Compounds and medicaments as DDR1 kinase inhibitors

Abstract

The present invention provides a compound having DDR1 inhibitory activity and represented by general formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical use thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to substituted bicyclic heterocyclic compounds useful as DDR1 kinase inhibitors and medicaments containing such compounds. Background Art

[0002] Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor belonging to the discoidin domain receptor family. It is known to be involved in cell proliferation and differentiation, as well as migration, invasion, and adhesion. It is primarily expressed on epithelial cells in the lung, kidney, breast, and digestive tract.

[0003] DDR1 binds to its ligand collagen through its discoidin domain, transmitting collagen signals into the cell. DDR1 is characterized by its recognition of fibrous collagens (such as type I collagen) and basal membrane collagens (such as type IV collagen) as ligands. After binding to collagen, specific tyrosine residues in the kinase domain of DDR1 on the cytoplasmic side of the receptor become phosphorylated. Binding to molecules with a Src homology 2 domain or a phosphotyrosine binding domain activates various downstream signaling pathways.

[0004] Activation of DDR1 is associated with various kidney diseases. For example, it is implicated in kidney diseases such as Alport syndrome (Non-Patent Documents 1 and 2), IgA nephropathy (Non-Patent Document 3), Goodpasture syndrome (Non-Patent Document 4), lupus nephritis (Non-Patent Document 4), ANCA (anti-neutrophil cytoplasmic antibody)-associated nephritis (Non-Patent Document 5), and diabetic nephropathy (Non-Patent Document 6).

[0005] Activation of DDR1 has also been reported to be involved in various fibrotic diseases, including pulmonary fibrosis (Non-Patent Document 7) and liver cirrhosis (Non-Patent Document 8).

[0006] Furthermore, DDR1 has been reported to be involved in the function of Th17 cells associated with autoimmune diseases or allergies (Non-Patent Document 9). Th17 cells are involved in the pathogenesis of diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and Crohn's disease.

[0007] DDR1 has also been reported to be involved in the pathogenesis of cancers such as acute myeloid leukemia (Non-Patent Document 10), acute lymphocytic leukemia (Non-Patent Document 11), chronic lymphocytic leukemia (Non-Patent Document 12), Hodgkin's lymphoma (Non-Patent Document 13), glioma (Non-Patent Document 14), non-small cell lung cancer (Non-Patent Document 15), breast cancer (Non-Patent Document 16), ovarian cancer (Non-Patent Document 17), prostate cancer (Non-Patent Document 18), and colorectal cancer (Non-Patent Document 19).

[0008] In addition, DDR1 has been reported to be associated with diseases such as systemic lupus erythematosus (Non-Patent Document 5), osteoarthritis (Non-Patent Document 20), heparin-induced thrombocytopenia (Non-Patent Document 21), atherosclerosis (Non-Patent Document 22), and vitiligo vulgaris (Non-Patent Document 23).

[0009] Treatments for these diseases are mostly limited to symptomatic treatment or suppressing disease progression and improving quality of life, making effective treatment extremely difficult. Therefore, DDR1 inhibitors could provide new treatments for these DDR1-related diseases.

[0010] Prior art literature

[0011] Non-patent literature

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[0015] [Non-patent document 4]: Kerroch et al., FASEB J. 2012 Oct; 26(10): 4079-91.

[0016] [Non-patent document 5]: Moll et al., J Transl Med. 2018 Jun 1; 16(1): 148.

[0017] [Non-patent document 6]: Salem et al., J Am Soc Nephrol. 2019 Oct; 30(10): 2000-2016.

[0018] [Non-patent document 7]: Matsuyama et al., J Immunol. 2005 May 15; 174(10): 6490-8.

[0019] [Non-patent document 8]: Shackel et al., Am J Pathol. 2002 Feb; 160(2): 641-54.

[0020] [Non-patent document 9]: Azreq et al., Oncotarget. 2016 Jul 19; 7(29): 44975-44990.

[0021] [Non-patent document 10]: Favreau et al., Cancer Med. 2014 Apr; 3(2): 265-72.

[0022] [Non-patent document 11]: Guo et al., Exp Ther Med. 2019 Mar; 17(3): 1593-1600.

[0023] [Non-patent document 12]: Barisione et al., Blood Cancer J. 2017 Jan 6; 6(1): e513.

[0024] [Non-patent document 13]: Cader et al., Blood. 2013 Dec 19; 122(26): 4237-45.

[0025] [Non-patent document 14]: Ram et al., J Neurooncol. 2006 Feb; 76(3): 239-48.

[0026] [Non-patent document 15]: Miao et al., Med Oncol. 2013; 30(3): 626.

[0027] [Non-patent literature 16]: Zhong et al., Oncol Rep. 2019 Dec; 42(6): 2844-2854.

[0028] [Non-patent document 17]: Heinzelmann-Schwarz et al., Clin Cancer Res. 2004 Jul 1; 10(13): 4427-36.

[0029] [Non-patent document 18]: Azizi et al., J Cell Physiol. 2019 Nov; 234(11): 19539-19552.

[0030] [Non-patent document 19]: Le et al., Front Cell Dev Biol. 2020 Jun 3;8:412.

[0031] [Non-patent document 20]: Han et al., PLoS One. 2020 Apr 24; 15(4): e0231501.

[0032] [Non-patent document 21]: Witten et al., J Mol Med. 2018 Aug; 96(8): 765-775.

[0033] [Non-patent document 22]: Franco et al., Circ Res. 2008 May 23; 102(10): 1202-11.

[0034] [Non-patent document 23]: Almasi-Nasrabadi et al., Gene. 2019 Jun 5; 700: 17-22. Summary of the Invention

[0035] Problems to be solved by the present invention

[0036] The object of the present invention is to provide a compound having DDR1 kinase inhibitory activity or a pharmaceutically acceptable salt or solvate thereof.

[0037] Solutions to the Problem

[0038] The present inventors have discovered that the following compounds, or pharmaceutically acceptable salts thereof, or solvates thereof have excellent DDR1 kinase inhibitory activity, thereby completing the present invention.

[0039] That is, the present invention includes the following embodiments (Item 1) to (Item 22).

[0040] (Item 1)

[0041] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

[0042] [Chemical Formula 1]

[0043]

[0044] in:

[0045] A is

[0046] [Chemical Formula 2]

[0047]

[0048] in

[0049] Y 1 、Y 2 、Y 3 and Y 4 Each independently is N or CR 5 , where Y 1 、Y 2 、Y 3 and Y 4 At most two of them are N, and the others are CR 5 ,

[0050] R 5 is hydrogen, halogen, cyano, alkoxy, or optionally substituted C1-C6 alkyl,

[0051] and

[0052] The dotted lines represent the bonding points.

[0053] or

[0054] [Chemical Formula 3]

[0055]

[0056] in

[0057] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are each independently hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl, and

[0058] Dashed lines indicate bonding points;

[0059] B is an optionally substituted 3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle;

[0060] X is N or CR 7 , where R 7 is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl;

[0061] R 1Each is independently selected from the group consisting of hydrogen, halogen, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted;

[0062] R 2 and R 3 are each independently hydrogen, halogen, or optionally substituted C1-C6 alkyl;

[0063] R 4 selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, mono- or bicyclic saturated carbocycle, mono- or bicyclic unsaturated carbocycle, mono- or bicyclic saturated heterocycle, and mono- or bicyclic unsaturated heterocycle, each of which may be optionally substituted; or

[0064] R 4 for-CONR 8 R 9 ,in:

[0065] R 8 and R 9 Each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or

[0066] R 8 and R 9 together with the atoms to which they are attached, form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring;

[0067] m is an integer from 0 to 3;

[0068] n is an integer from 0 to 3; and

[0069] Het is a 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring.

[0070] (Item 2)

[0071] The compound according to item 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula (I) is formula (II):

[0072] [Chemical Formula 4]

[0073]

[0074] Among them, B, R 1 、R 2 、R 3 、R 4 , Het, X, Y 1 、Y 2 、Y 3 、Y 4 , m and n are as defined in formula (I).

[0075] (Item 3)

[0076] The compound according to item 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula (I) is formula (III):

[0077] [Chemical Formula 5]

[0078]

[0079] Among them, B, R 1 、R 2 、R 3 、R 4 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , Het, X, m and n are as defined in formula (I).

[0080] (Item 4)

[0081] The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 1 Each is independently selected from the group consisting of hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

[0082] (Item 5)

[0083] The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4Selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

[0084] (Item 6)

[0085] The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 for-CONR 8 R 9 ,in:

[0086] R 8 and R 9 Each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or

[0087] R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring.

[0088] (Item 7)

[0089] The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is N.

[0090] (Item 8)

[0091] The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is CR 7 , where R 7 is hydrogen, halogen, cyano, or an optionally substituted C1-C6 alkyl.

[0092] (Item 9)

[0093] A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of the following compounds (1) to (295):

[0094] (1) 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0095] (2) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0096] (3) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0097] (4) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0098] (5) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0099] (6) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0100] (7) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0101] (8) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0102] (9) 4-[4-(4-fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine

[0103] (10) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0104] (11) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0105] (12) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0106] (13) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0107] (14) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0108] (15) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0109] (16) 2-{3-[1-(6-aminopyridazine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0110] (17) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[3,4-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0111] (18) 5-Fluoro-4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0112] (19) 4-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine hydrochloride

[0113] (20) 4-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0114] (21) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0115] (22) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0116] (23) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0117] (24) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0118] (25) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0119] (26) 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate

[0120] (27) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate

[0121] (28) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0122] (29) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate

[0123] (30) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0124] (31) 2-(3-{1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

[0125] (32) 2-[4,6-difluoro-3-(1-{2-[(oxetan-3-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0126] (33) 2-[4,6-difluoro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0127] (34) 4-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine

[0128] (35) 4-(3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine hydrochloride

[0129] (36) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one

[0130] (37) 4-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0131] (38) 4-{3-[4-fluoro-1-({1-[(oxetan-3-yl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0132] (39) 4-{4-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]piperidine-1-carbonyl}pyridin-2-amine

[0133] (40) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0134] (41) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0135] (42) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0136] (43) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate

[0137] (44) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one di-p-toluenesulfonate

[0138] (45) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0139] (46) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate

[0140] (47) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0141] (48) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0142] (49) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0143] (50) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0144] (51) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride

[0145] (52) 4-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0146] (53) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0147] (54) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0148] (55) 4-{3-[4-fluoro-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0149] (56) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one

[0150] (57) 4-(3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine

[0151] (58) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one di-p-toluenesulfonate

[0152] (59) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0153] (60) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0154] (61) 2-[4-chloro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide

[0155] (62) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide

[0156] (63) 2-(4-chloro-3-{1-[2-(methylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide

[0157] (64) 2-(4-chloro-3-{1-[2-(ethylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0158] (65) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0159] (66) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,7-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0160] (67) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0161] (68) 2-(3-{1-[2-(cyclobutylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0162] (69) 2-(4-Bromo-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0163] (70) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-bromo-5-fluoro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0164] (71) 2-[4-Fluoro-3-(1-{2-[(oxan-4-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride

[0165] (72) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0166] (73) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride

[0167] (74) 2-[4,6-difluoro-3-(1-{2-[(1-methylcyclopropyl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0168] (75) 2-[3-(1-{2-[(4,4-difluorocyclohexyl)amino]pyridine-4-carbonyl}azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0169] (76) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(pyrrolidin-1-yl)ethan-1-one

[0170] (77) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0171] (78) 2-{3-[1-(2-amino-5-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride

[0172] (79) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-methylmorpholin-4-yl]ethan-1-one hydrochloride

[0173] (80) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one hydrochloride

[0174] (81) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0175] (82) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0176] (83) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-(propan-2-yl)morpholin-4-yl]ethan-1-one

[0177] (84) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethan-1-one

[0178] (85) 2-{3-[1-(6-aminopyridine-3-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0179] (86) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]piperidin-4-yl}-4-fluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0180] (87) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0181] (88) 2-[4,6-difluoro-3-(1-{2-[(oxan-4-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0182] (89) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride

[0183] (90) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0184] (91) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0185] (92) 4-[3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0186] (93) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0187] (94) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0188] (95) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride

[0189] (96) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0190] (97) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0191] (98) 2-(3-{1-[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0192] (99) 2-(3-{1-[2-(cyclopropylamino)-4-methyl-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0193] (100) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0194] (101) 2-[4,6-difluoro-3-(1-{imidazo[1,2-a]pyridine-3-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0195] (102) 2-[4,6-difluoro-3-(1-{pyrazolo[3,2-b][1,3]thiazole-7-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0196] (103) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one hydrochloride

[0197] (104) 4-[3-(4-Fluoro-1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0198] (105) 2-{3-[1-(2-amino-1,3-oxazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0199] (106) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0200] (107) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-2-fluoro-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0201] (108) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0202] (109) 4-(3-{4-fluoro-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine

[0203] (110) 2-{3-[1-(2-amino-4-methyl-1,3-oxazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0204] (111) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0205] (112) 4-[3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0206] (113) 4-[3-(4-Fluoro-1-{[3-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0207] (114) 4-[3-(4-Fluoro-1-{[2-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0208] (115) 4-[3-(4-Fluoro-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride

[0209] (116) 4-[3-(4-Fluoro-1-{[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0210] (117) 4-{3-[4-fluoro-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0211] (118) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0212] (119) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0213] (120) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0214] (121) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0215] (122) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0216] (123) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S)-3-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0217] (124) 2-{3-[1-(2-aminopyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0218] (125) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S)-3-(difluoromethoxy)pyrrolidin-1-yl]ethan-1-one

[0219] (126) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-(difluoromethoxy)pyrrolidin-1-yl]ethan-1-one

[0220] (127) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(2,2-dimethylpyrrolidin-1-yl)ethan-1-one

[0221] (128) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0222] (129) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0223] (130) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0224] (131) 2-{3-[1-(6-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0225] (132) 2-{4,6-difluoro-3-[1-(pyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0226] (133) 2-{4,6-difluoro-3-[1-(3-methoxypyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0227] (134) 4-[4-(4-Fluoro-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine

[0228] (135) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0229] (136) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0230] (137) 4-[3-(4-fluoro-1-{[5-(oxan-4-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0231] (138) 4-[3-(4-fluoro-1-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0232] (139) 2-(3-{1-[2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0233] (140) 2-{4,6-difluoro-3-[1-(1H-indazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0234] (141) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[4,3-b]pyridine-5-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0235] (142) 2-{4,6-difluoro-3-[1-(3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0236] (143) 2-{3-[1-(3-chloropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0237] (144) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0238] (145) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0239] (146) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine hydrochloride

[0240] (147) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0241] (148) 4-[3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0242] (149) 2-{3-[1-(2-amino-4-chloro-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0243] (150) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0244] (151) 4-[3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0245] (152) 4-{3-[4,6-difluoro-1-(3-phenylprop-2-yn-1-yl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0246] (153) 4-[3-(4-Fluoro-1-{[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0247] (154) 4-[3-(4-fluoro-1-{[5-(6-methylpyridazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0248] (155) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0249] (156) 4-{3-[1-(3-cyclopropylprop-2-yn-1-yl)-4,6-difluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine

[0250] (157) 4-(3-{4,6-difluoro-1-[(1-phenylazetidin-3-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine

[0251] (158) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one

[0252] (159) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-1-one

[0253] (160) 4-[3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0254] (161) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(6-bromo-2,3-dihydro-1H-indol-1-yl)ethan-1-one

[0255] (162) 2-{4,6-difluoro-3-[1-(oxane-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0256] (163) 2-{4,6-difluoro-3-[1-(2-hydroxypyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0257] (164) 2-{4,6-difluoro-3-[1-(1H-pyrazole-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0258] (165) 2-{4,6-difluoro-3-[1-(5-methyl-1H-pyrazole-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0259] (166) 2-(4,6-difluoro-3-{1-[5-(trifluoromethyl)-1H-pyrazole-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0260] (167) 4-[3-(4,6-difluoro-1-{[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl}-1H-indazol-3-yl)azetidin-1-carbonyl]pyridin-2-amine

[0261] (168) 4-[3-(5-methyl-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0262] (169) 2-{3-[1-(1H-1,2,3-benzotriazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0263] (170) 4-[3-(4-Fluoro-1-{[3-(3-fluoropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0264] (171) 4-(3-{1-[(2,3-dihydro-1H-indene-2-yl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine

[0265] (172) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(6-cyclopropyl-2,3-dihydro-1H-indol-1-yl)ethan-1-one

[0266] (173) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0267] (174) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0268] (175) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one

[0269] (176) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(2,2-dimethylmorpholin-4-yl)ethan-1-one

[0270] (177) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0271] (178) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one dihydrochloride

[0272] (179) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethan-1-one

[0273] (180) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0274] (181) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0275] (182) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S,5S)-3,5-dimethylmorpholin-4-yl]ethan-1-one

[0276] (183) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one p-toluenesulfonate

[0277] (184) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate

[0278] (185) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate

[0279] (186) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one p-toluenesulfonate

[0280] (187) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0281] (188) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0282] (189) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-N-tert-butylacetamide

[0283] (190) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0284] (191) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one

[0285] (192) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0286] (193) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0287] (194) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0288] (195) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0289] (196) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0290] (197) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0291] (198) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butylacetamide

[0292] (199) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butylacetamide

[0293] (200) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0294] (201) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0295] (202) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0296] (203) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0297] (204) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0298] (205) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0299] (206) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0300] (207) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0301] (208) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-methoxy-2-methylpropan-2-yl)acetamide

[0302] (209) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4-methyloxan-4-yl)acetamide

[0303] (210) 2-{3-[1-(2-amino-5-chloropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0304] (211) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide

[0305] (212) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(2R)-1,1,1-trifluoropropan-2-yl]acetamide

[0306] (213) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]acetamide

[0307] (214) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(3,3-difluorocyclobutyl)acetamide

[0308] (215) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one

[0309] (216) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0310] (217) 4-[3-(1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0311] (218) 4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine

[0312] (219) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one

[0313] (220) tert-Butyl 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetate

[0314] (221) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(2,2-dimethylpyrrolidin-1-yl)ethan-1-one

[0315] (222) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-ethylpyrrolidin-1-yl]ethan-1-one

[0316] (223) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{2-azabicyclo[3.1.0]hexan-2-yl}ethan-1-one

[0317] (224) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(dicyclopropylmethyl)acetamide

[0318] (225) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluorocyclopentyl)acetamide

[0319] (226) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4-fluorophenyl)acetamide

[0320] (227) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[2-(trifluoromethoxy)ethyl]acetamide

[0321] (228) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethan-1-one

[0322] (229) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(cyclopropylmethyl)-N-methylacetamide

[0323] (230) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(3S)-3-methoxypyrrolidin-1-yl]ethan-1-one

[0324] (231) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(3R)-3-methoxypyrrolidin-1-yl]ethan-1-one

[0325] (232) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{2-oxa-6-azaspiro[3.4]octan-6-yl}ethan-1-one

[0326] (233) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(oxan-4-yl)acetamide

[0327] (234) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2-cyclopropylpropan-2-yl)acetamide

[0328] (235) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4,4-difluorocyclohexyl)acetamide

[0329] (236) (2S)-1-(2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetyl)pyrrolidine-2-carbonitrile

[0330] (237) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0331] (238) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-{bicyclo[2.2.1]heptan-2-yl}acetamide

[0332] (239) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-{bicyclo[1.1.1]pentan-1-yl}acetamide

[0333] (240) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0334] (241) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0335] (242) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-(2,2-difluoroethyl)acetamide

[0336] (243) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[trans-2-fluorocyclopropyl]acetamide

[0337] (244) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-cyanocyclopropyl)acetamide

[0338] (245) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(1R,2S)-2-fluorocyclopropyl]acetamide

[0339] (246) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(1S,2R)-2-fluorocyclopropyl]acetamide

[0340] (247) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-methyl-1H-pyrazol-5-yl)acetamide

[0341] (248) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluorocyclopropyl)acetamide

[0342] (249) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide

[0343] (250) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(3,3-difluorocyclobutyl)-N-methylacetamide

[0344] (251) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide

[0345] (252) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-cyclopropyl-N-methylacetamide

[0346] (253) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(propan-2-yl)acetamide

[0347] (254) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(oxetan-3-yl)acetamide

[0348] (255) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(oxan-4-yl)acetamide

[0349] (256) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(3,3-difluorocyclobutyl)methyl]-N-methylacetamide

[0350] (257) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(4,4-difluoropiperidin-1-yl)ethan-1-one

[0351] (258) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}ethan-1-one

[0352] (259) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[3-(trifluoromethyl)piperidin-1-yl]ethan-1-one

[0353] (260) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(4-methylpiperazin-1-yl)ethan-1-one

[0354] (261) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]acetamide

[0355] (262) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[(2R)-1,1,1-trifluoropropane-2-yl]acetamide

[0356] (263) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N,N-diethylacetamide

[0357] (264) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[2-(morpholin-4-yl)ethyl]acetamide

[0358] (265) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2-methoxyethyl)-N-methylacetamide

[0359] (266) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R,6S)-2,6-dimethylpiperidin-1-yl]ethan-1-one

[0360] (267) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N,N-bis(propan-2-yl)acetamide

[0361] (268) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butyl-N-methylacetamide

[0362] (269) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluoroethyl)-N-methylacetamide

[0363] (270) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0364] (271) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0365] (272) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(difluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0366] (273) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0367] (274) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0368] (275) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0369] (276) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0370] (277) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0371] (278) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0372] (279) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0373] (280) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0374] (281) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-hydroxyazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0375] (282) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0376] (283) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0377] (284) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0378] (285) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-fluoroazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0379] (286) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0380] (287) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0381] (288) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0382] (289) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0383] (290) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0384] (291) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methoxy-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0385] (292) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one

[0386] (293) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide

[0387] (294) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one, and

[0388] (295) 2-{3-[1-(2-Aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one.

[0389] (Item 10)

[0390] 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0391] (Item 11)

[0392] 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride or a solvate thereof.

[0393] (Item 12)

[0394] 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0395] (Item 13)

[0396] 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0397] (Item 14)

[0398] 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0399] (Item 15)

[0400] A methanesulfonic acid salt of 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a solvate thereof.

[0401] (Item 16)

[0402] A pharmaceutical composition comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0403] (Item 17)

[0404] A DDR1 kinase inhibitor comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0405] (Item 18)

[0406] A method for inhibiting DDR1 kinase, comprising administering the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.

[0407] (Item 19)

[0408] A preventive or therapeutic agent for a DDR1 kinase-related disease, comprising the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0409] (Item 20)

[0410] A therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change disease nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis, comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0411] (Item 21)

[0412] A method for preventing or treating a DDR1 kinase-related disease, comprising administering the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.

[0413] (Item 22)

[0414] A method for preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer or osteoarthritis, comprising administering to a subject in need thereof a compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0415] (Item 23)

[0416] The compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in preventing or treating a DDR1 kinase-related disease.

[0417] (Item 24)

[0418] The compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membrane proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer or osteoarthritis.

[0419] (Item 25)

[0420] Use of the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for manufacturing a preventive or therapeutic agent for a DDR1 kinase-related disease.

[0421] (Item 26)

[0422] Use of the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for manufacturing a preventive or therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

[0423] The terms used herein are defined as follows.

[0424] As used herein, "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. In particular, a fluorine atom or a chlorine atom is preferred.

[0425] As used herein, "alkyl" includes, for example, a linear or branched alkyl group having 1 to 8 carbon atoms (C1-C8), preferably 1 to 6 carbon atoms (C1-C6). Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, isopentyl, -CH(CH2CH3)2, hexyl, isohexyl, -CH2CH2C(CH3)3, -CH2CH(CH2CH3)2, heptyl, isoheptyl, octyl, isooctyl, and the like.

[0426] As used herein, "alkenyl" includes, for example, a straight or branched alkenyl group having one or two double bonds and 2 to 8 carbon atoms (C2-C8). Specific examples include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, and the like. Preferred examples are alkenyl groups having 2 to 6 carbon atoms, and more preferred examples are alkenyl groups having 2 to 4 carbon atoms.

[0427] As used herein, "alkynyl" includes, for example, a straight or branched chain alkynyl group having one or two triple bonds and 2 to 8 carbon atoms (C2-C8). Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, and the like. Preferred examples include alkynyl groups having 2 to 6 carbon atoms, and more preferred examples include alkynyl groups having 2 to 4 carbon atoms.

[0428] The alkyl moiety of "alkylcarbonyl", "monoalkylamino", "dialkylamino" and "aminoalkyl" as used herein includes the same examples as the above-mentioned "alkyl".

[0429] As used herein, "haloalkyl" includes, for example, the above-mentioned "alkyl" in which 1 to 3 hydrogen atoms are substituted by the above-mentioned "halogen". Specific examples thereof include: fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl (e.g., 2,2-difluoroethyl), trifluoromethyl, trichloromethyl, trifluoroethyl (e.g., 2,2,2-trifluoroethyl), and the like.

[0430] As used herein, "alkoxy" includes, for example, a straight or branched chain alkoxy group having 1 to 8 carbon atoms (C1-C8), preferably 1 to 6 carbon atoms (C1-C6). Specific examples thereof include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the like.

[0431] As used herein, "haloalkoxy" includes, for example, the above-mentioned "alkoxy" in which 1 to 3 hydrogen atoms are substituted by the above-mentioned "halogen". Specific examples thereof include: fluoromethoxy, chloromethoxy, fluoroethoxy, difluoromethoxy, dichloromethoxy, difluoroethoxy (e.g., 2,2-difluoroethoxy), trifluoromethoxy, trichloromethoxy, trifluoroethoxy (e.g., 2,2,2-trifluoroethoxy), and the like.

[0432] As used herein, "cycloalkyl" includes, for example, a cycloalkyl group having 3 to 10 carbon atoms (C3-C 10 ) of a monocyclic, bicyclic or tricyclic saturated hydrocarbon group. Specific examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl, adamantyl (also known as tricyclo[3.3.1.1 3,7 ]decyl) etc.

[0433] As used herein, "halocycloalkyl" includes, for example, "cycloalkyl" in which 1 to 3 hydrogen atoms are substituted by "halogen". Specific examples include 2-fluorocyclopropyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopentyl, and 4,4-difluorocyclohexyl.

[0434] As used herein, "cycloalkenyl" includes, for example, cycloalkenyl groups having 3 to 10 carbon atoms (C3-C 10 ) and one or two double bonds. Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

[0435] As used herein, "heterocycloalkyl" includes, for example, a monocyclic or bicyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms in the ring and consisting of 4 to 10 ring atoms. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrothienyl, and the like.

[0436] As used herein, "aryl" includes, for example, monocyclic, bicyclic, or tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specific examples thereof include: phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthrenyl, 2-phenanthrenyl, 3-phenanthrenyl, 4-phenanthrenyl, 10-phenanthrenyl, etc. In particular, phenyl is preferred.

[0437] As used herein, the "heteroaryl group" includes, for example, a monocyclic or bicyclic aromatic heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms in the ring and consisting of 5 to 10 ring atoms. Specific examples thereof include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) ), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl). More preferred are furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).

[0438] The "carbocycle" refers to a cyclic structure composed of carbon atoms, and examples thereof include the above-mentioned "cycloalkyl", "cycloalkenyl" and "aryl".

[0439] The "heterocycle" refers to a cyclic structure composed of, for example, one or more heteroatoms selected from nitrogen atoms, sulfur atoms, oxygen atoms, and carbon atoms, and examples thereof include the above-mentioned "heterocycloalkyl" and "heteroaryl".

[0440] As used herein, the "3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle" refers to, for example, a saturated or unsaturated monocyclic heterocycle having 1 to 4 nitrogen atoms in the ring and consisting of 3 to 8 ring atoms. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azoline, pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., 5-tetrazolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), 1,2,3,6-tetrahydropyridinyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), and the like.

[0441] As used herein, a "5- to 10-membered monocyclic or bicyclic saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle having 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms in the ring and consisting of 5 to 10 ring atoms. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrothienyl, and the like.

[0442] As used herein, "5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring" refers to a monocyclic or bicyclic aromatic heterocyclic ring or non-aromatic unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms in the ring and consisting of 5 to 10 ring atoms. Specific examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl), 1-Isoxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., For example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (for example, 2-pyrazinyl), benzimidazolyl (for example, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (for example, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), pyrazolo[5,1-b]thiazolyl, azaindazolyl (for example, 3-azaindazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl), , 7-azaindolyl), benzotriazolyl (e.g., 5-benzotriazolyl, 6-benzotriazolyl), azaindolyl (e.g., 5-azaindolyl, 6-azaindolyl, 7-azaindolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), pyridonyl (e.g., 2-pyridon-3-yl, 2-pyridon-4-yl, 2-pyridon-5-yl, 2-pyridon-6-yl).More preferred are furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), pyrazolo[5,1-b]thiazolyl, azaindazolyl (e.g., 3-azaindazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl), benzotriazolyl (e.g., 5-benzotriazolyl, 6-benzotriazolyl), azaindolyl (e.g., 5-azaindolyl, 6-azaindolyl, 7-azaindolyl), pyridonyl (e.g., 2-pyridon-3-yl, 2-pyridon-4-yl, 2-pyridon-5-yl, 2-pyridon-6-yl).

[0443] The "cyano group" refers to a group represented by -CN.

[0444] "Oxo" refers to a group represented by =O.

[0445] The "carbonyl group" refers to a group represented by -(C=O)-.

[0446] The "hydroxyl group" refers to a group represented by -OH.

[0447] "Optionally substituted" means that the specified group may be substituted or unsubstituted, i.e., may be optionally substituted or unsubstituted. For example, "optionally substituted alkyl" means both substituted alkyl and unsubstituted alkyl.

[0448] Substituents for the designated groups include alkyl, haloalkyl, alkoxy, cycloalkyl, halocycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl or heteroaryl, etc. as defined above, and combinations of these substituents (e.g., alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amino, aryl or heteroaryl substituted with at least one substituent selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl and heteroaryl).

[0449] The number of substituents of the designated group is, for example, 1 to 3, preferably 1 or 2, more preferably 1.

[0450] In the compounds of formulae (I) to (III), preferred embodiments of the groups represented by each symbol are shown below. Examples of the compounds of formulae (I) to (III) include those having all combinations of embodiments of each group shown below.

[0451] A is preferably

[0452] [Chemical Formula 6]

[0453]

[0454] in,

[0455] Y 1 、Y 2 、Y 3 and Y 4 Each independently is N or CR 5 , where Y 1 、Y 2 、Y 3 and Y 4 At most one of them is N, and the others are CR 5 ,

[0456] R 5 is hydrogen, halogen (e.g., fluorine atom, chlorine atom), alkoxy (e.g., methoxy), or optionally substituted C1-C6 alkyl (e.g., methyl), and

[0457] The dotted lines represent the bonding points.

[0458] or

[0459] [Chemical Formula 7]

[0460]

[0461] in,

[0462] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are each independently hydrogen, halogen (e.g., fluorine atom), or an optionally substituted C1-C6 alkyl group (e.g., methyl group), and

[0463] Dashed lines indicate bonding points.

[0464] A is more preferably

[0465] [Chemical Formula 8]

[0466]

[0467] in,

[0468] Y 1 、Y 2 、Y 3 and Y 4 CR 5 ,

[0469] R 5 is hydrogen, and

[0470] Dashed lines indicate bonding points.

[0471] B is preferably an optionally substituted 4- to 6-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle, more preferably azetidinyl, piperidinyl or 1,2,3,6-tetrahydropyridinyl, particularly preferably azetidinyl, which may be optionally substituted by C1-C6 alkyl (e.g. methyl).

[0472] X is preferably N or CR 7 , where R 7 It is preferably hydrogen, and more preferably N.

[0473] R 1 Preferably, each is independently selected from the group consisting of hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

[0474] R 1 More preferably, they are each independently hydrogen, halogen (e.g., fluorine atom, chlorine atom), oxo, C1-C6 alkyl (e.g., methyl), amino, or monoalkylamino (e.g., methylamino, ethylamino), wherein the amino group may be optionally substituted by a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, 1-methylcyclopropyl) or a heterocycloalkyl group (e.g., oxetanyl, tetrahydropyranyl), and the C1-C6 alkyl group may be optionally substituted by 1 to 3 halogen (e.g., fluorine atom).

[0475] R 1 More preferably, each independently represents hydrogen, a halogen (eg, a fluorine atom), or an amino group.

[0476] R 2 and R 3 Preferably, each independently represents hydrogen or a halogen (eg, a fluorine atom).

[0477] R 4It is preferably selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

[0478] R 4 More preferably, it is selected from the group consisting of: C2-C6 alkynyl (e.g., ethynyl), carboxyl, monocyclic or bicyclic saturated carbocycle (e.g., cyclohexyl), monocyclic or bicyclic unsaturated carbocycle (e.g., phenyl, 2,3-dihydro-1H-indenyl), monocyclic or bicyclic saturated heterocycle (e.g., azetidinyl), and monocyclic or bicyclic unsaturated heterocycle (e.g., pyridyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl),

[0479] in:

[0480] (1) C2-C6 alkynyl may be optionally replaced by C3-C 10 substituted by a cycloalkyl group (e.g., cyclopropyl) or an aryl group (e.g., phenyl),

[0481] (2) the carboxyl group may be optionally substituted by a C1-C6 alkyl group (e.g., tert-butyl group),

[0482] (3) The monocyclic or bicyclic saturated carbon ring may be optionally substituted by halogen (e.g., fluorine atom),

[0483] (4) The monocyclic or bicyclic unsaturated carbon ring may be optionally substituted by a haloalkyl group (e.g., trifluoromethyl),

[0484] (5) the monocyclic or bicyclic saturated heterocycle may be optionally substituted by an aryl group (e.g., phenyl) or a haloalkyl group (e.g., 2,2,2-trifluoroethyl), and

[0485] The monocyclic or bicyclic unsaturated heterocycle may be optionally substituted with a substituent selected from the following groups:

[0486] (i) haloalkyl (e.g. trifluoromethyl, 2,2,2-trifluoroethyl),

[0487] (ii) C3-C6 cycloalkyl (e.g. cyclopropyl, cyclobutyl) substituted by a haloalkyl (e.g. trifluoromethyl),

[0488] (iii) heterocycloalkyl (e.g. tetrahydropyranyl),

[0489] (iv) an aryl group (eg, a phenyl group) which may be optionally substituted with a halogen (eg, a fluorine atom) or a haloalkyl group (eg, a trifluoromethyl group),

[0490] (v) a heteroaryl group (e.g., pyridyl, pyridazinyl) which may be optionally substituted with a halogen (e.g., a fluorine atom) or a C1-C6 alkyl group (e.g., a methyl group), and

[0491] (vi) may be optionally substituted with a halocycloalkyl group (e.g., 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl), an aryl group (e.g., phenyl), a C3-C 10 C1-C6 alkyl (eg, methyl) substituted with cycloalkyl (eg, cyclopropyl) or heterocycloalkyl (eg, oxetanyl).

[0492] In addition, R 4 Preferably -CONR 8 R 9 , where R 8 and R 9 Each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or

[0493] R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring.

[0494] More preferably, R 8 and R 9 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, and heteroaryl, each of which may be optionally substituted;

[0495] More preferably,

[0496] (1) C1-C6 alkyl is, for example, methyl, ethyl, isopropyl, or tert-butyl, and may be optionally substituted by a substituent selected from the following groups:

[0497] (i) halogen (e.g. fluorine atom),

[0498] (ii) C1-C6 alkoxy (e.g., methoxy),

[0499] (iii) haloalkoxy (e.g. trifluoromethoxy),

[0500] (iv) heterocycloalkyl (e.g., tetrahydropyranyl, morpholinyl)

[0501] (v) halocycloalkyl (e.g., 3,3-difluorocyclobutyl), and

[0502] (vi) an aryl group (eg, a phenyl group) which may be optionally substituted with a halogen (eg, a fluorine atom),

[0503] (2) C3-C6 cycloalkyl is particularly cyclobutyl, cyclopentyl, cyclohexyl, which may be optionally substituted by halogen (e.g. fluorine atom) or cyano,

[0504] (3) Heterocycloalkyl groups such as oxetanyl and tetrahydropyranyl, which may be substituted, and

[0505] (4) Heteroaryl is exemplified by pyrazolyl, which may be optionally substituted by halogen (eg, fluorine atom).

[0506] Preferably, R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring,

[0507] More preferably,

[0508] (1) A 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo[3.1.0]hexyl, azaspiro[3.4]octyl, bicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, or azabicyclo[3.2.1]octyl, which may be optionally substituted by a substituent selected from the following groups:

[0509] (i) Halogen (e.g., fluorine atom, bromine atom)

[0510] (ii) C1-C6 alkyl (e.g. methyl, ethyl, isopropyl) which may be optionally substituted by hydroxy, C1-C6 alkoxy (e.g. methoxy), haloalkoxy (e.g. trifluoromethoxy) or heterocycloalkyl (e.g. morpholinyl),

[0511] (iii) C1-C6 alkoxy (e.g., methoxy),

[0512] (iv) haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl),

[0513] (v) C3-C6 cycloalkyl (e.g. cyclopropyl),

[0514] (vi) haloalkoxy (e.g., difluoromethoxy), and

[0515] (vii) cyano,

[0516] as well as

[0517] (2) 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic rings such as 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, or 2,3-dihydro-1H-indolyl.

[0518] Particularly preferably, R4 for-CONR 8 R 9 , where R 8 and R 9 Together with the atoms to which they are attached, they form a 5-membered monocyclic saturated heterocycle (eg, pyrrolidinyl) substituted with a haloalkyl group (eg, trifluoromethyl).

[0519] m is preferably an integer of 0 to 2, more preferably an integer of 2.

[0520] n is preferably an integer of 0 to 1, more preferably an integer of 1.

[0521] Het is preferably a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle, more preferably pyridyl, pyrimidinyl, 1,3-thiazolyl, pyridazinyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-thiazolyl, imidazo[1,2-a]pyridyl, pyrazolo[3,2-b][1,3]thiazolyl, 1,3-oxazolyl, 1H-indazolyl, pyrazolyl, 1H-1,2,3-benzotriazolyl, more preferably pyridyl. DETAILED DESCRIPTION

[0522] The compounds of the present invention can be prepared, for example, from known compounds themselves or intermediates that can be easily prepared from known compounds according to the following methods, the examples described below, or known methods. In the preparation of the compounds of the present invention, if the starting materials have substituents that affect the reaction, the reaction is usually carried out after the starting materials have been previously protected with appropriate protecting groups by known methods. After the reaction, the protecting groups can be deprotected by known methods.

[0523] Abbreviations used herein have the following meanings.

[0524] In the examples, the following abbreviations are used.

[0525] TFA: trifluoroacetic acid

[0526] 2-Azaadamantane-N-hydroxy

[0527] Pd-C: Palladium-carbon

[0528] PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride

[0529] Pd(OAc)2: Palladium(II) acetate

[0530] Pd(dppf)Cl2·CH2Cl2:[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride dichloromethane adduct

[0531] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0532] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0533] Boc: tert-Butoxycarbonyl

[0534] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0535] HBTU: O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0536] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0537] EDCI·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0538] DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0539] HOBt: 1-hydroxybenzotriazole

[0540] THF: Tetrahydrofuran

[0541] DMF: dimethylformamide

[0542] DMA: dimethylacetamide

[0543] DMSO: dimethyl sulfoxide

[0544] NMP: N-methylpyrrolidone

[0545] DIPEA: N,N-diisopropylethylamine

[0546] DMAP: 4-dimethylaminopyridine

[0547] NMM: 4-methylmorpholine

[0548] DAST: (diethylamino)sulfur trifluoride

[0549] MS: mass spectrometry

[0550] LCMS: high performance liquid chromatography mass spectrometry

[0551] ESI: electrospray ionization

[0552] M: molar concentration (mol / L)

[0553] Unless otherwise specified, the reactions in the steps of the following methods are carried out according to the methods described in, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 2nd Ed. by R.C. Larock, John Wiley & Sons, Inc., 1999; The Chemical Society of Japan, "Experimental Chemistry", 4th edition, Maruzen, 1992; L. Kuerti and B. Czako, "Strategic Applications of Named Reactions in Organic Synthesis", translated by Kiyoshi Tomioka, Kagaku-Dojin Publishing Company, Inc., 2006; G.S. Zweifel and M.H. Nantz, "Modern Organic Synthesis: An Introduction", translated by Tamejiro Hiyama, Kagaku-Dojin Publishing Company, Inc., 2009, or according to similar methods described in the Examples, and modified or combined as appropriate.

[0554] Synthesis of compound (G-1)

[0555] [Chemical Formula 9]

[0556]

[0557] Here, Y 1 、Y 2 、Y 3 、Y 4 、R 1 、R 2 、R 3 、R 4 , B as defined above. PG 1 represents a protecting group, such as tert-butyloxycarbonyl (hereinafter referred to as "Boc"), benzyloxycarbonyl (hereinafter referred to as "Cbz"), benzyl (hereinafter referred to as "Bn"), etc. 1 represents chlorine, bromine, or triflate).

[0558] Step 1

[0559] In this method, a commercially available or known compound A-1 is reacted with a commercially available or known compound B-1 in the presence of lithium diisopropylamide (LDA) in a solvent such as THF or diethyl ether at -78°C to 0°C, preferably -78°C to -60°C, more preferably -78°C, for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours to obtain compound C-1.

[0560] LDA is commercially available or can be prepared from diisopropylamine and n-butyllithium (n-BuLi).

[0561] Step 2

[0562] This step is to oxidize the hydroxyl group of compound C-1 to obtain D-1.

[0563] The reaction uses 2-azaadamantane-N-oxyl (AZADOL registered trademark), 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), Dess-Martin reagent, etc., in a solvent such as dichloromethane or dichloroethane, at 0°C to room temperature for 30 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 30 minutes to 3 hours to obtain D-1.

[0564] In reactions using AZADOL or TEMPO, iodobenzene diacetate, sodium hypochlorite (NaOCl), or the like is generally used as a co-oxidant.

[0565] Step 3

[0566] In this step, compound D-1 is reacted in the presence of hydrazine monohydrate in a solvent such as dioxane, THF, etc. at room temperature to reflux temperature, preferably in dioxane at 100°C for 1 hour to 48 hours, preferably 8 hours to 24 hours, to obtain Ea-1.

[0567] Step 4

[0568] In this step, compound Ea-1 is alkylated with an alkylating agent F-1 in the presence of a base to obtain compound G-1. This step can be carried out according to known alkylation reaction methods. The reaction of compound Ea-1 with the alkylating agent F-1 is carried out in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in a solvent such as dimethylformamide or tetrahydrofuran, at 0°C to 120°C, preferably room temperature to 120°C, for 1 to 48 hours, preferably 1 to 12 hours.

[0569] The above compounds C-1 and D-1 can be prepared by the following method.

[0570] [Chemical Formula 10]

[0571]

[0572] Here, Y 1 、Y 2 、Y 3 、Y 4 , B, PG 1 As defined above. 2 represents Br or I.

[0573] Path 1

[0574] In this method, a commercially available or known compound A-2 is reacted with a compound B-1 in the presence of butyl lithium (n-BuLi) in a solvent such as THF, diethyl ether, etc. at -78°C to 0°C, preferably -78°C to -60°C, more preferably -78°C, for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours to obtain a compound C-1.

[0575] Path 2

[0576] In this method, a commercially available or known compound A-1 is reacted with a commercially available or known compound B-2 in the presence of butyl lithium (n-BuLi) in a solvent such as THF, diethyl ether, etc. at -78°C to 0°C, preferably -78°C to 60°C, more preferably -78°C, for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours to obtain compound D-1.

[0577] Synthesis of compound (G-2)

[0578] [Chemical Formula 11]

[0579]

[0580] Here, A, R 1 、R 2 、R 3 、R 4 , B, X 1 PG 1 As defined above. 3 represents I, Cl or Br.

[0581] Step 1

[0582] This method involves halogenating compound H-1, which is commercially available or synthesized by known methods, to produce compound J-1. Halogenation can be performed using reactions commonly used for aromatic ring halogenation. Compound H-1 is reacted with chlorine, bromine, iodine, N-chlorosuccinimide (NCS), and N-bromosuccinamide (NBS) in a solvent such as dichloromethane, dichloroethane, carbon tetrachloride, or DMF at 0°C to room temperature for 30 minutes to 48 hours, preferably 1 hour to 12 hours, to produce compound J-1.

[0583] Step 2

[0584] In this step, compound J-1 is alkylated with an alkylating agent F-1 in the presence of a base to give compound K-1. Compound K-1 can be prepared by reacting under the same conditions as in step 4 of the synthesis of compound (G-1) above.

[0585] Step 3

[0586] The method involves a Negishi coupling reaction of compound K-1 and L-1 to obtain compound G-2. In this reaction, a palladium catalyst, such as tetrakis(triphenylphosphine)palladium (hereinafter referred to as "Pd(PPh3)4"), palladium(II) acetate (hereinafter referred to as "Pd(OAc)2"), bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as "Pd(PPh3)2Cl2"), [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride·dichloromethane adduct (hereinafter referred to as "Pd(dppf)2Cl2"), etc., and a commercially available or known method-synthesized compound L-1 are added to compound K-1, and the reaction is carried out under a nitrogen atmosphere or an argon atmosphere at 0°C to 150°C, preferably 60°C to 120°C, for 0.5 to 24 hours, preferably 1 to 12 hours, to obtain compound G-2.

[0587] Synthesis of compound (I)

[0588] [Chemical Formula 12]

[0589]

[0590] Here, A, B, R 1 、R 2 、R 3 、R 4 、Het、m、PG 1 As defined above

[0591] Step 1

[0592] This step is to deprotect the protecting group of compound G-2 to obtain compound M-1, and can be performed with reference to Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, or PJ Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005.

[0593] Step 2

[0594] In this step, compound M-1 is condensed with compound N-1 or its reactive compound N-1 in the presence of a condensing agent to obtain compound (I).

[0595] In this reaction, in the presence of an organic base such as TEA, DIPEA, N,N-dimethylaniline or DBU, in the presence of a condensing agent such as 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI"), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as "EDCI"), diisopropylcarbodiimide (hereinafter referred to as "DIC"), diethyl cyanophosphonate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro In the presence of phosphate (hereinafter referred to as "HBTU"), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HATU"), etc., in a solvent such as toluene, xylene, 1,4-dioxane, THF, DME, DMF, DMA, dichloromethane or dichloroethane, compound M-1 is reacted with compound N-1 at 0°C to 50°C, preferably at room temperature to 50°C to obtain compound (I).

[0596] In this step, the reactive compound of compound N-1 includes, for example, an acid halide (eg, acid chloride, acid bromide), a mixed acid anhydride, an acyl imidazole (imidazolide), an active amide, or other compounds commonly used in amide condensation reactions.

[0597] In this step, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt") may be added as needed.

[0598] Synthesis of compound (I-2)

[0599] (When R 4 for-CONR 8 R 9 )

[0600] [Chemical Formula 13]

[0601]

[0602] Here, A, B, PG 1 、R 1 、Het、R 8 、R 9 , m are as defined above. A It represents methyl, ethyl, n-propyl, and tert-butyl.

[0603] Step 1

[0604] This step is to deprotect the protecting group of compound G-2 to obtain compound M-2, and can be performed with reference to Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, or PJ Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005.

[0605] Step 2

[0606] This step involves condensing compound M-2 with compound N-1 or a reactive compound thereof in the presence of a condensing agent to obtain compound O-2. This step can be carried out in the same manner as step 2 in the synthesis of compound (I) above.

[0607] Step 3

[0608] This step is to remove the protective group (PG 2 ) is deprotected to obtain compound P-2, and can be performed with reference to Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, or PJ Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005.

[0609] Step 4

[0610] This step involves condensing compound Q-1 with compound P-2 or a reactive compound thereof in the presence of a condensing agent to obtain compound I-2. This step can be carried out in the same manner as step 2 in the synthesis of compound (I) above.

[0611] In the synthesis of compound I-2, the order of steps 1-2 and 3-4 can be switched to obtain compound I-2. Specifically, the carboxylic acid obtained by deprotection (hydrolysis) of RA in compound G-2 is condensed with compound Q-1. Subsequently, the amine obtained by deprotection of PG1 is condensed with compound N-1 to obtain compound I-2.

[0612] The compounds of the present invention can be used as pharmaceuticals as such, or in the form of pharmaceutically acceptable salts, solvates, or salts of solvates thereof according to known methods. Examples of pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; or salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by methods well known in the art.

[0613] For example, the hydrochloride salt of the compound of the present invention can be prepared by dissolving the free base of the compound of the present invention in hydrogen chloride in alcohol, hydrogen chloride in ethyl acetate, hydrogen chloride in 1,4-dioxane, hydrogen chloride in cyclopentyl methyl ether, or hydrogen chloride in diethyl ether.

[0614] The compounds of the present invention may be combined with solvent molecules and form solvates by exposure to the atmosphere or recrystallization, and such solvates are also included in the compounds of the present invention. Solvates include solvates containing solvent molecules, such as methanol solvates, ethanol solvates, isopropanol solvates, butanol solvates, dimethyl sulfoxide solvates, acetonitrile solvates, etc., as well as monohydrates, dihydrates, etc.

[0615] Some compounds of the present invention may have asymmetric carbons, and their corresponding stereoisomers and mixtures thereof are included in the present invention. Stereoisomers can be prepared by optical resolution from their racemates, for example, using optically active acids (such as tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) according to known methods, utilizing their alkalinity, or by using pre-prepared optically active compounds as starting materials. In addition, stereoisomers can also be prepared by optical resolution using chiral columns or by asymmetric synthesis.

[0616] The compounds of the present invention have DDR1 kinase inhibitory activity, as shown in the following test examples.

[0617] Therefore, one embodiment of the present invention provides a DDR1 kinase inhibitor comprising a compound of the present invention.

[0618] Furthermore, one embodiment of the present invention provides a method of inhibiting DDR1 kinase, comprising administering a compound of the present invention to a subject in need thereof.

[0619] Furthermore, one embodiment of the present invention provides a use of the compound of the present invention for inhibiting DDR1 kinase.

[0620] In addition, one embodiment of the present invention provides a use of the compound of the present invention for the manufacture of a DDR1 kinase inhibitor.

[0621] One embodiment of the present invention provides a preventive or therapeutic agent for a DDR1 kinase-related disease, comprising the compound of the present invention.

[0622] In addition, one embodiment of the present invention provides a method for preventing or treating a DDR1 kinase-related disease, comprising administering a compound of the present invention to a subject in need thereof.

[0623] In addition, one embodiment of the present invention provides a use of the compound of the present invention for preventing or treating DDR1 kinase-related diseases.

[0624] In addition, one embodiment of the present invention provides a use of the compound of the present invention for manufacturing a preventive or therapeutic agent for a DDR1 kinase-related disease.

[0625] Diseases to which the compounds of the present invention can be applied include, for example, Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglaucoma nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

[0626] Therefore, one embodiment of the present invention provides a preventive or therapeutic agent for the above-mentioned diseases, which comprises the compound of the present invention.

[0627] In addition, one embodiment of the present invention provides a method for preventing or treating the above-mentioned diseases, which comprises administering the compound of the present invention to a subject in need thereof.

[0628] In addition, one embodiment of the present invention provides a use of the compound of the present invention for preventing or treating the above-mentioned diseases.

[0629] In addition, one embodiment of the present invention provides a use of the compound of the present invention for manufacturing a preventive or therapeutic agent for the above-mentioned diseases.

[0630] "Subject" refers to a human or non-human animal that has or is suspected of having a DDR1-related disease. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0631] The compounds of the present invention can be used as therapeutic agents for the above-mentioned various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc., or as pharmaceutical compositions containing, for example, 0.001% to 99.5%, preferably 0.1% to 90% of the compounds in a pharmaceutically acceptable carrier.

[0632] The carrier can be one or more conventional solid, semisolid or liquid diluents, fillers and other excipients for formulation. The pharmaceutical composition of the present invention is preferably administered in unit dosage form. The pharmaceutical composition can be administered via intra-tissue, oral, intravenous, topical (transdermal, eye drops, intraperitoneal, intrathoracic, etc.) or rectal routes. The pharmaceutical composition is administered in a dosage form suitable for the mode of administration.

[0633] As a medicine, it is preferred to adjust the dosage according to the conditions such as the patient's age, weight, disease type and severity, route of administration, type of compound of the present invention (whether it is a salt) and type of salt. Generally, for adults, the effective amount of the compound of the present invention or its pharmaceutically acceptable salt, in the case of oral administration, is preferably in the range of 0.01mg to 5g / day, more preferably 1mg to 500mg / day. In some cases, it may be sufficient to only need a smaller dose, or a larger dose may be required. Generally, the dosage can be administered once a day or in divided doses multiple times a day; in the case of intravenous administration, the dosage can be quickly or continuously administered within 24 hours.

[0634] The compounds of the present invention can be used alone or in combination with other therapeutic agents, such as angiotensin converting enzyme inhibitors (ACE inhibitors) or angiotensin IIAT1 receptor antagonists (angiotensin receptor antagonists = ARBs). Examples of ARBs include candesartan, losartan, valsartan, olmesartan, azilsartan, irbesartan, telmisartan, etc. Examples of ACE inhibitors include ramipril, lisinopril, enalapril, imidapril, triamcinolone acetonide, etc.

[0635] One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be substituted with their respective isotopes. Examples of such isotopes include 2 H. 3 H. 11C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 123 I and 36 Cl, namely hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine. Compounds substituted with such isotopes are useful as pharmaceuticals, including all radiolabeled compounds of the present invention.

[0636] The compounds of the present invention can be prepared according to the following methods, the following examples or known methods, from compounds which are themselves known compounds or intermediates which can be easily prepared from known compounds.

[0637] If the solvents, reagents, and starting materials used in the following steps are commercially available, these commercially available products may be used directly. In addition, the compounds obtained in the following steps and the starting materials used may form salts and can be converted into another type of salt or free form by well-known methods. Alternatively, when the compounds obtained in the following steps or the starting materials used are in free form, they can be converted into the desired salt by known methods. Examples of such salts include salts similar to the salts described for the compounds of the present invention.

[0638] In the preparation of the compounds of the present invention, when the starting material has a substituent that can affect the reaction, a protecting group can be introduced into these substituents in advance by known methods, and if necessary, the target compound can be obtained by removing the protecting group after the reaction. Such protecting groups can be found in, for example, Wuts and Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition, John Wiley & Sons Inc., 2006, or PJ Kocienski, "Protecting Groups", 3rd edition, Thimeme, 2005, and can be appropriately selected according to the reaction conditions.

[0639] The compounds obtained in each step of the following methods can be isolated or purified by conventional methods, such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, chromatography, etc. Alternatively, the compounds can be used as a reaction mixture or crude product in the next step.

[0640] The present invention will be described in more detail with reference to, but not limited to, the following reference examples, embodiments, and test examples.

[0641] MS was performed using LCMS. ESI was used as the ionization method. Observed values ​​of the mass spectrum are expressed as m / z.

[0642] The LCMS conditions were as follows:

[0643] Instrument: ACQUITY UPLC MS / PDA system (Waters)

[0644] Mass spectrometer: ACQUITY QDa detector or Waters 3100MS detector

[0645] Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210 to 400 nm)

[0646] Column: Acquity BEH C18, 1.7μm, 2.1×50mm

[0647] Flow rate: 0.5 mL / min

[0648] Column temperature: 40°C

[0649] Solvent:

[0650] A: 0.1% formic acid / H2O (v / v; same below)

[0651] B: 0.1% formic acid / acetonitrile

[0652] The data were obtained using a JNM-ECS400 nuclear magnetic resonance spectrometer (JEOL RESONANCE Ltd.) 1 H NMR spectra. Observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets).

[0653] Microwave experiments were performed using an Initiator 60 (Biotage) with temperatures ranging from 40 to 250°C and pressures up to 20 bar.

[0654] The measurement conditions of the optical rotation are as follows.

[0655] Instrument: Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.)

[0656] The names of the compounds described herein were named according to the IUPAC nomenclature using the naming software ACD / NAME (registered trademark, Advanced Chemistry Development Inc.) or ChemBioDraw (version 18.2 or 19.1 or 20.1.1, Cambridge Soft), or according to the IUPAC nomenclature.

[0657] In the names of the compounds, the descriptors "r" and "s" (lower case) designate the stereochemistry of pseudoasymmetric carbon atoms according to IUPAC rules.

[0658] Reference Example 1 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoro Ethyl)acetamide hydrochloride (Compound RE-1)

[0659] [Chemical Formula 14]

[0660]

[0661] [Step 1] Preparation of intermediate RE-1A

[0662] [Chemical Formula 15]

[0663]

[0664] In a mixture of 2-chloro-1,4-difluorobenzene (1.2 g) and THF (11 mL), lithium diisopropylamide (1.08 M n-hexane / tetrahydrofuran solution, 7.50 mL) was added dropwise at -78 ° C. After stirring at -78 ° C for 1 hour, a solution of tert-butyl 3-formylazetidine-1-carboxylate (1.0 g) in THF (11 mL) was added dropwise and stirred at -78 ° C for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.65 g).

[0665] [Step 2] Preparation of intermediate RE-1B

[0666] [Chemical Formula 16]

[0667]

[0668] To a mixture of intermediate RE-1A (3.23 g) and dichloromethane (48 mL) were added iodobenzene diacetate (3.74 g) and (74 mg), stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.09 g). MS (m / z): 332.5 [M+H] +

[0669] [Step 3] Preparation of intermediate RE-1C

[0670] [Chemical Formula 17]

[0671]

[0672] A mixture of intermediate RE-1B (3.09 g), 1,4-dioxane (60 mL) and hydrazine monohydrate (4.54 mL) was stirred at 100°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.47 g). MS (m / z): 324.0 [MH] -

[0673] [Step 4] Preparation of intermediate RE-1D

[0674] [Chemical Formula 18]

[0675]

[0676] To a mixture of intermediate RE-1C (1.47 g) and DMF (23 mL) was added cesium carbonate (1.76 g) and ethyl 2-bromoacetate (0.600 mL) in sequence under ice bath conditions, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.76 g). MS (m / z): 412.3 [M+H] +

[0677] [Step 5] Preparation of intermediate RE-1E

[0678] [Chemical Formula 19]

[0679]

[0680] To a mixture of intermediate RE-1D (1.75 g), methanol (8.5 mL), and THF (8.5 mL) was added 2M aqueous sodium hydroxide solution (10.6 mL) at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid in an ice bath. The precipitate was filtered to obtain the title compound (1.56 g). MS (m / z): 382.4 [MH] -

[0681] [Step 6] Preparation of intermediate RE-1F

[0682] [Chemical Formula 20]

[0683]

[0684] To a mixture of intermediate RE-1E (800 mg), DMF (6.9 mL), DIPEA (1.1 mL) and 2,2,2-trifluoroethaneamine hydrochloride (367 mg) was added HATU (1.03 g) and stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (900 mg). MS (m / z): 463.4 [MH] -

[0685] [Step 7] Preparation of compound RE-1

[0686] To a mixture of intermediate RE-1F (78 mg) and methanol (1 mL) was added hydrogen chloride (2 M methanol solution, 1 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to obtain the title compound (72 mg). MS (m / z): 365.5 [M+H] +

[0687] Reference Example 2 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoro [methyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound RE-2)

[0688] [Chemical Formula 21]

[0689]

[0690] [Step 1] Preparation of intermediate RE-2A

[0691] [Chemical Formula 22]

[0692]

[0693] According to the method of Step 1 of Reference Example 1, using 1,3,5-trifluorobenzene (7.49 g) instead of 2-chloro-1,4-difluorobenzene, the title compound (9.74 g) was obtained.

[0694] [Step 2] Preparation of intermediate RE-2B

[0695] [Chemical Formula 23]

[0696]

[0697] According to the method of step 2 of Reference Example 1, using intermediate RE-2A (9.74 g) instead of intermediate RE-1A, the title compound (9.49 g) was obtained.

[0698] [Step 3] Preparation of intermediate RE-2C

[0699] [Chemical Formula 24]

[0700]

[0701] According to the method of step 3 of reference example 1, intermediate RE-2B (9.49 g) was used instead of intermediate RE-1B to obtain the title compound (8.25 g). MS (m / z): 308.3 [MH] -

[0702] [Step 4] Preparation of intermediate RE-2D

[0703] [Chemical Formula 25]

[0704]

[0705] The title compound (6.2 g) was obtained by the method of step 4 of Reference Example 1 using intermediate RE-2C (5.0 g) instead of intermediate RE-1C. MS (m / z): 296.0 [M-Boc+2H] +

[0706] [Step 5] Preparation of intermediate RE-2E

[0707] [Chemical Formula 26]

[0708]

[0709] According to the method of step 5 of reference example 1, intermediate RE-2D (2.23 g) was used instead of intermediate RE-1D to obtain the title compound (1.89 g). MS (m / z): 366.4 [MH] -

[0710] [Step 6] Preparation of intermediate RE-2F

[0711] [Chemical Formula 27]

[0712]

[0713] The title compound (1.32 g) was obtained by the method of step 6 of Reference Example 1, using intermediate RE-2E (1.04 g) instead of intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (596 mg) instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 511.2 [M+Na] +

[0714] [Step 7] Preparation of compound RE-2

[0715] According to the method of step 7 of reference example 1, intermediate RE-2F (125 mg) was used instead of intermediate RE-1F to obtain the title compound (117 mg). MS (m / z): 389.1 [M+H] +

[0716] Reference Example 3 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoro [methyl]pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-3)

[0717] [Chemical Formula 28]

[0718]

[0719] To a mixture of intermediate RE-2F (100 mg) and dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain the title compound (103 mg). MS (m / z): 389.1 [M+H] +

[0720] Reference Example 4 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrole [alkyl-1-yl]ethan-1-one trifluoroacetate (Compound RE-4)

[0721] [Chemical Formula 29]

[0722]

[0723] [Step 1] Preparation of intermediate RE-4A

[0724] [Chemical formula 30]

[0725]

[0726] To a mixture of 3-iodo-2H-indazole (9.11 g) and DMF (75 mL) was added cesium carbonate (14.6 g) and methyl 2-bromoacetate (4.24 mL) in an ice bath. After stirring for 30 minutes under an ice bath, the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (12.69 g). MS (m / z): 317.0 [M+H] +

[0727] [Step 2] Preparation of intermediate RE-4B

[0728] [Chemical Formula 31]

[0729]

[0730] A reaction vessel containing zinc (3.62 g) was heated under reduced pressure using a heat gun for 3 minutes and purged with argon. After being brought to room temperature, DMA (40 mL) was added, degassed with argon, and 1,2-dibromoethane (0.341 mL) and chloro(trimethyl)silane (0.602 mL) were added, and stirred at room temperature for 15 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.2 g) in DMA (40 mL) was added dropwise to the mixture using a dropping funnel. Stir at room temperature for 1 hour to prepare a DMA solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc (II) iodide.

[0731] Next, a mixture of intermediate RE-4A (5.00 g) and DMA (16 mL) was degassed with argon and Pd(dppf)Cl2·CH2Cl2 (1.29 g) and copper (I) iodide (392 mg) were added. The previously prepared DMA solution of [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc (II) iodide was added thereto at room temperature and stirred at 85°C for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.05 g). MS (m / z): 368.1 [M+Na] +

[0732] [Step 3] Preparation of intermediate RE-4C

[0733] [Chemical Formula 32]

[0734]

[0735] According to the method of step 5 of reference example 1, intermediate RE-4B (5.08 g) was used instead of intermediate RE-1D to obtain the title compound (4.99 g). MS (m / z): 330.4 [MH] -

[0736] [Step 4] Preparation of intermediate RE-4D

[0737] [Chemical Formula 33]

[0738]

[0739] To a mixture of intermediate RE-4C (150 mg), DMF (1.5 mL), DIPEA (0.235 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (95 mg) was added HBTU (206 mg), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 353.1 [M-Boc+2H] +

[0740] [Step 5] Preparation of compound RE-4

[0741] To a mixture of intermediate RE-4D (200 mg) and dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain the title compound (211 mg). MS (m / z): 353.1 [M+H] +

[0742] Reference Example 5 2-[3-(azetidin-3-yl)-5-chloro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-triazol-1-yl)- (fluoroethyl)acetamide trifluoroacetate (Compound RE-5)

[0743] [Chemical Formula 34]

[0744]

[0745] [Step 1] Preparation of intermediate RE-5A

[0746] [Chemical Formula 35]

[0747]

[0748] In a mixture of 2-bromo-4-chloro-1-fluorobenzene (2.57 g) and THF (20 mL), n-butyl lithium (1.57 M n-hexane solution, 7.82 mL) was added dropwise at -78 ° C. After stirring at -78 ° C for 1 hour, a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (2.0 g) (for example, synthesized according to the method described in WO20129649) in THF (20 mL) was added dropwise and stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.21 g). MS (m / z): 214.0 [M-Boc+2H] +

[0749] [Step 2] Preparation of intermediate RE-5B

[0750]

[0751] A mixture of intermediate RE-5A (1.21 g), 1,4-dioxane (39 mL), and hydrazine monohydrate (0.940 mL) was stirred at 100°C for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (635 mg). MS (m / z): 208.0 [M-Boc+2H] +

[0752] [Step 3] Preparation of intermediate RE-5C

[0753] [Chemical Formula 36]

[0754]

[0755] According to the method of step 1 of reference example 4, intermediate RE-5B (200 mg) was used instead of 3-iodo-2H-indazole to obtain the title compound (246 mg). MS (m / z): 402.3 [M+Na] +

[0756] [Step 4] Preparation of intermediate RE-5D

[0757]

[0758] According to the method of step 5 of reference example 1, intermediate RE-5C (246 mg) was used instead of intermediate RE-1D to obtain the title compound (184 mg). MS (m / z): 364.3 [MH] -

[0759] [Step 5] Preparation of intermediate RE-5E

[0760] [Chemical Formula 37]

[0761]

[0762] To a mixture of intermediate RE-5D (100 mg), acetonitrile (2 mL), 1-hydroxybenzotriazole monohydrate (50 mg), NMM (0.090 mL), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (49 mg) was added EDCI·HCl (63 mg), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the title compound (123 mg). MS (m / z): 483.2 [M+Na] +

[0763] [Step 6] Preparation of compound RE-5

[0764] According to the method of Reference Example 3, intermediate RE-5E (123 mg) was used instead of intermediate RE-2F to obtain the title compound (127 mg). MS (m / z): 361.2 [M+H] +

[0765] Reference Example 6 2-[3-(azetidin-3-yl)-6-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-triazol-1-yl)- (fluoroethyl)acetamide trifluoroacetate (Compound RE-6)

[0766] [Chemical Formula 38]

[0767]

[0768] [Step 1] Preparation of intermediate RE-6A

[0769] [Chemical Formula 39]

[0770]

[0771] To a mixture of 6-fluoro-3-iodo-1H-indazole (synthesized, for example, according to the method described in Bioorganic Med. Chem. Lett., 2010, 20, 6998-7003) (897 mg) and DMF (7 mL) was added cesium carbonate (1.34 g) and methyl 2-bromoacetate (0.39 mL) in sequence under ice bath conditions. After stirring for 10 minutes under ice bath conditions, the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.17 g). MS (m / z): 335.0 [M+H] +

[0772] [Step 2] Preparation of intermediate RE-6B

[0773] [Chemical Formula 40]

[0774]

[0775] A reaction vessel containing zinc (481 mg) was heated under reduced pressure using a heat gun for 5 minutes and purged with argon. After being brought to room temperature, DMA (5.25 mL) was added, degassed with argon, and 1,2-dibromoethane (0.045 mL) and chloro(trimethyl)silane (0.080 mL) were added, and stirred at room temperature for 15 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.49 g) in DMA (5.25 mL) was added dropwise to the mixture using a dropping funnel. The mixture was stirred at room temperature for 1 hour to prepare a solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc (II) iodide in DMA.

[0776] Next, a mixture of intermediate RE-6A (1.17 g) and DMA (3.5 mL) was degassed with argon, and Pd(dppf)Cl2·CH2Cl2 (286 mg) and copper (I) iodide (87 mg) were added. A previously prepared solution of [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc (II) iodide in DMA was added thereto at room temperature, and the mixture was stirred at 85°C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.54 g). MS (m / z): 386.3 [M+Na] +

[0777] [Step 3] Preparation of intermediate RE-6C

[0778] [Chemical Formula 41]

[0779]

[0780] To a mixture of intermediate RE-6B (1.54 g), methanol (6 mL), and THF (6 mL) was added 2 M aqueous sodium hydroxide solution (6.36 mL) at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, filtered, and acidified with 2 M hydrochloric acid in an ice bath. The precipitate was filtered to obtain the title compound (1.03 g). MS (m / z): 348.2 [MH] -

[0781] [Step 4] Preparation of intermediate RE-6D

[0782] [Chemical Formula 42]

[0783]

[0784] To a mixture of intermediate RE-6C (350 mg), acetonitrile (3 mL), 1-hydroxybenzotriazole monohydrate (184 mg), NMM (0.330 mL), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (180 mg) was added EDCI·HCl (231 mg), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain the title compound (318 mg). MS (m / z): 467.3 [M+Na] +

[0785] [Step 5] Preparation of compound RE-6

[0786] According to the method of Reference Example 3, intermediate RE-6D (318 mg) was used instead of intermediate RE-2F to obtain the title compound (285 mg). MS (m / z): 345.2 [M+H] +

[0787] Reference Example 7 2-[3-(3-Methylazetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)- [1-[(1-[(1-[(1-( ...

[0788] [Chemical Formula 43]

[0789]

[0790] [Step 1] Preparation of intermediate RE-7A

[0791] [Chemical Formula 44]

[0792]

[0793] To a mixture of 3-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-3-carboxylic acid (747 mg), acetonitrile (10 mL), HOBt (797 mg), NMM (2.30 mL), and N,O-dimethylhydroxylamine hydrochloride (677 mg) was added EDCI·HCl (1.13 g), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate.

[0794] Next, according to the method of step 1 of Reference Example 5, using 1-fluoro-2-iodobenzene (1.16 g) instead of 2-bromo-4-chloro-1-fluorobenzene and using the above-obtained 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylic acid tert-butyl ester instead of 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylic acid tert-butyl ester, the title compound (688 mg) was obtained. MS (m / z): 194.2 [M-Boc+2H] +

[0795] [Step 2] Preparation of intermediate RE-7B

[0796] [Chemical Formula 45]

[0797]

[0798] A mixture of intermediate RE-7A (620 mg), DMA (7 mL), hydrazine monohydrate (1.03 mL) and potassium carbonate (438 mg) was reacted in a microwave reaction apparatus at 150 ° C for 3 hours. After cooling, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-(1H-indazol-3-yl)-3-methylazetidine-1-carboxylate.

[0799] Next, according to the method of step 1 of Reference Example 4, using the above-mentioned tert-butyl 3-(1H-indazol-3-yl)-3-methylazetidine-1-carboxylate instead of 3-iodo-2H-indazole, the title compound (629 mg) was obtained. MS (m / z): 260.3 [M-Boc+2H] +

[0800] [Step 3] Preparation of intermediate RE-7C

[0801] [Chemical Formula 46]

[0802]

[0803] According to the method of step 5 of reference example 1, intermediate RE-7B (629 mg) was used instead of intermediate RE-1D to obtain the title compound (466 mg). MS (m / z): 344.3 [MH] -

[0804] [Step 4] Preparation of intermediate RE-7D

[0805] [Chemical Formula 47]

[0806]

[0807] HBTU (132 mg) was added to a mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), DIPEA (0.150 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (61 mg), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The reaction solution was purified by silica gel column chromatography to obtain the title compound (108 mg). MS (m / z): 489.4 [M+Na] +

[0808] [Step 5] Preparation of compound RE-7

[0809] According to the method of Reference Example 3, intermediate RE-7D (108 mg) was used instead of intermediate RE-2F to obtain the title compound (111 mg). MS (m / z): 367.3 [M+H] +

[0810] Reference Example 8 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-(3,3-dimethylmorpholin-4-yl) Ethan-1-one trifluoroacetate (Compound RE-8)

[0811] [Chemical Formula 48]

[0812]

[0813] [Step 1] Preparation of intermediate RE-8A

[0814] [Chemical Formula 49]

[0815]

[0816] Following the procedure of Step 4 of Reference Example 7, using Intermediate RE-4C (100 mg) instead of Intermediate RE-7C and 3,3-dimethylmorpholine (45 mg) instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride, the title compound (100 mg) was obtained. MS (m / z): 329.2 [M-Boc+2H] +

[0817] [Step 2] Preparation of compound RE-8

[0818] According to the method of Reference Example 3, intermediate RE-8A (100 mg) was used instead of intermediate RE-2F to obtain the title compound (96 mg). MS (m / z): 329.2 [M+H] +

[0819] Reference Example 9 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-[(2R)-2-(trifluoromethyl)- [4-[[(1- ...

[0820] [Chemical Formula 50]

[0821]

[0822] [Step 1] Preparation of intermediate RE-9A

[0823] [Chemical Formula 51]

[0824]

[0825] According to the method of step 4 of Reference Example 7, intermediate RE-4C (100 mg) was used instead of intermediate RE-7C, and (2R)-2-(trifluoromethyl)morpholine hydrochloride (69 mg) was used instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride to obtain the title compound (135 mg). MS (m / z): 369.1 [M-Boc+2H] +

[0826] [Step 2] Preparation of compound RE-9

[0827] According to the method of Reference Example 3, intermediate RE-9A (135 mg) was used instead of intermediate RE-2F to obtain the title compound (145 mg). MS (m / z): 369.1 [M+H] +

[0828] Reference Example 10 4-Fluoro-3-(piperidin-4-yl)-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazole trihydrate Fluoroacetate (Compound RE-10)

[0829] [Chemical Formula 52]

[0830]

[0831] [Step 1] Preparation of intermediate RE-10A

[0832] [Chemical Formula 53]

[0833]

[0834] The title compound (3.98 g) was obtained according to the method of Step 1 of Reference Example 1, using 1,3-difluorobenzene (2.41 g) instead of 2-chloro-1,4-difluorobenzene and tert-butyl 4-formylpiperidine-1-carboxylate (3.00 g) instead of tert-butyl 3-formylazetidine-1-carboxylate.

[0835] [Step 2] Preparation of intermediate RE-10B

[0836] [Chemical Formula 54]

[0837]

[0838] According to the method of Step 2 of Reference Example 1, using Intermediate RE-10A (3.98 g) instead of Intermediate RE-1A, the title compound (3.48 g) was obtained.

[0839] [Step 3] Preparation of intermediate RE-10C

[0840] [Chemical Formula 55]

[0841]

[0842] According to the method of step 3 of reference example 1, intermediate RE-10B (3.48 g) was used instead of intermediate RE-1B to obtain the title compound (3.31 g). MS (m / z): 318.3 [MH] -

[0843] [Step 4] Preparation of intermediate RE-10D

[0844]

[0845] To a mixture of intermediate RE-10C (50 mg) and acetonitrile (0.5 mL) were added cesium carbonate (77 mg) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (56 mg) in that order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (34 mg). MS (m / z): 379.1 [M-Boc+2H] +

[0846] [Step 5] Preparation of compound RE-10

[0847] According to the method of Reference Example 3, intermediate RE-10D (34 mg) was used instead of intermediate RE-2F to obtain the title compound (35 mg). MS (m / z): 379.2 [M+H] +

[0848] Reference Example 11 2-[4-Fluoro-3-(piperidin-4-yl)-1H-indol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound RE-11)

[0849] [Chemical Formula 56]

[0850]

[0851] [Step 1] Preparation of intermediate RE-11A

[0852] [Chemical Formula 57]

[0853]

[0854] A mixture of 4-fluoro-1H-indazole (750 mg), tert-butyl 4-oxopiperidine-1-carboxylate (1.22 g), potassium hydroxide (1.25 g), and methanol (18 mL) was stirred at 80°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain the title compound (660 mg). MS (m / z): 317.1 [M+H] +

[0855] [Step 2] Preparation of intermediate RE-11B

[0856] [Chemical Formula 58]

[0857]

[0858] 10% Pd-C (21 mg) was added to the intermediate RE-11A (500 mg), methanol (53 mL) and ammonium formate (1.30 g), and the mixture was stirred at 80°C overnight. The insoluble matter was filtered off, and the residue was concentrated under reduced pressure to obtain the title compound (400 mg). MS (m / z): 219.2 [M-Boc+2H] +

[0859] [Step 3] Preparation of intermediate RE-11C

[0860] [Chemical Formula 59]

[0861]

[0862] The title compound (450 mg) was obtained by the method of step 4 of Reference Example 1 using intermediate RE-11B (480 mg) instead of intermediate RE-1C. MS (m / z): 305.2 [M-Boc+2H] +

[0863] [Step 4] Preparation of intermediate RE-11D

[0864] [Chemical Formula 60]

[0865]

[0866] According to the method of step 5 of reference example 1, intermediate RE-11C (450 mg) was used instead of intermediate RE-1D to obtain the title compound (350 mg). MS (m / z): 375.2 [MH] -

[0867] [Step 5] Preparation of intermediate RE-11E

[0868] [Chemical Formula 61]

[0869]

[0870] A mixture of intermediate RE-11D (100 mg), DMF (0.5 mL), DIPEA (0.138 mL), and HATU (121 mg) was stirred at room temperature for 15 minutes. (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (56 mg) was added and stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain the title compound (120 mg). MS (m / z): 398.2 [M-Boc+2H] +

[0871] [Step 6] Preparation of compound RE-11

[0872] According to the method of step 7 of Reference Example 1, intermediate RE-11E (120 mg) was used instead of intermediate RE-1F to obtain the title compound (85 mg). MS (m / z): 398.2 [M+H] +

[0873] Reference Example 12 3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indole- tert-Butyl 3-yl)azetidine-1-carboxylate (Compound RE-12)

[0874] [Chemical Formula 62]

[0875]

[0876] [Step 1] Preparation of intermediate RE-12A

[0877] [Chemical Formula 63]

[0878]

[0879] To a mixture of indole (1 g), potassium hydroxide (527 mg), and methanol (11 mL) was added tert-butyl 3-oxoazetidine-1-carboxylate (1.61 g), and the mixture was stirred at 50°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain the title compound (920 mg). MS (m / z): 287.2 [MH] -

[0880] [Step 2] Preparation of intermediate RE-12B

[0881] [Chemical Formula 64]

[0882]

[0883] To a mixture of intermediate RE-12A (920 mg) and dichloromethane (6.4 mL) was added triethylsilane (3.82 mL) under ice-cooling conditions, followed by the slow addition of trifluoroacetic acid (0.811 mL), and the mixture was stirred under ice-cooling conditions for 10 minutes. A saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to obtain the title compound (370 mg). MS (m / z): 271.4 [MH] -

[0884] [Step 3] Preparation of intermediate RE-12C

[0885] [Chemical Formula 65]

[0886]

[0887] The title compound (400 mg) was obtained by the method of step 4 of Reference Example 1 using intermediate RE-12B (370 mg) instead of intermediate RE-1C. MS (m / z): 259.1 [M-Boc+2H] +

[0888] [Step 4] Preparation of intermediate RE-12D

[0889] [Chemical Formula 66]

[0890]

[0891] To a mixture of intermediate RE-12C (400 mg), methanol (10 mL), and THF (10 mL) was added 2M aqueous sodium hydroxide solution (2.79 mL) at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid in an ice bath. The solvent was removed under reduced pressure and purified by silica gel column chromatography to obtain the title compound (350 mg). MS (m / z): 329.1 [MH] -

[0892] [Step 5] Preparation of compound RE-12

[0893] The title compound (50 mg) was obtained by the method of step 5 of reference example 11 using intermediate RE-12D (50 mg) instead of intermediate RE-11D. MS (m / z): 352.1 [M-Boc+2H] +

[0894] Reference Example 13 3-(5-methyl-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}- Tert-butyl 1H-pyrazolo[4,3-b]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-13)

[0895] [Chemical Formula 67]

[0896]

[0897] [Step 1] Preparation of intermediate RE-13A

[0898] [Chemical Formula 68]

[0899]

[0900] The title compound (608 mg) was obtained by the method of step 1 of Reference Example 5, using 2-bromo-3-fluoro-6-methylpyridine (1.00 g) instead of 2-bromo-4-chloro-1-fluorobenzene and tert-butyl 3-formylazetidine-1-carboxylate (1.17 g) instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate. MS (m / z): 297.1 [M+H] +

[0901] [Step 2] Preparation of intermediate RE-13B

[0902] [Chemical Formula 69]

[0903]

[0904] To a mixture of intermediate RE-13A (608 mg) and dichloromethane (10 mL) were added iodobenzene diacetate (793 mg) and (16 mg), stirred at room temperature for 2 hours. (16 mg), and then stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (542 mg). MS (m / z): 295.1 [M+H] +

[0905] [Step 3] Preparation of intermediate RE-13C

[0906] [Chemical Formula 70]

[0907]

[0908] According to the method of step 2 of reference example 5, intermediate RE-13B (542 mg) was used instead of intermediate RE-5A to obtain the title compound (363 mg). MS (m / z): 289.2 [M+H] +

[0909] [Step 4] Preparation of intermediate RE-13D

[0910] [Chemical Formula 71]

[0911]

[0912] The title compound (359 mg) was obtained by the method of step 4 of Reference Example 1 using intermediate RE-13C (290 mg) instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0913] [Step 5] Preparation of intermediate RE-13E

[0914] [Chemical Formula 72]

[0915]

[0916] According to the method of step 5 of reference example 1, intermediate RE-13D (359 mg) was used instead of intermediate RE-1D to obtain the title compound (187 mg). MS (m / z): 347.1 [M+H] +

[0917] [Step 6] Preparation of compound RE-13

[0918] The title compound (100 mg) was obtained by the method of step 5 of reference example 11 using intermediate RE-13E (90 mg) instead of intermediate RE-11D. MS (m / z): 468.3 [M+H] +

[0919] Reference Example 14 2-[3-(azetidin-3-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl]-1-[(2S)-2- (Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one bis-trifluoroacetate (Compound RE-14)

[0920] [Chemical Formula 73]

[0921]

[0922] [Step 1] Preparation of intermediate RE-14A

[0923] [Chemical Formula 74]

[0924]

[0925] According to the method of Step 1 of Reference Example 1, using 2-chloro-4-fluoropyridine (1.07 g) instead of 2-chloro-1,4-difluorobenzene, the title compound (1.62 g) was obtained.

[0926] [Step 2] Preparation of intermediate RE-14B

[0927] [Chemical Formula 75]

[0928]

[0929] According to the method of step 2 of Reference Example 1, using intermediate RE-14A (1.62 g) instead of intermediate RE-1A, the title compound (1.47 g) was obtained.

[0930] [Step 3] Preparation of intermediate RE-14C

[0931]

[0932] A mixture of intermediate RE-14B (1.37 g), 1,4-dioxane (28 mL), and hydrazine monohydrate (0.65 mL) was stirred at 100°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.79 g). MS (m / z): 309.1 [M+H] +

[0933] [Step 4] Preparation of intermediate RE-14D

[0934] [Chemical Formula 76]

[0935]

[0936] According to the method of step 4 of reference example 1, intermediate RE-14C (0.79 g) was used instead of intermediate RE-1C to obtain the title compound (1.04 g). MS (m / z): 395.2 [M+H] +

[0937] [Step 5] Preparation of intermediate RE-14E

[0938] [Chemical Formula 77]

[0939]

[0940] 5% Pd-C (100 mg) was added to the intermediate RE-14D (300 mg), ethyl acetate (7.6 mL), and triethylamine (0.21 mL), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere (0.1 MPa). The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (249 mg). MS (m / z): 361.2 [M+H] +

[0941] [Step 6] Preparation of intermediate RE-14F

[0942] [Chemical Formula 78]

[0943]

[0944] According to the method of step 5 of reference example 1, intermediate RE-14E (249 mg) was used instead of intermediate RE-1D to obtain the title compound (210 mg). MS (m / z): 333.2 [M+H] +

[0945] [Step 7] Preparation of intermediate RE-14G

[0946] [Chemical Formula 79]

[0947]

[0948] The title compound (92 mg) was obtained by the method of step 5 of Reference Example 11 using intermediate RE-14F (100 mg) instead of intermediate RE-11D. MS (m / z): 454.3 [M+H] +

[0949] [Step 8] Preparation of compound RE-14

[0950] Following the method of Reference Example 3, intermediate RE-14G (92 mg) was used instead of intermediate RE-2F to obtain a brown oil. 39 mg of this oil was purified by silica gel column chromatography to obtain the title compound (30 mg). MS (m / z): 354.1 [M+H] +

[0951] Reference Example 15 3-{[3-(azetidin-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl]methane 1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole trifluoroacetate (Compound RE-15)

[0952] [Chemical formula 80]

[0953]

[0954] [Step 1] Preparation of intermediate RE-15A

[0955] [Chemical Formula 81]

[0956]

[0957] According to the method of Step 1 of Reference Example 1, using 3,5-difluoropyridine (2.80 g) instead of 2-chloro-1,4-difluorobenzene, the title compound (4.92 g) was obtained.

[0958] [Step 2] Preparation of intermediate RE-15B

[0959] [Chemical Formula 82]

[0960]

[0961] According to the method of step 2 of Reference Example 1, using intermediate RE-15A (4.86 g) instead of intermediate RE-1A, the title compound (4.64 g) was obtained.

[0962] [Step 3] Preparation of intermediate RE-15C

[0963] [Chemical Formula 83]

[0964]

[0965] A mixture of intermediate RE-15B (4.64 g), 1,4-dioxane (52 mL), and hydrazine monohydrate (1.16 mL) was stirred at 100°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.9 g). MS (m / z): 291.2 [MH] -

[0966] [Step 4] Preparation of intermediate RE-15D

[0967] [Chemical formula 84]

[0968]

[0969] According to the method of step 4 of Reference Example 10, using intermediate RE-15C (1.0 g) instead of intermediate RE-10C and 2-chloroacetonitrile (0.323 mL) instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine, the title compound (1.22 g) was obtained.

[0970] [Step 5] Preparation of intermediate RE-15E

[0971] [Chemical Formula 85]

[0972]

[0973] To a solution of potassium carbonate (0.95 g) in water (3.1 mL) were added hydroxylamine hydrochloride (0.48 g) and an ethanol (11.4 mL) solution of the intermediate RE-15D (1.22 g), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue to suspend it. The insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (0.72 g). MS (m / z): 365.1 [M+H] +

[0974] [Step 6] Preparation of intermediate RE-15F

[0975] [Chemical Formula 86]

[0976]

[0977] HATU (41 mg) was added to a mixture of intermediate RE-15E (39 mg), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (15 mg), DIPEA (0.019 mL), and DMF (0.3 mL), and the mixture was stirred overnight at room temperature. The mixture was then stirred at 120°C for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (27 mg). MS (m / z): 483.2 [M+H] +

[0978] [Step 7] Preparation of compound RE-15

[0979] According to the method of Reference Example 3, intermediate RE-15F (27 mg) was used instead of intermediate RE-2F to obtain the title compound (28 mg). MS (m / z): 383.1 [M+H] +

[0980] Reference Example 16 2-[3-(azetidin-3-yl)-4-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl]-1- [(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one bis-trifluoroacetate (Compound RE-16)

[0981] [Chemical Formula 87]

[0982]

[0983] [Step 1] Preparation of intermediate RE-16A

[0984] [Chemical Formula 88]

[0985]

[0986] The title compound (0.57 g) was obtained by the method of step 1 of Reference Example 5, using 3-bromo-2-fluoro-methylpyridine (0.63 g) instead of 2-bromo-4-chloro-1-fluorobenzene and 3-formylazetidine-1-carboxylic acid tert-butyl ester (0.74 g) instead of 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylic acid tert-butyl ester. MS (m / z): 197.1 [M-Boc+2H] +

[0987] [Step 2] Preparation of intermediate RE-16B

[0988] [Chemical Formula 89]

[0989]

[0990] The title compound (241 mg) was obtained by the method of step 2 of Reference Example 1 using intermediate RE-16A (0.57 g) instead of intermediate RE-1A. MS (m / z): 195.0 [M-Boc+2H] +

[0991] [Step 3] Preparation of intermediate RE-16C

[0992] [Chemical formula 90]

[0993]

[0994] According to the method of step 3 of reference example 1, intermediate RE-16B (241 mg) was used instead of intermediate RE-1B to obtain the title compound (148 mg). MS (m / z): 289.1 [M+H] +

[0995] [Step 4] Preparation of intermediate RE-16D

[0996] [Chemical Formula 91]

[0997]

[0998] The title compound (166 mg) was obtained by the method of step 4 of reference example 1 using intermediate RE-16C (148 mg) instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0999] [Step 5] Preparation of intermediate RE-16E

[1000] [Chemical Formula 92]

[1001]

[1002] The title compound (139 mg) was obtained by the method of step 5 of reference example 1 using intermediate RE-16D (166 mg) instead of intermediate RE-1D. MS (m / z): 347.1 [M+H] +

[1003] [Step 6] Preparation of intermediate RE-16F

[1004] [Chemical Formula 93]

[1005]

[1006] The title compound (88 mg) was obtained by the method of step 5 of reference example 11 using intermediate RE-16E (70 mg) instead of intermediate RE-11D. MS (m / z): 412.1 [M-(tBu+2H)] +

[1007] [Step 7] Preparation of compound RE-16

[1008] According to the method of Reference Example 3, intermediate RE-16F (88 mg) was used instead of intermediate RE-2F to obtain the title compound (130 mg). MS (m / z): 368.0 [M+H] +

[1009] Reference Example 17 3-(azetidin-3-yl)-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methane 1H-indazole trifluoroacetate (Compound RE-17)

[1010] [Chemical Formula 94]

[1011]

[1012] [Step 1] Preparation of intermediate RE-17A

[1013] [Chemical Formula 95]

[1014]

[1015] In a mixture of 1-fluoro-2-iodobenzene (8.31 g) and THF (62 mL) at -78 ° C, n-butyl lithium (1.57 M n-hexane solution, 23.8 mL) was added dropwise. After stirring at -78 ° C for 1 hour, a solution of tert-butyl 3-formylazetidine-1-formate (4.6 g) in THF (62 mL) was added dropwise and stirred at -78 ° C for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-formate.

[1016] To the mixture of the above tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-carboxylate and dichloromethane (124 mL) were added iodobenzene diacetate (9.6 g) and (190 mg), stirred at room temperature for 2 hours. Add iodobenzene diacetate (4.85 g) and (190 mg), stirred at room temperature for 30 minutes. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.29 g). MS (m / z): 280.1 [M+H] +

[1017] [Step 2] Preparation of intermediate RE-17B

[1018] [Chemical Formula 96]

[1019]

[1020] A mixture of intermediate RE-17A (5.15 g), NMP (50 mL), and hydrazine monohydrate (8.99 mL) was stirred at 150° C. for 2 days. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate / n-hexane (1 / 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (4.39 g). MS (m / z): 274.1 [M+H] +

[1021] [Step 3] Preparation of intermediate RE-17C

[1022] [Chemical Formula 97]

[1023]

[1024] To a mixture of intermediate RE-17B (200 mg) and acetonitrile (2.4 mL) were added cesium carbonate (358 mg) and 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (205 mg) in this order. The mixture was stirred at room temperature for 4 hours and then at 60°C overnight. 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (137 mg) was added, and the mixture was stirred at room temperature for 72 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (94 mg). MS (m / z): 422.2 [MH] -

[1025] [Step 4] Preparation of compound RE-17

[1026] According to the method of Reference Example 3, intermediate RE-17C (94 mg) was used instead of intermediate RE-2F to obtain the title compound (98 mg). MS (m / z): 324.0 [M+H] +

[1027] Reference Example 18 3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4- [Fluoro-1H-indazol-3-yl]azetidine-1-carboxylic acid tert-butyl ester (Compound RE-18)

[1028] [Chemical Formula 98]

[1029]

[1030] [Step 1] Preparation of intermediate RE-18A

[1031] [Chemical Formula 99]

[1032]

[1033] According to the method of Step 1 of Reference Example 1, using 1,3-difluorobenzene (1.85 g) instead of 2-chloro-1,4-difluorobenzene, the title compound (2.72 g) was obtained.

[1034] [Step 2] Preparation of intermediate RE-18B

[1035] [Chemical Formula 100]

[1036]

[1037] According to the method of step 2 of reference example 1, intermediate RE-18A (2.72 g) was used instead of intermediate RE-1A to obtain the title compound (2.39 g). MS (m / z): 298.0 [M+H] +

[1038] [Step 3] Preparation of intermediate RE-18C

[1039] [Chemical Formula 101]

[1040]

[1041] According to the method of step 3 of reference example 1, intermediate RE-18B (2.39 g) was used instead of intermediate RE-1B to obtain the title compound (2.15 g). MS (m / z): 290.3 [MH] -

[1042] [Step 4] Preparation of intermediate RE-18D

[1043] To a mixture of intermediate RE-18C (1.02 g) and DMF (12 mL) were added potassium carbonate (726 mg) and propargyl bromide (0.332 mL) in this order, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.01 g). MS (m / z): 230.1 [M-Boc+2H] +

[1044] [Step 5] Preparation of compound RE-18

[1045] Sodium azide (84.7 mg) was added to a mixture of (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate (synthesized, for example, according to the method described in WO2014205234) (300 mg) and DMF (3 mL). The mixture was stirred at 120°C overnight to prepare a DMF solution of 3-(azidomethyl)-1,1-difluorocyclobutane (approximately 0.36 mol / L). After cooling, copper (I) iodide (2.9 mg) was added to a mixture of the prepared 3-(azidomethyl)-1,1-difluorocyclobutane (DMF solution, approximately 0.36 mol / L, 0.839 mL), intermediate RE-18D (50 mg), DMF (2 mL), and methanol (0.2 mL). The mixture was stirred at 60°C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (56 mg).

[1046] Reference Example 19 3-(azetidin-3-yl)-4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl] Methyl}-1H-indazole trifluoroacetate (Compound RE-19)

[1047] [Chemical Formula 102]

[1048]

[1049] [Step 1] Preparation of intermediate RE-19A

[1050] [Chemical Formula 103]

[1051]

[1052] The title compound (65 mg) was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C (40 mg) instead of Intermediate RE-10C and 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (35 mg) instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 368.1 [M-Boc+2H] +

[1053] [Step 2] Preparation of compound RE-19

[1054] According to the method of Reference Example 3, intermediate RE-19A (65 mg) was used instead of intermediate RE-2F to obtain the title compound (67 mg). MS (m / z): 368.1 [M+H] +

[1055] Reference Example 20 2-[3-(azetidin-3-yl)-4-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoromethyl)- (fluoroethyl)acetamide trifluoroacetate (Compound RE-20)

[1056] [Chemical Formula 104]

[1057]

[1058] [Step 1] Preparation of intermediate RE-20A

[1059] [Chemical Formula 105]

[1060]

[1061] According to the method of step 4 of Reference Example 1, using intermediate RE-18C (500 mg) instead of intermediate RE-1C, the title compound (638 mg) was obtained.

[1062] MS (m / z): 278.0 [M-Boc+2H] +

[1063] [Step 2] Preparation of intermediate RE-20B

[1064] [Chemical Formula 106]

[1065]

[1066] The title compound (476 mg) was obtained by the method of step 5 of reference example 1 using intermediate RE-20A (638 mg) instead of intermediate RE-1D. MS (m / z): 348.4 [MH] -

[1067] [Step 3] Preparation of intermediate RE-20C

[1068] [Chemical Formula 107]

[1069]

[1070] According to the method of step 5 of reference example 5, intermediate RE-20B (64 mg) was used instead of intermediate RE-5D to obtain the title compound (81 mg). MS (m / z): 468.3 [M+Na] +

[1071] [Step 4] Preparation of compound RE-20

[1072] According to the method of Reference Example 3, intermediate RE-20C (81 mg) was used instead of intermediate RE-2F to obtain the title compound (84 mg). MS (m / z): 345.2 [M+H] +

[1073] Reference Example 21 2-[3-(azetidin-3-yl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-1-[(2S)-2- (Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-21)

[1074] [Chemical Formula 108]

[1075]

[1076] [Step 1] Preparation of intermediate RE-21A

[1077] [Chemical Formula 109]

[1078]

[1079] According to the method of step 1 of Reference Example 4, 3-iodo-4,5,6,7-tetrahydro-1H-indazole (synthesized according to the method described in US2014171432) (1.63 g) was used instead of 3-iodo-2H-indazole to obtain a mixture of the title compound and approximately 10% positional isomers (2.14 g). MS (m / z): 321.1 [M+H] +

[1080] [Step 2] Preparation of intermediate RE-21B

[1081] [Chemical Formula 110]

[1082]

[1083] According to the method of step 2 of reference example 4, intermediate RE-21A (2.14 g) obtained in step 1 of reference example 21 was used instead of intermediate RE-4A to obtain the title compound (0.39 g). MS (m / z): 372.3 [M+Na] +

[1084] [Step 3] Preparation of intermediate RE-21C

[1085] [Chemical Formula 111]

[1086]

[1087] The title compound (34 mg) was obtained by the method of step 5 of reference example 1 using intermediate RE-21B (0.39 g) instead of intermediate RE-1D. MS (m / z): 334.2 [MH] -

[1088] [Step 4] Preparation of intermediate RE-21D

[1089] [Chemical formula 112]

[1090]

[1091] The title compound (16 mg) was obtained by the method of step 5 of reference example 11 using intermediate RE-21C (34 mg) instead of intermediate RE-11D. MS (m / z): 457.3 [M+H] +

[1092] [Step 5] Preparation of compound RE-21

[1093] According to the method of Reference Example 3, intermediate RE-21D (16 mg) was used instead of intermediate RE-2F to obtain the title compound (16 mg). MS (m / z): 357.2 [M+H] +

[1094] Reference Example 22 2-[3-(azetidin-3-yl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl]- 1-[(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-22)

[1095] [Chemical Formula 113]

[1096]

[1097] [Step 1] Preparation of intermediate RE-22A

[1098] [Chemical Formula 114]

[1099]

[1100] A reaction vessel equipped with diethyl ether (30 mL) was placed on ice for cooling, and 60% sodium hydride (596 mg) was added thereto. Subsequently, ethanol (0.087 mL) was added and stirred under ice bath conditions for 20 minutes. A diethyl ether (10 mL) solution of 4,4-difluorocyclohexane-1-one (2.0 g) and ethyl formate (1.80 mL) was added dropwise therein over 10 minutes using a dropping funnel. It was gradually restored to room temperature and stirred overnight. Ethanol (0.3 mL) was added to the reaction solution and stirred at room temperature for 1 hour. Water was added to the reaction solution and washed with diethyl ether. The aqueous layer was acidified with 2M HCl and extracted with diethyl ether. After the organic layer was washed with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the title compound (1.35 g). MS (m / z): 163.1 [M+H] +

[1101] [Step 2] Preparation of intermediate RE-22B

[1102] [Chemical Formula 115]

[1103]

[1104] To a mixture of intermediate RE-22A (1.35 g) and methanol (8.3 mL) was added hydrazine monohydrate (0.487 mL) dropwise and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (0.65 g). MS (m / z): 159.1 [M+H] +

[1105] [Step 3] Preparation of intermediate RE-22C

[1106] [Chemical Formula 116]

[1107]

[1108] To a mixture of intermediate RE-22B (0.65 g) and DMF (8.2 mL) was added potassium hydroxide (0.92 g) and iodine (2.1 g) in sequence under ice-cooling conditions, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (468 mg). MS (m / z): 284.8 [M+H] +

[1109] [Step 4] Preparation of intermediate RE-22D

[1110] [Chemical Formula 117]

[1111]

[1112] Following the procedure of step 1 of Reference Example 4, intermediate RE-22C (468 mg) was used instead of 3-iodo-2H-indazole to obtain a mixture of the title compound and approximately 24% positional isomers (582 mg). MS (m / z): 356.8 [M+H] +

[1113] [Step 5] Preparation of intermediate RE-22E

[1114] [Chemical Formula 118]

[1115]

[1116] According to the method of step 2 of reference example 4, intermediate RE-22D (582 mg) was used instead of intermediate RE-4A to obtain the title compound (360 mg). MS (m / z): 408.3 [M+Na] +

[1117] [Step 6] Preparation of intermediate RE-22F

[1118] [Chemical Formula 119]

[1119]

[1120] According to the method of step 5 of reference example 1, intermediate RE-22E (360 mg) was used instead of intermediate RE-1D to obtain the title compound (103 mg). MS (m / z): 370.2 [MH] -

[1121] [Step 7] Preparation of intermediate RE-22G

[1122] [Chemical Formula 120]

[1123]

[1124] The title compound (60 mg) was obtained by the method of step 5 of reference example 11, using intermediate RE-22F (50 mg) instead of intermediate RE-11D. MS (m / z): 515.3 [M+Na] +

[1125] [Step 8] Preparation of compound RE-22

[1126] According to the method of Reference Example 3, intermediate RE-22G (60 mg) was used instead of intermediate RE-2F to obtain the title compound (62 mg). MS (m / z): 393.3 [M+H] +

[1127] Reference Example 23 2-(Cyclopropylamino)pyridine-4-carboxylic acid (Compound RE-23)

[1128] [Chemical Formula 121]

[1129]

[1130] [Step 1] Preparation of intermediate RE-23A

[1131] [Chemical Formula 122]

[1132]

[1133] To a mixture of 2-fluoropyridine-4-carbonitrile (500 mg), NMP (4.0 mL), and DIPEA (2.1 mL) was added cyclopropaneamine (0.57 mL), and the mixture was stirred at 80°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate / n-hexane (1 / 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (550 mg).

[1134] [Step 2] Preparation of compound RE-23

[1135] Potassium hydroxide (970 mg) was added to a mixture of intermediate RE-23A (550 mg), ethanol (2 mL), and water (2 mL), and the mixture was stirred at 80°C overnight. The solvent was removed under reduced pressure, and 2M hydrochloric acid was added to the residue until the pH was between 7 and 8. The precipitate was filtered to obtain the title compound (313 mg). MS (m / z): 179.1 [M+H] +

[1136] Reference Example 24 2-Amino-5-fluoropyridine-4-carboxylic acid hydrochloride (Compound RE-24)

[1137] [Chemical formula 123]

[1138]

[1139] A mixture of tert-butyl 2-bromo-5-fluoropyridine-4-carboxylate (synthesized, for example, according to the method described in WO202186879) (2.00 g), tert-butyl carbonate (1.02 g), Xantphos (168 mg), cesium carbonate (3.30 g) and 1,4-dioxane (24 mL) was degassed with argon, and Pd(OAc)2 (33 mg) was added and stirred at 90°C overnight. The insoluble matter was filtered off, and the mother liquor was washed with water and saturated brine in sequence, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain tert-butyl 2-{[(tert-butoxy)carbonyl]amino}-5-fluoropyridine-4-carboxylate.

[1140] Next, a mixture of the obtained tert-butyl 2-{[(tert-butoxy)carbonyl]amino}-5-fluoropyridine-4-carboxylate and hydrogen chloride (4M 1,4-dioxane solution, 9 mL) was stirred at 70°C for 6 hours. After cooling, the formed precipitate was filtered to obtain the title compound (1.33 g). MS (m / z): 157.0 [M+H] +

[1141] Reference Example 25 2-Amino-3-methylpyridine-4-carboxylic acid trifluoroacetate (Compound RE-25)

[1142] [Chemical Formula 124]

[1143]

[1144] [Step 1] Preparation of intermediate RE-25A

[1145] [Chemical Formula 125]

[1146]

[1147] A mixture of methyl 2-chloro-3-methylpyridine-4-carboxylate (2.50 g), (4-methoxyphenyl)methanamine (2.63 mL), rac-BINAP (839 mg), cesium carbonate (13.2 g) and 1,4-dioxane (45 mL) was degassed with argon, and Pd(OAc)2 (151 mg) was added, followed by stirring at 100°C overnight. The insoluble matter was filtered off, the mother liquor was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (4.07 g). MS (m / z): 287.1 [M+H] +

[1148] [Step 2] Preparation of intermediate RE-25B

[1149] [Chemical Formula 126]

[1150]

[1151] The title compound (4.02 g) was obtained by the method of step 5 of reference example 1 using intermediate RE-25A (4.07 g) instead of intermediate RE-1D. MS (m / z): 273.0 [M+H] +

[1152] [Step 3] Preparation of compound RE-25

[1153] A mixture of intermediate RE-25B (1.64 g) and trifluoroacetic acid (20 mL) was stirred at 70°C overnight. The mixture was concentrated under reduced pressure, and the residual slurry was washed with ethyl acetate to obtain the title compound (1.25 g). MS (m / z): 153.0 [M+H] +

[1154] Reference Example 26 2-Amino-5-fluoropyrimidine-4-carboxylic acid (Compound RE-26)

[1155] [Chemical Formula 127]

[1156]

[1157] [Step 1] Preparation of intermediate RE-26A

[1158] [Chemical Formula 128]

[1159]

[1160] A mixture of 4-chloro-5-fluoropyrimidin-2-amine (1.36 g), tributyl(1-ethoxyvinyl)tin (3.66 g), and DMF (18 mL) was degassed with argon, and PdCl2(PPh3)2 (129 mg) was added, and the mixture was stirred at 90°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate / n-hexane (1 / 4). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.46 g). MS (m / z): 184.2 [M+H] +

[1161] [Step 2] Preparation of intermediate RE-26B

[1162] [Chemical Formula 129]

[1163]

[1164] To a mixture of intermediate RE-26A (1.46 g) and 1,4-dioxane (24 mL) was added a solution of sodium periodate (3.41 g) in water (24 mL) and potassium permanganate (252 mg) at room temperature. Potassium permanganate (252 mg) was then added three times every two hours, and the mixture was stirred for another two hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was diluted with ethyl acetate and stirred for 2 hours. Filter and remove insoluble matter. Extract the mother liquor with ethyl acetate. Wash the organic layer with saturated brine and dry over anhydrous magnesium sulfate. Remove the solvent under reduced pressure to obtain the title compound (400 mg). MS (m / z): 186.2 [M+H] +

[1165] [Step 3] Preparation of compound RE-26

[1166] According to the method of step 5 of reference example 1, intermediate RE-26B (400 mg) was used instead of intermediate RE-1D to obtain the title compound (140 mg). MS (m / z): 158.1 [M+H] +

[1167] Reference Example 27 tert-Butyl 6-(cyclopropylamino)pyrimidine-4-carboxylate (Compound RE-27)

[1168] [Chemical Formula 130]

[1169]

[1170] To a mixture of tert-butyl 6-chloropyrimidine-4-carboxylate (synthesized, for example, according to the method described in US9598419, 2017, B1) (58 mg), DIPEA (0.01 mL) and ethanol (1 mL) was added cyclopropylamine (77 mg) and reacted in a microwave reaction apparatus at 140 ° C for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (46 mg). 1 H-NMR (400MHz, CDCl3) δ8.66(s,1H),7.32(s,1H),5.69(brs,1H),2.62(s,1H),1.63(s,9H),0.92-0.90(m,2H),0.65-0.62(m,2H)

[1171] Reference Example 28 2-(1-Methylcyclopropylamino)pyridine-4-carboxylic acid (Compound RE-28)

[1172] [Chemical Formula 131]

[1173]

[1174] [Step 1] Preparation of intermediate RE-28A

[1175] [Chemical Formula 132]

[1176]

[1177] 1-Methylcyclopropane-1-amine hydrochloride (77 mg) was added to a mixture of 2-fluoropyridine-4-carbonitrile (200 mg), DIPEA (0.85 mL), and NMP (1.6 mL), and the mixture was reacted at 80°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (110 mg). 1H-NMR(400MHz, CDCl3)δ8.18(d,1H),6.89(s,1H),6.78(dd,1H),5.53(brs,1H),1.39(s,3H),0.83-0.75(m,4H)

[1178] [Step 2] Preparation of compound RE-28

[1179] To a mixture of intermediate RE-28A (110 mg), ethanol (2 mL) and water (2 mL) was added potassium hydroxide (0.2 g), and the mixture was reacted at 80° C. overnight. The solvent was removed under reduced pressure, the pH of the residue was adjusted to 7 to 8 with 2 M hydrochloric acid, and the resulting precipitate was filtered, washed with water, and dried to give the title compound (63 mg). 1 H-NMR(400MHz,DMSO-d6)δ8.12(d,1H),7.10(s,1H),7.03(s,1H),6.92(dd,1H),1.32(s,3H),0.65(d,4H)

[1180] Reference Example 29 2-[(4,4-difluorocyclohexyl)amino]pyridine-4-carboxylic acid (Compound RE-29)

[1181] [Chemical Formula 133]

[1182]

[1183] Compound RE-29 was prepared according to the same synthetic route described for compound RE-28 using 4,4-difluorocyclohexane-1-amine hydrochloride. 1 H-NMR(400MHz,DMSO-d6)δ8.09(d,1H),6.99(s,1H),6.86-6.83(m,2H),3.95(brs,1H),2.06-1.92(m,6H),1.60-1.51(m,2H)

[1184] Reference Example 30 2-[3-(azetidin-3-yl)-4-chloro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl) Acetamide hydrochloride (Compound RE-30)

[1185] [Chemical Formula 134]

[1186]

[1187] [Step 1] Preparation of intermediate RE-30A

[1188] [Chemical Formula 135]

[1189]

[1190] The title compound was obtained by the method of step 1 of Reference Example 1, using 1-chloro-3-fluorobenzene instead of 2-chloro-1,4-difluorobenzene. MS (m / z): 316.1 [M+H] +

[1191] [Step 2] Preparation of intermediate RE-30B

[1192] [Chemical Formula 136]

[1193]

[1194] To a mixture of intermediate RE-30A (600 mg) and dichloromethane (19 mL) was added sodium bicarbonate (479 mg) and 1,1-triacetoxy-1,1-dihydro-1,2-benzoiodine oxaline-3-(1H)-one (1.21 g) under ice cooling, and stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (557 mg). 1 H-NMR (400MHz, CDCl3) δ7.39-7.33(m,1H),7.24(d,1H),7.07(t,1H),4.23-4.20(m,2H),4.09(t,2H),3.97-3.88(m,1H),1.45(s,9H)

[1195] [Step 3] Preparation of intermediate RE-30

[1196] Compound RE-30 was prepared from intermediate RE-30B according to the procedure similar to that described in steps 3 to 7 for preparing compound RE-1 in Reference Example 1. MS (m / z): 347.0 [M+H] +

[1197] Reference Example 31 2-[3-(azetidin-3-yl)-4,7-difluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoro Ethyl)acetamide hydrochloride (Compound RE-31)

[1198] [Chemical Formula 137]

[1199]

[1200] [Step 1] Preparation of intermediate RE-31A

[1201] [Chemical Formula 138]

[1202]

[1203] A mixture of intermediate RE-1B (1.34 g), ethanol (10 mL) and hydrazine monohydrate (3.94 mL) was reacted in a microwave reaction apparatus at 140 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (218 mg). MS (m / z): 310.5 [M + H] +

[1204] [Step 2] Preparation of intermediate RE-31B

[1205] [Chemical Formula 139]

[1206]

[1207] To a mixture of intermediate RE-31A (218 mg) and DMF (3.5 mL) was added cesium carbonate (276 mg) and 2-bromopropyl acetate (153 mg) in this order under ice-cooling conditions, and the mixture was stirred at room temperature. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (238 mg). 1 H-NMR(400MHz, CDCl3)δ7.00-6.90(m,1H),6.70-6.60(m,1H),5.22(s,2H),4.40-4.27(m ,4H),4.25-4.17(m,1H),4.16-4.11(m,2H),1.70-1.59(m,2H),1.46(s,9H),0.89(t,3H)

[1208] [Step 3] Preparation of compound RE-31

[1209] Compound RE-31 was prepared from intermediate RE-31A according to procedures similar to those described in steps 5 to 7 for preparing compound RE-1 in Reference Example 1. MS (m / z): 349.0 [M+H] +

[1210] Reference Example 32 2-[3-(azetidin-3-yl)-4-bromo-5-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoro Ethyl)acetamide hydrochloride (Compound RE-32)

[1211] [Chemical Formula 140]

[1212]

[1213] [Step 1] Preparation of intermediate RE-32A

[1214] [Chemical Formula 141]

[1215]

[1216] The title compound was obtained according to the method of Step 1 of Reference Example 1, except that 2-bromo-1,3-difluorobenzene was used instead of 2-chloro-1,4-difluorobenzene. 1 H-NMR (400MHz, CDCl3) δ7.12-7.02(m,2H),5.38(t,1H),4.19-4.10(m,1H),4.06-3.98(m,1 H),3.87-3.80(m,1H),3.65-3.60(m,1H),3.30-3.18(m,1H),2.59-2.51(m,1H),1.44(s,9H)

[1217] [Step 2] Preparation of intermediate RE-32B

[1218] [Chemical Formula 142]

[1219]

[1220] The title compound was obtained according to the procedure of Step 2 of Reference Example 30 using Intermediate RE-32A instead of Intermediate RE-30A. 1 H-NMR (400MHz, CDCl3) δ7.22-7.16(m,1H),7.14-7.09(m,1H),4.37-4.30(m,2H),4.10(t,2H),3.97-3.88(m,1H),1.45(s,9H)

[1221] [Step 3] Preparation of intermediate RE-32C

[1222] [Chemical Formula 143]

[1223]

[1224] Intermediate RE-32C was prepared starting from Intermediate RE-32B according to procedures similar to those described in Steps 1 to 2 of the preparation of Intermediate RE-31B in Reference Example 31. 1 H-NMR (400MHz, CDCl3) δ7.22-7.16(m,2H),5.10(s,2H),4.37-4.30(m,4H),4.15-4.11(m,3H),1.70-1.61(m,2H),1.45(s,9H),0.89(t,3H)

[1225] [Step 4] Preparation of compound RE-32

[1226] Compound RE-32 was prepared from intermediate RE-32C according to procedures similar to those described in steps 5 to 7 for the preparation of compound RE-1 in Reference Example 1. MS (m / z): 407.1 [MH] -

[1227] Reference Example 33 3-(4-methyl-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}- Tert-butyl 1H-pyrazolo[4,3-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-33)

[1228] [Chemical formula 144]

[1229]

[1230] [Step 1] Preparation of intermediate RE-33A

[1231] [Chemical Formula 145]

[1232]

[1233] A mixture of compound RE-14D (200 mg), trimethylboroxine (70 mg), potassium carbonate (280 mg), Pd(dppf)Cl2·CH2Cl2 (41 mg) and 1,4-dioxane (2.5 mL) was degassed and stirred at 110°C for 5 hours under an argon atmosphere. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (98 mg). MS (m / z): 375.1 [M+H] +

[1234] [Step 2] Preparation of compound RE-33

[1235] To a mixture of intermediate RE-33A (98 mg), methanol (1 mL) and THF (1 mL) was added 2M aqueous sodium hydroxide solution (1 mL) at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid under ice bath conditions. Saturated sodium bicarbonate solution was added to adjust to neutrality and the solvent was concentrated. DMF (2 mL) was added to the residue, followed by DIPEA (0.2 mL), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (60 mg) and HATU (129 mg), and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (97 mg). MS (m / z): 468.2 [M+H] +

[1236] Reference Example 34 3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-pyrazolo[iota] Tert-butyl [4,3-b]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-34)

[1237] [Chemical Formula 146]

[1238]

[1239] [Step 1] Preparation of intermediate RE-34A

[1240] [Chemical Formula 147]

[1241]

[1242] To a mixture of 3-fluoropyridine (674 mg) and THF (9 mL) was added lithium diisopropylamide (1.08 M n-hexane / tetrahydrofuran solution, 6.4 mL) at -78 ° C. After stirring at -78 ° C for 1 hour, a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1.13 g) (synthesized according to the method described in WO20129649) in THF (9 mL) was added dropwise and stirred at -78 ° C for 2 hours. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (490 mg). MS (m / z): 281.0 [M + H] +

[1243] [Step 2] Preparation of intermediate RE-34B

[1244] [Chemical Formula 148]

[1245]

[1246] The title compound was obtained by the method of step 1 of Reference Example 31 using intermediate RE-34A instead of intermediate RE-1B. MS (m / z): 275.1 [M+H] +

[1247] [Step 3] Preparation of compound RE-34

[1248] Compound RE-34 was prepared from intermediate RE-34B according to procedures similar to those described in steps 1 to 2 for the preparation of compound RE-33 in Reference Example 33. MS (m / z): 454.3 [M+H] +

[1249] Reference Example 35 3-(5-methyl-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridine-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-35)

[1250] [Chemical Formula 149]

[1251]

[1252] [Step 1] Preparation of intermediate RE-35A

[1253] [Chemical Formula 150]

[1254]

[1255] The title compound was obtained according to the procedure of Step 1 of Reference Example 34 using 2-chloro-5-fluoropyridine instead of 3-fluoropyridine. 1 H-NMR(400MHz, CDCl3)δ8.43(d,1H),7.76(d,1H),4.22-4.15(m,4H),4.08-3.95(m,1H),1.44(s,9H)

[1256] [Step 2] Preparation of intermediate RE-35B

[1257] [Chemical Formula 151]

[1258]

[1259] The title compound was obtained by the method of step 1 of Reference Example 31 using intermediate RE-35A instead of intermediate RE-1B. MS (m / z): 309.1 [M+H] +

[1260] [Step 3] Preparation of intermediate RE-35C

[1261] [Chemical formula 152]

[1262]

[1263] To a mixture of intermediate RE-35B (100 mg) and DMF (2 mL) were added cesium carbonate (211 mg) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (116 mg), and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (134 mg). MS (m / z): 467.2 [M+H] +

[1264] [Step 4] Preparation of compound RE-35

[1265] A mixture of intermediate RE-35C (134 mg), trimethylcyclotriboroxane (72 mg), potassium carbonate (159 mg), Pd(dppf)Cl2·CH2Cl2 (23 mg) and 1,4-dioxane (1.4 mL) was degassed and stirred at 110°C for 5 hours under an argon atmosphere. Pd(dppf)Cl2·CH2Cl2 (23 mg) was added and stirred at 90°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (58 mg). MS (m / z): 447.3 [M+H] +

[1266] Reference Example 36 3-(5-methyl-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H- Tert-butyl pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-36)

[1267] [Chemical Formula 153]

[1268]

[1269] [Step 1] Preparation of intermediate RE-36A

[1270] [Chemical formula 154]

[1271]

[1272] A mixture of intermediate RE-35B (280 mg), trimethylboroxine (171 mg), potassium carbonate (376 mg), Pd(dppf)Cl2·CH2Cl2 (148 mg), and 1,4-dioxane (3 mL) was reacted in a microwave reactor at 130°C for 1 hour, followed by stirring at 150°C for 1 hour. Trimethylboroxine (0.8 mL) was added, and the mixture was reacted in a microwave reactor at 180°C for 5 minutes. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (66 mg). MS (m / z): 289.2 [M+H] +

[1273] [Step 2] Preparation of intermediate RE-36B

[1274] [Chemical formula 155]

[1275]

[1276] Compound RE-36B was prepared from intermediate RE-36A according to procedures similar to those described in steps 4 to 5 for preparing compound RE-1E in Reference Example 1. MS (m / z): 347.1 [M+H] +

[1277] [Step 3] Preparation of compound RE-36

[1278] A mixture of intermediate RE-36B (30 mg), (2R)-2-(trifluoromethyl)morpholine hydrochloride (20 mg), HBTU (39 mg), DMF (0.3 mL), and DIPEA (0.004 mL) was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (40 mg). MS (m / z): 484.3 [M+H] +

[1279] Reference Example 37 2-[3-(azetidin-3-yl)-5-methyl-1H-indazol-1-yl]-1-[(2S)-2-(trifluoro [Methyl]pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-37)

[1280] [Chemical formula 156]

[1281]

[1282] [Step 1] Preparation of intermediate RE-37A

[1283] [Chemical Formula 157]

[1284]

[1285] The title compound was obtained by the method of step 1 of Reference Example 5, using 2-bromo-1-fluoro-4-methylbenzene instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m / z): 294.0 [M+H] +

[1286] [Step 2] Preparation of intermediate RE-37B

[1287] [Chemical Formula 158]

[1288]

[1289] A mixture of intermediate RE-37A (1.87 g), 1,4-dioxane (64 mL) and hydrazine monohydrate (1.55 mL) was stirred at 100 ° C for 3 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3- (5-methyl-1H-indazole-3-yl) azetidine-1-carboxylate. Cesium carbonate (644 mg) and methyl bromoacetate (330 mg) were added to a mixture of tert-butyl 3- (5-methyl-1H-indazole-3-yl) azetidine-1-carboxylate (473 mg) and DMF (8 mL) obtained under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate. To a mixture of the obtained tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate (467 mg), methanol (2 mL) and THF (2 mL), 2M aqueous sodium hydroxide solution (1.9 mL) was added at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid under ice bath conditions. The resulting precipitate was filtered to give the title compound (383 mg). MS (m / z): 344.2 [MH] -

[1290] [Step 3] Preparation of intermediate RE-37C

[1291] [Chemical Formula 159]

[1292]

[1293] The title compound was obtained by the method of step 4 of reference example 4, using intermediate RE-37B instead of intermediate RE-4C. MS (m / z): 467.3 [M+H]

[1294] [Step 4] Preparation of compound RE-37

[1295] To a mixture of intermediate RE-37C (171 mg) and dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and toluene was added to the resulting residue. The solvent was then removed under reduced pressure. Ethyl acetate and hexane were added to the resulting residue, and the solvent was then removed under reduced pressure to obtain the title compound (145 mg). MS (m / z): 367.2 [M+H] +

[1296] Reference Example 38 2-[3-(azetidin-3-yl)-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)- [1-[(1-[(1-[(1-( ...

[1297] [Chemical formula 160]

[1298]

[1299] [Step 1] Preparation of intermediate RE-38A

[1300] [Chemical Formula 161]

[1301]

[1302] The title compound was obtained by the method of step 1 of Reference Example 5, using 1,4-difluoro-2-iodobenzene instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m / z): 298.1 [M+H] +

[1303] [Step 2] Preparation of intermediate RE-38B

[1304] [Chemical formula 162]

[1305]

[1306] The title compound was obtained by the method of step 3 of Reference Example 1, using intermediate RE-38A instead of intermediate RE-1B. MS (m / z): 290.1 ​​[MH] -

[1307] [Step 3] Preparation of intermediate RE-38C

[1308] [Chemical formula 163]

[1309]

[1310] To a mixture of intermediate RE-38B (176 mg) and DMF (3 mL) was added cesium carbonate (236 mg) and methyl bromoacetate (111 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (183 mg). 1 H-NMR (400MHz, CDCl3) δ7.37(d,1H),7.25-7.15(m,2H),5.10(s,2H),4.41(t,2H),4.29(t,2H),4.13-4.03(m,1H),3.77(s,3H),1.48(s,9H)

[1311] [Step 4] Preparation of intermediate RE-38D

[1312] [Chemical formula 164]

[1313]

[1314] The title compound was obtained by the method of step 5 of Reference Example 1 using intermediate RE-38C instead of intermediate RE-1D. MS (m / z): 348.4 [MH] -

[1315] [Step 5] Preparation of intermediate RE-38E

[1316] [Chemical Formula 165]

[1317]

[1318] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-38D instead of intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 471.3 [M+H] +

[1319] [Step 6] Preparation of compound RE-38

[1320] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-38E instead of intermediate RE-37C. MS (m / z): 371.2 [M+H] +

[1321] Reference Example 39 2-[3-(1-{2-[3-(azetidin-3-yl)-1H-indazol-1-yl]acetyl}azetidine tert-Butyl]-1H-indazol-1-yl]-1H-indazol-1-yl acetate (Compound RE-39)

[1322] [Chemical Formula 166]

[1323]

[1324] [Step 1] Preparation of intermediate RE-39A

[1325] [Chemical Formula 167]

[1326]

[1327] A mixture of 1-benzyloxycarbonylazetidine-3-carboxylic acid (120 mg), di(pyridin-2-yl) carbonate (100 mg), DMAP (6 mg) and dichloromethane (1.2 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (94 mg). MS (m / z): 313.1 [M+H] +

[1328] [Step 2] Preparation of intermediate RE-39B

[1329] [Chemical Formula 168]

[1330]

[1331] A mixture of intermediate RE-39A (630 mg), (2-fluorophenyl)boronic acid (560 mg), triphenylphosphine (160 mg), and 1,4-dioxane (6.7 mL) was degassed, and then Pd(OAc)2 (45 mg) was added. The mixture was stirred overnight at 50°C under an argon atmosphere. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (207 mg). MS (m / z): 314.0 [M+H] +

[1332] [Step 3] Preparation of intermediate RE-39C

[1333] [Chemical Formula 169]

[1334]

[1335] A mixture of intermediate RE-39B (5.50 g), hydrazine monohydrate (4.3 mL) and NMP (35 mL) was stirred at 150° C. overnight. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.26 g). MS (m / z): 308.1 [M+H] +

[1336] [Step 4] Preparation of intermediate RE-39D

[1337] [Chemical Formula 170]

[1338]

[1339] To a mixture of intermediate RE-39C (1.00 g) and DMF (11 mL) was added cesium carbonate (1.27 g) and tert-butyl 2-bromoacetate (762 mg) under ice cooling and stirred for 30 minutes. The mixture was then stirred at room temperature overnight. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (875 mg). MS (m / z): 444.2 [M+Na] +

[1340] [Step 5] Preparation of compound RE-39

[1341] To a mixture of intermediate RE-39D (875 mg) and methanol (21 mL) was added 5% Pd-C (440 mg), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere (0.1 MPa). The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (473 mg). MS (m / z): 288.2 [M+H] +

[1342] Reference Example 40 4-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazole- 3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (Compound RE-40)

[1343] [Chemical Formula 171]

[1344]

[1345] [Step 1] Preparation of intermediate RE-40A

[1346] [Chemical formula 172]

[1347]

[1348] In a mixture of 3-bromo-1H-indazole (2 g) and DMF (34 mL) under ice cooling, cesium carbonate (1.27 g) and methyl bromoacetate (1.86 g) were added and stirred for 30 minutes. Subsequently, it was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.88 g). 1 H-NMR (400MHz, CDCl3) δ7.64(d,1H),7.50-7.44(m,1H),7.32(d,1H),7.27(t,1H),5.13(s,2H),3.75(s,3H)

[1349] [Step 2] Preparation of intermediate RE-40B

[1350] [Chemical formula 173]

[1351]

[1352] A mixture of intermediate RE-40A (200 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (345 mg), sodium carbonate (236 mg), Pd(dppf)Cl2·CH2Cl2 (91 mg), 1,4-dioxane (1.5 mL) and water (0.5 mL) was degassed and stirred at 95°C overnight under an argon atmosphere. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (255 mg). MS (m / z): 356.3 [MH] -

[1353] [Step 3] Preparation of compound RE-40

[1354] HBTU (162 mg) was added to a mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (75 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (105 mg). MS (m / z): 479.3 [M+H] +

[1355] Reference Example 41 4-(1-{[methyl(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazol-3-yl)-1, tert-Butyl 2,3,6-tetrahydropyridine-1-carboxylate (Compound RE-41)

[1356] [Chemical formula 174]

[1357]

[1358] HBTU (162 mg) was added to a mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and 2,2,2-trifluoroethaneamine hydrochloride (64 mg), and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (104 mg). MS (m / z): 475.2 [M+Na] +

[1359] Reference Example 42 2-[3-(azetidin-3-yl)-5-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoromethyl)- (fluoroethyl)acetamide trifluoroacetate (Compound RE-42)

[1360] [Chemical Formula 175]

[1361]

[1362] [Step 1] Preparation of intermediate RE-42A

[1363] [Chemical Formula 176]

[1364]

[1365] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-38D instead of intermediate RE-1E and 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride. MS (m / z): 467.2 [M+Na] +

[1366] [Step 2] Preparation of compound RE-42

[1367] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-42A instead of intermediate RE-37C. MS (m / z): 345.1 [M+H] +

[1368] Reference Example 43 2-[3-(azetidin-3-yl)-5,6-difluoro-1H-indazol-1-yl]-N-methyl-N-(2,2, 2-(Trifluoroethyl)acetamide trifluoroacetate (Compound RE-43)

[1369] [Chemical Formula 177]

[1370]

[1371] [Step 1] Preparation of intermediate RE-43A

[1372] [Chemical Formula 178]

[1373]

[1374] Iodine (1.01 g) was added to a mixture of 5,6-difluoro-1H-indazole (513 mg), potassium hydroxide (374 mg), and DMF (1.3 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate was added to the reaction solution, and the resulting precipitate was filtered and washed with water. The mixture was dried to obtain the title compound (899 mg). MS (m / z): 281.0 [M+H] +

[1375] [Step 2] Preparation of intermediate RE-43B

[1376] [Chemical Formula 179]

[1377]

[1378] Intermediate RE-43B was prepared from intermediate RE-43A according to procedures similar to those described in steps 1 to 3 for the preparation of compound RE-6C in Reference Example 6. MS (m / z): 366.2 [MH] -

[1379] [Step 3] Preparation of intermediate RE-43C

[1380] [Chemical formula 180]

[1381]

[1382] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-43B instead of intermediate RE-1E and 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 485.2 [M+Na] +

[1383] [Step 4] Preparation of compound RE-43

[1384] The title compound was obtained by the method of step 4 of Reference Example 37, using intermediate RE-43C instead of intermediate RE-37C. MS (m / z): 363.1 [M+H] +

[1385] Reference Example 44 2-[3-(azetidin-3-yl)-5,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)-1H-indazol-1-yl]- [(1-fluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-44)

[1386] [Chemical Formula 181]

[1387]

[1388] Intermediate RE-44 was prepared from intermediate RE-43B according to the procedure similar to that described in steps 5 to 6 for the preparation of compound RE-38 in Reference Example 38. MS (m / z): 389.2 [M+H] +

[1389] Reference Example 45 2-[3-(3-Hydroxyazetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)- [1-[(1-[(1-[(1-( ...

[1390] [Chemical formula 182]

[1391]

[1392] [Step 1] Preparation of intermediate RE-45A

[1393] [Chemical formula 183]

[1394]

[1395] 60% sodium hydride (260 mg) was added to a mixture of 3-hydroxyazetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.0 g) and DMF (14 mL) under ice cooling and stirred for 50 minutes. Benzyl bromide (1.10 g) was subsequently added and stirred at room temperature for 5 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.07 g). 1 H-NMR (400MHz, CDCl3) δ7.40-7.30(m,5H),4.50(s,2H),4.26(d,2H),4.06(d,2H),3.84(s,3H),1.56(s,9H)

[1396] [Step 2] Preparation of intermediate RE-45B

[1397] [Chemical formula 184]

[1398]

[1399] To a mixture of intermediate RE-45A (1.07 g), methanol (8 mL), and THF (8 mL) was added a 2M aqueous sodium hydroxide solution and stirred at room temperature. The solvent was removed under reduced pressure, 2M hydrochloric acid was added for neutralization, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was washed with hexane and dried to obtain the title compound (866 mg). MS (m / z): 306.1 [MH] -

[1400] [Step 3] Preparation of intermediate RE-45C

[1401] [Chemical formula 185]

[1402]

[1403] A mixture of intermediate RE-45B (866 mg), N,O-dimethylhydroxylamine (412 mg), 1-hydroxybenzotriazole monohydrate (561 mg), EDCI·HCl (702 mg), DIPEA (1.46 mL), and DMF (9.4 mL) was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (961 mg). MS (m / z): 373.0 [M+H] +

[1404] [Step 4] Preparation of intermediate RE-45D

[1405] [Chemical formula 186]

[1406]

[1407] The title compound was obtained by the method of step 1 of Reference Example 5, using 1-fluoro-2-iodobenzene instead of 2-bromo-4-chloro-1-fluorobenzene and intermediate RE-45C instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate. MS (m / z): 286.2 [M-Boc+2H] + , 1 H-NMR(400MHz,DMSO-d6)δ7.75-7.68(m,2H),7.35(dd,2H),7.22-7.20(m, 3H),6.93-6.90(m,2H),4.36(d,2H),4.23(s,2H),4.13(d,2H),1.41(s,9H)

[1408] [Step 5] Preparation of intermediate RE-45E

[1409] [Chemical Formula 187]

[1410]

[1411] A mixture of intermediate RE-45D (785 mg), hydrazine monohydrate (0.99 mL), potassium carbonate (844 mg) and DMA (15 mL) was reacted at 100 ° C in a microwave reaction apparatus for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and methyl bromoacetate (467 mg) was added to the obtained residue and a mixture of cesium carbonate (1.99 g) and DMA (7 mL) under ice cooling, and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (709 mg). MS (m / z): 474.3 [M + Na] +

[1412] [Step 6] Preparation of intermediate RE-45F

[1413] [Chemical formula 188]

[1414]

[1415] To a mixture of intermediate RE-45E (709 mg) and THF (20 mL) was added 5% Pd-C (600 mg), and the mixture was stirred at 40°C for 6 hours under a hydrogen atmosphere (0.3 MPa). Then, the mixture was stirred at 50°C for 11 hours and then heated with The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (425 mg). MS (m / z): 384.2 [M+Na] +

[1416] [Step 7] Preparation of intermediate RE-45G

[1417] [Chemical formula 189]

[1418]

[1419] The title compound was obtained by the method of step 5 of Reference Example 1, using intermediate RE-45F instead of intermediate RE-1D. MS (m / z): 346.1 [MH] -

[1420] [Step 8] Preparation of intermediate RE-45H

[1421] [Chemical formula 190]

[1422]

[1423] To a mixture of intermediate RE-45G (159 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (121 mg), HOBt (93 mg), DIPEA (0.24 mL), and DMF (0.3 mL) was added EDCI·HCl (132 mg), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (193 mg). MS (m / z): 491.3 [M+Na] +

[1424] [Step 9] Preparation of compound RE-45

[1425] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-45H instead of intermediate RE-37C. MS (m / z): 369.2 [M+H] +

[1426] Reference Example 46 3-Fluoro-3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H- tert-Butyl (indazol-3-yl)azetidine-1-carboxylate (Compound RE-46)

[1427] [Chemical Formula 191]

[1428]

[1429] To a mixture of intermediate RE-45H (96 mg) and dichloromethane (4 mL) was added DAST (50 mg) at -78 ° C and stirred for 3 hours. Subsequently, the mixture was stirred for 30 minutes under ice cooling. A saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (47 mg). MS (m / z): 493.2 [M + Na] +

[1430] Reference Example 47 2-[3-(azetidin-3-yl)-5-methyl-1H-indazol-1-yl]-N-methyl-N-(2,2,2- (Trifluoroethyl)acetamide trifluoroacetate (Compound RE-47)

[1431] [Chemical formula 192]

[1432]

[1433] [Step 1] Preparation of intermediate RE-47A

[1434] [Chemical formula 193]

[1435]

[1436] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-37B instead of intermediate RE-1E and 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 463.3 [M+Na] +

[1437] [Step 2] Preparation of compound RE-47

[1438] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-47A instead of intermediate RE-37C. MS (m / z): 341.0 [M+H] +

[1439] Reference Example 48 3-(5-methoxy-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}- tert-Butyl (1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-48)

[1440] [Chemical formula 194]

[1441]

[1442] [Step 1] Preparation of intermediate RE-48A

[1443] [Chemical formula 195]

[1444]

[1445] Intermediate RE-48A was prepared from 3-iodo-5-methoxy-1H-indazole according to procedures similar to those described in steps 1 to 3 for preparing intermediate RE-6C in Reference Example 6. MS (m / z): 360.2 [MH] -

[1446] [Step 2] Preparation of compound RE-48

[1447] The title compound was obtained by the method of Step 6 of Reference Example 1, using Intermediate RE-48A instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 505.2 [M+Na] +

[1448] Reference Example 49 2-[3-(azetidin-3-yl)-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-49)

[1449] [Chemical Formula 196]

[1450]

[1451] [Step 1] Preparation of intermediate RE-49A

[1452] [Chemical Formula 197]

[1453]

[1454] Intermediate RE-49A was prepared from 3-iodo-5,5-dimethyl-1,4,6,7-tetrahydroindazole (synthesized, for example, according to the method described in Journal of Medicinal Chemistry 2013, 56(4), 1677-1692) according to procedures similar to those described in Steps 1 to 3 for the preparation of Intermediate RE-6C in Reference Example 6. MS (m / z): 362.3 [MH] -

[1455] [Step 2] Preparation of intermediate RE-49B

[1456] [Chemical formula 198]

[1457]

[1458] The title compound was obtained by the method of Step 6 of Reference Example 1, using Intermediate RE-49A instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 485.4 [M+H]+

[1459] [Step 3] Preparation of compound RE-49

[1460] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-49B instead of intermediate RE-37C. MS (m / z): 385.4 [M+H] +

[1461] Reference Example 50 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(tri [(1-fluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-50)

[1462] [Chemical Formula 199]

[1463]

[1464] To a mixture of intermediate RE-1E (200 mg), HATU (258 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (119 mg), and DMF (1.7 mL) was added DIPEA (0.3 mL), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain tert-butyl 3-(4-chloro-5-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (250 mg). To a mixture of tert-butyl 3-(4-chloro-5-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (250 mg) and dichloromethane (0.5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and toluene was added to the resulting residue, followed by ethyl acetate and hexane. The solvent was then removed under reduced pressure to obtain the title compound (260 mg). MS (m / z): 405.1 [M+H] +

[1465] Reference Example 51 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-N-methyl-N-(2, 2,2-Trifluoroethyl)acetamide trifluoroacetate (Compound RE-51)

[1466] [Chemical Formula 200]

[1467]

[1468] [Step 1] Preparation of intermediate RE-51A

[1469] [Chemical Formula 201]

[1470]

[1471] The title compound was obtained by the method of step 6 of Reference Example 1, using 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 501.2 [M+Na] +

[1472] [Step 2] Preparation of compound RE-51

[1473] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-51A instead of intermediate RE-37C. MS (m / z): 378.9 [M+H] +

[1474] Reference Example 52 3-(4,6-difluoro-1-{[(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazole-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-52)

[1475] [Chemical Formula 202]

[1476]

[1477] According to the method of step 6 of Reference Example 1, using intermediate RE-2E instead of intermediate RE-1E, the title compound was obtained. 1 H-NMR(400MHz, CDCl3)δ6.85(dd,1H),6.71-6.65(m,1H),6.50(brs,1H),4.9 7(s,2H),4.41-4.35(m,2H),4.30-4.16(m,3H),3.96-3.88(m,2H)1.46(s,9H)

[1478] Reference Example 53 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)-1H-indazol-1-yl]- [(1-fluoromethyl)pyrrolidin-1-yl]propan-1-one hydrochloride (Compound RE-53)

[1479] [Chemical Formula 203]

[1480]

[1481] Compound RE-53 was prepared from intermediate RE-2C using methyl 2-chloropropionate instead of ethyl 2-bromoacetate according to the procedure similar to that described in steps 4 to 7 of Reference Example 2 for preparing compound RE-2. MS (m / z): 403.2 [M+H] +

[1482] Reference Example 54 3-(4,6-difluoro-1-{1-fluoro-2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl] tert-Butyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-54)

[1483] [Chemical Formula 204]

[1484]

[1485] Compound RE-54 was prepared from intermediate RE-2C using a procedure similar to that described in steps 4 to 6 of Reference Example 2 for preparing intermediate RE-2F, using ethyl bromofluoroacetate instead of ethyl 2-bromoacetate. MS (m / z): 529.2 [M+Na] +

[1486] Reference Example 55 3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine Tert-Butyl 1-Methyloxanecarboxylate (Compound RE-55)

[1487] [Chemical Formula 205]

[1488]

[1489] A mixture of intermediate RE-2C (50 mg), 4-methylbenzenesulfonic acid (4,4-difluorocyclohexyl) methyl ester (59 mg), cesium carbonate (79 mg) and DMF (0.8 mL) was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (80 mg). MS (m / z): 342.1 [M-Boc+2H] +

[1490] Reference Example 56 3-[4,6-difluoro-1-(3-phenylprop-2-yn-1-yl)-1H-indazol-3-yl]azetidine- tert-Butyl 1-formate (Compound RE-56)

[1491] [Chemical Formula 206]

[1492]

[1493] The title compound was obtained by the method of Reference Example 55 using (3-phenylprop-2-yn-1-yl)-4-methylbenzenesulfonate instead of (4,4-difluorocyclohexyl)methyl-4-methylbenzenesulfonate. MS (m / z): 342.1 [M-Boc+2H] +

[1494] Reference Example 57 3-[1-(3-cyclopropylprop-2-yn-1-yl)-4,6-difluoro-1H-indazol-3-yl]azetidine Tert-Butyl 1-Methyl-2-oxo-1-oxo-1-oxo-2 ...

[1495] [Chemical Formula 207]

[1496]

[1497] The title compound was obtained by the method of Reference Example 55, using 4-methylbenzenesulfonic acid (3-cyclopropylprop-2-yn-1-yl) ester instead of 4-methylbenzenesulfonic acid (4,4-difluorocyclohexyl)methyl ester. MS (m / z): 288.2 [M-Boc+2H] +

[1498] Reference Example 58 3-{4,6-difluoro-1-[(1-phenylazetidin-3-yl)methyl]-1H-indazol-3-yl}nitrogen Heterocyclobutane-1-carboxylic acid tert-butyl ester (Compound RE-58)

[1499] [Chemical Formula 208]

[1500]

[1501] [Step 1] Preparation of intermediate RE-58A

[1502] [Chemical Formula 209]

[1503]

[1504] A mixture of intermediate RE-2C (300 mg), benzyl 3-(p-toluenesulfonyloxymethyl)azetidine-1-carboxylate (437 mg), cesium carbonate (474 ​​mg) and DMF (3.9 mL) was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography, and the obtained tert-butyl 3-[1-({1-[(benzyloxy)carbonyl]azetidine-3-yl}methyl)-4,6-difluoro-1H-indazole-3-yl]azetidine-1-carboxylate was stirred with a mixture of 10% Pd-C (200 mg), hydrogen chloride (2M methanol solution, 0.04 mL) and methanol (3.9 mL) under a hydrogen atmosphere at room temperature for 4 hours. Use The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (270 mg). MS (m / z): 379.2 [M+H] +

[1505] [Step 2] Preparation of compound RE-58

[1506] A mixture of intermediate RE-58A (30 mg), bromobenzene (15 mg), Pd(OAc)2 (2 mg), Xantphos (9 mg), cesium carbonate (52 mg), and 1,4-dioxane (0.3 mL) was stirred at 90°C for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (6 mg). MS (m / z): 455.3 [M+H] +

[1507] Reference Example 59 3-(4,6-difluoro-1-{[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl}-1H- tert-Butyl (indazol-3-yl)azetidine-1-carboxylate (Compound RE-59)

[1508] [Chemical formula 210]

[1509]

[1510] To a mixture of intermediate RE-58A (30 mg), DIPEA (0.04 mL), and THF (0.3 mL) was added (2,2,2-trifluoroethyl) trifluoromethanesulfonate (37 mg), and stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (10 mg). MS (m / z): 461.2 [M+H] +

[1511] Reference Example 60 3-{1-[(2,3-dihydro-1H-inden-2-yl)methyl]-4,6-difluoro-1H-indazol-3-yl}azepine tert-Butyl cyclobutane-1-carboxylate (Compound RE-60)

[1512] [Chemical Formula 211]

[1513]

[1514] The title compound was obtained by the method of Reference Example 55 using indan-2-ylmethyl 4-methylbenzenesulfonate instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate. MS (m / z): 340.1 [M-Boc+2H] +

[1515] Reference Example 61 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2R)-2-(trifluoromethyl)-1H-indazol-1-yl]- [(4-( ...

[1516] [Chemical formula 212]

[1517]

[1518] [Step 1] Preparation of intermediate RE-61A

[1519] [Chemical formula 213]

[1520]

[1521] HBTU (124 mg) was added to a mixture of intermediate RE-2E (100 mg), DMF (0.9 mL), DIPEA (0.14 mL), and (2R)-2-(trifluoromethyl)morpholine hydrochloride (63 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (131 mg). MS (m / z): 405.1 [M-Boc+2H] +

[1522] [Step 2] Preparation of compound RE-61

[1523] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-61A instead of intermediate RE-37C. MS (m / z): 405.1 [M+H] +

[1524] Reference Example 62 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-N-methyl-N-(2,2, 2-(Trifluoroethyl)acetamide trifluoroacetate (Compound RE-62)

[1525] [Chemical formula 214]

[1526]

[1527] Compound RE-62 was prepared from intermediate RE-2E according to the procedure similar to that described in steps 1 to 2 for preparing compound RE-51 in Reference Example 51. MS (m / z): 363.1 [M+H] +

[1528] Reference Example 63 2-[3-(Azetidin-3-yl)-1H-indazol-1-yl]-N-tert-butylacetamide trifluoroacetic acid Salt (Compound RE-63)

[1529] [Chemical formula 215]

[1530]

[1531] Compound RE-63 was prepared from intermediate RE-4C using 2-methylpropan-2-amine in place of (2R)-2-(trifluoromethyl)morpholine hydrochloride according to the procedure similar to that described in steps 1 to 2 of Reference Example 61 for preparing compound RE-61. MS (m / z): 287.2 [M+H] +

[1532] Reference Example 64 2-[3-(Azetidin-3-yl)-1H-indazol-1-yl]-N,N-bis(propan-2-yl)acetamide Trifluoroacetate (Compound RE-64)

[1533] [Chemical formula 216]

[1534]

[1535] Compound RE-64 was prepared from intermediate RE-4C according to the procedure similar to that described in steps 1 to 2 of Reference Example 51 for preparing compound RE-51, using diisopropylamine instead of 2,2,2-trifluoro-N-methylethylamine hydrochloride. MS (m / z): 315.3 [M+H] +

[1536] Reference Example 65 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-tert-butyl-N-methylacetamide Fluoroacetate (Compound RE-65)

[1537] [Chemical Formula 217]

[1538]

[1539] Compound RE-65 was prepared from intermediate RE-4C using N,2-dimethylpropane-2-amine instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride according to the procedure similar to that described in steps 1 to 2 for preparing compound RE-51 in Reference Example 51. MS (m / z): 301.2 [M+H]+

[1540] Reference Example 66 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)- 4-(4-Methyl)acetamide trifluoroacetate (Compound RE-66)

[1541] [Chemical formula 218]

[1542]

[1543] [Step 1] Preparation of intermediate RE-66A

[1544] [Chemical formula 219]

[1545]

[1546] To a mixture of intermediate RE-4C (350 mg), 2,2,2-trifluoro-N-methylethaneamine hydrochloride (190 mg), 1-hydroxybenzotriazole monohydrate (194 mg), NMM (0.35 mL), and acetonitrile (3 mL) was added EDCI·HCl (243 mg), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (280 mg). MS (m / z): 449.3 [M+Na] +

[1547] [Step 2] Preparation of compound RE-66

[1548] The title compound was obtained by the method of step 4 of Reference Example 37 using intermediate RE-66A instead of intermediate RE-37C. MS (m / z): 327.2 [M+H] +

[1549] Reference Example 67 3-(5-Chloro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indole tert-Butyl oxazol-3-yl)azetidine-1-carboxylate (Compound RE-67)

[1550] [Chemical Formula 220]

[1551]

[1552] HBTU (143 mg) was added to a mixture of intermediate RE-5D (115 mg), DMF (1 mL), DIPEA (0.16 mL), and (2R)-2-(trifluoromethyl)morpholine hydrochloride (72 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (86 mg). MS (m / z): 503.2 [M+H] +

[1553] Reference Example 68 2-[3-(azetidin-3-yl)-5-chloro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)- [1-[(1-[(1-[(1-( ...

[1554] [Chemical Formula 221]

[1555]

[1556] To a mixture of intermediate RE-5D (115 mg), DMF (0.6 mL), DIPEA (0.16 mL) and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (66 mg) was added HATU (143 mg) and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the compound (116 mg). To a mixture of the obtained compound (116 mg) and dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature. The solvent was removed under reduced pressure to obtain the title compound (119 mg). MS (m / z): 387.1 [M+H] +

[1557] Reference Example 69 2-[3-(azetidin-3-yl)-6-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)- [1-[(1-[(1-[(1-( ...

[1558] [Chemical formula 222]

[1559]

[1560] According to the procedure similar to that described in Steps 1 to 2 of the preparation of compound RE-66 in Reference Example 66, (2S ) -2-(trifluoromethyl ) Compound RE-69 was prepared from intermediate RE-6C using pyrrolidine hydrochloride instead of 2,2,2-trifluoro-N-methylethylamine hydrochloride. MS (m / z): 371.3 [M+H] +

[1561] Reference Example 70 3-Methyl-3-(1-{[methyl(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazole- tert-Butyl 3-yl)azetidine-1-carboxylate (Compound RE-70)

[1562] [Chemical Formula 223]

[1563]

[1564] To a mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), HBTU (132 mg), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (52 mg) was added DIPEA (0.15 mL), and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (109 mg). MS (m / z): 463.4 [M+Na] +

[1565] Reference Example 71 2-[4-Fluoro-3-(piperidin-4-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrole [Methyl-1-alkyl]ethan-1-one (Compound RE-71)

[1566] [Chemical Formula 224]

[1567]

[1568] [Step 1] Preparation of intermediate RE-71A

[1569] [Chemical Formula 225]

[1570]

[1571] Compound RE-71A was prepared from intermediate RE-10C according to procedures similar to those described in steps 4 to 5 for the preparation of intermediate RE-2E in Reference Example 2. MS (m / z): 376.4 [MH] -

[1572] [Step 2] Preparation of compound RE-71

[1573] A mixture of intermediate RE-71A (800 mg), HATU (967 mg), DIPEA (1.1 mL) and DMF (4.2 mL) was stirred at room temperature for 15 minutes. (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (447 mg) was added and stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and ethyl acetate (5 mL) and hydrogen chloride (4M ethyl acetate solution, 0.4 mL) were added to the residue and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (280 mg). MS (m / z): 399.2 [M+H] +

[1574] Reference Example 72 4-(4-Fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indole tert-Butyl oxazol-3-yl)piperidine-1-carboxylate (Compound RE-72)

[1575] [Chemical Formula 226]

[1576]

[1577] A mixture of intermediate RE-10C (80 mg), HATU (97 mg), DIPEA (0.1 mL), and DMF (0.4 mL) was stirred at room temperature for 15 minutes. (2S)-2-(trifluoromethyl)morpholine hydrochloride (49 mg) was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction solution was purified by silica gel column chromatography to obtain the title compound (70 mg). MS (m / z): 415.2 [M-Boc+2H] +

[1578] Reference Example 73 4-(4-Fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indole tert-Butyl oxazol-3-yl)piperidine-1-carboxylate (Compound RE-73)

[1579] [Chemical Formula 227]

[1580]

[1581] The title compound was obtained by the method of Reference Example 72 using (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)morpholine hydrochloride. MS (m / z): 537.1 [M+Na] +

[1582] Reference Example 74 4-(4-Fluoro-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-indazol-3-yl)piperidin-1- Tert-Butyl formate (Compound RE-74)

[1583] [Chemical Formula 228]

[1584]

[1585] The title compound was obtained by the method of step 4 of Reference Example 10, using 5-(chloromethyl)-2-(trifluoromethyl)pyridine instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 501.2 [M+Na] +

[1586] Reference Example 75 4-(4-Fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H- Indol-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (Compound RE-75)

[1587] [Chemical Formula 229]

[1588]

[1589] Compound RE-75 was prepared from intermediate RE-11A according to the procedure similar to that described in steps 3 to 5 of Reference Example 11 for the preparation of intermediate RE-11E. MS (m / z): 396.2 [M-Boc+2H] +

[1590] Reference Example 76 4-(4-Fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indole tert-Butyl (3-indole)piperidine-1-carboxylate (Compound RE-76)

[1591] [Chemical Formula 230]

[1592]

[1593] Compound RE-76 was prepared from intermediate RE-11B according to the procedure similar to that described in steps 3 to 5 of Reference Example 11 for preparing intermediate RE-11E, using (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m / z): 536.2 [M+Na] +

[1594] Reference Example 77 4-(4-Fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indole tert-Butyl (3-indole)piperidine-1-carboxylate (Compound RE-77)

[1595] [Chemical Formula 231]

[1596]

[1597] Compound RE-77 was prepared from intermediate RE-11B using (2S)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride according to procedures similar to those described in steps 3 to 5 of Reference Example 11 for the preparation of intermediate RE-11E. MS (m / z): 536.2 [M+Na] +

[1598] Reference Example 78 2-[3-(azetidin-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl]-1- [(2R)-2-(Trifluoromethyl)morpholin-4-yl]ethan-1-one dihydrochloride (Compound RE-78)

[1599] [Chemical formula 232]

[1600]

[1601] [Step 1] Preparation of intermediate RE-78A

[1602] [Chemical formula 233]

[1603]

[1604] The title compound was obtained by the method of Reference Example 67 using Intermediate RE-13D instead of Intermediate RE-5D. MS (m / z): 484.2 [M+H] +

[1605] [Step 2] Preparation of compound RE-78

[1606] The title compound was obtained by the method of step 7 of Reference Example 1 using intermediate RE-78A instead of intermediate RE-1F. MS (m / z): 384.2 [M+H] +

[1607] Reference Example 79 2-[3-(azetidin-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl]-1- (3,3-Dimethylmorpholin-4-yl)ethan-1-one dihydrochloride (Compound RE-79)

[1608] [Chemical formula 234]

[1609]

[1610] [Step 1] Preparation of intermediate RE-79A

[1611] [Chemical Formula 235]

[1612]

[1613] To a mixture of intermediate RE-13D (52 mg), DMF (1.0 mL), HBTU (74 mg), and 3,3-dimethylmorpholine (22 mg) was added DIPEA (0.08 mL), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (50 mg). MS (m / z): 444.3 [M+H] +

[1614] [Step 2] Preparation of compound RE-79

[1615] The title compound was obtained by the method of step 7 of Reference Example 1 using intermediate RE-79A instead of intermediate RE-1F. MS (m / z): 344.2 [M+H] +

[1616] Reference Example 80 3-(4-Fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-pyrrolidone Tert-butyl oxazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-80)

[1617] [Chemical Formula 236]

[1618]

[1619] [Step 1] Preparation of intermediate RE-80A

[1620] [Chemical Formula 237]

[1621]

[1622] Intermediate RE-80A was prepared from intermediate RE-15C according to a procedure similar to that described in steps 4 to 5 for preparing intermediate RE-1E in Reference Example 1. MS (m / z): 351.0 [M+H] +

[1623] [Step 2] Preparation of compound RE-80

[1624] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-80A instead of intermediate RE-1E and (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 488.2 [M+H] +

[1625] Reference Example 81 3-(4-Fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H- Tert-butyl pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-81)

[1626] [Chemical Formula 238]

[1627]

[1628] The title compound was obtained by the method of step 6 of Reference Example 1, using intermediate RE-80A instead of intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS (m / z): 472.2 [M+H] +

[1629] Reference Example 82 3-(4-Fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[3,4-c]pyrrolidone tert-Butyl benzoate (3-pyridin-3-yl)azetidine-1-carboxylate (Compound RE-82)

[1630] [Chemical Formula 239]

[1631]

[1632] The title compound was obtained by the method of step 4 of Reference Example 10, using intermediate RE-15C instead of intermediate RE-10C. MS (m / z): 452.2 [M+H] +

[1633] Reference Example 83 3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridine-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-83)

[1634] [Chemical Formula 240]

[1635]

[1636] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-15C instead of Intermediate RE-10C and 1-(bromomethyl)-4-(trifluoromethyl)benzene instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 451.2 [M+H] +

[1637] Reference Example 84 3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-pyrazolo[3-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl) ...]-1H-pyrazolo[3-(4- Tert-butyl [3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-84)

[1638] [Chemical Formula 241]

[1639]

[1640] The title compound was obtained by the method of Step 6 of Reference Example 15, using 2-fluorobenzoic acid instead of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid. MS (m / z): 469.2 [M+H] +

[1641] Reference Example 85 3-(4-Fluoro-1-{[3-(3-fluoropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-pyrrolidone Tert-butyl oxazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-85)

[1642] [Chemical Formula 242]

[1643]

[1644] To a mixture of intermediate RE-80A (40 mg), 3-fluoro-N'-hydroxy-pyridine-4-carboxamide (synthesized, for example, according to the method described in European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1376–1394) (19 mg), DIPEA (0.02 mL) and DMF (0.4 mL) was added HATU (48 mg) and stirred at room temperature overnight. Then, the mixture was stirred at 120° C. for 2 hours. After standing and cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (15 mg). MS (m / z): 470.2 [M+H] +

[1645] Reference Example 86 2-[3-(azetidin-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl]-1- [(2R)-2-(Trifluoromethyl)morpholin-4-yl]ethan-1-one dihydrochloride (Compound RE-86)

[1646] [Chemical formula 243]

[1647]

[1648] The title compound was obtained by the method of step 7 of Reference Example 1, using compound RE-80 instead of intermediate RE-1F. MS (m / z): 388.1 [M+H] +

[1649] Reference Example 87 2-[3-(azetidin-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl]-1- [(2S)-2-[(Trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one dihydrochloride (Compound RE-87)

[1650] [Chemical formula 244]

[1651]

[1652] [Step 1] Preparation of intermediate RE-87A

[1653] [Chemical Formula 245]

[1654]

[1655] To a mixture of intermediate RE-80A (80 mg), DMF (0.8 mL), HBTU (130 mg), and (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (56 mg) was added DIPEA (0.2 mL), and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (60 mg). MS (m / z): 502.3 [M+H] +

[1656] [Step 2] Preparation of compound RE-87

[1657] The title compound was obtained by the method of step 7 of Reference Example 1, using intermediate RE-87A instead of intermediate RE-1F. MS (m / z): 402.2 [M+H] +

[1658] Reference Example 88 3-(azetidin-3-yl)-1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methane 1H-indazole (Compound RE-88)

[1659] [Chemical Formula 246]

[1660]

[1661] [Step 1] Preparation of intermediate RE-88A

[1662] [Chemical Formula 247]

[1663]

[1664] Compound RE-88A was prepared from intermediate RE-17B according to procedures similar to those described in steps 4 to 5 for the preparation of intermediate RE-15E in Reference Example 15. MS (m / z): 346.2 [M+H] +

[1665] [Step 2] Preparation of compound RE-88

[1666] A mixture of intermediate RE-88A (99 mg), toluene (2 mL), and trifluoroacetic anhydride (66 mg) was stirred at 60°C overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (49 mg). MS (m / z): 324.0 [M+H] +

[1667] Reference Example 89 3-{4-Fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl}nitrogen Heterocyclobutane-1-carboxylic acid tert-butyl ester (Compound RE-89)

[1668] [Chemical Formula 248]

[1669]

[1670] To a mixture of intermediate RE-18D (74 mg), azidobenzene (54 mg), DMF (2 mL), and methanol (0.2 mL) was added copper (I) iodide (4 mg), and the mixture was stirred at 60° C. for 3 hours under an argon atmosphere. The reaction solution was diluted with ethyl acetate and washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (62 mg). 1H-NMR (400MHz, CDCl3) δ7.88(s,1H),7.68(d,2H),7.51-7.46(m,2H),7.45-7.29(m ,3H),6.77(dd,1H),5.73(s,2H),4.40-4.30(m,4H),4.29-4.22(m,1H),1.46(s,9H)

[1671] Reference Example 90 3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl}nitrogen Heterocyclobutane-1-carboxylic acid tert-butyl ester (Compound RE-90)

[1672] [Chemical Formula 249]

[1673]

[1674] The title compound was obtained according to the method of Reference Example 89, using azidomethylbenzene instead of azidobenzene. 1 H-NMR (400MHz, CDCl3) δ7.39-7.22(m,8H),6.75(t,1H),5.61(s,2H),5.47(s,2H),4.38-4.18(m,4H),4.17-4.10(m,1H),1.47(s,9H)

[1675] Reference Example 91 3-(4-Fluoro-1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-1H- tert-Butyl (indazol-3-yl)azetidine-1-carboxylate (Compound RE-91)

[1676] [Chemical Formula 250]

[1677]

[1678] The title compound was obtained by the method of Reference Example 89 using 2-azido-1,1,1-trifluoroethane instead of azidobenzene. MS (m / z): 355.0 [M-Boc+2H] +

[1679] Reference Example 92 3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazole- tert-Butyl 3-yl)azetidine-1-carboxylate (Compound RE-92)

[1680] [Chemical Formula 251]

[1681]

[1682] The title compound was obtained by the method of Reference Example 89 using azidomethylcyclobutane instead of azidobenzene. MS (m / z): 341.1 [M-Boc+2H] +

[1683] Reference Example 93 3-{4-Fluoro-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-indazol-3-yl}azepine tert-Butyl cyclobutane-1-carboxylate (Compound RE-93)

[1684] [Chemical formula 252]

[1685]

[1686] To a mixture of intermediate RE-18C (50 mg) and THF (0.6 mL) was added 60% sodium hydride (5 mg) under ice cooling, and the mixture was stirred for 5 minutes. 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (30 mg) was then added, and the mixture was stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (41 mg). MS (m / z): 288.0 [M-Boc+2H] +

[1687] Reference Example 94 3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine- tert-Butyl 1-formate (Compound RE-94)

[1688] [Chemical formula 253]

[1689]

[1690] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C instead of Intermediate RE-10C and 1-(bromomethyl)-4-(trifluoromethyl)benzene instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[1691] Reference Example 95 3-(4-Fluoro-1-{[3-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine- tert-Butyl 1-formate (Compound RE-95)

[1692] [Chemical formula 254]

[1693]

[1694] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C instead of Intermediate RE-10C and 1-(bromomethyl)-3-(trifluoromethyl)benzene instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[1695] Reference Example 96 3-(4-Fluoro-1-{[2-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine- tert-Butyl 1-formate (Compound RE-96)

[1696] [Chemical formula 255]

[1697]

[1698] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C instead of Intermediate RE-10C and 1-(bromomethyl)-2-(trifluoromethyl)benzene instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[1699] Reference Example 97 3-(4-Fluoro-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazole-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-97)

[1700] [Chemical formula 256]

[1701]

[1702] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C instead of Intermediate RE-10C and 5-(chloromethyl)-3-trifluoromethyl-1,2,4-oxadiazole instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 342.1 [M-Boc+2H] +

[1703] Reference Example 98 3-(4-Fluoro-1-{[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazole-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-98)

[1704] [Chemical Formula 257]

[1705]

[1706] [Step 1] Preparation of intermediate RE-98A

[1707] [Chemical formula 258]

[1708]

[1709] Intermediate RE-98A was prepared from Intermediate RE-18C according to procedures similar to those described in Steps 4 to 5 for the preparation of Intermediate RE-15E in Reference Example 15. MS (m / z): 364.2 [M+H] +

[1710] [Step 2] Preparation of compound RE-98

[1711] A mixture of intermediate RE-98A (51 mg), 4-fluorobenzoic acid (18 mg), DIPEA (0.02 mL), HATU (54 mg), and DMF (0.4 mL) was stirred at room temperature overnight. The mixture was then stirred at 120°C for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (13 mg). MS (m / z): 368.1 [M-Boc+2H] +

[1712] Reference Example 99 3-[4-Fluoro-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H- [Indazol-3-yl]azetidine-1-carboxylic acid tert-butyl ester (Compound RE-99)

[1713] [Chemical Formula 259]

[1714]

[1715] The title compound was obtained by the method of Reference Example 98 using 3-trifluoromethylbenzoic acid instead of 4-fluorobenzoic acid. MS (m / z): 418.1 [M-Boc+2H] +

[1716] Reference Example 100 3-(4-Fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazole-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-100)

[1717] [Chemical Formula 260]

[1718]

[1719] The title compound was obtained by the method of Step 4 of Reference Example 10, using Intermediate RE-18C instead of Intermediate RE-10C and 2-(chloromethyl)-5-trifluoromethyl-1,3,4-oxadiazole instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 440.2 [MH] -

[1720] Reference Example 101 3-(4-Fluoro-1-{[5-(oxan-4-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazole- tert-Butyl 3-yl)azetidine-1-carboxylate (Compound RE-101)

[1721] [Chemical Formula 261]

[1722]

[1723] The title compound was obtained by the method of Reference Example 98 using tetrahydropyran-4-carboxylic acid instead of 4-fluorobenzoic acid. MS (m / z): 358.2 [M-Boc+2H] +

[1724] Reference Example 102 3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}methyl]- tert-Butyl 1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-103) (Compound RE-102)

[1725] [Chemical Formula 262]

[1726]

[1727] The title compound was obtained by the method of Reference Example 98 using 1-(trifluoromethyl)cyclobutanecarboxylic acid instead of 4-fluorobenzoic acid. MS (m / z): 518.2 [M+Na] +

[1728] Reference Example 103 3-[4-Fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl]- tert-Butyl 1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-103)

[1729] [Chemical formula 263]

[1730]

[1731] The title compound was obtained by the method of Reference Example 98 using 1-(trifluoromethyl)cyclopropanecarboxylic acid instead of 4-fluorobenzoic acid. MS (m / z): 504.2 [M+Na] +

[1732] Reference Example 104 3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazole-3-yl) tert-Butyl)azetidine-1-carboxylate (Compound RE-104)

[1733] [Chemical formula 264]

[1734]

[1735] The title compound was obtained by the method of Reference Example 98 using 2-fluorobenzoic acid instead of 4-fluorobenzoic acid. MS (m / z): 368.1 [M-Boc+2H] +

[1736] Reference Example 105 3-(4-Fluoro-1-{[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indole tert-Butyl oxazol-3-yl)azetidine-1-carboxylate (Compound RE-105)

[1737] [Chemical Formula 265]

[1738]

[1739] The title compound was obtained by the method of Reference Example 98 using 5-fluoropyridine-2-carboxylic acid instead of 4-fluorobenzoic acid. MS (m / z): 369.1 [M-Boc+2H] +

[1740] Reference Example 106 3-(4-Fluoro-1-{[5-(6-methylpyridazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H- tert-Butyl (indazol-3-yl)azetidine-1-carboxylate (Compound RE-106)

[1741] [Chemical Formula 266]

[1742]

[1743] The title compound was obtained by the method of Reference Example 98 using 6-methylpyridazine-3-carboxylic acid instead of 4-fluorobenzoic acid. MS (m / z): 366.1 [M-Boc+2H] +

[1744] Reference Example 107 3-(Azetidin-3-yl)-4-fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3- 1H-indazole (compound RE-107)

[1745] [Chemical Formula 267]

[1746]

[1747] A mixture of intermediate RE-98A (70 mg), toluene (1 mL), and trifluoroacetic anhydride (45 mg) was stirred at 60°C overnight. Trifluoroacetic anhydride (81 mg) was added, and after stirring at 60°C for 2 hours, the reaction solution was purified by silica gel column chromatography to obtain the title compound (13 mg). MS (m / z): 342.1 [M+H] +

[1748] Reference Example 108 2-[3-(azetidin-3-yl)-4-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)- (4-Methyl)acetamide hydrochloride (Compound RE-108)

[1749] [Chemical Formula 268]

[1750]

[1751] Compound RE-108 was prepared from intermediate RE-20B according to the procedure similar to that described in steps 6 to 7 for preparing compound RE-1 in Reference Example 1. MS (m / z): 331.5 [M+H] +

[1752] Reference Example 109 3-[4-Fluoro-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)- tert-Butyl 1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-109)

[1753] [Chemical Formula 269]

[1754]

[1755] A mixture of intermediate RE-20B (47 mg), N'-hydroxy-3-(trifluoromethyl)benzimidamide (30 mg), DIPEA (0.03 mL), HATU (56 mg), and DMF (0.5 mL) was stirred at room temperature overnight. The mixture was then stirred at 120°C for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (45 mg). MS (m / z): 418.1 [M-Boc+2H] +

[1756] Reference Example 110 3-(4-Fluoro-1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazole-3- tert-Butyl)azetidine-1-carboxylate (Compound RE-110)

[1757] [Chemical Formula 270]

[1758]

[1759] The title compound was obtained by the method of Reference Example 109 using 4-fluoro-N'-hydroxybenzamidine instead of N'-hydroxy-3-(trifluoromethyl)benzamidine. MS (m / z): 368.1 [M-Boc+2H] +

[1760] Reference Example 111 3-(4-Fluoro-1-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazole- tert-Butyl 3-yl)azetidine-1-carboxylate (Compound RE-111)

[1761] [Chemical Formula 271]

[1762]

[1763] The title compound was obtained according to the method of Reference Example 109, using N'-hydroxypyridine-4-carboximidamide instead of N'-hydroxy-3-(trifluoromethyl)benzimidamide. 1 H-NMR(400MHz, CDCl3)δ8.76(d,2H),7.90(d,2H),7.42-7.36(m,1H),7.25(d,1 H),6.85(t,1H),5.84(s,2H),4.40-4.30(m,4H),4.29-4.21(m,1H),1.46(s,9H)

[1764] Reference Example 112 3-{1-[({bicyclo[2.2.1]heptane-2-yl}carbamoyl)methyl]-4-fluoro-1H-indazole tert-Butyl 3-yl}azetidine-1-carboxylate (Compound RE-112)

[1765] [Chemical Formula 272]

[1766]

[1767] The title compound was obtained by the method of Step 1 of Reference Example 87, using Intermediate RE-20B instead of Intermediate RE-80A and norbiquinone hydrochloride instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 343.2 [M+H] +

[1768] Reference Example 113 3-{1-[({Bicyclo[1.1.1]pentan-1-yl}carbamoyl)methyl]-4-fluoro-1H-indazole tert-Butyl 3-yl}azetidine-1-carboxylate (Compound RE-113)

[1769] [Chemical Formula 273]

[1770]

[1771] The title compound was obtained by the method of Step 1 of Reference Example 87, using Intermediate RE-20B instead of Intermediate RE-80A and bicyclo[1.1.1]pentan-1-amine instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 413.3 [MH] -

[1772] Reference Example 114 3-(1-{[(2,2-difluoroethyl)carbamoyl]methyl}-4-fluoro-1H-indazol-3-yl)azepine tert-Butyl cyclobutane-1-carboxylate (Compound RE-114)

[1773] [Chemical Formula 274]

[1774]

[1775] The title compound was obtained by the method of Step 1 of Reference Example 87, using Intermediate RE-20B instead of Intermediate RE-80A and 2,2-difluoroethaneamine instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 313.1 [M-Boc+2H] +

[1776] Reference Example 115 4-{4-[4-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl]piperidine-1-carbonyl}pyridine- 2-Amine (Compound RE-115)

[1777] [Chemical Formula 275]

[1778]

[1779] To a mixture of intermediate RE-10C (70 mg) and DMF (0.7 mL) were added potassium carbonate (45 mg) and propargyl bromide (29 mg) and stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and trifluoroacetic acid (0.5 mL) was added to a mixture of the obtained residue (78 mg) and dichloromethane (2 mL), and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue (81 mg) was dissolved in a small amount of DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (24 mg), DMF (1.7 mL), DIPEA (0.2 mL) and HBTU (86 mg) was stirred at room temperature overnight, and then a DMF solution of the residue prepared separately was added and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (65 mg). MS (m / z): 378.2 [M+H] +

[1780] Reference Example 116 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indole oxazol-1-yl}acetic acid (Compound RE-116)

[1781] [Chemical Formula 276]

[1782]

[1783] [Step 1] Preparation of intermediate RE-116A

[1784] [Chemical Formula 277]

[1785]

[1786] A mixture of intermediate RE-2D (280 mg), ethanol (2 mL) and hydrogen chloride (2 M ethanol solution, 1.8 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was stirred at room temperature overnight with a mixture of ethanol (2 mL) and hydrogen chloride (2 M ethanol solution, 1.8 mL). The solvent was then removed under reduced pressure and the obtained residue (220 mg) was dissolved in DMF (2 mL). In a separate container, HBTU (327 mg) was added to a mixture of 2-aminopyridine-4-carboxylic acid (119 mg), DMF (2.2 mL) and DIPEA (0.92 mL). After stirring at room temperature for 15 minutes, a DMF solution of the residue prepared separately was added under ice cooling and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (130 mg). MS (m / z): 416.1 [M+H] +

[1787] [Step 2] Preparation of compound RE-116

[1788] To a mixture of intermediate RE-116A (343 mg) and methanol (4.1 mL) was added 2M aqueous sodium hydroxide solution (0.5 mL) under ice cooling, and the mixture was stirred at room temperature overnight. 2M hydrochloric acid was added for neutralization, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (183 mg). MS (m / z): 388.1 [M+H] +

[1789] Reference Example 117 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- ethyl}acetic acid trifluoroacetate (Compound RE-117)

[1790] [Chemical Formula 278]

[1791]

[1792] [Step 1] Preparation of intermediate RE-117A

[1793] [Chemical Formula 279]

[1794]

[1795] To a mixture of compound RE-39 (473 mg), compound RE-24 (349 mg), HOBt (289 mg), EDCI·HCl (410 mg), and DMF (5.5 mL) was added DIPEA (0.85 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (409 mg). MS (m / z): 426.2 [M+H] +

[1796] [Step 2] Preparation of compound RE-117

[1797] To a mixture of intermediate RE-117A (389 mg) and dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and toluene was added to the resulting residue, followed by ethyl acetate and hexane, and the solvent was removed under reduced pressure. The residue was washed with diethyl ether and dried to obtain the title compound (396 mg). MS (m / z): 370.2 [M+H] +

[1798] Reference Example 118 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazole-1- Acetic acid (Compound RE-118)

[1799] [Chemical formula 280]

[1800]

[1801] [Step 1] Preparation of intermediate RE-118A

[1802] [Chemical Formula 281]

[1803]

[1804] A mixture of intermediate RE-20A (300 mg) and hydrogen chloride (2M ethanol solution, 2 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the obtained residue (232 mg) was dissolved in a small amount of DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (80 mg), DMF (5.8 mL), DIPEA (0.8 mL), and HBTU (286 mg) was stirred at room temperature for 2 hours, and then a DMF solution of the residue prepared separately was added and stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (83 mg). MS (m / z): 397.8 [M+H] +

[1805] [Step 2] Preparation of compound RE-118

[1806] To a mixture of intermediate RE-118A (83 mg) and methanol (2 mL) was added 2M aqueous sodium hydroxide solution (0.1 mL) under ice cooling, and the mixture was stirred at room temperature overnight. 2M hydrochloric acid was added for neutralization, and the solvent was removed under reduced pressure to obtain the title compound (77 mg). MS (m / z): 370.0 [M+H] +

[1807] Reference Example 119 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-dione Fluoro-1H-indazol-1-yl}acetic acid (Compound RE-119)

[1808] [Chemical formula 282]

[1809]

[1810] Compound RE-119 was prepared from intermediate RE-2D using 2-amino-3-methylpyridine-4-carboxylic acid in place of 2-aminopyridine-4-carboxylic acid according to procedures similar to those described in steps 1 to 2 for preparing compound RE-116 in Reference Example 116. MS (m / z): 402.1 [M+H] +

[1811] Reference Example 120 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro- 1H-Indazol-1-yl}acetic acid (Compound RE-120)

[1812] [Chemical formula 283]

[1813]

[1814] Compound RE-120 was prepared from intermediate RE-2D using compound RE-24 instead of 2-aminopyridine-4-carboxylic acid according to procedures similar to those described in steps 1 to 2 for preparing compound RE-116 in Reference Example 116. MS (m / z): 406.1 [M+H] +

[1815] Reference Example 121 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}ethyl Acid (Compound RE-121)

[1816] [Chemical formula 284]

[1817]

[1818] Compound RE-121 was prepared from intermediate RE-4B according to a procedure similar to that described in steps 1 to 2 of Reference Example 116 for preparing compound RE-116. MS (m / z): 352.1 [M+H] +

[1819] Reference Example 122 4-{3-[4-Fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl]azetidine-1-carbonyl} Pyridin-2-amine (Compound RE-122)

[1820] [Chemical Formula 285]

[1821]

[1822] A mixture of intermediate RE-18D (100 mg) and hydrogen chloride (4 M 1,4-dioxane solution, 2 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue (80 mg) was dissolved in a small amount of DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (32 mg), DMF (2.3 mL), DIPEA (0.4 mL) and HBTU (114 mg) was stirred at room temperature for 2 hours, and then a DMF solution of the residue prepared separately was added and stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (34 mg). MS (m / z): 350.1 [M+H] +

[1823] Example 12-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro- 1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound E-1)

[1824] [Chemical formula 286]

[1825]

[1826] [Step 1] Preparation of 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Compound E-1A)

[1827] [Chemical Formula 287]

[1828]

[1829] To a mixture of compound RE-1 (30 mg) obtained in Step 7 of Reference Example 1, compound RE-23 (16 mg) obtained in Step 2 of Reference Example 23, DMF (1 mL), and DIPEA (0.091 mL) was added HATU (37 mg), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (15 mg).

[1830] [Step 2] Preparation of compound E-1

[1831] Compound E-1A (15 mg) was dissolved in methanol (2 mL), and 1 M hydrochloric acid (0.032 mL) was added. The mixture was then stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to obtain the title compound (13 mg). MS (m / z): 525.5 [M+H] +

[1832] Elemental analysis value (in C 23 H 21 (Calculated as ClF4N6O2·HCl+1.3H2O)

[1833] Calculated values ​​(%): C: 47.24, H: 4.24, N: 14.37

[1834] Measured values ​​(%): C: 47.37, H: 4.58, N: 13.98

[1835] Example 22-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazole- 1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-2)

[1836] [Chemical formula 288]

[1837]

[1838] [Step 1] Preparation of 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-2A)

[1839] [Chemical Formula 289]

[1840]

[1841] To a mixture of 2-aminopyridine-4-carboxylic acid (13 mg), HBTU (35 mg), and DMF (1 mL) was added DIPEA (0.098 mL), and the mixture was stirred at room temperature for 15 minutes. Compound RE-2 (30 mg), obtained in Step 7 of Reference Example 2, was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (34 mg).

[1842] [Step 2] Preparation of compound E-2

[1843] Compound E-2A (34 mg) was dissolved in methanol (2 mL), and 1 M hydrochloric acid (0.074 mL) was added. The mixture was stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to obtain the title compound (28 mg). MS (m / z): 509.1 [M+H] +

[1844] optical rotation

[1845] [α] 58925 =-4.7° (0.01 g, methanol, 1 mL, 50 mm)

[1846] Elemental analysis value (in C 23 H 21 F5N6O2·HCl+1.2H2O)

[1847] Calculated values ​​(%): C: 48.76, H: 4.34, N: 14.83

[1848] Measured values ​​(%): C: 48.50, H: 4.73, N: 14.68

[1849] Example 32-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-3)

[1850] [Chemical Formula 290]

[1851]

[1852] To a mixture of compound RE-4 (20 mg) obtained in step 5 of Reference Example 4, compound RE-24 (9.1 mg) obtained in Reference Example 24, HOBt (7.5 mg), EDCI·HCl (10.7 mg), and DMF (0.5 mL) was added DIPEA (0.022 mL), and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (12 mg). MS (m / z): 491.1 [M+H] +

[1853] Example 42-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazole-1- methyl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-4)

[1854] [Chemical Formula 291]

[1855]

[1856] The title compound (24 mg) was obtained by the method of Example 3, using compound RE-5 (43 mg) obtained in step 6 of Reference Example 5 instead of compound RE-4, and 2-aminopyrimidine-4-carboxylic acid (15 mg) instead of compound RE-24. MS (m / z): 482.3 [M+H] +

[1857] Example 52-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazole- 1-methyl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-5)

[1858] [Chemical Formula 292]

[1859]

[1860] According to the method of Example 3, compound RE-6 (40 mg) obtained in step 5 of Reference Example 6 was used instead of compound RE-4 to obtain the title compound (32 mg). MS (m / z): 483.3 [M+H] +

[1861] Example 62-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-6)

[1862] [Chemical Formula 293]

[1863]

[1864] According to the method of step 1 of Example 2, compound RE-7 (55 mg) obtained in step 5 of Reference Example 7 was used instead of compound RE-2 to obtain the title compound (7 mg). MS (m / z): 487.4 [M+H] +

[1865] Example 72-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indole Oxazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (Compound E-7)

[1866] [Chemical Formula 294]

[1867]

[1868] The title compound (12 mg) was obtained by the method of Example 3, using compound RE-8 (15 mg) obtained in step 2 of Reference Example 8 instead of compound RE-4, and 2-amino-4-methyl-1,3-thiazole-5-carboxylic acid (5.9 mg) instead of compound RE-24. MS (m / z): 469.2 [M+H] +

[1869] Example 82-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- methyl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (Compound E-8)

[1870] [Chemical Formula 295]

[1871]

[1872] The title compound (15 mg) was obtained by the method of step 1 of Example 2, using compound RE-9 (20 mg) obtained in step 2 of Reference Example 9 instead of compound RE-2, and compound RE-25 (14 mg) obtained in step 3 of Reference Example 25 instead of 2-aminopyridine-4-carboxylic acid. MS (m / z): 503.2 [M+H] +

[1873] Example 94-[4-(4-fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-3-yl)piperidine- 1-Carbonyl]pyridin-2-amine (Compound E-9)

[1874] [Chemical Formula 296]

[1875]

[1876] According to the method of step 1 of Example 2, compound RE-10 (35 mg) obtained in step 5 of Reference Example 10 was used instead of compound RE-2 to obtain the title compound (25 mg). MS (m / z): 499.3 [M+H] +

[1877] Example 102-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-10)

[1878] [Chemical Formula 297]

[1879]

[1880] According to the method of Example 3, compound RE-11 (46 mg) obtained in step 6 of Reference Example 11 was used instead of compound RE-4 to obtain the title compound (17 mg). MS (m / z): 536.3 [M+H] +

[1881] Example 112-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indol-1-yl}-1- [(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-11)

[1882] [Chemical Formula 298]

[1883]

[1884] To a mixture of compound RE-12 (50 mg) obtained in Step 5 of Reference Example 12 and ethyl acetate (0.4 mL) was added hydrogen chloride (4 M ethyl acetate solution, 0.14 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain 2-[3-(azetidin-3-yl)-1H-indol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride.

[1885] Next, according to the method of step 1 of Example 2, using the above-obtained 2-[3-(azetidin-3-yl)-1H-indol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride instead of compound RE-2, the title compound (14 mg) was obtained. MS (m / z): 472.3 [M+H] +

[1886] Example 122-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[3-(2-aminopyridine-4-carbonyl)azetidin-3-yl) ... [4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-12)

[1887] [Chemical Formula 299]

[1888]

[1889] To a mixture of compound RE-13 (100 mg) obtained in step 6 of Reference Example 13 and methanol (1 mL) was added hydrogen chloride (2 M methanol solution, 0.53 mL), and the mixture was stirred at room temperature overnight. Since the starting material remained, hydrogen chloride (2 M methanol solution, 0.53 mL) was added, and the mixture was stirred at room temperature for 7 hours. Hydrogen chloride (2 M methanol solution, 0.53 mL) was further added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to obtain 2-[3-(azetidin-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride.

[1890] Next, according to the method of step 1 of Example 2, using the above-obtained 2-[3-(azetidin-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (33 mg) instead of compound RE-2, the title compound (12 mg) was obtained. MS (m / z): 488.2 [M+H] +

[1891] Example 132-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c] Pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-13)

[1892] [Chemical Formula 300]

[1893]

[1894] [Step 1] Preparation of 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-13A)

[1895] [Chemical Formula 301]

[1896]

[1897] According to the method of Step 1 of Example 2, using Compound RE-14 (30 mg) obtained in Step 8 of Reference Example 14 instead of Compound RE-2, the title compound (22 mg) was obtained.

[1898] [Step 2] Preparation of compound E-13

[1899] According to the method of step 2 of Example 2, compound E-13A (22 mg) was used instead of compound E-2A to obtain the title compound (18 mg). MS (m / z): 474.2 [M+H] +

[1900] Example 144-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl 1H-pyrazolo[3,4-c]pyridin-3-yl]azetidine-1-carbonyl}pyridin-2-amine (Compound E-14)

[1901] [Chemical Formula 302]

[1902]

[1903] According to the method of step 1 of Example 2, compound RE-15 (27.5 mg) obtained in step 7 of Reference Example 15 was used instead of compound RE-2 to obtain the title compound (22.3 mg). MS (m / z): 503.2 [M+H] +

[1904] Example 152-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[3-(2-aminopyridine-4-carbonyl)azetidin-3-yl) ... [3,4-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-15)

[1905] [Chemical Formula 303]

[1906]

[1907] According to the method of step 1 of Example 2, compound RE-16 (43 mg) obtained in step 7 of Reference Example 16 was used instead of compound RE-2 to obtain the title compound (27 mg). MS (m / z): 488.1 [M+H] +

[1908] Example 162-{3-[1-(6-aminopyridazine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazole- 1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-16)

[1909] [Chemical Formula 304]

[1910]

[1911] According to the method of step 1 of Example 2, compound RE-3 (20 mg) obtained in Reference Example 3 was used instead of compound RE-2, and 6-aminopyridazine-4-carboxylic acid (8.3 mg) was used instead of 2-aminopyridine-4-carboxylic acid to obtain the title compound (5 mg). MS (m / z): 510.3 [M+H] +

[1912] Example 172-[4,6-difluoro-3-(1-{1H-pyrazolo[3,4-b]pyridine-4-carbonyl}azetidine-3- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-17)

[1913] [Chemical Formula 305]

[1914]

[1915] To a mixture of 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (7.8 mg), EDCI·HCl (9.2 mg), HOBt (6.5 mg), and DMF (0.5 mL) was added DIPEA (0.021 mL), and the mixture was stirred at room temperature for 10 minutes. Compound RE-3 (20 mg) obtained in Reference Example 3 was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (8 mg). MS (m / z): 534.3 [M+H] +

[1916] Example 185-Fluoro-4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazole- 3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-18)

[1917] [Chemical Formula 306]

[1918]

[1919] The title compound (12 mg) was obtained by the method of step 1 of Example 2, using compound RE-17 (49 mg) obtained in step 4 of Reference Example 17 instead of compound RE-2, and compound RE-24 (32 mg) obtained in Reference Example 24 instead of 2-aminopyridine-4-carboxylic acid. MS (m / z): 462.2 [M+H] +

[1920] Example 194-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)- 4-Fluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine hydrochloride (Compound E-19)

[1921] [Chemical Formula 307]

[1922]

[1923] [Step 1] Preparation of 4-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (Compound E-19A)

[1924] [Chemical Formula 308]

[1925]

[1926] According to the method of step 7 of reference example 1, compound RE-18 (56 mg) was used instead of intermediate RE-1F to obtain 3-(azetidin-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride.

[1927] Next, according to the method of step 1 of Example 2, using the above-obtained 3-(azetidin-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride instead of compound RE-2, the title compound (14 mg) was obtained.

[1928] [Step 2] Preparation of compound E-19

[1929] According to the method of step 2 of Example 2, compound E-19A (14 mg) was used instead of compound E-2A to obtain the title compound (5.4 mg). MS (m / z): 497.1 [M+H] +

[1930] Example 204-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazole- 3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-20)

[1931] [Chemical Formula 309]

[1932]

[1933] According to the method of step 1 of Example 2, compound RE-19 (67 mg) obtained in step 2 of Reference Example 19 was used instead of compound RE-2 to obtain the title compound (53 mg). MS (m / z): 488.2 [M+H] +

[1934] Example 212-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indole Oxazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-21)

[1935] [Chemical Formula 310]

[1936]

[1937] According to the method of Example 3, compound RE-5 (43 mg) obtained in step 6 of Reference Example 5 was used instead of compound RE-4, and compound RE-26 (17 mg) obtained in step 3 of Reference Example 26 was used instead of compound RE-24 to obtain the title compound (6 mg). MS (m / z): 500.3 [M+H] +

[1938] Example 222-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-22)

[1939] [Chemical Formula 311]

[1940]

[1941] According to the method of Example 3, compound RE-26 (16 mg) obtained in step 3 of Reference Example 26 was used instead of compound RE-24 to obtain the title compound (22 mg). MS (m / z): 492.2 [M+H] +

[1942] Example 232-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indole Oxazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-23)

[1943] [Chemical formula 312]

[1944]

[1945] The title compound (19 mg) was obtained by the method of Example 3, using compound RE-20 (41 mg) obtained in step 4 of Reference Example 20 instead of compound RE-4, and compound RE-26 (17 mg) obtained in step 3 of Reference Example 26 instead of compound RE-24. MS (m / z): 484.3 [M+H] +

[1946] Example 242-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,5,6,7-tetrafluoroethylene Hydrogen-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-24)

[1947] [Chemical formula 313]

[1948]

[1949] The title compound (9 mg) was obtained by the method of Example 3 using compound RE-21 (16 mg) obtained in step 6 of Reference Example 21 instead of compound RE-4. MS (m / z): 495.3 [M+H] +

[1950] Example 252-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-difluoro-4, 5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E- 25)

[1951] [Chemical formula 314]

[1952]

[1953] According to the method of Example 3, compound RE-22 (62 mg) obtained in step 8 of Reference Example 22 was used instead of compound RE-4 to obtain the title compound (40 mg). MS (m / z): 531.3 [M+H] +

[1954] Example 26 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5- (1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (Compound E-26)

[1955] [Chemical Formula 315]

[1956]

[1957] Compound E-1A (145 mg) was dissolved in THF (10 mL) under heating, and p-toluenesulfonic acid monohydrate (58 mg) was added, followed by stirring at room temperature for 5 minutes. The solvent was removed under reduced pressure, and the residue was washed with a mixed solvent of methanol and diethyl ether and dried to obtain the title compound (150 mg). MS (m / z): 525.4 [M+H] +

[1958] Elemental analysis value (in C 23 H 21 ClF4N6O2·C7H8O3S+2.7H2O)

[1959] Calculated values ​​(%): C: 48.32, H: 4.65, N: 11.27

[1960] Measured values ​​(%): C: 48.35, H: 4.44, N: 10.95

[1961] Example 272-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazole- 1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (Compound E-27)

[1962] [Chemical formula 316]

[1963]

[1964] Compound E-2A (1.80 g) was dissolved in THF (36 mL) under heating, and methanesulfonic acid (344 mg) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in acetonitrile under heating. After standing to cool, the precipitated solid was filtered and dried to obtain the title compound (1.45 g). MS (m / z): 509.3 [M+H] +

[1965] 1 H-NMR(400MHz,DMSO-D6)δ8.01(d,1H),8.00(brs,1H),7.38(d,1H),7.12(s,1H),7.04(t,1H),6.95(d,1H),5.44( s,2H),4.81-4.69(m,2H),4.60-4.45(m,2H),4.43-4.30(m,2H),3.80-3.70(m,1H),2.32(s,3H),2.11-2.00(m,4H)

[1966] Optical rotation

[1967] [α] 589 25 =-4.4° (0.01 g, methanol, 1 mL, 50 mm)

[1968] Elemental analysis value (in C 23 H 21 F5N6O2·CH4O3S+0.5H2O)

[1969] Calculated values ​​(%): C: 46.98, H: 4.27, N: 13.70

[1970] Measured values ​​(%): C: 46.73, H: 3.89, N: 13.62

[1971] Example 282-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-28)

[1972] [Chemical Formula 317]

[1973]

[1974] According to the method of step 2 of Example 2, using compound E-3 instead of compound E-2A, the title compound was obtained. MS (m / z): 474.2 [M+H] +

[1975] Optical rotation

[1976] [α] 589 25 =-2.78° (0.01 g, methanol, 1 mL, 50 mm)

[1977] Elemental analysis value (in C 23 H 22 F4N6O2·HCl+0.9H2O)

[1978] Calculated values ​​(%): C: 50.86, H: 4.60, N: 15.47

[1979] Measured values ​​(%): C: 51.13, H: 4.75, N: 15.14

[1980] Example 292-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazole-1- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (Compound E-29)

[1981] [Chemical formula 318]

[1982]

[1983] Compound E-3 (50 mg) was dissolved in THF (2 mL), and methanesulfonic acid (11 mg) was added thereto. The mixture was then stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was washed with a mixed solvent of methanol and diethyl ether. The resulting product was dissolved in methanol, the solvent was removed under reduced pressure, and the residue was washed with a mixed solvent of 2-propanol and hexane, and dried to obtain the title compound (22 mg). MS (m / z): 491.2 [M+H] +

[1984] Optical rotation

[1985] [α] 589 20 =-2.2° (0.3 g, methanol, 10 mL, 100 mm)

[1986] Elemental analysis value (in C 23 H 22 F4N6O2·CH4O3S)

[1987] Calculated values ​​(%): C: 49.14, H: 4.47, N: 14.33

[1988] Measured values ​​(%): C: 49.10, H: 4.50, N: 14.36

[1989] Example 302-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro- 1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound E-30)

[1990] [Chemical formula 319]

[1991]

[1992] [Step 1] Preparation of 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Compound E-30A)

[1993] [Chemical Formula 320]

[1994]

[1995] Compound RE-52 (125 mg) was dissolved in methanol (1 mL), and hydrogen chloride (2 M methanol solution, 1 mL) was added thereto. The mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure, and HATU (59 mg) was added to a mixture of the obtained residue (50 mg), compound RE-23 (28 mg), DIPEA (0.16 mL), and DMF (1 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (32 mg).

[1996] [Step 2] Preparation of compound E-30

[1997] The title compound was obtained by the method of step 2 of Example 2, using compound E-30A instead of compound E-2A. MS (m / z): 509.5 [M+H] +

[1998] Example 312-(3-{1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidin-3-yl}-4,6-difluoro- 1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Compound E-31)

[1999] [Chemical Formula 321]

[2000]

[2001] [Step 1] Preparation of 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate

[2002] A mixture of compound RE-27 (46 mg), dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure to obtain the title compound (56 mg).

[2003] [Step 2] Preparation of compound E-31

[2004] Compound RE-52 (125 mg) was dissolved in methanol (1 mL), and hydrogen chloride (2 M methanol solution, 1 mL) was added thereto. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and HBTU (30 mg) was added to the obtained residue (20 mg), 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate (23 mg), DIPEA (0.04 mL) and DMF (1 mL) at room temperature, and stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (16 mg). MS (m / z): 510.1 [M+H] +

[2005] Example 322-[4,6-difluoro-3-(1-{2-[(oxetane-3-yl)amino]pyridine-4-carbonyl}azacyclo (butane-3-yl)-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Compound E-32)

[2006] [Chemical Formula 322]

[2007]

[2008] [Step 1] Preparation of 2-{3-[1-(2-bromopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide (Compound E-32A)

[2009] [Chemical Formula 323]

[2010]

[2011] Compound RE-52 (125 mg) was dissolved in methanol (1 mL), and hydrogen chloride (2 M methanol solution, 1 mL) was added thereto. The mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure, and the obtained residue (84 mg) was dissolved in DMF (2 mL). In a separate container, DIPEA (0.1 mL) was added to a mixture of 2-bromopyridine-4-carboxylic acid (57 mg), HBTU (108 mg) and DMF (3 mL), and the mixture was stirred at room temperature for 15 minutes. A DMF solution of the residue prepared separately was added and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (72 mg). MS (m / z): 532.0 [M+H] +

[2012] [Step 2] Preparation of compound E-32

[2013] A mixture of compound E-32A (25 mg), rac-BINAP (18 mg), cesium carbonate (46 mg), 3-oxetaneamine (10 mg), and 1,4-dioxane (2 mL) was degassed with argon, and Pd(OAc)2 (2 mg) was added, followed by stirring at 100°C for 3 hours. The insoluble matter was filtered off, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3 mg). MS (m / z): 525.1 [M+H] +

[2014] Example 332-[4,6-difluoro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidine-3- 1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-33)

[2015] [Chemical Formula 324]

[2016]

[2017] [Step 1] Preparation of 2-[4,6-difluoro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-33A)

[2018] [Chemical Formula 325]

[2019]

[2020] A mixture of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (17 mg), HOBt (14 mg), DIPEA (0.05 mL), DMF (0.3 mL), and EDCI·HCl (20 mg) was stirred at room temperature for 10 minutes. Compound RE-2 (30 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain the title compound (37 mg).

[2021] [Step 2] Preparation of compound E-33

[2022] The title compound was obtained by the method of step 2 of Example 2, using compound E-33A instead of compound E-2A. MS (m / z): 533.2 [M+H] +

[2023] Example 344-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl} Azetidine-1-carbonyl)pyridin-2-amine (Compound E-34)

[2024] [Chemical Formula 326]

[2025]

[2026] [Step 1] Preparation of tert-butyl N-[4-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-yl]carbamate (Compound E-34A)

[2027] [Chemical Formula 327]

[2028]

[2029] A mixture of compound RE-89 (62 mg) and hydrogen chloride (2 M ethanol solution, 2 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the obtained residue (49 mg) was dissolved in a small amount of DMF. In a separate container, a DMF solution of the residue prepared separately was added to a mixture of 2-(tert-butoxycarbonylamino)pyridine-4-carboxylic acid (39 mg), DMF (5.4 mL), DIPEA (0.2 mL) and HATU (62 mg), and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (48 mg). MS (m / z): 569.2 [M+H] +

[2030] [Step 2] Preparation of compound E-34

[2031] A mixture of compound E-34A (48 mg) and hydrogen chloride (2 M in 1,4-dioxane, 2 mL) was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (14 mg). MS (m / z): 469.2 [M+H] +

[2032] Example 35 4-(3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl} Azetidine-1-carbonyl)pyridin-2-amine hydrochloride (Compound E-35)

[2033] [Chemical Formula 328]

[2034]

[2035] [Step 1] Preparation of tert-butyl N-[4-(3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-yl]carbamate (Compound E-35A)

[2036] [Chemical Formula 329]

[2037]

[2038] The title compound was obtained by the method of step 1 of Example 34 using compound RE-90 instead of compound RE-89. MS (m / z): 583.3 [M+H] +

[2039] [Step 2] Preparation of compound E-35

[2040] A mixture of compound E-35A (141 mg), hydrogen chloride (4 M in 1,4-dioxane, 2 mL), and 1,4-dioxane (2 mL) was stirred at room temperature overnight. 4 M hydrochloric acid (3 mL) was added and stirred, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (64 mg). MS (m / z): 483.2 [M+H] +

[2041] Example 362-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazole- 1-yl}-1-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-36)

[2042] [Chemical Formula 330]

[2043]

[2044] DMTMM (21 mg) was added to a mixture of compound RE-116 (20 mg), D-prolinol (8 mg), DIPEA (0.03 mL), and methanol (0.5 mL), and the mixture was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography to obtain the title compound (5 mg). MS (m / z): 471.2 [M+H] +

[2045] Example 374-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indole [(1-oxazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (Compound E-37)

[2046] [Chemical Formula 331]

[2047]

[2048] [Step 1] Preparation of 4-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-37A)

[2049] [Chemical formula 332]

[2050]

[2051] Copper (I) iodide (7 mg) was added to a mixture of compound RE-122 (120 mg), azidomethylcyclopropane (83 mg), DMF (2 mL), and methanol (0.2 mL), and the mixture was stirred at 60°C overnight under an argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain the title compound (28 mg). MS (m / z): 447.2 [M+H] +

[2052] [Step 2] Preparation of compound E-37

[2053] A mixture of compound E-37A (28 mg), 4M hydrochloric acid (0.02 mL), and 1,4-dioxane (2 mL) was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure and dried to obtain the title compound (14 mg). MS (m / z): 447.2 [M+H] +

[2054] Example 384-{3-[4-fluoro-1-({1-[(oxetan-3-yl)methyl]-1H-1,2,3-triazol-4-yl} methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (Compound E-38)

[2055] [Chemical formula 333]

[2056]

[2057] The title compound was obtained by the method of step 1 of Example 37 using 3-(azidomethyl)oxetane instead of azidomethylcyclopropane. MS (m / z): 463.2 [M+H] +

[2058] Example 39 4-{4-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]piperidine-1-carbonyl}pyridin-2-amine (Compound E-39)

[2059] [Chemical formula 334]

[2060]

[2061] The title compound was obtained by the method of step 1 of Example 37, using compound RE-115 instead of compound RE-122 and 3-(azidomethyl)-1,1-difluorocyclobutane instead of azidomethylcyclopropane. MS (m / z): 525.3 [M+H] +

[2062] Example 402-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1- [(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-40)

[2063] [Chemical Formula 335]

[2064]

[2065] The title compound was obtained by the method of step 1 of Example 2 using compound RE-4 instead of compound RE-2. MS (m / z): 473.2 [M+H] +

[2066] Example 412-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1- [(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-41)

[2067] [Chemical Formula 336]

[2068]

[2069] Compound E-40 (3.2 g) was dissolved in methanol (23 mL), and 2 M hydrochloric acid (3.6 mL) was added thereto. The mixture was then stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 2-propanol, and hexane was added thereto. The precipitated solid was then filtered and dried under reduced pressure to give the title compound (3.47 g). MS (m / z): 473.2 [M+H] +

[2070] [α] 589 25=-3.93° (0.02 g, methanol, 5 mL, 100 mm)

[2071] Elemental analysis value (in C 23 H 23 F3N6O2·HCl+3H2O)

[2072] Calculated values ​​(%): C: 49.07, H: 5.37, N: 14.93

[2073] Measured values ​​(%): C: 49.54, H: 5.81, N: 14.51

[2074] Example 422-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H- Indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (Compound E-42)

[2075] [Chemical Formula 337]

[2076]

[2077] According to the method of Example 3, compound RE-61 was used instead of compound RE-4 to obtain the title compound. MS (m / z): 543.2 [M+H] +

[2078] Example 432-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H- Indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate (Compound E-43)

[2079] [Chemical formula 338]

[2080]

[2081] Compound E-42 (32 mg) was dissolved in THF (2 mL), and p-toluenesulfonic acid monohydrate (13 mg) was added. The mixture was then stirred at room temperature for 1 hour. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (36 mg). MS (m / z): 543.2 [M+H] +

[2082] [α] 589 25 = +7.42° (0.001 g, methanol, 1 mL, 100 mm)

[2083] Elemental analysis value (in C 23 H 20 F6N6O3·C7H8O3S+1.4H2O)

[2084] Calculated values ​​(%): C: 48.70, H: 4.20, N: 11.36

[2085] Measured values ​​(%): C: 49.01, H: 4.05, N: 10.89

[2086] Example 442-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyridine Oxazo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one dimethylbenzyl Benzenesulfonate (Compound E-44)

[2087] [Chemical Formula 339]

[2088]

[2089] [Step 1] Preparation of 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one (Compound E-44A)

[2090] A mixture of compound RE-25 (14 mg), HBTU (20 mg), DIPEA (0.07 mL) and DMF (1 mL) was stirred at room temperature for 10 minutes, and compound RE-87 (19 mg) was added thereto. Subsequently, it was stirred at room temperature for 4 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (17 mg).

[2091] [Step 2] Preparation of compound E-44

[2092] Compound E-44A (17 mg) was dissolved in ethyl acetate (2 mL), and p-toluenesulfonic acid monohydrate (13 mg) was added. Stirring was then performed at room temperature. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (19 mg). MS (m / z): 536.2 [M+H] +

[2093] Example 452-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N- Methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-45)

[2094] [Chemical Formula 340]

[2095]

[2096] To a mixture of compound RE-121 (20 mg), 2,2,2-trifluoro-N-methylethaneamine hydrochloride (13 mg), HBTU (33 mg), and DMF (0.3 mL) was added DIPEA (0.05 mL), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (16 mg). MS (m / z) 447.2 [M+H] +

[2097] Example 462-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N- Methyl-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (Compound E-46)

[2098] [Chemical Formula 341]

[2099]

[2100] Compound E-45 (50 mg) was dissolved in THF (1.1 mL), and p-toluenesulfonic acid monohydrate (23 mg) was added thereto. The mixture was then stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in methanol. Diethyl ether was added, and the precipitated solid was filtered. Drying under reduced pressure gave the title compound (69 mg). MS (m / z): 447.2 [M+H] +

[2101] Elemental analysis value (in C 21 H 21 F3N6O2·C7H8O3S+3.5H2O)

[2102] Calculated values ​​(%): C: 49.33, H: 5.32, N: 12.33

[2103] Measured values ​​(%): C: 49.34, H: 5.01, N: 11.93

[2104] Example 472-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole oxazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-47)

[2105] [Chemical formula 342]

[2106]

[2107] A mixture of compound RE-40 (105 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature. The solvent was removed under reduced pressure, and toluene was added to the resulting residue, followed by ethyl acetate and hexane. The solvent was then removed under reduced pressure. In a separate container, EDCI·HCl (50 mg) was added to a mixture of compound RE-24 (51 mg), DIPEA (0.1 mL), HOBt (35 mg) and DMF (0.5 mL), and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was added to the previously obtained residue and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (12 mg). MS (m / z): 517.3 [M+H]

[2108] Example 48 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-N-methyl N-(2,2,2-trifluoroethyl)acetamide (Compound E-48)

[2109] [Chemical formula 343]

[2110]

[2111] [Step 1] Preparation of 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-48A)

[2112] [Chemical formula 344]

[2113]

[2114] The title compound was obtained by using compound RE-41 instead of compound RE-40 according to the method of Example 47. MS (m / z): 491.3 [M+H] +

[2115] [Step 2] Preparation of compound E-48

[2116] 10% Pd—C (13 mg) was added to compound E-48A (47 mg), methanol (3 mL), and ammonium formate (79 mg), and the mixture was stirred at 80° C. overnight. Insoluble matter was removed by filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (24 mg). MS (m / z): 493.3 [M+H] +

[2117] Example 492-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-1- [(2S)-2-(Trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-49)

[2118] [Chemical Formula 345]

[2119]

[2120] The title compound was obtained by the method of step 2 of Example 48 using compound E-47 instead of compound E-48A. MS (m / z): 519.3 [M+H] +

[2121] Example 502-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazole- 1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-50)

[2122] [Chemical Formula 346]

[2123]

[2124] A mixture of compound RE-116 (20 mg), (2R)-2-(trifluoromethyl)pyrrolidine hydrochloride (14 mg), HATU (29 mg), DIPEA (0.03 mL), and DMF (0.3 mL) was stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (21 mg). MS (m / z): 509.1 [M+H] +

[2125] Example 512-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro- 1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride (Compound E-51)

[2126] [Chemical Formula 347]

[2127]

[2128] [Step 1] Preparation of 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (Compound E-51A)

[2129] A mixture of compound RE-119 (19 mg), (2R)-2-(trifluoromethyl)morpholine hydrochloride (46 mg), HATU (27 mg), DIPEA (0.04 mL) and DMF (1 mL) was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (31 mg).

[2130] [Step 2] Preparation of (Compound E-51)

[2131] Compound E-51A (31 mg) was dissolved in methanol (2 mL), and 1 M hydrochloric acid (0.06 mL) was added. The mixture was stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure, and the residue was washed with a mixed solvent of ethanol and diethyl ether and dried to obtain the title compound (18 mg). MS (m / z): 539.2 [M+H] +

[2132] Example 524-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro- 1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (Compound E-52)

[2133] [Chemical Formula 348]

[2134]

[2135] [Step 1] Preparation of 4-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-52A)

[2136] Compound RE-91 (42 mg) was dissolved in 1,4-dioxane (1 mL), and 4 M hydrochloric acid (1 mL) was added thereto. The mixture was subsequently stirred at 50 ° C for 3 hours. The solvent was removed under reduced pressure, and the obtained residue was dissolved in DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (10 mg), HBTU (36 mg), DIPEA (0.1 mL) and DMF (0.7 mL) was stirred at room temperature for 2 hours, and a DMF solution of the residue prepared separately was added and stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (17 mg).

[2137] [Step 2] Preparation of compound E-68

[2138] A mixture of compound E-52A (17 mg) and hydrogen chloride (4 M in 1,4-dioxane, 0.02 mL) was stirred at room temperature. The solvent was removed under reduced pressure, and the residue was washed with a mixed solvent of methanol and diethyl ether and dried to obtain the title compound (8 mg). MS (m / z): 475.1 [M+H] +

[2139] Example 532-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[3-(2-aminopyridine-4-carbonyl)azetidin-3-yl) ... [4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-53)

[2140] [Chemical Formula 349]

[2141]

[2142] A mixture of compound RE-33 (97 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL) was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure, toluene was added to the obtained residue, the solvent was removed under reduced pressure, ethyl acetate and hexane were subsequently added, the solvent was removed under reduced pressure to give a solid (132 mg). In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (13 mg), DIPEA (0.13 mL), HBTU (36 mg) and DMF (1 mL) was stirred at room temperature for 30 minutes, the previously obtained residue (44 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to give the title compound (25 mg). MS (m / z): 488.1 [M+H] +

[2143] Example 542-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3, 4-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-54)

[2144] [Chemical F...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: [Chemical Formula 1] in: A is [Chemical Formula 2] in Y 1 、Y 2 、Y 3 and Y 4 Each independently is N or CR 5 , where Y 1 、Y 2 、Y 3 and Y 4 At most two of them are N, and the others are CR 5 , R 5 is hydrogen, halogen, cyano, alkoxy, or optionally substituted C1-C6 alkyl, and Dashed lines indicate bonding points or [Chemical Formula 3] in R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are each independently hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl, and Dashed lines indicate bonding points; B is an optionally substituted 3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle; X is N or CR 7 , where R 7 is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl; R 1 Each is independently selected from the group consisting of hydrogen, halogen, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; R 2 and R 3 are each independently hydrogen, halogen, or optionally substituted C1-C6 alkyl; R 4 selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, mono- or bicyclic saturated carbocycle, mono- or bicyclic unsaturated carbocycle, mono- or bicyclic saturated heterocycle, and mono- or bicyclic unsaturated heterocycle, each of which may be optionally substituted; or R 4 for-CONR 8 R 9 ,in: R 8 and R 9 Each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or R 8 and R 9 together with the atoms to which they are attached, form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring; m is an integer from 0 to 3; n is an integer from 0 to 3; Het is a 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula (I) is formula (II): [Chemical Formula 4] In the formula, B, R 1 、R 2 、R 3 、R 4 , Het, X, Y 1 、Y 2 、Y 3 、Y 4 , m and n are as defined in formula (I).

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound of formula (I) is formula (III): [Chemical Formula 5] In the formula, B, R 1 、R 2 、R 3 、R 4 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h , Het, X, m and n are as defined in formula (I).

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 1 Each is independently selected from the group consisting of hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 Selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxyl, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 4 for-CONR 8 R 9 ,in R 8 and R 9 Each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or R 8 and R 9 Together with the atoms to which they are attached, they form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocyclic ring, or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocyclic ring. 7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is N.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is CR 7 , where R 7 is hydrogen, halogen, cyano, or an optionally substituted C1-C6 alkyl.

9. A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of the following compounds (1) to (295): (1) 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (2) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (3) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (4) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (5) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (6) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (7) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (8) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (9) 4-[4-(4-fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine (10) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (11) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (12) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (13) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (14) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl]azetidine-1-carbonyl}pyridin-2-amine (15) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (16) 2-{3-[1-(6-aminopyridazine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (17) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[3,4-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (18) 5-Fluoro-4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (19) 4-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine hydrochloride (20) 4-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (21) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (22) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (23) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (24) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (25) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (26) 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (27) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (28) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (29) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (30) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (31) 2-(3-{1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (32) 2-[4,6-difluoro-3-(1-{2-[(oxetan-3-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (33) 2-[4,6-difluoro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (34) 4-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (35) 4-(3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine hydrochloride (36) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (37) 4-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (38) 4-{3-[4-fluoro-1-({1-[(oxetan-3-yl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (39) 4-{4-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]piperidine-1-carbonyl}pyridin-2-amine (40) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (41) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (42) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (43) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate (44) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one di-p-toluenesulfonate (45) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (46) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (47) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (48) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (49) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (50) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (51) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride (52) 4-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (53) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (54) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (55) 4-{3-[4-fluoro-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-1H-indazol-3-yl]azetidin-1-carbonyl}pyridin-2-amine (56) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one (57) 4-(3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (58) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one di-p-toluenesulfonate (59) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (60) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (61) 2-[4-chloro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (62) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide (63) 2-(4-chloro-3-{1-[2-(methylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (64) 2-(4-chloro-3-{1-[2-(ethylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (65) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (66) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,7-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (67) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (68) 2-(3-{1-[2-(cyclobutylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (69) 2-(4-Bromo-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-fluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (70) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-bromo-5-fluoro-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (71) 2-[4-Fluoro-3-(1-{2-[(oxan-4-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (72) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (73) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride (74) 2-[4,6-difluoro-3-(1-{2-[(1-methylcyclopropyl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (75) 2-[3-(1-{2-[(4,4-difluorocyclohexyl)amino]pyridine-4-carbonyl}azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (76) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(pyrrolidin-1-yl)ethan-1-one (77) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (78) 2-{3-[1-(2-amino-5-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (79) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-methylmorpholin-4-yl]ethan-1-one hydrochloride (80) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one hydrochloride (81) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (82) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (83) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-(propan-2-yl)morpholin-4-yl]ethan-1-one (84) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethan-1-one (85) 2-{3-[1-(6-aminopyridine-3-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (86) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]piperidin-4-yl}-4-fluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (87) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (88) 2-[4,6-difluoro-3-(1-{2-[(oxan-4-yl)amino]pyridine-4-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (89) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride (90) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (91) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (92) 4-[3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (93) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (94) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (95) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one hydrochloride (96) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (97) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (98) 2-(3-{1-[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (99) 2-(3-{1-[2-(cyclopropylamino)-4-methyl-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (100) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (101) 2-[4,6-difluoro-3-(1-{imidazo[1,2-a]pyridine-3-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (102) 2-[4,6-difluoro-3-(1-{pyrazolo[3,2-b][1,3]thiazole-7-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (103) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one hydrochloride (104) 4-[3-(4-Fluoro-1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (105) 2-{3-[1-(2-amino-1,3-oxazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (106) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (107) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-2-fluoro-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (108) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (109) 4-(3-{4-fluoro-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (110) 2-{3-[1-(2-amino-4-methyl-1,3-oxazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (111) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidin-1-yl]ethan-1-one (112) 4-[3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (113) 4-[3-(4-Fluoro-1-{[3-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (114) 4-[3-(4-Fluoro-1-{[2-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (115) 4-[3-(4-Fluoro-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine hydrochloride (116) 4-[3-(4-Fluoro-1-{[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (117) 4-{3-[4-fluoro-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (118) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (119) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (120) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (121) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one 122) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (123) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S)-3-(trifluoromethyl)morpholin-4-yl]ethan-1-one (124) 2-{3-[1-(2-aminopyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (125) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S)-3-(difluoromethoxy)pyrrolidin-1-yl]ethan-1-one (126) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3R)-3-(difluoromethoxy)pyrrolidin-1-yl]ethan-1-one (127) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(2,2-dimethylpyrrolidin-1-yl)ethan-1-one (128) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (129) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (130) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidin-3-yl}-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (131) 2-{3-[1-(6-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (132) 2-{4,6-difluoro-3-[1-(pyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (133) 2-{4,6-difluoro-3-[1-(3-methoxypyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (134) 4-[4-(4-Fluoro-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine (135) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (136) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (137) 4-[3-(4-fluoro-1-{[5-(oxan-4-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (138) 4-[3-(4-fluoro-1-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (139) 2-(3-{1-[2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carbonyl]azetidin-3-yl}-4,6-difluoro-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (140) 2-{4,6-difluoro-3-[1-(1H-indazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (141) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[4,3-b]pyridine-5-carbonyl}azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (142) 2-{4,6-difluoro-3-[1-(3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (143) 2-{3-[1-(3-chloropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (144) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (145) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (146) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine hydrochloride (147) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (148) 4-[3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (149) 2-{3-[1-(2-amino-4-chloro-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (150) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine (151) 4-[3-(4-Fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine (152) 4-{3-[4,6-difluoro-1-(3-phenylprop-2-yn-1-yl)-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (153) 4-[3-(4-Fluoro-1-{[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (154) 4-[3-(4-fluoro-1-{[5-(6-methylpyridazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (155) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (156) 4-{3-[1-(3-cyclopropylprop-2-yn-1-yl)-4,6-difluoro-1H-indazol-3-yl]azetidine-1-carbonyl}pyridin-2-amine (157) 4-(3-{4,6-difluoro-1-[(1-phenylazetidin-3-yl)methyl]-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (158) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethan-1-one (159) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-1-one (160) 4-[3-(4-Fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine (161) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(6-bromo-2,3-dihydro-1H-indol-1-yl)ethan-1-one (162) 2-{4,6-difluoro-3-[1-(oxane-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (163) 2-{4,6-difluoro-3-[1-(2-hydroxypyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (164) 2-{4,6-difluoro-3-[1-(1H-pyrazole-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (165) 2-{4,6-difluoro-3-[1-(5-methyl-1H-pyrazole-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (166) 2-(4,6-difluoro-3-{1-[5-(trifluoromethyl)-1H-pyrazole-4-carbonyl]azetidin-3-yl}-1H-indazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (167) 4-[3-(4,6-difluoro-1-{[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl}-1H-indazol-3-yl)azetidin-1-carbonyl]pyridin-2-amine (168) 4-[3-(5-methyl-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine (169) 2-{3-[1-(1H-1,2,3-benzotriazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (170) 4-[3-(4-Fluoro-1-{[3-(3-fluoropyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carbonyl]pyridin-2-amine (171) 4-(3-{1-[(2,3-dihydro-1H-indene-2-yl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (172) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(6-cyclopropyl-2,3-dihydro-1H-indol-1-yl)ethan-1-one (173) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (174) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (175) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one (176) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(2,2-dimethylmorpholin-4-yl)ethan-1-one (177) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (178) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one dihydrochloride (179) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethan-1-one (180) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (181) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (182) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(3S,5S)-3,5-dimethylmorpholin-4-yl]ethan-1-one (183) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one p-toluenesulfonate (184) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate (185) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate (186) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one p-toluenesulfonate (187) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (188) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (189) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-N-tert-butylacetamide (190) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (191) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (192) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (193) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (194) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (195) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (196) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (197) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (198) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butylacetamide (199) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butylacetamide (200) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (201) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (202) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (203) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (204) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (205) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (206) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (207) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (208) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-methoxy-2-methylpropan-2-yl)acetamide (209) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4-methyloxan-4-yl)acetamide (210) 2-{3-[1-(2-amino-5-chloropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (211) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2,2-trifluoroethyl)acetamide (212) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(2R)-1,1,1-trifluoropropan-2-yl]acetamide (213) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]acetamide (214) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(3,3-difluorocyclobutyl)acetamide (215) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (216) 4-[3-(4-Fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (217) 4-[3-(1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (218) 4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (219) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (220) tert-Butyl 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetate (221) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(2,2-dimethylpyrrolidin-1-yl)ethan-1-one (222) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R)-2-ethylpyrrolidin-1-yl]ethan-1-one (223) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{2-azabicyclo[3.1.0]hexan-2-yl}ethan-1-one (224) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(dicyclopropylmethyl)acetamide (225) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluorocyclopentyl)acetamide (226) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4-fluorophenyl)acetamide (227) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[2-(trifluoromethoxy)ethyl]acetamide (228) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethan-1-one (229) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(cyclopropylmethyl)-N-methylacetamide (230) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(3S)-3-methoxypyrrolidin-1-yl]ethan-1-one (231) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(3R)-3-methoxypyrrolidin-1-yl]ethan-1-one (232) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{2-oxa-6-azaspiro[3.4]octan-6-yl}ethan-1-one (233) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(oxan-4-yl)acetamide (234) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2-cyclopropylpropan-2-yl)acetamide (235) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(4,4-difluorocyclohexyl)acetamide (236) (2S)-1-(2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetyl)pyrrolidine-2-carbonitrile (237) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidin-1-yl]ethan-1-one (238) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-{bicyclo[2.2.1]heptan-2-yl}acetamide (239) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-{bicyclo[1.1.1]pentan-1-yl}acetamide (240) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (241) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (242) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}-N-(2,2-difluoroethyl)acetamide (243) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[trans-2-fluorocyclopropyl]acetamide (244) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-cyanocyclopropyl)acetamide (245) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(1R,2S)-2-fluorocyclopropyl]acetamide (246) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(1S,2R)-2-fluorocyclopropyl]acetamide (247) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(1-methyl-1H-pyrazol-5-yl)acetamide (248) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluorocyclopropyl)acetamide (249) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide (250) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(3,3-difluorocyclobutyl)-N-methylacetamide (251) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (252) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-cyclopropyl-N-methylacetamide (253) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(propan-2-yl)acetamide (254) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(oxetan-3-yl)acetamide (255) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(oxan-4-yl)acetamide (256) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-[(3,3-difluorocyclobutyl)methyl]-N-methylacetamide (257) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(4,4-difluoropiperidin-1-yl)ethan-1-one (258) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}ethan-1-one (259) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[3-(trifluoromethyl)piperidin-1-yl]ethan-1-one (260) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-(4-methylpiperazin-1-yl)ethan-1-one (261) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]acetamide (262) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[(2R)-1,1,1-trifluoropropane-2-yl]acetamide (263) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N,N-diethylacetamide (264) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-[2-(morpholin-4-yl)ethyl]acetamide (265) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2-methoxyethyl)-N-methylacetamide (266) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2R,6S)-2,6-dimethylpiperidin-1-yl]ethan-1-one (267) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N,N-bis(propan-2-yl)acetamide (268) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-tert-butyl-N-methylacetamide (269) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-(2,2-difluoroethyl)-N-methylacetamide (270) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (271) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (272) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(difluoromethyl)pyrrolidin-1-yl]ethan-1-one (273) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (274) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (275) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (276) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (277) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (278) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (279) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (280) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (281) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-hydroxyazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (282) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (283) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (284) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (285) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-fluoroazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (286) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (287) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4-chloro-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (288) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (289) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (290) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (291) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5-methoxy-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (292) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (293) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (294) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one, and (295) 2-{3-[1-(2-Aminopyrimidine-4-carbonyl)azetidin-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one.

10. 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt or solvate thereof.

11. 2-{3-[1-(2-Aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride or a solvate thereof.

12. 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

13. 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt or solvate thereof.

14. 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one or a pharmaceutically acceptable salt or solvate thereof.

15. 2-{3-[1-(2-Amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate or a solvate thereof. 16 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate thereof. 17 . A DDR1 kinase inhibitor comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

18. A method for inhibiting DDR1 kinase, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof. A preventive or therapeutic agent for a DDR1 kinase-related disease, comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. A therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change disease nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis, comprising as an active ingredient a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

21. A method for preventing or treating a DDR1 kinase-related disease, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof.

22. A method for preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

23. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in preventing or treating a DDR1 kinase-related disease.

24. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change disease nephrotic syndrome, mesangial proliferative glomerulonephritis, membrane proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

25. Use of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for manufacturing a preventive or therapeutic agent for a DDR1 kinase-related disease.

26. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for manufacturing a preventive or therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular subglacial membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpuric nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change disease nephrotic syndrome, mesangial proliferative glomerulonephritis, membrane proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

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