl]aniline (50 g, 203 mmol, 1 equiv.) in DMF (1 L) was added NIS (54.8 g, 243 mmol, 1.2 equiv.) in portions. The reaction was stirred for 3 h and then quenched by the addition of water (500 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with brine (2×500 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 2,4-difluoro-3-[1-iodoimidazo[1,5-a]pyrazin-6-yl]aniline (35 g, 46% yield) as an off-white solid. LCMS (ES, m / z): [M+H] + :373 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.90 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 0.7 Hz, 1H), 8.55 (s, 1H), 7.00-6.78 (m, 2H), 5.14 (s, 2H). Example 12 Synthesis of methyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (intermediate 13) [ka] Intermediate 13: Synthesis of methyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate

[0244] To a stirred mixture of 5-bromo-2-fluoropyridine (130 g, 739 mmol, 1 equiv.) and methyl 2-isocyanoacetate (88 g, 886 mmol, 1.2 equiv.) in DMF (4 L) was added t-BuOK (887 mL, 1.2 equiv., 1 mol / L in THF) dropwise under nitrogen atmosphere at 0° C. The mixture was stirred for 3 h and then poured into water / ice (1 L) and the resulting mixture was cooled to 5° C. 2 Cl 2 (4×1 L). The combined organics were washed with brine (2×1 L) and extracted with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give methyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (60 g, 32% yield) as a white solid. LCMS (ES, m / z): [M+H] + :255, 257 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.90 (dd, J = 1.7, 1.0 Hz, 1H), 8.45- 8.39 (m, 1H), 7.92 (dt, J = 9.6, 0.9 Hz, 1H), 7.33 (dd, J = 9.6, 1.7 Hz, 1H), 3.84 (s, 3H). (Example 13) Synthesis of methyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (Intermediate 14) [ka] Intermediate 14: Synthesis of methyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate

[0245] Into a 1 L three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added methyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (40 g, 157 mmol, 1 equiv.), bis(pinacolato)diboron (47.8 g, 188 mmol, 1.2 equiv.), dioxane (500 mL), KOAc (31 g, 314 mmol, 2 equiv.), and Pd(dppf)Cl. 2 (11.5 g, 16 mmol, 0.1 equiv.) was added at room temperature. The resulting solution was stirred at 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with H 2 O (100 mL), K 2 CO 3 (43 g, 311 mmol, 2 equiv.), 3-bromo-2,4-difluoroaniline (48.5 g, 233 mmol, 1.5 equiv.) and Pd(dppf)Cl 2 (11.4 g, 15.6 mmol, 0.1 equiv.) was added. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The residue was subjected to a silica gel column eluting with ethyl acetate / petroleum ether (4:1) to give methyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (32 g, 68% yield) as a white solid. LCMS (ES, m / z): [M+H] + :304 Example 14 Synthesis of ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (intermediate 15) [ka] Int.15-a: Synthesis of ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate

[0246] In a 50 L four-neck round bottom flask was added a solution of 2,5-dibromopyrazine (1.3 kg, 5465 mmol, 1 equiv.) in NMP (25 L), K 2 CO 3 (1522 g, 10930 mmol, 2 equiv.), ethyl 2-[(diphenylmethylidene)amino]acetate (1534 g, 5738 mmol, 1.05 equiv.) and tetrabutylammonium bromide (1762 g, 5465 mmol, 1 equiv.). The resulting solution was stirred at 100° C. for 10 h. The reaction was cooled and quenched by the addition of 20 L of water / ice. The resulting solution was extracted with 3×15 L of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1×10 L of brine and then concentrated under vacuum. This gave crude ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate (2710 g) as a brown solid. LC-MS: (ES, m / z): [M+H] 424 Int.15-b: Synthesis of ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate

[0247] A 50 L four-neck round bottom flask was charged with a solution of ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate (2500 g, 60% purity) in THF (10 L) and HCl (1M, 10 L). The resulting solution was stirred at 10° C. for 30 min. The reaction was washed with dichloromethane (2×20 L) and the pH was adjusted with NH 4 The pH was adjusted to 8 with OH. The resulting solution was extracted with 3×15 L of dichloromethane and the organic layers were combined. The organics were washed with 10 L of brine and concentrated in vacuo to give crude ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate (1000 g) as a yellow solid. LC-MS: (ES, m / z): [M+H] 260 Intermediate 15: Synthesis of ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate

[0248] A 10 L four-neck round bottom flask was charged with ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate (1 kg, 3076 mmol, 1 equiv, 80%) and triethyl orthoformate (5 L). The resulting solution was stirred at 80° C. for 1 h and then cooled to 0° C. in a water / ice bath. The solid was collected by filtration and dried to give ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (351 g, 42% yield) as a pink solid. LCMS (ES, m / z): [M+H] 270 1 H NMR: (300 MHz, DMSO-d 6 , ppm): δ 9.21 (dd, J = 1.6, 0.6 Hz, 1H), 8.87 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 0.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). Example 15 Synthesis of ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (Intermediate 16) [ka] Int.16-a: Synthesis of ethyl 2-(5-bromopyridin-2-yl)acetate

[0249] A 20 L 4-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of 5-bromo-2-methylpyridine (300 g, 1744 mmol, 1 equiv) in THF (10.5 L). The solution was cooled to 0° C. and a 1 M solution of LiHMDS in THF (4 L) was added dropwise with stirring at 0° C. The solution was stirred at low temperature for 30 min, then diethyl carbonate (311 g, 2633 mmol, 1.5 equiv) was added. The resulting solution was stirred at room temperature for 5 h. The reaction solution was extracted with 5 L of ethyl acetate and the organics were dried over anhydrous sodium sulfate. Concentration afforded ethyl 2-(5-bromopyridin-2-yl)acetate (400 g, 94% yield) as a black oil. Int.16-b: Synthesis of ethyl (2Z)-2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate

[0250] A 5 L 4-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl 2-(5-bromopyridin-2-yl)acetate (400 g, 1639 mmol, 1 equiv.) and AcOH (800 mL). After cooling to 0° C., H 2 NaNO in O (280 mL) 2 (114 g, 1652 mmol, 1.01 equiv) was added dropwise. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched by the addition of 1 L of water and the resulting solution was extracted with 1 L of ethyl acetate. The organics were dried over anhydrous sodium sulfate and concentrated. This gave ethyl (2Z)-2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate (450 g) as a crude black oil. Int.16-c: Synthesis of ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate

[0251] A 10 L 4-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with ethyl (2Z)-2-(5-bromopyridin-2-yl)-2-(N-hydroxyimino)acetate (450 g, 1648 mmol, 1 equiv) and AcOH (4.5 L). The mixture was cooled to 0° C. and Zn (318 g, 4862 mmol, 2.95 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. The solids were removed by filtration and the filtrate was concentrated to give ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate (379 g, 89% yield) as a black oil. Int.16-d: Synthesis of ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate

[0252] A 2 L four-neck round bottom flask was charged with ethyl 2-amino-2-(5-bromopyridin-2-yl)acetate (379 g, 1463 mmol, 1 equiv.) and triethyl orthoformate (645 mL). The resulting solution was stirred at 130° C. for 10 min and then concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:3). The collected fractions were combined and concentrated to give ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (125 g, 32% yield) as a black oil. Int.16-e: Synthesis of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate

[0253] Into a 5 L four-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (125 g, 465 mmol, 1 equiv.), dioxane (3125 mL), bis(pinacolato)diboron (178 g, 700 mmol, 1.5 equiv.), Pd(dppf)Cl 2 (38 g, 52 mmol, 0.11 equiv) and KOAc (138 g, 1406 mmol, 3.03 equiv). The resulting solution was stirred at 85° C. for 1 h and then concentrated. The residue was suspended in 1 L of EA and the solids were removed by filtration. The filtrate was concentrated to give ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (150 g) as a crude black solid. Intermediate 16: Synthesis of ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate

[0254] Into a 10 L four-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (100 g, 316 mmol, 1 equiv.), 3-bromo-2,4-difluoroaniline (65.5 g, 315 mmol, 1 equiv.), dioxane (5 L), Pd(dppf)Cl 2 .CH 2 Cl 2 (25.8g, 35mmol, 0.11eq), K 2 CO 3 (131 g, 947 mmol, 2.99 equiv.) and H 2 0 (1 L) was added. The resulting solution was stirred at 85 °C for 2 h and then concentrated. The resulting mixture was extracted with 1 L of ethyl acetate and the organics were concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:4). The collected fractions were combined and concentrated to give ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (53 g, 53% yield) as a brown solid. LCMS(ES, m / z): 318[M+H]+ 1H NMR (300 MHz, Methanol-d4, ppm): δ 8.58 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 9.4 Hz, 1H), 7.33 (d, J = 9.5 Hz, 1H), 6.96 - 6.83 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.21 (s, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.20 (s, 1H). Example 16 Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 1) [ka] 1-a: Synthesis of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate

[0255] Ethyl 6-bromoimidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.75 mmol, 1 equiv.), bis(pinacolato)diboron (284 mg, 1.1 mmol, 1.5 equiv.), Pd(dppf)Cl 2 (55 mg, 0.075 mmol, 0.1 equiv) and AcOK (219 mg, 2.24 mmol, 3 equiv) were suspended in dioxane (5 mL). The resulting solution was stirred in an oil bath at 85° C. for 1 h, then cooled and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:10). Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (188 mg) was isolated as a white solid. LCMS (ES, m / z): [M+H] + :317 1-b: Synthesis of ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate

[0256] Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (188 mg, 0.6 mmol, 1 equiv.), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (246 mg, 0.6 mmol, 1 equiv.), Pd(dppf)Cl 2 (44 mg, 0.06 mmol, 0.1 equiv.) and K 2 CO 3 (246 mg, 1.8 mmol, 3 equiv.) in dioxane (10 mL) and H 2The mixture was suspended in 2 mL of 0. The resulting solution was stirred in an oil bath at 85° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). Ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate (155 mg) was isolated as a white solid. LCMS (ES, m / z): [M+H] + :523 1-c: Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid

[0257] Ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate (155 mg, 0.3 mmol, 1 equiv.) in MeOH (10 mL) was stirred at room temperature for 2 h at 4°C. 2 The resulting solution was stirred at room temperature for 1 h and then concentrated. The residue was washed with 10 mL of H 2 The mixture was diluted with 500 mL of HO and the pH was adjusted to 5-6 with HCl (2 mol / L). The resulting solution was extracted with 2 × 10 mL of ethyl acetate. The organic solution was washed with 20 ml of brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum to give 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (103 mg) as a white solid, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :495 Compound 1: Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0258] 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (103 mg, 0.21 mmol, 1 equiv.), CH 3 NH 2 .H 2 O (14 mg, 0.21 mmol, 1 equiv), HATU (116 mg, 0.31 mmol, 1.5 equiv) and DIEA (40 mg, 0.31 mmol, 1.5 equiv) were dissolved in DMF (5 mL). The resulting solution was stirred at room temperature for 2 h. Concentration gave the crude product (150 mg), which was purified using the following conditions: (IntelFlash®-1): welch Ultimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: water (0.05% NH 3 .H 2 Purification by flash preparative HPLC using HPLC at 220 nm, mobile phase B: ACN, gradient: 10-35% B; detector at 220 nm. 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (23 mg) was isolated as a white solid. LCMS (ES, m / z): [M+H] + :508 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 8.60 (s, 1H), 8.54-8.46 (m, 2H), 8.19-8.05 (m, 3H), 7.44-7.30 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.02 (d, J = 9.5 Hz, 1H), 3.92 (s, 3H), 2.81 (d, J = 4.7 Hz, 3H). (Example 17) Synthesis of 5-chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide (compound 2) [ka] 2-a: Synthesis of 2-(5-bromopyridin-2-yl)-2-[(diphenylmethylidene)amino]acetonitrile

[0259] 5-Bromo-2-fluoropyridine (50 g, 284 mmol, 1 equiv.) in DMF (1000 mL), Cs 2 CO 3 A solution of (278 g, 852 mmol, 3 equiv.) and 2-[(diphenylmethylidene)amino]acetonitrile (62.6 g, 284 mmol, 1 equiv.) was stirred at 100° C. overnight. The mixture was allowed to cool to room temperature, diluted with water (3000 mL) and then extracted with EA (3×1000 mL). The combined organic layers were washed with brine (2×500 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3 / 1) to give 2-(5-bromopyridin-2-yl)-2-[(diphenylmethylidene)amino]acetonitrile (75 g, 70% yield) as a pink oil. LCMS (ES, m / z): [M+H] + :376 2-b: Synthesis of 2-amino-2-(5-bromopyridin-2-yl)acetonitrile

[0260] To a stirred solution of 2-(5-bromopyridin-2-yl)-2-[(diphenylmethylidene)amino]acetonitrile (75 g, 199 mmol, 1 equiv.) in THF (400 mL) was added 2 M hydrochloric acid (300 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to remove THF. The mixture was diluted with saturated NaHCO 3 The mixture was basified to pH 8 with aqueous EA (3×500 mL). The combined organic layers were washed with brine (300 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to give 2-amino-2-(5-bromopyridin-2-yl)acetonitrile (23.9 g, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :212 2-c: Synthesis of 6-bromoimidazo[1,5-a]pyridine-1-carbonitrile

[0261] A solution of 2-amino-2-(5-bromopyridin-2-yl)acetonitrile (23.9 g, 113 mmol, 1 equiv) in triethyl orthoformate (100 mL) was stirred for 30 min at 100° C. The mixture was cooled to 0° C. and the solid that formed was collected by filtration and dried under vacuum to give 6-bromoimidazo[1,5-a]pyridine-1-carbonitrile (14 g, 56% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :222 2-d: Synthesis of 2-[6-bromoimidazo[1,5-a]pyridin-1-yl]-1H-imidazole

[0262] CH 3 To a stirred solution of 6-bromoimidazo[1,5-a]pyridine-1-carbonitrile (14 g, 63 mmol, 1 equiv.) in OH (100 mL) was added NaOMe (13.6 g, 252 mmol, 4 equiv.) in portions at 0° C. The resulting mixture was stirred at 50° C. for 3 h and then cooled to room temperature. To this was added 2,2-dimethoxyethan-1-amine (5 g, 47 mmol, 1.2 equiv.) and AcOH (11.8 g, 197 mmol, 5 equiv.) and the mixture was stirred at 50° C. for 1 h. After cooling to room temperature, MeOH (168 mL) was added followed by dropwise addition of 6 M hydrochloric acid (84 mL) at 0° C. The resulting mixture was stirred at 100° C. for 5 h. The mixture was allowed to cool and concentrated under vacuum. The resulting mixture was then diluted with H 23H-imidazole (15.1 g) as a black solid, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :263 2-e: Synthesis of 2-[6-bromoimidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole

[0263] To a stirred solution of 2-[6-bromoimidazo[1,5-a]pyridin-1-yl]-1H-imidazole (15 g, 57.3 mmol, 1 equiv) in tetrahydrofuran (150 mL) was added NaH (4.8 g, 200 mmol, 3.5 equiv, 60%) in portions at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. SEM-Cl (15.3 mL, 91 mmol, 1.5 equiv) was added dropwise over 10 min at 0° C. and the resulting mixture was stirred at room temperature for 1 h. The reaction was cooled to room temperature and cooled to room temperature. 2 The mixture was quenched by the addition of 2×O (500 mL) and extracted with EA (3×200 mL). The combined organics were washed with brine (2×100 mL) and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 2-[6-bromoimidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole (8 g, 36% yield) as a brown oil. LCMS (ES, m / z): [M+H] + :393 2-f: Synthesis of 2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole

[0264] To a stirred solution of 2-[6-bromoimidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole (8 g, 20 mmol, 1 equiv.), KOAc (4 g, 41 mmol, 2 equiv.) and bis(pinacolato)diboron (5.7 g, 22 mmol, 1.1 equiv.) in dioxane (100 mL) was added Pd(dppf)Cl 2 (1.5 g, 2.03 mmol, 0.1 equiv) was added in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and then diluted with water (500 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and then with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole (8.1 g, 90% yield) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :441 2-g: Synthesis of 5-chloro-N-[2,4-difluoro-3-[1-(1-[[2-(trimethylsilyl)ethoxy]methyl]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide

[0265] Dioxane (80 mL) and H 2 To a stirred solution of 2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridin-1-yl]-1-[[2-(trimethylsilyl)ethoxy]methyl]imidazole (8.1 g, 18.4 mmol, 1 equiv.) and N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (9.13 g, 22 mmol, 1.2 equiv.) in 20O (8 mL) was added K 2 CO 3(7.6 g, 55 mmol, 3 equiv.) and Pd(dppf)Cl 2 (1.35 g, 1.8 mmol, 0.1 equiv) was added in portions. The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature and then diluted with water (200 mL). The resulting mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1 / 1) to give 5-chloro-N-[2,4-difluoro-3-[1-(1-[[2-(trimethylsilyl)ethoxy]methyl]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide (5.88 g, 49% yield) as a white solid. LCMS (ES, m / z): [M+H] + :647 Compound 2: Synthesis of 5-chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide

[0266] A solution of 5-chloro-N-[2,4-difluoro-3-[1-(1-[[2-(trimethylsilyl)ethoxy]methyl]imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide (5.9 g, 9.1 mmol, 1 equiv.) in TFA (50 mL) was stirred at 70° C. for 1 h. The resulting mixture was concentrated under reduced pressure and then diluted with water (50 mL). The mixture was diluted with saturated NaHCO 3 The mixture was basified to pH 8 with aqueous EA (3×100 mL). The combined organic layers were washed with brine (100 mL) and then with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by elution with the following conditions: column, welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.1% NH in water 3 H 2 Purification by preparative HPLC using 220 nm HO, mobile phase B: MeCN (25–65% over 15 min), detector A: MeCN (25–65%) to give 5-chloro-N-[2,4-difluoro-3-[1-(1H-imidazol-2-yl)imidazo[1,5-a]pyridin-6-yl]phenyl]-2-methoxypyridine-3-sulfonamide (2.05 g, 44% yield) as a white solid. LCMS (ES, m / z): [M+H] + :517 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.52 (d, J = 4.5 Hz, 3H), 8.24 (d, J = 9.4 Hz, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.38 (td, J = 8.9, 6.0 Hz, 1H), 7.25 (t, J = 9.5 Hz, 1H), 7.08 (s, 2H), 6.84 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H). (Example 18) Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide (compound 3) [ka] 3-a: Synthesis of ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate

[0267] 2,5-Dibromopyrazine (10 g, 42 mmol, 1 equiv.), ethyl 2-[(diphenylmethylidene)amino]acetate (11.8 g, 44 mmol, 1.05 equiv.), TBAB (13.6 g, 42 mmol, 1 equiv.) and K in NMP (200 mL). 2 CO3 (17.4 g, 126 mmol, 3 equiv.) was stirred at 100° C. overnight in an oil bath. The reaction mixture was cooled and filtered. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 2×200 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 2×200 ml of water. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate / PE (1 / 10). The collected fractions were combined and concentrated to give ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate (8 g, 45% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :424 3-b: Synthesis of ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate

[0268] A 250 mL round bottom flask was charged with ethyl 2-(5-bromopyrazin-2-yl)-2-[(diphenylmethylidene)amino]acetate (8 g, 18.8 mmol, 1 equiv), THF (10 mL) and HCl (aq, 1 M) (20 mL). The resulting solution was stirred at 25° C. for 30 min. The formed solution was diluted with 50 mL of water and extracted with 2×50 mL of dichloromethane. The aqueous layer was diluted with NH 3 .H 2 The mixture was adjusted to pH 8 with O and further extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate (4.7 g, 96% yield) was isolated as a yellow solid, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :260 3-c: Synthesis of ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate

[0269] A 50 mL round bottom flask was charged with ethyl 2-amino-2-(5-bromopyrazin-2-yl)acetate (4.2 g, 0.02 mol, 1 eq.) and triethyl orthoformate (20 mL). The resulting solution was stirred in an oil bath at 80° C. for 2 h. The reaction mixture was cooled and the solid was collected by filtration. Air drying afforded ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (2.2 g, 50% yield) as a brown solid. LCMS (ES, m / z): [M+H] + :270 3-d: Synthesis of 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0270] 3-Bromo-2,4-difluoroaniline (10 g, 48 mmol, 1 equiv.), Pd(dppf)Cl 2 (3.5 g, 4.8 mmol, 0.1 equiv), bis(pinacolato)diboron (18.3 g, 72 mmol, 1.5 equiv) and KOAc (14.2 g, 144.2 mmol, 3 equiv) were dissolved in dioxane (240 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction mixture was cooled and the solids were removed by filtration. The filtrate was concentrated and diluted with DCM (100 mL), then washed with 2×100 mL of water and 100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1 / 10). 2,4-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8 g, 65% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :256 3-e: Synthesis of ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate

[0271] Dioxane (10 mL) and H 2Ethyl 6-bromoimidazo[1,5-a]pyrazine-1-carboxylate (500 mg, 1.9 mmol, 1 equiv.), 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (708 mg, 2.8 mmol, 1.5 equiv.), Pd(dppf)Cl in O (2 mL). 2 (135mg, 0.2mmol, 0.1eq), K 2 CO 3 (767 mg, 5.6 mmol, 3 equiv.) was stirred in an oil bath at 60° C. for 1 h. The reaction mixture was cooled, diluted with water (20 ml) and extracted with 3×20 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / PE (1 / 2). Ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate (200 mg, 34% yield) was isolated as a brown solid. LCMS (ES, m / z): [M+H] + :319 3-f: Synthesis of ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylate

[0272] Ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyrazine-1-carboxylate (150 mg, 0.5 mmol, 1 equiv.) in DCM (5 mL) was treated with pyridine (186 mg, 2.3 mmol, 5 equiv.) followed by 5-chloro-2-methoxypyridine-3-sulfonyl chloride (137 mg, 0.6 mmol, 1.2 equiv.). The resulting solution was stirred overnight. The resulting mixture was concentrated and purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm; mobile phase: 0.1% formic acid / 5-70% MeCN over 15 min; detector, 254 and 220 nm. Ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylate (320 mg 97% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :524 3-g: Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylic acid

[0273] Ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylate (200 mg, 0.4 mmol, 1 equiv.), MeOH (2 mL), THF (2 mL), H 2 2 mL of HO and LiOH (27 mg, 1.1 mmol, 3 equiv.) were stirred in an oil bath at 60° C. for 1 h. After concentration, the crude product was purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm; mobile phase: 5-60% MeCN / 0.1% ammonia over 15 min; detector, 254 nm. 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylic acid (170 mg, 90% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :496 Compound 3: Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide

[0274] 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrazine-1-carboxylic acid (170 mg, 0.3 mmol, 1 equiv.) in DMF (4 mL) was treated with DIEA (133 mg, 1 mmol, 3 equiv.), methylamine hydrochloride (16 mg, 0.5 mmol, 1.5 equiv.) and HATU (195 mg, 0.5 mmol, 1.5 equiv.). The resulting solution was stirred for 1 h and then concentrated. The crude product was purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase: 5-60% MeCN / 0.1% formic acid over 20 min. 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrazine-1-carboxamide (43 mg, 25% yield) was isolated as an off-white solid. LCMS (ES, m / z): [M+H] + :509 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.46 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 5.0 Hz, 2H), 8.51 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.42 (td, J = 8.8, 5.8 Hz, 1H), 7.25 (td, J = 9.3, 1.4 Hz, 1H), 3.92 (s, 3H), 2.84 (d, J = 4.7 Hz, 3H). (Example 19) Synthesis of 2-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (compound 4) [ka] 4-a: Synthesis of ethyl 2-(6-chloropyridazin-3-yl)-2-[(diphenylmethylidene)amino]acetate

[0275] Into a 500 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was added 3,6-dichloropyridazine (5 g, 33.5 mmol, 1 equiv.), dioxane (160 mL), TBAB (10.8 g, 34 mmol, 1 equiv.), Cs 2 CO 3 (32.8 g, 100 mmol, 3 equiv.) and ethyl 2-[(diphenylmethylidene)amino]acetate (9 g, 34 mmol, 1 equiv.). The resulting solution was stirred overnight at 80° C. in an oil bath and then cooled. The resulting mixture was concentrated and the residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:5). The appropriate fractions were combined and concentrated to give ethyl 2-(6-chloropyridazin-3-yl)-2-[(diphenylmethylidene)amino]acetate (6 g, 47% yield) as a brown oil. LCMS (ES, m / z): [M+H] + :380 4-b: Synthesis of ethyl 2-amino-2-(6-chloropyridazin-3-yl)acetate

[0276] A 250 mL round bottom flask was charged with ethyl 2-(6-chloropyridazin-3-yl)-2-[(diphenylmethylidene)amino]acetate (6.80 g, 17.9 mmol, 1 equiv), THF (20 mL) and HCl (6 M in water) (20 mL). The resulting solution was stirred at 25° C. for 30 min. The resulting solution was diluted with 50 mL of water and extracted with 2×50 mL of dichloromethane. The aqueous layer was diluted with NH 3 .H 2The pH was adjusted to 8 with O and extracted with an additional 2×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give ethyl 2-amino-2-(6-chloropyridazin-3-yl)acetate (3.2 g) as a yellow solid, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :216 4-c: Synthesis of ethyl 2-chloroimidazo[1,5-b]pyridazine-5-carboxylate

[0277] A 250 mL round bottom flask was charged with ethyl 2-amino-2-(6-chloropyridazin-3-yl)acetate (3.1 g, 14.4 mmol, 1 equiv.) and triethoxymethane (50 mL). The resulting solution was stirred in an oil bath at 80° C. for 1 h. After concentration, the residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1). The appropriate fractions were combined and concentrated to give ethyl 2-chloroimidazo[1,5-b]pyridazine-5-carboxylate (2.4 g, 74% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :226 4-d: Synthesis of ethyl 2-(3-amino-2,6-difluorophenyl)imidazo[1,5-b]pyridazine-5-carboxylate

[0278] In a 40 mL vial, add ethyl 2-chloroimidazo[1,5-b]pyridazine-5-carboxylate (500 mg, 2.2 mmol, 1 equiv.), H 2 O (2 mL), dioxane (10 mL), Sphos (182 mg, 0.4 mmol, 0.2 equiv.), SPhosPdGen.3 (173 mg, 0.2 mmol, 0.1 equiv.), 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.1 g, 4.4 mmol, 2 equiv.), and K 2 CO 3(766 mg, 5.5 mmol, 2.5 equiv.). The resulting solution was stirred in an oil bath at 80° C. for 1 h. The reaction mixture was cooled and concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1 / 1). The appropriate fractions were combined and concentrated to give ethyl 2-(3-amino-2,6-difluorophenyl)imidazo[1,5-b]pyridazine-5-carboxylate (340 mg, 48% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :319 4-e: Synthesis of 2-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-b]pyridazine-5-carboxamide

[0279] A 50 mL round bottom flask was charged with ethyl 2-(3-amino-2,6-difluorophenyl)imidazo[1,5-b]pyridazine-5-carboxylate (330 mg, 1 mmol, 1 equiv.) and methylamine (5 mL, 33% in alcohol). The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction mixture was cooled and concentrated. The crude product was purified by flash preparative HPLC using the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase: 5-60% MeCN / 0.1% formic acid over 20 min; detector, UV 254 nm. 2-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (240 mg, 76% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :304 Compound 4: Synthesis of 2-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide

[0280] An 8 mL vial was charged with 2-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (70 mg, 0.2 mmol, 1 eq.), DCM (2 mL), pyridine (91 mg, 1.1 mmol, 5 eq.) and 5-chloro-2-methoxypyridine-3-sulfonyl chloride (84 mg, 0.3 mmol, 1.5 eq.). The resulting solution was stirred overnight at 36° C. in an oil bath. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.1% FA in water, mobile phase B: ACN (from 44% phase B to 58% in 8 min); detector, 220 nm. 2-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (69 mg, 59% yield) was isolated as an off-white solid. LCMS (ES, m / z): [M+H] + :509[M+H] + 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.87 (s, 1H), 8.58 (d, J = 9.5 Hz, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.33 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.50 (td, J = 9.0, 5.9 Hz, 1H), 7.30 (td, J = 9.1, 1.6 Hz, 1H), 7.13 (dt, J = 9.4, 1.3 Hz, 1H), 3.91 (s, 3H), 2.82 (d, J = 4.7 Hz, 3H). (Example 20) Synthesis of 2-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (compound 5) [ka] 5-a: Synthesis of 3-bromo-5-chloro-2-methylpyridine

[0281] Into a round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added 2,3-dibromo-5-chloropyridine (5 g, 18 mmol, 1 equiv.), dioxane (90 mL), K 2 CO 3 (7.6g, 55mmol, 3eq.), Pd(PPh 3 ) 4 (2.1 g, 1.8 mmol, 0.1 equiv.), and a 50% yield solution of trimethyl-1,3,5,2,4,6-trioxatriborinane (2.3 g, 18.3 mmol, 1 equiv.) in THF were charged. The resulting solution was stirred in an oil bath at 110° C. for 3 days, and a 50% solution of trimethyl-1,3,5,2,4,6-trioxatriborinane (2.3 g, 18.3 mmol, 1 equiv.) in THF was added every day. The reaction mixture was cooled, and the resulting mixture was concentrated at low temperature (the product has a low boiling point and can be easily removed together with the solvent). The residue was applied to a silica gel column eluted with ethyl acetate / petroleum ether (1:10). 3-Bromo-5-chloro-2-methylpyridine (2 g, 53% yield) was obtained as an off-white solid. LCMS (ES, m / z): [M+H] + :205 5-b: Synthesis of 3-(benzylsulfanyl)-5-chloro-2-methylpyridine

[0282] Into a 50 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was added 3-bromo-5-chloro-2-methylpyridine (850 mg, 4 mmol, 1 equiv.), dioxane (20 mL), DIEA (1.06 g, 8.2 mmol, 2 equiv.), Xantphos (476 mg, 0.8 mmol, 0.2 equiv.), Pd 2 (dba) 3(377 mg, 0.4 mmol, 0.1 equiv) and benzyl mercaptan (767 mg, 6.1 mmol, 1.5 equiv). The resulting solution was stirred in an oil bath at 100° C. for 2 h. The reaction mixture was cooled and concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:20). 3-(benzylsulfanyl)-5-chloro-2-methylpyridine (500 mg, 49% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :250 5-c: Synthesis of 5-chloro-2-methylpyridine-3-sulfonyl chloride

[0283] A 20 mL vial was charged with MeCN (6 mL) and HCl (6 M in water, 1.2 mL). This was followed by the addition of NCS (428 mg, 3.2 mmol, 4 equiv) in portions at 0° C. The mixture was stirred for 10 min, then 3-(benzylsulfanyl)-5-chloro-2-methylpyridine (200 mg, 0.8 mmol, 1 equiv) was added in portions at 0° C. The resulting solution was stirred in a water / ice bath at 0° C. for 30 min. The reaction was quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane and the organic layers were combined. The organics were washed with 2×20 mL of water and the mixture was dried over anhydrous sodium sulfate before being concentrated. 5-Chloro-2-methylpyridine-3-sulfonyl chloride (300 mg crude) was isolated as a yellow oil, which was used directly in the next step without further purification. Compound 5: Synthesis of 2-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide

[0284] An 8 mL vial was charged with 2-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (60 mg, 0.2 mmol, 1 equiv.), DCM (2 mL), pyridine (313 mg, 4 mmol, 20 equiv.) and 5-chloro-2-methylpyridine-3-sulfonyl chloride (268 mg, 1.2 mmol, 6 equiv.). The resulting solution was stirred overnight at 36 °C in an oil bath. The reaction mixture was concentrated and the crude product was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50 × 250 mm, 10 μm mobile phase, 30-60% MeCN / 0.1% formic acid in water over 20 min; detector, UV 254 nm. 2-[3-(5-chloro-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (68 mg, 69% yield) was obtained as an off-white solid. LCMS (ES, m / z): [M+H] + :493 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 8.86 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 9.5 Hz, 1H), 8.32 (q, J = 4.6 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.50 (td, J = 8.9, 5.8 Hz, 1H), 7.32 (td, J = 9.1, 1.6 Hz, 1H), 7.10 (dt, J = 9.4, 1.3 Hz, 1H), 2.82 (d, J = 4.8 Hz, 3H), 2.77 (s, 3H). Example 21 Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 6) [ka] 6-a: Synthesis of N-(3-bromo-2,4-difluorophenyl)-5-fluoro-2-methylpyridine-3-sulfonamide

[0285] A 25 mL three-neck round-bottom flask was charged with 3-bromo-2,4-difluoroaniline (596 mg, 2.9 mmol, 1 equiv), DCM (10 mL), pyridine (679 mg, 8.6 mmol, 3 equiv) and 5-fluoro-2-methylpyridine-3-sulfonyl chloride (600 mg, 2.9 mmol, 1 equiv). The resulting solution was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE:EA (2:1) to give N-(3-bromo-2,4-difluorophenyl)-5-fluoro-2-methylpyridine-3-sulfonamide (760 mg, 70% yield) as a yellow oil. LCMS (ES, m / z): [M+H] + :381 6-b: Synthesis of ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate

[0286] In a 25 mL three-neck round bottom flask, add ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.6 mmol, 1 equiv.), dioxane (10 mL), N-(3-bromo-2,4-difluorophenyl)-5-fluoro-2-methylpyridine-3-sulfonamide (241 mg, 0.6 mmol, 1 equiv.), K 2 CO 3 (262mg, 1.9mmol, 3eq), H 2 O (0.8 mL) and Pd(dppf)Cl 2 (46 mg, 0.06 mmol, 0.1 equiv.) 2 The resulting solution was poured into a flask at room temperature under N 2The mixture was stirred at 85° C. in an oil bath under atmospheric pressure for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE:EA (1:1) to give ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg, 64% yield) as a brown solid. LCMS (ES, m / z): [M+H] + :491 6-c: Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid

[0287] In a 25 mL round-bottom flask, add ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.4 mmol, 1 equiv.), MeOH (10 mL), H 2 2 mL) and LiOH (30 mg, 1.3 mmol, 3 equiv). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was suspended in water (20 mL) and EA (10 mL). The aqueous was extracted with 2×10 mL ethyl acetate and then the pH was adjusted to 2 with HCl (4 M). This was extracted with 3×10 mL ethyl acetate and the organic layers were combined. The resulting mixture was washed with 10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (153 mg) as a white solid, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :463 Compound 6: Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0288] In a 25 mL round-bottom flask, add 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (153 mg, 0.3 mmol, 1 equiv.), DMF (5 mL), CH 3 NH 2 HCl (22 mg, 0.3 mmol, 1 equiv), HATU (184 mg, 0.5 mmol, 1.5 equiv) and DIEA (60 mg, 0.5 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with H 2 The mixture was quenched with 20 mL of HO (20 mL) and the aqueous layer was extracted with 2×20 mL of dichloromethane. The organics were combined and washed with water (20 mL×3) and brine (20 mL), then dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography using the following conditions: welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.05% NH in water 4 HCO 3 , mobile phase B: MeCN (15–40% over 15 min) and purified by preparative HPLC to give 6-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (22.6 mg, 14% yield) as a white solid. LCMS (ES, m / z): [M+H] + :476 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 8.70 (d, J = 2.8 Hz, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.18-8.06 (m, 2H), 7.95 (dd, J = 8.3, 2.8 Hz, 1H), 7.40-7.27 (m, 1H), 7.20 (t, J = 9.3 Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.77 (d, J = 1.2 Hz, 3H). Example 22 Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 7) [ka] 7-a: Synthesis of ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate

[0289] A 25 mL round bottom flask was charged with DCM (5 mL), ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (150 mg, 0.5 mmol, 1 equiv.), pyridine (112 mg, 1.5 mmol, 3 equiv.) and 5-fluoro-2-methoxypyridine-3-sulfonyl chloride (120 mg, 0.5 mmol, 1 equiv.). The resulting solution was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure to give crude ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :507 7-b: Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid

[0290] In a 50 mL round-bottom flask, add MeOH (10 mL), ethyl 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.4 mmol, 1 equiv.), H 20 (2 mL) and LiOH (29 mg, 1.2 mmol, 3 equiv). The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was diluted with water (20 mL) and EA (10 mL). The aqueous layer was extracted with 2×10 mL ethyl acetate. The aqueous layer was adjusted to pH 2 with HCl (4 M) and then extracted with 3×10 mL ethyl acetate. The organic layers were combined, washed with 10 mL brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded crude 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (120 mg) as a light yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :479 Compound 7: Synthesis of 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0291] In a 25 mL round-bottom flask, add DMF (5 mL), 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (120 mg, 0.3 mmol, 1 equiv.), CH 3 NH 2 HCl (17 mg, 0.3 mmol, 1 equiv), HATU (143 mg, 0.4 mmol, 1.5 equiv) and DIEA (49 mg, 0.4 mmol, 1.5 equiv). The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated and the residue was purified by column chromatography under the following conditions: welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.05% NH in water 4 HCO 3, mobile phase B: MeCN (20% to 50% over 15 min) and purified by preparative HPLC to give 6-[2,6-difluoro-3-(5-fluoro-2-methoxypyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (50 mg, 39% yield) as a white solid. LCMS (ES, m / z): [M+H] + :491 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.60 (s, 1H), 8.52-8.44 (m, 2H), 8.19-8.08 (m, 2H), 8.04 (dd, J = 7.3, 3.0 Hz, 1H), 7.37 (td, J = 8.9, 5.8 Hz, 1H), 7.31-7.19 (m, 1H), 7.01 (dd, J = 9.5, 1.5 Hz, 1H), 3.91 (s, 3H), 2.84-2.77 (m, 3H). (Example 23) Synthesis of 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 8) [ka] 8-a: Synthesis of ethyl 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate

[0292] A 25 mL round bottom flask was charged with DCM (5 mL), ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (150 mg, 0.5 mmol, 1 equiv.), pyridine (112 mg, 1.4 mmol, 3 equiv.) and 5-cyano-2-methoxypyridine-3-sulfonyl chloride (110 mg, 0.5 mmol, 1 equiv.). The resulting solution was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure to give crude ethyl 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :514 8-b: Synthesis of 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid

[0293] In a 50 mL round-bottom flask, add MeOH (10 mL), ethyl 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.4 mmol, 1 equiv.), H 2 2H2O (2 mL) and LiOH (28 mg, 1.2 mmol, 3 equiv.) were charged. The resulting solution was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The aqueous layer was adjusted to pH 2 with HCl (4 M) and then extracted with ethyl acetate (3 x 10 mL). The organics were combined, washed with brine (10 mL) and dried over anhydrous sodium sulfate. Concentration afforded crude 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (120 mg) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :486 Synthesis of compound 8: 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0294] In a 25 mL round-bottom flask, add DMF (5 mL), 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyridine-1-carboxylic acid (120 mg, 0.3 mmol, 1 equiv.), CH 3 NH 2 HCl (16 mg, 0.3 mmol, 1 equiv.), HATU (141 mg, 0.4 mmol, 1.5 equiv.) and DIEA (48 mg, 0.4 mmol, 1.5 equiv.). The resulting solution was stirred at room temperature for 2 h and then diluted with H 2 The resulting solution was extracted with 2×50 mL of dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using the following conditions: welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.05% NH in water. 4 HCO 3 , mobile phase B: MeCN (20% to 40% over 10 min) to give 6-[3-(5-cyano-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (13 mg, 10%) as a white solid. LCMS (ES, m / z): [M+H] + :498 1 H NMR (300 MHz, DMSO-d 6) δ 8.83 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.17-8.05 (m, 2H), 7.30 (d, J = 6.8 Hz, 1H), 7.10 (s, 1H), 7.03 (d, J = 9.5 Hz, 1H), 3.96 (s, 3H), 2.80 (d, J = 4.7 Hz, 3H). (Example 24) Synthesis of 6-[3-(5-cyano-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 9) [ka] 9-a: Synthesis of methyl 5-bromo-6-iodopyridine-3-carboxylate

[0295] To a stirred solution of methyl 5-bromo-6-chloropyridine-3-carboxylate (40 g, 0.16 mol, 1 equiv.) in MeCN (1.2 L) was added TMSI (33 g, 0.17 mol, 1.05 equiv.) and NaI (72 g, 0.48 mol, 3 equiv.). The mixture was stirred at room temperature overnight and then concentrated. 2 O (0.8 L) was added and the solution was made basic with 2M aqueous NaOH. The mixture was extracted with DCM (800 mL x 3) and the organic layer was diluted with Na 2 SO 4 After concentration, the residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give methyl 5-bromo-6-iodopyridine-3-carboxylate (40 g, 73% yield) as a grey solid. LCMS (ES, m / z): [M+H] + :342 9-b: Synthesis of methyl 5-bromo-6-methylpyridine-3-carboxylate

[0296] To a stirred solution of methyl 5-bromo-6-iodopyridine-3-carboxylate (10 g, 29 mmol, 1 equiv) in dioxane (293 mL) was added K2 CO 3 (12 g, 88 mmol, 3 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (3.7 g, 29 mmol, 1 equiv.) and Pd(PPh 3 ) 4 (3.4 g, 2.9 mmol, 0.1 equiv) was added. After stirring overnight at 110° C. under nitrogen atmosphere, LCMS showed 50% desired product and 50% starting material remained, so another batch of trimethyl-1,3,5,2,4,6-trioxatriborinane (3.7 g, 29 mmol, 1 equiv) was added and the resulting mixture was stirred at 110° C. overnight. After cooling, the resulting mixture was filtered and the filter cake was washed with EA (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give methyl 5-bromo-6-methylpyridine-3-carboxylate (5 g, 74% yield) as a white solid. LCMS (ES, m / z): [M+H] + :230 9-c: Synthesis of 5-bromo-6-methylpyridine-3-carboxamide

[0297] Methyl-5-bromo-6-methylpyridine-3-carboxylate (3.5 g) was dissolved in 7M NH 3 (70 mL) and stirred overnight in a sealed tube at 90° C. The reaction solution was concentrated directly to give 5-bromo-6-methylpyridine-3-carboxamide (4 g, crude) as a grey solid. LCMS (ES, m / z): [M+H] + :215 9-d: Synthesis of 5-bromo-6-methylpyridine-3-carbonitrile

[0298] To a stirred solution of 5-bromo-6-methylpyridine-3-carboxamide (3 g, 14 mmol, 1 equiv) in THF (60 mL) was added TEA (3.5 g, 35 mmol, 2.5 equiv) and TFAA (6 g, 28 mmol, 2 equiv). The reaction was stirred at room temperature for 2 h and then concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA (20:1) to give 5-bromo-6-methylpyridine-3-carbonitrile (2 g, 74% yield) as a white solid. LCMS (ES, m / z): [M+H] + :197 9-e: Synthesis of 5-(benzylsulfanyl)-6-methylpyridine-3-carbonitrile

[0299] To a stirred solution of 5-bromo-6-methylpyridine-3-carbonitrile (2 g, 10 mmol, 1 equiv.) in dioxane (26 mL) was added benzyl mercaptan (1.9 g, 15 mmol, 1.5 equiv.), DIEA (2.6 g, 20 mmol, 2 equiv.), Xantphos (1.2 g, 2 mmol, 0.2 equiv.) and Pd 2 (dba) 3 .CHCl 3 (1g, 1mmol, 0.1eq) 2 The mixture was added under atmospheric pressure. The resulting solution was stirred at 120° C. for 2 h and then directly concentrated. The residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give 5-(benzylsulfanyl)-6-methylpyridine-3-carbonitrile (2 g, 82% yield) as a red solid. LCMS (ES, m / z): [M+H] + :241 9-f: Synthesis of 5-cyano-2-methylpyridine-3-sulfonyl chloride

[0300] To a stirred solution of 5-(benzylsulfanyl)-6-methylpyridine-3-carbonitrile (0.5 g, 2.1 mmol, 1 equiv.) in MeCN (10 mL) was added 6 M HCl (5 mL) dropwise at 0° C., followed by NCS (1.1 g, 8.4 mmol, 4 equiv.). The reaction was stirred at 0° C. for 10 min. The resulting mixture was diluted with H 2 The aqueous layer was diluted with O (10 mL) and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with PE:EA (5:1) to give 5-cyano-2-methylpyridine-3-sulfonyl chloride (0.24 g, 53% yield) as a yellow oil. Compound 9: Synthesis of 6-[3-(5-cyano-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0301] To a stirred solution of 6-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-a]pyridine-1-carboxamide (180 mg, 0.6 mmol, 1 equiv) in DCM (3 mL) was added 5-cyano-2-methylpyridine-3-sulfonyl chloride (206 mg, 0.95 mmol, 1.6 equiv) and pyridine (141 mg, 1.8 mmol, 3 equiv) at 0° C. The reaction was stirred at room temperature for 30 min and then concentrated. The residue was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (10% to 50% over 15 min) to give 6-[3-(5-cyano-2-methylpyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (121 mg, 42% yield) as a white solid. LCMS (ES, m / z): [M+H] + :483. 1 H NMR (300 MHz, DMSO-d 6) δ 10.88 (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.20 -8.05 (m, 2H), 7.42-7.34 (m, 1H), 7.26 (td, J = 9.1, 1.5 Hz, 1H), 7.03-6.92 (m, 1H), 2.89 (s, 3H), 2.83-2.79 (m, 3H). (Example 25) Synthesis of 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 10) [ka] 10-a1: Synthesis of 1,3-diethyl 2-[(2-bromo-4-fluorophenyl)methyl]propanedioate

[0302] A 50 mL round bottom flask was charged with NaH (1.1 g, 46 mmol, 2.5 equiv) and 1,2-dimethoxyethane (5 mL). This was followed by the dropwise addition of diethyl malonate (4.3 mL) in 1,2-dimethoxyethane (10 mL) at 0° C. The resulting solution was stirred at room temperature for 1.5 h. To this was added dropwise 2-bromo-1-(bromomethyl)-4-fluorobenzene (5.0 g, 18.7 mmol, 1 equiv) in 1,2-dimethoxyethane (10 mL) at 0° C. The resulting solution was stirred at 85° C. for 1.5 h. The reaction was quenched with 100 mL of water / ice and extracted with 3×30 mL of ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC under the following conditions: column, silica gel; mobile phase, 0-20% ethyl acetate in petroleum ether; detector, 254 / 280 nm. 1,3-Diethyl 2-[(2-bromo-4-fluorophenyl)methyl]propanedioate (6 g, 93% yield) was isolated as a solid. 10-a2: Synthesis of 3-(2-bromo-4-fluorophenyl)propanoic acid

[0303] In a 100 mL round-bottom flask, add 1,3-diethyl 2-[(2-bromo-4-fluorophenyl)methyl]propanedioate (6.0 g, 17 mmol, 1 equiv.) and H 2 HO (40 mL) was added. This was followed by the addition of KOH (2.0 g, 36 mmol, 2.1 equiv). The resulting solution was stirred at 100° C. for 4.5 h and then cooled to 0° C. 2 SO 4 (4.0 mL, 75 mmol, 4.3 equiv) was added and the resulting solution was stirred overnight at 120° C. The solid was removed by filtration and dried to give 3-(2-bromo-4-fluorophenyl)propanoic acid (1.6 g, 37% yield) as a solid. 10-a3: Synthesis of 4-bromo-6-fluoro-2,3-dihydroinden-1-one

[0304] A 100 mL round bottom flask was charged with 3-(2-bromo-4-fluorophenyl)propanoic acid (1.6 g, 6.5 mmol, 1 equiv.) in DCM (16 ml). Oxalyl chloride (0.6 ml, 7.2 mmol) was added dropwise at 0° C. and the resulting solution was stirred at room temperature for 18 h. The mixture was concentrated. The acid chloride was dissolved in DCM (30 ml) and AlCl 3 (1 g, 1.20 equiv.) was added at 0° C. and the resulting solution was stirred at 40° C. for 2 h. The reaction was quenched by the addition of 100 mL of water and extracted with 3×20 mL of dichloromethane. The combined organics were washed with 50 ml of 1M NaOH, dried over anhydrous sodium sulfate, and concentrated. 4-Bromo-6-fluoro-2,3-dihydroinden-1-one (314 mg, 21% yield) was isolated as a solid. 10-a4: Synthesis of 4-(benzylsulfanyl)-6-fluoro-2,3-dihydroinden-1-one

[0305] A 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-bromo-6-fluoro-2,3-dihydroinden-1-one (1.8 g, 7.6 mmol, 1 equiv), benzyl mercaptan (1.1 mL, 1.6 mmol, 1.2 equiv), toluene (20 mL), DIEA (2.5 mL, 15 mmol, 2 equiv) and Xantphos (444 mg, 0.77 mmol, 0.1 equiv). The resulting solution was stirred at 90 °C for 2 h and then concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% ethyl acetate / petroleum ether to give 4-(benzylsulfanyl)-6-fluoro-2,3-dihydroinden-1-one (1.1 g, 53% yield) as a solid. 10-a: Synthesis of 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-ol

[0306] To a stirred solution of 4-(benzylsulfanyl)-6-fluoro-2,3-dihydroinden-1-one (600 mg, 2.2 mmol, 1 equiv) in MeOH (12 mL) was added NaBH 4 (416 mg, 11 mmol, 5 equiv) was added at 0° C. and the reaction was stirred at room temperature for 30 min. The solution was concentrated and diluted with DCM (5 mL) and then H 2 The organic layer was dried (MgSO 4 ), concentrated, and the residue was purified by silica gel column chromatography eluting with PE:EA (3:1) to give 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-ol (0.6 g, 99%) as a yellow solid. LCMS (ES, m / z): [M+H] + :275 10-b: Synthesis of 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate

[0307] A 50 mL three-neck round bottom flask was charged with 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-ol (680 mg, 2.5 mmol, 1 equiv), DCM (20 mL), TEA (301 mg, 3.0 mmol, 1.2 equiv) and DMAP (30 mg, 0.25 mmol, 0.1 equiv). This was followed by dropwise addition of acetic anhydride (380 mg, 3.7 mmol, 1.5 equiv) with stirring at 0° C. The resulting solution was stirred at 25° C. for 2 h. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×30 mL of dichloromethane and the combined organics were washed with 50 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE:EA (3:1) to give 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate (580 mg, yield 74%) as a white solid. LCMS (ES, m / z): [M+H] + :317 10-c: Synthesis of 4-(chlorosulfonyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate

[0308] In a 50 mL three-neck round-bottom flask, add 4-(benzylsulfanyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate (520 mg, 1.6 mmol, 1 equiv.), CH 3 CN (10 mL) and HCl (6 mol / L, 5 mL) were charged. This was followed by the addition of NCS (878 mg, 6.6 mmol, 4 equiv) in portions at 0° C. The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 50 mL of water and extracted with 3×30 mL of ethyl acetate. The combined organics were washed with 50 ml of water and 50 mL of brine, then dried over anhydrous sodium sulfate. Concentration gave crude 4-(chlorosulfonyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate (450 mg), which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] +:293 10-d: Synthesis of 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0309] A 40 mL vial was charged with 4-(chlorosulfonyl)-6-fluoro-2,3-dihydro-1H-inden-1-yl acetate (116 mg, 0.4 mmol, 1.2 equiv), DCM (10 mL), pyridine (79 mg, 0.1 mmol, 3 equiv) and 6-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-a]pyridine-1-carboxamide (100 mg, 0.3 mmol, 1 equiv). The resulting solution was stirred at 25° C. for 2 days. The mixture was concentrated under vacuum and purified by preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (10-80% over 15 min) to give 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (103 mg, 62% yield) as a white solid. LCMS (ES, m / z): [M+H] + :559 Compound 10: Synthesis of 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0310] In a 40 mL vial, add 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (100 mg, 0.18 mmol, 1 equiv.), THF (10 mL), H 2HO (1 mL) and NaOH (14 mg, 0.36 mmol, 2 equiv.). The resulting solution was stirred at 60 °C for 24 h. The reaction mixture was cooled, concentrated under vacuum, and the pH of the solution was adjusted to 7 with HCl. After further concentration, the crude product was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50 × 250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (10-15% over 15 min) to give 6-[2,6-difluoro-3-(6-fluoro-1-hydroxy-2,3-dihydro-1H-indene-4-sulfonamido)phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (35 mg, 38% yield) as a white solid. LCMS (ES, m / z): [M+H] + :517 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.54 (s, 1H), 8.47 (d, J = 0.6 Hz, 1H), 8.18-8.04 (m, 2H), 7.48-7.18 (m, 4H), 6.96 (dd, J = 9.4, 1.5 Hz, 1H), 5.60 (d, J = 5.6 Hz, 1H), 5.12-5.00 (m, 1H), 3.13-2.99 (m, 1H), 2.84-2.72 (m, 3H), 2.44-2.27 (m, 1H), 1.84-1.66 (m, 1H). (Example 26) Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethylimidazo[1,5-a]pyridine-1-carboxamide (compound 11) [ka] 11-a: Synthesis of ethyl 2-(5-bromo-6-methylpyridin-2-yl)-2-[(diphenylmethylidene)amino]acetate

[0311] To a solution of 3-bromo-6-fluoro-2-methylpyridine (5 g, 26 mmol, 1 equiv.) in MeCN (100 mL), ethyl 2-[(diphenylmethylidene)amino]acetate (8.44 g, 31.2 mmol, 1.2 equiv.), Cs 2 CO 3 (12.86 g, 40 mmol, 1.5 equiv.) and TBAB (4.24 g, 13 mmol, 0.5 equiv.) were added at room temperature. The resulting mixture was stirred at 80° C. for 12 h. After cooling to room temperature, water (500 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluent: PE:EA 8:1) to give ethyl 2-(5-bromo-6-methylpyridin-2-yl)-2-[(diphenylmethylidene)amino]acetate (3.2 g, 28% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :437 11-b: Synthesis of ethyl 2-amino-2-(5-bromo-6-methylpyridin-2-yl)acetate hydrochloride

[0312] A solution of ethyl 2-(5-bromo-6-methylpyridin-2-yl)-2-[(diphenylmethylidene)amino]acetate (3.1 g, 7 mmol, 1 equiv.) in 4 M HCl solution in ethyl acetate (50 mL) was stirred at room temperature for 4 h. The resulting solid was collected by filtration and dried to give ethyl 2-amino-2-(5-bromo-6-methylpyridin-2-yl)acetate hydrochloride (1.6 g, 73%) as a white solid. LCMS (ES, m / z): [M+H] + :273 11-c: Synthesis of ethyl 6-bromo-5-methylimidazo[1,5-a]pyridine-1-carboxylate

[0313] A solution of ethyl 2-amino-2-(5-bromo-6-methylpyridin-2-yl)acetate (1 g, 3.6 mmol, 1 equiv.) in triethyl orthoformate (10 mL) was stirred at 90° C. for 2 h. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluent: PE:EA 1:1) to give ethyl 6-bromo-5-methylimidazo[1,5-a]pyridine-1-carboxylate (400 mg, yield 39%) as a yellow solid. LCMS (ES, m / z): [M+H] + :283 11-d: Synthesis of ethyl 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate

[0314] A solution of ethyl 6-bromo-5-methylimidazo[1,5-a]pyridine-1-carboxylate (500 mg, 1.7 mmol, 1 equiv.) in dioxane (20 mL) was treated with bis(pinacolato)diboron (896 mg, 3.5 mmol, 2 equiv.), KOAc (346 mg, 3.5 mmol, 2 equiv.) and Pd(dppf)Cl 2 (129 mg, 0.17 mmol, 0.1 equiv) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give ethyl 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (400 mg, crude) as a brown solid, which was used in the next step without further purification. LCMS (ES, m / z): [M+H] + :331 11-e: Synthesis of ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-[1,5-a]pyridine-1-carboxylate

[0315] Dioxane / H 2 To a stirred solution of ethyl 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine-1-carboxylate (300 mg, 0.9 mmol, 1 equiv.) in 20O (5:1, 12 mL), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (450 mg, 1 mmol, 1.2 equiv.), K 2 CO 3 (314 mg, 2.2 mmol, 2.5 equiv) and SPhos (74 mg, 182 μmol, 0.2 equiv) were added, followed by the addition of SPhos Pd G3 (70 mg, 91 μmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 16 h under nitrogen atmosphere. After the mixture was cooled to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluent: PE:EA 1:1) to give ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methylimidazo[1,5-a]pyridine-1-carboxylate (200 mg, 41% yield) as a brown solid. LCMS (ES, m / z): [M+H] + :537 Synthesis of compound 11: 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethylimidazo[1,5-a]pyridine-1-carboxamide

[0316] CH in MeOH 3 NH 2 (30%, 5 mL) was added ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methylimidazo[1,5-a]pyridine-1-carboxylate (60 mg, 112 μmol, 1 equiv.) at room temperature. The resulting solution was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC under the following conditions: column, welch Vltimate XB-C18, 50×250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (30%-60% over 15 min), detector at 220 nm to give 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N,5-dimethylimidazo[1,5-a]pyridine-1-carboxamide (50 mg, 64% yield) as a white solid. LCMS (ES, m / z): [M+H] + :522 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 8.50 (d, J = 2.3 Hz, 2H), 8.21-7.99 (m, 3H), 7.52-7.37 (m, 1H), 7.26 (t, J = 8.9 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H), 3.94 (s, 3H), 2.84-2.78 (m, 3H), 2.28 (s, 3H). Example 27 Synthesis of 2-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (compound 12) [ka] Compound 12: Synthesis of 2-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide

[0317] To a stirred mixture of 2-(3-amino-2,6-difluorophenyl)-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (90 mg, 0.3 mmol, 1 equiv) and pyridine (140 mg, 1.8 mmol, 6 equiv) in DCM (3 mL) was added a solution of 5-fluoro-2-methylpyridine-3-sulfonyl chloride (186 mg, 0.9 mmol, 3 equiv) in DCM (1 mL) dropwise at 0° C. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50 × 250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (23-43% over 10 min) to give 2-[2,6-difluoro-3-(5-fluoro-2-methylpyridine-3-sulfonamido)phenyl]-N-methylimidazo[1,5-b]pyridazine-5-carboxamide (40 mg, 28% yield) as a pale yellow solid. LCMS (ES, m / z): [M+H] + :477 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 8.86 (s, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.58 (d, J = 9.4 Hz, 1H), 8.31 (d, J = 5.0 Hz, 1H), 7.96 (dd, J = 8.2, 2.9 Hz, 1H), 7.56-7.42 (m, 1H), 7.31 (t, J = 8.7 Hz, 1H), 7.10 (d, J = 9.4 Hz, 1H), 2.86-2.81 (m, 3H), 2.78 (d, J = 1.2 Hz, 3H). (Example 28) Synthesis of 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 13) [ka] 13-a: Synthesis of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine

[0318] A 25 mL round bottom flask was charged with 25% NaOMe in MeOH (10 mL), 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (3 g, 11 mmol, 1 equiv.). The resulting solution was stirred in an oil bath at 70° C. for 1 h. The resulting solution was diluted with 10 mL of H 2 The mixture was diluted with 2×30 mL of dichloromethane and extracted with 2×10 mL of dichloromethane. After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure to give crude 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (1.6 g) as a yellow oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :256 130-b: Synthesis of 3-(benzylsulfanyl)-2-methoxy-5-(trifluoromethyl)pyridine

[0319] In a 50 mL round-bottom flask, add toluene (32 mL), 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine (1.6 g, 6.3 mmol, 1 equiv.), benzyl mercaptan (776 mg, 6.3 mmol, 1 equiv.), Pd 2 (dba) 3(286 mg, 0.3 mmol, 0.05 equiv), Xantphos (253 mg, 0.4 mmol, 0.07 equiv) and DIEA (2.4 g, 18.8 mmol, 3 equiv). The resulting solution was stirred in an oil bath at 80° C. for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give 3-(benzylsulfanyl)-2-methoxy-5-(trifluoromethyl)pyridine (1.5 g, 80% yield) as a white solid. LCMS (ES, m / z): [M+H] + :300 13-c: Synthesis of 2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

[0320] In a 50 mL round-bottom flask, add CH 3 CN (30 mL), NCS (2.6 g, 20 mmol, 3 equiv), HCl (1 M) (7 mL) and 3-(benzylsulfanyl)-2-methoxy-5-(trifluoromethyl)pyridine (2 g, 6.7 mmol, 1 equiv). The resulting solution was stirred at room temperature for 30 min and then concentrated in vacuo. The resulting mixture was diluted with 25 mL of H 2 The mixture was diluted with 2×25 mL of ethyl acetate and extracted with 2×25 mL of ethyl acetate. The combined organics were washed with 20 mL of brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded crude 2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (1.4 g) as a colorless oil, which was used directly in the next step without further purification. 13-d: Synthesis of ethyl 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]imidazo[1,5-a]pyridine-1-carboxylate

[0321] A 25 mL round-bottom flask was charged with ethyl 6-(3-amino-2,6-difluorophenyl)imidazo[1,5-a]pyridine-1-carboxylate (450 mg, 1.4 mmol, 1 equiv), DCM (15 mL), pyridine (336 mg, 4.3 mmol, 3 equiv) and 2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (391 mg, 1.4 mmol, 1 equiv). The resulting solution was stirred at room temperature for 30 min and then concentrated under vacuum. The residue was diluted with 20 mL of EA and washed with 2 × 20 mL of H 2 After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure to give crude ethyl 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]imidazo[1,5-a]pyridine-1-carboxylate (600 mg) as a colorless oil, which was used directly in the next step without further purification. LCMS (ES, m / z): [M+H] + :557 Synthesis of Compound 13: 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0322] In a 25 mL round-bottom flask, add ethyl 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]imidazo[1,5-a]pyridine-1-carboxylate (600 mg, 1.1 mmol, 1 equiv.) and 33% CH 3 NH 2 / EtOH (10 mL) was added. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC using the following conditions: column: welch Vltimate XB-C18, 50 x 250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (20-50% over 20 min) to give 6-[2,6-difluoro-3-[2-methoxy-5-(trifluoromethyl)pyridine-3-sulfonamido]phenyl]-N-methylimidazo[1,5-a]pyridine-1-carboxamide (39 mg, 7% yield) as a white solid. LCMS (ES, m / z): [M+H] + :542 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19-8.07 (m, 2H), 7.44-7.33 (m, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 9.4 Hz, 1H), 3.99 (s, 3H), 2.84-2.77 (m, 3H) (Example 29) Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 14) [ka] 14-a: Synthesis of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)acetate

[0323] To a stirred solution of 3-bromo-2-fluoro-6-methylpyridine (6 g, 31.5 mmol, 1 equiv.) in THF (79 mL) was added a 1M solution of LiHMDS in THF (63 mL, 63 mmol, 2 equiv.) 2The mixture was added dropwise under atmospheric pressure at -78°C. The reaction was stirred at low temperature for 30 min, then diethyl carbonate (5.6 g, 47.4 mmol, 1.5 equiv) was added. The resulting solution was stirred at room temperature for 1 h, then heated at 0°C for 1 h. 2 The mixture was quenched by the addition of 2H2O (60 mL). The mixture was extracted with EA (50 mL x 3) and the combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE:EA (20:1) to give ethyl 2-(5-bromo-6-fluoropyridin-2-yl)acetate (6.6 g, yield 80%) as a yellow solid. LCMS (ES, m / z): [M+H] + :262 14-b: Synthesis of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-diazoacetate

[0324] To a stirred solution of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)acetate (4.6 g, 17.5 mmol, 1 equiv) in MeCN (60 mL) was added 4-acetamidobenzenesulfonyl azide (4.4 g, 18.4 mmol, 1.05 equiv) and DBU (2.9 g, 19.3 mmol, 1.1 equiv) at 0° C. The reaction was stirred at this temperature for 1 h and then diluted with H 2 The mixture was diluted with O (50 mL) and extracted with EA (50 mL × 3). The combined organics were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-diazoacetate (5 g, 99% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :288 14-c: Synthesis of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-[(tert-butoxycarbonyl)amino]acetate

[0325] To a stirred solution of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-diazoacetate (4.5 g, 15.6 mmol, 1 equiv.) in DCE (156 mL) was added tert-butyl carbamate (2.7 g, 23.4 mmol, 1.5 equiv.) and Rh 2 (OAc) 4 (690 mg, 1.56 mmol, 0.1 equiv) was added at 0° C. The reaction was stirred at room temperature for 3 h. The resulting solution was concentrated and the residue was purified by silica gel column chromatography eluting with PE:EA (10:1) to give ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-[(tert-butoxycarbonyl)amino]acetate (5.5 g, 93% yield) as a yellow oil. LCMS (ES, m / z): [M+H] + :377 14-d: Synthesis of ethyl 2-amino-2-(5-bromo-6-fluoropyridin-2-yl)acetate

[0326] Ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-[(tert-butoxycarbonyl)amino]acetate (7 g) was dissolved in 4 M HCl in 1,4-dioxane (35 mL) and stirred at room temperature for 1 h. The mixture was diluted with saturated NaHCO 3 The mixture was basified to pH 8 with aqueous solution and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-amino-2-(5-bromo-6-fluoropyridin-2-yl)acetate (5.4 g, crude) as a red oil, which was used in the next step without further purification. LCMS (ES, m / z): [M+H] + :277 14-e: Synthesis of ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-formamide acetate

[0327] To a stirred solution of ethyl 2-amino-2-(5-bromo-6-fluoropyridin-2-yl)acetate (3 g, 10.8 mmol, 1 equiv.) in THF (54 mL) was added acetic formic anhydride (1.4 g, 16.2 mmol, 1.5 equiv.). The reaction was stirred at 60° C. for 1 h and then concentrated. The residue was suspended in DCM (50 mL) and diluted with H 2 The organic layer was washed with anhydrous NaCl. 2 SO 4 The residue was purified by silica gel column chromatography eluting with PE:EA (3:1) to give ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-formamide acetate (2 g, yield 61%) as a yellow solid. LCMS (ES, m / z): [M+H] + :305 14-f: Synthesis of ethyl 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate

[0328] Ethyl 2-(5-bromo-6-fluoropyridin-2-yl)-2-formamide acetate (1 g, 3.3 mmol, 1 equiv.) was dissolved in POCl in a 40 mL vial. 3 (10 mL) and stirred at 60° C. for 1 h. The resulting solution was cooled to room temperature, poured onto ice, and then extracted with EA (20 mL×3). The organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with PE:EA (5:1) to give ethyl 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate (0.8 g, 85% yield) as a grey solid. LCMS (ES, m / z): [M+H] + :287 14-g: Synthesis of 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid

[0329] To a stirred solution of ethyl 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate (200 mg, 0.77 mmol, 1 equiv) in DMSO (2 mL) and pH 7 buffer (4 mL) was added the enzyme catalyst Novozym 435B (100 mg). The reaction was stirred at 36° C. for 48 h and then filtered. The filtrate was concentrated and the residue was purified by flash preparative HPLC using the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase, 40-80% MeCN / 0.1% formic acid in water over 20 min; detector, 220 nm to give 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (86 mg, 48% yield) as a grey solid. LCMS (ES, m / z): [M+H] + :259. 14-h: Synthesis of 6-bromo-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0330] To a stirred solution of 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (70 mg, 0.27 mmol, 1 equiv.) in DMF (2 mL) was added HATU (123 mg, 0.32 mmol, 1.2 equiv.) and DIEA (105 mg, 0.81 mmol, 3 equiv.). The reaction was stirred at room temperature for 30 min and then cooled to 0° C. in an ice bath. Methylamine hydrochloride (18 mg, 0.27 mmol, 1 equiv.) was added and the resulting solution was stirred at room temperature for an additional 30 min. The resulting mixture was diluted with H 2 The mixture was diluted with O (3 mL) and the aqueous layer was extracted with EA (5 mL × 3). The combined organics were concentrated and purified by silica gel column chromatography eluting with PE:EA (1:2) to give 6-bromo-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (70 mg, 95% yield) as a white solid. LCMS (ES, m / z): [M+H] + :272. 14-i: Synthesis of 6-(3-amino-2,6-difluorophenyl)-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0331] Dioxane (2 mL) and H 2 To a solution of 6-bromo-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (100 mg, 0.37 mmol, 1 equiv.) and 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (188 mg, 0.74 mmol, 2 equiv.) in 2O (0.2 mL) was added K 2 CO 3 (127 mg, 0.92 mmol, 2.5 equiv), S-Phos (30 mg, 0.074 mmol, 0.2 equiv) and SPhos Pd Gen.3 (29 mg, 0.037 mmol, 0.1 equiv) were added. The reaction was stirred at 100° C. under nitrogen atmosphere for 2 h. The resulting mixture was filtered and the filter cake was washed with dioxane (5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase, 40-80% MeCN / 0.1% formic acid in water over 20 min; detector, 220 nm to give 6-(3-amino-2,6-difluorophenyl)-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (90 mg, 76% yield) as a white solid. LCMS (ES, m / z): [M+H] + :321. Synthesis of compound 14: 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0332] To a stirred solution of 6-(3-amino-2,6-difluorophenyl)-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (60 mg, 0.19 mmol, 1 equiv.) in DCM (3 mL) was added 5-chloro-2-methoxypyridine-3-sulfonyl chloride (54 mg, 0.23 mmol, 1.2 equiv.) and pyridine (29 mg, 0.38 mmol, 2 equiv.). The mixture was stirred at room temperature for 2 days. The solution was concentrated directly and the residue was purified by preparative HPLC under the following conditions: column, welch Vltimate XB-C18, 50 × 250 mm, 10 μm; mobile phase: 30-70% MeCN / 0.1% formic acid in water over 15 min; detector, 220 nm to give 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoro-N-methylimidazo[1,5-a]pyridine-1-carboxamide (40 mg, 41% yield) as a white solid. LCMS (ES, m / z): [M+H] + :526. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 8.67 (d, J = 0.7 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 8.01 (d, 1H), 7.50-7.44 (m, 1H), 7.36 - 7.26 (m, 1H), 7.18 - 7.07 (m, 1H), 3.91 (s, 3H), 2.82 (d, J = 4.7 Hz, 3H). (Example 30) Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxy-N-methylimidazo[1,5-a]pyridine-1-carboxamide (compound 15) [ka] 15-a: Synthesis of 1-(ethoxycarbonyl)-5-fluoroimidazo[1,5-a]pyridin-6-ylboronic acid

[0333] To a stirred solution of 6-bromo-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate (1 g, 3.5 mmol, 1 equiv.) and bis(pinacolato)diboron (1.8 g, 7 mmol, 2 equiv.) in dioxane (18 mL) was added KOAc (684 mg, 7 mmol, 2 equiv.) and Pd(dppf)Cl 2 (255 mg, 0.35 mmol, 0.1 equiv.) was added. After stirring at 100° C. for 1 h under nitrogen atmosphere, the mixture was concentrated and the residue was purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase, 5-45% MeCN / 0.1% formic acid in water over 25 min; detector, 220 nm to give 1-(ethoxycarbonyl)-5-fluoroimidazo[1,5-a]pyridin-6-ylboronic acid (400 mg, 45% yield) as a white solid. LCMS (ES, m / z): [M+H] + :253 15-b: Synthesis of ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate

[0334] Dioxane (7 mL) and H 2 To a stirred solution of 1-(ethoxycarbonyl)-5-fluoroimidazo[1,5-a]pyridin-6-ylboronic acid (400 mg, 1.6 mmol, 1 equiv.) and N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (788 mg, 1.9 mmol, 1.2 equiv.) in 20O (1.4 mL) was added 10 mL of KCl. 2 CO 3(548 mg, 4 mmol, 2.5 equiv), SPhos Pd Gen.3 (124 mg, 0.16 mmol, 0.1 equiv) and S-Phos (130 mg, 0.32 mmol, 0.2 equiv) were added. After stirring at 100° C. for 2 h under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (1:1) to give ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate (80 mg, 9% yield) as a red solid. LCMS (ES, m / z): [M+H] + :541 15-c: Synthesis of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxyimidazo[1,5-a]pyridine-1-carboxylic acid

[0335] THF (2 mL), MeOH (2 mL) and H 2 To a stirred solution of ethyl 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-fluoroimidazo[1,5-a]pyridine-1-carboxylate (60 mg, 0.11 mmol, 1 equiv.) in a mixture of O (1 mL) was added LiOH (8 mg, 0.33 mmol, 3 equiv.) The reaction was then stirred at 60° C. for 30 min. The mixture was concentrated under vacuum and the residue was purified by flash preparative HPLC under the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase, 40-70% MeCN / 0.1% formic acid in water over 15 min; detector, 220 nm to give 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxyimidazo[1,5-a]pyridine-1-carboxylic acid (40 mg, 69% yield) as a white solid. LCMS (ES, m / z): [M+H] + :525 Synthesis of compound 15: 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxy-N-methylimidazo[1,5-a]pyridine-1-carboxamide

[0336] To a stirred solution of 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxyimidazo[1,5-a]pyridine-1-carboxylic acid (70 mg, 0.13 mmol, 1 equiv.) in MeCN (2 mL) was added TCFH (41 mg, 0.15 mmol, 1.1 equiv.), NMI (33 mg, 0.4 mmol, 3 equiv.) and CH 3 NH 2 HCl (9 mg, 0.13 mmol, 1 equiv) was added and the reaction was stirred at room temperature for 1 h. The resulting mixture was 2 The mixture was diluted with 2,4-dimethylformamide (3 mL) and extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, welch Vltimate XB-C18, 50 × 250 mm, 10 μm mobile phase, mobile phase A: 0.1% formic acid in water, mobile phase B: MeCN (30-70% over 15 min), detector, 220 nm to give 6-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-5-methoxy-N-methylimidazo[1,5-a]pyridine-1-carboxamide (10 mg, 14% yield) as a grey solid. LCMS (ES, m / z): [M+H] + :538. 1 H NMR (300 MHz, Methanol-d 4) δ 8.39 (s, 1H), 8.37 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.66-7.58 (m, 1H), 7.15 (t, J = 8.6 Hz, 1H), 6.94 (d, J = 9.3 Hz, 1H), 4.06 (s, 3H), 3.65 (s, 3H), 2.99 (s, 3H). (Example 31) Synthesis of 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide (compound 16) [ka]

[0337] 16-a: Synthesis of 2-(5-bromopyrimidin-2-yl)-2-[(diphenylmethylidene)amino]acetate

[0338] In a 250 mL three-neck round-bottom flask, add 5-bromo-2-chloropyrimidine (10 g, 52 mmol, 1 equiv.), ethyl 2-[(diphenylmethylidene)amino]acetate (13.8 g, 52 mmol, 1 equiv.), K 2 CO 3 (21.4g, 155mmol, 3eq), Bu 4 NBr (16.6 g, 52 mmol, 1 equiv.) and NMP (100 mL) were charged. The resulting solution was stirred in an oil bath at 80° C. for 16 h. The reaction was then quenched by the addition of 100 mL of water / ice. The resulting solution was extracted with 3×200 mL of dichloromethane and the organics were washed with 2×100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column eluting with ethyl acetate / petroleum ether (1:5) to give ethyl 2-(5-bromopyrimidin-2-yl)-2-[(diphenylmethylidene)amino]acetate (5.5 g, 25% yield) as a white solid. LCMS (ES, m / z): [M+H]+ :424 16-b: Synthesis of ethyl 2-amino-2-(5-bromopyrimidin-2-yl)acetate

[0339] A 250 mL three-neck round bottom flask was charged with ethyl 2-(5-bromopyrimidin-2-yl)-2-[(diphenylmethylidene)amino]acetate (5.5 g, 13 mmol, 1 equiv.) in DCM (55 mL). This was followed by the dropwise addition of HCl (1M) (10 mL) with stirring at room temperature. The resulting solution was stirred for 1 h and then diluted with 100 mL of water. The pH of the solution was adjusted with NaHCO 3 The solution was adjusted to 8 with (1M) and then extracted with 3×50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was subjected to a silica gel column eluting with ethyl acetate / petroleum ether (1:5) to give ethyl 2-amino-2-(5-bromopyrimidin-2-yl)acetate (2.2 g, 65% yield) as a yellow solid. LCMS(ES, m / z):[M+H]+:260 16-c: Synthesis of ethyl 3-bromoimidazo[1,5-a]pyrimidine-8-carboxylate

[0340] A 100 mL three-neck round bottom flask was charged with ethyl 2-amino-2-(5-bromopyrimidin-2-yl)acetate (2 g, 7.6 mmol, 1 eq.) and triethyl orthoformate (20 mL). The resulting solution was stirred in an oil bath at 110° C. for 16 h. The mixture was cooled to room temperature and diluted with 10 mL of PE. The solid was collected by filtration and dried to give ethyl 3-bromoimidazo[1,5-a]pyrimidine-8-carboxylate (2.0 g, 96% yield) as a white solid. LCMS (ES, m / z): [M+H] + :270 16-d: Synthesis of 8-(ethoxycarbonyl)imidazo[1,5-a]pyrimidin-3-ylboronic acid

[0341] Into a 100 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added ethyl 3-bromoimidazo[1,5-a]pyrimidine-8-carboxylate (2 g, 7.4 mmol, 1 equiv.), bis(pinacolato)diboron (2.8 g, 11 mmol, 1.5 equiv.), dioxane (20 mL), KOAc (1.45 g, 15 mmol, 2 equiv.), and Pd(dppf)Cl. 2 (1.08 g, 1.5 mmol, 0.2 equiv.). The resulting solution was stirred in an oil bath at 80° C. for 3 h. The solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 330 g; mobile phase: 5% MeCN / 0.1% formic acid in water; detector, 220 nm to give 8-(ethoxycarbonyl)imidazo[1,5-a]pyrimidin-3-ylboronic acid (1.6 g, 92% yield) as a yellow solid. LCMS (ES, m / z): [M+H] + :236 16-e: Synthesis of ethyl 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylate

[0342] Into a 25 mL three-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen was added 8-(ethoxycarbonyl)imidazo[1,5-a]pyrimidin-3-ylboronic acid (255 mg, 1.9 mmol, 1.5 equiv.), N-(3-bromo-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide (300 mg, 1.3 mmol, 1 equiv.), dioxane (10 mL), H 2 O (1 mL), K 2 CO 3 (200 mg, 2.6 mmol, 2 equiv.) and Pd(dppf)Cl 2(53 mg, 0.07 mol, 0.1 equiv.). The resulting solution was stirred in an oil bath at 80° C. for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative HPLC using the following conditions: column, WelFlash® C18-I, Spherical C18 20-40 μm, 120 g; mobile phase: 70-95% MeCN / 0.1% formic acid in water over 12 min; detector, 220 nm. Ethyl 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylate (150 mg, 39% yield) was isolated as a yellow solid. LCMS (ES, m / z): [M+H] + :524 16-f: Synthesis of 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylic acid

[0343] An 8 mL round bottom flask was charged with ethyl 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylate (600 mg, 1.1 mmol, 1 equiv), Novozym 435A (200% SM) and pH 7 buffer (10 mL). The resulting solution was stirred at 36° C. for 24 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC using the following conditions: column, welch Vltimate XB-C18, 50 x 250 mm, 10 μm mobile phase: 10-65% MeCN / 0.1% formic acid in water over 12 min to give 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylic acid (200 mg, 35% yield) as a white solid. LCMS (ES, m / z): [M+H] + :496 Synthesis of Compound 16: 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide

[0344] A 25 mL round bottom flask was charged with 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]imidazo[1,5-a]pyrimidine-8-carboxylic acid (200 mg, 0.4 mmol, 1 equiv), DMF (5 mL), HATU (199 mg, 0.5 mmol, 1.3 equiv), DIEA (104 mg, 0.8 mmol, 2 equiv) and methylamine (25.05 mg, 0.8 mmol, 2 equiv). The resulting solution was stirred at room temperature for 3 h. The reaction was quenched by the addition of 10 mL of water and extracted with 3×10 mL of dichloromethane. The combined organics were washed with 1×10 ml of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column, welch Vltimate XB-C18, 50 x 250 mm, 10 μm; mobile phase, 30-60% MeCN / 0.1% formic acid in water over 15 min; detector, UV to give 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide (105 mg, 51% yield) as a white solid. LCMS (ES, m / z): [M+H] + :509 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H), 8.49-8.39 (m, 2H), 8.10 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 4.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.36-7.27 (m, 1H), 3.94 (s, 3H), 2.85 (d, J = 4.7 Hz, 3H). Example 32 Synthesis of 3-[3-(5-chloro-2-methoxypyridine-3-sulfonamido)-2,6-difluorophenyl]-2-methoxy-N-methylimidazo[1,5-a]pyrimidine-8-carboxamide (compound 17) [ka] 17-a: Synthesis of methyl 3-(3-amino-2,6-difluorophenyl)-2-methoxyimidazo[1,5-a]pyrimidine-8-carboxylate

[0345] Into a 40 mL vial purged and maintained under an inert atmosphere of nitrogen was added methyl 3-bromo-2-methoxyimidazo[1,5-a]pyrimidine-8-carboxylate (500 mg, 1.7 mmol, 1 equiv.), 2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (891 mg, 3.5 mmol, 2 equiv.), SphosPdG3 (136 mg, 0.2 mmol, 0.1 equiv.), Sphos (143 mg, 0.3 mmol, 0.2 equiv.), dioxane (8 mL), H 2 O (1.6 mL) and K 2 CO 3 (724 mg, 5.2 mmol, 3 equiv.). The resulting solution was stirred in an oil bath at 80° C. for 2 h. The reaction mixture was cooled and concentrated. The residue was dissolved in 50 mL of DCM and the mixture was filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column eluted with ethyl acetate / petroleum ether (1:1) to give methyl 3-(3-amino-2,6-difluorophenyl)-2-methoxyimidazo[1,5-a]pyrimidine-8-carboxylate (100 mg, 17% yield) as a yellow s...

Claims

1. Compounds represented by formula (Ia) 【Chemical 277】 or a pharma- ceutically acceptable salt thereof, C is a 7-10 membered bicyclic heterocyclyl, an 8 membered bicyclic heteroaryl, or 【Chemical 278】 wherein the 7-10 membered bicyclic heterocyclyl, 8 membered bicyclic heteroaryl, or 9 membered bicyclic heteroaryl is selected from the group consisting of R ３ and wherein said 7-10 membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, said 8 membered bicyclic heteroaryl contains at least two nitrogen atoms, and when said 7-10 membered bicyclic heterocyclyl, 8 membered bicyclic heteroaryl, or 9 membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; X is CH, C(R ８ ), and N; R ３ represents independently at each occurrence a halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, C １～６ Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, １～６ Alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ４ is halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ４ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ５ is hydrogen, halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ５ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ６ is halogen, C １～６ Alkyl, Cyano, C １～６ Alkoxyl, and C ３～６ cycloalkyl, １～６ Alkyl and C ３～６ Cycloalkyl is R ６ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ７ is selected from the group consisting of fluoro, chloro, methyl, and cyano; R ８ is halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ８ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from Or X is C(R ８ ), then R ８ and R ５ can optionally combine together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which may be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when said 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from the group consisting of C １～６ optionally substituted with alkyl; R Ａ is hydrogen or C １～６ is alkyl, R Ｂ is hydrogen, C １～６ Alkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; １～６ Alkyl or phenyl is R ｅ and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ３ａ each occurrence independently represents halogen, cyano, hydroxyl, C １～６ Alkyl, phenyl, C ３～６ Cycloalkyl, 5- to 6-membered heterocyclyl, and —CO ２ (C １～６ alkyl), １～６ The alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when said 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; R ４ａ is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R ５ａ is selected from the group consisting of halogen, hydroxyl, and phenyl, R ６ａ is, independently at each occurrence, a halogen; R ８ａ is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R ｅ Each occurrence independently represents a halogen, a hydroxyl, C １～６ Alkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, -N(R Ｃ ) (R Ｄ ), and -S(O) ２ C １～６ alkyl, C １～６ Alkyl or 5- to 6-membered heterocyclyl includes oxo and -N(R Ｃ ) (R Ｄ ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R Ｃ and R Ｄ are each independently hydrogen and C １～６ alkyl, The compound of formula (Ib) 【Chemical 279】 isn't it].

2. Compounds represented by formula (Ia) 【Chemistry 280】 or a pharma- ceutically acceptable salt thereof, C is a 9-membered bicyclic heterocyclyl; 【Chemistry 281】 【Chemical 282】 wherein said 9-membered bicyclic heterocyclyl or 8-9-membered bicyclic heteroaryl is selected from the group consisting of R ３ and wherein said 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when said 9-membered bicyclic heterocyclyl or 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; X is CH, C(R ８ ) and N; R ３ represents independently at each occurrence a halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, C １～６ Alkoxyl, hydroxyl, oxo, phenyl, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, １～６ Alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ４ is halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ４ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ５ is halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ５ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ６ is halogen, C １～６ Alkyl, Cyano, C １～６ Alkoxyl, and C ３～６ cycloalkyl, １～６ Alkyl and C ３～６ Cycloalkyl is R ６ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ７ is selected from the group consisting of fluoro, chloro, methyl, and cyano; R ８ is halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, cyano, hydroxyl, oxo, C １～６ Alkoxyl, -O-C ３～６ Cycloalkyl, -N(R Ａ ) (R Ｂ ), -N(R Ａ )-C(O)(R Ｂ ), -(C １～６ alkylene)-N(R Ａ ) (R Ｂ ), -CO ２ H, -CO ２ (C １～６ alkyl), and -S-(C １～６ alkyl), １～６ Alkyl, C １～６ Alkoxyl, and -S-(C １～６ alkyl) is R ８ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from Or X is C(R ８ ), then R ８ and R ５ can optionally combine together with the atom to which they are attached to form a 3- to 7-membered carbocyclyl, a 3- to 7-membered heterocyclyl, or a 5- to 10-membered heteroaryl, which may be optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents, and when said 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from the group consisting of C １～６ optionally substituted with alkyl; R Ａ is hydrogen or C １～６ is alkyl, R Ｂ is hydrogen, C １～６ Alkyl, C ３～６ cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; １～６ Alkyl or phenyl is R ｅ and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ３ａ each occurrence independently represents halogen, cyano, hydroxyl, C １～６ Alkyl, phenyl, C ３～６ Cycloalkyl, 5- to 6-membered heterocyclyl, and —CO ２ (C １～６ alkyl), １～６ The alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when said 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; R ４ａ is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R ５ａ is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R ６ａ is, independently at each occurrence, a halogen; R ８ａ is independently selected at each occurrence from the group consisting of halogen, hydroxyl, and phenyl; R ｅ Each occurrence independently represents a halogen, a hydroxyl, C １～６ Alkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, -N(R Ｃ ) (R Ｄ ), and -S(O) ２ C １～６ alkyl, C １～６ Alkyl or 5- to 6-membered heterocyclyl includes oxo and -N(R Ｃ ) (R Ｄ ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R Ｃ and R Ｄ are each independently hydrogen and C １～６ alkyl.

3. Compounds represented by formula (Ia) 【Chemistry 283】 or a pharma- ceutically acceptable salt thereof, C is a 9-membered bicyclic heterocyclyl; 【Chemical 284】 wherein said 9-membered bicyclic heterocyclyl or 8-9-membered bicyclic heteroaryl is selected from the group consisting of R ３ and wherein said 9-membered bicyclic heterocyclyl is partially unsaturated and contains at least two nitrogen atoms, and when said 9-membered bicyclic heterocyclyl or 8- to 9-membered bicyclic heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; X is CH, C(R ８ ) and N; R ３ represents independently at each occurrence a halogen, C １～６ Alkyl, C １～６ Alkoxyl, oxo, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, １～６ Alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ４ is halogen, C １～６ alkyl, and cyano; １～６ Alkyl is R ４ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ５ is C １～６ Alkyl, cyano, hydroxyl, C １～６ Alkoxyl, and -O-C ３～６ cycloalkyl, １～６ Alkyl and C １～６ Alkoxyl is R ５ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ８ is cyano, Or X is C(R ８ ), then R ８ and R ５ can optionally combine together with the atoms to which they are attached to form a 3- to 7-membered carbocyclyl, which is optionally substituted on one or more available carbons with one, two, three or more hydroxyl substituents; R ６ is hydrogen, halogen, C １～６ alkyl, and cyano; １～６ Alkyl is R ６ａ and optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R ７ is a halogen, R Ａ is hydrogen, R Ｂ is hydrogen, C １～６ is selected from the group consisting of alkyl, phenyl, 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl; １～６ Alkyl or phenyl is R ｅ and when said 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ optionally substituted with alkyl; R ３ａ each occurrence independently represents halogen, cyano, hydroxyl, C １～６ Alkyl, phenyl, C ３～６ Cycloalkyl, 5- to 6-membered heterocyclyl, and —CO ２ (C １～６ alkyl), １～６ The alkyl may be optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from halogen, hydroxyl, and phenyl, and when said 5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is selected from C １～６ optionally substituted with alkyl; R ４ａ is, independently at each occurrence, a halogen; R ５ａ is independently selected at each occurrence from halogen and phenyl; R ６ａ is a halogen, R ｅ Each occurrence independently represents a halogen, a hydroxyl, C １～６ Alkyl, 3- to 6-membered cycloalkyl, 5- to 6-membered heterocyclyl, -N(R Ｃ ) (R Ｄ ), and -S(O) ２ C １～６ alkyl, １～６ Alkyl or 5- to 6-membered heterocyclyl includes oxo and -N(R Ｃ ) (R Ｄ ) optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from R Ｃ and R Ｄ are each independently hydrogen and C １～６ alkyl.

4. R ４ are independently selected from chloro, fluoro, cyano, hydroxyl, oxo, CH ３ , C.F. ３ , —O—CH ３ , —O—CH ２ CH ３ , —O—CH(CH ３ ) ２ , —O—CH ２ CH (CH ３ ) ２ , —O—CH ２ CF ３ , 【Chemistry 285】 2. The compound of claim 1, selected from the group consisting of:

5. R ４ is chloro, fluoro, cyano, and CF ３ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

6. R ５ is chloro, fluoro, cyano, hydroxyl, oxo, CH ３ , C.F. ３ , —O—CH ３ , —O—CH ２ CH ３ , —O—CH(CH ３ ) ２ , —O—CH ２ CH (CH ３ ) ２ , —O—CH ２ CF ３ , 【Chemistry 286】 2. The compound of claim 1, selected from the group consisting of:

7. R ５ が、CH ３ 、-O-CH ３ 、-O-CH ２ -CH ３ 、-O-CH ２ -CF ３ 、-O-CH ２ -C(H)(CH ３ ) ２ 、-O-CH-(CH ３ ) ２ 、 【Chemistry 287】 7. The compound of claim 6, selected from the group consisting of:

8. 8. The compound according to any one of claims 1 to 7, wherein X is N, or a pharma- ceutically acceptable salt thereof.

9. X is (R ８ 8. The compound according to claim 1, wherein R is an integer from 1 to 7;

10. R ８ and R ５ or a pharma- ceutically acceptable salt thereof, wherein, together with the atom to which they are attached, form a 3- to 7-membered carbocyclyl, said 3- to 7-membered carbocyclyl optionally substituted with hydroxyl.

11. R ６ But hydrogen, halogen, C １～６ 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from the group consisting of alkyl, and cyano.

12. R ６ is hydrogen, chloro, fluoro, cyano, and CH ３ 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

13. R ６ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

14. R ７ The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein is fluoro or chloro.

15. R ７ The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

16. R ６ is methyl, R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

17. R ６ is fluoro, R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

18. R ６ is chloro, R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

19. R ６ is fluoro, R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

20. R ６ is cyano, and R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

21. R ６ is methyl, R ７ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

22. C, 【Chemistry 288】 C is selected from the group consisting of halogen, C １～６ Alkyl, C １～６ Alkoxyl, oxo, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ one, two, three or more independent R selected from the group consisting of 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; ３ Substituents may optionally be substituted on one or more available carbons, １～６ alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

23. C, 【Chemical 289】 【Chemistry 290】 C is selected from the group consisting of halogen, C １～６ Alkyl, C １～６ Alkoxyl, oxo, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ one, two, three or more independent R selected from the group consisting of 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; ３ Substituents may optionally be substituted on one or more available carbons, １～６ alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

24. C, 【Chemical 291】 C is selected from the group consisting of halogen, C １～６ Alkyl, C １～６ Alkoxyl, oxo, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ ), 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; ３ is substituted with a substituent, １～６ alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

25. R ３ But, C １～６ Alkyl, -C(O)N(R Ａ ) (R Ｂ ), 5-10 membered heterocyclyl, and 5-10 membered heteroaryl, １～６ Alkyl and 5-10 membered heteroaryl are chloro, cyano, hydroxyl, CH ３ , C.F. ３ , -CH ２ CH (CH ３ ) ２ , -CH ２ OH, -C(O)OCH ３ , cyclopropyl, phenyl, 【Chemical 292】 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted on one or more available carbons with one, two, three or more substituents independently selected at each occurrence from the group consisting of:

26. R Ａ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

27. R Ｂ is hydrogen, -CH ３ -, -CH ２ CH ３ -, -CH(CH ３ ). ２ -, -CH ２ CH(CH ３ ). ２ -, -CH ２ CF ３ , CH ２ CH ２ OH, -CH ２ CH ２ N(CH ３ ). ２ -, -(CH ２ ). ３ N(CH ３ ). ２ -, -CH ２ CH ２ S(O) ２ CH ３ , 【Chemical 293】 【Chemical 294】 27. The compound according to any one of claims 1 to 26, wherein:

28. R ３ But -CH ２ O.H. 【Chemistry 295】 【Chemical 296】 【Chemical Formula 297】 28. The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

29. C, 【Chemical Formula 298】 【Chemical 299】 【Chemistry 300】 【Chemistry 301】 【Chemistry 302】 【Chemistry 303】 【Chemistry 304】 29. The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

30. C, 【Chemistry 305】 C is selected from the group consisting of halogen, C １～６ Alkyl, C １～６ Alkoxyl, oxo, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ two independent R selected from the group consisting of 5- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; ３ is substituted with a substituent, １～６ alkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl is R ３ａ and wherein, when said 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted on one or more available carbons with one, two, three or more substituents each independently selected from １～６ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

31. R ３ each occurrence independently represents halogen, oxo, C １～６ Alkyl, C １～６ Alkoxyl, -C(O)N(R Ａ ) (R Ｂ ), -N(R Ａ ) (R Ｂ 31. The compound of any one of claims 1 to 24 and 30, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted with chloro.

32. R Ａ 32. The compound of any one of claims 1 to 24, 30, and 31, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

33. R Ｂ But -CH ３ 33. The compound according to any one of claims 1 to 24 and 30 to 32, or a pharma- ceutically acceptable salt thereof.

34. R ３ is fluoro, oxo, -CH ３ , —O—CH ３ , -NHCH ３ , 【Chemistry 306】 34. The compound according to any one of claims 1 to 24 and 30 to 33, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

35. C, 【Chemistry 307】 【Chemistry 308】 35. The compound according to any one of claims 1 to 24 and 30 to 34, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

36. A compound selected from any of the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

37. 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

38. A composition comprising a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, for treating cancer in a subject in need thereof.

39. 39. The composition or pharmaceutical composition of claim 38, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, sweat gland carcinoma, sebaceous gland carcinoma, thyroid cancer, kidney cancer, uterine cancer, esophageal cancer, liver cancer, head cancer, neck cancer, throat cancer, oral cancer, bone cancer, breast cancer, lymph node cancer, eye cancer, mesothelioma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or any combination thereof.

40. 39. The composition or pharmaceutical composition of claim 38, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, lung cancer, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, leukemia, or lymphoma.

41. A composition comprising a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, for treating a neurodegenerative disease in a subject in need thereof.

42. 42. The composition or pharmaceutical composition of claim 41, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or spinocerebellar ataxia.

43. A composition comprising a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, for treating doxorubicin-induced cardiotoxicity in a subject in need thereof.

44. The composition or pharmaceutical composition according to any one of claims 38 to 43, wherein the subject is a human.

45. A composition comprising a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, for use in a method of modulating the activity of GCN2, the method comprising the step of exposing GCN2 to the compound, composition or pharmaceutical composition to modulate the activity of GCN2.

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