N-phenyl-pyrazolo [1, 5-a] pyridine-3-carboxamide derivatives as wild-type C-KIT kinase inhibitors for treatment of urticaria

Abstract

Disclosed herein is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in formula (I) are defined herein. The compounds of formula (I) are useful for inhibiting human or non-human wild-type c-kit kinases and for the treatment of human or non-human conditions and diseases mediated by wild-type c-kit kinases.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 428,804, filed November 30, 2022, and U.S. Provisional Application No. 63 / 445,787, filed February 15, 2023, the entire teachings of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to novel compounds and their use as selective inhibitors of wild-type c-kit kinase, a cell surface receptor that serves as a major regulator of mast cell survival and function. Background Art

[0004] Mast cells are part of the immune system. They are the primary drivers of allergic inflammatory responses and are found in connective and vascularized tissues throughout the body, most notably along surface boundaries exposed to the external environment: the skin, respiratory tract, and gastrointestinal tract. Dysfunctional mast cell activity is associated with the pathophysiology of a wide range of allergic and other inflammatory conditions, including urticaria, asthma, and gastrointestinal disorders.

[0005] Given that many mast cell-driven conditions involve a variety of proinflammatory mediators, to date, for many people suffering from allergic diseases, the inhibition of mast cell-derived mediators (including histamine, leukotrienes and prostaglandins) has resulted in insufficient therapeutic value. A type of such mast cell-driven condition is chronic urticaria, which is defined as the occurrence of wheals, angioedema or both lasting for more than 6 weeks. The International Urticaria Guidelines classify the disease as chronic spontaneous urticaria (CSU, also known as chronic idiopathic urticaria), which does not involve a clear predisposing factor, or as chronic induced urticaria (CIndU), in which a defined and clear predisposing factor can repeatedly trigger signs and symptoms and is necessary for its occurrence. The point prevalence of chronic urticaria is approximately 0.5% to 1%. The course and duration of chronic urticaria are unpredictable, and it may last for several years in many patients. Chronic urticaria is a disabling disease that greatly worsens the quality of life. In addition, psychosocial factors such as anxiety, depression, somatization, interpersonal sensitivity, insomnia, and stressful life events are present in many patients with chronic urticaria. Furthermore, caring for patients with chronic urticaria is time-consuming and expensive. There is no curative treatment for chronic urticaria, and all currently recommended treatment options are aimed only at controlling and preventing the symptoms of chronic urticaria.

[0006] Wild-type c-kit plays a key role in mast cell survival, proliferation and activation. Recently in clinical trials, c-kit inhibition has shown a positive response in mast cell-mediated diseases. For example, in Phase I trials (induction) and Phase 1 and Phase 2 trials (spontaneous) using monoclonal antibodies, it has been shown that c-kit inhibition in chronic induced urticaria and chronic spontaneous urticaria is an effective treatment, and in normal healthy volunteers, c-kit small molecule inhibitors have also been shown to regulate the mast cell mediator tryptase, and in Phase 1 trials of chronic induced urticaria, it has been shown that the inhibitor is an effective treatment. It is necessary to directly target mast cells by highly selectively inhibiting c-kit to achieve a wide range of symptom relief in a series of mast cell-mediated diseases. Summary of the Invention

[0007] Provided herein are compounds or pharmaceutically acceptable salts thereof and compositions useful for inhibiting wild-type c-kit kinase and for treating diseases or conditions mediated by wild-type c-kit kinase. The compounds of the present disclosure are potent inhibitors of c-kit kinase (see Table 2 in Example 290). Some compounds of the present disclosure are orally bioavailable, selective for other kinases such as FLT3 kinase and PDGFR, and have minimal CNS penetration to reduce CNS side effects.

[0008] One embodiment of the present disclosure is a compound represented by formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] Ring A is selected from tetrazole or triazole, wherein the tetrazole or the triazole is optionally replaced by R a replace;

[0012] where R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 0-5 Alkylphenyl, C 0-5 Alkyl C 3-6 Cycloalkyl, C 0-5 Alkyl C 6-10 Spiroalkyl, C 0-5 Alkyl C 5-10 The bridged bicycloalkyl and C each containing at least one N or O 0-5 Alkyl (4-6 membered heterocyclic) or C 0-5 Alkyl (7-10 membered spiroheterocyclic) or C 0-5Alkyl(5-10 membered bridged bicyclic heterocycle), wherein the alkyl, haloalkyl, phenyl, cycloalkyl, spiroalkyl, bridged bicyclic alkyl, heterocycle, spiroheterocycle or bridged bicyclic heterocycle is optionally substituted by 1 to 5 R b replace;

[0013] Each R b Independently selected from OH, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-5 Cycloalkoxy, SO2C 1-4 Alkyl, SO2C 1-4 Haloalkyl, C(O)OC 1-4 Alkyl, SO2(C 0-2 alkyl) (4-6 membered heterocyclic ring containing at least one O or N), SO2 (C 1-4 Alkyl)C 1-4 Halogenated alkoxy, SO2(C 1-4 Alkyl)C 1-4 Alkoxy (C 0-1 Alkoxy), SO2(C 1-4 alkyl)OH, SO2(C 0-2 Alkyl)C 3-6 Cycloalkyl, C 1-3 Alkyl, C 1-5 Haloalkyl, halogen and C 1-2 AlkylOH, in addition wherein the cycloalkyl group is optionally C 1-3 Alkyl substitution;

[0014] Each R 1 independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 0-4 Alkyl OH, C 6-10 Spiroalkyl, C 0-6 Alkyl C 1-6 Alkoxy, C 0-4 Alkyl C 1-6 Haloalkoxy, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, NH-(4-6 membered heterocycle or 5-6 membered heteroaryl containing at least one O or N) and 4-6 membered heterocycle or 7-10 membered fused bicyclic heterocycle or 7-10 membered spiro heterocycle, or 5-6 membered heteroaryl containing at least two N, wherein the alkyl, the haloalkyl, the alkoxy, the cycloalkyl, the spiroalkyl, the heterocycle or the heteroaryl are optionally substituted by 1 to 3 R e replace;

[0015] Each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, CN, CHF2, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 2-5 Alkyl (OH) 2, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy), C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C 1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 Alkyl OH or C 1-3 Alternatively, each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, CN, CHF2, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 In another alternative, each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C 1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 Alkyl OH substitution;

[0016] Each R 9 Independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, halogen, CN and C 3-4 Cycloalkyl;

[0017] n is 1 or 2; and

[0018] p is 0, 1, or 2.

[0019] Another embodiment of the present disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In one aspect, the composition is used to treat a disease or condition mediated by wild-type c-kit kinase. In another aspect, the composition is used to inhibit wild-type c-kit kinase.

[0020] Another embodiment of the present disclosure is a method of treating a subject having a disease or condition mediated by wild-type c-kit kinase, comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0021] Another embodiment of the present disclosure is a method of inhibiting wild-type c-kit kinase in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0022] Another embodiment of the present disclosure is the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient, in the manufacture of a medicament for treating a medical condition mediated by wild-type c-kit kinase.

[0023] Another embodiment of the present disclosure is the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient, in the manufacture of a medicament for inhibiting wild-type c-kit kinase in a subject in need thereof.

[0024] Another embodiment of the present disclosure is a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient, for use in treating a medical condition mediated by wild-type c-kit kinase.

[0025] Another embodiment of the present disclosure is a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier or excipient, for use in inhibiting wild-type c-kit kinase in a subject in need thereof. DETAILED DESCRIPTION

[0026] The goal of the present disclosure is to provide novel compounds and compositions that are highly selective and potent against wild-type c-kit kinase for safe and effective treatment of mast cell-related diseases in subjects. For example, the IC values ​​for inhibition of phospho-kit provided in Table 2 of Example 290 are: 50 The values ​​demonstrate that these compounds are potent inhibitors of c-kit. The term "KIT" or "kit" refers to the human tyrosine kinase which may also be referred to as mast cell / stem cell growth factor receptor (SCFR), proto-oncogene c-kit, tyrosine-protein kinase kit, or CD117.

[0027] In the treatment of these mast cell related diseases, especially chronic conditions (such as urticaria and asthma), any new therapy should be fully tolerated. The compounds of the present disclosure are intended to provide treatments with desired efficacy, safety and pharmaceutical properties for the treatment of c-kit mediated diseases. In some aspects, the compounds of the present disclosure are orally administered. In some aspects, the compounds of the present disclosure are selective inhibitors of c-kit kinases. Selective inhibitors selectively reduce target signaling activity relative to off-target signaling activity via direct or indirect interactions with the target, which results in an increased likelihood of clinical success compared to non-selective inhibitors. In some aspects, the compounds of the present disclosure have low CNS penetration, which is a desired characteristic for reducing and minimizing the side effects of chronic treatment. Compounds with low CNS penetration typically have high levels or active transport out of the brain, i.e., a high efflux ratio from the CNS.

[0028] The compounds of the present disclosure are selective c-kit inhibitors. As used herein, "selective c-kit inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that has the ability to selectively inhibit c-kit kinase relative to other targets. More specifically, a selective c-kit inhibitor has the ability to selectively inhibit c-kit relative to another kinase. In some aspects, the compounds of the present disclosure are selective for c-kit relative to FLT3 kinase and PDGFR kinase. Selective c-kit inhibitors have the ability to selectively reduce target signaling activity relative to off-target signaling activity via direct or indirect interaction with the target. The ability of the compounds of the present disclosure or their pharmaceutically acceptable salts to selectively target c-kit provides advantages in terms of improved efficacy, less off-target activity and increased likelihood of clinical success compared to non-selective compounds or salts.

[0029] Some compounds disclosed herein are inhibitors of KIT exons 9 and / or 11. Mutations in exons 9 and 11 of KIT are the major driver mutations in approximately 10% of gastrointestinal tumors, and high-dose imatinib (a KIT ex9 / 11 inhibitor) has been shown to be an effective treatment option.

[0030] In one embodiment, the compounds of the present disclosure are represented by formula (I). The variables in formula (I) are as described above.

[0031] In a first aspect, the compounds of the present disclosure are represented by any one of Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formulas (IV)-(XLIII):

[0032]

[0033]

[0034]

[0035]

[0036] or a pharmaceutically acceptable salt of any of the foregoing. The variables are as described for Formula (I). In one aspect, for Formula (IIa)-(IIb), (IIIa)-(IIIb), (IV)-(V), (VI)-(VII), (XXIV)-(XXV), (XXVI)-(XXVII), and (XXVII), p is 0, and the remaining variables are as described for Formula (I). Alternatively, for Formula (IIa)-(IIb), (IIIa)-(IIIb), (IV)-(V), (VI)-(VII), (XXIV)-(XXV), (XXVI)-(XXVII), and (XXVII), p is 1, and the remaining variables are as described for Formula (I).

[0062] Alternatively, for Formula (IIa)-(IIb)-(IIId)-(IIId)-(IIId)-(IV)-(V)-(VI)-(VII)-XXIV (XXV)-(XXVI)-(XXVII) and (XXVII), p is 2, and the remaining variables are as described for Formula (I). In another alternative, for Formula (IIa)-(IIb)-(IIId)-(IV)-(V)-(VI)-(VII)-XXIV (XXV)-(XXVI) and (XXVII), p is 1 or 2, and the remaining variables are as described for Formula (I).

[0037] In a second aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII),

[0038] in:

[0039] R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 0-3 Alkylphenyl, C 0-4 Alkyl C 3-6 Cycloalkyl, C 0-3 Alkyl C 6-10 Spiroalkyl, C 0-3 Alkyl (C 5-8 Bridged bicycloalkyl), C 0-5 Alkyl (4-6 membered heterocyclic ring containing at least one N or O), C 0-3 Alkyl (7-10 membered spiroheterocyclic ring containing at least one N or O) and C 0-3Alkyl (a 5-10 membered bridged bicyclic heterocycle containing at least one O or N), wherein:

[0040] The alkyl group or the haloalkyl group is optionally substituted by 1 to 5 R groups independently selected from the following b Replaces: C 1-5 Alkoxy, C 1-5 Halogenated alkoxy, C 3-6 Cycloalkyl, OH and CN;

[0041] The cycloalkyl group, the spirocycloalkyl group or the phenyl group is optionally substituted by 1 to 2 R groups independently selected from the following b Substitution: methyl, halogen, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 0-3 Alkyl OH; and

[0042] The heterocyclic ring is optionally replaced by an R selected from the following b Replaces: SO2C 1-5 Alkyl, SO2C 1-5 Haloalkyl, C(O)OC 1-4 Alkyl, SO2 (4-6 membered heterocyclic ring containing at least one O or N), SO2 (C 1-3 Alkyl)C 1-3 Halogenated alkoxy, SO2(C 1-3 Alkyl)C 1-3 Alkoxy, SO2(C 1-4 alkyl)OH, SO2(C 1-3 Alkyl)C 1-3 Alkoxy (methoxy), SO2 (C 0-2 Alkyl)C 3-6 Cycloalkyl and C 1-4 haloalkyl, wherein the cycloalkyl group is optionally replaced by C 1-2 Alkyl substitution;

[0043] And the remaining variables are as described for formula (I) or the first aspect.

[0044] In a third aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII),

[0045] in:

[0046] R a Selected from C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 0-3 Alkyl C 3-6 Cycloalkyl, C 0-3Alkyl (containing at least one O or N 4-6 membered heterocyclic ring), C 0-2 Alkyl C 6-10 Spiroalkyl, C 0-2 Alkyl (7-9 membered spiro heterocycle containing at least one O), C 0-1 Alkylphenyl, C 0-2 Alkyl (a 6-8 membered bridged bicyclic heterocycle containing at least one O or N) and C 1-2 Alkyl (C 5-7 bridged bicycloalkyl) wherein:

[0047] The alkyl group or the haloalkyl group is optionally substituted by 1 to 3 R groups independently selected from the following b Substitution: OH, CN, C 1-3 Alkoxy, C 1-4 Haloalkoxy and C 3-5 Cycloalkyl;

[0048] The cycloalkyl group, the spirocycloalkyl group or the phenyl group is optionally substituted by 1 to 3 R groups independently selected from the following b Substitution: halogen, methyl, C 1-3 Halogenated alkyl, C 1-2 Alkoxy and C 1-2 Alkyl OH; and

[0049] The heterocyclic ring is optionally substituted by 1 to 2 R b Replacement: C(O)OC 1-4 Alkyl, SO2C 1-4 Alkyl, SO2C 1-4 Halogenated alkyl, SO2 (4-5 membered heterocyclic ring containing one O), SO2 (C 1-2 Alkyl)C 1-2 Halogenated alkoxy, SO2(C 1-2 Alkyl)C 1-2 Alkoxy, SO2(C 1-3 Alkyl)OH, SO2C 3-4 Cycloalkyl, SO2(C 1-2 Alkyl)C 1-2 Alkoxy (methoxy), C 1-4 haloalkyl, wherein the cycloalkyl group is optionally replaced by C 1-2 Alkyl substitution;

[0050] And the remaining variables are as described for formula (I) or the first aspect.

[0051] In a fourth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII),

[0052] in:

[0053] R a Selected from C 1-5 Alkyl, C 2-5 Haloalkyl, cyclobutyl, cyclopropyl, methylcyclopropyl, CH(CH3)cyclopropyl, methylcyclobutyl, C 0-2 Alkyl (tetrahydropyranyl), C 6-10 Spiroalkyl, C 0-2 alkyl (8-membered spiroheterocycle containing at least one O), benzyl, CH2 (6-membered bridged bicyclic heterocycle containing one O), CH2 (bridged bicycloalkyl), and azetidinyl, wherein:

[0054] The alkyl group or the haloalkyl group is optionally substituted by 1 to 5 R groups independently selected from the following b Replaces: C 2-3 Alkoxy, C 2-3 Halogenated alkoxy, C 3-4 Cycloalkyl, OH and CN;

[0055] The cyclobutyl, cyclopropyl, methylcyclopropyl, methylcyclobutyl, spiroalkyl or benzyl is optionally substituted by 1 to 3 R groups independently selected from the following b Substituted: halogen, methyl, halomethyl, methoxy, and methylhydroxy; and

[0056] The azetidinyl group is optionally replaced by an R selected from the following b Replaces: SO2C 1-3 Alkyl, SO2C 1-3 Halogenated alkyl, SO2 tetrahydrofuran, SO2 oxetane, SO2 (C2 alkyl) C2 haloalkoxy, SO2 (C 1-2 alkyl)methoxy, SO2(C 1-2 alkyl)OH, SO2 cyclopropyl, SO2(C 1-2 Alkyl)C 1-2 Alkoxy (methoxy), C(O)OC 1-2 Alkyl and C 1-2 haloalkyl, further wherein the cyclopropyl is optionally substituted with methyl;

[0057] And the remaining variables are as described for formula (I) or the first aspect.

[0058] In a fifth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII),

[0059] in

[0060] R a independently selected from hydrogen, methyl, ethyl, 2-isopropyl, 2-(cyclopropylmethyl), (S)-(2,2-difluorocyclopropyl)methyl, (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutyl, (S)-4,4,4-trifluoro-3-hydroxy-3-methylbutyl, (R)-1-cyclopropylethyl, (S)-1-cyclopropylethyl, (R)-(2,2-difluorocyclopropyl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, (R)-1-(tetrahydro-2H-pyran-4-yl)methyl 1-(tetrahydro-2H-pyran-4-yl)ethyl, (S)-1-(tetrahydro-2H-pyran-4-yl)ethyl, 2-isopropoxyethyl, 2-cyclobutoxyethyl, (2,2,2-trifluoroethoxy)ethyl, 4,4,4-trifluorobutyl, cyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, (1s,3s)-3-(trifluoromethyl)cyclobutyl, (1r,3r)-3-(trifluoromethyl)cyclobutyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, (1r,3r)-3-(hydroxymethyl)cyclobutyl, (1s,3s)-3-methoxycyclobutyl,

[0061] (2-fluorobenzyl), CH(CH3)(2-fluorophenyl), 1-(methylsulfonyl)azetidin-3-yl, (ethylsulfonyl)azetidin-3-yl, 1-(propylsulfonyl)azetidin-3-yl, 1-(isopropylsulfonyl)azetidin-3-yl, (2-methoxyethyl)sulfonyl)azetidin-3-yl, 1-(cyclopropylsulfonyl)azetidin-3-yl, 1-((cyclobutylmethyl)sulfonyl)azetidin-3-yl, 1-((1-methylcyclopropyl)sulfonyl)azetidin-3-yl )azetidin-3-yl, 1-((trifluoromethyl)sulfonyl)azetidin-3-yl, 1-((3,3-difluoropropyl)sulfonyl)azetidin-3-yl, (2-(2-methoxyethoxy)ethyl)sulfonyl)azetidin-3-yl, (4-cyanobutyl)sulfonyl)azetidin-3-yl, (2,2,2-trifluoroethyl)azetidin-3-yl, (2-hydroxyethyl)sulfonyl)azetidin-3-yl, and (2-(2,2-difluoroethoxy)ethyl)sulfonyl)azetidin-3-yl;

[0062] And the remaining variables are as described for formula (I) or the first aspect.

[0063] In a sixth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII), wherein:

[0064] Each R 1 independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 0-4 Alkyl C 1-6 Alkoxy, C 0-4 Alkyl C 1-6 Halogenated alkoxy, C 3-4 Cycloalkyl, NH2, NHC 1-5 Alkyl, N(C 1-3 alkyl)2, NH-(4-6 membered heterocycle containing at least one O), NH-(5-6 membered heteroaryl containing at least one N), 4-6 membered heterocycle or 7-9 membered fused bicyclic heterocycle or 7-10 membered spiroheterocycle each containing at least one O or N, and 5-6 membered heteroaryl containing at least one N, wherein:

[0065] The alkyl group, the haloalkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: Deuterium, Deuterated C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Halogenated alkoxy, C 1-4 Alkoxy, C 1-2 Alkoxy C 1-2 Alkoxy, OH, halogen, and a 4-6 membered heterocyclic ring containing at least one O or N;

[0066] The heterocyclic ring or the cycloalkyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: deuterated C 1-3 Alkyl, di(C 1-3 Alkyl)amine, S(O)2C 1-3 Alkyl, halogen, 4-6 membered heterocyclic ring containing one O, C 1-3 Alkyl, C 0-4 Alkyl OH and C 1-2 Alkyl C 1-3 alkoxy; and

[0067] The heteroaryl group is optionally substituted by 1 to 3 R groups independently selected from the following e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 1-4 Alkyl OH, C 2-5 Alkyl (OH)2, C 2-4 Alkyl (OH) (methoxy), C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy), S(O)2C1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 2 OH or C 1-3 Alternatively, the heteroaryl group is optionally substituted by 1 to 3 R groups independently selected from the following e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 1-4 Alkyl OH, C 2-4 Alkyl (OH) (methoxy), S (O) 2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted with 1 to 2 OH groups. In another alternative, the heteroaryl group is optionally substituted with 1 to 3 R groups each independently selected from the following: e Replaces: C 1-4 Alkyl, C 1-4 Alkyl OH, S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocycle containing at least one O or N), wherein the heterocycle is optionally substituted with 1 to 2 OH groups;

[0068] and the remaining variables are as described for formula (I) or the first, second, third, fourth or fifth aspect.

[0069] In a seventh aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I)-(IIa)-(IIb)-(IIIa), (IIIb), or (IV)-(XLIII), wherein:

[0070] Each R 1 independently selected from halogen, C 1-3 Alkyl, C 1-4 Alkyl OH, C 0-4 Alkyl C 1-5 Alkoxy, C0-4 Alkyl C 1-5 Haloalkoxy, cyclopropyl, NH2, NHC 1-4 Alkyl, N(C 1-2 alkyl)2, NH-(a 5-membered heterocyclic ring containing one O), NH-(a 5-membered heteroaryl ring containing two N), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino and pyrazolyl, wherein:

[0071] The alkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: deuterium, C 1-3 Alkyl, C 1-3 Haloalkoxy, deuterated methoxy, OH, C 1-4 Alkoxy, C 1-2 Alkoxy C 1-2 Alkoxy, halogen and 4-6 membered heterocyclic ring containing at least one O;

[0072] The azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuran or morpholino is optionally substituted by 1 to 2 R groups independently selected from the following: e Substitution: deuterated C 1-3 Alkyl, di(C 1-3 alkyl)amine, S(O)2CH3, halogen, C 0-3 AlkylOH, 4-6 membered heterocyclic ring containing one O, C 1-2 Alkyl, C 1-2 Haloalkyl and C 1-2 Alkyl C 1-3 alkoxy; and

[0073] The pyrazolyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 0-4 Alkyl OH, C 2-5 Alkyl (OH)2, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 1-3 Alkyl (OH) (C 1-3 Alkoxy) (C 1-3 Alkoxy), S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(a 6-membered heterocyclic ring containing at least one O or N), wherein the 6-membered heterocyclic ring is optionally substituted by 1 to 2 OH or C 1-3Alternatively, the pyrazolyl group is optionally substituted by 1 to 3 R e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 0-4 Alkyl OH, C 2-4 Alkyl (OH) (methoxy), S (O) 2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocyclic ring containing at least one O or N), wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 2 OH groups. In another alternative, each R e Independently selected from C 1-4 Alkyl, C 0-4 Alkyl OH, S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocyclic ring containing at least one O or N), further wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 2 OH groups;

[0074] and the remaining variables are as described for formula (I) or the first, second, third, fourth or fifth aspect.

[0075] In an eighth aspect, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I)-(IIa)-(IIb)-(IIIa), (IIIb), or (IV)-(XLIII), wherein:

[0076] Each R 1 independently selected from halogen, C 1-3 Alkyl, C 2-3 Alkyl OH, C 0-3 Alkyl C 1-5 Alkoxy, cyclopropyl, NH2, NH(C 1-4 alkyl), N(C 1-2 alkyl) 2, NH-tetrahydrofuryl, NH-pyrazolyl, NH-oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino and pyrazolyl, wherein:

[0077] The alkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: OH, halogen, deuterium, C 1-3Alkyl, methoxy, ethoxymethoxy, deuterated methoxy, haloethoxy, butoxy, and a 4-6 membered heterocyclic ring containing one O;

[0078] The azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl or morpholino is optionally substituted by 1 to 2 R groups independently selected from the following: e Substitution: S(O)2CH3, halogen, C 0-2 AlkylOH, oxetane, C1 alkyl, C2 haloalkyl, deuterated C 1-3 Alkyl, di(C 1-3 alkyl)amine and C1 alkylC1 alkoxy; and

[0079] The pyrazolyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Substituted: methyl, ethyl, propyl, butyl, cyclopropyl, ethylhydroxy, isobutylhydroxy, CH2CH(OH)C(CH3)2(OH), CH2CH(OH)CH2OH, CH2C(OH)(CH3)CH2OH, CH(CH2OH)2, propyl(OH)methoxy, CH2CH(OH)CH2OCH2CH2OCH3, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl) P(O)(CH3)2, wherein the morpholino, the piperazinyl and the tetrahydropyranyl are optionally substituted with 1 to 2 OH or methyl groups. Alternatively, the pyrazolyl is optionally substituted with 1 to 3 R groups each independently selected from the following: e Substituted: methyl, ethyl, propyl, butyl, cyclopropyl, ethylhydroxy, propyl (OH) methoxy, isobutylhydroxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3, (C 2-3 alkyl) P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups. In another alternative, said pyrazolyl is optionally substituted with 1 to 3 R groups each independently selected from the following e Substituted: methyl, ethyl, propyl, butyl, ethylhydroxy, isobutylhydroxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3, (C 2-3alkyl) P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups;

[0080] and the remaining variables are as described for formula (I) or the first, second, third, fourth or fifth aspect.

[0081] In the ninth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII), wherein each R 1independently selected from 1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, 1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl, 3-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-3-cyclopropyl-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methyl (S)-1-(2-hydroxy-3-methoxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, (S)-1 -(2-hydroxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-3-cyclopropyl-1-(2,3-dihydroxy-3-methylbutyl)-1H-pyrazol-4-yl, (R)-3-cyclopropyl-1-(2,3-dihydroxy-3-methylbutyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1 -(2-hydroxypropyl)-5-methyl-1H-pyrazol-4-yl, (R)-1-(2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-((2R,3S)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl, 1-((2S,3R)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl, 1-((2S,3S)-3-hydroxybutan-2-yl)-5-methyl-1H-pyrazol-4-yl, 1-((2R,3R)-3-hydroxybutan-2-yl)-5-methyl-1H-pyrazol-4-yl, 1-((R)-2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl (2 73), 3,5-dimethyl-1-((4-methylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl (274), (S)-1-(2,3-dihydroxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, 1-(1,3-dihydroxypropan-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxypropyl)- 3-methyl-1H-pyrazol-4-yl, (S)-(1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl (283), (R)-1-(2-hydroxy-3- (2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl, 1-((2R,3R)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl and 1-((2S,3S)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl; and the remaining variables are as described for Formula (I) or the first, second, third, fourth or fifth aspects.

[0082] In the tenth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII), wherein each R 1independently selected from methyl, -NH2, methylamino, ethylamino, dimethylamino, (2-hydroxyethyl)amino, (S)-(2-hydroxypropyl)amino, (2-hydroxyethyl)(methyl)amino, (2-hydroxy-2-methylpropyl)amino, (2-(tert-butoxy)ethyl)amino, (2-methoxyethyl)amino, (2-(methoxy-d3)ethyl)amino, (2-methoxyethoxy)amino, (R)-(1-methoxyprop-2-yl)amino, (S)-(2-methoxypropyl)amino, (2-methoxy-2-methylpropyl)amino, (2-methoxyethoxy)ethyl)amino, (2,2-difluoroethyl)amino, (2,2-difluoropropyl)amino, (2,2-difluoro-3-hydroxypropyl)amino, (S)-(tetrahydrofuran-3-yl)amino amino, (oxetan-2-ylmethyl)amino, oxetan-3-ylamino, (oxetan-3-ylmethyl)amino, (1H-pyrazol-4-yl)amino, cyclopropyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, (2,2-difluoroethoxy)methyl, (2,2-difluoroethoxy)ethyl, fluoro, methoxy, 3-hydroxy-3-methylbutoxy, 2-methoxyethoxy, 2-hydroxyethoxy, 3-hydroxyazetidin-1-yl, (S)-2-(hydroxymethyl)azetidin-1-yl, 3-methylazetidin-1-yl, (R)-2-(methoxymethyl)azetidin-1-yl, (S)-2-(methoxymethyl)azetidin-1-yl, 3-(methylsulfonyl)azetidin-1-yl 3-(Hydroxymethyl)azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-(dimethylamino)pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, (S)-3-hydroxypiperidin-1-yl, (R)3-hydroxypiperidin-1-yl, 4-(methyl-d3)piperazin-1-yl, 4-(2,2-difluoroethyl)piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydrofuran-3-yl, morpholino, (R)-2-(hydroxymethyl)morpholino, 1H-pyrazol-4-yl, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxypropyl)-1H-pyrazol-4-yl), (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl,

[0083]

[0084] and the remaining variables are as described for formula (I) or the first, second, third, fourth or fifth aspect.

[0085] In the eleventh aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by any one of Formula (I), Formula (IIa), Formula (IIb), Formula (IIIa), Formula (IIIb), or Formula (IV)-(XLIII), wherein each R 9 is independently selected from CH3, Cl, F, CD3, CN and cyclopropyl; and the remaining variables are as described for Formula (I) or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth aspect.

[0086] In a twelfth aspect, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is represented by either Formula (XLIV) or Formula (XLV):

[0087]

[0088] in:

[0089] Ring A in Formula XLIV is triazolyl or tetrazolyl;

[0090] Each R 9 is independently selected from CH3, Cl, F, CD3, CN and cyclopropyl. Alternatively, each R 9 is independently selected from CH3, Cl, F, CD3 and CN. In another alternative, each R 9 Independently selected from CH3, F, CD3 and CN.

[0091] R e Selected from C 1-4 Alkyl, C 0-4 Alkyl OH, C 1-4 Alkyl (OH) (C 1-4 Alkoxy), S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocyclic ring containing at least one O or N), wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 2 OH groups. Alternatively, R e Selected from C 1-4 Alkyl, C 0-4 Alkyl OH, S(O)2C 1-3 Alkyl, C 1-3Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocyclic ring containing at least one O or N), wherein the 6-membered heterocyclic ring is optionally substituted with 1 to 2 OH groups. In another alternative, R e Selected from methyl, ethyl, propyl, butyl, ethylhydroxy, isobutylhydroxy, propyl (OH) methoxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl)P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups. In another alternative, R e Selected from methyl, ethyl, propyl, butyl, ethylhydroxy, isobutylhydroxy, propyl (OH) methoxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl)P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups. In another alternative, R e yes R 10 and R 11 are independently H, CH3, CH2OCH3, provided that R 10 and R 11 Not all CH2OCH3, or R 10 and R 11 together is 4-tetrahydropyranyl; and R e1 is selected from H, CH3 and cyclopropyl.

[0092] In the thirteenth aspect, the compounds of the present disclosure are shown in Table 1 and the Exemplary below. Pharmaceutically acceptable salts and corresponding neutral forms thereof are included in the present disclosure.

[0093] Table 1

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation and allergic response, and commensurate with a reasonable benefit / risk ratio.

[0149] Pharmaceutically acceptable salts are known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19. The compounds of the present disclosure having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present disclosure having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0150] The following abbreviations and terms have the indicated meanings throughout:

[0151] The term "alkyl" used alone or as part of a larger moiety (such as "alkoxy," "alkylphenyl," "alkylspirocycloalkyl," etc.) means a saturated aliphatic straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (C 1-6 alkyl) (i.e., 1, 2, 3, 4, 5, or 6), alternatively 1 to 4 carbon atoms (C 1-4 alkyl) (i.e., 1, 2, 3 or 4), alternatively 1 to 3 carbon atoms (C 1-3 Examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like.

[0152] The term "alkoxy," used alone or as part of a larger moiety such as haloalkoxy or alkylalkoxy, means a saturated aliphatic straight or branched chain monovalent radical consisting of an alkyl group bonded to an oxygen. Unless otherwise specified, an alkoxy group typically has from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms and an oxygen atom (C 1-6 alkoxy), alternatively 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms and oxygen atoms (C 1-4 Examples of the alkoxy group include methoxy, ethoxy, and the like.

[0153] The term "halogen" or "halo" refers to fluorine (or fluoro) (F), chlorine (or chloro) (Cl), or bromine (or bromo) (Br).

[0154] The term "haloalkyl," used alone or as part of a larger moiety (such as haloalkoxy or alkylhaloalkoxy), means an alkyl group in which at least one hydrogen substituent is replaced by a halogen radical. Unless otherwise specified, a haloalkyl group typically has from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms (C 1-6 haloalkyl), alternatively 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms (C 1-4 Examples include trifluoromethyl, trifluoroethyl, difluoroethyl, and the like.

[0155] The term "haloalkoxy," used alone or as part of a larger moiety such as alkylhaloalkoxy, means an alkoxy group in which at least one hydrogen substituent is replaced by a halogen. Unless otherwise specified, a haloalkoxy group typically has from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) carbon atoms (C 1-6 haloalkoxy), alternatively 1 to 4 (i.e., 1, 2, 3 or 4) carbon atoms (C 1-4 Examples include difluoroethoxy and the like.

[0156] The term "cycloalkyl" used alone or as part of a larger moiety (such as alkylcycloalkyl) means a saturated aliphatic monocyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl radical has from 3 to 6 (i.e., 3, 4, 5, or 6) ring carbon atoms (C 3-6 cycloalkyl), alternatively 3 to 5 (i.e., 3, 4, or 5) ring carbon atoms (C 3-5 cycloalkyl), alternatively 3 to 4 carbon atoms (C 3-4 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, and the like.

[0157] The term " spiroalkyl " used alone or as a part of a larger group (such as an alkyl spiroalkyl) means a group comprising two cycloalkyl groups sharing a common ring atom. Unless otherwise indicated, spiroalkyl has 6 to 11 (i.e., 6, 7, 8, 9, 10 or 11) ring carbon atoms. Examples include 3,4-bicyclooctyl, 4,4-bicyclononyl, 3,5-bicyclononyl, 3,6-bicyclodecyl, 4,5-bicyclodecyl, 3,7-bicycloundecyl, 4,6-bicycloundecyl and 5,5-bicycloundecyl.

[0158] The term "bridged bicycloalkyl" used alone or as part of a larger moiety (such as an alkyl-bridged bicycloalkyl) means a group comprising two cycloalkyl groups that share 3 or 4 adjacent ring atoms. Unless otherwise specified, a bridged bicycloalkyl group has 5 to 10 ring carbon atoms. Examples include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.1]nonyl.

[0159] Unless otherwise indicated, the term "heterocycle" as used alone or as part of a larger moiety (such as an alkyl heterocycle) refers to a monocyclic non-aromatic ring group containing 4 to 6 ring atoms (i.e., "4-membered, 5-membered, or 6-membered") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen (N) and oxygen (O). Nitrogen-containing heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc. Oxygen-containing heterocycles include oxetane, tetrahydrofuranyl, tetrahydropyranyl, etc. Heterocycles containing N and O include morpholinyl, etc.

[0160] The term " spiro heterocycle " used alone or as a part for a larger portion (such as an alkyl spiro heterocycle) refers to a bicyclic non-aromatic ring group, which includes a heterocycle sharing a ring atom with a cycloalkyl or a second heterocycle. Unless otherwise indicated, spiro heterocycle has 7 to 11 ring atoms (that is, " 7 yuan, 8 yuan, 9 yuan, 10 yuan or 11 yuan ") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen and oxygen. The example of 7 to 11 nitrogen-containing spiro ring systems includes but is not limited to 3,3- azabicycloheptyl, 3,4- azabicyclooctyl, 4,4- azabicyclononyl, 3,5- azabicyclononyl, 3,6- azabicyclodecyl, 4,5- azabicyclodecyl, 3,7- azabicycloundecyl, 4,6- azabicycloundecyl and 5,5- azabicycloundecyl. Examples of 7-11 oxygen-containing spiro ring systems include, but are not limited to, 3,3-oxobicycloheptyl, 3,4-oxobicyclooctyl, 4,4-oxobicyclononyl, 3,5-oxobicyclononyl, 3,6-oxobicyclodecyl, 4,5-oxobicyclodecyl, 3,7-oxobicycloundecyl, 4,6-oxobicycloundecyl, 5,5-oxobicycloundecyl, 2-oxa-6λ- 2 -azaspiro[3,3]heptyl, 2-oxa-6λ 2 -azaspiro[3,4]octyl, 2-oxa-6λ 2 -azaspiro[3,5]nonyl, 6-oxa-2λ 2 -azaspiro[3,3]heptyl, 6-oxa-2λ 2 -azaspiro[3,4]octyl and 6-oxa-2λ 2 -azaspiro[3,5]nonyl.

[0161] The term "fused bicyclic heterocycle" refers to a bicyclic non-aromatic ring group in which heterocycle shares two adjacent ring atoms with cycloalkyl or a second heterocycle. Unless otherwise indicated, bicyclic heterocycle has 7 to 10 ring atoms (that is, "7 yuan, 8 yuan, 9 yuan or 10 yuan") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen and oxygen. The example of nitrogen-containing bicyclic heterocycle includes but is not limited to azabicyclo [3.2.0] heptyl, azabicyclo [4.2.0] octyl, azabicyclo [3.3.0] octyl, azabicyclo [4.3.0] nonyl, azabicyclo [5.2.0] nonyl, diazabicyclo [3.2.0] heptyl, diazabicyclo [3.3.0] octyl and diazabicyclo [4.3.0] nonyl. Examples of oxygen-containing bicyclic heterocycles include, but are not limited to, oxobicyclo[3.2.0]heptyl, oxobicyclo[4.2.0]octyl, oxobicyclo[3.3.0]octyl, oxobicyclo[4.3.0]nonyl, oxobicyclo[5.2.0]nonyl, dioxobicyclo[3.2.0]heptyl, dioxobicyclo[3.3.0]octyl, and dioxobicyclo[4.3.0]nonyl. Examples of fused bicyclic heterocycles containing nitrogen and oxygen atoms include hexahydro-1H-2λ-pyrrolo-[2,1-c]pyrazine.

[0162] The term "bridged bicyclic heterocycle " used alone or as a part of a larger portion (such as an alkyl bridged bicyclic heterocycle) refers to a bicyclic non-aromatic ring group, which includes a heterocycle sharing three or four adjacent ring atoms with a cycloalkyl or a second heterocycle. Unless otherwise indicated, bridged bicyclic heterocycle has 5 to 10 ring atoms (that is, " 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan ") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen and oxygen. The example of nitrogen-containing bridged bicyclic includes but is not limited to azabicyclo [2.2.1] heptyl, azabicyclo [2.2.2] octyl, azabicyclo [3.2.1] octyl, azabicyclo [3.2.2] nonyl, azabicyclo [3.3.1] nonyl, diazabicyclo [2.2.1] heptyl, diazabicyclo [3.2.1] octyl and diazabicyclo [3.3.1] nonyl. Examples of oxygen-containing bridged bicyclic rings include, but are not limited to, oxobicyclo[2.2.1]heptyl, oxobicyclo[2.2.2]octyl, oxobicyclo[3.2.1]octyl, oxobicyclo[3.2.2]nonyl, and oxobicyclo[3.3.1]nonyl. Examples of bridged bicyclic heterocycles containing oxygen and nitrogen atoms include: oxa-azabicyclo[2.2.1]heptyl, oxa-azabicyclo[3.2.1]octyl, and oxa-azabicyclo[3.3.1]nonyl.

[0163] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring system having 1 to 4 (i.e., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, wherein N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to form sulfoxides and sulfones. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the like.

[0164] The term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For illustration, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be understood that if more than one substitution is present on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise indicated).

[0165] When a substituent is described as a string or series of groups (such as "C 0-5 Alkylphenyl", "C 0-5 Alkyl C 3-6 Cycloalkyl", "C 0-5 Alkyl C 6-10 Spirocycloalkyl" or "C 0-5 Alkyl C 5-10 When a "bridged bicycloalkyl" is present, the substituent is attached to the remainder of the compound via the first group in the sequence. For example, C 0-5 The alkylphenyl group is then attached to the C 0-5 The alkyl group is attached to the rest of the compound. 0-5 Alkylphenyl can also be represented as -(CH2) 0-5 Phenyl. C 0-5 Alkyl C 3-6 The cycloalkyl group is further bonded to the C 3-6 Cycloalkyl C 0-5 The alkyl group is attached to the rest of the compound. 0-5 Alkyl C 3-6 Cycloalkyl can also be represented as -(CH2) 0-5 (C 3-6 cycloalkyl). C 0-5 Alkyl C 6-10 The spiroalkyl group is further bonded to the C 6-10 Spiroalkyl C 0-5 The alkyl group is attached to the rest of the compound. 0-5 Alkyl C 6-10 Spiroalkyl can also be represented by -(CH2) 0-5 (C6-10 Spirocycloalkyl. C 0-4 Alkyl C 1-6 The alkoxy group is then attached to the C 1-6 Alkoxy C 04 The alkyl group is attached to the rest of the compound. 0-4 Alkyl C 1-6 Alkoxy can also be represented as -(CH2) 0-4 (C 1-6 alkoxy). "C 1-4 Alkyl (OH) C1-C4 alkoxy (e.g., propyl (OH) methoxy) refers to a C1-C4 alkoxy group bonded to a hydroxyl group and an alkoxy group. 1-4 alkyl; and “C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy)" refers to C 2-5 Alkyl groups bonded to hydroxyl groups and C 1-5 Alkoxy and wherein C 1-5 The alkoxy group is further bonded to another C 1-5 Alkoxy.

[0166] If a group is described as "optionally substituted," the group may be (1) unsubstituted or (2) substituted. If a group is described as optionally substituted with up to a specified number of non-hydrogen substituents, the group may be (1) unsubstituted; or (2) substituted with up to the specified number of non-hydrogen substituents or with up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as being optionally substituted with up to 3 non-hydrogen substituents, any cycloalkyl group having fewer than 3 substitutable positions may be optionally substituted with up to as many non-hydrogen substituents as the cycloalkyl group has substitutable positions.

[0167] Compounds with one or more chiral centers can exist in multiple stereoisomeric forms, i.e., each chiral center can have the R or S configuration, or can be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are not identical and are not mirror images of each other.

[0168] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., where the configuration is indicated by a "wedge-shaped" bond), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%.

[0169] The "enrichment of the indicated configuration relative to the opposite configuration" is a molar % and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configuration.

[0170] When two or more stereoisomers are depicted by their chemical names or structures and the names or structures are linked by "or", one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above.

[0171] When a disclosed compound having a chiral center is depicted by a structure without showing the configuration at the chiral center, the structure is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without using "S" or "R" to indicate the configuration at the chiral center, the name is intended to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0172] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure mixtures, enantiomerically enriched mixtures, diastereomerically pure mixtures, diastereomerically enriched mixtures and racemic and diastereomeric mixtures of the compounds described herein.

[0173] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically pure or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0174] "Peak 1" or "first eluting isomer" or "Isomer 1" in the Experimental Section refers to the desired reaction product compound obtained from chromatographic separation / purification that elutes earlier than the second desired reaction product compound from the same previous reaction. The second desired product compound is referred to as "Peak 2" or "second eluting isomer" or "Isomer 2."

[0175] When a compound is represented by a name or structure indicating a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or depicted enantiomers divided by the total weight of the mixture of the two enantiomers.

[0176] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, stereoisomeric purity is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0177] The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a molar % and is obtained by dividing the number of compounds with deuterium enrichment at the enrichment site by the number of compounds with hydrogen or deuterium at the enrichment site. Deuterated groups (such as "deuterated alkyl" or "deuterated alkoxy") have hydrogen atoms at one or more positions that are replaced or enriched with deuterium.

[0178] The c-kit kinase inhibitors described herein can be used to treat diseases and conditions mediated by wild-type c-kit. In some aspects, c-kit-mediated diseases and conditions include mast cell-related disorders, eosinophil-related disorders, cancer, asthma, inflammatory disorders, rheumatoid arthritis, allergic inflammation, inflammatory bowel disease, gastrointestinal disorders, or fibrosis.

[0179] Wild-type KIT plays a key role in mast cell survival, proliferation and activation. Specifically, c-kit inhibitors can be used to inhibit and / or remove mast cells and are therefore useful for treating mast cell-related disorders. As used herein, the term "mast cell-related disorder" or "mast cell-related disorders" or "mast cell-mediated disorder" or "mast cell-mediated disorder" refers to a disorder in which mast cell activity leads to pathology and / or abnormal amounts (such as higher than normal amounts or lower than normal amounts) of mast cells are found in different parts of the body. For example, a mast cell-related disorder can exhibit the accumulation of pathological mast cells and / or its characteristics can be that mast cells are abnormally activated and / or abnormally release one or more mast cell mediators, such as inflammatory mediators, in potentially any or all organs and tissues. Non-limiting examples of inflammatory mediators released by mast cells include any of the following: (i) granule-associated mediators, including histamine, serotonin (5-hydroxytryptamine), and various proteases, such as tryptase and chymosin, and peptidases; (ii) eicosanoids, such as prostaglandin D2 (PGD2) and leukotriene C4 (LTC4); and (iii) cytokines, including interleukin-2 (IL-2), IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNFa), and chemokines, including CCL-2, CCL-3, CCL-5, and CXCL8.

[0180] Compounds of the present disclosure can be used to treat chronic urticaria. Chronic urticaria includes chronic spontaneous urticaria (CSU), chronic idiopathic urticaria and chronic induced urticaria (i.e., chronic induced urticaria (CIndU)). In some aspects, mast cell related conditions are CSU. In some aspects, mast cell related conditions are CindU. Chronic induced urticaria is a form of urticaria with an attributable triggering factor associated therewith, typically leading to skin inflammation characterized by wheals (hives) or angioedema. Complications of CSU and CIndU include swelling / hives and acute allergies in inappropriate parts (oral cavity, airway, genitals). Sleep interruption, stress and anxiety caused by severe itching are the main causes of disease burden. In particular aspects, chronic induced urticaria is cold urticaria (ColdU). People suffering from cold urticaria experience symptoms such as itching, burning wheals and angioedema when their skin is exposed to temperatures below skin temperature. In another aspect, chronic induced urticaria is a symptomatic skin scratching phenomenon (SD). The symptomatic skin scratching phenomenon is characterized by producing a wheal and flushing reaction in response to stroking, scratching, or rubbing of the skin, and typically occurs within a few minutes of an inciting stimulus. In another aspect, chronic induced urticaria is a cholinergic urticaria. Cholinergic urticaria is triggered by the body's sweating response to active or passive body warming and is characterized by small (1-4 mm) wheals surrounded by bright red flushes. Common triggers include exercise, hot baths / showers, fever, wearing tight clothing, eating spicy foods, and emotional stress. In another aspect, chronic induced urticaria is a heat urticaria. In another specific embodiment, chronic induced urticaria is a delayed pressure urticaria. In another aspect, chronic induced urticaria is a solar urticaria. In another specific embodiment, chronic induced urticaria is a vibration urticaria. In another aspect, chronic induced urticaria is a contact urticaria. In one aspect, vibratory urticaria is characterized by a missense mutation in EMR2. In another aspect, chronic inducible urticaria is aquagenic urticaria.

[0181] Other mast cell-associated conditions and diseases include skin disorders, including atopic dermatitis and allergic contact dermatitis; idiopathic angioedema; idiopathic allergies; asthma, including allergic asthma; hereditary alpha-trypsinemia (HAT); idiopathic mast cell activation syndrome (MCAS); monoclonal MCAS; neurofibromatosis; idiopathic pulmonary fibrosis; bullous pemphigoid; and prurigo nodularis.

[0182] Other diseases in which mast cells are involved include age-related macular degeneration; allergic conjunctivitis; allergic rhinitis; nonallergic rhinitis; alpha-1 antitrypsin deficiency; Alzheimer's disease; amyotrophic lateral sclerosis (AML); bronchiectasis; celiac disease; chronic graft-versus-host disease; chronic sinusitis with nasal polyps; allergic fungal sinusitis; aspirin-exacerbated respiratory disease; allergic bronchopulmonary aspergillosis; colorectal cancer; dermatitis herpetiformis; irritable bowel syndrome (IBS), including diarrhea-predominant IBS; fibromyalgia; fibrosis, including liver fibrosis, lung fibrosis, and cardiac fibrosis; food allergies, including Igf-mediated food allergies and peanut allergies; insect venom allergies; drug allergies; insulin-dependent diabetes mellitus; mast cell leukemia; migraine headaches; multiple sclerosis; Parkinson's disease; psoriasis; and rheumatoid arthritis.

[0183] Other diseases modulated by c-kit include pulmonary arterial hypertension (PAH); inflammatory bowel disease (IBD); cholestatic pruritus; uremic pruritus; chronic pruritus of unknown origin; pulmonary fibrosis; scleroderma; skin diseases; dermatitis herpetiformis; melanoma; gastrointestinal stromal tumors; mast cell tumors; allergic syndromes; idiopathic allergy; type I or type II diabetes mellitus; eosinophilic esophagitis (EoE); eosinophilic gastritis and duodenitis; interstitial cystitis / painful bladder syndrome, chronic prostatitis / chronic pelvic pain syndrome; endometriosis; and mastocytosis, including cutaneous mastocytosis and systemic mastocytosis.

[0184] The compounds disclosed herein can be used to treat gastrointestinal stromal tumors (GIST). GIST is the most common malignant subepithelial lesion of the gastrointestinal tract, and the most common symptoms of GIST are gastrointestinal bleeding, acute melena (dark stool containing blood), hematemesis (hematemesis) accompanied by anemia, weakness, and abdominal pain and bloating. Nearly 80% of metastatic GISTs have major activating mutations in the extracellular region (exon 9) or juxtamembrane (JM) domain (exon 11) of KIT. Imatinib is the standard therapy for treating GIST. Side effects of imatinib include mild stomach discomfort, diarrhea, muscle pain, and rash. New therapies for treating GIST are needed.

[0185] Compounds of the present disclosure can be administered in combination with another agent. In one aspect, compounds of the present disclosure are administered in combination with one or more antihistamines (such as loratadine, cetirizine, fexofenadine, cimetidine, famotidine or diphenhydramine). In another aspect, compounds of the present disclosure are administered in combination with one or more asthma agents (such as montelukast and zafirlukast).

[0186] In another aspect, the compound of the present disclosure can be used in combination with one or more other agents for the treatment of urticaria. For example, the compound of the present disclosure is used in combination with omalizumab, dupilumab, reslizumab, mepolizumab and benralizumab. In some aspects, the compound of the present disclosure can be used together with novel anti-IgE monoclonal antibodies (such as ligelizumab and UB-221). The compound of the present disclosure can also be used together with monoclonal antibodies (AK002) for Siglec-8, Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), spleen tyrosine kinase inhibitors and dupilumab. The compound of the present disclosure and agent can be used together or in an alternating scheme. In some aspects, the compound of the present disclosure can be used together with an antihistamine. Examples of antihistamines include classic H1 antihistamines with sedative side effects, including chlorpheniramine, hydroxyzine, and diphenhydramine; non-sedating second-generation H1 antihistamines, including loratadine, cetirizine, terfenadine, and mizolastine; second-generation H1 antihistamine derivatives, including desloratadine, levocetirizine, and fexofenadine; and H2 antihistamines, including cimetidine, ranitidine, famotidine, and nizatadine. Other antihistamines include bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and rupatadine. In some aspects, the compounds of the present disclosure may be administered in combination with MRGPRX2 inhibitors. Examples of MRGPRX2 inhibitors are EP-262 and EVO-756.

[0187] In some aspects, the compounds of the present disclosure are administered to a subject in need thereof. In some aspects, the compounds of the present disclosure are administered as pharmaceutical formulations, wherein the compounds are combined with one or more pharmaceutically acceptable excipients or carriers. Therefore, in some aspects, compositions are disclosed herein comprising at least one entity selected from a compound of Formula I and a pharmaceutically acceptable salt thereof and optionally further comprising at least one pharmaceutically acceptable excipient.

[0188] The compounds of the present disclosure or their pharmaceutically acceptable salts can be formulated for administration in any manner convenient for use in human or veterinary medicine. In certain embodiments, the compounds included in the pharmaceutical formulations may themselves be active, or may be prodrugs, e.g., prodrugs that can be converted into active compounds under physiological conditions.

[0189] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0190] Examples of pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. solution); (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrin; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0191] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0192] Solid dosage forms (e.g., capsules, tablets, pills, lozenges, powders, granules, etc.) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) ) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0193] Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof.

[0194] Suspensions, in addition to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth, and mixtures thereof.

[0195] Ointments, pastes, creams and gels may contain, in addition to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0196] In addition to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or a mixture of these substances. Sprays may additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0197] The formulations can generally be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. The amount of the compound of the present disclosure or its pharmaceutically acceptable salt that can be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.

[0198] Dosage forms for topical or transdermal administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0199] When the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to humans and animals as pharmaceutical agents, they can be administered per se or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredients in combination with pharmaceutically acceptable carriers.

[0200] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcutaneously, or by inhalation.

[0201] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0202] The term "effective amount" means an amount that produces a beneficial or desired result (including clinical results, such as inhibition, containment or alleviation of the symptoms of the treated disorder of the subject compared to a control) when administered to a subject or patient. For example, an effective amount can be given in a unit dosage form (e.g., 0.1 mg to about 50 g / day, alternatively 1 mg to about 5 grams / day). The exact amount of the compound or its pharmaceutically acceptable salt administered to provide an "effective amount" to the subject will depend on the mode of administration, the type and severity of the disease or disorder, and the characteristics of the subject, such as the general route of administration of the specific active ingredient employed, the time of administration, the rate of excretion, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific active ingredient employed, the age, sex, weight, disorder, general health and previous medical history of the treated patient, and similar factors well known in the medical field. A skilled person will be able to determine an appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known and can be adjusted by a skilled artisan based on the subject's condition, the type of condition being treated, and the amount of the disclosed compound or a pharmaceutically acceptable salt thereof being used, by following, for example, the dosages reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003). A physician with ordinary skill in the art can readily determine the effective amount of the pharmaceutical composition required and prescribe it. For example, a physician can start the dosage of the disclosed compound used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0203] In general, a suitable daily dose of a compound of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[0204] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable the delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.

[0205] The specific mode of administration and dosage regimen will be selected by the attending clinician based on the specific circumstances of the case (e.g., the subject, the disease, the disease state involved, the specific treatment, and whether the treatment is prophylactic). Treatment may involve daily or multi-day or less than daily (such as weekly or monthly, etc.) dosages over a period of several days to several months or even years.

[0206] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation of an active agent and / or the administration of an active agent to a subject and / or absorption by a subject, and that can be included in the compositions of the present disclosure without producing significant adverse toxicological effects on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such formulations can be sterilized and, if desired, mixed with adjuvants that do not adversely react with or interfere with the activity of the compounds provided herein, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances. Those of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0207] A "subject" or "patient" is a mammal in need of medical treatment, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In one aspect, the patient is a human. In one aspect, the patient is an adult.

[0208] The compounds of the present disclosure can be prepared according to the following general synthetic methods.

[0209] General synthetic methods

[0210]

[0211] Solution 1

[0212]

[0213] LG is a leaving group, usually Cl, Br, I or mesylate.

[0214] In Scheme 1, ring A is connected to R via Na of tetrazole.

[0215] Aryl nitrile compounds (ii) and (v) can be treated with an azide source (such as Bu3SnN3 or TMSN3) in the presence of Bu2SnO or NaN3 and NH4Cl in DMF or toluene at elevated temperature, optionally under microwave irradiation, to obtain tetrazoles (iii) (A) and (vi) (A), respectively.

[0216] R can be precipitated using a base such as DIPEA or K2CO3 in DMF. a LG alkylates tetrazoles (iii)(A) ​​and (vi)(A) ​​to obtain compounds (iv)(A) and (vii)(A), respectively.

[0217] Alternatively, tetrazoles (iii)(A) ​​and (vi)(A) ​​can be subjected to reaction with R a Mitsunobu reaction of OH to obtain compounds (iv)(A) and (vii)(A), respectively.

[0218] Alternatively, tetrazoles (iii)(A) ​​and (vi)(A) ​​can be subjected to reaction with R a Chan-Lam type coupling reaction of B(OH)2 to obtain compounds (iv)(A) and (vii)(A), respectively.

[0219] Nitroaryl groups (ii), (iii)(A) ​​and (iv)(A) can be reduced to the corresponding anilines under hydrogenation conditions (such as Pd / C or Pt on C under H2) or by reduction with Fe under acidic conditions in an alcoholic solvent to obtain compounds (v), (vi)(A) ​​and (vii)(A), respectively.

[0220] Option 2

[0221]

[0222] In Scheme 2, ring A is connected to R via N a tetrazole or triazole, and R a Is R b Substituted 4-6 membered heterocyclic ring containing at least one nitrogen atom.

[0223] Tetrazole (iii) (A) or (D) can be obtained by Alkylate or undergo The Mitsunobu reaction of oxazolidinone (IX) and oxazolidinone (IX) is carried out as previously described in Scheme 1 to obtain compound (viii) (A) or (D). Compound (viii) (A) or (D) can be deprotected under Boc deprotection conditions such as HCl or TFA to obtain amine (ix) (A) or (D).

[0224] where R b It is SO2R 4 、C(O)OR 5 、C 1-3 Alkyl, C 1-3 Alkoxy, CH2OR 3 or C 3-4 Cycloalkyl, can be used in the presence of base b LG treatment of amine (ix)(A) or (D) to obtain compound (x)(A) or (D). Compound (x)(A) or (D) can be reduced using the reduction method described previously in Scheme 1 to obtain amine (xi)(A) ​​or (D).

[0225] Option 3

[0226]

[0227] In Scheme 3, ring A is connected to R via N a tetrazole, and R a Is R b Substituted 4-6 membered heterocyclic ring containing at least one nitrogen atom.

[0228] Tetrazole (xiii) (A) can be obtained from nitrile (xii) and an azide source as previously described in Scheme 1. Tetrazole (xiii) (A) can be reacted with The reaction is carried out under Mitsunobu-type conditions to obtain compound (xiv)(A). Compound (xiv)(A) can be deprotected under Boc deprotection conditions such as HCl or TFA to obtain amine (xi)(A).

[0229] Option 4

[0230]

[0231] X is Cl, OH or O(C1-C4)alkyl.

[0232] In Scheme 4, ring A is connected to R via N a of tetrazole.

[0233] Wherein X is Cl, compound (xvi) can be obtained by reaction of acid chloride (xv) with aniline (v) in the presence of an organic base such as pyridine, TEA or DIPEA.

[0234] Where X is OH, an amide coupling agent such as EDCI, Acid (xv) is coupled with aniline (v) using hydroxybenzoyl chloride (HBr or HATU) or an activating agent such as 2,4,6-trichlorobenzoyl chloride or via in situ preparation of the acid chloride to obtain compound (xvi).

[0235] Wherein X is O(C1-C4)alkyl, ester (xv) can be coupled with aniline (v) using trimethylaluminum or LiHMDS to obtain compound (xvi).

[0236] Tetrazole (xvii) (A) can be obtained as previously described in Scheme 1 from nitrile (xvi) and an azide source.

[0237] Option 5

[0238]

[0239] X and LG are as described previously.

[0240] Hal is a halogen, preferably Br or Cl.

[0241] In Scheme 5, ring A is connected to R via N a of tetrazole.

[0242] Aniline (v) can be coupled with compound (xviii) using the conditions previously described in Scheme 4 to obtain compound (xix). Compound (xx)(A) can be obtained from compound (xix) and an azide source using the conditions previously described in Scheme 1. Compound (xx)(A) can be obtained from compound (xx) and R using the conditions previously described in Scheme 1. a LG obtains compound (xxi) (A).

[0243] Option 6

[0244]

[0245] In Scheme 6, ring A is connected to R via N a The tetrazole LG was as described previously.

[0246] The conditions described previously in Scheme 2 can be used under alkaline conditions. Tetrazoles (xvii)(A) ​​are alkylated to afford (xxii)(A).Compounds (xxii)(A) ​​can be deprotected under Boc deprotection conditions such as HCl or TFA to afford amines (xxiii)(A).

[0247] Option 7

[0248]

[0249] In Scheme 7, ring A is connected to R via N a X is as defined previously.

[0250] Aniline (xxiv) can be coupled to compound (xv) using the conditions previously described in Scheme 4 to provide compound (xxv). Compound (xxv) can be treated with trimethyl(2-(tributylstannyl)ethynyl)silane under palladium coupling conditions, followed by removal of the TMS protecting group, to provide compound (xxvi). Compound (xxvi) can be treated with a suitable azide source to provide triazole (xvii) (D).

[0251] Option 8

[0252]

[0253] In Scheme 8, Ring A is attached to R via a C atom. a .

[0254] Compound (xxvii) can be coupled with an aromatic bromide (xxviii) under palladium coupling conditions to obtain compound (iv) (B) or (C). Compound (iv) (B) or (C) can be reduced using the methods described previously in Scheme 1 to obtain aniline (vii) (B) or (C). Alternatively, compound (xxvii) can be coupled with a boronic acid (xxix) under Chan-Lam type coupling conditions to obtain compound (vii) (B) or (C). Aniline (vii) (B) or (C) can be coupled with compound (xviii) as described previously in Scheme 4 to obtain amide (xxi) (B) or (C).

[0255] Option 9

[0256]

[0257] In Scheme 9, Ring A is attached to R via a C atom. a .

[0258] Compound (xxx) can be coupled to bromide (xxviii) under palladium coupling conditions to obtain compound (viii) (B) or (C). Compound (viii) (B) or (C) can be reduced using the method described in the previous scheme 1 to obtain aniline (xxxi). Alternatively, aniline (xxxi) can be obtained by reacting compound (xxx) with boronic acid (xxix) under Chan-Lam type reaction conditions. Aniline (xxxi) can be coupled with compound (xv) using the conditions described in the previous scheme 4 to obtain amide (xxii) (B) or (C). Compound (xxii) (B) or (C) can be obtained by deprotecting compound (xxii) (B) or (C) using the conditions described in the previous scheme 6.

[0259] Plan 10

[0260]

[0261] Aniline (vii) can be coupled with compound (xviii) using the conditions previously described in Scheme 4 to afford amide (xxi).

[0262] Plan 11

[0263]

[0264] Aniline (vi) can be coupled with compound (xv) using the conditions previously described in Scheme 4 to afford amide (xvii).

[0265] [Scheme 12 intentionally omitted]

[0266] Plan 13

[0267]

[0268] LG is as defined previously.

[0269] In Scheme 13, Ring A is attached to R via the N atom. a .

[0270] R can be used under alkaline conditions a LG alkylates compound (xvii)(A) ​​or (D) to obtain amide (I)(A) or (D).

[0271] Plan 14

[0272]

[0273] In Scheme 14, Ring A is attached to R via the N atom. a .

[0274] Compound (xvii) (A) or (D) can be combined with R a B(OH)2 is coupled under Chan-Lam type coupling conditions to afford amides (I) (A) or (D).

[0275] Plan 15

[0276]

[0277] In Scheme 15, Ring A is attached to R via the N atom. a .

[0278] Available through R a The Mitsunobu-type reaction of OH yields compound (I) (A) or (D) from compound (xvii) (A) or (D).

[0279] Plan 16

[0280]

[0281] W is a suitable boronate ester, such as a pinacol ester.

[0282] R 1 is a C-linked heterocycle or an optionally substituted C1-C6 alkyl group.

[0283] The halide (xxi) can react with the borate ester R 1 BW is coupled under Suzuki reaction conditions to obtain amide (I).

[0284] Plan 17

[0285]

[0286] where R 1 Is a C1-C6 alkyl group, which can be 1 Photocatalytic iridium-nickel cross-coupling of OH affords compound (I) from halide (xxi).

[0287] Plan 18

[0288]

[0289] In Scheme 18, R 1 It is NR 2 R 2a OR 2b .

[0290] The halides of formula (xxi) and amines NHR can be prepared by palladium-catalyzed cross-coupling reactions in the presence of a suitable phosphine ligand and a suitable inorganic base in a solvent at elevated temperature using a suitable palladium catalyst. 2 R 2A OR 2b The compound of formula (I) is obtained.

[0291] Plan 19

[0292]

[0293] Anilines (vii) can be coupled with carboxylic acid derivatives (xv) using the coupling conditions previously described in Scheme 4 to afford amides (I).

[0294] Plan 20

[0295]

[0296] LG is a suitable leaving group as defined previously.

[0297] where R b It is SO2R 4 、C(O)OR 5 、C 1-3 Alkyl, C 1-3 Alkoxy, CH2OR 3 or C 3-4 Cycloalkyl groups can be formed by reacting with R as previously described in Scheme 2. b LG reaction obtains amide (I) from compound (xxiii).

[0298] Plan 21

[0299]

[0300] PG is a suitable protecting group for a N or O atom, such as THP for protecting a heteroaromatic N atom, Boc for protecting a primary or secondary N, or TBDMS for protecting an aliphatic alcohol.

[0301] Compound (xxi) can be combined with PG-R 2 R 2A NH or PG-R 2b OH is coupled under palladium coupling conditions to obtain compound (xxxii). Alternatively, compound (xxi) can be reacted with PG-R 1 BW is coupled under Suzuki-type reaction conditions to obtain compound (xxxii). Compound (xxxii) can be deprotected under typical conditions (such as TBAF to remove the TBDMS group, or TFA to remove the THP group) to obtain compound (I).

[0302] Plan 22

[0303]

[0304] Compound (xxi) can be treated with (BPin)2 under palladium coupling conditions to afford the boronate ester (xxxiii). 1 Compound (xxxiii) is treated with Br to obtain compound (I).

[0305] Plan 23

[0306] Compounds of formula (I) (wherein R b It is C(O)OR 5 ) is reduced to a compound of formula (I) (wherein Rb is CH2OH).

[0307]

[0308] Compounds containing one or more stereocenters can be separated into their individual stereoisomers by typical methods, such as chiral SFC or chiral HPLC techniques as indicated in the Examples below.

[0309] Compounds of formula (i) to formula (xxxiii) can be converted into alternative compounds of formula (i) to formula (xxxiii) by chemical transformation. Examples of these transformations include, but are not limited to:

[0310] Using Zn(CN)2 cyanoaryl bromide under palladium coupling conditions;

[0311] Aryl bromides are converted to arylalkyls by reaction with alkylboronic acids under Chan-Lam type coupling conditions;

[0312] Alkylation of aryl amines with alkyl halides to obtain secondary amines;

[0313] Alkylation of the heterocyclic N atom with an alkyl halide or epoxide to obtain an N-substituted heterocycle, and

[0314] Reductive amination of primary or secondary amines with aldehydes provides secondary or tertiary amines.

[0315] Compounds (ii), (iii), (x), (xii), (xv), (xviii), (xxiv), (xxvii), (xxviii), (xxix) and (xxx) are commercially available or can be prepared by the methods described in the intermediates and examples below.

[0316] Those skilled in the art will appreciate that it may be necessary to use an appropriate protecting group strategy to prepare compounds of formula (I), formula (II) or formula (III). Typical protecting groups may include carbamates, and in certain aspects include Boc or CBz groups for protecting primary or secondary aliphatic amines.

[0317] The present invention is illustrated by the following examples, which are not intended to be limiting in any way.

[0318] Example

[0319] abbreviation

[0320] Abbreviations and acronyms used herein include the following:

[0321] AcOH means acetic acid;

[0322] AlMe3 means trimethylaluminum;

[0323] Aq. means aqueous solution;

[0324] Boc means tert-butoxycarbonyl;

[0325] Brettphos means 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl;

[0326] BrettPhos Pd G3 means [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II);

[0327] BrettPhos Pd G4 means dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; methanesulfonic acid; N-methyl-2-phenylaniline; palladium

[0328] Bu3SnN3 means azido(tributyl)stannane;

[0329] Bu2SnO means dibutyl(oxy)tin;

[0330] d means double peak;

[0331] dd means the double peak of the double peak;

[0332] ddd means double peak of double peak;

[0333] DDT means a triplet of a doublet of a triplet;

[0334] dq means doublet of quartet;

[0335] dt means the doublet of the triplet;

[0336] DCE means 1,2-dichloroethane;

[0337] DCM means dichloromethane;

[0338] DIAD means diisopropyl azodicarboxylate;

[0339] DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine;

[0340] DMA means N,N-dimethylacetamide;

[0341] DMAP means N,N-dimethylpyridin-4-amine;

[0342] DMF means N,N-dimethylformamide;

[0343] DMSO means dimethyl sulfoxide;

[0344] DMSO-d6 means trideutero(trideuteromethylsulfinyl)methane;

[0345] EDCI means 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide;

[0346] EtOAc means ethyl acetate;

[0347] EtOH means ethanol;

[0348] FA means formic acid;

[0349] HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0350] HPLC means high performance liquid chromatography;

[0351] IPA means 2-propanol;

[0352] LG means leaving group;

[0353] LCMS means liquid chromatography mass spectrometry;

[0354] m means multiplet;

[0355] MeCN means acetonitrile;

[0356] MeI means methyl iodide;

[0357] MeOH means methanol;

[0358] MSm / z means mass spectrum peak;

[0359] NMR means nuclear magnetic resonance;

[0360] PE means petroleum ether;

[0361] Pd2(dba)3 means ginseno(dibenzylideneacetone)dipalladium(0);

[0362] Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

[0363] q means quartet;

[0364] rt means room temperature;

[0365] s means single peak;

[0366] sat. means saturation;

[0367] SFC means supercritical fluid chromatography;

[0368] t means triplet;

[0369] td means triplet of doublet;

[0370] tq means triplet of quartet;

[0371] tt means triplet of triplet;

[0372] It means 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide;

[0373] TBAF means tetrabutylammonium fluoride;

[0374] TBDMS means tert-butyldimethylsilane;

[0375] TEA means triethylamine;

[0376] TFA means trifluoroacetic acid;

[0377] THF means tetrahydrofuran;

[0378] THP means tetrahydropyran;

[0379] TLC means thin layer chromatography;

[0380] TMSN3 means trimethylsilyl azide;

[0381] Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0382] XPhos means dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;

[0383] XPhos Pd G3 means dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; mesylate; palladium; 2-phenylaniline.

[0384] HPLC conditions

[0385] Alkaline:

[0386] Method A: XBridge preparative OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min;

[0387] Method B: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.1% NH₃.H₂O), mobile phase B: ACN; flow rate: 60 mL / min;

[0388] Method B2: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.05% NH₃.H₂O), mobile phase B: ACN; flow rate: 60 mL / min;

[0389] Method C: XBridge preparative OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min;

[0390] Method D: XBridge OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min;

[0391] Method E: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min;

[0392] Method F: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 60 mL / min;

[0393] Method G: Aeris PEPTIDE 5 μm XB-C18 Axia, 21.2 mm × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min;

[0394] Method H: Sunfire preparative C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min;

[0395] Method I: Xselect CSH F-pheny OBD column, 19 x 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃ + 0.1% NH₃.H₂O), mobile phase B: ACN; flow rate: 25 mL / min;

[0396] Acidic:

[0397] Method J: Xselect CSH C18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min;

[0398] Method K: XBridge preparative OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min;

[0399] Method L: XBridge preparative OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min;

[0400] Method M: Sunfire preparative C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min;

[0401] Method N: Column: XSelect CSH Fluoro Pheny, 130*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min;

[0402] Method O: Column: XBridge Preparative Phenyl OBD column, 19*250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min;

[0403] Method P: CHIRALPAK IC, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL / min;

[0404] Method Q: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM; flow rate: 20 mL / min;

[0405] Method R: Lux 5um Cellulose-2 2.12*25cm, 5μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: MeOH:EtOH=1:1; flow rate: 20mL / min.

[0406] Preparation of intermediates

[0407] Intermediate 1

[0408] N-(2-Methyl-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0409]

[0410] Step 1: Synthesis of N-(5-cyano-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[0411] To a stirred solution of 3-amino-4-methylbenzonitrile (18.74 g, 141.8 mmol) in pyridine (300 mL) at 0 ° C., pyrazolo[1,5-a]pyridine-3-carbonyl chloride (25.6 g, 141.8 mmol) was added portionwise. The resulting mixture was stirred at rt for another 1 h and then concentrated under reduced pressure. The residue was poured into water, the precipitated solid was filtered, the filter cake was washed with water and dried to obtain the title compound (37 g, 94.5%) as a light brown solid. LCMS m / z = 277 [M + H] + .

[0412] Step 2: Synthesis of N-(2-methyl-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[0413] A solution of N-(5-cyano-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (37.0 g, 133.9 mmol) and Bu3SnN3 (88.9 g, 267.8 mmol) in DMF (370 mL) was stirred at 100 ° C for 16 h. The mixture was cooled to rt and poured into a saturated NaHCO3 solution. KF solution was added and the mixture was washed with PE / MTBE=1 / 1 (2 L×3) and the aqueous layer was adjusted to pH 3 with HCl. The mixture was filtered and the filter cake was washed with PE / MTBE=1 / 1 (500 mL) and dried to provide the title compound (25.0 g, 58.5%) as an off-white solid. LCMSm / z=320[M+H] + .

[0414] Intermediate 2

[0415] N-(2-Chloro-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0416]

[0417] Step 1: Synthesis of N-(2-chloro-5-cyanophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0418] Pyrazolo[1,5-a]pyridine-3-carbonyl chloride (0.6 g, 3.32 mmol) was added portionwise to a solution of 3-amino-4-chlorobenzonitrile (507 mg, 3.32 mmol) in pyridine (7 mL). The mixture was diluted with DCM (7 mL) and stirred at rt overnight. The mixture was concentrated in vacuo, the residue was triturated with water, and the resulting solid was filtered off to obtain the title compound (904 mg, 92%) as a brown solid. LCMS m / z=297 [M+H] + .

[0419] Step 2: Synthesis of N-(2-chloro-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0420] A mixture of N-(2-chloro-5-cyanophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 0.34 mmol), sodium azide (66 mg, 1.01 mmol) and NHCl (54 mg, 1.01 mmol) in DMF (1 mL) was heated at 150 ° C. for 1 h under microwave irradiation. The reactants were added dropwise to stirred water (25 mL), the pH was adjusted to 3 using 1M HCl and the resulting mixture was stirred for 45 min. The mixture was filtered, the resulting solid was washed with water and dried to provide the title compound (92 mg, 80%). LCMS m / z=340 [M+H] + .

[0421] Intermediate 3

[0422] N-(2,4-Dimethyl-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0423]

[0424] Following a similar 2-step procedure as described in Intermediate 2, the title compound (545 mg) was obtained as a white solid from 5-amino-2,4-dimethylbenzonitrile and pyrazolo[1,5-a]pyridine-3-carbonyl chloride. LCMS m / z = 334 [M+H] + .

[0425] Intermediate 4

[0426] 5-Bromo-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0427]

[0428] Step 1: Synthesis of 2-(3,3-difluorocyclobutyl)-5-(4-methyl-3-nitrophenyl)-2H-tetrazolyl

[0429] To a stirred solution of 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612, 2 g, 9.75 mmol) and PPh 3 (5.11 g, 19.5 mmol) in THF (20 mL) was added DIAD (3.94 g, 19.5 mmol) dropwise at 0° C., and the reaction mixture was stirred at 50° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (15 / 1) to provide the title compound (1.6 g, 55.6%) as a white solid. LCMS m / z=296 [M+H] + .

[0430] Step 2: Synthesis of 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline

[0431] To a stirred solution of 2-(3,3-difluorocyclobutyl)-5-(4-methyl-3-nitrophenyl)-1,2,3,4-tetrazole (20 g, 67.7 mmol) and NHCl (36.23 g, 677 mmol) in EtOH (180 mL) and H2O (20 mL) was added Fe powder (37.9 g, 677 mmol) at rt, and the solution was stirred at 80 ° C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOH (3×30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2 / 1) to provide the title compound (12.3 g, 67.0%) as a white solid. LCMSm / z=266[M+H] + .

[0432] Step 3: Synthesis of 5-bromo-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0433] A suspension of 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (500mg, 2.07mmol) and DMF (0.1mL) in DCM (20mL) is cooled to 0 DEG C and slowly treated with oxalyl chloride (1.3g, 10.35mmol). The mixture is taken out from the cold bath and stirred at rt for 2.5h. The mixture is filtered through filter paper and concentrated in vacuo to provide a crude acyl chloride as a yellow solid. This solid is added to a mixture of 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline (549mg, 2.07mmol) in DCM (8mL) and pyridine (8mL), and the reaction mixture is stirred at rt for 3h. The resulting solution is concentrated in vacuo and the product is purified by column chromatography (DCM:MeOH 90:10) to obtain the title compound (400mg, 39.6%) as a yellow solid. LCMS m / z=488,490[M+H] + .

[0434] Intermediate 5

[0435] 5-Bromo-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0436]

[0437] Step 1: Synthesis of 2-((2,2-difluorocyclopropyl)methyl)-5-(4-methyl-3-nitrophenyl)-2H-tetrazolyl

[0438] To a stirred solution of 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (1 g, 4.87 mmol) in DMF (10 mL) was added DIPEA (1.88 g, 14.6 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (998 mg, 5.84 mmol) at rt. The mixture was stirred at 120 ° C for 3 h and then cooled to rt. Water (10 mL) was added and the resulting solution was extracted with EtOAc (3×40 mL) and the combined organic phases were washed with brine (3×10 mL), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column using PE: EtOAc = 3: 1 to obtain the title compound (1 g, 70%) as a colorless oil. LCMS: m / z = 296 [M + H] + .

[0439] Step 2: Synthesis of 5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylaniline

[0440] To a stirred solution of 2-((2,2-difluorocyclopropyl)methyl)-5-(4-methyl-3-nitrophenyl)-2H-tetrazole (990 mg, 3.35 mmol) in EtOAc (10 mL) was added Pd / C (35.5 mg, 0.34 mmol) at rt. The flask was evacuated and filled with N2 (3×) and then H2, and the reaction was stirred at rt under an atmosphere of H2 (balloon) for 4 h. The mixture was filtered, the filter cake was washed with EtOAc, and the filtrate was concentrated in vacuo to afford the title compound (850 mg, 96%) as a white solid. LCMS: m / z=266 [M+H] + .

[0441] Step 3: Synthesis of 5-bromo-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0442] To a stirred solution of 5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylaniline (150 mg, 0.565 mmol) and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (272 mg, 1.13 mmol) in THF (3 mL) was added (537 mg, 1.69 mmol) and pyridine (89.2 mg, 1.13 mmol). The mixture was stirred at 60 ° C for 12 h and then cooled to rt. Water was added and the resulting solution was extracted with DCM (3×20 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by silica gel column eluting with PE: EtOAc = 1: 1 to obtain the title compound (210 mg; 76%) as an off-white solid. LCMS m / z = 488, 490 [M + H] + .

[0443] Intermediate 6

[0444] 5-Bromo-N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0445]

[0446] Following a similar 3-step procedure to that described for Intermediate 5, the title compound (220 mg) was obtained as a white solid from 5-(4-methyl-3-nitrophenyl)-2H-1,2,3,4-tetrazolyl, (1r,3r)-1-bromo-3-(trifluoromethyl)cyclobutane and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 522 [M+H]+ .

[0447] Intermediate 7

[0448] 5-Bromo-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0449]

[0450] Step 1: Synthesis of 4-fluoro-2-methyl-5-(2H-tetrazol-5-yl)aniline

[0451] To a solution of 5-amino-2-fluoro-4-methylbenzonitrile (500 mg, 3.32 mmol) in DMF (5 mL) was added Bu 3 SnN 3 (3.30 g, 9.95 mmol), and the reaction mixture was stirred at 100 ° C for 12 h. The mixture was diluted with EtOAc (50 mL) and water (50 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (30 mL). The organic layer was dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC using PE: EtOAc = 3: 1 to obtain the title compound (330 mg, 51%) as a white solid. LCMSm / z = 194 [M + H] + .

[0452] Step 2: Synthesis of 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0453] To a solution of 4-fluoro-2-methyl-5-(2H-tetrazol-5-yl)aniline (200 mg, 1.03 mmol) in THF (5 mL) was added 3,3-difluorocyclobutane-1-ol (166 mg, 1.54 mmol), PPh3 (540 mg, 2.06 mmol) and DIAD (416 mg, 2.06 mmol) at 0 ° C. The mixture was stirred at rt for 3 h and then diluted with EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL) and the combined organic phase was washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH=15:1) to obtain the title compound (200 mg, 68%) as a white solid. LCMSm / z=282[M+H] + .

[0454] Step 3: Synthesis of 5-bromo-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0455] To a solution of 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline (200 mg, 0.71 mmol) and pyridine (111 mg, 1.41 mmol) in THF (5 mL) were added 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (203 mg, 0.85 mmol) and (670 mg, 2.11 mmol), and the reaction mixture was stirred at 60 ° C for 3 h. The mixture was diluted with EtOAc (30 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by preparative TLC (DCM: MeOH = 15: 1) to obtain the title compound (200 mg, 56%) as a white solid. LCMSm / z = 506 [M + H] + .

[0456] Intermediate 8

[0457] 5-Bromo-N-(2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0458]

[0459] Step 1: Synthesis of 2-chloro-4-fluoro-5-(2H-tetrazolyl-5-yl)aniline

[0460] To a solution of 5-amino-4-chloro-2-fluorobenzonitrile (880 mg, 5.15 mmol) in DMF (8 mL) was added Bu 3 SnN 3 (5.12 g, 15.4 mmol), and the reaction mixture was heated to 100 ° C and maintained for 24 h. Saturated NaHCO 3 solution was added and the mixture was washed with MTBE: PE = 1: 1 (3 × 30 mL). The aqueous phase was adjusted to pH 4-5 with 1M HCl and the resulting solution was extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated under vacuum. The crude product was purified by silica gel column using DCM: MeOH = 10: 1 to obtain the title compound (773 mg, 90%) as an off-white solid. LCMS: m / z = 214 [M + H] + .

[0461] Step 2: Synthesis of 2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoroaniline

[0462] Following the procedure described in step 2 of intermediate 7, the title compound was obtained as a white solid (250 mg, 88% yield) from 2-chloro-4-fluoro-5-(2H-tetrazol-5-yl)aniline and 3,3,-difluorocyclobutan-3-ol. LCMS m / z = 302 [M+H] + .

[0463] Step 3: Synthesis of 5-bromo-N-(2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0464] Following the procedure described in step 3 of Intermediate 5, the title compound (350 mg, 84%) was obtained as a white solid from 2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoroaniline and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 526 [M+H] + .

[0465] Intermediate 9

[0466] 5-Bromo-N-(4-fluoro-2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0467]

[0468] Step 1: Synthesis of 4-fluoro-2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)aniline

[0469] To a solution of step 1 (300 mg, 1.55 mmol) of intermediate 7 and DIPEA (399 mg, 3.10 mmol) in DMF (5 mL) was added (1r, 3r)-1-bromo-3-(trifluoromethyl)cyclobutane (470 mg, 2.32 mmol) at rt. The mixture was stirred at 100 ° C for 2 h and cooled to rt. Water (30 mL) and EtOAc (50 mL) were added, the layers were separated, and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated. The crude product was purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (300 mg; 61%) as a yellow solid. LCMS: m / z=316 [M+H] + .

[0470] Step 2: Synthesis of N-(4-fluoro-2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0471] Following the procedure described in step 3 of Intermediate 7, the title compound was obtained as a yellow solid (60 mg, 70% yield) from 4-fluoro-2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)aniline and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 538 [M+H] + .

[0472] Intermediate 10

[0473] Methyl 3-(5-(3-amino-4-chlorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0474]

[0475] Steps 1 and 2: Synthesis of methyl 3-(5-(3-((tert-butoxycarbonyl)amino)-4-chlorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0476] Following the same 2-step procedure described in steps 1-2 of Intermediate 7, the title compound (2.8 g) was obtained as a white solid from tert-butyl N-(2-chloro-5-cyanophenyl)carbamate and methyl 3-hydroxyazetidine-1-carboxylate. LCMS: m / z = 409 [M+H] + .

[0477] Step 3: Synthesis of methyl 3-(5-(3-amino-4-chlorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0478] TFA (10 mL) was added dropwise to methyl 3-(5-(3-((tert-butoxycarbonyl)amino)-4-chlorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (2.8 g, 6.84 mmol) in DCM (30 mL), and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo, the residue was diluted with DCM, and the pH was adjusted to 8-9 with (saturated) NaHCO (aq). The organic layer was dried over NaSO and evaporated under reduced pressure to afford the title compound (1.9 g, 90%) as a white solid. LCMS: m / z=309 [M+H] + .

[0479] Intermediate 11

[0480] 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[0481]

[0482] Step 1: Synthesis of tert-butyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0483] DIAD (38.24 g, 189.1 mmol) was added dropwise to 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612; 2011, 19.4 g, 94.6 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (24.57 g, 141.8 mmol) and PPh (49.60 g, 189.1 mmol) in THF (200 mL) at 0° C. under N2, and the resulting mixture was stirred at 50° C. for another 16 h. The reaction mixture was extracted with EtOAc (3×500 mL), the combined organic layers were washed with brine (2×600 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The solid was washed with anhydrous ether, and the precipitated solid was filtered off to obtain the title compound as a brown solid (32.9 g, 96.6%). LCMS: m / z=361 [M+H] + .

[0484] Step 2: Synthesis of 2-(azetidin-3-yl)-5-(4-methyl-3-nitrophenyl)-2H-tetrazolyl trifluoroacetate

[0485] A solution of tert-butyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (32.9 g, 91.29 mmol) and TFA (161.6 mL) in DCM (300 mL) was stirred at rt for 1 h. The resulting mixture was concentrated under reduced pressure and the residue was washed with DCM (3×50 mL). The solid was washed with anhydrous ether, and the precipitated solid was filtered and dried to obtain the title compound (22.5 g, 94.70%) as a brown solid. LCMS m / z=261 [M+H] + .

[0486] Step 3: Synthesis of methyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0487] To a solution of 2-(azetidin-3-yl)-5-(4-methyl-3-nitrophenyl)-1,2,3,4-tetrazole (8.6 g, 33.0 mmol) trifluoroacetate and TEA (10.03 g, 99.1 mmol) in DCM (90 mL) was added methyl chloroformate (6.24 g, 66.1 mmol) dropwise at 0 ° C., and the reaction mixture was stirred at rt for 45 min. The resulting mixture was diluted with water, the layers were separated, and the aqueous layer was extracted with DCM (3×150 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound (8.1 g, 77.0%) as a light brown solid. LCMSm / z=319[M+H] + .

[0488] Step 4: Synthesis of methyl 3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0489] At rt, Pd / C (0.76 g, 7.163 mmol) was added to methyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (3.8 g, 11.9 mmol) in EtOAc (50 mL). The flask was evacuated and filled with N2 three times, then filled with H2. The mixture was stirred under H2 (balloon) atmosphere for 2 h at rt. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (3.24 g, 94.3%) as a white solid. LCMSm / z=289[M+H] + .

[0490] Step 5: Synthesis of methyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0491] 3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester (600 mg, 2.1 mmol), 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (549 mg, 2.3 mmol), A mixture of 4-[4-[4-[4-(4-oxo-3-nitropropene]-1-yl]propanediol (5 mL, 50% in EtOAc), pyridine (3 mL) and THF (15 mL) was stirred at 60° C. for 2 h. The mixture was concentrated to dryness and the residue was purified by silica gel column to provide the title compound (700 mg, 66%) as an off-white solid. LCMS m / z=511[M+H] + .

[0492] Intermediate 12

[0493] 5-Bromo-N-(2-methyl-5-(2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0494]

[0495] Step 1: Synthesis of 5-(4-methyl-3-nitrophenyl)-2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazole

[0496] To a stirred solution of 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612, 440 mg, 2.14 mmol) in DMF (0.50 mL) was added portionwise DIPEA (553 mg, 4.28 mmol) and (1r, 3r)-1-bromo-3-(trifluoromethyl)cyclobutane (434 mg, 2.14 mmol) at rt, and the solution was stirred at 120 ° C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE: EtOAc = 3: 1) to provide the title compound (550 mg, 78.5%) as a yellow solid. LCMS: m / z = 328 [M + H] + .

[0497] Step 2: Synthesis of 2-methyl-5-(2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)aniline

[0498] Following the procedure described in step 2 of Intermediate 5, the title compound was obtained as a yellow solid from 5-(4-methyl-3-nitrophenyl)-2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazole (160 mg, 88.3%). LCMS: m / z = 298 [M+H] + .

[0499] Step 3: Synthesis of 5-bromo-N-(2-methyl-5-(2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0500] To a solution of 2-methyl-5-(2-(3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)aniline (200 mg, 0.67 mmol) and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (194 mg, 0.81 mmol) in DMF (4 mL) was added HATU (380 mg, 1.0 mmol) and DIPEA (173 mg, 1.34 mmol) dropwise at rt, and the solution was stirred at 80° C. for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (PE:EtOAc=2:1) ​​to provide the title compound (160 mg, 45.9%) as a yellow solid. LCMS: m / z=522 [M+H] + .

[0501] Intermediate 13

[0502] 5-Bromo-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0503]

[0504] Step 1: Synthesis of 2-methyl-5-(4-methyl-3-nitrophenyl)-2H-1,2,3,4-tetrazolyl:

[0505] To a solution of 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612, 1 g, 4.87 mmol) and K CO (1.34 g, 9.74 mmol) in DMF / dioxane (10 / 10 mL) was added MeI (823 mg, 5.84 mmol) dropwise at 0 ° C. under N2, and the reaction mixture was stirred at rt for 2 h. The mixture was quenched with ice water and extracted with DCM. The organic layer was washed with brine, concentrated in vacuo, and the residue was purified by silica gel column eluting with PE: EtOAc = 1: 1 to obtain the title compound (0.8 g, 75%) as a white solid. LCMS m / z = 220 [M + H] + .

[0506] Step 2: Synthesis of 2-methyl-5-(2-methyl-2H-1,2,3,4-tetrazolyl-5-yl)aniline:

[0507] To a solution of 2-methyl-5-(4-methyl-3-nitrophenyl)-2H-tetrazole (0.8 g, 3.64 mmol) in MeOH (10 mL) was added Pd / C (771 mg, 7.27 mmol, 10%). The flask was evacuated and filled with N2, and then filled with H2. The mixture was stirred at rt under an atmosphere of H2 (balloon) for 2 h. The reaction mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated under vacuum to obtain the title compound (0.6 g; 87%) as a white solid. LCMSm / z=190[M+H] + .

[0508] Step 3: Synthesis of 5-bromo-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[0509] To a stirred solution of 2-methyl-5-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)aniline (0.6 g, 3.17 mmol) and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (915 mg, 3.80 mmol) in THF (10 mL) was added pyridine (501 mg, 6.34 mmol) and (190 mg, 4.75 mmol). The reaction was stirred at 60 ° C for 2 h and quenched with water. The mixture was extracted with DCM (100 mL×2), and the combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The product was purified by preparative TLC using PE: EtOAc = 2: 1 to obtain the title compound (0.7 g, 53%) as a white solid. LCMS m / z = 412 [M + H] + .

[0510] Intermediate 14

[0511] Ethyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0512]

[0513] Step 1: Synthesis of ethyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0514] Ethyl chloroformate (375 mg, 3.46 mmol) was added dropwise to a solution of step 2 (750 mg, 2.88 mmol) of intermediate 11 and pyridine (684 mg, 8.65 mL) in DCM (10 mL) in an ice bath, and the reaction mixture was stirred at rt for 30 min. The mixture was concentrated in vacuo and the residue was partitioned between water and DCM. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to provide the title compound (806 mg, 84%) as a brown solid. LCMS m / z=333 [M+H] + .

[0515] Step 2: Synthesis of ethyl 3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0516] A mixture of ethyl 3-(5-(4-methyl-3-nitrophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (806 mg, 2.53 mmol) and 80 mg of 1% Pt / 2% V on carbon in MeOH (25 mL) was hydrogenated under balloon pressure for 2 h. The mixture was filtered and evaporated to give the title compound as an off-white foam (700 mg, 95%).

[0517] Step 3: Synthesis of ethyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0518] 5-Bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (600 mg, 2.31 mmol) was added portionwise to a solution of ethyl 3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (699 mg, 2.31 mmol) and pyridine (183 mg, 2.31 mmol) in DCM (12 mL) in an ice bath, and the reaction was then stirred at rt for 30 min. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to obtain the crude product. This crude product was purified by ISCO chromatography (0 to 8% MeOH / DCM) to obtain the title compound (1.14 g, 94%) as an off-white solid. LCMSm / z=526[M+H] + .

[0519] Intermediate 15

[0520] N-(5-(2-(azetidin-3-yl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0521]

[0522] Step 1: Synthesis of tert-butyl 3-(5-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0523] At rt under N2, to a stirred solution of intermediate 1 (2.5 g, 7.82 mmol) and DIPEA (2.01 g, 15.6 mmol) in DMF (10 mL) was added tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (2.94 g, 11.7 mmol). The mixture was stirred at 120 ° C for 2 h and then cooled to rt. Water (10 mL) was added and the resulting solution was extracted with DCM (3×30 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column using DCM:MeOH=10:1 to obtain the title compound (3.4 g; 92%) as a white solid. LCMS: m / z=475[M+H] + .

[0524] Step 2: Synthesis of N-(5-(2-(azetidin-3-yl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0525] To a stirred solution of tert-butyl 3-(5-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (3.2 g, 6.74 mmol) in DCM (20 mL) was added TFA (5 mL). The mixture was stirred at rt for 2 h and concentrated. The pH of the mixture was adjusted to 7 with saturated NaHCO solution. The mixture was filtered and the filter cake was washed with water (10 mL) and then dried in vacuo to obtain the title compound (2.1 g; 83%) as a white solid. LCMS m / z=475[M+H] + .

[0526] Intermediate 16

[0527] N-(5-(4-(azetidin-3-yl)-2H-1,2,3-triazol-2-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0528]

[0529] Step 1: Synthesis of tert-butyl 3-(2-(3-amino-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0530] To a solution of tert-butyl 3-(2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (190 mg, 0.85 mmol) and (3-amino-4-chlorophenyl)boronic acid (289 mg, 1.69 mmol) in DCE (5 mL) was added Cu(OAc) (153 mg, 0.85 mmol), NaCO (179 mg, 1.69 mmol) and 2,2'-bipyridine (132 mg, 0.85 mmol) at rt, and the reaction mixture was heated at 60 ° C under O for 3 h. The mixture was filtered and the filter cake was washed with DCM (10 mL). Water was added to the filtrate and the resulting solution was extracted with DCM (3×20 mL). The organic layer was dried over NaSO and concentrated under vacuum. The crude product was purified by silica gel column using PE:EtOAc=1:1 to obtain the title compound (248 mg, 84%) as a pink oil. LCMS: m / z=348 [MH].

[0531] Step 2: Synthesis of tert-butyl 3-(2-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0532] Following a similar procedure to that described in step 3 of Intermediate 14, the title compound was obtained as a yellow oil (324 mg, 98%) from tert-butyl 3-(2-(3-amino-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate and pyrazolo[1,5-a]pyridine-3-carbonyl chloride. LCMS: m / z = 492 [M-1].

[0533] Step 3: Synthesis of N-(5-(4-(azetidin-3-yl)-2H-1,2,3-triazol-2-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0534] The title compound was obtained as an off-white solid (320 mg, crude) from tert-butyl 3-(2-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate following the procedure described in step 3 of Intermediate 10. LCMS: m / z = 394 [M+H] + .

[0535] Intermediate 17

[0536] N-(5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0537]

[0538] Step 1: Synthesis of tert-butyl 3-(2-(3-amino-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0539] The title compound was obtained as a yellow oil (1 g, 22%) from tert-butyl 3-(2H-1,2,3,4-tetrazol-5-yl)azetidine-1-carboxylate and (3-amino-4-methylphenyl)boronic acid following the procedure described in step 1 of intermediate 16. LCMS m / z = 331 [M+1-56].

[0540] Step 2: Synthesis of tert-butyl 3-(2-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0541] Following the procedure described in step 3 of Intermediate 7, the title compound was obtained as a yellow solid (280 mg, 65%) from tert-butyl 3-(2-(3-amino-4-methylphenyl)-2H-1,2,3,4-tetrazol-5-yl)azetidine-1-carboxylate and pyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS m / z = 419 [M+H] + .

[0542] Step 3: N-(5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0543] Following the procedure described in step 3 of Intermediate 10, the title compound was obtained as a white solid from tert-butyl 3-(2-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate (70 mg, 89%). LCMS m / z = 375 [M+H] + .

[0544] Intermediate 18

[0545] 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylic acid methyl ester

[0546]

[0547] Step 1: Synthesis of tert-butyl 3-(2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0548] A mixture of tert-butyl 3-ethynylazetidine-1-carboxylate (2.5 g, 13.8 mmol), TMSN3 (2.38 g, 20.7 mmol) and CuI (131 mg, 0.69 mmol) in DMF (20 mL) and MeOH (5 mL) was heated at 100 ° C overnight. The cooled reaction mixture was poured into water (125 mL), EtOAc (75 mL) was added and the mixture was stirred vigorously. The biphasic mixture was filtered and then washed with EtOAc.The layers were separated and the organic layer was washed with water, brine and dried over Na2SO4, filtered and evaporated to give the title compound as a light yellow / green semisolid (2.22 g, 71.7%).

[0549] Step 2: Synthesis of tert-butyl 3-(2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0550] A large pressure vessel was purged with N2, and tert-butyl 3-(2H-1,2,3-triazole-4-yl)azetidine-1-carboxylate (2.20 g, 9.81 mmol), 4-bromo-1-methyl-2-nitrobenzene (2.12 g, 9.81 mmol), K3PO4 (4.17 g, 19.6 mmol) and toluene (15 mL) were added. A septum-capped vial was charged with Pd2(dba)3 (79 mg, 0.1 mmol) and Me4-tert-butylxphos (94 mg, 0.2 mmol), purged with N2, toluene (5 mL) was added and the mixture was stirred at 120°C for 5 min. The cooled mixture was transferred to a pressure vessel under N2 by a syringe and the reaction mixture was stirred at 120°C overnight. The mixture was diluted with EtOAc and filtered through Filtered and evaporated.The crude product was purified by silica gel ISCO chromatography (0 to 60% EtOAc / hexanes) to give the title compound as a yellow foam (2.79 g).

[0551] Step 3: Synthesis of 4-(azetidin-3-yl)-2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazole

[0552] A solution of tert-butyl 3-(2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (306 mg, 0.85 mmol) in DCM (4 mL) and TFA (0.66 mL) was stirred at rt overnight. The solution was evaporated, and the residue was partitioned between 5% MeOH / DCM and NaHCO (aq), and the organic layer was dried over NaSO, filtered, and evaporated to afford the title compound as an off-white foam. 771 mg, 91% yield.

[0553] Step 4: Synthesis of methyl 3-(2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0554] Methyl chloroformate (0.09 mL, 1.16 mmol) was added to a solution of 4-(azetidin-3-yl)-2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazole (200 mg, 0.77 mmol) in DCM (3 mL) and pyridine (0.31 mL), and the reaction mixture was stirred at rt for 45 min. The reactant was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to obtain a crude product. This crude product was purified by silica gel ISCO chromatography (0 to 75% EtOAc / hexane) to obtain the title compound (233 mg) as a light yellow viscous oil. LCMSm / z=318[M+H] + .

[0555] Step 5: Synthesis of methyl 3-(2-(3-amino-4-methylphenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0556] The title compound was obtained as a white semisolid from methyl 3-(2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate following the procedure described in step 2 of intermediate 14. LCMS m / z = 288 [M+H] + .

[0557] Step 6: Synthesis of methyl 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0558] Following the procedure described in step 3 of Intermediate 14, the title compound (415 mg, 85%) was obtained as a white foam from methyl 3-(2-(3-amino-4-methylphenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate and 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride. LCMS m / z = 512 [M+H] + .

[0559] Intermediate 19:

[0560] 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylic acid methyl ester

[0561]

[0562] Step 1: Synthesis of 5-(4-(azetidin-3-yl)-2H-1,2,3-triazol-2-yl)-2-chloroaniline trifluoroacetate

[0563] To a stirred solution of step 1 of intermediate 16 (300 mg, 0.86 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0°C. The reaction was stirred at 0°C for 2 h and then evaporated under reduced pressure to afford the title compound (185 mg, 86.4%) as a light yellow solid. LCMS: m / z = 249 [M+H] + .

[0564] Step 2: Synthesis of methyl 3-(2-(3-amino-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0565] Dimethyl dicarbonate (150.4 mg, 1.12 mmol) was added dropwise to 5-(4-(azetidin-3-yl)-2H-1,2,3-triazol-2-yl)-2-chloroaniline trifluoroacetate (280 mg, 1.12 mmol) and TEA (567.4 mg, 5.61 mmol) in DCM (3 mL), and the reaction was stirred at 0 ° C for 2 h. The resulting mixture was extracted with EtOAc (20 mL), and the organic layer was washed with H2O (3×10 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (DCM:MeOH=20:1) to provide the title compound (215 mg, 62.3%) as a light yellow solid. LCMS: m / z=308[M+H] + .

[0566] Step 3: Methyl 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate

[0567] To a mixture of methyl 3-(2-(3-amino-4-chlorophenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylate (140 mg, 0.46 mmol) and methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (139.3 mg, 0.55 mmol) in toluene (2 mL) was added dropwise AlMe (65.6 mg, 0.91 mmol) at 0 ° C., and the reaction was stirred at 100 ° C. under N2 for 2 h. The reaction mixture was extracted with EtOAc (25 mL), and the organic layer was washed with H2O (3×10 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=20:1) to provide the title compound (150 mg, 62.1%) as a light yellow solid. LCMS m / z=532[M+H] + .

[0568] Intermediate 20

[0569] 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylic acid methyl ester

[0570]

[0571] Step 1: Synthesis of 5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-methylaniline

[0572] To a solution of step 1 (1.0 g, 3.02 mmol) of intermediate 17 in DCM (8 mL) was added TFA (4 mL) at rt. The reactant was stirred at rt for 2 h and concentrated. The residue was dissolved in DCM (10 mL), washed with saturated NaHCO solution and concentrated. The crude product was purified by preparative TLC using DCM: MeOH = 10: 1 to obtain the title compound (0.6 g; 86%) as a yellow oil. LCMS: m / z = 231 [M + H] + .

[0573] Step 2: Synthesis of methyl 3-(2-(3-amino-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0574] To a solution of 5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-methylaniline (0.4 g, 1.73 mmol) and TEA (349 mg, 3.46 mmol) in DCM (5 mL) was added dimethyl dicarbonate (231 mg, 1.73 mmol) at 0 ° C. under N2, and the reaction mixture was stirred at rt for 1 h. The mixture was quenched with ice water and extracted with DCM (3×20 mL). The organic layer was concentrated and purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (0.4 g, 80%) as a white solid. LCMS: m / z=289[M+H] + .

[0575] Step 3: Synthesis of methyl 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0576] Following the procedure described in step 3 of Intermediate 7, the title compound (190 mg, 53%) was obtained as a yellow solid from methyl 3-(2-(3-amino-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 511 [M+H] + .

[0577] Intermediate 21

[0578] N-(5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0579]

[0580] Step 1: Synthesis of tert-butyl 3-(2-(3-amino-4-chlorophenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0581] The title compound was obtained as a yellow solid (270 mg, 17%) from tert-butyl 3-(2H-1,2,3,4-tetrazol-5-yl)azetidine-1-carboxylate and (3-amino-4-chlorophenyl)boronic acid following the procedure described in step 1 of intermediate 16. LCMS: m / z = 295 [M+1-56].

[0582] Step 2: Synthesis of tert-butyl 3-(2-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0583] To a solution of tert-butyl 3-(2-(3-amino-4-chlorophenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate (400 mg, 1.14 mmol) in pyridine (2 mL) was added pyrazolo[1,5-a]pyridine-3-carbonyl chloride (308 mg, 1.71 mmol) at 0 ° C. under N2. The reaction was stirred at rt for 1 h and concentrated under vacuum. The residue was purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (300 mg, 53%) as a white solid. LCMS: m / z=439 [M+1-56].

[0584] Step 3: Synthesis of N-(5-(5-(azetidin-3-yl)-2H-tetrazol-2-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0585] To a solution of tert-butyl 3-(2-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate (20 mg, 0.04 mmol) in DCM (1.5 mL) was added TFA (0.5 mL), and the reaction was stirred at rt for 2 h and concentrated under vacuum. The residue was dissolved in DCM (20 mL), washed with saturated NaHCO solution (3×10 mL) and concentrated. The crude product was purified by preparative HPLC method C, 17% to 42% gradient to obtain the title compound (9.7 mg, 61%) as a white solid. LCMS: m / z=395[M+H] + .

[0586] Intermediate 22

[0587] 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-chlorophenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylic acid methyl ester

[0588]

[0589] Steps 1 and 2: Synthesis of methyl 3-(2-(3-amino-4-chlorophenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0590] The title compound (90 mg) was obtained as a yellow solid from step 2 of intermediate 21 following the same 2-step procedure as described in steps 1 and 2 of intermediate 20. LCMS m / z = 309 [M+H] + .

[0591] Step 3: Synthesis of methyl 3-(2-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-chlorophenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylate

[0592] Following a similar procedure to that described in step 3 of Intermediate 14, the title compound (100 mg, 54%) was obtained as a white solid from 1-(3-(2-(3-amino-4-chlorophenyl)-2H-tetrazol-5-yl)azetidin-1-yl)ethan-1-one and 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride. LCMS: m / z = 531 [M+H] + .

[0593] Intermediate 23

[0594] 5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0595]

[0596] Step 1: Synthesis of ethyl 5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[0597] A mixture of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1 g, 3.71 mmol), 2-methoxyethan-1-amine (833 mg, 11.1 mmol), Pd2(dba)3 (68 mg, 74 μmol), XantPhos (43 mg, 74 μmol) and Cs2CO3 (2.41 g, 7.42 mmol) in dioxane (30 mL) was stirred at 100°C for 2 h. The resulting mixture was concentrated to dryness and purified on preparative TLC (PE:EtOAc=1:1) to provide the title compound (850 mg, 87%) as a light brown solid. LCMS: m / z=264 [M+H] + .

[0598] Step 2: Synthesis of 5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0599] A mixture of ethyl 5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate (1.1 g, 4.17 mmol) and NaOH (333 mg, 8.34 mmol) in EtOH (15 mL) and H2O (5 mL) was stirred at 70°C for 3 h. The resulting mixture was diluted with H2O (50 mL) and acidified to pH = 3. The resulting mixture was extracted with EtOAc (50 mL x 2), and the combined organic layers were dried over Na2SO4 and concentrated to provide the title compound (600 mg, 61%) as a light brown solid. LCMS m / z = 236 [M+H] + .

[0600] Intermediate 24

[0601] 6-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0602]

[0603] Following the 2-step procedure described in Intermediate 23, the title compound (600 mg) was obtained as a light brown solid from ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate and 2-methoxyethan-1-amine. LCMS: m / z = 236 [M+H] + .

[0604] Intermediate 25

[0605] 5-Morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

[0606]

[0607] Step 1: Synthesis of ethyl 5-morpholinopyrazolo[1,5-a]pyridine-3-carboxylate

[0608] A mixture of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (3 g, 11.1 mmol), morpholine (2.90 g, 33.3 mmol), Cs2CO3 (7.23 g, 22.2 mmol), Pd2(dba)3 (508 mg, 0.55 mmol) and BINAP (691 mg, 1.11 mmol) in toluene (50 mL) was heated at 100°C for 4 h. The cooled mixture was concentrated under vacuum and the residue was purified by silica gel column using DCM:MeOH=10:1 to obtain the title compound (3 g, 98.3%) as a yellow solid, LCMS: m / z=276 [M+H] + .

[0609] Step 2: Synthesis of 5-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

[0610] KOH (2.42 g, 43.2 mmol) was added to ethyl 5-morpholinopyrazolo[1,5-a]pyridine-3-carboxylate (3 g, 10.8 mmol) in EtOH (24 mL) and H2O (6 mL), and the reaction mixture was stirred at 80 ° C for 3 h. The mixture was concentrated and then diluted with water (50 mL) and EtOAc (50 mL) and the layers were separated. The pH of the aqueous phase was adjusted to 6.0 with HCl (1 M) and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (2 g, 74.9%) as a yellow solid. LCMS: m / z = 248 [M + H] + .

[0611] Intermediate 26

[0612] 5-Morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0613]

[0614] Following the procedure described in step 2 of Intermediate 25, the title compound was obtained as an off-white solid from 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate and morpholine (200 mg, 66% yield). LCMS: m / z = 302 [M+H] + .

[0615] Intermediate 27

[0616] 6-Morpholinopyrazolo[1,5-a]pyridine-3-carbonyl chloride hydrochloride

[0617]

[0618] Step 1: Synthesis of methyl 6-morpholinopyrazolo[1,5-a]pyridine-3-carboxylate

[0619] A mixture of methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (400 mg, 1.57 mmol), morpholine (164 mg, 1.88 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), NaOtBu (226 mg, 2.35 mmol) and [1,1'-biphenyl]-2-yldi-tert-butylphosphane (47 mg, 0.16 mmol) in toluene (3 mL) was heated to 90°C for 4 h. The mixture was diluted with EtOAc and washed with water. Filtration and evaporation gave the crude product. This crude product was purified by silica gel ISCO chromatography (10 to 100% EtOAc / hexanes) to afford the title compound (93 mg yellow solid). LCMS m / z = 262 [M+H]+ .

[0620] Step 2: Synthesis of 6-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid

[0621] A mixture of methyl 6-morpholinopyrazolo[1,5-a]pyridine-3-carboxylate (93 mg, 0.36 mmol) and LiOH (60 mg, 1.42 mmol) in THF (1.5 mL) and water (0.5 mL) was stirred at 70° C. for 6 h. The mixture was concentrated in vacuo, the residue was diluted with water, and the pH was adjusted to 2 using 1N HCl. The resulting solid was filtered off and washed with water to give the title compound (70 mg, 80%) as a yellow solid.

[0622] Step 3: Synthesis of 6-morpholinopyrazolo[1,5-a]pyridine-3-carbonyl chloride hydrochloride

[0623] A drop of DMF was added to a mixture of 6-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid (70 mg, 0.28 mmol) in DCM (3 mL) and oxalyl chloride (2 M, 0.71 mL, 1.42 mmol), and the reaction mixture was stirred at rt overnight. The mixture was evaporated under reduced pressure and azeotroped with DCM to obtain the title compound (94 mg brown solid). LCMS m / z=262 [M-Cl+OMe] + .

[0624] Intermediate 28

[0625] 2-(Methoxy-d3)ethan-1-amine trifluoroacetate

[0626]

[0627] Step 1: Synthesis of tert-butyl (2-(methoxy-d3)ethyl)carbamate

[0628] At 0 ° C, NaH (991 mg, 24.8 mmol, 60%) was added to tert-butyl N- (2-hydroxyethyl) carbamate (2.0 g, 12.4 mmol) in DMF (20 mL) in batches, and the mixture was stirred at 0 ° C for 30 min. Iodo (D3) methane (5.39 g, 37.2 mmol) was added, and the reaction mixture was stirred at rt for 16 h. The mixture was quenched with ice water (10 mL), diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed with brine (50 mL × 2), dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using PE: EtOAc = 5: 1 to provide the title compound (500 mg) as a colorless oil. LCMS: m / z = 123 [M-56].

[0629] Step 2: Synthesis of 2-(methoxy-d3)ethan-1-amine trifluoroacetate

[0630] TFA (3 mL) was added dropwise to tert-butyl (2-(methoxy-d3)ethyl)carbamate (500 mg, 2.80 mmol) in DCM (10 mL), and the reaction was stirred at rt for 2 h. The mixture was evaporated under reduced pressure to provide the title compound (200 mg) as a yellow solid. LCMS: m / z=79 [M+H] + .

[0631] Intermediate 29

[0632] 5-Bromo-N-(5-(2-isopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0633]

[0634] Step 1: Synthesis of 5-bromo-N-(5-cyano-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0635] To a solution of 3-amino-4-methylbenzonitrile (1 g, 7.56 mmol) and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (1.82 g, 7.56 mmol) in THF (10 mL) was added pyridine (1.19 g, 15.1 mmol) and (3.70 g, 11.3 mmol), and the reaction was stirred at 60 ° C for 2 h. The mixture was concentrated, MeOH (10 mL) was added, and the resulting precipitate was filtered and dried to provide the title compound as a white solid (1.7 g; 63%). LCMS: m / z = 355 [M + H] + .

[0636] Step 2: Synthesis of 5-bromo-N-(2-methyl-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0637] Following the procedure described in step 1 of intermediate 8, the title compound (1.4 g, 83%) was obtained as a yellow solid from 5-bromo-N-(5-cyano-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide. LCMS: m / z = 398 [M+H] + .

[0638] Step 3: Synthesis of 5-bromo-N-(5-(2-isopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0639] At rt, 2-iodopropane (102 mg, 0.60 mmol) was added to 5-bromo-N-(2-methyl-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (200 mg, 0.50 mmol) and K2CO3 (138 mg, 1.0 mmol) in DMF (4 mL), and the reaction was stirred at 100 ° C for 2 h. The mixture was diluted with water (50 mL), then extracted with DCM (3×20 mL) and the combined organic extracts were concentrated in vacuo. The crude product was purified by preparative TLC using DCM / MeOH=10:1 to obtain the title compound (120 mg, 54%) as a white solid. LCMS: m / z=440[M+H] + .

[0640] Intermediate 30

[0641] 5-Bromo-N-(5-(2-cyclopropyl-1,2,3,4-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0642]

[0643] Step 1: Synthesis of 2-cyclopropyl-5-(4-methyl-3-nitrophenyl)-1,2,3,4-tetrazolyl:

[0644] Following a similar procedure to that described in step 1 of Intermediate 16, the title compound was obtained as a yellow solid from 5-(4-methyl-3-nitrophenyl)-2H-tetrazole and cyclopropylboronic acid (300 mg, 50.2%). LCMS: m / z = 246 [M+H] + .

[0645] Step 2: Synthesis of 5-(2-cyclopropyl-1,2,3,4-tetrazol-5-yl)-2-methylaniline:

[0646] Following the procedure described in step 2 of intermediate 12, the title compound was obtained as a yellow solid from 2-cyclopropyl-5-(4-methyl-3-nitrophenyl)-1,2,3,4-tetrazolyl (250 mg, 95%). LCMS: m / z = 216 [M+H] + .

[0647] Step 3: Synthesis of 5-bromo-N-(5-(2-cyclopropyl-1,2,3,4-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[0648] Following a similar procedure to that described in step 3 of Intermediate 12, the title compound (240 mg, 65.5%) was obtained as a yellow solid from 5-(2-cyclopropyl-1,2,3,4-tetrazol-5-yl)-2-methylaniline and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 438 [M+H] + .

[0649] Intermediate 31

[0650] 4-Amino-2-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0651]

[0652] Steps 1 and 2: Synthesis of 4-bromo-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline

[0653] Following a similar procedure to that described in steps 1 and 2 of Intermediate 10, the title compound (210 mg) was obtained as a light yellow solid from 5-amino-2-bromo-4-methylbenzonitrile and 3,3-difluorocyclobutan-1-ol. LCMS: m / z = 344 [M+H] + .

[0654] Step 3: Synthesis of 4-amino-2-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-5-methylbenzonitrile

[0655] A mixture of 4-bromo-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline (210 mg, 0.61 mmol), Zn(CN)2 (215 mg, 1.83 mmol), Pd(dppf)Cl2 (49.7 mg, 0.06 mmol) and TEA (186 mg, 1.83 mmol) in DMF (5 mL) was stirred at 80 ° C under N2 for 2 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL×2), the organic layer was dried over (Na2SO4) and concentrated under vacuum. The residue was purified by silica gel column using PE:EtOAc=18:1 to provide the title compound (110 mg, 52%) as an off-white solid. LCMS: m / z=291[M+H] + .

[0656] Intermediate 32

[0657] 4-Cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline

[0658]

[0659] Following a similar procedure to that described in step 3 of Example 117, the title compound was obtained as an off-white solid from step 2 of intermediate 31 and cyclopropylboronic acid. LCMS: m / z = 306 [M+H] + .

[0660] Intermediate 33

[0661] 2,4-Dichloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[0662]

[0663] Step 1: Synthesis of 5-amino-2,4-dichlorobenzonitrile

[0664] 2,4-dichloro-5-nitrobenzonitrile (WO 03086371, 1.4g,6.45mmol A mixture of 2-[4-[(2-[(2-[(2-[(2-[(2-[2-[2-[2-[2-1-dimethylamino]-1-oxo-1-yl)-1-nitropropene]-1-yl)-1-nitropropene]-1-nitropropene]-1-nitropropene]-1-nitropropene) ... 1 H NMR (400MHz, DMSO-d6) δ7.66(s,1H),7.19(s,1H),6.05(s,2H).

[0665] Step 2: Synthesis of 2,4-dichloro-5-(2H-tetrazol-5-yl)aniline

[0666] Under rt, 5-Amino-2,4-dichlorobenzonitrile ( 700mg , 3.74mmol ) in toluene were added TMSN3 (1.28 g, 11.2 mmol) and Bu2SnO (931 mg, 3.73 mmol). The mixture was stirred at 100°C for 16 h and then cooled to rt. The mixture was concentrated under vacuum and the residue was purified by column chromatography to obtain the title compound as a white solid (500 mg, yield: 58.1%). LCMS: m / z = 230 [M+H] + .

[0667] Step 3: Synthesis of 2,4-dichloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[0668] Following the procedure described in step 2 of intermediate 7, 2,4-dichloro-5-(2H-tetrazol-5-yl)aniline was prepared from 3,3-diol Fluorocyclobutan-1-ol The title compound was obtained as a white solid (300 mg, 43%). LCMS: m / z = 320 [M+H] + .

[0669] Intermediate 34

[0670] 4-Chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline

[0671] N-(4-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[0672]

[0673] Step 1: Synthesis of 4-chloro-2-methyl-5-(2H-tetrazol-5-yl)aniline

[0674] To a mixture of 5-amino-2-chloro-4-methylbenzonitrile (400 mg, 2.40 mmol) and Bu2SnO (1.19 g, 4.80 mmol) in toluene (25 mL) was added TMSN3 (553 mg, 4.80 mmol) at rt, and the reaction mixture was stirred at 100°C for 16 h. The cooled mixture was concentrated to dryness and the residue was purified on preparative TLC using DCM:MeOH = 30:1 to provide the title compound (220 mg, yield: 43.7%) as an off-white solid. LCMS: m / z = 210 [M+H] + .

[0675] Step 2: Synthesis of 4-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylaniline

[0676] Following a similar procedure to that described in step 2 of intermediate 7, the title compound (120 mg, 60%) was obtained from 4-chloro-2-methyl-5-(2H-tetrazol-5-yl)aniline and 3,3-difluorocyclobutan-1-ol. LCMS: m / z = 300 [M+H] + .

[0677] Intermediate 35

[0678] 2-Chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[0679]

[0680] Step 1: Synthesis of tert-butyl (2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)carbamate

[0681] Following a similar procedure to that described in step 1 of intermediate 4, the title compound was obtained as a white solid from intermediate 10 of step 1 and 3,3-difluorocyclobutan-1-ol (300 mg, 46%). LCMS: m / z = 386 [M+H] + .

[0682] Step 2: Synthesis of 2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[0683] Following a similar procedure to that described in step 3 of Intermediate 18, the title compound (120 mg, 54%) was obtained from tert-butyl (2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)carbamate. LCMS: m / z = 286 [M+H] + .

[0684] Intermediate 36

[0685] 2-Chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-methylaniline

[0686]

[0687] Step 1: tert-Butyl (2-chloro-5-cyano-4-methylphenyl)carbamate

[0688] A mixture of 5-amino-4-chloro-2-methylbenzonitrile (1.2 g, 7.20 mmol), DMAP (1.31 g, 10.8 mmol), (Boc)2O (4.71 g, 21.6 mmol) and TEA (1.09 g, 10.8 mmol) in toluene (15 mL) was stirred at 100° C. for 16 h. The solvent was evaporated and the residue was purified by silica gel column eluting with 1% MeOH in DCM to provide the title compound (1.2 g, 78.1%) as a yellow solid. LCMS: m / z=267 [M+H] + .

[0689] Step 2: Synthesis of tert-butyl (2-chloro-4-methyl-5-(2H-tetrazol-5-yl)phenyl)carbamate

[0690] A mixture of tert-butyl N-(2-chloro-5-cyano-4-methylphenyl)carbamate (1.2 g, 4.49 mmol), TMSN3 (1.03 g, 8.98 mmol) and Bu2SnO (2.23 g, 8.98 mmol) in toluene (20 mL) was stirred at 100° C. for 16 h. The solvent was evaporated and the residue was purified by silica gel column eluting with 10% MeOH in DCM to provide the title compound as a yellow solid (700 mg, 50.3%). LCMS: m / z=310 [M+H] + .

[0691] Step 3 and Step 4: Synthesis of 2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-methylaniline

[0692] Following a similar 2-step procedure as described in Intermediate 35, the title compound was obtained as a white solid from tert-butyl (2-chloro-4-methyl-5-(2H-tetrazol-5-yl)phenyl)carbamate and 3,3-difluorocyclobutan-1-ol.

[0693] Intermediate 37

[0694] 5-Bromo-N-(2-methyl-5-(5-methyl-2H-tetrazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0695]

[0696] Step 1: Synthesis of 2-methyl-5-(5-methyl-2H-tetrazol-2-yl)aniline

[0697] Following a similar procedure to that described in step 1 of Intermediate 16, the title compound was obtained as a white solid from 5-methyl-2H-tetrazole and (3-amino-4-methylphenyl)boronic acid (850 mg, 24%). LCMS: m / z = 190 [M+H] + .

[0698] Step 2: Synthesis of 5-bromo-N-(2-methyl-5-(5-methyl-2H-tetrazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0699] Following the procedure described in step 3 of Intermediate 19, the title compound (469 mg, 72%) was obtained as a white solid from 2-methyl-5-(5-methyl-2H-1,2,3,4-tetrazol-2-yl)aniline and methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate. LCMS: m / z = 412 [M+H] + .

[0700] Intermediate 38

[0701] 5-Bromo-N-(5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0702]

[0703] Step 1: Synthesis of 5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylaniline

[0704] Following the procedure described in step 1 of intermediate 16, the title compound was obtained as a red solid from 5-cyclopropyl-2H-1,2,3,4-tetrazolyl and (3-amino-4-methylphenyl)boronic acid (276 mg, 28%). LCMS: m / z = 216 [M+H] + .

[0705] Step 2: Synthesis of 5-bromo-N-(5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0706] Following a similar procedure to that described in step 3 of Intermediate 5, the reaction mixture was obtained as a white solid from 5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylaniline and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (80 mg, 31.8%). LCMS: m / z = 438 [M+H] + .

[0707] Intermediate 39

[0708] 5-Bromo-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0709]

[0710] Step 1: Synthesis of 5-(4-methyl-3-nitrophenyl)-2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazolyl

[0711] To a stirred solution of step 2 (5.5 g, 21.1 mmol) of intermediate 11 and TEA (6.42 g, 63.4 mmol) in DCM (55 mL) at 0 ° C., methanesulfonic anhydride (4.79 g, 27.4 mmol) was added portionwise, and the reaction was then stirred at rt for 2 h. The resulting mixture was washed with NaHCO 3 and extracted with DCM (3×80 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to provide the title compound (5.2 g, 72.7%) as a light brown solid. LCMS m / z=339 [M+H] + .

[0712] Step 2: Synthesis of 2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)aniline

[0713] At rt, Pd / C (1 g, 9.4 mmol) was added to 2-(1-methylsulfonylazetidin-3-yl)-5-(4-methyl-3-nitrophenyl)-1,2,3,4-tetrazole (5.2 g, 15.4 mmol) in EtOAc (60 mL). The flask was evacuated and filled with N2 three times, then filled with H2. The mixture was stirred under a H2 (balloon) atmosphere for 2 h at rt. The reaction mixture was filtered, the filter cake was washed with MeOH:EtOAc:NH3 H2O=(50:10:1) (3×15 mL) and the filtrate was evaporated under reduced pressure to obtain the title compound (2.61 g, 55.0%) as a light brown solid. LCMSm / z=309[M+H] + .

[0714] Step 3: Synthesis of 5-bromo-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0715] Will A mixture of 4-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)aniline (2 mL, 1.62 mmol), 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (390 mg, 1.62 mmol) in THF (4 mL) was heated at 50 ° C under N 2 for 16 h. The reaction mixture was diluted with EtOAc (120 mL) and washed with water (60 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated under vacuum. The crude product was purified by preparative TLC, eluting with DCM:MeOH=20: 1 to obtain the title compound (219 mg) as a white solid. LCMS: m / z=531 [M+H] + .

[0716] Intermediate 40

[0717] N-(5-(2-(azetidin-3-yl)-2H-tetrazol-5-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0718]

[0719] Step 1: Synthesis of tert-butyl 3-(5-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0720] A mixture of intermediate 2 (250 mg, 0.74 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (250 mg, 0.88 mmol) and K2CO3 (153 mg, 1.1 mmol) in DMF was heated at 90 ° C overnight. The mixture was concentrated in vacuo and the residue was partitioned between 5% MeOH / DCM and water and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated to obtain the crude product. This crude product was purified by ISCO chromatography (0 to 100% EtOAc / hexane) to obtain the title compound (253 mg, 69.5%) as a white foam. LCMSm / z=495[M+H] + .

[0721] Step 2: Synthesis of N-(5-(2-(azetidin-3-yl)-2H-tetrazol-5-yl)-2-chlorophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0722] A solution of tert-butyl 3-(5-(4-chloro-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (253 mg, 0.51 mmol) and TFA (583 mg, 5.1 mmol) in DCM (2 mL) was stirred at rt for 3 h. The solution was evaporated under reduced pressure, the residue was diluted with water and the pH was adjusted to 10 using 1N NaOH solution. The resulting solid was filtered off, washed with water and dried to afford the title compound (206 mg) as an off-white solid. LCMS m / z=395 [M+H] + .

[0723] Intermediate 41

[0724] Ethyl 5-((tert-Butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate

[0725]

[0726] Step I: Synthesis of tert-butyl N-(3-chloropyridin-4-yl)carbamate:

[0727] Na2CO3 (8.22 g, 77.6 mmol) was added to di-tert-butyl dicarbonate (8.46 g, 38.8 mmol) and 3-chloropyridin-4-amine (5 g, 38.8 mmol) in dioxane / H2O (160 mL / 40 mL), and the reactants were stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (300 mL), washed with water (200 mL×3) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product. This crude product was purified by preparative TLC using PE:EtOAc=5:1 to provide the title compound (8.5 g, 95.8%) as an off-white solid. LCMS: m / z=229[M+H] + .

[0728] Step 2: Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate

[0729] A solution of tert-butyl N-(3-chloropyridin-4-yl)carbamate (8.5 g, 37.1 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (14.7 g, 74.2 mmol) in MeCN (200 mL) was stirred at 50 ° C for 40 h. The mixture was evaporated under reduced pressure to provide crude 1-amino-4-(((tert-butoxy)carbonyl)amino)-3-chloropyridin-1-ium 2,4-dinitrobenzyl-1-olate, which was dissolved in DMF (200 mL) and K2CO3 (27.0 g, 196 mmol) was added. The mixture was stirred at rt for 1 h, ethyl prop-2-ynoate (9.61 g, 98.0 mmol) was added, and the reaction was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (400 mL) and washed with water (300 mL×3) and brine (300 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product, which was purified by silica gel column using PE:EtOAc=4:1 to obtain ethyl 5-(((tert-butoxycarbonyl)amino)-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate as a yellow solid and ethyl 5-((tert-butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate as a yellow solid. LCMS m / z=340 [M+H] + .

[0730] Intermediate 42

[0731] Methyl 6-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[0732]

[0733] A mixture of methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 0.78 mmol), Cs2CO3 (508 mg, 1.56 mmol), BrettPhos Pd G3 (71.0 mg, 0.08 mmol), BrettPhos (83.7 mg, 0.16 mmol) and 2-methoxyethyl-1-amine (117 mg, 1.56 mmol) in dioxane (3 mL) was stirred at 80 ° C under N2 for 4 h, and then cooled to rt. Water (10 mL) was added and the resulting solution was extracted with DCM (3×20 mL). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column using PE:EtOAc=1:1 to obtain the title compound (150 mg, 77%) as an off-white solid. LCMS: m / z=250[M+H] + .

[0734] Intermediate 43

[0735] 2-Chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-methylaniline

[0736]

[0737] Step 1: Synthesis of tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-methylphenyl)carbamate

[0738] Following a similar procedure to that described in step 1 of Intermediate 16, the title compound was obtained as a light yellow solid from tert-butyl (2-chloro-4-methyl-5-(2H-tetrazol-5-yl)phenyl)carbamate and cyclopropylboronic acid (200 mg, 66%). LCMS: m / z = 350 [M+H] + .

[0739] Step 2: Synthesis of 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-methylaniline

[0740] TFA (3 mL) was added to tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-methylphenyl)carbamate ( 200mg ,0. 595mmol ). The resulting mixture was stirred for 2 h. The mixture was diluted with DCM (100 mL) and washed with aqueous sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:EtOAc=25:1 to obtain the title compound (130 mg, 65%) as a white solid. LCMS: m / z=250[M+H] + .

[0741] Intermediate 44

[0742] Methyl 5-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0743]

[0744] Pd(dppf)Cl2 (159 mg, 0.196 mmol) was added to methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, 1.96 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (521 mg, 1.96 mmol) and K2CO3 (407 mg, 2.94 mmol) in HO (4 mL) and dioxane (16 mL) at rt. The resulting mixture was stirred at 80 ° C. under N2 for 2 h. The mixture was diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:MeOH=20:1 to obtain the title compound (400 mg, 80%) as a white solid. LCMS: m / z=315 [M+H] + .

[0745] Intermediate 45

[0746] Methyl 5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate and methyl 5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Intermediate 45-1)

[0747]

[0748] Step 1: Synthesis of a mixture of 4-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol and 4-((5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol

[0749] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.40 mmol), 1,6-dioxaspiro[2.5]octane (547 mg, 4.80 mmol) and Cs2CO3 (1.16 g, 3.59 mmol) in DMF (20 mL) was stirred at 80° C. under N2 for 2 h. The solvent was evaporated and the residue was purified on a silica gel column eluted with 5% MeOH in DCM to provide a mixture of the title compounds as a colorless oil (600 mg, 77.6%). LCMS: m / z=323 [M+H] + .

[0750] Step 2: Synthesis of intermediate 45 5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and intermediate 45-1 5-(1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0751] 4-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol and 4-((5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)tetrahydro-2H-pyran-4-ol (6 A mixture of 4-(2-[ ... + Intermediate 45 (300 mg, 43.5%) was then eluted as an off-white solid. LCMS: m / z = 371 [M+H] + .

[0752] Intermediate 46

[0753] 2-Chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)aniline

[0754]

[0755] Step 1: Synthesis of tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)phenyl)carbamate

[0756] Following a similar procedure to that described in step 1 of intermediate 16, the title compound was obtained from step 1 of intermediate 10 and cyclopropylboronic acid as a light yellow solid (200 mg, 66%). LCMS: m / z = 336 [M+H] + .

[0757] Step 2: Synthesis of 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)aniline

[0758] Following a similar procedure to that described in step 2 of Intermediate 43, the title compound was obtained as a yellow solid from tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)phenyl)carbamate (100 mg, 50%). LCMS: m / z = 236 [M+H] + .

[0759] Intermediate 47

[0760] 5-Bromo-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0761]

[0762] Step 1: Synthesis of 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride

[0763] SOCl2 (10 mL) was added to 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (10 g, 29.88 mmol) at rt. The resulting mixture was stirred at 60 °C for 2 h. The mixture was concentrated under vacuum to provide the title compound (9.5 g, 95%) as a brown solid. LCMS: m / z = 259 [M+H] + .

[0764] Step 2: Synthesis of 5-bromo-N-(2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0765] At rt, 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (8.25 g, 31.8 mmol) was added to intermediate 46 (5 g, 21.2 mmol) in pyridine (35 mL), and the reaction mixture was stirred for 3 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column using DCM:EtOAc=18:1 to produce the title compound (6.8 g) as an off-white solid. LCMS: m / z=459[M+H] + .

[0766] Intermediate 48

[0767] (S)-1-Methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0768]

[0769] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3 g, 15.5 mmol), (S)-2-(methoxymethyl)oxirane (1.63 g, 18.5 mmol) and CsCO (5.04 g, 15.5 mmol) in DMF (30 mL) was stirred at 100 ° C. under N 2 for 3 h. The solvent was evaporated and the residue was purified by silica gel column eluting with 5% MeOH in DCM to provide the title compound (4 g, 91.8%) as a yellow solid. LCMS: m / z = 282 [M + H] + .

[0770] Intermediate 49

[0771] 5-(2-Cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0772]

[0773] A mixture of step 1 of intermediate 7 (300 mg, 1.55 mmol), K2CO3 (641 mg, 4.65 mmol), [CuOH(TMEDA)]2Cl2 (143 mg, 0.310 mmol) and cyclopropylboronic acid (266 mg, 3.10 μmol) in DCE (10 mL) was stirred at 60 ° C under O2 for 24 h and then cooled to rt. The mixture was filtered and the residue was washed with a solution of DCM:MeOH=10:1. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column using PE:EtOAc (2:1) to obtain the title compound (60 mg, 17%) as a yellow solid. LCMS: m / z=234[M+H]+ .

[0774] Intermediate 50

[0775] 2-Methyl-1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 2-methyl-1-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0776]

[0777] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7 g, 33.6 mmol), 2,2-dimethyloxirane (2.90 g, 40.3 mmol) and Cs2CO3 (10.9 g, 33.6 mmol) in DMF (100 mL) was stirred at 100 ° C. under N2 for 3 h. The solvent was evaporated and the residue was purified by silica gel column using 5% MeOH in DCM to provide the title compound (7.5 g, 89.6%) as a yellow solid. LCMS: m / z=281 [M+H] + .

[0778] Intermediate 51

[0779] Intermediate 51A

[0780] 5-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0781] Intermediate 51B

[0782] 5-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0783]

[0784] A mixture of intermediate 50 (6 g, 21 mmol), methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (5.5 g, 21 mmol), Cs2CO3 (13.9 g, 42 mmol) and Pd(pddf)Cl2 (171 mg, 2 mmol) in dioxane (50 mL) and water (5 mL) was stirred at 100 ° C. under N2 for 3 h. The solvent was evaporated and the residue was purified on a silica gel column using 5% MeOH in DCM to obtain intermediate 51, a mixture of the title compounds (51A and 51B). LCMS m / z = 329 [M+H]+. The regioisomer mixture was separated by SFC (column: Green Sep Basic, 4.6*100 mm, 3 m; mobile phase B: MeCN:MeOH = 80:20 (1% 2M NH3-MeOH)) to produce peak 1, intermediate 51A (0.9 g) as a solid. 1H NMR(400MHz,DMSO-d6)δ8.87-8.81(m,1H),8.41(s,1H),8.04-7.99(m,1H),7.89(s, 1H),7.29(dd,1H),4.70(s,1H),4.07(s,2H),3.84(s,3H),2.54(s,3H),1.17(s,6H).

[0785] Further elution provided peak 2, intermediate 51B (2.3 g, 33%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.30 (dd, 1H), 4.73 (s, 1H), 4.00 (s, 2H), 3.84 (s, 3H), 2.44 (s, 3H), 1.12 (s, 6H).

[0786] Intermediate 52

[0787] 1-(4-Bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-Bromo-5-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0788]

[0789] To a solution of 4-bromo-3-cyclopropyl-1H-pyrazole (2 g, 10.7 mmol) in DMF (30 mL) was added Cs2CO3 (3.48 g, 10.7 mmol) followed by 2,2-dimethyloxirane (0.92 g, 12.8 mmol) and the reaction mixture was stirred at 80 ° C for 3 h. The solvent was evaporated and the residue was purified by silica gel column eluting with 5% MeOH in DCM to provide the title compound (2.5 g, 90.2%) as a yellow solid. The ratio of the two isomers was 4:1 (1-(4-bromo-3-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol / 1-(4-bromo-5-cyclopropyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol). LCMS: m / z=259, 261 [M+H] + .

[0790] Intermediate 53

[0791] Methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0792]

[0793] A mixture of methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (3.2 g, 11.6 mmol), (BPin)2 (3.8 g, 11.6 mmol), Pd(dppf)Cl2 (170 mg, 232 μmol) and Cs2CO3 (2.7 g, 11.6 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 100°C for 16 h. The solvent was evaporated and the residue was purified on a silica gel column using EtOAc / PE (60 / 40) to provide the title compound (3.2 g, 40.9%) as a yellow oil. LCMS: m / z = 371 [M+H] + .

[0794] Intermediate 54

[0795] 5-(3-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and 5-(5-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0796]

[0797] A mixture of intermediate 52 (2.1 g, 8.28 mmol), intermediate 53 (2.5 g, 8.28 mmol), Pd(dppf)Cl2 (121 mg, 0.166 mmol) and Cs2CO3 (2.7 g, 8.28 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 100°C for 16 h. The solvent was evaporated and the residue was purified on a silica gel column using EtOAc / PE (60 / 40) to provide the title compound (1.2 g, 40.9%) as a yellow oil. LCMS: m / z = 355 [M+H] + .

[0798] Intermediate 55

[0799] 5-(2-Cyclopropyl-2H-tetrazol-5-yl)-2-methylaniline

[0800]

[0801] Step 1: Synthesis of 2-cyclopropyl-5-(4-methyl-3-nitrophenyl)-2H-tetrazolyl

[0802] A mixture of step 1 of intermediate 13 (20 g, 97.4 mmol), cyclopropylboronic acid (16.6 g, 194 mmol), Cu(OAc)2 (17.7 g, 97.4 mmol), 2,2'-bipyridine (15.2 g, 97.4 mmol) and Na2CO3 (20.5 g, 194 mmol) in DCE (1000 mL) was heated at 60 ° C for 16 h. The mixture was extracted with EtOAc (3×500 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column using PE:EtOAc=8:1 to obtain the title compound (11.5 g, 48%) as a yellow solid. LCMS: m / z=246[M+H] + .

[0803] Step 2: Synthesis of 5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylaniline

[0804] A mixture of 2-cyclopropyl-5-(4-methyl-3-nitrophenyl)-2H-tetrazole (11.5 g, 46.8 mmol), Fe (26.2 g, 468 mmol), and NH4Cl (25.2 g, 468 mmol) in EtOH / H2O (500 mL / 100 mL) was heated to 80°C for 2 h. The mixture was extracted with EtOAc (3 x 300 mL), and the combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford the title compound (9 g, 90%) as a yellow solid. LCMS: m / z = 216 [M+H] +.

[0805] Intermediate 56

[0806] 5-Bromo-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0807]

[0808] A mixture of pyridine (25 mL) and PPh3 (25 mL), 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (8 g, 33.1 mmol) and intermediate 55 (10.6 g, 49.6 mmol) in THF (30 mL) was stirred at 50 ° C for 3 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column using DCM: EtOAc = 18: 1 to provide the title compound (7.8 g, 97.5%) as an off-white solid. LCMS: m / z = 438 [M + H] + .

[0809] Intermediate 57

[0810] 5-(3-cyclopropyl-1H-pyrazol-4-yl)-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0811]

[0812] Step 1: Synthesis of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0813] A mixture of intermediate 56 (1 g, 2.28 mmol), KOAc (447 mg, 4.56 mmol), Pd(dppf)Cl2 (186 mg, 228 μmol) and (BPin)2 (1.15 g, 4.56 mmol) in dioxane (10 mL) was stirred at 80° C. under N2 for 2 h. The crude product was used directly in the next step without further purification. LCMS: m / z = 486 [M+H] + .

[0814] Step 2: Synthesis of 5-(3-cyclopropyl-1H-pyrazol-4-yl)-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0815] A mixture of N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (Step 1, 1.10 g, 2.26 mmol), Pd(dppf)Cl2 (369 mg, 0.452 mmol), Cs2CO3 (1.47 g, 4.52 mmol) and 4-bromo-3-cyclopropyl-1H-pyrazole (632 mg, 3.38 mmol) in dioxane (9 mL) and H2O (3 mL) was stirred at 100 °C under N2 for 12 h. The mixture was cooled to rt, water was added and the resulting solution was extracted with DCM (3×100 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column using DCM:MeOH=20:1 to give the title compound (500 mg, 48%) as a reddish brown solid. LCMS: m / z=466[M+H] + .

[0816] Intermediate 58

[0817] 1-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

[0818]

[0819] A mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.50 mmol), 2,2-dimethyloxirane (486 mg, 6.75 mmol) and CsCO (2.19 g, 6.75 mmol) in DMF (20 mL) was stirred at 100 ° C. under N 2 for 3 h. The solvent was evaporated and the residue was purified by silica gel column using 5% MeOH in DCM to provide the title compound (1.2 g, 90.9%) as a yellow solid. LCMS: m / z = 295 [M + H] + .

[0820] Intermediate 59

[0821] 5-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0822]

[0823] A mixture of intermediate 58 (300 mg, 1.01 mmol), methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (385 mg, 1.51 mmol), Cs2CO3 (491 mg, 1.51 mmol) and Pd(pddf)Cl2 (41.7 mg, 50 μmol) in dioxane (9 mL) and water (3 mL) was stirred at 100°C for 3 h. The solvent was evaporated and the residue was purified on preparative TLC using DCM:MeOH=20:1 to provide the title compound (240 mg, 69.5%) as a yellow solid. LCMS: m / z=343 [M+H] + .

[0824] Intermediate 60

[0825] (S)-1-(4-Bromo-3-cyclopropyl-1H-pyrazol-1-yl)-3-methoxypropan-2-ol and (S)-1-(4-Bromo-5-cyclopropyl-1H-pyrazol-1-yl)-3-methoxypropan-2-ol

[0826]

[0827] Following the procedure described in Intermediate 48, the title compound (3.5 g, 79%) was obtained from 4-bromo-3-cyclopropyl-1H-pyrazole and (S)-2-(methoxymethyl)oxirane in a 3:1 ratio. LCMS: m / z = 275, 277 [M+H] + .

[0828] Intermediates 61 to 64

[0829] The compounds in the table below were prepared following the procedure described in Intermediate 48 from the appropriate 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and ethylene oxide.

[0830]

[0831]

[0832]

[0833] Intermediate 67

[0834] 1-Methoxy-2-methyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 1-Methoxy-2-methyl-3-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0835]

[0836] Step 1: Synthesis of 3-methyl-1-((2-methyloxiran-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-methyl-1-(2-methyloxiran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0837] A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 19.2 mmol), 2-(chloromethyl)-2-methyloxirane (3.05 g, 28.7 mmol) and Cs2CO3 (6.25 g, 19.2 mmol) in DMF (40 mL) was stirred at 100 ° C for 3 h. The cooled reaction was quenched with water and extracted with EtOAc (3×50 mL), the organic layer was dried with Na2SO4 and concentrated in vacuo. The crude product was purified by preparative TLC using PE:EtOAc=30:1 to obtain a mixture of the title compounds (5 g, 93.6%). LCMS: m / z=279[M+H] + .

[0838] Step 2: Synthesis of 1-methoxy-2-methyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 1-methoxy-2-methyl-3-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0839] A mixture of the compound of step 1 (5 g, 17.9 mmol) and MeONa (966 mg, 17.9 mmol) in MeOH (80 mL) was stirred at 100 ° C under N 2 for 16 h. The cooled reaction mixture was diluted with water (8 mL), extracted with EtOAc (2×50 mL), and the combined organic extracts were washed with brine. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The product was purified by preparative TLC using DCM:MeOH=30:1 to obtain a mixture of the title compounds (3.0 g, 54%). LCMS: m / z=311[M+H] + .

[0840] Intermediate 68

[0841] (S)-1-(2-Methoxyethoxy)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0842]

[0843] Step 1: Synthesis of (S)-1-(oxiran-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[0844] Following the procedure described in Intermediate 48, the title compound was obtained as a white solid from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 2-(chloromethyl)oxirane (2.5 g, 64.9%). LCMS m / z = 251 [M+H] + .

[0845] Step 2: Synthesis of (S)-1-(2-methoxyethoxy)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0846] To a mixture of (S)-1-(oxiran-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 4.39 mmol) and 2-methoxyethan-1-ol (668 mg, 8.78 mmol) in DMF (25 mL) was added NaH (60%, 349 mg, 8.78 mmol), and the reaction mixture was stirred at 60 ° C for 2 h. The reaction was quenched with water (10 mL), and the mixture was evaporated under reduced pressure. The residue was purified on a silica gel column using 5% MeOH in DCM to provide the title compound (800 mg, 55.9%) as a yellow oil. LCMS: m / z = 327 [M + H] + .

[0847] Intermediate 69

[0848] (R)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and (R)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and (S)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and (S)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0849]

[0850] Steps 1 and 2: Synthesis of (S)-1-(2-methoxyethoxy)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol, (R)-1-(2-methoxyethoxy)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol -2-ol, (S)-1-(2-methoxyethoxy)-3-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and (R)-1-(2-methoxyethoxy)-3-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

[0851] The title compound was obtained from 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (2R)-2-(chloromethyl)oxirane following the 2-step procedure described in Intermediate 68. LCMS m / z = 341 [M+H] + .

[0852] Step 3: Synthesis of (S)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester, (R)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester methyl ester, (S)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate and (R)-5-(1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0853] A mixture of the compound mixture of step 2 (100 mg, 306 μmol), methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (78.0 mg, 306 μmol), Pd(dppf)Cl2 (15 mg, 18.3 μmol) and Cs2CO3 (199 mg, 612 μmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 100°C for 3 h. The reactants were evaporated under reduced pressure, and the residue was purified by preparative TLC using DCM:MeOH = 20:1 to provide a mixture of the title compounds (70 mg, 61.4%). LCMSm / z=389[M+H] + .

[0854] Intermediate 70

[0855] 6-(1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester and 6-(1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester

[0856]

[0857] Into a 20-mL pressure tank reactor purged and maintained under N2 was placed intermediate 50 (280 mg, 1 mmol), methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (254 mg, 1 mmol), K2CO3 (276 mg, 2 mmol) and Pd(dppf)Cl2 (75 mg, 0.1 mmol) in dioxane (4 mL) and H2O (1 mL), and the reaction mixture was stirred at 80 ° C under N2 for 1 h. The reaction was quenched with water / ice (10 mL) and the solid was filtered off. The resulting solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column (DCM / MeOH (20 / 1)) to obtain a mixture of the title compounds as a solid (150 mg, 45.7%). LCMS: m / z=329[M+H] + .

[0858] Intermediate 71

[0859] Racemic-2-chloro-5-(5-((1R,2S)-2-fluorocyclopropyl)-2H-tetrazol-2-yl)aniline

[0860]

[0861] Following the procedure described in step 1 of intermediate 16, the title compound was obtained as a brown solid from rac-5-((1R,2S)-2-fluorocyclopropyl)-2H-tetrazole and (3-amino-4-chlorophenyl)boronic acid (300 mg, 15%). LCMS: m / z = 254 [M+H] + .

[0862] Intermediate 72

[0863] 4-Fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline:

[0864]

[0865] A mixture of 5-bromo-4-fluoro-2-methylaniline (200 mg, 0.98 mmol), (BPin)2 (496 mg, 1.96 mmol), Pd(dppf)Cl2 (71.8 mg, 0.098 mmol) and KOAc (96 mg, 0.98 mmol) in dioxane (5 mL) was stirred at 100 ° C under N2 for 12 h. The mixture was diluted with EtOAc (30 mL) and water (30 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:MeOH=5:1 to obtain the title compound (100 mg, 41%) as a yellow solid. LCMS: m / z=252[M+H] + .

[0866] Intermediate 73

[0867] 2-Chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoroaniline

[0868]

[0869] Step 1: tert-Butyl (2-chloro-5-cyano-4-fluorophenyl)carbamate

[0870] (Boc) O (7.63 g, 35.0 mmol) was added to a solution of 5-amino-4-chloro-2-fluorobenzonitrile (3 g, 17.5 mmol), TEA (3.54 g, 35.0 mmol) and DMAP (427 mg, 3.50 mmol) in toluene (50 mL) at 0 ° C under N 2, and the reaction mixture was heated at 100 ° C for 4 h. The mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with saturated NaHCO 3 (2×50 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The solution was purified by silica gel column (PE:EtOAc, 100 / 0 to 0 / 100) to obtain the title compound (3 g, 63.4%) as a brown oil. LCMS: m / z=269 [MH].

[0871] Step 2: Synthesis of tert-butyl (2-chloro-4-fluoro-5-(2H-tetrazol-5-yl)phenyl)carbamate

[0872] At rt under N2, to a mixture of tert-butyl N-(2-chloro-5-cyano-4-fluorophenyl)carbamate (2 g, 7.38 mmol) and K2CO3 (3.04 g, 22.0 mmol) in toluene (30 mL) was added Bu2SnO (2.3 g, 7.38 mmol) and TMSN3 (1.7 g, 14.76 mmol), and the reaction mixture was heated at 100 ° C overnight. The mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with saturated NaHCO3 aqueous solution (2×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The mixture was purified by silica gel column (EtOAc / PE 0 to 100%) to obtain the title compound (2 g, 86.9%) as a yellow oil. LCMS: m / z=314[M+H]+.

[0873] Step 3: Synthesis of tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)carbamate

[0874] Following the procedure described in step 1 of intermediate 16, the title compound (1 g, 59.1%) was obtained from tert-butyl (2-chloro-4-fluoro-5-(2H-tetrazol-5-yl)phenyl)carbamate and cyclopropylboronic acid. LCMS: m / z = 354 [M+H] + .

[0875] Step 4: Synthesis of 2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoroaniline

[0876] Following the procedure described in step 3 of intermediate 10, the title compound was obtained as a yellow oil from tert-butyl (2-chloro-5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluorophenyl)carbamate (450 mg, 63%). LCMS: m / z = 254 [M+H] + .

[0877] Intermediate 74

[0878] 2-Chloro-5-(2-ethyl-2H-tetrazol-5-yl)aniline

[0879]

[0880] Step 1: Synthesis of tert-butyl (2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)phenyl)carbamate

[0881] A mixture of tert-butyl (2-chloro-5-(2H-tetrazol-5-yl)phenyl)carbamate (5 g, 16.9 mmol), CsCO (11.0 g, 33.8 mmol) and iodoethane (5.27 g, 33.8 mmol) in MeCN (150 mL) was stirred at 80° C. for 3 h. The cooled reaction was concentrated to dryness and the residue was purified on a silica gel column using 40% EtOAc in PE to provide the title compound (3 g, 54.8%) as an off-white solid. LCMS: m / z=324 [M+H] + .

[0882] Step 2: Synthesis of 2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)aniline

[0883] The title compound (1.6 g, 86%) was obtained as an off-white solid from tert-butyl (2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)phenyl)carbamate following the procedure described in step 3 of intermediate 10. LCMS m / z = 224 [M+H] + .

[0884] Intermediate 75

[0885] 2-Chloro-5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoroaniline

[0886]

[0887] Step 1: Synthesis of tert-butyl (2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)-4-fluorophenyl)carbamate

[0888] A mixture of step 2 of intermediate 73 (2.06 g, 6.88 mmol), iodoethane (1.60 g, 10.3 mmol) and K2CO3 (1.13 g, 8.25 mmol) in DMF (20 mL) was stirred at rt under N2 for 16 h. The reaction mixture was diluted with EtOAc (120 mL) and washed with water (60 mL). The organic phase was concentrated in vacuo and the residue was purified by silica gel column (DCM:MeOH=100:1) to obtain the title compound (1.38 g) as an off-white solid. LCMS: m / z=342 [M+H] + .

[0889] Step 2: Synthesis of 2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoroaniline

[0890] The title compound (1.12 g) was obtained as a white solid from tert-butyl (2-chloro-5-(2-ethyl-2H-tetrazol-5-yl)-4-fluorophenyl)carbamate following the procedure described in step 3 of intermediate 10. LCMS: m / z = 242 [M+H] + .

[0891] Intermediate 76

[0892] 5-Bromo-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-6-fluoropyrazolo[1,5-a]pyridine-3-carboxamide

[0893]

[0894] Step 1: Synthesis of ethyl 5-bromo-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate:

[0895] At 0 ° C, a solution of NaNO2 (4.16 g, 60.4 mmol) in water (67 mL) was added dropwise to a solution of step 3 (9 g, 40.3 mmol) of Example 171 in concentrated HBr (45 mL). After 10 min, a solution of CuBr (11.5 g, 80.6 mmol) in concentrated HBr (45 mL) was added and the reaction mixture was heated at 50 ° C for 15 min until gas evolution stopped. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2×400 mL). The combined organic extracts were dried (Na2SO4) and the solvent was concentrated in vacuo. The crude product was purified by silica gel column (PE: EtOAc = 3: 1) to provide the title compound (3 g, 26%) as a yellow solid. LCMS: m / z = 287 [M + H] +.

[0896] Step 2: Synthesis of 5-bromo-N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-6-fluoropyrazolo[1,5-a]pyridine-3-carboxamide

[0897] Following the procedure described in step 3 of Example 45, the title compound (600 mg, 72.7%) was obtained as a solid from ethyl 5-bromo-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate and Intermediate 49. LCMS: m / z = 474 [M+H] + .

[0898] Intermediate 77

[0899] 5-Bromo-N-(5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0900]

[0901] Step 1: Synthesis of 5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylaniline

[0902] The title compound (410 mg, 89%) was obtained from step 1 of intermediate 7 and iodoethane following the procedure described in step 3 of intermediate 29. LCMS: m / z = 222 [M+1].

[0903] Step 2: Synthesis of 5-bromo-N-(5-(2-ethyl-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0904] Following the procedure described in step 2 of Example 207, the title compound (230 mg, 57%) was obtained from 5-(2-ethyl-2H-1,2,3,4-tetrazol-5-yl)-4-fluoro-2-methylaniline and methyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate. LCMS: m / z = 444 [M+H] + .

[0905] Example 1

[0906] N-(2-Methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0907]

[0908] To a solution of intermediate 1 (45 mg, 0.14 mmol) and K2CO3 (29 mg, 0.21 mmol) in DMF (0.5 mL) was added 4-bromo-1,1,1-trifluorobutane (32 mg, 0.17 mmol), and the reaction mixture was stirred at 90 ° C for 1 h. The mixture was partitioned between water and 5% MeOH / DCM, the layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by reverse phase ISCO (5% to 100% MeCN / water containing 0.1% TFA). The fractions containing the product were concentrated in vacuo, and the residue was triturated with aqueous NaHCO3. The mixture was filtered and the resulting solid was dried under vacuum to obtain the title compound (27.7 mg, 45.8%) as an off-white solid. LCMSm / z=430[M+H] +;1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.86(d,1H),8.79(s,1H),8.25(d,1H),8.17(d,1H),7.85 (dd,1H),7.54(dd,1H),7.48(d,1H),7.13(t,1H),4.84(t,2H),2.48-2.34(m,5H),2.23(p,2H).

[0909] Example 2

[0910] N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (X)

[0911]

[0912] To a solution of intermediate 1 (50 mg, 0.16 mmol) and K2CO3 (64.9 mg, 0.47 mmol) in DMF (1 mL) was added iodomethane (66.7 mg, 0.47 mmol), and the reaction mixture was stirred at 90 ° C overnight. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were evaporated under reduced pressure. The residue was purified by reverse phase HPLC (water / 0.1% TFA / MeCN / 0.1% TFA) to obtain the title compound (8.9 mg, 17%). LCMSm / z = 334 [M + H] + ;1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.78(d,1H),8.71(d,1H),8.10(s,1H),7 .76(d,1H),7.46(t,1H),7.40(d,1H),7.05(t,1H),4.36(d,3H),2.29(s,3H).

[0913] Examples 3 to 21

[0914] The compounds in the table below were prepared using methods similar to those described in Example 2 from Intermediate 1, Intermediate 2 and Intermediate 3 and the appropriate alkylating agents and purification conditions listed in the table below.

[0915]

[0916]

[0917]

[0918]

[0919] Example 22

[0920] N-(2-Chloro-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0921]

[0922] A mixture of intermediate 2 (47 mg, 0.14 mmol), K2CO3 (29 mg, 0.21 mmol) and 2-(2-chloroethoxy)-1,1,1-trifluoroethane (27 mg, 0.17 mmol) in DMF (0.5 mL) was heated at 90 ° C for 4 h. 2-(2-chloroethoxy)-1,1,1-trifluoroethane (27 mg, 0.17 mmol) was added and the reaction mixture was heated at 90 ° C for 90 min and then heated at rt for 3 days. The mixture was diluted with water, stirred for 1 h, then filtered and the solid was dried under vacuum. This solid was recrystallized from EtOH to provide the title compound (32 mg, 49.7%) as a light brown solid. LCMSm / z=466[M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.89(s,1H),8.88(d,1H),8.83(s,1H),8.43(d,1H),8.26(d,1H),7. 94(dt,1H),7.78(d,1H),7.57(dd,1H),7.16(t,1H),5.00(t,2H),4.21(t,2H),4.13(q,2H).

[0923] Examples 23 and 24

[0924] N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and N-(2-methyl-5-(2-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0925]

[0926] At rt, to a stirred solution of intermediate 1 (200 mg, 0.63 mmol) in DMF (2 mL) was added KCO (258 mg, 1.87 mmol) and 1-bromo-3-(trifluoromethyl)cyclobutane (253 mg, 1.25 mmol). The mixture was heated at 100 ° C for 6 h, then cooled to rt and diluted with water (10 mL). The resulting solution was extracted with EtOAc (3 × 20 mL) and the combined organic phase was washed with brine (3 × 10 mL). The organic layer was dried over NaSO and concentrated in vacuo. The crude product was purified by silica gel column using PE: EtOAc = 3: 2 to first provide isomer 1 and then elute isomer 2.

[0927] Isomer 1 was further purified by preparative HPLC method B, 40% to 65% gradient to afford N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide or N-(2-methyl-5-(2-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide as a white solid (73.2 mg, yield: 26%). LCMS: m / z = 442 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.86(dt,1H),8.79(s,1H),8.24(dt,1H),8.18(d,1H),7.88(dd,1H), 7.58-7.45(m,2H),7.13(td,1H),5.64(p,1H),3.49(ddd,1H),3.03(ddd,2H),2.87(ddd,2H),2.36(s,3H).

[0928] Isomer 2 was further purified by preparative HPLC method B, 40% to 65% gradient to afford N-(2-methyl-5-(2-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide or N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide as a white solid (63.9 mg; yield: 23%). LCMS: m / z = 442 [M+H] +,1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.85(d,1H),8.78(s,1H),8.24(dd,,1H),8.15(d,1H),7.86(dd,1H), 7.57-7.49(m,1H),7.48(d,1H),7.12(td,1H),5.57(p,1H),3.25(dd,1H),2.96-2.73(m,4H),2.36(s,3H).

[0929] Examples 25 and 26

[0930] (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0931]

[0932] Example 6 (28 mg, 0.07 mmol) was purified by chiral HPLC as follows: column: CHIRALPAK IF, 2*25 cm, 5 μm; mobile phase A: hexane (0.2% DEA), mobile phase B: MeOH:DCM=2:1; flow rate: 20 mL / min; isocratic: 35% B; to obtain peak 1 (isomer 1), i.e., (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide or (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (7.3 mg, 26%) as a white solid. LCMS: m / z=410[M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.85(dt,1H),8.79(s,1H),8.24(dt,1H),8.16(d,1H),7.86(dd,1H),7.5 3(ddd,1H),7.48(d,1H),7.13(td,1H),4.99-4.83(m,2H),2.36(s,3H),1.90-1.76(m,1H),1.73-1.60(m,1H).

[0933] and Peak 2 (Isomer 2), i.e., (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide or (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (8.2 mg, 29%) as a white solid. LCMS: m / z=410 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.85(dt,1H),8.79(s,1H),8.24(dt,1H),8.16(d,1H),7.86(dd,1H),7.5 3(ddd,1H),7.48(d,1H),7.13(td,1H),4.99-4.83(m,2H),2.36(s,3H),1.90-1.76(m,1H),1.73-1.62(m,1H).

[0934] Example 27

[0935] 5-amino-N-(2-chloro-5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0936]

[0937] Step 1: Synthesis of 5-bromo-N-(2-chloro-5-cyanophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0938] To a solution of 3-amino-4-chlorobenzonitrile (250 mg, 1.64 mmol) in pyridine (8 mL) was added 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (425 mg, 1.64 mmol) and the reaction mixture was stirred for 30 min. The reaction was quenched with water and the resulting solid was filtered off and dried to obtain the title compound (507 mg, 82%). LCMS m / z = 377 [M+H] + .

[0939] Step 2: Synthesis of 5-amino-N-(2-chloro-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0940] To a solution of 5-bromo-N-(2-chloro-5-cyanophenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (589 mg, 1.57 mmol) and ammonium chloride (252 mg, 4.70 mmol) in DMF (7.84 mL) was added sodium azide (306 mg, 4.70 mmol) at rt. The mixture was heated at 150 ° C for 1 h under microwave irradiation. The mixture was quenched with water and acidified with HCl until pH = 2. The solid was filtered off and purified by reverse phase HPLC to obtain the title compound (35 mg, 6.29%). LCMSm / z = 355 [M + H] + .

[0941] Step 3: Synthesis of 5-amino-N-(2-chloro-5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0942] Following the procedure described in Example 2, the title compound (6.3 mg, 14.4% yield) was obtained from 5-amino-N-(2-chloro-5-(2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and 2-(bromomethyl)-1,1-difluorocyclopropane. LCMS m / z = 445 [M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.38(s,1H),8.51(q,2H),8.41(dd,1H),7.88(d,1H),7.74(dd,1H), 7.15(d,1H),6.57-6.48(m,2H),6.22(s,2H),5.00-4.87(m,2H),1.84(dq,1H),1.67(dt,1H).

[0943] Example 28

[0944] N-(5-(2-Cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0945]

[0946] To a stirred solution of intermediate 1 (100 mg, 0.31 mmol) in DCE (2 mL) was added Cu(OAc) (56.8 mg, 0.31 mmol), NaCO (66.3 mg, 0.63 mmol), 2,2'-bipyridine (48.8 mg, 0.31 mmol) and cyclopropylboronic acid (53.7 mg, 0.63 mmol), and the reaction was heated to 60 ° C under O and stirred for 12 h. The mixture was cooled to rt and filtered. The filter cake was washed with DCM (20 mL) and the filtrate was concentrated under vacuum. Water (20 mL) was added and the resulting solution was extracted with DCM (3×20 mL). The organic layer was dried over NaSO and concentrated under vacuum. The crude product was purified by preparative HPLC method E, gradient: 38% B to 55% B in 8 min to obtain the title compound (29.4 mg, 26%) as a white solid. LCMS: m / z=360[M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.85(dt,1H),8.78(s,1H),8.24(dt,1H),8.13(d,1H),7.83(dd,1H),7 .53(ddd,1H),7.46(d,1H),7.13(td,1H),4.47(tt,1H),2.35(s,3H),1.45-1.30(m,2H),1.33-1.21(m,2H).

[0947] Example 29

[0948] N-(5-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0949]

[0950] Step 1: Synthesis of N-(5-bromo-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0951] A mixture of pyrazolo[1,5-a]pyridine-3-carboxylic acid (500 mg, 3.08 mmol), 5-bromo-2-methylaniline (573 mg, 3.08 mmol), DMAP (564 mg, 4.62 mmol) and EDCI (885 mg, 4.62 mmol) in DMF (10 mL) was stirred at 50 ° C for 3 h. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column using 5% MeOH in DCM to obtain the title compound (300 mg, 29.7%) as a yellow solid. LCMS: m / z = 330 [M + H] + .

[0952] Step 2: Synthesis of N-(2-methyl-5-((trimethylsilyl)ethynyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0953] To a solution of N-(5-bromo-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (300 mg, 0.91 mmol) and Pd(PPh 3 ) 2 Cl 2 (64 mg, 0.91 mmol) in DMF (10 mL) at 0° C., trimethyl(2-(tributylstannyl)ethynyl)silane (1.05 g, 2.72 mmol) was added, and the reaction mixture was stirred at 100° C. for 2 h. The cooled mixture was concentrated to dryness and the residue was purified by silica gel column using PE:EtOAc=3:1 to obtain the title compound (200 mg, 63.4%) as a yellow solid. LCMS: m / z=348[M+H] + .

[0954] Step 3: Synthesis of N-(5-ethynyl-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0955] A mixture of N-(2-methyl-5-((trimethylsilyl)ethynyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (200 mg, 0.58 mmol) and TBAF (449 mg, 1.72 mmol) in THF (10 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to dryness and the residue was purified on a silica gel column using 5% MeOH in DCM to afford the title compound (120 mg, 75.9%) as a yellow solid. LCMS: m / z=276 [M+H] + .

[0956] Step 4: Synthesis of N-(2-methyl-5-(2H-1,2,3-triazol-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0957] To a stirred solution of N-(5-ethynyl-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (120 mg, 0.44 mmol), CuSO4·5H2O (22 mg, 0.09 mmol) and sodium ascorbate (5 mg, 21 μmol) in t-BuOH / H2O (1.5 mL / 1.5 mL) was added TMSN3 (250 mg, 2.18 mmol) dropwise, and the reaction mixture was heated at 80 ° C for 16 h. The mixture was cooled to rt, diluted with DCM / H2O (10 mL / 2 mL), the phases were separated, and the aqueous phase was extracted with DCM (10 mL). The combined organic extracts were dried and concentrated. The residue was purified by reverse phase chromatography (MeCN / H2O=30%) to obtain the title compound (70 mg, 50%) as a yellow oil. LCMS: m / z=319 [M-56+H] + .

[0958] Step 5: Synthesis of N-(5-(2-cyclopropyl-2H-1,2,3-triazol-4-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0959] Following a procedure similar to that described in Example 28, the title compound (6.8 mg, 8.7%) was obtained as an off-white solid from N-(2-methyl-5-(2H-1,2,3-triazol-4-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and cyclopropylboronic acid. The crude product was purified by HPLC Method C, 31% to 59% gradient. LCMS: m / z = 359 [M+H] + ,1HNMR(400MHz,DMSO-d6)δ9.70(s,1H),8.84(d,1H),8.77(s,1H),8.27-8.18(m,2H),7.85(d,1H),7.62(dd,1 H),7.56-7.48(m,1H),7.36(d,1H),7.15-7.08(m,1H),4.15(tt,1H),2.29(s,3H),1.24(s,2H),1.11(td,2H).

[0960] Example 30

[0961] N-(5-(2-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0962]

[0963] To a solution of intermediate 1 (80 mg, 0.25 mmol), PPh3 (131 mg, 0.50 mmol) and (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (58.0 mg, 0.50 mmol) in THF (5 mL) was added DIAD (101 mg, 0.50 mmol) at 0 ° C., and the reaction mixture was stirred at rt for 2 h. The resulting solution was washed with water and extracted with EtOAc (3×50 mL), and the combined organic phases were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative TLC using EtOAc:PE=2:1 and further purified by preparative HPLC method B, 35% to 68% gradient to obtain the title compound (37.0 mg, 35%) as a white solid. LCMS: m / z=418[M+H] + ,1H NMR(300MHz,DMSO-d6)δ9.76(s,1H),8.86(d,1H),8.80(s,1H),8.25(d,1H),8.15(d,1H),7.85 (dd,1H),7.60-7.48(m,1H),7.48(d,1H),7.13(td,1H),5.14(s,2H),2.37(s,3H),2.08(d,6H).

[0964] Examples 31 to 35

[0965] The compounds in the table below were prepared from Intermediate 1 and the appropriate alcohol following conditions similar to those described in Example 30.

[0966]

[0967]

[0968] Example 36

[0969] N-(2,4-Dimethyl-5-(2-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0970]

[0971] To a solution of intermediate 3 (50 mg, 0.15 mmol) and 4,4,4-trifluoro-3-methylbutane-1,3-diol (WO2018215801, 23.7 mg, 0.15 mmol) in THF (1 mL) was added DIAD (35.0 μL, 0.18 mmol) and PPh3 (47.2 mg, 0.18 mmol), and the reaction mixture was stirred for 4 h. The mixture was filtered and purified by reverse phase HPLC to produce the title compound (13.3 mg, 18.7%). LCMS m / z = 474 [M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.62(s,1H),8.77(d,1H),8.69(d,1H),8.16(d,1H),7.91(d,1H),7.44(t,1H),7.24(s,1H),7.0 4(t,1H),6.18(s,1H),4.92-4.82(m,1H),4.82-4.74(m,1H),2.50(d,3H),2.37-2.29(m,1H),2.24(d,4H),1.26(s,3H).

[0972] Examples 37 to 42

[0973] The compounds in the table below were obtained from Intermediate 1 and the appropriate alcohol following a procedure similar to that described in Example 30. The resulting racemic compounds were separated by chiral HPLC as detailed in the table to provide the desired compounds.

[0974]

[0975]

[0976]

[0977] Example 43

[0978] N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0979]

[0980] A mixture of intermediate 13 (100 mg, 0.24 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70.4 mg, 0.36 mmol), XPhos (15 mg, 0.03 mmol), XPhos Pd G3 (15 mg, 0.02 mmol) and Cs2CO3 (118 mg, 0.36 mmol) in dioxane (9 mL) and H2O (3 mL) was stirred at 100 ° C for 3 h. The reaction was concentrated to dryness, and the residue was purified by preparative TLC using DCM:MeOH=20:1. The product was purified by preparative HPLC method B, 20% to 44% gradient to provide the title compound (33.6 mg, 34.7%) as a white solid. LCMS: m / z=400 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.62(s,1H),8.82(dd,1H),8.73(s,1H),8.51-8.33(m ,2H),8.23(d,1H),8.09(s,1H),7.82(dd,1H),7.50-7.38(m,2H),4.43(s,3H),2.38(s,3H).

[0981] Example 44

[0982] N-(2-methyl-5-(2-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0983]

[0984] A mixture of intermediate 12 (130 mg, 0.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (72.7 mg, 0.38 mmol), XPhos Pd G3 (31.72 mg, 0.04 mmol) and K2CO3 (69.06 mg, 0.50 mmol) in THF (2 mL) and H2O (0.4 mL) was stirred at 80°C under N2 for 16 h, and the reaction was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc=2:1) ​​and the product was further purified by the following preparative SFC: column: Lux 3um Cellulose-4, 4.6*100 mm, 3um; mobile phase B: MeOH (0.5% 2M NH3-MeOH); flow rate: 4 mL / min; gradient: isocratic 50% B; to obtain Peak 1, N-(2-methyl-5-(2-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or N-(2-methyl-5-(2-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (27.8 mg, 9.5%) as a white solid. LCMS: m / z=508[M+H] + ;1H NMR(400MHz,DMSO-d6)δ13.20(s,1H),9.69(s,1H),8.87-8.80(m,1H),8.74(s,1H),8.46(s,1H),8.39-8.33(m,1H),8.21(d,1H ),8.10(s,1H),7.87(dd,1H),7.53-7.40(m,2H),5.58(p,1H),3.30-3.18(m,1H),2.94-2.88(m,2H),2.81(dt,2H),2.39(s,3H).

[0985] Example 45

[0986] Methyl 3-(5-(3-(5-((2-methoxyethyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0987]

[0988] Step I: Synthesis of ethyl 5-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate

[0989] TFA (3 mL) was added to intermediate 41 (600 mg, 1.76 mmol) in DCM (8 mL), and the reaction was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 aqueous solution (100 mL×3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide the title compound (300 mg, 71.2%) as a yellow solid. LCMS: m / z=239.0 [M+H] + .

[0990] Step 2: Synthesis of ethyl 4-chloro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[0991] Following the procedure described in Intermediate 28, the title compound was obtained as a brown solid from ethyl 5-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate and 1-bromo-2-methoxyethane (300 mg, 80.6%). LCMS: m / z = 298 [M+H] + .

[0992] Step 3: Synthesis of methyl 3-(5-(3-(4-chloro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0993] To ethyl 4-chloro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate (300 mg, 1.0 mmol) and methyl 3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (step 4 of Intermediate 11, 288 mg, 1 mmol) in toluene (10 mL) was added MeAl (2 M in toluene, 1 mL) dropwise at 0 °C and the reaction was heated to 100 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL×3) and saturated brine (100 mL). The organic layer was dried over NaSO, filtered and evaporated. The residue was purified by preparative TLC using DCM:MeOH=30:1 to provide the title compound (110 mg, 20.4%) as a brown solid. LCMS: m / z=540[M+H] + .

[0994] Step 4: Synthesis of methyl 3-(5-(3-(5-((2-methoxyethyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[0995] Following a similar procedure to that described in Example 44, the title compound (3.6 mg) was obtained as a white solid from methyl 3-(5-(3-(4-chloro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane. The residue was purified by preparative HPLC method 0, 25% to 45% gradient. LCMS: m / z = 520 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.46(d,,1H),8.31(s,1H),8.21(d,1H),7.83(dd,1H),7.44(d,1H),6.73(d,1H),5.91(tt, 1H),5.68(s,1H),4.56(t,2H),4.39(s,2H),3.63(s,3H),3.50(d,2H),3.43(s,2H),3.21-3.31(m,3H),2.40(s,3H),2.35(s,3H).

[0996] Example 46

[0997] N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0998]

[0999] A mixture of intermediate 4 (150 mg, 0.31 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (73.1 mg, 0.31 mmol), Pd(dppf)Cl (22.4 mg, 0.031 mmol) and NaCO (65.1 mg, 0.61 mmol) in dioxane (8 mL) and H0 (2 mL) was stirred at 100 °C under N for 3 h. The reaction mixture was cooled to rt and then diluted with water (25 mL). The resulting solution was extracted with EtOAc (2 x 40 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under vacuum. The product was purified by HPLC method E, 38% to 58% gradient to afford the title compound as a white solid (55.1 mg, 34.6%). LCMS: m / z = 520 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ9.66(s,1H),8.81(dd,1H),8.73(s,1H),8.40(d,1H),8.32(dd,1H),8.21(d,1H),8.05(d,1H),7.85(dd, 1H),7.47(d,1H),7.37(dd,1H),5.67-5.50(m,1H),5.02-4.87(m,1H),4.18(t,2H),3.77(d,2H),3.63-3.35(m,4H),2.37(s,3H).

[1000] Example 47

[1001] 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1002]

[1003] To a solution of intermediate 13 (80 mg, 0.19 mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (46.1 mg, 0.19 mmol) in dioxane (2 mL) and H2O (0.5 mL) was added K2CO3 (26.7 mg, 0.19 mmol) and Pd(dppf)Cl2 (158 mg, 0.19 mmol) at rt under N2, and the reaction mixture was stirred at 80 °C for 2 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated under vacuum and purified by preparative HPLC method C, 13% to 43% gradient to afford the title compound (5.6 mg, 6%) as a white solid. LCMS: m / z=444[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.86-8.70(m,2H),8.43(d,1H),8.34(dd,1H),8.24(d,1H),8.07(d ,1H),7.82(dd,1H),7.50-7.34(m,2H),4.97(t,1H),4.43(s,3H),4.19(t,2H),3.78(q,2H),2.38(s,3H).

[1004] Examples 48 to 52

[1005] The compounds in the table below were prepared following similar procedures to those described in Example 47 from the appropriate bromopyrazolo[1,5-a]pyridine and boronate ester.

[1006]

[1007] Examples 53 and 54

[1008] (R)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and (S)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1009]

[1010] A mixture of intermediate 13 (200 mg, 0.49 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (244 mg, 0.97 mmol), Pd(dppf)Cl (20 mg, 24.4 μmol) and CsCO (316 mg, 0.97 mmol) in dioxane (10 mL) and H0 (3 mL) was stirred at 100 °C under N for 2 h. The mixture was concentrated to dryness and the residue was purified by preparative TLC using DCM:MeOH = 20:1. The product was further purified by HPLC using the following column: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2M NH3-MeOH), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL / min; isocratic: 70% B to provide peak 1 (isomer 1), i.e. (R)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and (S)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (54.4 mg) as white solids. LCMS: m / z=458[M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.82(d,1H),8.74(s,1H),8.39(s,1H),8.34(d,1H),8.24(d,1H),8.06(s,1H) ,7.82(dd,1H),7.47(d,1H),7.38(dd,1H),4.97(d,1H),4.43(s,3H),4.08-4.00(m,3H),2.38(s,3H),1.07(d,3H).

[1011] and Peak 2 (Isomer 2), i.e., (S)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide or (R)-5-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (54.9 mg) as a white solid. LCMS: m / z=458 [M+H] +,1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.82(d),8.73(s,1H),8.39(s,1H),8.36-8.31(m,1H),8.23(d,1H),8.05(s,1H ),7.82(dd,1H),7.47(d,1H),7.38(dd,1H),4.97(d,1H),4.43(s,3H),4.08-4.00(m,3H),2.38(s,3H),1.07(d,3H).

[1012] Examples 55 and 56

[1013] (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide and (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1014]

[1015] To a solution of intermediate 5 (100 mg, 0.20 mmol) in dioxane (1 mL) and H2O (0.3 mL) was added Pd(dppf)Cl2 (14.8 mg, 0.02 mmol), K2CO3 (56.3 mg, 0.41 mmol), (1H-pyrazol-4-yl)boronic acid (45.6 mg, 0.41 mmol), and the reaction was stirred at 100 ° C. under N2 for 2 h and then cooled to rt. Water (10 mL) was added and the resulting solution was extracted with DCM (3×20 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column using PE:EtOAc=1:3 to obtain N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (85 mg; 88%) as a light yellow solid.

[1016] This solid was further purified by the following preparative chiral HPLC: column: CHIRALPAK ID, 2*25 cm, 5 μm; mobile phase A: hexane (0.2% DEA), mobile phase B: EtOH: MeOH = 2:1; flow rate: 20 mL / min; isocratic: 50% B; to obtain Peak 1 (Isomer 1): (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (23.3 mg; 28%) as a white solid. LCMS: m / z=476[M+H] + ,1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.65(s,1H),8.82(dd,1H),8.73(s,1H),8.46(s,1H),8.35(dd,1H),8.21(d,1H),8.08(s,1H) ,7.85(dd,1H),7.48(d,1H),7.42(dd,1H),4.99-4.83(m,2H),2.56-2.54(m,1H),2.38(s,3H),1.90-1.76(m,1H),1.71-1.64(m,1H).

[1017] and Peak 2 (Isomer 2): (S)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or (R)-N-(5-(2-((2,2-difluorocyclopropyl)methyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (27.2 mg; 32%) as a white solid. LCMS: m / z=476 [M+H +], 1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.65(s,1H),8.82(dd,1H),8.73(s,1H),8.45(s,1H),8.36(dd,1H),8.21(d,1H),8.09(s,1H),7.85(d d,1H),7.48(d,1H),7.42(dd,1H),4.99-4.89(m,1H),4.88(dd,1H),2.54-2.52(m,1H),(2.38(s,3H),1.85-1.82(m,1H),1.73-1.60(m,1H).

[1018] Example 57

[1019] 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1020]

[1021] Step 1: Synthesis of 5-bromo-N-(2-methyl-5-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1022] Following the procedure described in step 1 of Example 27, the title compound was obtained as an off-white solid (199 mg, 90% yield) from 2-methyl-4-(4-methyl-2H-1,2,3-triazol-2-yl)aniline and 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride. LCMS m / z = 411 [M+H] + .

[1023] Step 2: Synthesis of 5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-N-(2-methyl-5-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1024] A mixture of 5-bromo-N-(2-methyl-5-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (50 mg, 0.12 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (35 mg, 0.15 mmol), Pd(dppf)Cl2 (4.45 mg, 0.006 mmol) and Na2CO3 (39 mg, 0.37 mmol) was combined in dioxane (0.75 mL) and water (0.25 mL) under N2 and heated to 90°C for 5 h. The mixture was concentrated in vacuo and purified by reverse phase ISCO (5% to 100% MeCN / water with 0.1% TFA) to afford the title compound as an off-white solid (26.8 mg). LCMS: m / z = 443 [M+H] + , 1 H NMR(500MHz,DMSO-d6)δ9.59(s,1H),8.82(dd,1H),8.74(d,1H),8.43(d,1H),8.34(s,1H),8.21(d,,1H),8.07(d ,1H),7.88(d,1H),7.74(d,1H),7.43(d,1H),7.39(d,1H),4.95(dt,1H),4.20(t,2H),3.79(q,2H),2.37(d,6H).

[1025] Example 58

[1026] 3-(5-(3-(5-(3-methoxypropyl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1027]

[1028] NHC-1 (85.7 mg, 0.217 mmol) was added to 3-methoxypropan-1-ol (24.5 mg, 0.27 mmol) in t-BuOMe (4 mL) at rt, the mixture was purged with N2, then pyridine (16.0 mg, 0.27 mmol) in t-BuOMe (4 mL) was added, and the reaction mixture was stirred for 10 min to obtain solution 1.

[1029] At rt, a mixture of intermediate 11 (70 mg, 0.14 mmol), Ir (ppy) 2 (dtbbpy) PF6 (12.4 mg, 0.27 mmol), NiBr2 (dtbbpy) (15 mg, 0.32 mmol) and quinuclidine (30.1 mg, 0.27 mmol) in DMA (5 mL) was purged with N2. Filter and then add solution 1, and the reaction mixture was stirred under a blue LED light for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL × 2), the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC using DCM: MeOH = 25: 1. The product was further purified by preparative HPLC method B, 27% to 47% gradient to obtain the title compound (3.4 mg) as an off-white solid. LCMS: m / z = 505 [M + H] + ;1H NMR(400MHz,DMSO-d6)δ9.69(s,1H),8.78-8.71(m,2H),8.19(d,1H),8.04(dd,1H),7.87(dd,1H),7.48(d,1H),7.01(dd,1H),5. 91(tt,1H),4.57(s,2H),4.38(s,2H),3.63(s,3H),3.34(s,2H),3.24(s,3H),2.79-2.71(m,2H),2.36(s,3H),1.93-1.81(m,2H).

[1030] Example 59

[1031] N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-4-fluoro-2-methylphenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[1032]

[1033] To a stirred solution of intermediate 7 (200 mg, 0.40 mmol) in dioxane (5 mL) was added morpholine (68.8 mg, 0.79 mmol), Cs2CO3 (257 mg, 0.79 mmol), RuPhos (36.8 mg, 0.08 mmol) and RuPhos Pd G3 (33 mg, 0.04 mmol), and the reaction was stirred at 80 ° C under N2 for 3 h. The mixture was diluted with EtOAc (50 mL) and water (50 mL), the aqueous phase was extracted with EtOAc (3×40 mL) and the combined organic phases were washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC method F, 43% to 58% gradient to obtain the title compound (33 mg, 16%) as a white solid. LCMS: m / z=513[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.63-8.56(m,2H),8.10(d,1H),7.43-7.33(m,2H) ,6.99(dd,1H),5.62(dd,1H),3.76(t,4H),3.50-3.42(m,4H),3.29(t,4H),2.35(s,3H).

[1034] Examples 60 to 64

[1035] The compounds in the table below were prepared following similar procedures to those described in Example 59 from the appropriate 5-bromopyrazolo[1,5-a]pyridine and amine.

[1036]

[1037]

[1038] Example 65

[1039] 3-(5-(3-(5-(3-hydroxy-3-methylbutyloxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1040]

[1041] To a solution of intermediate 11 (30 mg, 0.06 mmol) and 3-methylbutane-1,3-diol (12.22 mg, 0.12 mmol) in toluene (1 mL) was added RuPhos Pd G3 (4.92 mg, 5.87 μmol) and Cs2CO3 (57.3 mg, 0.18 mmol) under N2, and the reaction mixture was heated at 90 ° C overnight. The reaction was quenched with water and extracted with EtOAc. The residue was purified by reverse phase HPLC and then by preparative TLC to give the title compound (2.2 mg, 7.0%). LCMSm / z=535[M+H] + .

[1042] Example 66

[1043] 3-(5-(4-methyl-3-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1044]

[1045] A mixture of intermediate 11 (70 mg, 0.14 mmol), 1-methylpiperidine (21 mg, 0.21 mol), RuPhos Pd G3 (5.73 mg, 0.07 mmol) and Cs2CO3 (134 mg, 0.41 mmol) in dioxane (1 mL) was stirred at 90° C. under N2 for 1 h. The reaction was diluted with EtOAc and purified by The mixture was filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by reverse phase chromatography using ISCO (5% to 100% MeCN / water containing 0.1% TFA) and the product was partitioned between 10% MeOH / DCM and aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title compound (45.8 mg) as a white foam. LCMS m / z = 531 [M+H] + , 1H NMR (500 MHz, DMSO-d6) δ9.44 (s, 1H), 8.59 (d, 1H), 8.58-8.55 (m, 1H), 8.22 (d, 1H), 7.88-7.81 (m, 1H), 7.50-7.44 (m, 1H), 7.37 (t, 1H), 6.99 (dt, 1H), 5.92 (tp, 1H), 4.57 (t, 2H), 4.39 (d, 2H), 3.64 (d, 3H), 2.47 (t, 4H), 2.37 (s, 3H), 2.24 (s, 3H). The four hexahydropyrazine protons are buried under the DMSO peak.

[1046] Examples 67 to 84

[1047] The compounds in the table below were prepared from the appropriate bromopyrazolo[1,5-a]pyridine, intermediate 4, 11, 14 or 18 and an amine following similar procedures as described in Example 66 using the alternative purification conditions described in the table below.

[1048]

[1049]

[1050]

[1051]

[1052] Example 85

[1053] (S)-3-(5-(3-(5-(2-(methoxymethyl)azetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester or (R)-3-(5-(3-(5-(2-(methoxymethyl)azetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1054]

[1055] A mixture of intermediate 11 (100 mg, 0.20 mmol), 2-(methoxymethyl)azetidine (29.5 mg, 0.29 mmol), RuPhos Pd G3 (94.4 mg, 0.29 mmol) and Cs 2 CO 3 (17.1 mg, 0.20 mmol) in dioxane (10 mL) was stirred at 100 ° C under N 2 for 16 h. The reaction was concentrated to dryness and the residue was purified by preparative TLC using DCM: MeOH = 20: 1. The product was purified by preparative chiral HPLC (column: DZ-CHIRALPAK The product was separated on IH-3, 4.6*50mm, 3.0μm; mobile phase A: hexane (0.2% DEA): (EtOH: DCM = 1: 1) = 75:25) to provide Peak 1 (Isomer 1), i.e., (S)-3-(5-(3-(5-(2-(methoxymethyl)azetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester or (R)-3-(5-(3-(5-(2-(methoxymethyl)azetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester (12.1 mg) as a white solid. LCMS: m / z=532[M+H] + ;1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.58-8.50(m,2H),8.23-8.18(m,1H),7.87-7.80(m,1H),7.45(d,1H),7.01(d,1H),6.62( dd,1H),5.92(td,1H),4.56(s,2H),4.38(s,3H),3.97(s,1H),3.73(d,1H),3.63(d,5H),3.36(s,3H),2.35(s,4H),2.17(d,1H).

[1056] Example 86

[1057] (S)-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or (R)-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1058]

[1059] Following the procedure described in Example 85, N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (80 mg) was obtained as a yellow solid from intermediate 4 and 3-methylpyrrolidin-3-ol.

[1060] This compound was further purified by the following chiral preparative HPLC: column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: hexane (0.2% DEA), mobile phase B: EtOH: DCM = 1:1; flow rate: 20 mL / min; isocratic gradient: 50% B to provide Peak 1 (Isomer 1) (20.7 mg, white solid) and Peak 2 (Isomer 2): (S)-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide or (R)-N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (21.3 mg) as a white solid. LCMS: m / z=509 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.55-8.48(m,2H),8.20(d,1H),7.82(dd,1H),7.45(d,1H),6.91(d,1H),6.58(dd ,1H),5.60(ddd,1H),4.90(s,1H),3.48-3.38(m,2H),3.32(s,6H),3.28(d,2H),2.36(s,3H),1.95(t,2H),1.37(s,3H).

[1061] Example 87

[1062] 5-((2-methoxyethyl)amino)-N-(2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1063]

[1064] To a solution of intermediate 13 (80 mg, 0.194 mmol) and 2-methoxyethyl-1-amine (17.4 mg, 0.39 mmol) in dioxane (2 mL) was added CsCO (127 mg, 0.39 mmol), Xantphos (11.2 mg, 19.4 μmol) and Pd(dba) (177 mg, 0.19 mmol) under N2, and the reaction mixture was stirred at 80 ° C for 2 h. The reaction was washed with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was concentrated under vacuum and purified by preparative HPLC method C, 58% to 75% gradient to obtain the title compound (36.0 mg, 45%) as a white solid. LCMSm / z=407[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.49(s,1H),8.39(d,1H),8.21(d,1H),7.78(dd,1H),7.43(d,1H ),6.97(d,1H),6.78(t,1H),6.60(dd,1H),4.43(s,3H),3.55(t,2H),3.33-3.23(m,5H),2.35(s,3H).

[1065] Example 88

[1066] N-(5-(2-cyclopropyl-2H-tetrazol-5-yl)-2-methylphenyl)-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamide

[1067]

[1068] Following a similar procedure to that described in Example 87, the title compound (45.7 mg, 30.9%) was obtained as a white solid from intermediate 30 and 2-methoxyethylamine. The crude product was purified by reverse phase HPLC method F, 37% to 56% gradient. LCMS: m / z = 433 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.49(s,1H),8.39(d,1H),8.16(d,1H),7.78(dd,1H),7.43(d,1H),6.97(d,1H),6.7 8(t,1H),6.60(dd,1H),4.47(tt,1H),3.55(t,2H),3.29-3.22(m,2H),2.34(s,3H),1.47-1.36(m,2H),1.35-1.19(m,2H).

[1069] Example 89

[1070] 3-(5-(3-(5-((2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1071]

[1072] A mixture of intermediate 11 (100 mg, 0.20 mmol), 1-amino-2-methylpropan-2-ol (52.1 mg, 0.59 mmol), Pd2(dba)3 (35.7 mg, 0.04 mmol), XantPhos (45.1 mg, 0.08 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in dioxane (4 mL) was stirred at 100 ° C under N2 atmosphere for 2 h. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (EtOAc). The product was further purified by preparative HPLC-method C, 28% to 47% gradient to provide the title compound (23.6 mg, 22.7%) as a white solid. LCMS: m / z=520 [M+H + ], 1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.48(s,1H),8.37(d,1H),8.22(d,1H),7.83(dd,1H),7.45(d,1H),7.00(d,1H),6.74(d d,1H),6.51(t,1H),5.91(m,1H),4.61(s,1H),4.57(m,2H),4.39(m,2H),3.63(s,3H),3.01(d,2H),2.35(s,3H),1.19(s,6H).

[1073] Example 90

[1074] (S)-methyl 3-(5-(3-(5-(2-(hydroxymethyl)azetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1075]

[1076] A mixture of intermediate 11 (100 mg, 0.2 mmol), ((2S)-azetidin-2-yl)methanol (50.9 mg, 0.59 mmol), Pd2(dba)3 (35.7 mg, 0.4 mmol), XantPhos (45.1 mg, 0.08 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in dioxane (4 mL) was stirred at 100 ° C under N2 for 2 h. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (EtOAc). The crude product was purified by preparative HPLC-Method C, 19% to 49% gradient to provide the title compound (32.3 mg, 31.1%) as an off-white solid. LCMS: m / z=518 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.57-8.49(m,2H),8.20(d,1H),7.83(dd,1H),7.45(d,1H),6.98(d,1H),6.67(dd,1H),5.93-5.89(m,1 H),5.11(t,1H),4.56(s,2H),4.38(s,2H),4.25(s,1H),4.01-3.91(m ,1H),3.73-3.67(m,3H),3.63(s,3H),2.35(s,4H),2.18-2.16(m,1H).

[1077] Examples 91 to 113

[1078] The compounds in the table below were prepared from appropriate intermediates and amines following similar procedures as described in Example 90. Alternative purification conditions are highlighted in the table below.

[1079]

[1080]

[1081]

[1082]

[1083]

[1084] Example 114

[1085] 3-(5-(2-fluoro-5-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1086]

[1087] Step 1: Synthesis of methyl 3-(5-(5-amino-2-fluoro-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1088] To a solution of step 1 (150 mg, 0.78 mmol) of intermediate 7, methyl 3-hydroxyazetidine-1-carboxylate (152 mg, 1.16 mmol) and PPh3 (607 mg, 2.32 mmol) in THF (5 mL) was added DIAD (313 mg, 1.55 mmol) at 0 ° C under N2, and the reaction mixture was stirred at rt for 2 h. Water (30 mL) and EtOAc (50 mL) were added, the organic phase was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to obtain a crude product. This crude product was purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (120 mg, 51%) as a white solid. LCMS: m / z=307[M+H] + .

[1089] Step 2: Synthesis of methyl 3-(5-(5-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-2-fluoro-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1090] 3-(5-(5-amino-2-fluoro-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester (50 mg, 0.16 mmol), pyridine (25.7 mg, 0.33 mmol), 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (58.8 mg, 0.24 mmol) and A mixture of (155 mg, 0.49 mmol) in THF (3 mL) was stirred at 60 ° C for 2 h and cooled to rt. Water (30 mL) and EtOAc (50 mL) were added, the organic phase was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated. The crude product was purified by preparative TLC using EtOAc to obtain the title compound (60 mg, 69%) as a white solid. LCMS m / z = 529 [M + H] + .

[1091] Step 3: Synthesis of methyl 3-(5-(2-fluoro-5-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1092] To a stirred solution of methyl 3-(5-(5-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-2-fluoro-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (50 mg, 0.09 mmol), XantPhos (5.45 mg, 0.09 mmol), Pd(dba) (8.63 mg, 0.09 mmol), and CsCO (61.0 mg, 0.19 mmol) in dioxane (4 mL) was added 2-methoxyethan-1-amine (10.5 mg, 0.14 mmol) under N. The mixture was stirred at 80° C. for 2 h and cooled to rt. Water (30 mL) and EtOAc (50 mL) were added, the organic phase was separated, and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated. The crude product was purified by preparative TLC using EtOAc and then by preparative HPLC-method B, 23% to 47% gradient to afford the title compound as a white solid (12.9 mg; 26%). LCMS: m / z = 524 [M+H] + ,1H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.47(s,1H),8.39(d,1H),8.11(d,1H),7.39(d,1H),6.95(d,1H),6.77(t,1H),6. 60(dd,1H),5.93(tt,1H),4.56(d,2H),4.39(s,2H),3.62(s,3H),3.54(t,2H),3.29(s,3H),3.25(q,2H),2.35(s,3H).

[1093] Example 115

[1094] 3-(5-(4-fluoro-3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1095]

[1096] Steps 1 to 3: Synthesis of methyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-fluorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1097] Following a similar 3-step procedure to that described in Intermediate 7, the title compound (35 mg) was obtained as a yellow solid from 3-amino-4-fluorobenzonitrile, methyl 3-hydroxyazetidine-1-carboxylate and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 516 [M+H] + .

[1098] Step 4: Synthesis of methyl 3-(5-(4-fluoro-3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1099] Following the procedure described in step 3 of Example 114, the title compound was obtained as a white solid (3.4 mg, 11.4% yield) from methyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-fluorophenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate and 2-methoxyethan-1-amine. LCMS: m / z = 510 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.58-8.51(m,1H),8.53(s,1H),8.40(d,1H),7.90(ddd,1H),7.49(dd,1H),6.99(d,1H ),6.82(t,1H),6.62(dd,1H),5.92(td,1H),4.57(s,2H),4.39(s,2H),3.63(s,3H),3.55(t,2H),3.32(s,3H),3.28(s,2H).

[1100] Example 116

[1101] 5-((2-methoxyethyl)amino)-N-(2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1102]

[1103] Step 1: Synthesis of 5-(4-methyl-3-nitrophenyl)-2-(4,4,4-trifluorobutyl)-2H-tetrazole

[1104] At 0 ° C, DIAD (590 mg, 2.92 mmol) was added dropwise to 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612, 300 mg, 1.46 mmol), 4,4,4-trifluorobutan-1-ol (280 mg, 2.19 mmol) and PPh3 (574 mg, 2.19 mmol) in THF (20 mL). The resulting mixture was stirred at 60 ° C for 2 h and then concentrated to dryness. The residue was purified on preparative TLC using PE: EtOAc = 8: 1 to provide the title compound (400 mg, 86.9%) as a colorless oil. LCMS: m / z = 316 [M + H] + .

[1105] Step 2: Synthesis of 2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)aniline

[1106] A mixture of 5-(4-methyl-3-nitrophenyl)-2-(4,4,4-trifluorobutyl)-2H-1,2,3,4-tetrazolyl (400 mg, 1.26 mmol) and SnCl2 (955 mg, 5.04 mmol) in EtOH (25 mL) was stirred at 80°C for 2 h and concentrated to dryness. The residue was purified on a silica gel column to provide the title compound (300 mg, 83.5%) as a yellow solid. LCMS: m / z = 286 [M+H] + .

[1107] Step 3: Synthesis of 5-bromo-N-(2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1108] Following a procedure similar to that described in step 2 of Example 114, the title compound (120 mg, 45.1%) was obtained as a yellow solid from 2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)aniline and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 510 [M+H] + .

[1109] Step 4: Synthesis of 5-((2-methoxyethyl)amino)-N-(2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1110] Following a procedure similar to that described in step 3 of Example 114, the title compound (71.1 mg, 56.4%) was obtained as a white solid from 5-bromo-N-(2-methyl-5-(2-(4,4,4-trifluorobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and 2-methoxyethan-1-amine. LCMS: m / z = 503 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.49(s,1H),8.39(d,1H),8.20(d,1H),7.80(dd,1H),7.44(d,1H),6.97(d,1H), 6.77(t,1H),6.60(dd,1H),4.84(t,2H),3.55(t,2H),3.32-3.22(m,5H),2.48-2.37(m,2H),2.35(s,3H),2.22(p,2H).

[1111] Example 117

[1112] N-(2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[1113]

[1114] Step 1: Synthesis of 4-bromo-2-chloro-5-(2H-tetrazol-5-yl)aniline

[1115] Following the procedure described in step 1 of intermediate 8, the title compound was obtained from 5-amino-2-bromo-4-chlorobenzonitrile as a yellow solid (300 mg, 50%). LCMS: m / z = 274 [M+H] + .

[1116] Step 2: Synthesis of 4-bromo-2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[1117] Following the procedure described in step 2 of intermediate 7, the title compound was obtained as a white solid from 4-bromo-2-chloro-5-(2H-tetrazol-5-yl)aniline and 3,3-difluorocyclobutan-1-ol (250 mg, 63%). LCMS: m / z = 364 [M+H] + .

[1118] Step 3: Synthesis of 2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline

[1119] To a stirred solution of 4-bromo-2-chloro-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline (100 mg, 0.27 mmol) and cyclopropylboronic acid (28.1 mg, 0.33 mmol) in dioxane (2 mL) and H2O (0.5 mL) was added K2CO3 (75.6 mg, 0.55 mmol) and Pd(dppf)Cl2 (22.3 mg, 27.4 μmol) at rt under N2. The reaction was stirred at 100 ° C. for 2 h and then cooled to rt. The mixture was diluted with water and extracted with DCM (2×30 mL). The organic layer was concentrated and purified by preparative TLC using PE:EtOAc=1:1 to obtain the title compound (80 mg; 89%) as a yellow solid. LCMS: m / z=326[M+H] + .

[1120] Step 4: Synthesis of 5-bromo-N-(2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1121] To a stirred solution of 2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)aniline (80 mg, 0.25 mmol) in pyridine (2 mL) was added 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (127 mg, 0.49 mmol), and the reaction was stirred at rt for 1 h and concentrated. The crude product was purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (90 mg; 67%) as a white solid. LCMS: m / z=548 [M+H] + .

[1122] Step 5: Synthesis of N-(2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[1123] Following a similar procedure to that described in step 3 of Example 114, the title compound (12.2 mg, 30%) was obtained as a grey solid from 5-bromo-N-(2-chloro-4-cyclopropyl-5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide and morpholine. The crude product was purified by preparative HPLC method J, 45% to 55% gradient. LCMS: m / z = 555 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.60(d,2H),8.14(s,1H),7.34(d,1H),7.26(s,1H),7.00(dd,1H),5.70 -5.56(m,1H),3.75(t,4H),3.44(dtd,4H),3.28(d,4H),2.57(td,1H),1.03-0.94(m,2H),0.82-0.74(m,2H).

[1124] Example 118

[1125] 3-(5-(3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1126]

[1127] Step 1: Synthesis of methyl 3-(5-(3-amino-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate

[1128] A mixture of intermediate 10 (80 mg, 0.26 mmol), 2-(methyl-d3)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75.1 mg, 0.52 mmol), XPhos Pd G3 (21.1 mg, 0.03 mmol) and K2CO3 (71.5 mg, 0.52 mmol) in dioxane / H2O (2 mL / 0.5 mL) was stirred at 80°C under N2 for 16 h. The reaction was extracted with EtOAc (50 mL×3), and the combined organic layers were concentrated in vacuo and purified by preparative TLC (PE:EtOAc=2:1) ​​to provide the title compound (65 mg; 86.2%) as a white solid. LCMS: m / z=292 [M+H] + .

[1129] Step 2: Synthesis of methyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1130] Following the procedure described in step 2 of Example 114, the title compound (50 mg, 47.6%) was obtained as a light yellow solid from methyl 3-(5-(3-amino-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate and 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 514 [M+H] + .

[1131] Step 3: Synthesis of methyl 3-(5-(3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1132] Following a similar procedure to that described in Example 89, the title compound (9.2 mg, 18.6%) was obtained as a white solid from methyl 3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-(methyl-d3)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate and 2-methoxyethan-1-amine. The crude compound was further purified by preparative HPLC method A, 27% to 45% gradient. LCMS: m / z = 509 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.49(s,1H),8.39(d,1H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),6.97(d,1H ),6.77(t,1H),6.60(dd,1H),5.91(tt,1H),4.56(t,2H),4.39(s,2H),3.63(s,3H),3.54(t,2H),3.32-3.22(m,5H).

[1133] Examples 119 to 124

[1134] The compounds in the table below were prepared from the appropriate 5-bromopyrazolo[1,5-a]pyridine and amine following similar procedures to those described in Example 89 and separating the diastereomers by HPLC as described in the table below.

[1135]

[1136]

[1137]

[1138] Example 125

[1139] 3-(2-(3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-5-yl)azetidine-1-carboxylic acid methyl ester

[1140]

[1141] To a solution of 2-methoxyethane-1-amine (17.5 mg, 0.23 mmol) and intermediate 20 (100 mg, 0.20 mmol) in dioxane (2 mL) was added CsCO (127 mg, 0.39 mmol), XantPhos (127 mg, 0.39 mmol) and Pd(dba) (17.8 mg, 0.02 mmol) under N2, and the reaction was stirred at 80 ° C for 2 h. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were concentrated under vacuum. The crude product was purified by preparative HPLC method B, 25% to 50% gradient to obtain the title compound (25 mg, 25%) as a white solid. LCMS: m / z=506[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.50(s,1H),8.40(d,1H),8.31(d,1H),7.81(dd,1H),7.52(d,1H),6.97(d ,1H),6.80(t,1H),6.61(dd,1H),4.44-4.12(m,5H),3.60(s,3H),3.55(t,2H),3.30-3.26(m,5H),2.39(s,3H).

[1142] Example 126

[1143] Ethyl 3-(5-(4-methyl-3-(5-(methylamino)pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1144]

[1145] A mixture of BrettPhos Pd G4 (6.76 mg, 7.33 μmol), intermediate 14 (75 mg, 0.15 mmol), methylamine hydrochloride (15 mg, 0.22 mmol) and Cs2CO3 (167 mg, 0.51 mmol) in dioxane (10 mL) was stirred at 90 ° C under N2 overnight. The mixture was concentrated in vacuo, the residue was partitioned between DCM and water and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated to obtain the crude product. This crude product was purified by silica gel ISCO chromatography (0 to 8% MeOH / DCM) to obtain a yellow glassy solid. This solid was further purified by reverse phase ISCO (0 to 100% MeCN / water containing 0.1% TFA). The fractions containing the product were concentrated in vacuo, the residue was triturated with aqueous NaHCO3, the resulting solid was filtered, washed with water and dried to obtain a white solid (26 mg). This solid was triturated with hot EtOH (1 mL), filtered, washed with EtOH and dried to afford the title compound as an off-white solid (15.7 mg, 22.5%). LCMS m / z = 476 [M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.50(d,1H),8.39(dd,1H),8.22(s,1H),7.84(d,1H),7.49-7.43(m,1H),6.92(d,1H),6.7 7-6.70(m,1H),6.56-6.48(m,1H),5.91(dt,1H),4.56(t,2H),4.39(d,2H),4.08(q,2H),2.77(s,3H),2.36(s,3H),1.21(t,3H).

[1146] Examples 127 to 130

[1147] The compounds in the following table were prepared following similar procedures to those described in Example 126 from appropriate intermediates and amines.

[1148]

[1149] Example 131

[1150] 3-(5-(3-(5-((2,2-difluoroethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1151]

[1152] A mixture of intermediate 11 (85 mg, 0.17 mmol), Cs2CO3 (162 mg, 0.5 mmol), 2,2-difluoroethane-1-amine (20 mg, 0.25 mmol) and Brettphos Pd G4 (7.66 mg, 8.31 μmol) in dioxane (1 mL) was heated to 90 ° C and maintained for 1 h. The mixture was concentrated in vacuo and the residue was partitioned between 5% MeOH / DCM and water and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated to obtain the crude product. This crude product was purified by silica gel chromatography on ISCO (0 to 8% MeOH / DCM) to obtain the title compound (6.4 mg, 76%) as a light yellow foam. LCMSm / z=512[M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.75(d,1H),8.86(d,1H),8.79(d,1H),8.26(d,1H),8.20(s,1H),7.90(d,1H),7.58-7.48(m,2H),7.13(t,1H),6.0 4-5.92(m,1H),4.49(dt,4H),3.79-3.69(m,2H),3.65-3.51(m,3H),3 .48-3.39(m,1H),3.23-3.15(m,1H),2.37(s,3H),1.90-1.70(m,2H).

[1153] Examples 132 to 141

[1154] The compounds in the table below were prepared from the appropriate bromopyrazolo[1,5-a]pyridine and amine following procedures similar to those described in Example 131. Alternative purification conditions are listed in the table below.

[1155]

[1156]

[1157]

[1158] A=DMF was used as the reaction solvent

[1159] Example 142

[1160] 3-(5-(3-(5-((2-hydroxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1161]

[1162] A mixture of intermediate 11 (100 mg, 0.20 mmol), 2-aminoethan-1-ol (17.8 mg, 0.29 mmol), RockPhos PdG3 (23 mg, 0.03 mmol) and Cs2CO3 (95.1 mg, 0.29 mmol) in dioxane (10 mL) was stirred at 100 ° C under N2 for 3 h. The mixture was concentrated to dryness and the residue was purified on preparative TLC using DCM:MeOH=20:1. The product was purified by preparative HPLC method C, 34% to 63%, as a white solid (9.1 mg, 9.5%). LCMS: m / z=492 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.51-8.33(m,2H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),6.97(d,1H),6.72(t ,1H),6.59(dd,1H),5.97-5.86(m,1H),4.81(t,1H),4.56(s,2H),4.38(s,2H),3.61(d,5H),3.16(q,2H),2.35(s,3H).

[1163] Example 143

[1164] 3-(5-(3-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1165]

[1166] Step 1: Synthesis of methyl 3-(5-(3-(6-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1167] To a stirred solution of Intermediate 11, step 4 (1.5 g, 5.20 mmol) in THF (15 mL) was added at rt. (4.96 g, 15.6 mmol), pyridine (821 mg, 10.4 mmol) and 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (2.50 g, 10.4 mmol). The mixture was stirred at 80 ° C for 12 h and then cooled to rt. Water (5 mL) was added and the resulting solution was extracted with DCM (3×20 mL). The organic layer was dried over Na 2 SO 4 and concentrated under vacuum. The crude product was purified by silica gel column using PE: EtOAc=1:2 to obtain the title compound (1.8 g, 68%) as an off-white solid. LCMS: m / z=511 [M+H] + .

[1168] Step 2: Synthesis of methyl 3-(5-(3-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1169] Following a similar procedure to that described in Example 142, the title compound (19.6 mg, 25%) was obtained as a white solid from methyl 3-(5-(3-(6-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate and 2-methoxyethan-1-ol. The crude product was purified by preparative HPLC method A, 30% to 52% gradient to obtain the title compound (19.6 mg, 25%) as a white solid. LCMS: m / z = 507 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.68(s,1H),8.58(d,1H),8.19-8.09(m,2H),7.88(dd,1H),7.48(d,1H),7.34(dd,1 H),5.91(td,1H),4.55(d,2H),4.38(s,2H),4.24-4.17(m,2H),3.74-3.67(m,2H),3.63(s,3H),3.34(s,3H),2.36(s,3H).

[1170] Example 144

[1171] Methyl 3-(5-(3-(5-((2-methoxyethyl)amino)-6-methylpyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1172]

[1173] Step 1: Synthesis of ethyl 6-bromo-5-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[1174] A solution of tert-butyl (3-bromopyridin-4-yl)carbamate (5 g, 18.3 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (9.09 g, 45.7 mmol) in MeCN (100 mL) was stirred at 50 ° C for 40 h. The mixture was evaporated under reduced pressure to obtain 1-amino-3-bromo-4-(((tert-butoxy)carbonyl)amino)pyridin-1-ium 2,4-dinitrobenzyl-1-olate (crude, 15 g). This alkoxide was dissolved in DMF (100 mL), K2CO3 (21.3 g, 155 mmol) was added, and the reaction mixture was stirred at rt for 1 h. Ethyl prop-2-ynoate (5.08 g, 51.8 mmol) was added, and the reaction mixture was stirred at rt for 18 h. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL × 3) and saturated brine (200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product. This crude product was purified by silica gel column using PE: EtOAc = 5: 1 to obtain the title compound (580 mg) and ethyl 4-bromo-5-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate (880 mg) as a yellow solid. LCMSm / z = 384 [M + H] + .

[1175] Step 2: Synthesis of ethyl 5-amino-6-bromopyrazolo[1,5-a]pyridine-3-carboxylate

[1176] TFA (2 mL) was added to ethyl 6-bromo-5-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate in DCM (8 mL), and the solution was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 solution (100 mL×3) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to obtain the title compound (200 mg, 90.4%) as a yellow solid. LCMS m / z=284 [M+H] + .

[1177] Step 3: Synthesis of ethyl 6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[1178] At 0 ° C, NaH (56.0 mg, 1.40 mmol) was added to 5-amino-6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (200 mg, 0.70 mmol) in DMF (10 mL) and after stirring for 30 min, 1-bromo-2-methoxyethane (145 mg, 1.05 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL×3) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide a crude product. This crude product was purified by preparative TLC using PE:EtOAc=4:1 to provide the title compound (140 mg, 58.3%) as a brown solid. LCMSm / z=342[M+H] + .

[1179] Step 4: Synthesis of 6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[1180] At rt, NaOH (32.7 mg, 0.82 mmol) was added to ethyl 6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate (140 mg, 0.41 mmol) in MeOH / H2O (2 mL / 6 mL), and the reaction mixture was heated to 60°C for 16 h. The residue was diluted with water and then adjusted to pH 3 with HCl (1 M). The mixture was extracted with EtOAc (3×100 mL), and the organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound (115 mg, 89.8%) as a yellow solid. LCMS m / z=314 [M+H] + .

[1181] Step 5: Synthesis of methyl 3-(5-(3-(6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1182] Following the procedure described in step 2 of Example 114, the title compound (80 mg, 43.2%) was obtained as a yellow solid from 6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid and step 4 of Intermediate 11. LCMS m / z = 584.4 [M+H] + .

[1183] Step 6: Synthesis of methyl 3-(5-(3-(5-((2-methoxyethyl)amino)-6-methylpyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1184] A mixture of Pd(PPh3)4 (11.7 mg, 10.2 μmol), K2CO3 (21.1 mg, 0.15 mmol), methyl 3-(5-(3-(6-bromo-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (60 mg, 0.10 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborane (15.3 mg, 0.12 mmol) in DMF (5 mL) was stirred at 100 ° C. under N2 for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL×3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide the crude product. The crude product was purified by preparative TLC using DCM:MeOH=35:1. The residue was purified by preparative HPLC method C, 22% to 51% gradient to provide the title compound (6.8 mg, 12.8%) as a white solid. LCMS: m / z=520 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.46(s,1H),8.40(d,1H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),7.03(s,1H),5.91(dq,2H) ,4.56(s,2H),4.38(s,2H),3.63(s,3H),3.57(t,2H),3.30-3.33(m,1H),3.34-3.36(m,1H),3.29(s,3H),2.35(s,3H),2.15(d,3H).

[1185] Example 145

[1186] 3-(5-(3-(6-chloro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1187]

[1188] Following a 5-step procedure similar to that described in steps 1 to 5 of Example 144, the title compound was obtained as a white solid from tert-butyl (3-chloropyridin-4-yl)carbamate and step 4 of Intermediate 11. LCMS: m / z = 540.0 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.99(s,1H),8.58(s,1H),8.19(d,1H),7.85(dd,1H),7.46(d,1H),7.18(s,1H),6 .22(t,1H),5.91(ddd,1H),4.56(t,2H),4.38(s,2H),3.63(s,3H),3.58(t,2H),3.39(q,2H),3.29(s,3H),2.35(s,3H).

[1189] Example 146

[1190] 3-(5-(3-(5-((2-(2-methoxyethoxy)ethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1191]

[1192] A mixture of intermediate 11 (100 mg, 0.2 mmol), 1-(2-aminoethoxy)-2-methoxyethane (23.2 mg, 0.2 mmol), Pd-PEPPSI-IPentCl-o-picoline (14 mg, 16.7 μmol) and Cs2CO3 (95.1 mg, 0.29 mmol) in dioxane (10 mL) was stirred at 100 ° C for 3 h. The cooled mixture was concentrated to dryness. The residue was purified by preparative TLC using DCM:MeOH=20:1. The crude product was purified by preparative HPLC method B, gradient: 23% B to 48% to provide the title compound (25.2 mg) as a white solid. LCMS: m / z=550 [M+H] +;1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.51-8.34(m,2H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),6.98(d,1H),6.77(t,1H),6.60(dd,1 H),5.91(m,1H),4.56(s,2H),4.38(s,2H),3.62(d,5H),3.59-3.52(m,2H),3.49-3.42(m,2H),3.26(d,2H),3.23(s,3H),2.35(s,3H).

[1193] Example 147

[1194] 3-(5-(3-(5-(4,4-difluoropiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1195]

[1196] Following the procedure described in Example 146, the title compound was obtained from intermediate 11 and 4,4-difluoropiperidine as a white solid (10.6 mg, 9.8%). LCMS: m / z = 552 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.61(t,2H),8.21(d,1H),7.85(dd,1H),7.50-7.41(m,2H),7.04(d d,1H),5.91(m,1H),4.56(s,2H),4.38(s,2H),3.63(s,3H),3.52(t,4H),2.36(s,3H),2.15-2.03(m,4H).

[1197] Example 148

[1198] 3-(5-(3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1199]

[1200] Intermediate 23 (200 mg, 0.85 mmol), Step 4 of Intermediate 11 (291 mg, 1.01 mmol), A solution of 4-[4-[4-[4-[4-(4-oxo-3-nitropropene]-1-yl]-1-oxo-4-nitropropene ... + ,1HNMR(400MHz,DMSO-d6)δ9.32(s,1H),8.49(s,1H),8.40(d,1H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),6.98(d, 1H),6.77(t,1H),6.61(dd,1H),5.91(m,1H),4.57(m,4H),3.63(s,3H),3.54(t,2H),3.32-3.22(m,5H),2.35(s,3H).

[1201] Example 149

[1202] Ethyl 3-(5-(3-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1203]

[1204] Following the procedure described in Example 148, the title compound (47.1 mg, 27.4%) was obtained as a white solid from step 2 of intermediate 14 and intermediate 23. LCMS: m / z = 520 [M+H] + ,1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.51-8.36(m,2H),8.21(d,1H),7.83(dd,1H),7.45(d,1H),6.98(d,1H),6.77(m,1H),6 .60(dd,1H),5.96-5.85(m,1H),4.56(m,4H),4.07(m,2H),3.54(m,2H),3.29(s,3H),3.26(m,2H),2.35(s,3H),1.20(t,3H).

[1205] Example 150

[1206] 5-((2-methoxyethyl)amino)-N-(2-methyl-5-(2-(spiro[3.3]hept-2-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1207]

[1208] Step 1: Synthesis of 5-(4-methyl-3-nitrophenyl)-2-(spiro[3.3]hept-2-yl)-2H-tetrazole:

[1209] Using a similar procedure to that described in step 1 of intermediate 4, the title compound (330 mg, 61.3%) was obtained as a white solid from 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54(6), 1599-1612, 370 mg, 1.80 mmol) and spiro[3.3]heptan-2-ol. LCMS: m / z = 300 [M+H] + .

[1210] Step 2: Synthesis of 2-methyl-5-(2-(spiro[3.3]hept-2-yl)-2H-tetrazol-5-yl)aniline:

[1211] Following the procedure described in step 2 of Intermediate 14, the title compound was obtained as a brown solid from 5-(4-methyl-3-nitrophenyl)-2-(spiro[3.3]hept-2-yl)-2H-tetrazole (280 mg, 94.5% yield). LCMS: m / z = 270 [M+H] + .

[1212] Step 3: Synthesis of 5-((2-methoxyethyl)amino)-N-(2-methyl-5-(2-(spiro[3.3]hept-2-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1213] Following a similar procedure to that described in Example 148, the title compound (20.3 mg, 9.2%) was obtained as an off-white solid from 2-methyl-5-(2-(spiro[3.3]hept-2-yl)-2H-tetrazol-5-yl)aniline and Intermediate 23. LCMS: m / z = 487 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.49(s,1H),8.39(d,1H),8.16(d,1H), 7.80(dd,1H),7.43(d,1H),6.97(d,1H),6.77(t,1H),6.60(dd,1H),5.40-5. 36(m,1H),3.54(t,2H),3.29(s,3H),3.29-3.24(m,2H),2.77-2.68(m,2H),2 .68-2.59(m,2H),2.34(s,3H),2.16(t,2H),2.05(dd,2H),1.91-1.78(m,2H).

[1214] Example 151

[1215] N-(5-(2-(3-fluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamide

[1216]

[1217] Following a 3-step procedure similar to that described in Example 150, the title compound was obtained as a white solid from 5-(4-methyl-3-nitrophenyl)-2H-1,2,3,4-tetrazolyl, 3-fluorocyclobutan-1-ol and Intermediate 23. LCMS: m / z = 465 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.49(s,1H),8.39(d,1H),8.19(d,1H),7.82(dd,1H),7.44(d,1H),6.97(d,1H),6.77( t,1H),6.60(dd,1H),5.23-5.01(m,2H),3.54(t,2H),3.29-3.24(m,5H),3.21-3.11(m,2H),2.99-2.81(m,2H),2.35(s,3H).

[1218] Example 152

[1219] N-(5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1220]

[1221] Step 1: Synthesis of 5-(5-cyclopropyl-2H-1,2,3,4-tetrazol-2-yl)-2-methylaniline:

[1222] Following a similar procedure to that described in step 1 of Intermediate 21, the title compound was obtained as a brown solid from (3-amino-4-methylphenyl)boronic acid and 5-cyclopropyl-2H-1,2,3,4-tetrazole (400 mg, 40%). LCMS: m / z = 216 [M+H] + .

[1223] Step 2: Synthesis of N-(5-(5-cyclopropyl-2H-tetrazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1224] Following a similar procedure to that described in Example 148, the title compound (6.1 mg) was obtained as a white solid from 5-(5-cyclopropyl-2H-1,2,3,4-tetrazol-2-yl)-2-methylaniline and pyrazolo[1,5-a]pyridine-3-carboxylic acid. LCMS: m / z = 360 [M+H] + ,1H NMR(300MHz,DMSO-d6)δ9.78(s,1H),8.87(d,1H),8.80(s,1H),8.30-8.17(m,2H),7.82(dd,1H),7.61- 7.49(m,2H),7.16-7.11(m,1H),2.39(s,3H),2.39-2.31(m,1H),1.20-1.16(m,2H),1.12-0.99(m,2H).

[1225] Example 153

[1226] 5-Methoxy-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1227]

[1228] A mixture of 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.52 mmol), step 2 of intermediate 39 (160 mg, 0.52 mmol), HATU (197 mg, 0.52 mmol) and DIPEA (143 mg, 1.03 mmol) in DMF (4 mL) was stirred at 50 ° C for 16 h. The mixture was extracted with EtOAc (2×50 mL), and the combined organic extracts were washed with water (20 mL) and then dried over Na 2 SO 4. The organic layer was concentrated and the residue was purified by preparative HPLC method H, 40% to 50% gradient to obtain the title compound (12.2 mg) as a white solid. LCMS: m / z=483 [M+H]+ ,1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.69(s,1H),8.56(d,1H),8.19(d,1H),8.13(d,1H),7.88(dd,1H ),7.49(d,1H),7.33(dd,1H),5.93(td,1H),4.55-4.43(m,4H),3.87(s,3H),3.18(s,3H),2.36(s,3H).

[1229] Example 154

[1230] 5-((2,2-difluoroethoxy)methyl)-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1231]

[1232] Step I: Synthesis of ethyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1233] At rt, (tributyltinyl)methanol (3.56 g, 11.1 mmol) was added to 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (2 g, 7.43 mmol) and Pd(PPh3)4 (858 mg, 0.74 mmol) in DMF (20 mL), and the reaction mixture was stirred at 100 ° C under N2 for 3 h. The mixture was diluted with EtOAc (200 mL) and washed with water (50 mL×2), the organic layer was dried with Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:EtOAc=18:1 to obtain the title compound (1.5 mg, 75%) as a white solid. LCMS: m / z=221[M+H] + .

[1234] Step 2: Synthesis of ethyl 5-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1235] At 0 ° C, mesylate (1.42 g, 8.17 mmol) was added to ethyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (1.5 g, 6.81 mmol) and TEA (694 mg, 6.81 mmol) in DCM (30 mL), and the reaction mixture was stirred at 25 ° C for 1.5 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column using DCM:MeOH=18:1 to obtain the title compound (850 mg, 56.6%) as a yellow solid. LCMS: m / z = 299 [M + H] + .

[1236] Step 3: Synthesis of ethyl 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1237] At 0 ° C, NaH (66.8 mg, 1.67 mmol) was added to 2,2-difluoroethane-1-ol (411 mg, 5.01 mmol) in THF (10 mL), and the reaction mixture was stirred at 25 ° C for 0.5 h. 5-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (500 mg, 1.67 mmol) was added, and the reaction mixture was stirred at rt under N2 for 2 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL×2), the organic layer was dried with Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using PE:EtOAc=15:1 to obtain the title compound (150 mg, 30%) as an off-white solid. LCMS: m / z=285[M+H] + .

[1238] Step 4: Synthesis of 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[1239] NaOH (126 mg, 3.16 mmol) was added to ethyl 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (150 mg, 0.53 mmol) in EtOH (8 mL) and H O (2 mL), and the reaction was stirred at 100 ° C for 10 h. Diluted HCl was added to acidify to pH 6, the mixture was diluted with EtOAc (100 mL), washed with brine (50 mL×2), the organic layer was dried over Na SO and concentrated under vacuum. The residue was purified by silica gel column using DCM:MeOH=18:1 to obtain the title compound (850 mg, 42.5%) as a yellow solid. LCMS: m / z=257 [M+H] + .

[1240] Step 5: 5-((2,2-difluoroethoxy)methyl)-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1241] 2,4,6-Trichlorobenzoyl chloride (99.7 mg, 0.409 mmol) and TEA (78.4 mg, 0.682 mmol) were added to 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (70 mg, 0.27 mmol) in THF (6 mL) at 0 ° C., and the solution was stirred for 1 h. Step 2 of intermediate 39 (50 mg, 0.16 mmol) was added, and the reaction mixture was stirred at 80 ° C. under N2 for 4 h. The mixture was diluted with DCM (100 mL), washed with brine (50 mL×2), the organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using PE:EtOAc=15:1 to obtain the title compound (8.2 mg) as a white solid. LCMS: m / z=520[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.83(dd,2H),8.25-8.18(m,2H),7.89(dd,1H),7.49(d,1H),7.05(dd,1 H),6.24(t,1H),5.95(tt,1H),4.77-4.72(m,2H),4.57-4.41(m,4H),3.82(td,2H),3.18(s,3H),2.37(s,3H).

[1242] Example 155

[1243] 5-(3-Hydroxy-3-methylbutyl)-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1244]

[1245] Step I: Synthesis of ethyl 5-(3-hydroxy-3-methylbutyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1246] Following a similar procedure to that described in Example 58, the title compound was obtained as a yellow solid from 3-methylbutane-1,3-diol and ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (270 mg, 33.8%). LCMS: m / z = 277 [M+H] + .

[1247] Step 2: Synthesis of 5-(3-hydroxy-3-methylbutyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[1248] Following the procedure described in step 4 of Example 154, the title compound was obtained as a yellow solid from ethyl 5-(3-hydroxy-3-methylbutyl)pyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 40%). LCMS: m / z = 249 [M+H] + .

[1249] Step 3: Synthesis of 5-(3-hydroxy-3-methylbutyl)-N-(2-methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1250] Following the procedure described in step 5 of Example 154, the title compound (14.6 mg) was obtained as a white solid from 5-(3-hydroxy-3-methylbutyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid and step 2 of Intermediate 39. LCMS: m / z = 539 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.74(d,2H),8.21(d,1H),8.04(s,1H),7.88(dd,1H),7.49(d,1H),6.99(dd,1H), 6.00-5.89(m,1H),4.45(dd,4H),4.33(s,1H),3.18(s,3H),2.80-2.71(m,2H),2.44(s,3H),2.37(s,2H),1.16(s,6H).

[1251] Example 156

[1252] N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2,4-dimethylphenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[1253]

[1254] Steps 1 and 2: Synthesis of 2-(3,3-difluorocyclobutyl)-5-(2,4-dimethyl-5-nitrophenyl)-2H-tetrazolyl

[1255] Following a 2-step procedure similar to that described in steps 1 and 2 of Intermediate 10, the title compound (600 mg) was obtained as a white solid from 2,4-dimethyl-5-nitrobenzonitrile and 3,3-difluorocyclobutan-1-ol. LCMS: m / z = 310 [M+H] + .

[1256] Step 3: Synthesis of 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2,4-dimethylaniline

[1257] At rt, Fe (651 mg, 11.64 mmol) was added to 2-(3,3-difluorocyclobutyl)-5-(2,4-dimethyl-5-nitrophenyl)-2H-tetrazole (600 mg, 1.94 mmol) in EtOH (1 drop of HCl (conc.) in 10 mL) and H O (1 mL), and the reaction was stirred at 80 ° C for 16 h. The cooled mixture was filtered, the filtrate was extracted with EtOAc (2×100 mL), and the combined extracts were washed with brine (50 mL), dried over anhydrous Na SO and concentrated under vacuum. The residue was purified by preparative TLC using DCM:MeOH=10:1 to obtain the title compound (300 mg, 55.4%) as a yellow solid, LCMS: m / z=280 [M+H] + .

[1258] Step 4: Synthesis of N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2,4-dimethylphenyl)-5-morpholinopyrazolo[1,5-a]pyridine-3-carboxamide

[1259] At 0 ° C, DMF (0.1 mL) was added to 5-morpholinopyrazolo[1,5-a]pyridine-3-carboxylic acid (intermediate 25, 132 mg, 0.54 mmol) and (COCl) (340 mg, 0.54 mmol) in DCM (10 mL), and the solution was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum, and the residue was added to 5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2,4-dimethylaniline (150 mg, 0.54 mmol) in pyridine (10 mL) at rt. The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum. The crude product was purified by preparative HPLC method A, 37% to 62% gradient to obtain the title compound (70.4 mg, 25.7%) as a white solid. LCMS: m / z=509[M+H] + .1 H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.59(d,2H),8.02(s,1H),7.45-7.21(m,2H),6.98( dd,1H),5.61(p,1H),3.76(t,4H),3.43(dtd,4H),3.27(t,4H),2.57(s,3H),2.31(s,3H).

[1260] Example 157

[1261] 3-(5-(4-chloro-3-(6-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1262]

[1263] At 0 ° C, SOCl2 (1 mL) was added to a solution of intermediate 23 (100 mg, 0.42 mmol) in DCM (5 mL), and the solution was stirred for 1 h. The mixture was concentrated to dryness, the residue was diluted with DCM (2 mL) and added to a solution of intermediate 10 (131 mg, 0.42 mmol) and TEA (127 mg, 1.26 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 16 h. The reaction mixture was quenched with H2O (10 mL), extracted with DCM (3 × 30 mL), and the organic layer was concentrated to dryness. The crude product was purified by preparative TLC using EtOAc and then by preparative HPLC method I, 32% to 52% gradient to obtain the title compound (24.0 mg) as a white solid, LCMS: m / z = 526 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.54-8.48(m,2H),8.41(d,1H),7.91(dd,1H),7.74(d,1H),6.97(d,1H),6.84(t,1H ),6.62(dd,1H),5.94-5.92(m,1H),4.57(s,2H),4.40(s,2H),3.63(s,3H),3.55(t,2H),3.30(s,3H),3.28-3.26(m,2H).

[1264] Example 158

[1265] N-(2-Methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1266]

[1267] Step 1: Synthesis of 5-(4-methyl-3-nitrophenyl)-2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazole:

[1268] To a stirred solution of 2-(2,2,2-trifluoroethoxy)ethan-1-ol (800 mg, 5.55 mmol) and TEA (1.12 g, 11.1 mmol) in DCM (5 mL) was added MsCl (762 mg, 6.66 mmol) at 0 ° C under N2. The reaction was stirred at rt for 2 h and quenched with ice water. The mixture was extracted with DCM (3 × 50 mL) and the organic layer was evaporated under reduced pressure to obtain 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (1.1 g; 89%) as a yellow oil.

[1269] To a solution of 5-(4-methyl-3-nitrophenyl)-2H-tetrazole (J. Med. Chem. 54 (6), 1599-1612, 500 mg, 2.43 mmol) and 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (646 mg, 2.91 mmol) in DMF (5 mL) was added KCO (670 mg, 4.86 mmol) at rt under N2. The reactants were stirred at 90 ° C for 2 h and cooled to rt. Water (10 mL) was added and the mixture was extracted with DCM (3×50 mL). The organic layer was washed with brine (30 mL) and concentrated under vacuum. The crude product was purified by preparative TLC, eluting with DCM:MeOH=10:1 to obtain the title compound (510 mg, 63%) as a white solid. LCMSm / z=332[M+H] + .

[1270] Step 3: Synthesis of 2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)aniline:

[1271] Following the procedure described in step 2 of Intermediate 13, the title compound was obtained as a white solid from 5-(4-methyl-3-nitrophenyl)-2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-1,2,3,4-tetrazole (450 mg, 82%). LCMS m / z = 302 [M+H] + .

[1272] Step 4: Synthesis of N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1273] To a stirred solution of 2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)aniline (600 mg, 1.99 mmol) in pyridine (6 mL) was added pyrazolo[1,5-a]pyridine-3-carbonyl chloride (429 mg, 2.38 mmol) at rt under N2. The reaction was stirred at rt for 15 min and concentrated under vacuum. The mixture was dissolved in DCM (50 mL) and washed with water (30 mL). The organic layer was concentrated and purified by preparative HPLC method C, 30% to 55% gradient to obtain the title compound (583 mg, 65%) as a white solid. LCMS: m / z=446[M+H] + , 1 H NMR(300MHz,DMSO-d6)δ9.75(s,1H),8.87(dd,1H),8.80(s,1H),8.26(dt,1H),8.17(d,1H), 7.86(dd,1H),7.59-7.44(m,2H),7.13(td,1H),4.98(t,2H),4.27-4.06(m,4H),2.37(s,3H).

[1274] Example 159

[1275] 3-(5-(4-methyl-3-(6-morpholinopyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1276]

[1277] A mixture of intermediate 27 (45 mg, 0.13 mmol), step 4 of intermediate 11 (38 mg, 0.13 mmol) and pyridine (53 mg, 0.66 mmol) in DCM (1 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was purified by reverse phase ISCO (5% to 100% MeCN / water containing 0.1% TFA). The fractions containing the product were evaporated, triturated with NaHCO3 / water and filtered to obtain the title compound (25 mg, 36.3%) as a brown solid. LCMSm / z=518[M+H] +;1HNMR(500MHz,DMSO-d6)δ9.57(s,1H),8.56(s,1H),8.16(s,1H),8.11(s,1H),8.03(d,1H),7.79(d,1H),7.48(d,1H),7 .40(d,1H),5.89-5.77(m,1H),4.55-4.44(m,2H),4.37-4.24(m,2H),3.70(t,4H),3.55(s,3H),3.06(t,4H),2.28(s,3H).

[1278] Example 160

[1279] 3-(2-(4-methyl-3-(6-morpholinopyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-1,2,3-triazol-4-yl)azetidine-1-carboxylic acid methyl ester

[1280]

[1281] Following the procedure described in Example 159, the title compound was obtained as an off-white solid from Intermediate 27 and Step 5 of Intermediate 18 (10 mg, 20.5%). LCMS m / z = 517 [M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.62(s,1H),8.65(d,1H),8.24(s,1H),8.15(d,2H),8.11(dd,1H),7.76(dd,1H),7. 60-7.54(m,1H),7.44(d,1H),4.35(s,2H),4.08(t,3H),3.78(s,4H),3.60(s,3H),3.15(q,4H),2.34(s,3H).

[1282] Example 161

[1283] N-(5-(4-(3,3-difluorocyclobutyl)-2H-1,2,3-triazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1284]

[1285] Step 1: Synthesis of 4-(3,3-difluorocyclobutyl)-2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazole

[1286] Under N2, a mixture of Pd2(dba)3 (2.12 mg) and Me4 tert-butyl Xphos (2.23 mg) in toluene (0.5 mL) was heated to 120 ° C. Under N2, this solution was added to a mixture of 4-bromo-1-methyl-2-nitrobenzene (50 mg, 0.23 mmol) and 4-(3,3-difluorocyclobutyl)-2H-1,2,3-triazole (44 mg, 0.28 mmol) in toluene (0.5 mL), and the reaction mixture was heated to 120 ° C. and maintained for 2 h. The cooled mixture was diluted with EtOAc and filtered through Filter and evaporate the filtrate to obtain the crude product. This crude product was purified by ISCO chromatography (0 to 40% EtOAc / hexanes) to obtain the title compound (41 mg, 60.2%) as a colorless oil. LCMS m / z = 295 [M+H] + .

[1287] Step 2: Synthesis of 5-(4-(3,3-difluorocyclobutyl)-2H-1,2,3-triazol-2-yl)-2-methylaniline

[1288] 1% Pt / 2% V on carbon (4 mg) was added to a solution of 4-(3,3-difluorocyclobutyl)-2-(4-methyl-3-nitrophenyl)-2H-1,2,3-triazole (41 mg, 0.14 mmol) in MeOH (2 mL), and the mixture was stirred under H2 atmosphere for 1 h. The mixture was filtered and the filtrate was evaporated to give the title compound as a solid (35 mg). LCMS m / z=266[M+H] + .

[1289] Step 3: Synthesis of N-(5-(4-(3,3-difluorocyclobutyl)-2H-1,2,3-triazol-2-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1290] 5-(4-(3,3-difluorocyclobutyl)-2H-1,2,3-triazol-2-yl)-2-methylaniline (35 mg, 0.132 mmol) was dissolved in pyridine (0.5 mL), pyrazolo[1,5-a]pyridine-3-carbonyl chloride (24 mg, 0.132 mmol) was added, and the reaction mixture was stirred at rt for 45 min. The mixture was concentrated in vacuo, the residue was partitioned between 5% MeOH / DCM and water, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the crude product. The product was triturated with MeCN, the mixture was filtered, and the resulting solid was dried to obtain the title compound (41 mg, 76% yield) as a white solid. LCMSm / z=409[M+H] +;1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.86(d,1H),8.79(d,1H),8.25(d,1H),8.13(d,1H),8.08(d,1H),7.77(dt,1 H),7.54(t,1H),7.45(d,1H),7.13(t,1H),3.66-3.56(m,1H),3.15-3.03(m,2H),2.95-2.82(m,2H),2.35(s,3H).

[1291] Example 162

[1292] 3-(5-(3-(5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1293]

[1294] Step 1: Synthesis of methyl 5-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1295] Following the procedure described in step 2 of Example 154, the title compound was obtained as a yellow solid from methyl 5-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 37.5%). LCMS: m / z = 285 [M+H] + .

[1296] Step 2: Synthesis of methyl 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate

[1297] 2,2-Difluoroethane-1-ol (114 mg, 1.40 mmol) and K2CO3 (144 mg, 1.05 mmol) were added to methyl 5-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (200 mg, 0.70 mmol) in DMF (10 mL), and the reaction mixture was stirred at 30 ° C for 10 h. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL×2), the organic layer was dried with Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:EtOAc=18:1 to obtain the title compound (100 mg, 50%) as a yellow solid. LCMS: m / z=271[M+H] + .

[1298] Step 3: Synthesis of methyl 3-(5-(3-(5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1299] AlMe3 (52.6 mg, 0.33 mmol) was added to a mixture of methyl 5-((2,2-difluoroethoxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate (60 mg, 0.22 mmol) and step 4 of intermediate 11 (52.6 mg, 0.33 mmol) in toluene, and the reaction mixture was stirred at 100 ° C under N2 for 3 h. The mixture was diluted with EtOAc (50 mL) and washed with brine (20 mL×2), the organic layer was dried with Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column using DCM:MeOH=18:1. The product was further purified by preparative HPLC method J, 40% to 51% gradient to obtain the title compound (16 mg) as a yellow solid. LCMS: m / z=527[M+H] + ;1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.86-8.80(m,2H),8.25-8.17(m,2H),7.88(dd,1H),7.49(d,1H),7.05(dd,1H ),6.24(t,1H),5.97-5.86(m,1H),4.75(s,2H),4.56(d,2H),4.38(d,2H),3.82(td,2H),3.63(s,3H),2.37(s,3H).

[1300] Examples 163 to 170

[1301] The compounds in the following table were prepared from the appropriate esters and amines following similar procedures as described in Example 162. Alternative purification conditions are described in the table below.

[1302]

[1303]

[1304] Example 171

[1305] 3-(5-(3-(6-fluoro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1306]

[1307] Steps 1 and 2: Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate

[1308] Following a similar 2-step procedure as described in Intermediate 41, the title compound (2.3 g) was obtained from 3-fluoropyridin-4-amine as a white solid. LCMS: m / z = 324 [M+H] + .

[1309] Step 3: Synthesis of ethyl 5-amino-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate

[1310] TFA (2 mL) was added to ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (600 mg, 1.85 mmol) in DCM (8 mL), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 solution (100 mL×3) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to provide the title compound (350 mg, 84.9%) as a yellow solid. LCMS: m / z=224[M+H] + .

[1311] Step 4: Synthesis of ethyl 6-fluoro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate

[1312] Following the procedure described in step 3 of Example 144, the title compound was obtained as a brown solid from ethyl 5-amino-6-fluoropyrazolo[1,5-a]pyridine-3-carboxylate and 1-bromo-2-methoxyethane (150 mg, 59.5%). LCMS: m / z = 282 [M+H] + .

[1313] Step 6: Synthesis of methyl 3-(5-(3-(6-fluoro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1314] Following a similar procedure to that described in step 3 of Example 162, the title compound (8.5 mg, 4.5%) was obtained as a white solid from ethyl 6-fluoro-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate and step 4 of Intermediate 11. The crude product was purified by preparative HPLC method A, 23% to 52% gradient. LCMS: m / z = 524 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.92(d,1H),8.55(s,1H),8.19(d,1H),7.85(dd,1H),7.46(d,1H),7.16(d,1H), 6.63(s,1H),6.02-5.82(m,1H),4.55(d,2H),4.38(s,2H),3.63(s,3H),3.56(t,2H),3.38-3.34(m,3H),2.35(s,3H).

[1315] Example 172

[1316] N-(2-Methyl-5-(2-(1-(methylsulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1317]

[1318] To a solution of intermediate 15 (50 mg, 0.13 mmol) and 1 M NaHCO3 aqueous solution (0.53 mL, 0.53 mmol) in THF (0.33 mL) and water (0.33 mL) was added methanesulfonyl chloride (22.9 mg, 0.20 mmol) at 0°C, and the reaction mixture was stirred for 10 min. The reaction mixture was diluted with EtOAc (3 mL), washed with water (3 mL×3) and saturated brine (3 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC to produce the title compound (9.8 mg, 16.2%). LCMSm / z=453[M+H] + ;1H NMR(500MHz,MeOD-d4)δ8.61-8.52(m,2H),8.20(d,1H),8.12(d,1H),7.89(dd,1H),7.4 5-7.36(m,2H),7.01(t,1H),5.80(p,1H),4.51-4.41(m,4H),3.02(d,3H),2.32(s,3H).

[1319] Examples 173 to 180

[1320] The compounds in the table below were prepared following similar procedures to those described in Example 172 from intermediate 15 and the appropriate sulfonyl chloride.

[1321]

[1322]

[1323] Example 181

[1324] N-(2-methyl-5-(2-(1-((1-methylcyclopropyl)sulfonyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1325]

[1326] At rt under N2, to a solution of intermediate 15 (100 mg, 0.27 mmol) and TEA (53.9 mg, 0.53 mmol) in DCM (5 mL) was added 1-methylcyclopropane-1-sulfonyl chloride (61.8 mg, 0.40 mmol). The mixture was stirred for 2 h, and then water (10 mL) was added. The resulting solution was extracted with DCM (3 × 20 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC method F, 40% to 55% gradient to obtain the title compound (41.9 mg, 32%) as a white solid. LCMS: m / z=493[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.86(dt,1H),8.79(s,1H),8.25(dt,1H),8.19(d,1H),7.88(dd,1H),7.58-7. 47(m,2H),7.13(td,1H),6.00(p,1H),4.47(d,4H),2.37(s,3H),1.51(s,3H),1.23-1.16(m,2H),1.00-0.88(m,2H).

[1327] Examples 182 to 190

[1328] The following compounds were prepared from the appropriate azetidine and the appropriate sulfonyl chloride following similar procedures as described in Example 181. Alternative purification conditions are described in the table below.

[1329]

[1330]

[1331] Example 191

[1332] 3-(5-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1333]

[1334] Methyl chloroformate (0.01 mL, 0.14 mmol) was added to a solution of intermediate 15 (45 mg, 0.12 mmol) in DCM (1 mL) and pyridine (0.05 mL, 0.60 mmol), and the reaction mixture was stirred at rt for 2 h. The mixture was diluted with water, washed with water, and the organic layer was dried over Na2SO4, filtered, and evaporated to obtain a crude product. This crude product was purified by reverse phase ISCO chromatography (5% to 100% MeCN / water containing 0.1% TFA). The fractions containing the product were concentrated and the residue was triturated with NaHCO3 and water, and then filtered and suction dried to obtain the title compound (24.5 mg, 47%) as a white solid. LCMSm / z=433[M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),8.86(d,1H),8.79(d,1H),8.26(d,1H),8.19(d,1H),7.93-7.83(m,1 H),7.59-7.45(m,2H),7.13(t,1H),5.92(ddd,1H),4.57(t,2H),4.39(dd,2H),3.63(s,3H),2.37(s,3H).

[1335] Examples 192 to 194

[1336] The compounds in the table below were prepared from the appropriate azetidine and methyl chloroformate following procedures similar to those described in Example 191. Alternative purification conditions are described in the table below.

[1337]

[1338] Example 195

[1339] N-(2-Chloro-5-(2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1340]

[1341] A mixture of intermediate 40 (50 mg, 0.13 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.06 mL, 0.38 mmol) and DIPEA (0.03 mL, 0.51 mmol) in DMF (0.5 mL) was stirred at 90 ° C for 1 h. The mixture was concentrated in vacuo, the residue was triturated with water and filtered to give a white solid (48 mg). This solid was triturated with MeCN (1 mL), stirred for 30 min, filtered and dried to give the title compound (36.7 mg, 60.8%). LCMS m / z = 477 [M + H] + ;1H NMR(500MHz,DMSO-d6)δ9.91(s,1H),8.88(d,1H),8.83(d,1H),8.44(d,1H),8.26(d,1H),7.97(dt,1H ),7.78(dd,1H),7.57(t,1H),7.16(t,1H),5.75(p,1H),4.06(t,2H),3.94(t,2H),3.48-3.38(m,2H).

[1342] Example 196

[1343] N-(2-Methyl-5-(2-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1344]

[1345] The title compound was obtained from intermediate 15 and 2,2,2-trifluoroethyl trifluoromethanesulfonate following a similar procedure as described in Example 195. LCMS m / z = 457 [M+H] + ;1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),8.86(d,1H),8.79(s,1H),8.25(d,1H),8.18(s,1H),7.88(d,1H),7 .54(t,1H),7.49(d,1H),7.13(t,1H),5.73(p,1H),4.06(t,2H),3.93(t,2H),3.42(q,2H),2.37(s,3H).

[1346] Example 197

[1347] N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1348]

[1349] Step 1: Synthesis of 5-bromo-N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1350] A suspension of 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (200 mg, 0.83 mmol) and DMF (0.1 mL) in DCM (10 mL) was cooled to 0 ° C and slowly treated with oxalyl chloride (627 mg, 4.97 mmol). The mixture was removed from the cold bath and stirred at rt for 2.5 h. The mixture was filtered through filter paper to remove undissolved precipitates and then concentrated in vacuo to provide 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (crude) as a yellow solid. To a mixture of step 3 (249 mg, 0.83 mmol) of Example 158 in pyridine (8 mL) was added 5-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride (210 mg, 0.83 mmol) at 0 ° C, and the reaction mixture was stirred at rt for 3 h. The resulting solution was concentrated in vacuo and the crude product was purified by silica gel column chromatography (eluting with DCM:MeOH 90:10) to afford the title compound as a yellow solid (180 mg, 41.3%). LCMS: m / z = 427 [M+H + ].

[1351] Step 2: Synthesis of N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1352] A mixture of 5-bromo-N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (180 mg, 0.34 mmol), 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (105 mg, 0.38 mmol), Pd(dppf)Cl (11.5 mg, 0.02 mmol) and KCO (94.7 mg, 0.69 mmol) in dioxane (8 mL) and H0 (2 mL) was stirred at 80° C. under N for 3 h. The reaction mixture was cooled to rt, the resulting solution was diluted with water (25 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (eluted with DCM:MeOH 95:5) to afford the title compound (150 mg, 73.5%) as a yellow solid. LCMS m / z = 427 [M+H] + .

[1353] Step 3: Synthesis of N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1354] A mixture of N-(2-methyl-5-(2-(2-(2,2,2-trifluoroethoxy)ethyl)-2H-tetrazol-5-yl)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (100 mg, 0.17 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC method E, 30% to 60% gradient to afford the title compound (29.4 mg, 34.2%) as a white solid. LCMS: m / z = 427 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.20(s,1H),9.65(s,1H),8.83(dd,1H),8.74(s,1H),8.46(s,1H),8.36(dd,1H),8.22( d,1H),8.10(s,1H),7.89-7.83(m,1H),7.48(d,1H),7.42(dd,1H),4.98(t,2H),4.33-4.08(m,4H),2.38(s,3H).

[1355] Example 198

[1356] N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1357]

[1358] Step 1: Synthesis of N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1359] Following the procedure described in step 2 of Example 197, the title compound was obtained as a white solid (180 mg, 78.6% yield) from intermediate 4 and 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS m / z = 560 [M+H] + .

[1360] Step 2: Synthesis of N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide:

[1361] A mixture of N-(5-(2-(3,3-difluorocyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (150 mg, 0.27 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC method J, 32% to 52% gradient to afford the title compound (84.3 mg, 66.3%) as a white solid. LCMS: m / z=476 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),9.68(s,1H),8.83(d,1H),8.74(s,1H),8.29(d d,4H),7.87(dd,1H),7.64-7.36(m,2H),5.61(q,1H),3.64-3.36(m,4H),2.39(s,3H).

[1362] Example 199

[1363] 3-(5-(3-(5-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylic acid methyl ester

[1364]

[1365] Step 1: Synthesis of methyl 3-(5-(3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1366] Following a similar procedure to that described in Example 65, the title compound (38.6 mg, 43.4%) was obtained as a white solid from intermediate 11 and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol.

[1367] Step 2: Synthesis of methyl 3-(5-(3-(5-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate

[1368] Methyl 3-(5-(3-(5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)azetidine-1-carboxylate (38 mg, 0.06 mmol) was dissolved in THF (0.75 mL) and 1M TBAF (0.19 mL, 0.19 mmol) in THF solution was added and the reaction mixture was stirred at rt overnight. The reaction was diluted with EtOAc, washed with water and brine, and then dried over Na2SO4. The mixture was filtered and concentrated in vacuo to give the crude product. This crude product was purified by reverse phase ISCO (5% to 100% MeCN / water with 0.1% TFA). The product-containing fractions were concentrated in vacuo, the residue was triturated with aqueous Na2CO3 solution, the mixture was filtered, washed with water and dried to afford the title compound as a white solid (16.8 mg, 54.5%). LCMS m / z = 493 [M+H] +;1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),8.68(d,1H),8.57(d,1H),8.18(s,1H),8.14(dd,1H),7.88(d,1H),7.49(d,1H),7.34(dd ,1H),5.92(ttd,1H),4.96(s,1H),4.57(t,2H),4.46-4.33(m,2H),4.10(t,2H),3.81-3.73(m,2H),3.64(d,1H),2.37(s,3H).

[1369] Example 200

[1370] N-(5-(2-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1371]

[1372] Step 1: Synthesis of methyl (1r,3r)-3-(5-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate:

[1373] At 0 ° C under N 2, DIAD (252 mg, 1.25 mmol) was added to intermediate 1 (200 mg, 0.63 mmol), (1s, 3s)-3-hydroxycyclobutane-1-carboxylic acid methyl ester (81 mg, 0.63 mmol) and PPh 3 (327 mg, 1.25 mmol) in THF (5 mL), and the reaction was stirred at rt for 3 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column using 5% MeOH in DCM to provide the title compound (100 mg, 37%) as a white solid. LCMS m / z = 432 [M + H] + .

[1374] Step 2: Synthesis of N-(5-(2-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[1375] NaBH4 (5 mg, 0.12 mmol) was added to a solution of (1r,3r)-3-(5-(4-methyl-3-(pyrazolo[1,5-a]pyridine-3-carboxamido)phenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylic acid methyl ester (50 mg, 0.12 mmol) in MeOH (3 mL), and the reaction mixture was stirred at rt for 3 h. The reaction was concentrated under vacuum and purified by preparative HPLC method A, 29% to 42% gradient to provide the title compound (36.9 mg, 37%) as a white solid. LCMS: m / z = 404 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.86(d,1H),8.79(s,1H),8.25(dt,1H),8.16(d,1H),7.86(dd,1H),7.53(ddd,1H),7.47 (d,1H),7.13(td,1H),5.54(p,1H),4.81(t,1H),3.57(t,2H),2.79-2.67(m,2H),2.62-2.53(m,1H),2.46(d,1H),2.36(s,4H).

[1376] Example 201

[1377] N-(5-(2-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamide

[1378]

[1379] Step 1: Synthesis of methyl (1r,3r)-3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate

[1380] Following the procedure described in step 2 of intermediate 7, the title compound was obtained as a brown solid (60 mg, 31%) from 2-methyl-5-(2H-tetrazol-5-yl)aniline and methyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate. LCMS: m / z = 288 [M+H] + .

[1381] Step 2: Synthesis of methyl (1r,3r)-3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate

[1382] To a stirred solution of (1r,3r)-3-(5-(3-amino-4-methylphenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylic acid methyl ester (30 mg, 0.10 mmol) in MeCN (2 mL) was added 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (37.6 mg, 0.16 mmol), N-methylimidazole (29.8 mg, 0.36 mmol) and TCFH (34.7 mg, 0.12 mmol), and the reaction mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (5 mL) and water (5 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3×3 mL) and the combined organic phases were washed with brine (10 mL). The organic layer was dried over NaSO and concentrated under vacuum. The residue was purified by preparative TLC using PE:EtOAc=2:3 to obtain the title compound (30 mg; 57%) as a yellow solid. LCMS: m / z=528 [M+H] + .

[1383] Step 3: Synthesis of methyl (1r,3r)-3-(5-(5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate

[1384] Following the procedure described in step 4 of Example 115, the title compound was obtained as a yellow solid (20 mg, 67%) from methyl (1r,3r)-3-(5-(3-(5-bromopyrazolo[1,5-a]pyridine-3-carboxamido)-4-methylphenyl)-2H-tetrazol-2-yl)cyclobutane-1-carboxylate and 2-methoxyethan-1-amine. LCMS: m / z = 505 [M+H] + .

[1385] Step 4: Synthesis of N-(5-(2-((1r,3r)-3-(hydroxymethyl)cyclobutyl)-2H-tetrazol-5-yl)-2-methylphenyl)-5-((2-methoxyethyl)amino)pyrazolo[1,5-a]pyridine-3-carboxamide

[1386] Following...

Claims

1. A compound having the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from tetrazole or triazole, wherein the tetrazole or the triazole is optionally replaced by R a replace; where R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 0-5 Alkylphenyl, C 0-5 Alkyl C 3-6 Cycloalkyl, C 0-5 Alkyl C 6-10 Spiroalkyl, C 0-5 Alkyl C 5-10 The bridged bicycloalkyl and C each containing at least one N or O 0-5 Alkyl (4-6 membered heterocyclic) or C 0-5 Alkyl (7-10 membered spiroheterocyclic) or C 0-5 Alkyl (5-10 membered bridged bicyclic heterocycle, wherein the alkyl, the haloalkyl, the phenyl, the cycloalkyl, the spiroalkyl, the bridged bicyclic alkyl, the heterocycle, the spiroheterocycle or the bridged bicyclic heterocycle is optionally substituted by 1 to 5 R b Replace, where: Each R b Independently selected from OH, CN, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-5 Cycloalkoxy, SO2C 1-4 Alkyl, SO2C 1-4 Haloalkyl, C(O)OC 1-4 Alkyl, SO2(C 0-2 alkyl) (4-6 membered heterocyclic ring containing at least one O or N), SO2 (C 1-4 Alkyl)C 1-4 Halogenated alkoxy, SO2(C 1-4 Alkyl)C 1-4 Alkoxy (C 0-1 Alkoxy), SO2(C 1-4 alkyl)OH, SO2(C 0-2 Alkyl)C 3-6 Cycloalkyl, C 1-3 Alkyl, C 1-5 Haloalkyl, halogen and C 1-2 AlkylOH, in addition wherein the cycloalkyl group is optionally C 1-3 Alkyl substitution; Each R 1 independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 0-4 Alkyl OH, C 6-10 Spiroalkyl, C 0-6 Alkyl C 1-6 Alkoxy, C 0-4 Alkyl C 1-6 Haloalkoxy, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, NH-(4-6 membered heterocycle or 5-6 membered heteroaryl containing at least one O or N) and 4-6 membered heterocycle or 7-10 membered fused bicyclic heterocycle or 7-10 membered spiro heterocycle, or 5-6 membered heteroaryl containing at least two N, wherein the alkyl, the haloalkyl, the alkoxy, the cycloalkyl, the spiroalkyl, the heterocycle or the heteroaryl are optionally substituted by 1 to 3 R e replace; Each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, CN, CHF2, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 2-5 Alkyl (OH) 2, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy), C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C 1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 Alkyl OH or C 1-3 Alkyl substitution; Each R 9 Independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, halogen, CN and C 3-4 Cycloalkyl; n is 1 or 2; and p is 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, CN, CHF2, C 3-6 Cycloalkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C 1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 Alkyl OH substitution.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R e Independently selected from deuterium, deuterated C 1-4 Alkyl, deuterated C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, C 0-3 Alkyl-S(O)2C 1-3 Alkyl, C 0-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-4 alkyl)P(O)(C 1-3 Alkyl), C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 0-4 Alkyl C 1-4 Alkoxy, C 1-3 Alkoxy C 1-3 Alkoxy, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2 and (C 0-4 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 3 C 0-3 Alkyl OH substitution.

4. The compound of claim 1, 2 or 3, which has the structure of formula (IIa): or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, 2 or 3, which has the structure of formula (IIb): or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, 2 or 3, which has the structure of formula (IIIa): or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, 2 or 3, which has the structure of formula (IIIb): or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, 2 or 3, having a structure selected from formula (IV-VII): or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, 2 or 3, having a structure selected from Formula (VIII-XI): or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, 2 or 3, having a structure selected from Formula (XII-XV): or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, 2 or 3, having a structure selected from Formula (XVI-XIX): or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, 2 or 3, having a structure selected from Formula (XX-XXIII): or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, 2 or 3, having a structure selected from Formula (XXIV-XXVII): or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, 2 or 3, having a structure selected from Formula (XXVIII-XXXI): or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, 2 or 3, having a structure selected from Formula (XXXII-XXXV): or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, 2 or 3, having a structure selected from Formula (XXXVI-XXIX): or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, 2 or 3, having a structure selected from Formula (XXXX-XXXXIII): or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1 to 8 or 13, or a pharmaceutically acceptable salt thereof, wherein p is 0.

19. The compound of any one of claims 1 to 8 or 13, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 0-3 Alkylphenyl, C 0-4 Alkyl C 3-6 Cycloalkyl, C 0-3 Alkyl C 6-10 Spiroalkyl, C 0-3 Alkyl (C 5-8 Bridged bicycloalkyl), C 0-5 Alkyl (4-6 membered heterocyclic ring containing at least one N or O), C 0-3 Alkyl (7-10 membered spiroheterocyclic ring containing at least one N or O) and C 0-3 Alkyl (a 5-10 membered bridged bicyclic heterocycle containing at least one O or N), wherein: i) the alkyl group or the haloalkyl group is optionally substituted by 1 to 5 R groups independently selected from the following b Replaces: C 1-5 Alkoxy, C 1-5 Halogenated alkoxy, C 3-6 Cycloalkyl, OH and CN; ii) the cycloalkyl group, the spirocycloalkyl group or the phenyl group is optionally substituted by 1 to 2 R groups independently selected from the following: b Substitution: methyl, halogen, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and C 0-3 Alkyl OH; and iii) the heterocyclic ring is optionally substituted by an R selected from the following b Replaces: SO2C 1-5 Alkyl, SO2C 1-5 Haloalkyl, C(O)OC 1-4 Alkyl, SO2 (4-6 membered heterocyclic ring containing at least one O or N), SO2 (C 1-3 Alkyl)C 1-3 Halogenated alkoxy, SO2(C 1-3 Alkyl)C 1-3 Alkoxy, SO2(C 1-4 alkyl)OH, SO2(C 1-3 Alkyl)C 1-3 Alkoxy (methoxy), SO2 (C 0-2 Alkyl)C 3-6 Cycloalkyl and C 1-4 haloalkyl, wherein the cycloalkyl group is optionally replaced by C 1-2 Alkyl substitution.

21. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R a Selected from C 1-5 Alkyl, C 1-5 Halogenated alkyl, C 0-3 Alkyl C 3-6 Cycloalkyl, C 0-3 Alkyl (containing at least one O or N 4-6 membered heterocyclic ring), C 0-2 Alkyl C 6-10 Spiroalkyl, C 0-2 Alkyl (7-9 membered spiro heterocycle containing at least one O), C 0-1 Alkylphenyl, C 0-2 Alkyl (a 6-8 membered bridged bicyclic heterocycle containing at least one O or N) and C 1-2 Alkyl (C 5-7 bridged bicycloalkyl) wherein: i) The alkyl group or the haloalkyl group is optionally substituted by 1 to 3 R groups independently selected from the following b Substitution: OH, CN, C 1-3 Alkoxy, C 1-4 Haloalkoxy and C 3-5 Cycloalkyl; ii) the cycloalkyl group, the spirocycloalkyl group or the phenyl group is optionally substituted by 1 to 3 R groups independently selected from the following: b Substitution: halogen, methyl, C 1-3 Halogenated alkyl, C 1-2 Alkoxy and C 1-2 Alkyl OH; and iii) the heterocyclic ring is optionally substituted by 1 to 2 R b Replacement: C(O)OC 1-4 Alkyl, SO2C 1-4 Alkyl, SO2C 1-4 Halogenated alkyl, SO2 (4-5 membered heterocyclic ring containing one O), SO2 (C 1-2 Alkyl)C 1-2 Halogenated alkoxy, SO2(C 1-2 Alkyl)C 1-2 Alkoxy, SO2(C 1-3 Alkyl)OH, SO2C 3-4 Cycloalkyl, SO2(C 1-2 Alkyl)C 1-2 Alkoxy (methoxy) and C 1-4 haloalkyl, wherein the cycloalkyl group is optionally replaced by C 1-2 Alkyl substitution.

22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R a Selected from C 1-5 Alkyl, C 2-5 Haloalkyl, cyclobutyl, cyclopropyl, methylcyclopropyl, CH(CH3)cyclopropyl, methylcyclobutyl, C 0-2 Alkyl (tetrahydropyranyl), C 6-10 Spiroalkyl, C 0-2 alkyl (8-membered spiroheterocycle containing at least one O), benzyl, CH2 (6-membered bridged bicyclic heterocycle containing one O), CH2 (bridged bicycloalkyl), and azetidinyl, wherein: i) The alkyl group or the haloalkyl group is optionally substituted by 1 to 5 R b Replaces: C 2-3 Alkoxy, C 2-3 Halogenated alkoxy, C 3-4 Cycloalkyl, OH and CN; ii) the cyclobutyl, the cyclopropyl, the methylcyclopropyl, the methylcyclobutyl, the spiroalkyl or the benzyl is optionally substituted by 1 to 3 R groups independently selected from the following b Substituted: halogen, methyl, halomethyl, methoxy, and methylhydroxy; and iii) the azetidinyl group is optionally replaced by an R selected from the group consisting of b Replaces: SO2C 1-3 Alkyl, SO2C 1-3 Halogenated alkyl, SO2 tetrahydrofuran, SO2 oxetane, SO2 (C2 alkyl) C2 haloalkoxy, SO2 (C 1-2 alkyl)methoxy, SO2(C 1-2 alkyl)OH, SO2 cyclopropyl, SO2(C 1-2 Alkyl)C 1-2 Alkoxy (methoxy), C(O)OC 1-2 Alkyl and C 1-2 haloalkyl, further wherein the cyclopropyl is optionally substituted with methyl.

23. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R a independently selected from the group consisting of hydrogen, methyl, ethyl, 2-isopropyl, 2-(cyclopropylmethyl), (S)-(2,2-difluorocyclopropyl)methyl, (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutyl, (S)-4,4,4-trifluoro-3-hydroxy-3-methylbutyl, (R)-1-cyclopropylethyl, (S)-1-cyclopropylethyl, (R)-(2,2-difluorocyclopropyl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, (R)-1-(tetrahydro-2H-pyran-4-yl)ethyl, (S)-1- (tetrahydro-2H-pyran-4-yl)ethyl, 2-isopropoxyethyl, 2-cyclobutoxyethyl, (2,2,2-trifluoroethoxy)ethyl, 4,4,4-trifluorobutyl, cyclopropyl, cyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, (1s,3s)-3-(trifluoromethyl)cyclobutyl, (1r,3r)-3-(trifluoromethyl)cyclobutyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, (1r,3r)-3-(hydroxymethyl)cyclobutyl, (1s,3s)-3-methoxycyclobutyl, (2-fluorobenzyl), CH(CH3)(2-fluorophenyl), 1-(methylsulfonyl)azetidin-3-yl, (ethylsulfonyl)azetidin-3-yl, 1-(propylsulfonyl)azetidin-3-yl, 1-(isopropylsulfonyl)azetidin-3-yl, (2-methoxyethyl)sulfonyl)azetidin-3-yl, 1-(cyclopropylsulfonyl)azetidin-3-yl, 1-((cyclobutylmethyl)sulfonyl)azetidin-3-yl, 1-((1-methylcyclopropyl)sulfonyl)azetidin-3-yl )azetidin-3-yl, 1-((trifluoromethyl)sulfonyl)azetidin-3-yl, 1-((3,3-difluoropropyl)sulfonyl)azetidin-3-yl, (2-(2-methoxyethoxy)ethyl)sulfonyl)azetidin-3-yl, (4-cyanobutyl)sulfonyl)azetidin-3-yl, (2,2,2-trifluoroethyl)azetidin-3-yl, (2-hydroxyethyl)sulfonyl)azetidin-3-yl, and (2-(2,2-difluoroethoxy)ethyl)sulfonyl)azetidin-3-yl.

24. A compound according to any one of claims 1 to 17 or 19 to 23, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 0-4 Alkyl OH, C 0-4 Alkyl C 1-6 Alkoxy, C 0-4 Alkyl C 1-6 Halogenated alkoxy, C 3-4 Cycloalkyl, NH2, NHC 1-5 Alkyl, N(C 1-3 alkyl)2, NH-(4-6 membered heterocycle containing at least one O), NH-(5-6 membered heteroaryl containing at least one N), 4-6 membered heterocycle or 7-9 membered fused bicyclic heterocycle or 7-10 membered spiroheterocycle each containing at least one O or N, and 5-6 membered heteroaryl containing at least one N, wherein: i) the alkyl group, the haloalkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: Deuterium, Deuterated C 1-3 Alkoxy, C 1-3 Alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkoxy, C 1-2 Alkoxy C 1-2 Alkoxy, OH, halogen, and a 4-6 membered heterocyclic ring containing at least one O or N; ii) the heterocyclic ring or the cycloalkyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: deuterated C 1-3 Alkyl, di(C 1-3 Alkyl)amine, S(O)2C 1-3 Alkyl, halogen, 4-6 membered heterocyclic ring containing one O, C 1-3 Alkyl, C 0-4 Alkyl OH and C 1-2 Alkyl C 1-3 alkoxy; and iii) the heteroaryl group is optionally substituted by 1 to 3 R groups independently selected from the following e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 1-4 Alkyl OH, C 2-5 Alkyl (OH)2, C 2-4 Alkyl (OH) (methoxy), C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy), S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocyclic ring containing at least one O or N), wherein the heterocyclic ring is optionally substituted by 1 to 2 OH or C 1-3 Alkyl substitution.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein: The heteroaryl group in subsection iii) is optionally substituted by 1 to 3 R groups independently selected from the following: e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 1-4 Alkyl OH, C 2-4 Alkyl (OH) (methoxy), S (O) 2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocycle containing at least one O or N), wherein the heterocycle is optionally substituted with 1 to 2 OH groups.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein The heteroaryl group in subsection iii) is optionally substituted by 1 to 3 R groups independently selected from the following: e Replaces: C 1-4 Alkyl, C 1-4 Alkyl OH, S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)C 1-3 Alkyl, (C 1-3 alkyl)P(O)(C 1-3 Alkyl)2 and (C 1-3 alkyl)-(4-6 membered heterocycle containing at least one O or N), wherein the heterocycle is optionally substituted with 1 to 2 OH groups.

27. A compound according to any one of claims 1 to 17 or 19 to 23, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from halogen, C 1-3 Alkyl, C 1-4 Alkyl OH, C 0-4 Alkyl C 1-5 Alkoxy, C 0-4 Alkyl C 1-5 Haloalkoxy, cyclopropyl, NH2, NHC 1-4 Alkyl, N(C 1-2 alkyl)2, NH-(a 5-membered heterocyclic ring containing one O), NH-(a 5-membered heteroaryl ring containing two N), azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino and pyrazolyl, wherein: i) The alkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: deuterium, C 1-3 Alkyl, C 1-3 Haloalkoxy, deuterated methoxy, OH, C 1-4 Alkoxy, C 1-2 Alkoxy C 1-2 Alkoxy, halogen and 4-6 membered heterocyclic ring containing at least one O; ii) the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, the tetrahydrofuran or the morpholino is optionally substituted by 1 to 2 R groups independently selected from the following e Substitution: deuterated C 1-3 Alkyl, di(C 1-3 alkyl)amine, S(O)2CH3, halogen, C 0-3 AlkylOH, 4-6 membered heterocyclic ring containing one O, C 1-2 Alkyl, C 1-2 Haloalkyl and C 1-2 Alkyl C 1-3 alkoxy; and iii) the pyrazolyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 0-4 Alkyl OH, C 2-5 Alkyl (OH)2, C 1-4 Alkyl (OH) (C1-C4 alkoxy), C 2-5 Alkyl (OH) (C 1-5 Alkoxy) (C 1-5 Alkoxy), S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(a 6-membered heterocyclic ring containing at least one O or N), wherein the 6-membered heterocyclic ring is optionally substituted by 1 to 2 OH or C 1-3 Alkyl substitution.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein: The pyrazolyl group in subsection iii) is optionally substituted by 1 to 3 R groups each independently selected from the following: e Replaces: C 1-4 Alkyl, CN, CHF2, cyclopropyl, C 0-4 Alkyl OH, C 1-4 Alkyl (OH) (C1-C4 alkoxy), S (O) 2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocycle containing at least one O or N), further wherein the 6-membered heterocycle is optionally substituted with 1 to 2 OH groups.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein the pyrazolyl group in iii) is optionally replaced by 1 to 3 R groups independently selected from the following: e Replaces: C 1-4 Alkyl, C 0-4 Alkyl OH, S(O)2C 1-3 Alkyl, C 1-3 Alkyl-S(O)(NH)CH3, (C 1-3 alkyl)P(O)(C 2-3 Alkyl)2 and (C 1-3 alkyl)-(6-membered heterocycle containing at least one O or N), further wherein the 6-membered heterocycle is optionally substituted with 1 to 2 OH groups.

30. A compound according to any one of claims 1 to 17 or 19 to 23, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from halogen, C 1-3 Alkyl, C 2-3 Alkyl OH, C 0-3 Alkyl C 1-5 Alkoxy, cyclopropyl, NH2, NH(C 1-4 alkyl), N(C 1-2 alkyl) 2, NH-tetrahydrofuryl, NH-pyrazolyl, NH-oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino and pyrazolyl, wherein: i) The alkyl group or the alkoxy group is optionally substituted by 1 to 3 R groups independently selected from the following e Substitution: OH, halogen, deuterium, C 1-3 Alkyl, methoxy, ethoxymethoxy, deuterated methoxy, haloethoxy, butoxy, and a 4-6 membered heterocyclic ring containing one O; ii) the azetidinyl, the pyrrolidinyl, the piperidinyl, the piperazinyl, the tetrahydrofuranyl or the morpholino is optionally substituted by 1 to 2 R groups independently selected from the following e Substitution: S(O)2CH3, halogen, C 0-2 AlkylOH, oxetane, C1 alkyl, C2 haloalkyl, deuterated C 1-3 Alkyl, di(C 1-3 alkyl)amine and C1 alkylC1 alkoxy; and iii) the pyrazolyl group is optionally substituted by 1 to 3 R groups independently selected from the following e Substituted: methyl, ethyl, propyl, butyl, cyclopropyl, ethylhydroxy, isobutylhydroxy, CH2CH(OH)C(CH3)2(OH), CH2CH(OH)CH2OH, CH2C(OH)(CH3)CH2OH, CH(CH2OH)2, propyl(OH)methoxy, CH2CH(OH)CH2OCH2CH2OCH3, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl)P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH or methyl groups.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein the pyrazolyl group in iii) is optionally replaced by 1 to 3 R groups independently selected from the following: e Substituted: methyl, ethyl, propyl, butyl, cyclopropyl, ethylhydroxy, isobutylhydroxy, propyl (OH) methoxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl)P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof, wherein the pyrazolyl group in iii) is optionally replaced by 1 to 3 R groups independently selected from the following: e Substituted: methyl, ethyl, propyl, butyl, ethylhydroxy, isobutylhydroxy, C 1-2 Alkyl (morpholino), C 1-2 Alkyl (piperazinyl), C 1-2 Alkyl (tetrahydropyranyl), S (= O) (= NH) CH3 and (C 2-3 alkyl)P(O)(CH3)2, further wherein said morpholino, said piperazinyl and said tetrahydropyranyl are optionally substituted with 1 to 2 OH groups.

33. A compound as described in any one of claims 1 to 17 or 19 to 23, or a pharmaceutically acceptable salt thereof, wherein each R 1 independently selected from 1-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, 1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-5-methyl-1H-pyrazol-4-yl, 3-cyclopropyl-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-3-cyclopropyl-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, yl)-3,5-dimethyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-1H-pyrazol-4-yl, (S)-1-( 2-hydroxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-3-cyclopropyl-1-(2,3-dihydroxy-3-methylbutyl)-1H-pyrazol-4-yl (258), (R)-3-cyclopropyl-1-(2,3-dihydroxy-3-methylbutyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)- 1-(2-Hydroxypropyl)-5-methyl-1H-pyrazol-4-yl, (R)-1-(2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-methoxy-2-methylpropyl)-1H-pyrazol-4-yl, 1-((2R,3S)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl, 1-((2S,3R)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl, 1-((2S,3S)-3-hydroxybutan-2-yl)-5-methyl-1H-pyrazol-4-yl, 1-((2R,3R)-3-hydroxybutan-2-yl)-5-methyl-1H-pyrazol-4-yl, 1-((R)-2,3-dihydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 3,5-dimethyl-1-((4-methylmorpholin-2-yl)methyl)-1H-pyrazol-4-yl, (S)-1-(2,3-dihydroxypropyl)-3,5-dimethyl-1H-pyrazol-4-yl, 1-(1,3-dihydroxypropan-2-yl)-3,5-dimethyl-1H-pyrazol-4-yl, (R)-1- (2-Hydroxy-3-methoxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-(1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-3-methyl-1H-pyrazol-4-yl, (S)-1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl, (R)-1-(2-hydroxy-3-(2-methoxyethoxy)propyl)-3-methyl-1H-pyrazol-4-yl, 1-((2R,3R)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl and 1-((2S,3S)-3-hydroxybutan-2-yl)-3-methyl-1H-pyrazol-4-yl, 34. A compound according to any one of claims 1 to 17 or 19 to 23, or a pharmaceutically acceptable salt thereof, wherein: Each R 1 independently selected from the group consisting of: methyl, -NH2, methylamino, ethylamino, dimethylamino, (2-hydroxyethyl)amino, (S)-(2-hydroxypropyl)amino, (2-hydroxyethyl)(methyl)amino, (2-hydroxy-2-methylpropyl)amino, (2-(tert-butoxy)ethyl)amino, (2-methoxyethyl)amino, (2-(methoxy-d3)ethyl)amino, (2-methoxyethoxy)amino, (R)-(1-methoxyprop-2-yl)amino, (S)-(2-methoxypropyl)amino, (2-methoxy-2-methylpropyl)amino, (2-methoxyethoxy)ethyl)amino, (2,2-difluoroethyl)amino, (2,2-difluoropropyl)amino, (2,2-difluoro-3-hydroxypropyl)amino, (S)-(tetrahydrofuran-3-yl)amino amino, (oxetan-2-ylmethyl)amino, oxetan-3-ylamino, (oxetan-3-ylmethyl)amino, (1H-pyrazol-4-yl)amino, cyclopropyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 3-methoxypropyl, (2,2-difluoroethoxy)methyl, (2,2-difluoroethoxy)ethyl, fluoro, methoxy, 3-hydroxy-3-methylbutoxy, 2-methoxyethoxy, 2-hydroxyethoxy, 3-hydroxyazetidin-1-yl, (S)-2-(hydroxymethyl)azetidin-1-yl, 3-methylazetidin-1-yl, (R)-2-(methoxymethyl)azetidin-1-yl, (S)-2-(methoxymethyl)azetidin-1-yl, 3-(methylsulfonyl)azetidin-1-yl 3-(Hydroxymethyl)azetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, (R)-3-(dimethylamino)pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, (S)-3-hydroxypiperidin-1-yl, (R)-3-hydroxypiperidin-1-yl, 4-(methyl-d3)piperazin-1-yl, 4-(2,2-difluoroethyl)piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4,4-difluoropiperidin-1-yl, tetrahydrofuran-3-yl, morpholino, (R)-2-(hydroxymethyl)morpholino, 1H-pyrazol-4-yl, 1-(2-hydroxyethyl)-1H-pyrazol-4-yl, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, (R)-1-(2-hydroxypropyl)-1H-pyrazol-4-yl, (S)-1-(2-hydroxypropyl)-1H-pyrazol-4-yl), (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl, 35. A compound as described in any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently selected from CH3, Cl, F, CD3, CN and cyclopropyl.

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

38. A method of treating a subject having a disease or condition mediated by wild-type c-kit kinase, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37.

39. The method of claim 38, wherein the disease or condition is selected from urticaria, skin diseases, idiopathic allergies, asthma, hereditary alpha trypsinemia (HAT), neurofibromatosis, idiopathic pulmonary fibrosis, bullous pemphigoid, prurigo nodularis, age-related macular degeneration, allergic conjunctivitis, allergic rhinitis, alpha-1 antitrypsin deficiency, Alzheimer's disease, amyotrophic lateral sclerosis (AML), bronchiectasis, celiac disease, chronic graft-versus-host disease, chronic sinusitis with Nasal polyps, colorectal cancer, dermatitis herpetiformis, irritable bowel syndrome (IBS), fibromyalgia, fibrosis, food allergies, insulin-dependent diabetes mellitus, mast cell leukemia, migraines, multiple sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, pulmonary arterial hypertension (PAH), inflammatory bowel disease (IBD), scleroderma, skin diseases, dermatitis herpetiformis, melanoma, gastrointestinal stromal tumors, mast cell tumors, allergic syndromes, idiopathic allergies, eosinophilic esophagitis, and mastocytosis.

40. The method of claim 38, wherein the disease or condition is chronic urticaria.

41. The method of claim 40, wherein the chronic urticaria is chronic spontaneous urticaria (CSU).

42. The method of claim 41, wherein the subject is resistant to antihistamine therapy (ie, the subject remains symptomatic despite antihistamine therapy).

43. A method of inhibiting wild-type c-kit kinase in a subject in need thereof, comprising the step of administering to the subject in need thereof an effective amount of the compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37.

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