Compounds and drugs as DDR1 kinase inhibitors

Abstract

Provided is a compound having DDR1 inhibitory activity and represented by general formula (I), or a pharmaceutically acceptable salt or solvate thereof, and pharmaceutical use of the same.

Description

[Technical Field]

[0001] The present invention relates to substituted bicyclic heterocyclic compounds useful as DDR1 kinase inhibitors and pharmaceuticals containing said compounds. [Background technology]

[0002] Discoidin Domain Receptor 1 (DDR1) is a tyrosine kinase receptor belonging to the discoidin domain receptor family, and is known to be involved in cell proliferation, differentiation, migration, invasion, and adhesion. It is mainly expressed in epithelial cells of the lung, kidney, mammary gland, and gastrointestinal tract.

[0003] DDR1 transmits collagen signals into cells by binding to its ligand, collagen, via its discoidin domain. DDR1 is unique in that it recognizes not only fibrillar collagens such as type I but also basement membrane collagens such as type IV collagen as ligands. When DDR1 binds to collagen, specific tyrosine residues in the kinase domain on the cytoplasmic side of the receptor are phosphorylated, and the binding of Src homology 2 and molecules with phosphotyrosine binding domains activates various downstream signaling pathways.

[0004] DDR1 activation is involved in various kidney diseases. DDR1 activation is involved in the pathology of various kidney diseases, including Alport syndrome (Non-Patent Documents 1 and 2), which is caused by a mutation in the type IV collagen gene, as well as 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, such as pulmonary fibrosis (Non-Patent Document 7) and liver cirrhosis (Non-Patent Document 8).

[0006] Furthermore, it has been reported that DDR1 is involved in the function of Th17 cells, which are involved in autoimmune diseases and 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] It has also been reported to be involved in the pathogenesis of cancer-related conditions, 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] DDR1 has also been reported to be involved in pathological conditions 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] Most of the treatments for these diseases are limited to symptomatic treatment, suppression of disease progression, and improvement of quality of life, and efficient treatment is extremely difficult. Therefore, DDR1 inhibitors may provide a new treatment for these DDR1-related diseases. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Gross et al., Matrix Biol. 2010 Jun;29(5):346-56. [Non-patent document 2] Richter et al., ACS Chem Biol. 2019 Jan 18;14(1):37-49. [Non-licensed document 3] Hahn et al., Int J Mol Med. 2010 May;25(5):785-91.

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Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a compound having DDR1 kinase inhibitory activity, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [Means for solving the problem]

[0012] The present inventors have discovered that the compounds described below, or pharmaceutically acceptable salts thereof, or solvates thereof, have excellent DDR1 kinase inhibitory activity, and have completed the present invention.

[0013] That is, the present invention includes the following aspects (Item 1) to (Item 22). (Section 1) Formula (I) [ka] [During the ceremony, A is, [ka] (In the formula, Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CR 5 and Here, the Y 1 , Y 2 , Y 3 and Y 4 At most two of them are N, and the rest are CR 5 and R 5 is hydrogen, halogen, cyano, alkoxy, or optionally substituted C1-C6 alkyl; (Dashed lines indicate attachment points) or [ka] (In the formula, R 6a , R 6b , R 6c , R6d , R 6e , R 6f , R 6g and R 6h are each independently hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl; (Dashed lines indicate attachment points) and 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 are each independently hydrogen, halogen, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 selected from the group consisting of cycloalkyl, C-C cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; R 2 and R 3 are each independently hydrogen, halogen, or optionally substituted C1-C6 alkyl; R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, a monocyclic or bicyclic saturated carbocycle, a monocyclic or bicyclic unsaturated carbocycle, a monocyclic or bicyclic saturated heterocycle, and a monocyclic or bicyclic unsaturated heterocycle, each of which is optionally substituted; or R 4 -CONR 8 R 9and where R 8 and R 9 each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 selected from the group consisting of cycloalkyl, C-C cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is 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 heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle; 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 heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle. or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Section 2) The compound of formula (I) may be a compound of formula (II): [ka] [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). Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is: (Section 3) The compound of formula (I) is represented by formula (III) [ka] [In the formula, B, R 1 , R 2 , R 3 , R4 , 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). Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is: (Section 4) R 1 are each independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted. (Section 5) R 4 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted. (Section 6) R 4 -CONR 8 R 9 and where R 8 and R 9 each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10selected from the group consisting of cycloalkyl, C-C cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is 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 heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle, Item 5. The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, (Section 7) Item 7. The compound according to any one of Items 1 to 6, wherein X is N, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Section 8) X is CR 7 where R 7

[0023] Items 1 to 6, the compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl. (Section 9) A compound selected from the group consisting of the following compounds (1) to (295), or a pharmaceutically acceptable salt thereof, or a solvate thereof: (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]azetidine-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)azetidine-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-inden-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-trifluoropropan-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-trifluoropropan-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. (Section 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 thereof, or a solvate thereof. (Section 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. (Section 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 thereof, or a solvate thereof. (Section 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 thereof, or a solvate thereof. (Section 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 thereof, or a solvate thereof. (Section 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. (Section 16) 16. 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. (Section 17) 16. 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. (Section 18) 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. (Section 19) 16. A preventive or therapeutic agent for a disease involving DDR1 kinase, comprising the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (Section 20) Item 16. A therapeutic agent for treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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 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. (Section 21) A method for preventing or treating a disease involving 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. (Section 22) Item 16. A method for preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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 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. (Section 23) Item 16. The compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of a disease involving DDR1 kinase. (Section 24) Item 12. The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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. (Section 25) Use of the compound according to any one of items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for preventing or treating a disease involving DDR1 kinase. (Section 26) Item 16. Use of the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an agent for preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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.

[0014] The definitions of the terms used in this specification are explained in detail below.

[0015] 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.

[0016] As used herein, the term "alkyl" refers to, for example, a straight-chain or branched alkyl having 1 to 8 carbon atoms (C1-C8), preferably 1 to 6 carbon atoms (C1-C6). Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, isoamyl, -CH(CH2CH3)2, hexyl, isohexyl, -CH2CH2C(CH3)3, -CH2CH(CH2CH3)2, heptyl, isoheptyl, octyl, isooctyl, and the like.

[0017] As used herein, "alkenyl" includes, for example, straight-chain or branched-chain alkenyl 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, and 1-methyl-4-pentenyl. Alkenyl having 2 to 6 carbon atoms is preferred, and alkenyl having 2 to 4 carbon atoms is more preferred.

[0018] As used herein, "alkynyl" includes, for example, straight-chain or branched-chain alkynyl having 2 to 8 carbon atoms (C2-C8) and one or two triple bonds. 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, and 1-methyl-4-pentynyl. Alkynyl having 2 to 6 carbon atoms is preferred, and alkynyl having 2 to 4 carbon atoms is more preferred.

[0019] The alkyl moiety of "alkylcarbonyl," "monoalkylamino," "dialkylamino," and "aminoalkyl" used herein can be the same as the above-mentioned "alkyl."

[0020] As used herein, the term "haloalkyl" includes, for example, the above-mentioned "alkyl" in which one to three hydrogen atoms have been substituted with the above-mentioned "halogen". Specific examples include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl (e.g., 2,2-difluoroethyl), trifluoromethyl, trichloromethyl, trifluoroethyl (e.g., 2,2,2-trifluoroethyl), and the like.

[0021] As used herein, the term "alkoxy" includes, for example, straight-chain or branched-chain alkoxy having 1 to 8 carbon atoms (C1-C8), preferably 1 to 6 carbon atoms (C1-C6). Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, etc.

[0022] As used herein, "haloalkoxy" includes, for example, groups in which one to three hydrogen atoms of the above-mentioned "alkoxy" are substituted by the above-mentioned "halogen." Specific examples include fluoromethoxy, chloromethoxy, fluoroethoxy, difluoromethoxy, dichloromethoxy, difluoroethoxy (e.g., 2,2-difluoroethoxy), trifluoromethoxy, trichloromethoxy, trifluoroethoxy (e.g., 2,2,2-trifluoroethoxy), and the like.

[0023] As used herein, "cycloalkyl" refers to, for example, a cycloalkyl having 3 to 10 carbon atoms (C3-C 10) and a saturated monocyclic, bicyclic, or tricyclic hydrocarbon group having the formula (I). 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 (tricyclo[3.3.1.1 3,7 ] decanyl) and the like.

[0024] As used herein, "halocycloalkyl" includes, for example, the above-mentioned "cycloalkyl" in which one to three hydrogen atoms have been substituted with the above-mentioned "halogen." Specific examples include 2-fluorocyclopropyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopentyl, 4,4-difluorocyclohexyl, etc.

[0025] As used herein, the term "cycloalkenyl" refers to, for example, cycloalkenyl having 3 to 10 carbon atoms (C3-C 10 ) and includes a monocyclic, bicyclic, or tricyclic unsaturated hydrocarbon group having one or two double bonds in the molecule. Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

[0026] As used herein, "heterocycloalkyl" refers to a monocyclic or bicyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in the ring and 4 to 10 ring-constituting atoms. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrothiophenyl, etc.

[0027] As used herein, "aryl" refers to, for example, a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Phenyl is particularly preferred.

[0028] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in the ring and 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-triazolyl), and the like. 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, isoxazolyl, 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- Examples of the alkyl group include benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, and 7-benzimidazolyl, indazolyl (for example, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, and 7-indazolyl), and isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, and 8-isoquinolyl).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), and pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl).

[0029] "Carbocycle" means a ring structure composed of carbon atoms, and "carbocycle" includes the above-mentioned "cycloalkyl", "cycloalkenyl", and "aryl".

[0030] The term "heterocycle" refers to a cyclic structure composed of carbon atoms and one or more heteroatoms selected from, for example, a nitrogen atom, a sulfur atom, and an oxygen atom, and includes the above-mentioned "heterocycloalkyl" and "heteroaryl".

[0031] As used herein, the term "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 3 to 8 ring-constituting atoms. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azocanyl, 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, 1,2,4-triazol-6-yl, 1,2,4-triazol-7-yl, 1,2,4-triazol-8-yl, 1,2,4-triazol-9-yl, 1,2,4-triazol-10-yl, 1,2,4-triazol-11-yl, 1,2,4-triazol-12-yl, 1,2,4-triazol-13-yl, 1,2,4-triazol-14-yl, 1,2,4-triazol-15-yl, 1,2,4-triazol-16-yl, 1,2,4-triazol-17-yl, 1,2,4-triazol-18-yl, 1,2,4-triazol-19-yl, 1,2,4-triazol-20-yl, 1,2,4-triazol-21-yl, 1,2,4-triazol-22-yl, 1,2,4-tri 3-triazol-4-yl), tetrazolyl (e.g., 5-tetrazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), 1,2,3,6-tetrahydropyridyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), and the like.

[0032] As used herein, the term "5- to 10-membered monocyclic or bicyclic saturated heterocycle" refers to a monocyclic or bicyclic saturated heterocycle having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in the ring and having 5 to 10 ring-constituting atoms. Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, and tetrahydrothiophenyl.

[0033] As used herein, the term "5- to 10-membered monocyclic or bicyclic unsaturated heterocycle" refers to a monocyclic or bicyclic aromatic heterocycle or non-aromatic unsaturated heterocycle that has 1 to 4 heteroatoms selected from, for example, a nitrogen atom, a sulfur atom, and an oxygen atom in the ring and is composed of 5 to 10 constituent 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, 4-oxazolyl), 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), pyrazolo[5,1-b]thiazolyl, azaidazolyl (e.g., 3-azaiidazolyl, 4-azaiidazolyl, 5-azaiidazolyl, 6-azaiidazolyl, Examples of the alkyl group include 1-azaindazolyl, 7-azaindazolyl), benztriazolyl (e.g., 5-benztriazolyl, 6-benztriazolyl), azaindolyl (e.g., 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), and 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), imidazolyl, 7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), pyrazolo[5,1-b]thiazolyl, azaidazolyl (e.g., 3-azaindazolyl, 4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl), benztriazolyl (e.g., 5-benztriazolyl, 6-benztriazolyl), azaindolyl (e.g., 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl), pyridonyl (e.g., 2-pyridon-3-yl, 2-pyridon-4-yl, 2-pyridon-5-yl, 2-pyridon-6-yl).

[0034] "Cyano" refers to a group represented by -CN.

[0035] "Oxo" refers to a group represented by =O.

[0036] "Carbonyl" refers to a group represented by -(C=O)-.

[0037] "Hydroxy" refers to a group represented by -OH.

[0038] "Optionally substituted" means that the specified group may or may not be substituted, i.e., substituted or unsubstituted. For example, "optionally substituted alkyl" refers to both unsubstituted and substituted alkyl. Examples of substituents substituting the specified group include alkyl, haloalkyl, alkoxy, cycloalkyl, halocycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl, or heteroaryl, as defined above, and combinations thereof (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). The number of substituents substituting a specified group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.

[0039] In the compounds of formulas (I) to (III), preferred embodiments of each group represented by a symbol are shown below. Examples of the compounds of formulas (I) to (III) include all combinations of specific examples of each group shown below.

[0040] A is preferably [ka] (In the formula, Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CR 5 and Here, the Y 1 , Y 2 , Y 3 and Y 4 At most one of them is N, and the others are CR 5 and R5 is hydrogen, halogen (e.g., fluorine atom, chlorine atom), alkoxy (e.g., methoxy), or optionally substituted C1-C6 alkyl (e.g., methyl), (Dashed lines indicate attachment points) or [ka] (In the formula, 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 optionally substituted C1-C6 alkyl (e.g., methyl), (Dashed lines indicate attachment points) is. A is more preferably [ka] (In the formula, Y 1 , Y 2 , Y 3 and Y 4 is CR 5 and R 5 is hydrogen, (Dashed lines indicate attachment points) is.

[0041] 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-tetrahydropyridyl, which may be substituted with C1-C6 alkyl (e.g., methyl), and particularly preferably azetidinyl.

[0042] X is preferably N or CR 7 where R 7is preferably hydrogen, more preferably N.

[0043] R 1 are preferably each independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted. R 1 are more preferably 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 amino is optionally substituted by cycloalkyl (e.g., cyclopropyl, cyclobutyl, 1-methylcyclopropyl) or heterocycloalkyl (e.g., oxetanyl, tetrahydropyranyl), and wherein C1-C6 alkyl is optionally substituted by 1 to 3 halogens (e.g., fluorine atoms). R 1 More preferably, each independently is hydrogen, halogen (for example, a fluorine atom), or amino.

[0044] R 2 and R 3 are preferably each independently hydrogen or halogen (for example, a fluorine atom).

[0045] R 4 is preferably hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10It is selected from the group consisting of cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted. R 4 is more preferably selected from the group consisting of C2-C6 alkynyl (e.g., ethynyl), carboxy, 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); where: (1) C2-C6 alkynyl is C3-C 10 optionally substituted with cycloalkyl (e.g., cyclopropyl) or aryl (e.g., phenyl); (2) carboxy may be substituted with C1-C6 alkyl (e.g., tert-butyl); (3) The monocyclic or bicyclic saturated carbocyclic ring may be substituted with a halogen (e.g., a fluorine atom); (4) the monocyclic or bicyclic unsaturated carbocyclic ring may be substituted with haloalkyl (e.g., trifluoromethyl); (5) The monocyclic or bicyclic saturated heterocycle may be substituted with aryl (e.g., phenyl) or haloalkyl (e.g., 2,2,2-trifluoroethyl), and The monocyclic or bicyclic unsaturated heterocycle may be substituted with a substituent selected from the following group: (i) haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), (ii) C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl) substituted with haloalkyl (e.g., trifluoromethyl); (iii) heterocycloalkyl (e.g., tetrahydropyranyl), (iv) aryl (e.g., phenyl) optionally substituted with halogen (e.g., fluorine atom) or haloalkyl (e.g., trifluoromethyl); (v) heteroaryl (e.g., pyridyl, pyridazinyl) optionally substituted with halogen (e.g., fluorine atom) or C1-C6 alkyl (e.g., methyl), and (vi) halocycloalkyl (e.g., 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl), aryl (e.g., phenyl), C3-C 10 C1-C6 alkyl (eg, methyl) optionally substituted with cycloalkyl (eg, cyclopropyl) or heterocycloalkyl (eg, oxetanyl).

[0046] Also, R 4 is preferably -CONR 8 R 9 and where R 8 and R 9 each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 selected from the group consisting of cycloalkyl, C-C cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is 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 heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle, It is something. More preferably, R 8 and R 9 each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, and heteroaryl, each of which is optionally substituted; Here, more preferably, (1) C1-C6 alkyl is, for example, methyl, ethyl, isopropyl, tert-butyl, and may be substituted with a substituent selected from the following group: (i) halogen (e.g., fluorine atom); (ii) C1-C6 alkoxy (e.g., methoxy), (iii) haloalkoxy (e.g., trifluoromethoxy), (iv) heterocycloalkyl (e.g., tetrahydropyranyl, morpholinyl) (v) halocycloalkyl (e.g., 3,3-difluorocyclobutyl), and (vi) aryl (e.g., phenyl) optionally substituted with halogen (e.g., fluorine atom); (2) C3-C6 cycloalkyl is in particular cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted with halogen (e.g., fluorine atom), cyano; (3) Heterocycloalkyl is, for example, oxetanyl, tetrahydropyranyl, and may be substituted with, and (4) Heteroaryl is, for example, pyrazolyl, which may be substituted with a halogen (for example, a fluorine atom). Also, R 8 and R 9 preferably, together with the atoms to which they are attached, form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle; Here, more preferably, (1) The 5- to 10-membered monocyclic or bicyclic saturated heterocycle is, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo[3.1.0]hexanyl, azaspiro[3.4]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or azabicyclo[3.2.1]octanyl, which may be substituted with a substituent selected from the following group: (i) Halogen (e.g., fluorine atom, bromine atom) (ii) C1-C6 alkyl (e.g., methyl, ethyl, isopropyl) optionally substituted with a hydroxy group, C1-C6 alkoxy (e.g., methoxy), haloalkoxy (e.g., trifluoromethoxy), or heterocycloalkyl (e.g., morpholinyl); (iii) C1-C6 alkoxy (e.g., methoxy), (iv) haloalkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), (v) C3-C6 cycloalkyl (e.g., cyclopropyl), (vi) haloalkoxy (e.g., difluoromethoxy), and (vii) cyano; and (2) 5- to 10-membered monocyclic or bicyclic unsaturated heterocycles include, for example, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, and 2,3-dihydro-1H-indolyl. is.

[0047] Particularly preferably, R 4 -CONR 8 R 9 where R 8 and R 9 are taken together with the atoms to which they are attached to form a 5-membered monocyclic saturated heterocycle (eg, pyrrolidinyl) substituted with haloalkyl (eg, trifluoromethyl).

[0048] m is preferably an integer of 0 to 2, and more preferably an integer of 2.

[0049] n is preferably an integer of 0 to 1, and more preferably an integer of 1.

[0050] 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, or 1H-1,2,3-benzotriazolyl, and even more preferably pyridyl. DETAILED DESCRIPTION OF THE INVENTION

[0051] The compound of the present invention can be produced using known compounds or intermediates that can be easily synthesized from known compounds, for example, by the methods described below, the Examples described below, or known methods. In producing the compound of the present invention, if the raw material has a substituent that affects the reaction, it is common to first protect the raw material with an appropriate protecting group by a known method before carrying out the reaction. The protecting group can be deprotected by a known method after the reaction.

[0052] The abbreviations used in this specification have the following meanings. The following abbreviations are used in the examples: TFA: Trifluoroacetic acid AZADOL®: 2-azaadamantane-N-hydroxyl Pd-C: Palladium-carbon PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2: Palladium(II) acetate Pd(dppf)Cl2·CH2Cl2:[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc: tert-butoxycarbonyl HATU:O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI·HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride HOBt: 1-hydroxybenzotriazole THF: tetrahydrofuran DMF: dimethylformamide DMA: Dimethylacetamide DMSO: dimethyl sulfoxide NMP: N-methylpyrrolidone DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine NMM: 4-methylmorpholine DAST: (Diethylamino)sulfur trifluoride MS: Mass spectrometry LCMS: High-performance liquid chromatography mass spectrometry ESI: Electrospray Ionization M: Molar concentration (mol / L)

[0053] Unless otherwise specified, the reactions in each step in the following production methods are carried out by known methods, such as those described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition" by R.C. Larock, John Wiley & Sons Inc., 1999; "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 4th Edition, Maruzen, 1992; "Organic Synthesis Strategies Learned from Named Reactions" by L. Kuerti and B. Czako, translated and supervised by Kiyoshi Tomioka, Kagaku Dojin, 2006; and "Latest Organic Synthesis Methods: Design and Strategy" by G.S. Zweifel and M.H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009, or methods described in the Examples, which may be modified or combined as appropriate.

[0054] Synthesis of compound (G-1) [ka] (Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 and B has the same meaning as above. 1 represents a protecting group, such as tert-butoxycarbonyl (hereinafter referred to as "Boc"), benzyloxycarbonyl (hereinafter referred to as "Cbz"), benzyl (hereinafter referred to as "Bn"), etc. 1 represents chloro, bromo, and triflate.)

[0055] Step 1 This step is a step of obtaining compound C-1 by reacting compound A-1, which is commercially available or synthesized by a known method, with compound B-1, which is commercially available or synthesized by a known method, 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. LDA may be commercially available or prepared from diisopropylamine and n-butyllithium (n-BuLi).

[0056] Step 2 This step is a reaction in which the hydroxyl group of compound C-1 is oxidized to obtain D-1. This reaction can be carried out using 2-azaadamantane-N-oxyl (AZADOL registered trademark), 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), Dess-Martin reagent, or the like, 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 synthesize D-1. In reactions using AZADOL or TEMPO, iodobenzene diacetate, sodium hypochlorite (NaOCl), etc. are usually used as co-oxidants.

[0057] Step 3 This step is a step of reacting compound D-1 with hydrazine monohydrate in a solvent such as dioxane or THF at room temperature to reflux temperature, preferably dioxane, at 100°C for 1 hour to 48 hours, preferably 8 hours to 24 hours, to obtain Ea-1.

[0058] Step 4 This step is a step in which compound Ea-1 is alkylated with alkylating agent F-1 in the presence of a base to obtain compound G-1, and can be carried out in accordance with a known method for alkylation reaction. The reaction can be obtained by reacting compound Ea-1 with alkylating agent F-1 in a solvent such as dimethylformamide or tetrahydrofuran in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, or cesium carbonate at 0°C to 120°C, preferably room temperature to 120°C, for 1 hour to 48 hours, preferably 1 hour to 12 hours.

[0059] The above C-1 and D-1 can also be produced by the following method. [ka] (Y 1 , Y 2 , Y 3 , Y 4 , B., P.G. 1 has the same meaning as above. X 2 represents Br, I.)

[0060] Route 1 This step is a step of obtaining compound C-1 by reacting compound A-2, which is commercially available or synthesized by a known method, with B-1 in the presence of butyllithium (n-BuLi) 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.

[0061] Route 2 This step is a step of obtaining compound D-1 by reacting compound A-1, which is commercially available or synthesized by a known method, with compound B-2, which is commercially available or synthesized by a known method, in the presence of butyllithium (n-BuLi) 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.

[0062] Synthesis of compound (G-2) [ka] (A, R 1 , R 2 , R 3 , R 4 , B, X 1 , P.G. 1 has the same meaning as above. X 3 represents I, Cl, Br)

[0063] Step 1 In this step, compound H-1, which is commercially available or synthesized by a known method, is halogenated to obtain J-1. The halogenation can be carried out by a reaction commonly used for halogenating aromatic rings. Compound H-1 is added with chlorine, bromine, iodine, N-chlorosuccinimide (NCS), or N-bromosuccinimide (NBS) in a solvent such as dichloromethane, dichloroethane, carbon tetrachloride, or DMF, and the reaction is carried out at 0°C to room temperature for 30 minutes to 48 hours, preferably 1 hour to 12 hours, to obtain compound J-1.

[0064] Step 2 In this step, compound J-1 is alkylated using alkylating agent F-1 in the presence of a base to obtain compound K-1. K-1 can be obtained by carrying out the reaction under the same conditions as in Step 4 in the synthesis of compound (G-1) above.

[0065] Step 3 This step is a step of obtaining compound G-2 by Negishi coupling reaction between compound K-1 and L-1. In this reaction, compound K-1 is added to a solvent such as dioxane, toluene, DMSO, DMF, DME, DMA, or THF in a palladium catalyst such as tetrakistriphenylphosphine 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"), or [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf)2Cl2"), and L-1, either commercially available or synthesized by a known method, and the reaction is carried out under a nitrogen or 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.

[0066] Synthesis of Compound (I) [ka] (A, B, R 1 , R 2 , R 3 , R 4 ,Het,m,PG 1 has the same meaning as above.)

[0067] Step 1 This step is a step of deprotecting the protecting group of compound G-2 to obtain M-1, and can be introduced by referring to "Greene's Protective Groups in Organic Synthesis" by Wuts and Greene, 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups" by PJ Kocienski, 3rd Edition, Thiemes, 2005.

[0068] Step 2 This step is a step of obtaining compound (I) by condensing compound M-1 with compound N-1 or a reactive compound thereof N-1 in the presence of a condensing agent. In this reaction, compound M-1, compound N-1, an organic base such as TEA, DIPEA, N,N-dimethylaniline, or DBU, 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 hexafluorophosphate (hereinafter referred to as "HBTU"), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Compound (I) can be obtained by carrying out the reaction in the presence of a condensing agent such as hexafluorophosphate (hereinafter referred to as "HATU") at 0°C to 50°C, preferably room temperature to 50°C. In this step, reactive compounds for compound N-1 include those typically used in amide condensation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and activated amides. In this step, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt"), etc. may be added as needed.

[0069] Synthesis of compound (I-2) (R 4 -CONR 8 R 9 in the case of) [ka] (A, B, PG 1 , R 1 ,Het,R 8 , R9 , m has the same meaning as above. A represents methyl, ethyl, n-propyl, and t-butyl)

[0070] Step 1 This step involves deprotecting the protecting group of compound G-2 to obtain M-2, which can be synthesized 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, Thiemes, 2005.

[0071] Step 2 This step is a step of obtaining compound O-2 by condensing compound M-2 with compound N-1 or a reactive compound thereof in the presence of a condensing agent, and can be synthesized by a method similar to Step 2 in the synthesis of compound (I) above.

[0072] Step 3 This step is to remove the protecting group (PG 2 ) to obtain P-2, which can be synthesized 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, Thiemes, 2005.

[0073] Step 4 This step is a step of obtaining compound I-2 by condensing compound Q-1 with compound P-2 or a reactive compound thereof in the presence of a condensing agent, and can be synthesized by a method similar to Step 2 in the synthesis of compound (I) above.

[0074] In addition, in the synthesis of I-2 above, compound I-2 can also be obtained by switching the order of Step 1-Step 2 and Step 3-Step 4. That is, R A The carboxylic acid obtained by deprotection (hydrolysis) is condensed with Q-1. Subsequently, the amine obtained by deprotection of PG1 is condensed with N-1 to synthesize I-2.

[0075] The compound of the present invention can be used as a pharmaceutical directly, or can be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt by a known method. Examples of pharmaceutically acceptable salts include salts of mineral 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; 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 conventional methods.

[0076] For example, when the compound of the present invention is a hydrochloride salt, the free base of the compound of the present invention can be obtained by dissolving it in hydrochloric acid, an alcoholic solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.

[0077] The compound of the present invention may take up solvent molecules to form a solvate when left in the air or when recrystallized, and such solvates are also included in the compound of the present invention. Examples of such solvates include solvates with solvent molecules such as methanol solvate, ethanol solvate, isopropyl alcohol solvate, butanol solvate, dimethyl sulfoxide solvate, and acetonitrile solvate, as well as monohydrates and dihydrates.

[0078] Some of the compounds of the present invention have asymmetric carbon atoms, and both optical isomers and mixtures thereof are included in the present invention. Stereoisomers can be produced, for example, by optical resolution of a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by known methods, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, stereoisomers can be produced by optical resolution using a chiral column or asymmetric synthesis.

[0079] As shown in the test examples below, the compound of the present invention has DDR1 kinase inhibitory activity.

[0080] Therefore, one embodiment of the present invention provides a DDR1 kinase inhibitor comprising a compound of the present invention.

[0081] Furthermore, in one embodiment of the present invention, there is provided a method of inhibiting DDR1 kinase, comprising administering a compound of the present invention to a subject in need thereof.

[0082] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention for use in inhibiting DDR1 kinase.

[0083] Furthermore, one embodiment of the present invention provides use of a compound of the present invention in the manufacture of a DDR1 kinase inhibitor.

[0084] One embodiment of the present invention provides a preventive or therapeutic agent for a disease involving DDR1 kinase, which comprises the compound of the present invention.

[0085] Furthermore, one embodiment of the present invention provides a method for preventing or treating a disease associated with DDR1 kinase, which comprises administering the compound of the present invention to a subject in need thereof.

[0086] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention for use in the prevention or treatment of a disease in which DDR1 kinase is involved.

[0087] Furthermore, one embodiment of the present invention provides use of the compound of the present invention in the manufacture of an agent for the prophylaxis or treatment of a disease involving DDR1 kinase.

[0088] Examples of diseases to which the compound of the present invention can be applied include Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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, and osteoarthritis.

[0089] Therefore, one embodiment of the present invention provides a preventive or therapeutic agent for the above-mentioned diseases, which contains the compound of the present invention.

[0090] Furthermore, 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.

[0091] Furthermore, in one embodiment of the present invention, there is provided a compound of the present invention for use in the prevention or treatment of the above-mentioned diseases.

[0092] Furthermore, one embodiment of the present invention provides use of the compound of the present invention in the manufacture of an agent for the prophylaxis or treatment of the above-mentioned diseases.

[0093] "Subject" refers to a human or non-human animal having or suspected of having a disease involving DDR1 or a disease involving DDR1. In one embodiment of the present invention, the subject is a mammal. In one embodiment of the present invention, the subject is a human.

[0094] The compound of the present invention can be used as a therapeutic agent for the above-mentioned various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys, either as such or by mixing with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.

[0095] The carrier may be one or more conventional pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. The pharmaceutical composition of the present invention is administered in a dosage form suitable for these administration methods.

[0096] The pharmaceutical dosage is preferably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether it is a salt, and the type of salt. However, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult, when administered orally, is usually within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Usually, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a rapid administration or continuously for up to 24 hours.

[0097] The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II A T1 receptor blockers (ARBs). Examples of ARBs include candesartan, losartan, valsartan, olmesartan, azilsartan, irbesartan, and telmisartan. Examples of ACE inhibitors include ramipril, lisinopril, enalapril, imidapril, and trandolapril.

[0098] One or more hydrogen, carbon, and / or other atoms of the compounds of the present invention may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes include 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I, and 36Cl, i.e., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Compounds substituted with such isotopes are also useful as pharmaceuticals, and include all radiolabeled compounds of the compounds of the present invention.

[0099] The compounds of the present invention can be produced from known compounds or intermediates that can be easily prepared from known compounds, for example, by the following methods, the Examples described below, or known methods.

[0100] When the solvents, reagents, and raw materials used in each step in the following production methods are commercially available, the commercially available products can be used as they are. Furthermore, the compounds obtained in each step in the production methods described below and the raw materials used may form salts, which can be converted into other types of salts or free forms by known methods. Conversely, when the compounds obtained in each step in the following production methods and the raw materials used are in free forms, they can be converted into the desired salts by known methods. Examples of such salts include the same salts as those used for the compounds of the present invention described above.

[0101] In the production of the compound of the present invention, when the raw material has a substituent that may affect the reaction, a protecting group may be introduced into the substituent in advance by a known method, and the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of such a protecting group include those described in Wuts and Greene, "Greene's Protective Groups in Organic Synthesis," 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups," 3rd Edition, Thieme, 2005, and the like, and these may be appropriately selected and used depending on the reaction conditions.

[0102] The compounds obtained in each step of the following production methods can be isolated or purified in accordance with conventional methods, such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or can be used in the next step in the form of a reaction mixture or a crude product.

[0103] The present invention will be explained in more detail below by way of Reference Examples, Examples, and Test Examples, but the present invention is not limited to these examples alone.

[0104] MS was measured by LCMS. ESI was used as the ionization method. The observed mass spectrometry values ​​are expressed as m / z.

[0105] The LCMS measurement conditions are as follows. Analytical equipment: ACQUITY UPLC MS / PDA system (Waters) Mass spectrometer: ACQUITY QDa detector or Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210-400 nm) Column: Acquity BEH C18, 1.7 μm, 2.1 × 50 mm Flow rate: 0.5mL / min Column temperature: 40℃ solvent; Solution A: 0.1% formic acid / H2O (v / v; hereinafter the same) Solution B: 0.1% formic acid / acetonitrile

[0106] 1 H-NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.). The observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0107] For microwave experiments, an Initiator 60 (Biotage) was used, which can achieve temperatures of 40-250°C and pressures up to 20 bar.

[0108] The conditions for measuring the optical rotation are as follows. Analytical equipment: Automatic polarimeter SEPA-500 (Horiba, Ltd.)

[0109] The compound names in this specification were created using ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), a naming software that complies with IUPAC rules, or ChemBioDraw (version 18.2, 19.1, or 20.1.1, Cambridge Soft), or were named according to the IUPAC nomenclature.

[0110] The r and s (lower case) in the compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.

[0111] Reference Example 1 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound RE-1) [ka] [Step 1] Preparation of intermediate RE-1A [ka] To 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 the mixture was stirred at -78°C for 3 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.65 g).

[0112] [Step 2] Preparation of intermediate RE-1B [ka] To a mixture of intermediate RE-1A (3.23 g) and dichloromethane (48 mL), iodobenzene diacetate (3.74 g) and AZADOL (registered trademark) (74 mg) were added sequentially, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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] +

[0113] [Step 3] Preparation of intermediate RE-1C [ka] 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 mixture, 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 evaporated 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] -

[0114] [Step 4] Preparation of intermediate RE-1D [ka] To a mixture of intermediate RE-1C (1.47 g) and DMF (23 mL), cesium carbonate (1.76 g) and ethyl 2-bromoacetate (0.600 mL) were added in an ice bath, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.76 g). MS (m / z): 412.3 [M+H] +

[0115] [Step 5] Preparation of intermediate RE-1E [ka] To a mixture of intermediate RE-1D (1.75 g), methanol (8.5 mL), and THF (8.5 mL), 2 M aqueous sodium hydroxide solution (10.6 mL) was added at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, and acidified with 2 M hydrochloric acid in an ice bath. The precipitate was collected by filtration to give the title compound (1.56 g). MS (m / z): 382.4 [MH] -

[0116] [Step 6] Preparation of intermediate RE-1F [ka] To a mixture of intermediate RE-1E (800 mg), DMF (6.9 mL), DIPEA (1.1 mL), and 2,2,2-trifluoroethanamine hydrochloride (367 mg), HATU (1.03 g) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (900 mg). MS (m / z): 463.4 [MH] -

[0117] [Step 7] Preparation of compound RE-1 To a mixture of intermediate RE-1F (78 mg) and methanol (1 mL), hydrogen chloride (2 M methanol solution, 1 mL) was added and stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (72 mg). MS (m / z): 365.5 [M+H] +

[0118] Reference Example 2 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound RE-2) [ka] [Step 1] Preparation of intermediate RE-2A [ka] The title compound (9.74 g) was obtained by a method similar to that of Step 1 of Reference Example 1, except that 1,3,5-trifluorobenzene (7.49 g) was used instead of 2-chloro-1,4-difluorobenzene.

[0119] [Step 2] Preparation of intermediate RE-2B [ka] The title compound (9.49 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-2A (9.74 g) was used instead of intermediate RE-1A.

[0120] [Step 3] Preparation of intermediate RE-2C [ka] The title compound (8.25 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-2B (9.49 g) was used instead of intermediate RE-1B. MS (m / z): 308.3 [MH] -

[0121] [Step 4] Preparation of intermediate RE-2D [ka] The title compound (6.2 g) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-2C (5.0 g) was used instead of intermediate RE-1C. MS (m / z): 296.0 [M-Boc+2H] +

[0122] [Step 5] Preparation of intermediate RE-2E [ka] The title compound (1.89 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-2D (2.23 g) was used instead of intermediate RE-1D. MS (m / z): 366.4 [MH] -

[0123] [Step 6] Preparation of intermediate RE-2F [ka] The procedure of Step 6 of Reference Example 1 was repeated, except that Intermediate RE-2E (1.04 g) was used instead of Intermediate RE-1E, and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (596 mg) was used instead of 2,2,2-trifluoroethanamine hydrochloride, to give the title compound (1.32 g). MS (m / z): 511.2 [M+Na] +

[0124] [Step 7] Preparation of compound RE-2 The title compound (117 mg) was obtained by a method similar to Step 7 of Reference Example 1, except that intermediate RE-2F (125 mg) was used instead of intermediate RE-1F. MS (m / z): 389.1 [M+H] +

[0125] Reference Example 3 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-3) [ka] To a mixture of intermediate RE-2F (100 mg) and dichloromethane (1 mL), trifluoroacetic acid (0.25 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the title compound (103 mg). MS (m / z): 389.1 [M+H] +

[0126] Reference Example 4 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-4) [ka] [Step 1] Preparation of intermediate RE-4A [ka] To a mixture of 3-iodo-2H-indazole (9.11 g) and DMF (75 mL), cesium carbonate (14.6 g) and methyl 2-bromoacetate (4.24 mL) were added in an ice bath. The mixture was stirred for 30 minutes in an ice bath and then at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 (12.69 g). MS (m / z): 317.0 [M+H] +

[0127] [Step 2] Preparation of intermediate RE-4B [ka] A reaction vessel containing zinc (3.62 g) was heated under reduced pressure using a heat gun for 3 minutes and then purged with argon. After returning to room temperature, DMA (40 mL) was added. After degassing with argon, 1,2-dibromoethane (0.341 mL) and chloro(trimethyl)silane (0.602 mL) were added and stirred at room temperature for 15 minutes. To this mixture, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.2 g) in DMA (40 mL) was added dropwise using a dropping funnel. The mixture was stirred at room temperature for 1 hour to prepare a solution of [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc(II) iodide in DMA. Next, a mixture of intermediate RE-4A (5.00 g) and DMA (16 mL) was degassed with argon and then Pd(dppf)Cl₂·CHCl₂ (1.29 g) and copper(I) iodide (392 mg) were added. The previously prepared [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc(II) iodide solution in DMA was added at room temperature and stirred at 85°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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] +

[0128] [Step 3] Preparation of intermediate RE-4C [ka] The title compound (4.99 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-4B (5.08 g) was used instead of intermediate RE-1D. MS (m / z): 330.4 [MH] -

[0129] [Step 4] Preparation of intermediate RE-4D [ka] 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), HBTU (206 mg) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (200 mg). MS (m / z): 353.1 [M-Boc+2H] +

[0130] [Step 5] Preparation of compound RE-4 To a mixture of intermediate RE-4D (200 mg) and dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the title compound (211 mg). MS (m / z): 353.1 [M+H] +

[0131] Reference Example 5 2-[3-(azetidin-3-yl)-5-chloro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (Compound RE-5) [ka] [Step 1] Preparation of intermediate RE-5A [ka] To a mixture of 2-bromo-4-chloro-1-fluorobenzene (2.57 g) and THF (20 mL), n-butyllithium (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) (synthesized, for example, according to the method described in WO20129649) in THF (20 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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]+

[0132] [Step 2] Preparation of intermediate RE-5B TIFF0007823226000036.tif44169 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 mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (635 mg). MS (m / z): 208.0 [M-Boc+2H] +

[0133] [Step 3] Preparation of intermediate RE-5C [ka] The procedure of Step 1 of Reference Example 4 was repeated except that intermediate RE-5B (200 mg) was used instead of 3-iodo-2H-indazole to give the title compound (246 mg). MS (m / z): 402.3 [M+Na] +

[0134] [Step 4] Preparation of intermediate RE-5D The title compound (184 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-5C (246 mg) was used instead of intermediate RE-1D. MS (m / z): 364.3 [MH] -

[0135] [Step 5] Preparation of intermediate RE-5E [ka] 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-methylethanamine hydrochloride (49 mg), EDCI·HCl (63 mg) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure to give the title compound (123 mg). MS (m / z): 483.2 [M+Na] +

[0136] [Step 6] Preparation of compound RE-5 The title compound (127 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-5E (123 mg) was used instead of intermediate RE-2F. MS (m / z): 361.2 [M+H] +

[0137] Reference Example 6 2-[3-(azetidin-3-yl)-6-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (Compound RE-6) [ka] [Step 1] Preparation of intermediate RE-6A [ka] To a mixture of 6-fluoro-3-iodo-1H-indazole (897 mg, synthesized, for example, according to the method described in Bioorganic Med. Chem. Lett., 2010, 20, 6998-7003) and DMF (7 mL), cesium carbonate (1.34 g) and methyl 2-bromoacetate (0.39 mL) were added sequentially in an ice bath. The mixture was stirred for 10 minutes in an ice bath and then stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.17 g). MS (m / z): 335.0 [M+H] +

[0138] [Step 2] Preparation of intermediate RE-6B [ka] A reaction vessel containing zinc (481 mg) was heated under reduced pressure using a heat gun for 5 minutes and purged with argon. After returning to room temperature, DMA (5.25 mL) was added. After degassing with argon, 1,2-dibromoethane (0.045 mL) and chloro(trimethyl)silane (0.080 mL) were added and stirred at room temperature for 15 minutes. To this mixture, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.49 g) in DMA (5.25 mL) was added dropwise using a dropping funnel. The mixture was stirred at room temperature for 1 hour to prepare a solution of [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc(II) iodide in DMA. Next, a mixture of intermediate RE-6A (1.17 g) and DMA (3.5 mL) was degassed with argon and then Pd(dppf)Cl₂·CHCl₂ (286 mg) and copper(I) iodide (87 mg) were added. The previously prepared [1-(tert-butoxycarbonyl)azetidin-3-yl]zinc(II) iodide solution in DMA was added at room temperature and stirred at 85°C for 1 hour. Water was added to the reaction mixture, which was then 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] +

[0139] [Step 3] Preparation of intermediate RE-6C [ka] To a mixture of intermediate RE-6B (1.54 g), methanol (6 mL), and THF (6 mL), 2 M aqueous sodium hydroxide solution (6.36 mL) was added at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, filtered, and acidified with 2 M hydrochloric acid in an ice bath. The precipitate was collected by filtration to give the title compound (1.03 g). MS (m / z): 348.2 [MH] -

[0140] [Step 4] Preparation of intermediate RE-6D [ka] 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-methylethanamine hydrochloride (180 mg), EDCI·HCl (231 mg) was added and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography to give the title compound (318 mg). MS (m / z): 467.3 [M+Na] +

[0141] [Step 5] Preparation of compound RE-6 The title compound (285 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-6D (318 mg) was used instead of intermediate RE-2F. MS (m / z): 345.2 [M+H] +

[0142] Reference Example 7 2-[3-(3-methylazetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-7) [ka] [Step 1] Preparation of intermediate RE-7A [ka] 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), EDCI·HCl (1.13 g) was added and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate. Subsequently, in accordance with a method similar to that of Step 1 of Reference Example 5, 1-fluoro-2-iodobenzene (1.16 g) was used instead of 2-bromo-4-chloro-1-fluorobenzene, and tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate obtained above was used instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate to obtain the title compound (688 mg). MS (m / z): 194.2 [M-Boc+2H] +

[0143] [Step 2] Preparation of intermediate RE-7B [ka] 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 reactor at 150°C for 3 hours. After cooling, saturated aqueous ammonium chloride was added to the reaction mixture, which was then 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-(1H-indazol-3-yl)-3-methylazetidine-1-carboxylate. Subsequently, the same procedure as in Step 1 of Reference Example 4 was repeated except that the above tert-butyl 3-(1H-indazol-3-yl)-3-methylazetidine-1-carboxylate was used instead of 3-iodo-2H-indazole to give the title compound (629 mg). MS (m / z): 260.3 [M-Boc+2H] +

[0144] [Step 3] Preparation of intermediate RE-7C [ka] The title compound (466 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-7B (629 mg) was used instead of intermediate RE-1D. MS (m / z): 344.3 [M−H] -

[0145] [Step 4] Preparation of intermediate RE-7D [ka] 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), HBTU (132 mg) was added and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The reaction mixture was purified by silica gel column chromatography to give the title compound (108 mg). MS (m / z): 489.4 [M+Na] +

[0146] [Step 5] Preparation of compound RE-7 The title compound (111 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-7D (108 mg) was used instead of intermediate RE-2F. MS (m / z): 367.3 [M+H] +

[0147] 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) [ka] [Step 1] Preparation of intermediate RE-8A [ka] The procedure of Step 4 of Reference Example 7 was repeated, except that intermediate RE-4C (100 mg) was used instead of intermediate RE-7C, and 3,3-dimethylmorpholine (45 mg) was used instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride, to give the title compound (100 mg). MS (m / z): 329.2 [M-Boc+2H] +

[0148] [Step 2] Preparation of compound RE-8 The title compound (96 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-8A (100 mg) was used instead of intermediate RE-2F. MS (m / z): 329.2 [M+H] +

[0149] Reference Example 9 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one trifluoroacetate (Compound RE-9) [ka] [Step 1] Preparation of intermediate RE-9A [ka] The procedure of Step 4 of Reference Example 7 was repeated, except that 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 give the title compound (135 mg). MS (m / z): 369.1 [M-Boc+2H] +

[0150] [Step 2] Preparation of compound RE-9 The title compound (145 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-9A (135 mg) was used instead of intermediate RE-2F. MS (m / z): 369.1 [M+H] +

[0151] Reference Example 10 4-fluoro-3-(piperidin-4-yl)-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazole trifluoroacetate (Compound RE-10) [ka] [Step 1] Preparation of intermediate RE-10A [ka] The procedure of Step 1 of Reference Example 1 was repeated, except that 1,3-difluorobenzene (2.41 g) was used instead of 2-chloro-1,4-difluorobenzene, and tert-butyl-4-formylpiperidine-1-carboxylate (3.00 g) was used instead of tert-butyl 3-formylazetidine-1-carboxylate, to give the title compound (3.98 g).

[0152] [Step 2] Preparation of intermediate RE-10B [ka] The title compound (3.48 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that Intermediate RE-10A (3.98 g) was used instead of Intermediate RE-1A.

[0153] [Step 3] Preparation of intermediate RE-10C [ka] The title compound (3.31 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-10B (3.48 g) was used instead of intermediate RE-1B. MS (m / z): 318.3 [MH] -

[0154] [Step 4] Preparation of intermediate RE-10D TIFF0007823226000058.tif41167 Cesium carbonate (77 mg) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (56 mg) were added sequentially to a mixture of intermediate RE-10C (50 mg) and acetonitrile (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (34 mg). MS (m / z): 379.1 [M-Boc+2H]+

[0155] [Step 5] Preparation of compound RE-10 The title compound (35 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-10D (34 mg) was used instead of intermediate RE-2F. MS (m / z): 379.2 [M+H] +

[0156] 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) [ka] [Step 1] Preparation of intermediate RE-11A [ka] 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 mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography to give the title compound (660 mg). MS (m / z): 317.1 [M+H] +

[0157] [Step 2] Preparation of intermediate RE-11B [ka] Intermediate RE-11A (500 mg), methanol (53 mL), and ammonium formate (1.30 g) were mixed with 10% Pd-C (21 mg) and stirred at 80° C. overnight. Insoluble matter was filtered off through Celite® filtration, and the residue was concentrated under reduced pressure to give the title compound (400 mg). MS (m / z): 219.2 [M-Boc+2H] +

[0158] [Step 3] Preparation of intermediate RE-11C [ka] The title compound (450 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-11B (480 mg) was used instead of intermediate RE-1C. MS (m / z): 305.2 [M-Boc+2H] +

[0159] [Step 4] Preparation of intermediate RE-11D [ka] The title compound (350 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-11C (450 mg) was used instead of intermediate RE-1D. MS (m / z): 375.2 [M−H] -

[0160] [Step 5] Preparation of intermediate RE-11E [ka] 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. To this mixture, (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (56 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (120 mg). MS (m / z): 398.2 [M-Boc+2H] +

[0161] [Step 6] Preparation of compound RE-11 The title compound (85 mg) was obtained by a method similar to that of Step 7 of Reference Example 1, except that intermediate RE-11E (120 mg) was used instead of intermediate RE-1F. MS (m / z): 398.2 [M+H] +

[0162] Reference Example 12 tert-Butyl 3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indol-3-yl)azetidine-1-carboxylate (Compound RE-12) [ka] [Step 1] Preparation of intermediate RE-12A [ka] To a mixture of indole (1 g), potassium hydroxide (527 mg), and methanol (11 mL), tert-butyl 3-oxoazetidine-1-carboxylate (1.61 g) was added, and the mixture was stirred at 50°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (920 mg). MS (m / z): 287.2 [MH] -

[0163] [Step 2] Preparation of intermediate RE-12B [ka] To a mixture of intermediate RE-12A (920 mg) and dichloromethane (6.4 mL), triethylsilane (3.82 mL) was added in an ice bath, followed by slow addition of trifluoroacetic acid (0.811 mL), and the mixture was stirred in an ice bath for 10 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with dichloromethane and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography to give the title compound (370 mg). MS (m / z): 271.4 [MH] -

[0164] [Step 3] Preparation of intermediate RE-12C [ka] The title compound (400 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-12B (370 mg) was used instead of intermediate RE-1C. MS (m / z): 259.1 [M-Boc+2H] +

[0165] [Step 4] Preparation of intermediate RE-12D [ka] To a mixture of intermediate RE-12C (400 mg), methanol (10 mL), and THF (10 mL), 2M aqueous sodium hydroxide solution (2.79 mL) was added at room temperature and stirred for 2 hours. The reaction mixture 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 the mixture was purified by silica gel column chromatography to give the title compound (350 mg). MS (m / z): 329.1 [MH] -

[0166] [Step 5] Preparation of compound RE-12 The title compound (50 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-12D (50 mg) was used instead of intermediate RE-11D. MS (m / z): 352.1 [M-Boc+2H] +

[0167] Reference Example 13 tert-butyl 3-(5-methyl-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-13) [ka] [Step 1] Preparation of intermediate RE-13A [ka] The procedure of Step 1 of Reference Example 5 was repeated, except that 2-bromo-3-fluoro-6-methylpyridine (1.00 g) was used instead of 2-bromo-4-chloro-1-fluorobenzene, and tert-butyl 3-formylazetidine-1-carboxylate (1.17 g) was used instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate to give the title compound (608 mg). MS (m / z): 297.1 [M+H] +

[0168] [Step 2] Preparation of intermediate RE-13B [ka] To a mixture of intermediate RE-13A (608 mg) and dichloromethane (10 mL), iodobenzene diacetate (793 mg) and AZADOL® (16 mg) were added sequentially, and the mixture was stirred at room temperature for 2 hours. AZADOL® (16 mg) was added, and the mixture was further stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (542 mg). MS (m / z): 295.1 [M+H] +

[0169] [Step 3] Preparation of intermediate RE-13C [ka] The title compound (363 mg) was obtained by a method similar to that of Step 2 of Reference Example 5, except that intermediate RE-13B (542 mg) was used instead of intermediate RE-5A. MS (m / z): 289.2 [M+H] +

[0170] [Step 4] Preparation of intermediate RE-13D [ka] The title compound (359 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-13C (290 mg) was used instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0171] [Step 5] Preparation of intermediate RE-13E [ka] The title compound (187 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-13D (359 mg) was used instead of intermediate RE-1D. MS (m / z): 347.1 [M+H] +

[0172] [Step 6] Preparation of compound RE-13 The title compound (100 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-13E (90 mg) was used instead of intermediate RE-11D. MS (m / z): 468.3 [M+H] +

[0173] 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 2-trifluoroacetate (Compound RE-14) [ka] [Step 1] Preparation of intermediate RE-14A [ka] The title compound (1.62 g) was obtained by a method similar to that of Step 1 of Reference Example 1, except that 2-chloro-4-fluoropyridine (1.07 g) was used instead of 2-chloro-1,4-difluorobenzene.

[0174] [Step 2] Preparation of intermediate RE-14B [ka] The title compound (1.47 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-14A (1.62 g) was used instead of intermediate RE-1A.

[0175] [Step 3] Preparation of intermediate RE-14C TIFF0007823226000079.tif39169 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 mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.79 g). MS (m / z): 309.1 [M+H] +

[0176] [Step 4] Preparation of intermediate RE-14D [ka] The title compound (1.04 g) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-14C (0.79 g) was used instead of intermediate RE-1C. MS (m / z): 395.2 [M+H] +

[0177] [Step 5] Preparation of intermediate RE-14E [ka] Intermediate RE-14D (300 mg), ethyl acetate (7.6 mL), and triethylamine (0.21 mL) were mixed with 5% Pd-C (100 mg) and stirred overnight at room temperature under a hydrogen atmosphere (0.1 MPa). Insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (249 mg). MS (m / z): 361.2 [M+H] +

[0178] [Step 6] Preparation of intermediate RE-14F [ka] The title compound (210 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-14E (249 mg) was used instead of intermediate RE-1D. MS (m / z): 333.2 [M+H] +

[0179] [Step 7] Preparation of intermediate RE-14G [ka] The title compound (92 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-14F (100 mg) was used instead of intermediate RE-11D. MS (m / z): 454.3 [M+H] +

[0180] [Step 8] Preparation of compound RE-14 A brown oil was obtained by the same method as in Reference Example 3, except that intermediate RE-14G (92 mg) was used instead of intermediate RE-2F. 39 mg of the oil was purified by silica gel column chromatography to give the title compound (30 mg). MS (m / z): 354.1 [M+H] +

[0181] Reference Example 15 3-{[3-(azetidin-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole trifluoroacetate (Compound RE-15) [ka] [Step 1] Preparation of intermediate RE-15A [ka] The title compound (4.92 g) was obtained by a method similar to that of Step 1 of Reference Example 1, except that 3,5-difluoropyridine (2.80 g) was used instead of 2-chloro-1,4-difluorobenzene.

[0182] [Step 2] Preparation of intermediate RE-15B [ka] The title compound (4.64 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that Intermediate RE-15A (4.86 g) was used instead of Intermediate RE-1A.

[0183] [Step 3] Preparation of intermediate RE-15C [ka] 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 mixture, 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 evaporated 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] -

[0184] [Step 4] Preparation of intermediate RE-15D [ka] The procedure of Step 4 of Reference Example 10 was repeated, except that intermediate RE-15C (1.0 g) was used instead of intermediate RE-10C, and 2-chloroacetonitrile (0.323 mL) was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine, to give the title compound (1.22 g).

[0185] [Step 5] Preparation of intermediate RE-15E [ka] To a solution of potassium carbonate (0.95 g) in water (3.1 mL), hydroxylamine hydrochloride (0.48 g) and a solution of intermediate RE-15D (1.22 g) in ethanol (11.4 mL) were added, and the mixture was stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, the residue was suspended in ethyl acetate and filtered through Celite (registered trademark), and insoluble matter was removed by filtration. 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] +

[0186] [Step 6] Preparation of intermediate RE-15F [ka] 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), HATU (41 mg) was added and the mixture was stirred at room temperature overnight. The mixture was then stirred at 120°C for 2 hours. After cooling, the reaction mixture was purified by silica gel column chromatography to give the title compound (27 mg). MS (m / z): 483.2 [M+H] +

[0187] [Step 7] Preparation of compound RE-15 The title compound (28 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-15F (27 mg) was used instead of intermediate RE-2F. MS (m / z): 383.1 [M+H] +

[0188] 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 2-trifluoroacetate (Compound RE-16) [ka] [Step 1] Preparation of intermediate RE-16A [ka] The procedure of Reference Example 5, Step 1, was repeated except that 2-bromo-4-chloro-1-fluorobenzene was replaced with 3-bromo-2-fluoromethylpyridine (0.63 g), and tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate was replaced with tert-butyl 3-formylazetidine-1-carboxylate (0.74 g), to give the title compound (0.57 g). MS (m / z): 197.1 [M-Boc+2H] +

[0189] [Step 2] Preparation of intermediate RE-16B [ka] The title compound (241 mg) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-16A (0.57 g) was used instead of intermediate RE-1A. MS (m / z): 195.0 [M-Boc+2H] +

[0190] [Step 3] Preparation of intermediate RE-16C [ka] The title compound (148 mg) was obtained by a method similar to Step 3 of Reference Example 1, except that intermediate RE-16B (241 mg) was used instead of intermediate RE-1B. MS (m / z): 289.1 [M+H] +

[0191] [Step 4] Preparation of intermediate RE-16D [ka] The title compound (166 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-16C (148 mg) was used instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0192] [Step 5] Preparation of intermediate RE-16E [ka] The title compound (139 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-16D (166 mg) was used instead of intermediate RE-1D. MS (m / z): 347.1 [M+H] +

[0193] [Step 6] Preparation of intermediate RE-16F [ka] The title compound (88 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-16E (70 mg) was used instead of intermediate RE-11D. MS (m / z): 412.1 [M-(tBu+2H)] +

[0194] [Step 7] Preparation of compound RE-16 The title compound (130 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-16F (88 mg) was used instead of intermediate RE-2F. MS (m / z): 368.0 [M+H] +

[0195] Reference Example 17 3-(azetidin-3-yl)-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazole trifluoroacetate (Compound RE-17) [ka] [Step 1] Preparation of intermediate RE-17A [ka] To a mixture of 1-fluoro-2-iodobenzene (8.31 g) and THF (62 mL), n-butyllithium (1.57 M n-hexane solution, 23.8 mL) was added dropwise at -78°C. After stirring at -78°C for 1 hour, a solution of tert-butyl 3-formylazetidine-1-carboxylate (4.6 g) in THF (62 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, 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 give tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-carboxylate. To the mixture of the above tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-carboxylate and dichloromethane (124 mL), iodobenzene diacetate (9.6 g) and AZADOL® (190 mg) were added sequentially and stirred at room temperature for 2 hours. Iodobenzene diacetate (4.85 g) and AZADOL® (190 mg) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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] +

[0196] [Step 2] Preparation of intermediate RE-17B [ka] 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 mixture, 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 evaporated 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] +

[0197] [Step 3] Preparation of intermediate RE-17C [ka] To a mixture of intermediate RE-17B (200 mg) and acetonitrile (2.4 mL), cesium carbonate (358 mg) and 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole (205 mg) were added sequentially, and the mixture was stirred at room temperature for 4 hours, followed by stirring 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 mixture was purified by silica gel column chromatography to give the title compound (94 mg). MS (m / z): 422.2 [MH] -

[0198] [Step 4] Preparation of compound RE-17 The title compound (98 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-17C (94 mg) was used instead of intermediate RE-2F. MS (m / z): 324.0 [M+H] +

[0199] Reference Example 18 tert-Butyl 3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-18) [ka] [Step 1] Preparation of intermediate RE-18A [ka] The title compound (2.72 g) was obtained by a method similar to that of Step 1 of Reference Example 1, except that 1,3-difluorobenzene (1.85 g) was used instead of 2-chloro-1,4-difluorobenzene.

[0200] [Step 2] Preparation of intermediate RE-18B [ka] The title compound (2.39 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-18A (2.72 g) was used instead of intermediate RE-1A. MS (m / z): 298.0 [M+H] +

[0201] [Step 3] Preparation of intermediate RE-18C [ka] The title compound (2.15 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-18B (2.39 g) was used instead of intermediate RE-1B. MS (m / z): 290.3 [MH] -

[0202] [Step 4] Preparation of intermediate RE-18D To a mixture of intermediate RE-18C (1.02 g) and DMF (12 mL), potassium carbonate (726 mg) and propargyl bromide (0.332 mL) were added sequentially, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.01 g). MS (m / z): 230.1 [M-Boc+2H] +

[0203] [Step 5] Preparation of compound RE-18 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), sodium azide (84.7 mg) was added and stirred overnight at 120 °C 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), and the mixture was stirred at 60 °C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (56 mg).

[0204] 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) [ka] [Step 1] Preparation of intermediate RE-19A [ka] The procedure of Step 4 of Reference Example 10 was repeated, except that Intermediate RE-18C (40 mg) was used instead of Intermediate RE-10C, and 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (35 mg) was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine to give the title compound (65 mg). MS (m / z): 368.1 [M-Boc+2H] +

[0205] [Step 2] Preparation of compound RE-19 The title compound (67 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-19A (65 mg) was used instead of intermediate RE-2F. MS (m / z): 368.1 [M+H] +

[0206] Reference Example 20 2-[3-(azetidin-3-yl)-4-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (Compound RE-20) [ka] [Step 1] Production of intermediate RE-20A [ka] The title compound (638 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-18C (500 mg) was used instead of intermediate RE-1C. MS(m / z):278.0[M-Boc+2H] +

[0207] [Step 2] Preparation of intermediate RE-20B [ka] The title compound (476 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-20A (638 mg) was used instead of intermediate RE-1D. MS (m / z): 348.4 [M−H] -

[0208] [Step 3] Preparation of intermediate RE-20C [ka] The title compound (81 mg) was obtained by a method similar to that of Step 5 of Reference Example 5, except that intermediate RE-20B (64 mg) was used instead of intermediate RE-5D. MS (m / z): 468.3 [M+Na] +

[0209] [Step 4] Preparation of compound RE-20 The title compound (84 mg) was obtained by a method similar to that described in Reference Example 3, except that intermediate RE-20C (81 mg) was used instead of intermediate RE-2F. MS (m / z): 345.2 [M+H] +

[0210] 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) [ka] [Step 1] Preparation of intermediate RE-21A [ka] By a method similar to Step 1 of Reference Example 4, using 3-iodo-4,5,6,7-tetrahydro-1H-indazole (synthesized, for example, according to the method described in US2014171432) (1.63 g) instead of 3-iodo-2H-indazole, the title compound and a mixture of about 10% regioisomers (2.14 g) were obtained. MS (m / z): 321.1 [M+H] +

[0211] [Step 2] Preparation of intermediate RE-21B [ka] The title compound (0.39 g) was obtained by a method similar to that of Step 2 of Reference Example 4, except that Intermediate RE-21A (2.14 g) obtained in Step 1 of Reference Example 21 was used instead of Intermediate RE-4A. MS (m / z): 372.3 [M+Na] +

[0212] [Step 3] Preparation of intermediate RE-21C [ka] The title compound (34 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-21B (0.39 g) was used instead of intermediate RE-1D. MS (m / z): 334.2 [M−H] -

[0213] [Step 4] Preparation of intermediate RE-21D [ka] The title compound (16 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-21C (34 mg) was used instead of intermediate RE-11D. MS (m / z): 457.3 [M+H] +

[0214] [Step 5] Preparation of compound RE-21 The title compound (16 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-21D (16 mg) was used instead of intermediate RE-2F. MS (m / z): 357.2 [M+H] +

[0215] 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) [ka] [Step 1] Preparation of intermediate RE-22A [ka] A reaction vessel containing diethyl ether (30 mL) was cooled on ice, and 60% sodium hydride (596 mg) was added. Ethanol (0.087 mL) was then added and the mixture was stirred in an ice bath for 20 minutes. A solution of 4,4-difluorocyclohexane-1-one (2.0 g) and ethyl formate (1.80 mL) in diethyl ether (10 mL) was added dropwise using a dropping funnel over 10 minutes. The temperature was gradually increased to room temperature, and the mixture was stirred overnight. Ethanol (0.3 mL) was then added to the reaction mixture, which was then stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then washed with diethyl ether. The aqueous layer was acidified with 2 M hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.35 g). MS (m / z): 163.1 [M+H] +

[0216] [Step 2] Preparation of intermediate RE-22B [ka] To a mixture of intermediate RE-22A (1.35 g) and methanol (8.3 mL), hydrazine monohydrate (0.487 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.65 g). MS (m / z): 159.1 [M+H] +

[0217] [Step 3] Preparation of intermediate RE-22C [ka] To a mixture of intermediate RE-22B (0.65 g) and DMF (8.2 mL), potassium hydroxide (0.92 g) and iodine (2.1 g) were added in an ice bath, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (468 mg). MS (m / z): 284.8 [M+H] +

[0218] [Step 4] Preparation of intermediate RE-22D [ka] By following the procedure of Step 1 of Reference Example 4, using intermediate RE-22C (468 mg) instead of 3-iodo-2H-indazole, the title compound and a mixture (582 mg) of approximately 24% regioisomers were obtained. MS (m / z): 356.8 [M+H] +

[0219] [Step 5] Preparation of intermediate RE-22E [ka] The title compound (360 mg) was obtained by a method similar to that of Step 2 of Reference Example 4, except that intermediate RE-22D (582 mg) was used instead of intermediate RE-4A. MS (m / z): 408.3 [M+Na] +

[0220] [Step 6] Preparation of intermediate RE-22F [ka] The title compound (103 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-22E (360 mg) was used instead of intermediate RE-1D. MS (m / z): 370.2 [M−H]-

[0221] [Step 7] Preparation of intermediate RE-22G [ka] The title compound (60 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-22F (50 mg) was used instead of intermediate RE-11D. MS (m / z): 515.3 [M+Na] +

[0222] [Step 8] Preparation of compound RE-22 The title compound (62 mg) was obtained by a method similar to that of Reference Example 3, except that intermediate RE-22G (60 mg) was used instead of intermediate RE-2F. MS (m / z): 393.3 [M+H] +

[0223] Reference Example 23 2-(cyclopropylamino)pyridine-4-carboxylic acid (compound RE-23) [ka] [Step 1] Preparation of intermediate RE-23A [ka] Cyclopropanamine (0.57 mL) was added to a mixture of 2-fluoropyridine-4-carbonitrile (500 mg), NMP (4.0 mL), and DIPEA (2.1 mL), and the mixture was stirred at 80°C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / n-hexane (1 / 1). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (550 mg).

[0224] [Step 2] Preparation of compound RE-23 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 evaporated under reduced pressure, and the residue was adjusted to pH 7-8 with 2M hydrochloric acid. The precipitate was collected by filtration to give the title compound (313 mg). MS (m / z): 179.1 [M+H] +

[0225] Reference Example 24 2-Amino-5-fluoropyridine-4-carboxylic acid hydrochloride (Compound RE-24) [ka] 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 then Pd(OAc)2 (33 mg) was added and stirred overnight at 90 °C. Insoluble matter was filtered off through Celite®, and the mother liquor was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give tert-butyl 2-{[(tert-butoxy)carbonyl]amino}-5-fluoropyridine-4-carboxylate. 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 resulting precipitate was collected by filtration to give the title compound (1.33 g). MS (m / z): 157.0 [M+H] +

[0226] Reference Example 25 2-Amino-3-methylpyridine-4-carboxylic acid trifluoroacetate (Compound RE-25) [ka] [Step 1] Production of intermediate RE-25A [ka] 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 then Pd(OAc) (151 mg) was added and stirred at 100°C overnight. Insoluble matter was filtered off through Celite®, and the mother liquor was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.07 g). MS (m / z): 287.1 [M+H] +

[0227] [Step 2] Preparation of intermediate RE-25B [ka] The title compound (4.02 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-25A (4.07 g) was used instead of intermediate RE-1D. MS (m / z): 273.0 [M+H] +

[0228] [Step 3] Preparation of compound RE-25 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 residue was slurry washed with ethyl acetate to give the title compound (1.25 g). MS (m / z): 153.0 [M+H] +

[0229] Reference Example 26 2-amino-5-fluoropyrimidine-4-carboxylic acid (compound RE-26) [ka] [Step 1] Preparation of intermediate RE-26A [ka] To a mixture of 4-chloro-5-fluoropyrimidin-2-amine (1.36 g), tributyl(1-ethoxyvinyl)tin (3.66 g), and DMF (18 mL), degassed with argon, PdCl2(PPh3)2 (129 mg) was added and stirred at 90 °C overnight. Water was added to the reaction mixture, which was then 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.46 g). MS (m / z): 184.2 [M+H] +

[0230] [Step 2] Preparation of intermediate RE-26B [ka] To a mixture of intermediate RE-26A (1.46 g) and 1,4-dioxane (24 mL), a solution of sodium periodate (3.41 g) in water (24 mL) and potassium permanganate (252 mg) were added 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 aqueous sodium bicarbonate was added to the reaction mixture, which was then diluted with ethyl acetate and filtered through Celite (registered trademark), and insoluble matter was removed by filtration. The mother liquor was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (400 mg). MS (m / z): 186.2 [M+H] +

[0231] [Step 3] Preparation of compound RE-26 The title compound (140 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-26B (400 mg) was used instead of intermediate RE-1D. MS (m / z): 158.1 [M+H] +

[0232] Reference Example 27 tert-Butyl 6-(cyclopropylamino)pyrimidine-4-carboxylate (Compound RE-27) [ka] 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), cyclopropylamine (77 mg) was added and the mixture was reacted in a microwave reactor at 140 °C for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 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)

[0233] Reference Example 28 2-(1-methylcyclopropylamino)pyridine-4-carboxylic acid (Compound RE-28) [ka] [Step 1] Preparation of intermediate RE-28A [ka] To a mixture of 2-fluoropyridine-4-carbonitrile (200 mg), DIPEA (0.85 mL), and NMP (1.6 mL), 1-methylcyclopropan-1-amine hydrochloride (77 mg) was added, and the mixture was allowed to react overnight at 80°C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (110 mg). 1 H-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)

[0234] [Step 2] Preparation of compound RE-28 Potassium hydroxide (0.2 g) was added to a mixture of intermediate RE-28A (110 mg), ethanol (2 mL), and water (2 mL), and the mixture was allowed to react overnight at 80°C. The solvent was evaporated under reduced pressure, and the residue was adjusted to pH 7-8 with 2 M hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The mixture was 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)

[0235] Reference Example 29 2-[(4,4-difluorocyclohexyl)amino]pyridine-4-carboxylic acid (Compound RE-29) [ka] Compound RE-29 was prepared following a similar synthetic route as described for compound RE-28 using 4,4-difluorocyclohexan-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) Reference Example 30 2-[3-(azetidin-3-yl)-4-chloro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound RE-30) [ka]

[0236] [Step 1] Production of intermediate RE-30A [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 1, except that 1-chloro-3-fluorobenzene was used instead of 2-chloro-1,4-difluorobenzene. MS (m / z): 316.1 [M+H] +

[0237] [Step 2] Preparation of intermediate RE-30B [ka] To a mixture of intermediate RE-30A (600 mg) and dichloromethane (19 mL), sodium bicarbonate (479 mg) and 1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (1.21 g) were added under ice-cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 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)

[0238] [Step 3] Preparation of intermediate RE-30 Compound RE-30 was synthesized starting from intermediate RE-30B according to a procedure similar to that described in steps 3 to 7 of Reference Example 1 for the preparation of compound RE-1. MS (m / z): 347.0 [M+H] +

[0239] Reference Example 31 2-[3-(azetidin-3-yl)-4,7-difluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound RE-31) [ka]

[0240] [Step 1] Preparation of intermediate RE-31A [ka] A mixture of intermediate RE-1B (1.34 g), ethanol (10 mL), and hydrazine monohydrate (3.94 mL) was reacted in a microwave reactor at 140°C for 1 hour. Water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (218 mg). MS (m / z): 310.5 [M+H]+

[0241] [Step 2] Preparation of intermediate RE-31B [ka] To a mixture of intermediate RE-31A (218 mg) and DMF (3.5 mL), cesium carbonate (276 mg) and propyl 2-bromoacetate (153 mg) were added sequentially in an ice bath, and the mixture was stirred at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 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)

[0242] [Step 3] Preparation of compound RE-31 Compound RE-31 was synthesized starting from intermediate RE-31A according to a procedure similar to that described in steps 5 to 7 of Reference Example 1 for the preparation of compound RE-1. MS (m / z): 349.0 [M+H] +

[0243] Reference Example 32 2-[3-(azetidin-3-yl)-4-bromo-5-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound RE-32) [ka]

[0244] [Step 1] Production of intermediate RE-32A [ka] The title compound was obtained by a method similar to that 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)

[0245] [Step 2] Preparation of intermediate RE-32B [ka] The title compound was obtained according to a method similar to Step 2 of Reference Example 30, except that Intermediate RE-32A was used 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)

[0246] [Step 3] Preparation of intermediate RE-32C [ka] Intermediate RE-32C was synthesized starting from intermediate RE-32B following a procedure similar to that described in steps 1 to 2 of Reference Example 31 for the preparation of intermediate RE-31B. 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)

[0247] [Step 4] Preparation of compound RE-32 Compound RE-32 was synthesized starting from intermediate RE-32C according to a procedure similar to that described in steps 5 to 7 of Reference Example 1 for the preparation of compound RE-1. MS (m / z): 407.1 [M−H] -

[0248] Reference Example 33 tert-butyl 3-(4-methyl-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-pyrazolo[4,3-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-33) [ka]

[0249] [Step 1] Preparation of intermediate RE-33A [ka] A mixture of compound RE-14D (200 mg), trimethylboroxine (70 mg), potassium carbonate (280 mg), Pd(dppf)Cl2·CHCl2 (41 mg), and 1,4-dioxane (2.5 mL) was degassed and then stirred at 110°C under an argon atmosphere for 5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, 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 (98 mg). MS (m / z): 375.1 [M+H] +

[0250] [Step 2] Preparation of compound RE-33 To a mixture of intermediate RE-33A (98 mg), methanol (1 mL), and THF (1 mL), 2M aqueous sodium hydroxide solution (1 mL) was added at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, and then acidified with 2M hydrochloric acid in an ice bath. Saturated sodium bicarbonate water was added to the mixture to neutralize it, 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 the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (97 mg). MS (m / z): 468.2 [M+H] +

[0251] Reference Example 34 tert-Butyl 3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-pyrazolo[4,3-b]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-34) [ka]

[0252] [Step 1] Preparation of intermediate RE-34A [ka] To a mixture of 3-fluoropyridine (674 mg) and THF (9 mL), lithium diisopropylamide (1.08 M solution in n-hexane / tetrahydrofuran, 6.4 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 (1.13 g) (synthesized, for example, according to the method described in WO20129649) in THF (9 mL) was added dropwise, and the mixture was stirred at -78°C for 2 hours. After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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] +

[0253] [Step 2] Preparation of intermediate RE-34B [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 31, except that Intermediate RE-34A was used instead of Intermediate RE-1B. MS (m / z): 275.1 [M+H] +

[0254] [Step 3] Preparation of compound RE-34 Compound RE-34 was synthesized starting from intermediate RE-34B according to a procedure similar to that described in Steps 1 to 2 of Reference Example 33 for the preparation of compound RE-33. MS (m / z): 454.3 [M+H] +

[0255] Reference Example 35 tert-butyl 3-(5-methyl-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-35) [ka]

[0256] [Step 1] Production of intermediate RE-35A [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 34, except that 2-chloro-5-fluoropyridine was used 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)

[0257] [Step 2] Preparation of intermediate RE-35B [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 31, except that Intermediate RE-35A was used instead of Intermediate RE-1B. MS (m / z): 309.1 [M+H] +

[0258] [Step 3] Preparation of intermediate RE-35C [ka] To a mixture of intermediate RE-35B (100 mg) and DMF (2 mL), cesium carbonate (211 mg) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (116 mg) were added under ice-cooling, and the mixture was stirred for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (134 mg). MS (m / z): 467.2 [M+H] +

[0259] [Step 4] Preparation of compound RE-35 A mixture of intermediate RE-35C (134 mg), trimethylboroxine (72 mg), potassium carbonate (159 mg), Pd(dppf)Cl2·CHCl2 (23 mg), and 1,4-dioxane (1.4 mL) was degassed and stirred at 110°C under an argon atmosphere for 5 hours. Pd(dppf)Cl2·CHCl2 (23 mg) was added, and the mixture was stirred overnight at 90°C. Water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (58 mg). MS (m / z): 447.3 [M+H] +

[0260] Reference Example 36 tert-Butyl 3-(5-methyl-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-36) [ka]

[0261] [Step 1] Preparation of intermediate RE-36A [ka] A mixture of intermediate RE-35B (280 mg), trimethylboroxine (171 mg), potassium carbonate (376 mg), Pd(dppf)Cl2·CHCl2 (148 mg), and 1,4-dioxane (3 mL) was reacted in a microwave reactor at 130°C for 1 hour, then stirred 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 give the title compound (66 mg). MS (m / z): 289.2 [M+H] +

[0262] [Step 2] Preparation of intermediate RE-36B [ka] Intermediate RE-36B was synthesized starting from intermediate RE-36A according to a procedure similar to that described in steps 4 to 5 of Reference Example 1 for the preparation of intermediate RE-1E. MS (m / z): 347.1 [M+H] +

[0263] [Step 3] Preparation of compound RE-36 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 mixture was purified by silica gel column chromatography to give the title compound (40 mg). MS (m / z): 484.3 [M+H] +

[0264] Reference Example 37 2-[3-(azetidin-3-yl)-5-methyl-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-37) [ka]

[0265] [Step 1] Preparation of intermediate RE-37A [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 2-bromo-1-fluoro-4-methylbenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m / z): 294.0 [M+H] +

[0266] [Step 2] Preparation of intermediate RE-37B [ka] 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 mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-(5-methyl-1H-indazol-3-yl)azetidine-1-carboxylate. To a mixture of the resulting tert-butyl 3-(5-methyl-1H-indazol-3-yl)azetidine-1-carboxylate (473 mg) and DMF (8 mL), cesium carbonate (644 mg) and methyl bromoacetate (330 mg) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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 (1.9 mL) was added at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid in an ice bath. The precipitate was collected by filtration to give the title compound (383 mg). MS (m / z): 344.2 [MH] -

[0267] [Step 3] Preparation of intermediate RE-37C [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 4, except that intermediate RE-37B was used instead of intermediate RE-4C. MS (m / z): 467.3 [M+H]

[0268] [Step 4] Preparation of compound RE-37 To a mixture of intermediate RE-37C (171 mg) and dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and toluene was added to the resulting residue, which was then evaporated under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was evaporated under reduced pressure to give the title compound (145 mg). MS (m / z): 367.2 [M+H] +

[0269] Reference Example 38 2-[3-(azetidin-3-yl)-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-38) [ka]

[0270] [Step 1] Preparation of intermediate RE-38A [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 1,4-difluoro-2-iodobenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m / z): 298.1 [M+H] +

[0271] [Step 2] Preparation of intermediate RE-38B [ka] The title compound was obtained by a method similar to that of Step 3 of Reference Example 1, except that Intermediate RE-38A was used instead of Intermediate RE-1B. MS (m / z): 290.1 ​​[MH] -

[0272] [Step 3] Preparation of intermediate RE-38C [ka] To a mixture of intermediate RE-38B (176 mg) and DMF (3 mL), cesium carbonate (236 mg) and methyl bromoacetate (111 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 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)

[0273] [Step 4] Preparation of intermediate RE-38D [ka] The title compound was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-38C was used instead of intermediate RE-1D. MS (m / z): 348.4 [MH] -

[0274] [Step 5] Preparation of intermediate RE-38E [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-38D was used instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 471.3 [M+H] +

[0275] [Step 6] Preparation of compound RE-38 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-38E was used instead of Intermediate RE-37C. MS (m / z): 371.2 [M+H] +

[0276] Reference Example 39 tert-Butyl 2-[3-(1-{2-[3-(azetidin-3-yl)-1H-indazol-1-yl]acetyl}azetidin-3-yl)-1H-indazol-1-yl]acetate (Compound RE-39) [ka]

[0277] [Step 1] Preparation of intermediate RE-39A [ka] 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (94 mg). MS (m / z): 313.1 [M+H] +

[0278] [Step 2] Preparation of intermediate RE-39B [ka] 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) (45 mg) was added. The mixture was stirred overnight at 50°C under an argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (207 mg). MS (m / z): 314.0 [M+H] +

[0279] [Step 3] Preparation of intermediate RE-39C [ka] 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 mixture, 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 evaporated 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] +

[0280] [Step 4] Preparation of intermediate RE-39D [ka] To a mixture of intermediate RE-39C (1.00 g) and DMF (11 mL), cesium carbonate (1.27 g) and tert-butyl 2-bromoacetate (762 mg) were added under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (875 mg). MS (m / z): 444.2 [M+Na] +

[0281] [Step 5] Preparation of compound RE-39 To a mixture of intermediate RE-39D (875 mg) and methanol (21 mL), 5% Pd-C (440 mg) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (0.1 MPa). Insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (473 mg). MS (m / z): 288.2 [M+H] +

[0282] Reference Example 40 tert-butyl 4-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (Compound RE-40) [ka]

[0283] [Step 1] Production of intermediate RE-40A [ka] To a mixture of 3-bromo-1H-indazole (2 g) and DMF (34 mL), cesium carbonate (1.27 g) and methyl bromoacetate (1.86 g) were added under ice-cooling and stirred for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 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)

[0284] [Step 2] Preparation of intermediate RE-40B [ka] 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·CHCl2 (91 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) was degassed and then stirred overnight at 95°C under an argon atmosphere. After filtering off insoluble matter through Celite®, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (255 mg). MS (m / z): 356.3 [MH] ―

[0285] [Step 3] Preparation of compound RE-40 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), HBTU (162 mg) was added and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (105 mg). MS (m / z): 479.3 [M+H] +

[0286] Reference Example 41 tert-butyl 4-(1-{[methyl(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazol-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (Compound RE-41) [ka] To a mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and 2,2,2-trifluoroethanamine hydrochloride (64 mg), HBTU (162 mg) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (104 mg). MS (m / z): 475.2 [M+Na] +

[0287] Reference Example 42 2-[3-(azetidin-3-yl)-5-fluoro-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (Compound RE-42) [ka]

[0288] [Step 1] Preparation of intermediate RE-42A [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-38D was used instead of Intermediate RE-1E, and 2,2,2-trifluoro-N-methylethanamine hydrochloride was used instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m / z): 467.2 [M+Na] +

[0289] [Step 2] Preparation of compound RE-42 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-42A was used instead of Intermediate RE-37C. MS (m / z): 345.1 [M+H] +

[0290] 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) [ka]

[0291] [Step 1] Preparation of intermediate RE-43A [ka] To a mixture of 5,6-difluoro-1H-indazole (513 mg), potassium hydroxide (374 mg), and DMF (1.3 mL), iodine (1.01 g) was added under ice cooling and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with water. The mixture was dried to obtain the title compound (899 mg). MS (m / z): 281.0 [M+H] +

[0292] [Step 2] Preparation of intermediate RE-43B [ka] Intermediate RE-43B was synthesized starting from intermediate RE-43A according to a procedure similar to that described in Steps 1 to 3 of Reference Example 6 for the preparation of compound RE-6C. MS (m / z): 366.2 [M−H] -

[0293] [Step 3] Preparation of intermediate RE-43C [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-43B was used instead of Intermediate RE-1E and 2,2,2-trifluoro-N-methylethanamine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 485.2 [M+Na] +

[0294] [Step 4] Preparation of compound RE-43 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-43C was used instead of Intermediate RE-37C. MS (m / z): 363.1 [M+H] +

[0295] Reference Example 44 2-[3-(azetidin-3-yl)-5,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-44) [ka] Compound RE-44 was synthesized starting from intermediate RE-43B according to a procedure similar to that described in steps 5 to 6 of Reference Example 38 for the preparation of compound RE-38. MS (m / z): 389.2 [M+H] +

[0296] Reference Example 45 2-[3-(3-hydroxyazetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-45) [ka]

[0297] [Step 1] Preparation of intermediate RE-45A [ka] To a mixture of 1-(tert-butyl) 3-methyl 3-hydroxyazetidine-1,3-dicarboxylate (1.0 g) and DMF (14 mL), 60% sodium hydride (260 mg) was added under ice-cooling and stirred for 50 minutes. Next, benzyl bromide (1.10 g) was added, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, 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 evaporated 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)

[0298] [Step 2] Preparation of intermediate RE-45B [ka] To a mixture of intermediate RE-45A (1.07 g), methanol (8 mL), and THF (8 mL), 2 M aqueous sodium hydroxide solution was added and stirred at room temperature. The solvent was evaporated under reduced pressure, and the mixture was neutralized with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated 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] ―

[0299] [Step 3] Preparation of intermediate RE-45C [ka] 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 water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (961 mg). MS (m / z): 373.0 [M+H] +

[0300] [Step 4] Preparation of intermediate RE-45D [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 1-fluoro-2-iodobenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene and intermediate RE-45C was used 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)

[0301] [Step 5] Preparation of intermediate RE-45E [ka] A mixture of intermediate RE-45D (785 mg), hydrazine monohydrate (0.99 mL), potassium carbonate (844 mg), and DMA (15 mL) was reacted in a microwave reactor at 100°C for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and methyl bromoacetate (467 mg) was added to a mixture of the resulting residue, cesium carbonate (1.99 g), and DMA (7 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (709 mg). MS (m / z): 474.3 [M+Na] +

[0302] [Step 6] Preparation of intermediate RE-45F [ka] To a mixture of intermediate RE-45E (709 mg) and THF (20 mL), 5% Pd-C (600 mg) was added and the mixture was stirred at 40°C under a hydrogen atmosphere (0.3 MPa) for 6 hours. After stirring at 50°C for 11 hours, insoluble matter was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (425 mg). MS (m / z): 384.2 [M+Na] +

[0303] [Step 7] Preparation of intermediate RE-45G [ka] The title compound was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-45F was used instead of intermediate RE-1D. MS (m / z): 346.1 [MH] -

[0304] [Step 8] Preparation of intermediate RE-45H [ka] 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), EDCI·HCl (132 mg) was added and stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (193 mg). MS (m / z): 491.3 [M+Na] +

[0305] [Step 9] Preparation of compound RE-45 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that intermediate RE-45H was used instead of intermediate RE-37C. MS (m / z): 369.2 [M+H] +

[0306] Reference Example 46 tert-butyl 3-fluoro-3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-46) [ka] To a mixture of intermediate RE-45H (96 mg) and dichloromethane (4 mL), DAST (50 mg) was added at -78°C and stirred for 3 hours. The mixture was then stirred under ice-cooling for 30 minutes. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (47 mg). MS (m / z): 493.2 [M+Na] +

[0307] 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) [ka]

[0308] [Step 1] Preparation of intermediate RE-47A [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-37B was used instead of Intermediate RE-1E, and 2,2,2-trifluoro-N-methylethanamine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 463.3 [M+Na] +

[0309] [Step 2] Preparation of compound RE-47 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-47A was used instead of Intermediate RE-37C. MS (m / z): 341.0 [M+H] + Reference Example 48 tert-butyl 3-(5-methoxy-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-48) [ka]

[0310] [Step 1] Preparation of intermediate RE-48A [ka] Intermediate RE-48A was synthesized starting from 3-iodo-5-methoxy-1H-indazole following a procedure similar to that described in Steps 1 to 3 of Reference Example 6 for the preparation of intermediate RE-6C. MS (m / z): 360.2 [M−H] ― [Step 2] Preparation of compound RE-48 The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-48A was used instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 505.2 [M+Na] +

[0311] Reference Example 49 2-[3-(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 trifluoroacetate (Compound RE-49) [ka]

[0312] [Step 1] Preparation of intermediate RE-49A [ka] Intermediate RE-49A was synthesized starting 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) following a procedure similar to that described in Steps 1 to 3 of Reference Example 6 for the preparation of intermediate RE-6C. MS (m / z): 362.3 [MH] ―

[0313] [Step 2] Preparation of intermediate RE-49B [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-49A was used instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 485.4 [M+H] +

[0314] [Step 3] Preparation of compound RE-49 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that intermediate RE-49B was used instead of intermediate RE-37C. MS (m / z): 385.4 [M+H] +

[0315] Reference Example 50 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-50) [ka] To a mixture of intermediate RE-1E (200 mg), HATU (258 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (119 mg), and DMF (1.7 mL), DIPEA (0.3 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give 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 this 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), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and toluene was added to the resulting residue and evaporated under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was evaporated under reduced pressure to give the title compound (260 mg). MS (m / z): 405.1 [M+H] +

[0316] 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) [ka]

[0317] [Step 1] Preparation of intermediate RE-51A [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that 2,2,2-trifluoro-N-methylethanamine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 501.2 [M+Na] +

[0318] [Step 2] Preparation of compound RE-51 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-51A was used instead of Intermediate RE-37C. MS (m / z): 378.9 [M+H] +

[0319] Reference Example 52 tert-Butyl 3-(4,6-difluoro-1-{[(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-52) [ka] The title compound was obtained according to a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-2E was used instead of Intermediate RE-1E. 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)

[0320] Reference Example 53 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one hydrochloride (Compound RE-53) [ka] Compound RE-53 was synthesized starting from intermediate RE-2C following a procedure similar to that described in Steps 4 to 7 of Reference Example 2 for the preparation of compound RE-2, using methyl 2-chloropropionate instead of ethyl 2-bromoacetate. MS (m / z): 403.2 [M+H] +

[0321] Reference Example 54 tert-butyl 3-(4,6-difluoro-1-{1-fluoro-2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-54) [ka] Compound RE-54 was synthesized starting from intermediate RE-2C following a procedure similar to that described in Steps 4 to 6 of Reference Example 2 for the preparation of intermediate RE-2F, using ethyl bromofluoroacetate instead of ethyl 2-bromoacetate. MS (m / z): 529.2 [M+Na] +

[0322] Reference Example 55 tert-Butyl 3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-55) [ka] A mixture of intermediate RE-2C (50 mg), (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate (59 mg), cesium carbonate (79 mg), and DMF (0.8 mL) was stirred at room temperature overnight. Saturated aqueous ammonium chloride was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (80 mg). MS (m / z): 342.1 [M-Boc+2H] +

[0323] Reference Example 56 tert-Butyl 3-[4,6-difluoro-1-(3-phenylprop-2-yn-1-yl)-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-56) [ka] The title compound was obtained by a method similar to that of Reference Example 55, except that 3-phenylprop-2-yn-1-yl 4-methylbenzenesulfonate was used instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate. MS (m / z): 342.1 [M-Boc+2H] +

[0324] Reference Example 57 tert-Butyl 3-[1-(3-cyclopropylprop-2-yn-1-yl)-4,6-difluoro-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-57) [ka] The title compound was obtained by a method similar to that of Reference Example 55, except that 3-cyclopropylprop-2-yn-1-yl 4-methylbenzenesulfonate was used instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate. MS (m / z): 288.2 [M-Boc + 2H] +

[0325] Reference Example 58 tert-Butyl 3-{4,6-difluoro-1-[(1-phenylazetidin-3-yl)methyl]-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-58) [ka]

[0326] [Step 1] Preparation of intermediate RE-58A [ka] 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 mixture, which was then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl 3-[1-({1-[(benzyloxy)carbonyl]azetidin-3-yl}methyl)-4,6-difluoro-1H-indazol-3-yl]azetidine-1-carboxylate. A mixture of this ester, 10% Pd-C (200 mg), hydrogen chloride (2 M in methanol, 0.04 mL), and methanol (3.9 mL) was stirred under a hydrogen atmosphere at room temperature for 4 hours. After removing the insoluble matter through Celite (registered trademark) filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (270 mg). MS (m / z): 379.2 [M+H] +

[0327] [Step 2] Preparation of compound RE-58 A mixture of intermediate RE-58A (30 mg), bromobenzene (15 mg), Pd(OAc) (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 mixture was purified by silica gel column chromatography to give the title compound (6 mg). MS (m / z): 455.3 [M+H] +

[0328] Reference Example 59 tert-Butyl 3-(4,6-difluoro-1-{[1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-59) [ka] To a mixture of intermediate RE-58A (30 mg), DIPEA (0.04 mL), and THF (0.3 mL), (2,2,2-trifluoroethyl)trifluoromethanesulfonate (37 mg) was added and stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (10 mg). MS (m / z): 461.2 [M+H] +

[0329] Reference Example 60 tert-Butyl 3-{1-[(2,3-dihydro-1H-inden-2-yl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-60) [ka] The title compound was obtained by a method similar to that of Reference Example 55, except that indan-2-ylmethyl 4-methylbenzenesulfonate was used instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate. MS (m / z): 340.1 [M-Boc+2H] +

[0330] Reference Example 61 2-[3-(azetidin-3-yl)-4,6-difluoro-1H-indazol-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one trifluoroacetate (Compound RE-61) [ka]

[0331] [Step 1] Preparation of intermediate RE-61A [ka] 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), HBTU (124 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (131 mg). MS (m / z): 405.1 [M-Boc+2H] +

[0332] [Step 2] Preparation of compound RE-61 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-61A was used instead of Intermediate RE-37C. MS (m / z): 405.1 [M+H] +

[0333] 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) [ka] Compound RE-62 was synthesized starting from intermediate RE-2E according to a procedure similar to that described in Steps 1 to 2 of Reference Example 51 for the preparation of compound RE-51. MS (m / z): 363.1 [M+H] +

[0334] Reference Example 63 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-tert-butylacetamide trifluoroacetate (Compound RE-63) [ka] Compound RE-63 was synthesized from intermediate RE-4C following a procedure similar to that described in Steps 1 and 2 of Reference Example 61 for the preparation of compound RE-61, except that 2-methylpropan-2-amine was used instead of (2R)-2-(trifluoromethyl)morpholine hydrochloride. MS (m / z): 287.2 [M+H] +

[0335] Reference Example 64 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N,N-bis(propan-2-yl)acetamide trifluoroacetate (Compound RE-64) [ka] Compound RE-64 was synthesized from intermediate RE-4C following a procedure similar to that described in Steps 1 and 2 of Reference Example 51 for the preparation of compound RE-51, except that diisopropylamine was used instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m / z): 315.3 [M+H] +

[0336] Reference Example 65 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-tert-butyl-N-methylacetamide trifluoroacetate (Compound RE-65) [ka] Compound RE-65 was synthesized from intermediate RE-4C following a procedure similar to that described in Steps 1 and 2 of Reference Example 51 for the preparation of compound RE-51, except that N,2-dimethylpropan-2-amine was used instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m / z): 301.2 [M+H] +

[0337] Reference Example 66: 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (Compound RE-66) [ka]

[0338] [Step 1] Preparation of intermediate RE-66A [ka] To a mixture of intermediate RE-4C (350 mg), 2,2,2-trifluoro-N-methylethanamine hydrochloride (190 mg), 1-hydroxybenzotriazole monohydrate (194 mg), NMM (0.35 mL), and acetonitrile (3 mL), EDCI·HCl (243 mg) was added and stirred overnight at room temperature. Saturated sodium bicarbonate water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (280 mg). MS (m / z): 449.3 [M+Na] +

[0339] [Step 2] Preparation of compound RE-66 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-66A was used instead of Intermediate RE-37C. MS (m / z): 327.2 [M+H] +

[0340] Reference Example 67 tert-butyl 3-(5-chloro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-67) [ka] To a mixture of intermediate RE-5D (115 mg), DMF (1 mL), DIPEA (0.16 mL), and (2R)-2-(trifluoromethyl)morpholine hydrochloride (72 mg), HBTU (143 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (86 mg). MS (m / z): 503.2 [M+H] +

[0341] Reference Example 68 2-[3-(azetidin-3-yl)-5-chloro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-68) [ka] 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), HATU (143 mg) was added and stirred overnight at room temperature. 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), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature. The solvent was evaporated under reduced pressure to obtain the title compound (119 mg). MS (m / z): 387.1 [M+H] +

[0342] Reference Example 69 2-[3-(azetidin-3-yl)-6-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (Compound RE-69) [ka] Compound RE-69 was synthesized from intermediate RE-6C according to a procedure similar to that described in Steps 1 and 2 of Reference Example 66 for the preparation of compound RE-66, using (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m / z): 371.3 [M+H] +

[0343] Reference Example 70 tert-butyl 3-methyl-3-(1-{[methyl(2,2,2-trifluoroethyl)carbamoyl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-70) [ka] To a mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), HBTU (132 mg), and 2,2,2-trifluoro-N-methylethanamine hydrochloride (52 mg), DIPEA (0.15 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (109 mg). MS (m / z): 463.4 [M+Na] +

[0344] Reference Example 71 2-[4-fluoro-3-(piperidin-4-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound RE-71) [ka]

[0345] [Step 1] Preparation of intermediate RE-71A [ka] Compound RE-71A was synthesized starting from intermediate RE-10C following a procedure similar to that described in Steps 4 to 5 of Reference Example 2 for the preparation of intermediate RE-2E. MS (m / z): 376.4 [M−H] ―

[0346] [Step 2] Preparation of compound RE-71 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 the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate (5 mL) and hydrogen chloride (4 M in ethyl acetate, 0.4 mL) were added to the residue, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (280 mg). MS (m / z): 399.2 [M+H] +

[0347] Reference Example 72 tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indazol-3-yl)piperidine-1-carboxylate (Compound RE-72) [ka] 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 mixture was purified by silica gel column chromatography to give the title compound (70 mg). MS (m / z): 415.2 [M-Boc+2H] +

[0348] Reference Example 73 tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indazol-3-yl)piperidine-1-carboxylate (Compound RE-73) [ka] The title compound was obtained by a method similar to that of Reference Example 72, except that (2R)-2-(trifluoromethyl)morpholine hydrochloride was used instead of (2S)-2-(trifluoromethyl)morpholine hydrochloride. MS (m / z): 537.1 [M+Na] +

[0349] Reference Example 74 tert-butyl 4-(4-fluoro-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-indazol-3-yl)piperidine-1-carboxylate (Compound RE-74) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that 5-(chloromethyl)-2-(trifluoromethyl)pyridine was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 501.2 [M+Na] +

[0350] Reference Example 75 tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-indol-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (Compound RE-75) [ka] Compound RE-75 was synthesized starting from intermediate RE-11A according to a 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] +

[0351] Reference Example 76 tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indol-3-yl)piperidine-1-carboxylate (Compound RE-76) [ka] Compound RE-76 was synthesized starting from intermediate RE-11B following a procedure similar to that described in steps 3 to 5 of Reference Example 11 for the preparation of intermediate RE-11E, except that (2R)-2-(trifluoromethyl)morpholine hydrochloride was used instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m / z): 536.2 [M+Na] +

[0352] Reference Example 77 tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-indol-3-yl)piperidine-1-carboxylate (Compound RE-77) [ka] Compound RE-77 was synthesized starting from intermediate RE-11B following a procedure similar to that described in steps 3 to 5 of Reference Example 11 for the preparation of intermediate RE-11E, except that (2S)-2-(trifluoromethyl)morpholine hydrochloride was used instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m / z): 536.2 [M+Na] +

[0353] 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) [ka]

[0354] [Step 1] Preparation of intermediate RE-78A [ka] The title compound was obtained by a method similar to that of Reference Example 67, except that intermediate RE-13D was used instead of intermediate RE-5D. MS (m / z): 484.2 [M+H] +

[0355] [Step 2] Preparation of compound RE-78 The title compound was obtained by a method similar to that of Step 7 of Reference Example 1, except that Intermediate RE-78A was used instead of Intermediate RE-1F. MS (m / z): 384.2 [M+H] +

[0356] 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) [ka]

[0357] [Step 1] Preparation of intermediate RE-79A [ka] To a mixture of intermediate RE-13D (52 mg), DMF (1.0 mL), HBTU (74 mg), and 3,3-dimethylmorpholine (22 mg), DIPEA (0.08 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (50 mg). MS (m / z): 444.3 [M+H] +

[0358] [Step 2] Preparation of compound RE-79 The title compound was obtained by a method similar to Step 7 of Reference Example 1, except that Intermediate RE-79A was used instead of Intermediate RE-1F. MS (m / z): 344.2 [M+H] +

[0359] Reference Example 80 tert-butyl 3-(4-fluoro-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-80) [ka]

[0360] [Step 1] Production of intermediate RE-80A [ka] Intermediate RE-80A was synthesized starting from intermediate RE-15C according to a procedure similar to that described in steps 4 to 5 of Reference Example 1 for the preparation of intermediate RE-1E. MS (m / z): 351.0 [M+H]+

[0361] [Step 2] Preparation of compound RE-80 The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-80A was used instead of Intermediate RE-1E and (2R)-2-(trifluoromethyl)morpholine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 488.2 [M+H] +

[0362] Reference Example 81 tert-butyl 3-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-81) [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that Intermediate RE-80A was used instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m / z): 472.2 [M+H] +

[0363] Reference Example 82 tert-butyl 3-(4-fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-82) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-15C was used instead of Intermediate RE-10C. MS (m / z): 452.2 [M+H] +

[0364] Reference Example 83 tert-butyl 3-(4-fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-83) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-15C was used instead of Intermediate RE-10C and 1-(bromomethyl)-4-(trifluoromethyl)benzene was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 451.2 [M+H] +

[0365] Reference Example 84 tert-butyl 3-(4-fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-pyrazolo[3,4-c]pyridin-3-yl)azetidine-1-carboxylate (Compound RE-84) [ka] The title compound was obtained by a method similar to that of Step 6 of Reference Example 15, except that 2-fluorobenzoic acid was used instead of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid. MS (m / z): 469.2 [M+H] +

[0366] Reference Example 85 tert-butyl 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-carboxylate (Compound RE-85) [ka] HATU (48 mg) was added 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, pp. 1376-1394) (19 mg), DIPEA (0.02 mL), and DMF (0.4 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 mixture was purified by silica gel column chromatography to obtain the title compound (15 mg). MS (m / z): 470.2 [M+H] +

[0367] 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) [ka] The title compound was obtained by a method similar to that of Step 7 of Reference Example 1, except that compound RE-80 was used instead of intermediate RE-1F. MS (m / z): 388.1 [M+H] +

[0368] 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) [ka]

[0369] [Step 1] Preparation of intermediate RE-87A [ka] To a mixture of intermediate RE-80A (80 mg), DMF (0.8 mL), HBTU (130 mg), and (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (56 mg), DIPEA (0.2 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (60 mg). MS (m / z): 502.3 [M+H] +

[0370] [Step 2] Preparation of compound RE-87 The title compound was obtained by a method similar to that of Step 7 of Reference Example 1, except that intermediate RE-87A was used instead of intermediate RE-1F. MS (m / z): 402.2 [M+H] +

[0371] Reference Example 88 3-(azetidin-3-yl)-1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazole (Compound RE-88) [ka]

[0372] [Step 1] Preparation of intermediate RE-88A [ka] Compound RE-88A was synthesized starting from intermediate RE-17B following a procedure similar to that described in steps 4 to 5 of Reference Example 15 for the preparation of intermediate RE-15E. MS (m / z): 346.2 [M+H] +

[0373] [Step 2] Preparation of compound RE-88 A mixture of intermediate RE-88A (99 mg), toluene (2 mL), and trifluoroacetic anhydride (66 mg) was stirred at 60° C. overnight. The reaction mixture was purified by silica gel column chromatography to give the title compound (49 mg). MS (m / z): 324.0 [M+H] +

[0374] Reference Example 89 tert-Butyl 3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-89) [ka] To a mixture of intermediate RE-18D (74 mg), azidobenzene (54 mg), DMF (2 mL), and methanol (0.2 mL), copper(I) iodide (4 mg) was added and stirred for 3 hours at 60° C. under an argon atmosphere. The reaction solution was diluted with ethyl acetate and washed with saturated brine, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (62 mg). 1 H-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)

[0375] Reference Example 90 tert-butyl 3-{1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-90) [ka] The title compound was obtained by a method similar to that of Reference Example 89, except that azidomethylbenzene was used 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)

[0376] Reference Example 91 tert-butyl 3-(4-fluoro-1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-91) [ka] The title compound was obtained by a method similar to that of Reference Example 89, except that 2-azido-1,1,1-trifluoroethane was used instead of azidobenzene. MS (m / z): 355.0 [M-Boc+2H] +

[0377] Reference Example 92 tert-Butyl 3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-92) [ka] The title compound was obtained by a method similar to that of Reference Example 89, except that azidomethylcyclobutane was used instead of azidobenzene. MS (m / z): 341.1 [M-Boc+2H] +

[0378] Reference Example 93 tert-butyl 3-{4-fluoro-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-93) [ka] To a mixture of intermediate RE-18C (50 mg) and THF (0.6 mL), 60% sodium hydride (5 mg) was added under ice-cooling and stirred for 5 minutes. Then, 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (30 mg) was added and stirred for 2 hours. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated 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] +

[0379] Reference Example 94 tert-butyl 3-(4-fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-94) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-18C was used instead of Intermediate RE-10C and 1-(bromomethyl)-4-(trifluoromethyl)benzene was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[0380] Reference Example 95 tert-butyl 3-(4-fluoro-1-{[3-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-95) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-18C was used instead of Intermediate RE-10C and 1-(bromomethyl)-3-(trifluoromethyl)benzene was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[0381] Reference Example 96 tert-butyl 3-(4-fluoro-1-{[2-(trifluoromethyl)phenyl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-96) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-18C was used instead of Intermediate RE-10C and 1-(bromomethyl)-2-(trifluoromethyl)benzene was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 350.1 [M-Boc+2H] +

[0382] Reference Example 97 tert-butyl 3-(4-fluoro-1-{[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-97) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-18C was used instead of Intermediate RE-10C, and 5-(chloromethyl)-3-trifluoromethyl-1,2,4-oxadiazole was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 342.1 [M-Boc+2H] +

[0383] Reference Example 98 tert-butyl 3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-98) [ka]

[0384] [Step 1] Preparation of intermediate RE-98A [ka] Intermediate RE-98A was synthesized starting from intermediate RE-18C following a procedure similar to that described in steps 4 to 5 of Reference Example 15 for the preparation of intermediate RE-15E. MS (m / z): 364.2 [M+H] +

[0385] [Step 2] Preparation of compound RE-98 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 mixture was purified by silica gel column chromatography to give the title compound (13 mg). MS (m / z): 368.1 [M-Boc+2H] +

[0386] Reference Example 99 tert-Butyl 3-[4-fluoro-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-99) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that 3-trifluoromethylbenzoic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 418.1 [M-Boc+2H] +

[0387] Reference Example 100 tert-butyl 3-(4-fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-100) [ka] The title compound was obtained by a method similar to that of Step 4 of Reference Example 10, except that Intermediate RE-18C was used instead of Intermediate RE-10C, and 2-(chloromethyl)-5-trifluoromethyl-1,3,4-oxadiazole was used instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS (m / z): 440.2 [MH] -

[0388] Reference Example 101 tert-butyl 3-(4-fluoro-1-{[5-(oxan-4-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-101) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that tetrahydropyran-4-carboxylic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 358.2 [M-Boc+2H] +

[0389] Reference Example 102 tert-Butyl 3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-103) (Compound RE-102) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that 1-(trifluoromethyl)cyclobutanecarboxylic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 518.2 [M+Na] +

[0390] Reference Example 103 tert-butyl 3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indazol-3-yl]azetidine-1-carboxylate (compound RE-103) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that 1-(trifluoromethyl)cyclopropanecarboxylic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 504.2 [M+Na] +

[0391] Reference Example 104 tert-butyl 3-(4-fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-104) [ka] The title compound was obtained by the same method as in Reference Example 98, except that 2-fluorobenzoic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 368.1 [M-Boc+2H] +

[0392] Reference Example 105 tert-butyl 3-(4-fluoro-1-{[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-105) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that 5-fluoropyridine-2-carboxylic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 369.1 [M-Boc+2H] +

[0393] Reference Example 106 tert-Butyl 3-(4-fluoro-1-{[5-(6-methylpyridazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-106) [ka] The title compound was obtained by a method similar to that of Reference Example 98, except that 6-methylpyridazine-3-carboxylic acid was used instead of 4-fluorobenzoic acid. MS (m / z): 366.1 [M-Boc+2H] +

[0394] Reference Example 107 3-(azetidin-3-yl)-4-fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-1H-indazole (Compound RE-107) [ka] 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 the mixture was stirred at 60° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (13 mg). MS (m / z): 342.1 [M+H] +

[0395] Reference Example 108 2-[3-(azetidin-3-yl)-4-fluoro-1H-indazol-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (Compound RE-108) [ka] Compound RE-108 was synthesized starting from intermediate RE-20B according to a procedure similar to that described in steps 6 to 7 of Reference Example 1 for the preparation of compound RE-1. MS (m / z): 331.5 [M+H] +

[0396] Reference Example 109 tert-Butyl 3-[4-fluoro-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)-1H-indazol-3-yl]azetidine-1-carboxylate (Compound RE-109) [ka] A mixture of intermediate RE-20B (47 mg), N'-hydroxy-3-(trifluoromethyl)benzamidine (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 mixture was purified by silica gel column chromatography to obtain the title compound (45 mg). MS (m / z): 418.1 [M-Boc+2H] +

[0397] Reference Example 110 tert-butyl 3-(4-fluoro-1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-110) [ka] The title compound was obtained by a method similar to that of Reference Example 109, except that 4-fluoro-N'-hydroxybenzamidine was used instead of N'-hydroxy-3-(trifluoromethyl)benzamidine. MS (m / z): 368.1 [M-Boc+2H] +

[0398] Reference Example 111 tert-butyl 3-(4-fluoro-1-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-111) [ka] The title compound was obtained by a method similar to that of Reference Example 109, except that N'-hydroxypyridine-4-carboxamidine was used instead of N'-hydroxy-3-(trifluoromethyl)benzamidine. 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)

[0399] Reference Example 112 tert-Butyl 3-{1-[({bicyclo[2.2.1]heptan-2-yl}carbamoyl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-112) [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 87, except that Intermediate RE-20B was used instead of Intermediate RE-80A and norbornan-2-amine hydrochloride was used instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 343.2 [M+H] +

[0400] Reference Example 113 tert-Butyl 3-{1-[({bicyclo[1.1.1]pentan-1-yl}carbamoyl)methyl]-4-fluoro-1H-indazol-3-yl}azetidine-1-carboxylate (Compound RE-113) [ka] The title compound was obtained by a method similar to that of Step 1 of Reference Example 87, except that Intermediate RE-20B was used instead of Intermediate RE-80A and bicyclo[1.1.1]pentan-1-amine was used instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 413.3 [MH] -

[0401] Reference Example 114 tert-butyl 3-(1-{[(2,2-difluoroethyl)carbamoyl]methyl}-4-fluoro-1H-indazol-3-yl)azetidine-1-carboxylate (Compound RE-114) [ka] The title compound was obtained by a method similar to Step 1 of Reference Example 87, except that Intermediate RE-20B was used instead of Intermediate RE-80A and 2,2-difluoroethanamine was used instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS (m / z): 313.1 [M-Boc+2H] +

[0402] Reference Example 115 4-{4-[4-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl]piperidine-1-carbonyl}pyridin-2-amine (Compound RE-115) [ka] To a mixture of intermediate RE-10C (70 mg) and DMF (0.7 mL), potassium carbonate (45 mg) and propargyl bromide (29 mg) were added and stirred overnight at room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and trifluoroacetic acid (0.5 mL) was added to a mixture of the resulting residue (78 mg) and dichloromethane (2 mL), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the resulting 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 overnight at room temperature. A separately prepared DMF solution of the residue was then added, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to yield the title compound (65 mg). MS(m / z):378.2[M+H] +

[0403] Reference Example 116 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}acetic acid (Compound RE-116) [ka]

[0404] [Step 1] Preparation of intermediate RE-116A [ka] A mixture of intermediate RE-2D (280 mg), ethanol (2 mL), and hydrogen chloride (2M ethanol solution, 1.8 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure, and a mixture of the residue, ethanol (2 mL), and hydrogen chloride (2M ethanol solution, 1.8 mL) was stirred overnight at room temperature. The solvent was then removed under reduced pressure, and the resulting residue (220 mg) was dissolved in DMF (2 mL). In a separate vessel, a mixture of 2-aminopyridine-4-carboxylic acid (119 mg), DMF (2.2 mL), and DIPEA (0.92 mL) was added with HBTU (327 mg) and stirred at room temperature for 15 minutes. A separately prepared DMF solution of the residue was then added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to give the title compound (130 mg). MS (m / z): 416.1 [M+H] +

[0405] [Step 2] Preparation of compound RE-116 To a mixture of intermediate RE-116A (343 mg) and methanol (4.1 mL), 2 M aqueous sodium hydroxide solution (0.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. 2 M hydrochloric acid was added to neutralize the mixture, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (183 mg). MS (m / z): 388.1 [M+H] +

[0406] Reference Example 117 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetic acid trifluoroacetate (Compound RE-117) [ka]

[0407] [Step 1] Preparation of intermediate RE-117A [ka] DIPEA (0.85 mL) was added 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), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction mixture, 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (409 mg). MS (m / z): 426.2 [M+H] +

[0408] [Step 2] Preparation of compound RE-117 To a mixture of intermediate RE-117A (389 mg) and dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 1 hour. Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and toluene was added to the resulting residue, which was evaporated under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether and dried to give the title compound (396 mg). MS (m / z): 370.2 [M+H] +

[0409] Reference Example 118 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl}acetic acid (Compound RE-118) [ka]

[0410] [Step 1] Preparation of intermediate RE-118A [ka] A mixture of intermediate RE-20A (300 mg) and hydrogen chloride (2 M ethanol solution, 2 mL) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting 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. A separately prepared DMF solution of the residue was then added, and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (83 mg). MS (m / z): 397.8 [M+H] +

[0411] [Step 2] Preparation of compound RE-118 To a mixture of intermediate RE-118A (83 mg) and methanol (2 mL), 2 M aqueous sodium hydroxide solution (0.1 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. 2 M hydrochloric acid was added to neutralize the mixture, and the solvent was evaporated under reduced pressure to give the title compound (77 mg). MS (m / z): 370.0 [M+H] +

[0412] Reference Example 119 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl}acetic acid (Compound RE-119) [ka] Compound RE-119 was synthesized starting from intermediate RE-2D following a procedure similar to that described in Steps 1 and 2 of Reference Example 116 for the preparation of compound RE-116, except that 2-amino-3-methylpyridine-4-carboxylic acid was used instead of 2-aminopyridine-4-carboxylic acid. MS (m / z): 402.1 [M+H] +

[0413] 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) [ka] Compound RE-120 was synthesized starting from intermediate RE-2D following a procedure similar to that described in Steps 1 and 2 of Reference Example 116 for the preparation of compound RE-116, using compound RE-24 instead of 2-aminopyridine-4-carboxylic acid. MS (m / z): 406.1 [M+H] +

[0414] Reference Example 121 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}acetic acid (Compound RE-121) [ka] Compound RE-121 was synthesized starting from intermediate RE-4B according to a procedure similar to that described in Steps 1 to 2 of Reference Example 116 for the preparation of compound RE-116. MS (m / z): 352.1 [M+H] +

[0415] 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) [ka] A mixture of intermediate RE-18D (100 mg) and hydrogen chloride (4 M in 1,4-dioxane, 2 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the resulting residue (80 mg) was dissolved in a small amount of DMF. In a separate vessel, 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, after which a separately prepared DMF solution of the residue was added and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (34 mg). MS (m / z): 350.1 [M+H] +

[0416] Example 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 (Compound E-1) [ka] [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) [ka] 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), HATU (37 mg) was added and stirred at room temperature for 1.5 hours. The reaction solution was purified by silica gel column chromatography to give the title compound (15 mg).

[0417] [Step 2] Preparation of Compound E-1 Compound E-1A (15 mg) was dissolved in methanol (2 mL), 1 M hydrochloric acid (0.032 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure to give the title compound (13 mg). MS (m / z): 525.5 [M+H] + Elemental analysis value (C 23 H 21 (as ClF4N6O2·HCl+1.3H2O) Calculated values ​​(%) C: 47.24, H: 4.24, N: 14.37 Actual measured values ​​(%) C: 47.37, H: 4.58, N: 13.98

[0418] Example 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 (Compound E-2) [ka] [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) [ka] To a mixture of 2-aminopyridine-4-carboxylic acid (13 mg), HBTU (35 mg), and DMF (1 mL), DIPEA (0.098 mL) was added and stirred at room temperature for 15 minutes. Compound RE-2 (30 mg) obtained in Step 7 of Reference Example 2 was added and stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (34 mg).

[0419] [Step 2] Preparation of Compound E-2 Compound E-2A (34 mg) was dissolved in methanol (2 mL), 1 M hydrochloric acid (0.074 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure to give the title compound (28 mg). MS (m / z): 509.1 [M+H] + optical rotation [α]58925 = -4.7° (0.01 g, methanol, 1 mL, 50 mm) Elemental analysis value (C 23 H 21 (as F5N6O2·HCl+1.2H2O) Calculated values ​​(%) C: 48.76, H: 4.34, N: 14.83 Actual measured values ​​(%) C: 48.50, H: 4.73, N: 14.68

[0420] Example 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 (Compound E-3) [ka] 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), DIPEA (0.022 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (12 mg). MS (m / z): 491.1 [M+H] +

[0421] Example 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 (Compound E-4) [ka] The procedure described in Example 3 was repeated except that Compound RE-5 (43 mg) obtained in Step 6 of Reference Example 5 was used instead of Compound RE-4, and 2-aminopyrimidine-4-carboxylic acid (15 mg) was used instead of Compound RE-24 to give the title compound (24 mg). MS (m / z): 482.3 [M+H] +

[0422] Example 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 (Compound E-5) [ka] The title compound (32 mg) was obtained by a method similar to that described in Example 3, except that compound RE-6 (40 mg) obtained in Step 5 of Reference Example 6 was used instead of compound RE-4. MS (m / z): 483.3 [M+H] +

[0423] Example 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 (Compound E-6) [ka] The title compound (7 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-7 (55 mg) obtained in Step 5 of Reference Example 7 was used instead of Compound RE-2. MS (m / z): 487.4 [M+H] +

[0424] Example 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 (Compound E-7) [ka] The procedure of Example 3 was repeated except that Compound RE-8 (15 mg) obtained in Step 2 of Reference Example 8 was used instead of Compound RE-4, and 2-amino-4-methyl-1,3-thiazole-5-carboxylic acid (5.9 mg) was used instead of Compound RE-24 to give the title compound (12 mg). MS (m / z): 469.2 [M+H] +

[0425] Example 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 (Compound E-8) [ka] The same procedure as in Step 1 of Example 2 was repeated except that Compound RE-9 (20 mg) obtained in Step 2 of Reference Example 9 was used instead of Compound RE-2, and Compound RE-25 (14 mg) obtained in Step 3 of Reference Example 25 was used instead of 2-aminopyridine-4-carboxylic acid to give the title compound (15 mg). MS (m / z): 503.2 [M+H] +

[0426] Example 9 4-[4-(4-fluoro-1-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine (Compound E-9) [ka] The title compound (25 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-10 (35 mg) obtained in Step 5 of Reference Example 10 was used instead of Compound RE-2. MS (m / z): 499.3 [M+H] +

[0427] Example 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 (Compound E-10) [ka] The title compound (17 mg) was obtained by a method similar to that described in Example 3, except that compound RE-11 (46 mg) obtained in Step 6 of Reference Example 11 was used instead of compound RE-4. MS (m / z): 536.3 [M+H] +

[0428] Example 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 (Compound E-11) [ka] To a mixture of Compound RE-12 (50 mg) obtained in Step 5 of Reference Example 12 and ethyl acetate (0.4 mL), hydrogen chloride (4 M ethyl acetate solution, 0.14 mL) was added and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 2-[3-(azetidin-3-yl)-1H-indol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride. Subsequently, the same procedure as in Step 1 of Example 2 was repeated except that 2-[3-(azetidin-3-yl)-1H-indol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride obtained above was used in place of compound RE-2 to give the title compound (14 mg). MS (m / z): 472.3 [M+H] +

[0429] Example 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 (Compound E-12) [ka] To a mixture of compound RE-13 (100 mg) obtained in Step 6 of Reference Example 13 and methanol (1 mL), hydrogen chloride (2 M methanol solution, 0.53 mL) was added and stirred at room temperature overnight. Hydrogen chloride (2 M methanol solution, 0.53 mL) was added to the remaining raw material, and the mixture was stirred at room temperature for 7 hours. Further hydrogen chloride (2 M methanol solution, 0.53 mL) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 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. Subsequently, in a manner similar to Step 1 of Example 2, the title compound (12 mg) was obtained by 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. MS (m / z): 488.2 [M+H] +

[0430] Example 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 (Compound E-13) [ka] [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) [ka] The title compound (22 mg) was obtained by a method similar to that in Step 1 of Example 2, except that Compound RE-14 (30 mg) obtained in Step 8 of Reference Example 14 was used instead of Compound RE-2.

[0431] [Step 2] Preparation of Compound E-13 The title compound (18 mg) was obtained by a method similar to Step 2 of Example 2, except that compound E-13A (22 mg) was used instead of compound E-2A. MS (m / z): 474.2 [M+H] +

[0432] Example 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 (Compound E-14) [ka] The title compound (22.3 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-15 (27.5 mg) obtained in Step 7 of Reference Example 15 was used instead of Compound RE-2. MS (m / z): 503.2 [M+H] +

[0433] Example 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 (Compound E-15) [ka] The title compound (27 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-16 (43 mg) obtained in Step 7 of Reference Example 16 was used instead of Compound RE-2. MS (m / z): 488.1 [M+H] +

[0434] Example 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 (Compound E-16) [ka] The same procedure as in Step 1 of Example 2 was repeated except that 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 give the title compound (5 mg). MS (m / z): 510.3 [M+H] +

[0435] Example 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 (Compound E-17) [ka] 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), DIPEA (0.021 mL) was added and stirred at room temperature for 10 minutes. Compound RE-3 (20 mg) obtained in Reference Example 3 was added and stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (8 mg). MS (m / z): 534.3 [M+H] +

[0436] Example 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 (Compound E-18) [ka] The procedure of Step 1 of Example 2 was repeated, except that Compound RE-17 (49 mg) obtained in Step 4 of Reference Example 17 was used instead of Compound RE-2, and Compound RE-24 (32 mg) obtained in Reference Example 24 was used instead of 2-aminopyridine-4-carboxylic acid to give the title compound (12 mg). MS (m / z): 462.2 [M+H] +

[0437] Example 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 (Compound E-19) [ka] [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) [ka] By a method similar to Step 7 of Reference Example 1, 3-(azetidin-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride was obtained using compound RE-18 (56 mg) instead of intermediate RE-1F. Subsequently, in a manner similar to Step 1 of Example 2, the title compound (14 mg) was obtained using 3-(azetidin-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride obtained above instead of compound RE-2.

[0438] [Step 2] Preparation of Compound E-19 The title compound (5.4 mg) was obtained by a method similar to Step 2 of Example 2, except that compound E-19A (14 mg) was used instead of compound E-2A. MS (m / z): 497.1 [M+H] +

[0439] Example 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 (Compound E-20) [ka] The title compound (53 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-19 (67 mg) obtained in Step 2 of Reference Example 19 was used instead of Compound RE-2. MS (m / z): 488.2 [M+H] +

[0440] Example 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 (Compound E-21) [ka] The same procedure as in Example 3 was repeated except that 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 give the title compound (6 mg). MS (m / z): 500.3 [M+H] +

[0441] Example 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 (Compound E-22) [ka] The title compound (22 mg) was obtained by a method similar to that of Example 3, except that compound RE-26 (16 mg) obtained in Step 3 of Reference Example 26 was used instead of compound RE-24. MS (m / z): 492.2 [M+H] +

[0442] Example 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 (Compound E-23) [ka] The same procedure as in Example 3 was repeated except that compound RE-20 (41 mg) obtained in Step 4 of Reference Example 20 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 give the title compound (19 mg). MS (m / z): 484.3 [M+H] +

[0443] Example 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 (Compound E-24) [ka] The title compound (9 mg) was obtained by a method similar to that described in Example 3, except that compound RE-21 (16 mg) obtained in Step 6 of Reference Example 21 was used instead of compound RE-4. MS (m / z): 495.3 [M+H] +

[0444] Example 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 (Compound E-25) [ka] The title compound (40 mg) was obtained by a method similar to that described in Example 3, except that compound RE-22 (62 mg) obtained in Step 8 of Reference Example 22 was used instead of compound RE-4. MS (m / z): 531.3 [M+H] +

[0445] Example 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 (Compound E-26) [ka] Compound E-1A (145 mg) was dissolved in THF (10 mL) by heating, and p-toluenesulfonic acid monohydrate (58 mg) was added and stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure, and the residue was washed with a mixture of methanol and diethyl ether and dried to obtain the title compound (150 mg). MS (m / z): 525.4 [M+H] + Elemental analysis value (C 23 H 21 (as ClF4N6O2·C7H8O3S+2.7H2O) Calculated values ​​(%) C: 48.32, H: 4.65, N: 11.27 Actual measured values ​​(%) C: 48.35, H: 4.44, N: 10.95

[0446] Example 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 (Compound E-27) [ka] Compound E-2A (1.80 g) was dissolved in THF (36 mL) by heating, and methanesulfonic acid (344 mg) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile by heating. The precipitated solid was allowed to cool, filtered, and dried to give the title compound (1.45 g). MS (m / z): 509.3 [M+H] + 1H-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) optical rotation [α] 589 25 =-4.4°(0.01g, methanol, 1mL, 50mm) Elemental analysis value (C 23 H 21 (as F5N6O2·CH4O3S+0.5H2O) Calculated values ​​(%) C: 46.98, H: 4.27, N: 13.70 Actual measured values ​​(%) C: 46.73, H: 3.89, N: 13.62

[0447] Example 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 (Compound E-28) [ka] The title compound was obtained by a method similar to Step 2 of Example 2, except that Compound E-3 was used instead of Compound E-2A. MS (m / z): 474.2 [M+H] + optical rotation [α] 589 25 =-2.78°(0.01g, methanol, 1mL, 50mm) Elemental analysis value (C 23 H 22 (as F4N6O2·HCl+0.9H2O) Calculated values ​​(%) C: 50.86, H: 4.60, N: 15.47 Actual measured values ​​(%) C: 51.13, H: 4.75, N: 15.14

[0448] Example 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 (Compound E-29) [ka] Compound E-3 (50 mg) was dissolved in THF (2 mL), methanesulfonic acid (11 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was washed with a mixture of methanol and diethyl ether. The resulting product was dissolved in methanol, and the solvent was removed under reduced pressure. The residue was washed with a mixture of 2-propanol and hexane, and dried to give the title compound (22 mg). MS (m / z): 491.2 [M+H] + optical rotation [α]589 20 :-2.2° (0.3g, methanol, 10mL, 100mm) Elemental analysis value (C 23 H 22 (as F4N6O2·CH4O3S) Calculated values ​​(%) C: 49.14, H: 4.47, N: 14.33 Actual measured values ​​(%) C: 49.10, H: 4.50, N: 14.36

[0449] Example 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 (Compound E-30) [ka]

[0450] [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) [ka] Compound RE-52 (125 mg) was dissolved in methanol (1 mL), hydrogen chloride (2 M methanol solution, 1 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and HATU (59 mg) was added to a mixture of the resulting 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 mixture was purified by silica gel column chromatography to obtain the title compound (32 mg). [Step 2] Preparation of Compound E-30 The title compound was obtained by a method similar to Step 2 of Example 2, except that Compound E-30A was used instead of Compound E-2A. MS (m / z): 509.5 [M+H] +

[0451] Example 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 (Compound E-31) [ka] [Step 1] Preparation of 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate 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 evaporated under reduced pressure to give the title compound (56 mg). [Step 2] Preparation of Compound E-31 Compound RE-52 (125 mg) was dissolved in methanol (1 mL), hydrogen chloride (2 M methanol solution, 1 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and HBTU (30 mg) was added to a mixture of the resulting residue (20 mg), 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate (23 mg), DIPEA (0.04 mL), and DMF (1 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (16 mg). MS (m / z): 510.1 [M+H] +

[0452] Example 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 (Compound E-32) [ka]

[0453] [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) [ka] Compound RE-52 (125 mg) was dissolved in methanol (1 mL), hydrogen chloride (2 M methanol solution, 1 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the resulting 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 separately prepared DMF solution of the residue was added, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (72 mg). MS (m / z): 532.0 [M+H] +

[0454] [Step 2] Preparation of Compound E-32 A mixture of compound E-32A (25 mg), rac-BINAP (18 mg), cesium carbonate (46 mg), 3-oxetanamine (10 mg), and 1,4-dioxane (2 mL) was degassed with argon, and then Pd(OAc) (2 mg) was added and stirred at 100°C for 3 hours. Insoluble matter was filtered off through Celite®, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (3 mg). MS (m / z): 525.1 [M+H] +

[0455] Example 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 (Compound E-33) [ka]

[0456] [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) [ka] 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, and then compound RE-2 (30 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to give the title compound (37 mg).

[0457] [Step 2] Preparation of Compound E-33 The title compound was obtained by a method similar to that of Step 2 of Example 2, except that Compound E-33A was used instead of Compound E-2A. MS (m / z): 533.2 [M+H] +

[0458] Example 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 (Compound E-34) [ka]

[0459] [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) [ka] 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 evaporated under reduced pressure, and the resulting residue (49 mg) was dissolved in a small amount of DMF. A separately prepared DMF solution of the residue 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) in a separate container, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (48 mg). MS (m / z): 569.2 [M+H] +

[0460] [Step 2] Preparation of Compound E-34 A mixture of compound E-34A (48 mg) and hydrogen chloride (2 M solution in 1,4-dioxane, 2 mL) was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (14 mg). MS (m / z): 469.2 [M+H] +

[0461] 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) [ka]

[0462] [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) [ka] The title compound was obtained by a method similar to that of Step 1 of Example 34, except that Compound RE-90 was used instead of Compound RE-89. MS (m / z): 583.3 [M+H] +

[0463] [Step 2] Preparation of Compound E-35 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 the mixture was stirred. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (64 mg). MS (m / z): 483.2 [M+H] +

[0464] Example 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 (Compound E-36) [ka] To a mixture of compound RE-116 (20 mg), D-prolinol (8 mg), DIPEA (0.03 mL), and methanol (0.5 mL), DMTMM (21 mg) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (5 mg). MS (m / z): 471.2 [M+H] +

[0465] Example 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 (Compound E-37) [ka]

[0466] [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) [ka] To a mixture of compound RE-122 (120 mg), azidomethylcyclopropane (83 mg), DMF (2 mL), and methanol (0.2 mL), copper(I) iodide (7 mg) was added and stirred overnight at 60°C under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography to give the title compound (28 mg). MS (m / z): 447.2 [M+H] +

[0467] [Step 2] Preparation of Compound E-37 A mixture of compound E-37A (28 mg), 4 M hydrochloric acid (0.02 mL), and 1,4-dioxane (2 mL) was stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (14 mg). MS (m / z): 447.2 [M+H] +

[0468] Example 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 (Compound E-38) [ka] The title compound was obtained by a method similar to that of Step 1 of Example 37, except that 3-(azidomethyl)oxetane was used instead of azidomethylcyclopropane. MS (m / z): 463.2 [M+H] +

[0469] 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) [ka] The title compound was obtained by a method similar to that of Step 1 of Example 37, except that Compound RE-115 was used instead of Compound RE-122 and 3-(azidomethyl)-1,1-difluorocyclobutane was used instead of azidomethylcyclopropane. MS (m / z): 525.3 [M+H] +

[0470] Example 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 (Compound E-40) [ka] The title compound was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-4 was used instead of Compound RE-2. MS (m / z): 473.2 [M+H] +

[0471] Example 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 (Compound E-41) [ka] Compound E-40 (3.2 g) was dissolved in methanol (23 mL), 2M hydrochloric acid (3.6 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in 2-propanol. Hexane was added, and the precipitated solid was collected by filtration. The mixture was dried under reduced pressure to obtain the title compound (3.47 g). MS (m / z): 473.2 [M+H] + [α]589 25 :-3.93°(0.02g, methanol, 5mL, 100mm) Elemental analysis value (C 23 H 23 (as F3N6O2·HCl+3H2O) Calculated values ​​(%) C: 49.07, H: 5.37, N: 14.93 Actual measured values ​​(%) C: 49.54, H: 5.81, N: 14.51

[0472] Example 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 (Compound E-42) [ka] The title compound was obtained by the same method as in Example 3, except that compound RE-61 was used instead of compound RE-4. MS (m / z): 543.2 [M+H] +

[0473] Example 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 (Compound E-43) [ka] Compound E-42 (32 mg) was dissolved in THF (2 mL), p-toluenesulfonic acid monohydrate (13 mg) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (36 mg). MS (m / z): 543.2 [M+H] + [α]589 25 =+7.42°(0.001g, methanol, 1mL, 100mm) Elemental analysis value (C 23 H 20 (as F6N6O3·C7H8O3S+1.4H2O) Calculated values ​​(%) C: 48.70, H: 4.20, N: 11.36 Actual measured values ​​(%) C: 49.01, H: 4.05, N: 10.89

[0474] Example 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 (Compound E-44) [ka]

[0475] [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) 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 and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (17 mg). [Step 2] Preparation of Compound E-44 Compound E-44A (17 mg) was dissolved in ethyl acetate (2 mL), p-toluenesulfonic acid monohydrate (13 mg) was added, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (19 mg). MS (m / z): 536.2 [M+H] +

[0476] Example 45 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-45) [ka] To a mixture of compound RE-121 (20 mg), 2,2,2-trifluoro-N-methylethanamine hydrochloride (13 mg), HBTU (33 mg), and DMF (0.3 mL), DIPEA (0.05 mL) was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (16 mg). MS (m / z) 447.2 [M+H] +

[0477] Example 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 (Compound E-46) [ka] Compound E-45 (50 mg) was dissolved in THF (1.1 mL), p-toluenesulfonic acid monohydrate (23 mg) was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, the residue was dissolved in methanol, diethyl ether was added, and the precipitated solid was collected by filtration. The mixture was dried under reduced pressure to obtain the title compound (69 mg). MS (m / z): 447.2 [M+H] + Elemental analysis value (C 21 H 21 (as F3N6O2·C7H8O3S+3.5H2O) Calculated values ​​(%) C: 49.33, H: 5.32, N: 12.33 Actual measured values ​​(%) C: 49.34, H: 5.01, N: 11.93

[0478] Example 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 (Compound E-47) [ka] 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, which was then removed under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was 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. This mixture was added to the previously obtained residue and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (12 mg). MS (m / z): 517.3 [M+H]

[0479] 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) [ka]

[0480] [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) [ka] The title compound was obtained by the same method as in Example 47, except that compound RE-41 was used instead of compound RE-40. MS (m / z): 491.3 [M+H] +

[0481] [Step 2] Preparation of Compound E-48 Compound E-48A (47 mg), methanol (3 mL), and ammonium formate (79 mg) were mixed with 10% Pd-C (13 mg) and stirred overnight at 80° C. Insoluble matter was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (24 mg). MS (m / z): 493.3 [M+H] +

[0482] Example 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 (Compound E-49) [ka] The title compound was obtained by a method similar to that of Step 2 of Example 48, except that Compound E-47 was used instead of Compound E-48A. MS (m / z): 519.3 [M+H] +

[0483] Example 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 (Compound E-50) [ka] 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 mixture was purified by silica gel column chromatography to give the title compound (21 mg). MS (m / z): 509.1 [M+H]+

[0484] Example 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 (Compound E-51) [ka]

[0485] [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) 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 overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to give the title compound (31 mg).

[0486] [Step 2] Preparation of Compound E-51 Compound E-51A (31 mg) was dissolved in methanol (2 mL), 1 M hydrochloric acid (0.06 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure, and the residue was washed with a mixture of ethanol and diethyl ether and dried to obtain the title compound (18 mg). MS (m / z): 539.2 [M+H] +

[0487] Example 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 (Compound E-52) [ka]

[0488] [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) Compound RE-91 (42 mg) was dissolved in 1,4-dioxane (1 mL), 4 M hydrochloric acid (1 mL) was added, and the mixture was stirred at 50 °C for 3 hours. The solvent was evaporated under reduced pressure, and the resulting 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 separately prepared DMF solution of the residue was added, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (17 mg). [Step 2] Preparation of Compound E-68 A mixture of compound E-52A (17 mg) and hydrogen chloride (4 M solution 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 mixture of methanol and diethyl ether and dried to give the title compound (8 mg). MS (m / z): 475.1 [M+H] +

[0489] Example 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 (Compound E-53) [ka] 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, and toluene was added to the resulting residue, which was then removed under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was removed under reduced pressure to obtain 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, and the previously obtained residue (44 mg) was added, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (25 mg). MS (m / z): 488.1 [M+H] +

[0490] Example 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 (Compound E-54) [ka]

[0491] [Step 1] Preparation of 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 (Compound E-54A) [ka] Compound RE-81 (51 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (30 mg), HBTU (82 mg), DIPEA (0.19 mL), and DMF (0.5 mL) was stirred at room temperature for 2 hours, and a separately prepared DMF solution of the residue was added and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (30 mg).

[0492] [Step 2] Preparation of Compound E-54 A mixture of compound E-54A (30 mg) and hydrogen chloride (4 M solution in 1,4-dioxane, 2 mL) was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the residue was washed with a mixture of methanol and diethyl ether and dried to give the title compound (28 mg). MS (m / z): 492.2 [M+H] +

[0493] Example 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 (Compound E-55) [ka] Compound RE-109 (45 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in DMF. In a separate container, a mixture of 2-aminopyridine-4-carboxylic acid (16 mg), HBTU (43 mg), DIPEA (0.15 mL), and DMF (0.3 mL) was stirred at room temperature for 2 hours, and a separately prepared DMF solution of the residue was added, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (18 mg). MS (m / z): 538.2 [M+H] +

[0494] Example 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 (Compound E-56) TIFF0007823226000357.tif41169 DIPEA (0.1 mL) was added to a mixture of compound RE-116 (30 mg), HBTU (38 mg), and DMF (0.5 mL) and stirred at room temperature for 5 minutes. (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (19 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (19 mg). MS (m / z): 539.2 [M+H] +

[0495] Example 57 4-(3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl}azetidine-1-carbonyl)pyridin-2-amine (Compound E-57) [ka] Compound RE-55 (80 mg) was dissolved in methanol (0.7 mL), hydrogen chloride (4 M in ethyl acetate, 0.03 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in DMF (0.5 mL). In a separate vessel, a mixture of 2-aminopyridine-4-carboxylic acid (30 mg), HBTU (103 mg), DIPEA (0.25 mL), and DMF (1.2 mL) was stirred at room temperature for 1.5 hours, and a separately prepared DMF solution of the residue was added, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to give the title compound (48 mg). MS (m / z): 462.3 [M+H] +

[0496] Example 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 (Compound E-58) [ka] [Step 1] Preparation of 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 (Compound E-58A) To a mixture of compound RE-87 (19 mg), compound RE-24 (8 mg), HOBt (8 mg), DIPEA (0.02 mL), and DMF (0.5 mL), EDCI·HCl (12 mg) was added and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (11 mg). [Step 2] Preparation of Compound E-58 Compound E-58A (11 mg) was dissolved in ethyl acetate (2 mL), p-toluenesulfonic acid monohydrate (8 mg) was added, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (19 mg). MS (m / z): 540.2 [M+H] + 1 H-NMR(400MHz,DMSO-D6)δ8.92(d,1H),8.22(d,1H),8.09(d,1H),7.47(d,4H),7.11(s,4H),5.55(d,2H),4 .61-4.52(m,2H),4.50-4.40(m,1H),4.37-4.28(m,2H),4.20-4.07(m,2H),2.29(s,6H),2.11-1.84(m,5H) Elemental analysis value (C 23 H 22 F5N7O3·C 14 H 16 (as O6S2+3.0H2O) Calculated values ​​(%) C: 47.38, H: 4.73, N: 10.45 Actual measured values ​​(%) C: 47.14, H: 4.72, N: 10.36

[0497] Example 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 (Compound E-59) [ka] A mixture of intermediate RE-20C (81 mg), dichloromethane (2 mL), and trifluoroacetic acid (0.7 mL) was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure, and toluene was added to the resulting residue, which was then removed under reduced pressure. Ethyl acetate and hexane were then added, and the solvent was removed under reduced pressure. A mixture of a portion of the resulting residue (41 mg), compound RE-24 (21 mg), HOBt (16 mg), DIPEA (0.08 mL), DMF (1 mL), and EDCI·HCl (22 mg) was stirred at room temperature for 2.5 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (18 mg). MS (m / z): 483.2 [M+H] +

[0498] Example 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 (Compound E-60) [ka] A mixture of compound RE-117 (50 mg), (2R)-2-(trifluoromethyl)pyrrolidine hydrochloride (24 mg), HOBt (18 mg), DIPEA (0.07 mL), DMF (0.5 mL), and EDCI·HCl (26 mg) was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography to give the title compound (20 mg). MS (m / z): 491.0 [M+H] +

[0499] The compounds of each example shown in Tables 1 to 32 below (in the tables, "XXX" in "E-XXX" indicates the example number) were produced by combining a reference example compound with a reactive fragment, and carrying out a condensation reaction, and if necessary, deprotection and salification, according to procedures similar to those described in the above-mentioned examples. In the table, a Reference Example indicates that the compound was produced by the method described in the Example number, or by a method similar to that production method using the corresponding starting material. For example, an Example compound with Reference Example number 1 means that it was produced by a method similar to Example 1. In the table, the data refers to instrumental analysis data of the compound, such as mass spectrometry data (m / z value).

[0500] [Table 1]

[0501] [Table 2]

[0502] [Table 3]

[0503] [Table 4]

[0504] [Table 5]

[0505] [Table 6]

[0506] [Table 7]

[0507] [Table 8]

[0508] [Table 9]

[0509] [Table 10]

[0510] Table 11

[0511] Table 12

[0512] Table 13

[0513] Table 14

[0514] Table 15

[0515] Table 16

[0516] Table 17

[0517] Table 18

[0518] Table 19

[0519] Table 20

[0520] Table 21

[0521] Table 22

[0522] Table 23

[0523] Table 24

[0524] Table 25

[0525] Table 26

[0526] Table 27

[0527] Table 28

[0528] Table 29

[0529] Table 30

[0530] Table 31

[0531] [Table 32]

[0532] Similarly, the compounds of each example shown in Tables 33 to 48 below (in the tables, "XXX" in "E-XXX" indicates the example) were produced by combining a reference example compound with a reactive fragment and carrying out a condensation reaction, and, if necessary, deprotection and salification, according to procedures similar to those described in the above-mentioned examples.

[0533] [Table 33]

[0534] [Table 34]

[0535] [Table 35]

[0536] [Table 36]

[0537] [Table 37]

[0538] [Table 38]

[0539] [Table 39]

[0540] [Table 40]

[0541] [Table 41]

[0542] [Table 42]

[0543] [Table 43]

[0544] [Table 44]

[0545] [Table 45]

[0546] [Table 46]

[0547] [Table 47]

[0548] [Table 48]

[0549] The numbers and chemical names of the example compounds are shown in Tables 49 to 72 below. In the tables, the chemical names represent the names of the compounds corresponding to the compound numbers.

[0550] [Table 49]

[0551] Table 50

[0552] Table 51

[0553] Table 52

[0554] Table 53

[0555] Table 54

[0556] Table 55

[0557] Table 56

[0558] Table 57

[0559] Table 58

[0560] Table 59

[0561] Table 60

[0562] Table 61

[0563] Table 62

[0564] Table 63

[0565] Table 64

[0566] Table 65

[0567] Table 66

[0568] Table 67

[0569] Table 68

[0570] Table 69

[0571] [Table 70]

[0572] [Table 71]

[0573] [Table 72]

[0574] The following are examples of biological tests of the compounds used in the present invention.

[0575] <Test Example 1: Evaluation of DDR1 kinase inhibitory effect> 1. Preparation of Test Substances Test substances were prepared at 10 mM with dimethyl sulfoxide (DMSO, Nacalai Tesque, 13445-74), and six concentrations were selected for each compound, which were then diluted with DMSO to final concentrations of 1000, 100, 10, 1, 0.1, 0.01, and 0.001 μM. Furthermore, this solution was diluted with a buffer containing 50 mM HEPES (Fujifilm Wako Pure Chemical Industries, 340-01371), 1 mM EGTA (DOJINDO, G002), 10 mM magnesium chloride hexahydrate (Nacalai Tesque, 20908-65), 2 mM dithiothreitol (Nacalai Tesque, 14112-52), and 0.01% Tween 20 (Tokyo Chemical Industry, T0543) to six concentrations of 330,000, 33,000, 330, 33, 3, 0.3, and 0.03 nM for each compound, and these were used as test substance solutions. 2. Measurement of inhibitory effects on the kinase activity of DDR1 kinase Six concentrations were selected for each compound, and the prepared test substance solutions were added to a 384-well plate (Corning, 4512) at 3 μL / well to achieve final concentrations of 10,000, 1,000, 100, 10, 1, 0.1, and 0.01 nM. DDR1 protein (Carna Biosciences, 08-113) was added at 2 μL / well to achieve a final concentration of 0.5 nM. LANCE Ultra ULight was used as the substrate. TM Poly GAT (PerkinElmer, TRF0101) and ATP (Sigma-Aldrich, A6559) were mixed to final concentrations of 50 nM and 100 μM, respectively, and added at 5 μL / well. After 2 hours of incubation at room temperature, 10 μL / well of LANCE Detection Buffer (PerkinElmer, CR97-100) containing 10 mM EDTA (DOJINDO, K001) and 1 nM Europium (PerkinElmer, AD0068) was added. After 1 hour of incubation at room temperature, fluorescence intensity at 615 nm and 665 nm was measured using an Envision (PerkinElmer) or SpectraMax iD5 (Molecular Devices). Tests were performed in duplicate. 3. Analysis of measurement results The fluorescence intensity at 665 nM was divided by the fluorescence intensity at 615 nM to calculate the inhibition rate of each test substance, with the maximum inhibition rate set at 100% and the minimum inhibition rate set at 0%...

Claims

1. 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.

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, or a solvate thereof.

3. 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.

4. 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.

5. 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.

6. 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.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. A DDR1 kinase inhibitor comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.

9. A preventive or therapeutic agent for a disease involving DDR1 kinase, comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. 10. A therapeutic agent for treating Alport syndrome, IgA nephropathy, Goodpature syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura 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 the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

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