Compounds and pharmaceuticals as DDR1 kinase inhibitors

Abstract

Provides DDR1 inhibitors [Solution] A compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is provided. TIFF2026086800000449.tif65169 In the formula, A is a benzene ring or a nitrogen-containing 6-membered ring, B is a substituted 3- to 8-membered monocyclic nitrogen-containing heterocycle, and Het is a 5- to 10-membered monocyclic or bicyclic heterocycle.

Description

[Technical Field]

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

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

[0003] DDR1 transmits collagen signals into cells by binding to its ligand, collagen, via its Discoidin Domain. A distinctive feature of DDR1 is its ability to recognize not only fibrous collagen such as type I collagen, but also basement membrane collagen such as type IV collagen. In DDR1 bound to collagen, specific tyrosine residues in the kinase domain on the cytoplasmic side of the receptor are phosphorylated, and molecules possessing Src homology 2 or a phosphotyrosine binding domain bind to it, activating various downstream signaling pathways.

[0004] DDR1 activation is involved in various kidney diseases. From Alport syndrome (Non-Patent Literature 1, 2), which is caused by type IV collagen gene mutations, to IgA nephropathy (Non-Patent Literature 3), Goodpasture syndrome (Non-Patent Literature 4), lupus nephritis (Non-Patent Literature 4), ANCA (anti-neutrophil cytoplasmic antibody)-associated nephritis (Non-Patent Literature 5), and diabetic nephropathy (Non-Patent Literature 6), DDR1 activation is involved in the pathogenesis of each of these kidney diseases.

[0005] Furthermore, DDR1 activation has been reported to be involved in various fibrotic diseases. For example, pulmonary fibrosis (Non-Patent Document 7) and liver cirrhosis (Non-Patent Document 8) are known to be associated with it.

[0006] Furthermore, DDR1 has been reported to be involved in the function of Th17 cells, which are involved in autoimmune diseases and allergies (Non-Patent Literature 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 diseases. For example, it is known to be involved in acute myeloid leukemia (Non-Patent Literature 10), acute lymphoblastic leukemia (Non-Patent Literature 11), chronic lymphocytic leukemia (Non-Patent Literature 12), Hodgkin lymphoma (Non-Patent Literature 13), glioma (Non-Patent Literature 14), non-small cell lung cancer (Non-Patent Literature 15), breast cancer (Non-Patent Literature 16), ovarian cancer (Non-Patent Literature 17), prostate cancer (Non-Patent Literature 18), and colorectal cancer (Non-Patent Literature 19).

[0008] Furthermore, DDR1 has been reported to be involved in other conditions such as systemic lupus erythematosus (Non-Patent Literature 5), osteoarthritis (Non-Patent Literature 20), heparin-induced thrombocytopenia (Non-Patent Literature 21), atherosclerosis (Non-Patent Literature 22), and vitiligo (Non-Patent Literature 23).

[0009] Much of the treatment for these diseases is limited to symptomatic relief, slowing disease progression, and improving quality of life, making effective treatment extremely difficult. Therefore, DDR1 inhibitors are thought to offer a new treatment option 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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Non-licensed literature 9

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Non-Patent Document 14

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Non-Patent Document 17

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

Means for Solving the Problems

[0012] The present inventors have found that the compound or a pharmaceutically acceptable salt thereof, or a solvate thereof described below has excellent DDR1 kinase inhibitory activity, and completed the present invention.

[0013] That is, the present invention includes the following aspects (Item 1) to (Item 22). (Item 1) Formula (I)

Chemical formula

Chemical formula

Chemical formula

[0014] The definitions of each term used in this specification are described in detail below.

[0015] As used herein, "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Fluorine atoms, or chlorine atoms, are particularly preferred.

[0016] Examples of the "alkyl" used herein include alkyl groups having one to eight carbon atoms (C1-C8), preferably one to six carbon atoms (C1-C6), in a linear or branched chain. Specifically, 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] Examples of "alkenyls" as used herein include linear or branched alkenyls with 2 to 8 carbon atoms (C2-C8) having one or two double bonds. Specifically, 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. Preferably, alkenyls have 2 to 6 carbon atoms, and more preferably, alkenyls have 2 to 4 carbon atoms.

[0018] Examples of "alkynyls" used herein include linear or branched alkynyls with 2 to 8 carbon atoms (C2-C8) having one or two triple bonds. Specifically, 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. Preferably, alkynyls have 2 to 6 carbon atoms, and more preferably, alkynyls have 2 to 4 carbon atoms.

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

[0020] Examples of "haloalkyl" as used herein include groups in which one to three hydrogen atoms of the above-mentioned "alkyl" are substituted with the above-mentioned "halogen". Specifically, 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] Examples of "alkoxy" as used herein include linear or branched alkoxys having one to eight carbon atoms (C1-C8), preferably one to six carbon atoms (C1-C6). Specifically, examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the like.

[0022] Examples of "haloalkoxy" as used herein include groups in which one to three hydrogen atoms of the above-mentioned "alkoxy" are substituted with the above-mentioned "halogen". Specifically, 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 group of 3 to 10 carbon atoms (C3-C3). 10Examples include monocyclic, bicyclic, or tricyclic saturated hydrocarbon groups having ). Specifically, these 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 Examples include (also known as decanil).

[0024] Examples of "halocycloalkyl" as used herein include groups in which one to three hydrogen atoms of the above-mentioned "cycloalkyl" are substituted with the above-mentioned "halogen". Specifically, examples include 2-fluorocyclopropyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopentyl, and 4,4-difluorocyclohexyl.

[0025] As used herein, "cycloalkenyl" refers to, for example, a cycloalkenyl with 3 to 10 carbon atoms (C3-C3). 10 Examples include monocyclic, bicyclic, or tricyclic unsaturated hydrocarbon groups having one or two double bonds within the molecule. Specifically, examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.

[0026] Examples of "heterocycloalkyl" as used herein include monocyclic or bicyclic saturated heterocyclic rings having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms within the ring, and composed of 4 to 10 ring-constituting atoms. Specifically, examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, 1,3-dioxolanil, 1,4-dioxolanil, and tetrahydrothiophenyl.

[0027] Examples of "aryl" as used herein include monocyclic, bicyclic, or tricyclic aromatic hydrocarbon groups having 6 to 14 carbon atoms. Specifically, examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Phenyle is particularly preferred.

[0028] As used herein, "heteroaryl" can refer to, for example, monocyclic or bicyclic aromatic heterocyclic groups having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in the ring, and consisting of 5 to 10 ring constituent atoms. Specifically, these 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-pyrrolyl, 4-pyrrolyl), and triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazolyl). (4-yl), tetrazolyl (e.g., 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, i Sothiazolyl (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-pyridazinyl, 4-pyridazinyl, 5-pyridinyl), pyrazinyl (e.g., 2-pyridazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4- Examples include benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl).More preferably, these 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] A "carbocyclic ring" refers to a cyclic structure composed of carbon atoms, and includes the aforementioned "cycloalkyl," "cycloalkenyl," and "aryl" groups.

[0030] A "heterocycle" refers to a cyclic structure composed of one or more heteroatoms selected from, for example, nitrogen, sulfur, and oxygen atoms, and carbon atoms. "Heterocycles" include the "heterocycloalkyl" and "heteroaryl" structures mentioned above.

[0031] As used herein, "3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle" means, for example, a saturated or unsaturated monocyclic heterocycle having 1 to 4 nitrogen atoms in the ring and composed of 3 to 8 ring constituent atoms. Specifically, this includes azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanil, azocanil, pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrrolyl, 4-pyrrolyl), triazolyl (e.g., 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2, Examples include 3-triazole-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-pyridazinyl, 4-pyridazinyl, 5-pyridinyl), pyrazinyl (e.g., 2-pyridazinyl), etc.

[0032] As used herein, "5- to 10-membered monocyclic or bicyclic saturated heterocycle" means a monocyclic or bicyclic saturated heterocycle having, for example, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms within the ring, and composed of 5 to 10 ring constituent atoms. Specifically, examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, 1,3-dioxolanil, 1,4-dioxolanil, tetrahydrothiophenyl, and the like.

[0033] As used herein, "5- to 10-membered monocyclic or bicyclic unsaturated heterocycle" means a monocyclic or bicyclic aromatic heterocycle or non-aromatic unsaturated heterocycle having, for example, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms within the ring, and consisting of 5 to 10 constituent atoms.Specifically, these 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-pyrrolyl, 4-pyrrolyl), triazolyl (e.g., 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2,3-triazole-4-yl), tetrazolyl (e.g., 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl) (e.g., 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl-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-pyrimidinyl), 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, azinadazolyl (e.g., 3-azinadazolyl, 4-azinadazolyl, 5-azinadazolyl, 6-a Examples include zindazolyl (7-azindazolyl), benztriazolyl (e.g., 5-benztriazolyl, 6-benztriazolyl), azaindolyl (e.g., 5-azindolyl, 6-azindolyl, 7-azindolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), and pyridonyl (e.g., 2-pyridone-3-yl, 2-pyridone-4-yl, 2-pyridone-5-yl, 2-pyridone-6-yl).More preferably, 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-pyridazinyl, 4-pyridazinyl, 5-pyrididinyl), pyrazinyl (e.g., 2-pyridazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) These include imidazolyl (7-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), pyrazolo[5,1-b]thiazolyl, azindazolyl (e.g., 3-azindazolyl, 4-azindazolyl, 5-azindazolyl, 6-azindazolyl, 7-azindazolyl), benztriazolyl (e.g., 5-benztriazolyl, 6-benztriazolyl), azaindyl (e.g., 5-azindyl, 6-azindyl, 7-azindyl), and pyridonyl (e.g., 2-pyridone-3-yl, 2-pyridone-4-yl, 2-pyridone-5-yl, 2-pyridone-6-yl).

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

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

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

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

[0038] "May be substituted in some cases" means that the specified group may or may not be substituted; in other words, it can be substituted or unsubstituted. For example, "alkyl that may be substituted in some cases" means both unsubstituted and substituted alkyl groups. Examples of substituents that substitute for a specified group include alkyl, haloalkyl, alkoxy, cycloalkyl, halocycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl, or heteroaryl substituents as defined above, as well as substituents in combination thereof (for example, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amino, aryl, or heteroaryl substituents that are 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 substituents). Furthermore, the number of substituents substituting the specified group is, for example, one to three, preferably one or two, and more preferably one.

[0039] The preferred embodiments of each group indicated by the symbols in the compounds of formulas (I) to (III) are shown below. As compounds of formulas (I) to (III), all combinations of the specific examples of each group shown below are illustrated.

[0040] A is preferably, [ka] (In the formula, Y 1 , Y 2 , Y 3 and Y 4 Each of these is independently N or CR 5 And, Here 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), the dashed line indicates the bonding point) or [Chemical formula] (wherein 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), the dashed line indicates the bonding point) is. A is more preferably [Chemical formula] (wherein Y 1 Y 2 Y 3 and Y 4 is C-R 5 and R 5 is hydrogen, the dashed line indicates the bonding point) 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 optionally substituted with C1-C6 alkyl (e.g., methyl), and particularly preferably azetidinyl.

[0042] X is preferably N or C-R 7 wherein the R 7The element is preferably hydrogen, and more preferably nitrogen.

[0043] R 1 Preferably, each independently, is hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3-C 10 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be substituted as needed. R 1 More preferably, each is independently hydrogen, a halogen (e.g., a fluorine atom, a chlorine atom), an oxo, a C1-C6 alkyl (e.g., methyl), an amino, or a monoalkylamino (e.g., methylamino, ethylamino), where the amino may be substituted with a cycloalkyl (e.g., cyclopropyl, cyclobutyl, 1-methylcyclopropyl) or a heterocycloalkyl (e.g., oxetanyl, tetrahydropyranil), and the C1-C6 alkyl may be substituted with one to three halogens (e.g., fluorine atoms). R 1 More preferably, each is independently hydrogen, a halogen (e.g., a fluorine atom), or an amino acid.

[0044] R 2 and R 3 Preferably, each of these is independently hydrogen and a halogen (for example, a fluorine atom).

[0045] R 4 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 10The group consists of cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl compounds, each of which may be substituted as needed. R 4 The more preferably selected from the group consisting of C2-C6 alkynyls (e.g., ethynyl), carboxyl, monocyclic or bicyclic saturated carbocyclics (e.g., cyclohexyl), monocyclic or bicyclic unsaturated carbocyclics (e.g., phenyl, 2,3-dihydro-1H-indenyl), monocyclic or bicyclic saturated heterocyclics (e.g., azetidinyl), and monocyclic or bicyclic unsaturated heterocyclics (e.g., pyridyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl), Here, (1) C2-C6 alkynyl is C3-C 10 They may be substituted with cycloalkyl (e.g., cyclopropyl) or aryl (e.g., phenyl), (2) The carboxyl group may be substituted with a C1-C6 alkyl group (e.g., tert-butyl). (3) Monocyclic or bicyclic saturated carbon rings may be substituted with halogens (e.g., fluorine atoms), (4) Monocyclic or bicyclic unsaturated carbon rings may be substituted with haloalkyl groups (e.g., trifluoromethyl groups). (5) Monocyclic or bicyclic saturated heterocycles may be substituted with aryl (e.g., phenyl) or haloalkyl (e.g., 2,2,2-trifluoroethyl), and Monocyclic or bicyclic unsaturated heterocycles may be substituted with substituents selected from the following group: (i) Haloalkyl (e.g., trifluoromethyl, 2,2,2-trifluoroethyl), (ii) C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl) substituted with a haloalkyl (e.g., trifluoromethyl), (iii) Heterocycloalkyl (e.g., tetrahydropyranyl), (iv) Aryl (e.g., phenyl) which may be substituted with a halogen (e.g., fluorine atom) or a haloalkyl (e.g., trifluoromethyl), (v) heteroaryls (e.g., pyridyl, pyridazinyl) which may be substituted with a halogen (e.g., a fluorine atom) or a C1-C6 alkyl (e.g., methyl), and (vi) Halocycloalkyl (e.g., 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl), aryl (e.g., phenyl), C3-C 10 A C1-C6 alkyl group (e.g., methyl) which may be substituted with a cycloalkyl group (e.g., cyclopropyl) or a heterocycloalkyl group (e.g., oxetanyl).

[0046] Also, R 4 Preferably, -CONR 8 R 9 And, Here, R 8 and R 9 Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Selected from the group consisting of cycloalkyl, C3-C6 cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be substituted as appropriate, or R 8 and R 9 These atoms, together with the atoms to which they are bonded, form a 5-10 member monocyclic or bicyclic saturated heterocycle or a 5-10 member monocyclic or bicyclic unsaturated heterocycle, which may be substituted in some cases. It is. Comfortable, R 8 and R 9 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycloalkyl, and heteroaryl, and each of these may be substituted as needed. Here, more preferably, (1) The C1-C6 alkyl group may be, for example, methyl, ethyl, isopropyl, or tert-butyl, and may be substituted with substituents selected from the following group: (i) Halogens (e.g., fluorine atoms), (ii) C1-C6 alkoxy (e.g., methoxy), (iii) Haloalkoxys (e.g., trifluoromethoxy), (iv) Heterocycloalkyl (e.g., tetrahydropyranyl, morpholinyl) (v) Halocycloalkyls (e.g., 3,3-difluorocyclobutyl), and (vi) Aryl (e.g., phenyl) which may be substituted with a halogen (e.g., fluorine atom), (2) C3-C6 cycloalkyl groups are particularly cyclobutyl, cyclopentyl, and cyclohexyl, and are often substituted with halogens (e.g., fluorine atoms) or cyano compounds. (3) The heterocycloalkyl is, for example, oxetanyl, tetrahydropyranyl, and may be substituted with, and (4) The heteroaryl is, for example, pyrazolyl and may be substituted with a halogen (for example, a fluorine atom). Also, R 8 and R 9 Preferably, these atoms form a 5-10 member monocyclic or bicyclic saturated heterocycle or a 5-10 member monocyclic or bicyclic unsaturated heterocycle, which may be substituted together with the atoms to which they are bonded. Here, more preferably, (1) 5-10 membered monocyclic or bicyclic saturated heterocycles include, 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, and azabicyclo[3.2.1]octanyl, which may be substituted with substituents selected from the following group: (i) Halogens (e.g., fluorine atom, bromine atom) (ii) C1-C6 alkyl (e.g., methyl, ethyl, isopropyl) which may be substituted with a hydroxyl group, a C1-C6 alkoxy (e.g., methoxy), a haloalkoxy (e.g., trifluoromethoxy), or a 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) Haloalkoxys (e.g., difluoromethoxy), and (vii) Cyano, (2) 5-10 membered monocyclic or bicyclic unsaturated heterocycles, for example, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 2,3-dihydro-1H-indolyl That is the case.

[0047] Particularly preferred, R 4 -CONR 8 R 9 And here, R 8 and R 9 These atoms, together with the atoms to which they are bonded, form a five-membered monocyclic saturated heterocycle (e.g., pyrrolidinyl) substituted with a haloalkyl group (e.g., trifluoromethyl).

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

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

[0050] Het is preferably a 5-10 member monocyclic or bicyclic unsaturated heterocycle, more preferably pyridyl, pyrimidinyl, 1,3-thiazolyl, pyridadinyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-thiazolyl, imidazo[1,2-a]pyridyl, pyrazolo[3,2-b][1,3]thiazolyl, 1,3-oxazolyl, 1H-indazolyl, pyrazolyl, 1H-1,2,3-benzotriazolyl, and even more preferably pyridyl. [Modes for carrying out the invention]

[0051] The compounds of the present invention can be produced using known compounds or intermediates readily synthesized from known compounds, for example, by the method described below, the examples described later, or other known methods. In the production of the compounds of the present invention, if the starting materials have substituents that affect the reaction, it is common practice to protect the starting materials with an appropriate protecting group beforehand using a known method before carrying out the reaction. The protecting group can be deprotected after the reaction using a known method.

[0052] The abbreviations used herein have the following meanings: The following abbreviations are used in the examples. TFA: Trifluoroacetic acid AZADOL(registered trademark): 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(diphenylphosphin)ferrocene]dichloropalladium(II) dichloromethane adduct Xantphos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene BINAP:2,2'-bis(diphenylphosphin)-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-triazine-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 of the following manufacturing methods are carried out by appropriately modifying or combining methods described in, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition" by R.C. Larock, John Wiley & Sons Inc., 1999; "Experimental Chemistry Course" 4th edition, edited by the Chemical Society of Japan, Maruzen, 1992; "Organic Synthesis Strategies Learned from Named Reactions" by L. Kuerti and B. C. Zako, supervised translation by Kiyoshi Tomioka, Kagaku Dojin, 2006; "Latest Organic Synthesis Methods: Design and Strategy" by GS Zweifel and M.H. Nantz, translated by Tamejiro Hiyama, Kagaku Dojin, 2009; or methods described in the examples.

[0054] Synthesis of compound (G-1) [ka] (Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , B is synonymous with the above. PG 1 The symbol represents a protecting group, and examples include tert-butoxycarbonyl (hereinafter referred to as "Boc"), benzyloxycarbonyl (hereinafter referred to as "Cbz"), benzyl (hereinafter referred to as "Bn"), etc. 1 (This represents chloro, bromo, and triflate.)

[0055] Step 1 This step involves reacting compound A-1, synthesized by a commercially available or known method, with compound B-1, synthesized by a commercially available or known method, in a solvent such as THF or diethyl ether in the presence of lithium diisopropylamide (LDA), at a temperature of -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, and even more preferably 30 minutes to 3 hours, to obtain compound C-1. LDA can be a commercially available product or one 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 uses 2-azadamantane-N-oxyl (AZADOL registered trademark), 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), Des-Martin reagent, etc., and reacts 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 and TEMPO, it is common to use co-oxidizing agents such as iodobenzene diacetate and sodium hypochlorite (NaOCl).

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

[0058] Step 4 This step involves alkylating compound Ea-1 with alkylating agent F-1 in the presence of a base to obtain compound G-1, and can be carried out according to known alkylation methods. The reaction can be carried out 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 a temperature of 0°C to 120°C, preferably room temperature to 120°C, for 1 to 48 hours, preferably 1 to 12 hours.

[0059] The above C-1 and D-1 can also be manufactured using the following method. [ka] (Y 1 , Y 2 , Y 3 , Y 4 , B, PG 1 This is synonymous with the above. X 2 (This represents Br, I.)

[0060] Route 1 This step involves reacting compound A-2, synthesized commercially or by known methods, with B-1 in a solvent such as THF or diethyl ether in the presence of butyllithium (n-BuLi) 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, and more preferably 30 minutes to 3 hours, to obtain compound C-1.

[0061] Route 2 This step involves reacting compound A-1, synthesized by a commercially available or known method, with compound B-2, synthesized by a commercially available or known method, in a solvent such as THF or diethyl ether in the presence of butyllithium (n-BuLi), 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, and more preferably 30 minutes to 3 hours, to obtain compound D-1.

[0062] Synthesis of compound (G-2) [ka] (A, R 1 , R 2 , R 3 , R 4 B, X 1 PG 1 This is synonymous with the above. X 3 (These represent I, Cl, and Br.)

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

[0064] Step 2 This step involves alkylating compound J-1 with 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 of the synthesis of compound (G-1).

[0065] Step 3 This step involves obtaining compound G-2 through a Negishi coupling reaction between compound K-1 and L-1. In this reaction, compound K-1 is added to 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"), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)·dichloromethane adduct (hereinafter referred to as "Pd(dppf)2Cl2"), along with L-1 synthesized by a commercially available or known method, in a solvent such as dioxane, toluene, DMSO, DMF, DME, DMA, or THF, and compound G-2 can be obtained by reacting the mixture 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.

[0066] Synthesis of compound (I) [ka] (A, B, R 1 , R 2 , R 3 , R 4 Het, m, PG 1 (This is synonymous with the above.)

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

[0068] Step 2 This process involves condensing compound M-1 with compound N-1 or its reactive compound N-1 in the presence of a condensing agent to obtain compound (I). In this reaction, compound M-1, compound N-1, organic bases such as TEA, DIPEA, N,N-dimethylaniline, or DBU, solvents such as toluene, xylene, 1,4-dioxane, THF, DME, DMF, DMA, dichloromethane, or dichloroethane are used to react with 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-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter referred to as "HBTU"), and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Compound (I) can be obtained by carrying out the reaction at 0°C to 50°C, preferably at room temperature to 50°C, in the presence of a condensing agent such as hexafluorophosphate (hereinafter referred to as "HATU"). In this process, examples of reactive compounds for compound N-1 include those commonly used in amide condensation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and activated amides. In this process, additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt"), N-hydroxysuccinimide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt") may be added as needed.

[0069] Synthesis of compound (I-2) (R 4 ga—CONR 8 R 9 in the case of) [ka] (A, B, PG 1 , R 1 , Het, R 8 , R9 ,m is synonymous with the above. R A (These represent methyl, ethyl, n-propyl, and t-butyl.)

[0070] Step 1 This step involves deprotecting compound G-2 to obtain M-2, and can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., Wuts and Greene, 2006, or "Protecting Groups," 3rd edition, Thiemes, 2005, PJ Kocienski.

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

[0072] Step 3 This process involves protecting the compound O-2 with a protective group (PG). 2 This is a step to deprotect P-2, and can be synthesized by referring to "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thiemes, 2005, by PJ Kocienski.

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

[0074] Furthermore, compound I-2 can also be obtained by reversing the order of Step 1-Step 2 and Step 3-Step 4 in the synthesis of I-2 described above. That is, the R of G-2 A The carboxylic acid obtained by deprotecting (hydrolyzing) is condensed with Q-1. Subsequently, the amine obtained by deprotecting PG1 is condensed with N-1 to synthesize I-2.

[0075] The compounds of the present invention can be used as pharmaceuticals as they are, but they can also be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts by known methods. 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; or salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and salts of organic bases such as ammonium salts. These salts can be formed by commonly used methods.

[0076] For example, if 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 compounds of the present invention may incorporate solvent molecules and become solvates when left in the atmosphere or by recrystallization, and such solvates are also included in the compounds of the present invention. Examples of such solvates include solvates with solvent molecules such as methanol, ethanol, isopropyl alcohol, butanol, dimethyl sulfoxide, and acetonitrile, as well as monohydrates and dihydrates.

[0078] Some of the compounds of the present invention have an asymmetric carbon, and each optical isomer and mixture thereof are included in the present invention. Stereoisomers can be produced, for example, by optical resolution from a racemate using an optically active acid (tartaric acid, dibenzoyl tartaric acid, mandelic acid, 10-camphor sulfonic acid, etc.) by known methods utilizing its basicity, or by using a pre-prepared optically active compound as a starting material. They can also be produced by optical resolution using a chiral column or by asymmetric synthesis.

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

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

[0081] Furthermore, one embodiment of the present invention provides a method for inhibiting DDR1 kinase, comprising administering the compound of the present invention to a target that requires it.

[0082] Furthermore, one embodiment of the present invention provides a compound for use in DDR1 kinase inhibition.

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

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

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

[0086] Furthermore, one embodiment of the present invention provides a compound for use in the prevention or treatment of diseases involving DDR1 kinase.

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

[0088] Diseases to which the compounds of the present invention can be applied include, for example, Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, Henoch-Schönlein 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 lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

[0089] Therefore, one embodiment of the present invention provides a preventive or therapeutic agent for the above-mentioned disease, 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 disease, comprising administering the compound of the present invention to a subject in need thereof.

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

[0092] Furthermore, one embodiment of the present invention provides the use of the compound of the present invention in the manufacture of a preventive or therapeutic agent for the above-mentioned disease.

[0093] "Subject" refers to a human or non-human animal that has or is 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 is, or mixed with a pharmaceutically acceptable carrier, to form a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, which can then be used as a therapeutic agent for various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, and monkeys.

[0095] As a carrier, one or more conventionally accepted pharmaceutically acceptable solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical composition according to the present invention is preferably administered in dose unit form. The pharmaceutical composition can be administered intratissue, orally, intravenously, topically (transdermally, ophthalmoscopy, intraperitoneally, intrathoracically, etc.), or rectally. The pharmaceutical composition according to the present invention is administered in a dosage form suitable for these administration methods.

[0096] The dosage of the compound used as a medicine should preferably be adjusted considering the patient's condition, such as age, weight, type and severity of the disease, the route of administration, the type of compound of the present invention, whether it is a salt or not, and the type of salt. However, for adults, the appropriate amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt is usually within the range of 0.01 mg to 5 g per adult per day, preferably within the range of 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may suffice, or conversely, a higher dose may be required. It is usually administered once a day or in several divided doses, or, in the case of intravenous administration, it can be administered rapidly or continuously over a period of 24 hours or less.

[0097] Furthermore, 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 A1 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 in the compounds of the present invention can 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, respectively. Compounds substituted with such isotopes are also useful as pharmaceuticals and encompass all radiolabeled forms of the compounds of the present invention.

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

[0100] If the solvents, reagents, and raw materials used in each step of the following manufacturing method are commercially available, they may be used as is. Furthermore, the compounds obtained in each step of the manufacturing method described below, and the raw materials used, may form salts and can be converted to other types of salts or free forms by known methods. Conversely, if the compounds obtained in each step of the following manufacturing method, or the raw materials used, are free forms, they can be converted to the desired salt by known methods. Examples of such salts include those similar to the salts used in the compounds of the present invention described above.

[0101] In the production of the compound of the present invention, if the starting material has substituents that may affect the reaction, protecting groups may be introduced to these substituents by known methods beforehand, and the target compound can be obtained by removing the protecting groups as needed after the reaction. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 4th edition, John Wiley & Sons Inc., 2006, by Wuts and Greene, or "Protecting Groups," 3rd edition, Thieme, 2005, by PJ Kocienski, and these may be appropriately selected and used depending on the reaction conditions.

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

[0103] The present invention will be described in more detail below with reference examples, examples, and test examples, but these are not the only examples that define the present invention.

[0104] Mass spectrometry (MS) was measured using LCMS. ESI (electrolysis-like infiltration) was used as the ionization method. The observed mass spectrometry values ​​are expressed in m / z.

[0105] The measurement conditions for LCMS are as follows: Analytical equipment: ACQUITY UPLC MS / PDA system (manufactured by Waters Corporation) Mass spectrometer: ACQUITY QDa detector or Waters 3100 MS detector Photodiode array detector: ACQUITY PDA detector (UV detection wavelength: 210~400nm) 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; the same applies below) Solution B: 0.1% formic acid / acetonitrile

[0106] 1 The 1H-NMR spectrum was measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE, Inc.). Observed peaks are expressed as chemical shift values ​​δ (ppm) (s=singlet, d=doublet, t=triplet, q=quartet, brs=broadsinglet, m=multiplet, dd=doubledoublet, dt=doubletriplet).

[0107] The microwave experiment was conducted using an Initiator 60 (manufactured by Biotage). It can achieve temperatures of 40-250°C and pressures up to 20 bar.

[0108] The measurement conditions for optical rotation are as follows: Analytical instrument: Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.)

[0109] The compound names used herein were named using IUPAC-compliant naming software, ACD / NAME (registered trademark, Advanced Chemistry Development Inc.), ChemBioDraw (version 18.2, 19.1, or 20.1.1, Cambridge Soft), or in accordance with IUPAC nomenclature.

[0110] The 'r' and 's' (lowercase) in compound names indicate the stereochemistry of the pseudo-chiral carbon atom, according to IUPAC rules.

[0111] Reference Example 1: 2-[3-(azetidine-3-yl)-4-chloro-5-fluoro-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound RE-1) [ka] [Step 1] Production 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 ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.65 g).

[0112] [Step 2] Production 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® (74 mg) were sequentially added, and the mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.09 g). MS (m / z): 332.5 [M+H] +

[0113] [Step 3] Production 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 overnight at 100°C. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.47 g). MS (m / z): 324.0 [MH] -

[0114] [Step 4] Production 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 sequentially added under an ice bath, and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.76 g). MS (m / z): 412.3 [M+H] +

[0115] [Step 5] Production of intermediate RE-1E [ka] A mixture of intermediate RE-1D (1.75 g), methanol (8.5 mL), and THF (8.5 mL) was mixed with 10.6 mL of 2 M sodium hydroxide aqueous solution at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, and then acidified with 2 M hydrochloric acid under an ice bath. The precipitated material was filtered to obtain the title compound (1.56 g). MS (m / z): 382.4 [MH] -

[0116] [Step 6] Production of intermediate RE-1F [ka] A mixture of intermediate RE-1E (800 mg), DMF (6.9 mL), DIPEA (1.1 mL), and 2,2,2-trifluoroethanamine hydrochloride (367 mg) was mixed with HATU (1.03 g) and stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (900 mg). MS (m / z): 463.4 [MH] -

[0117] [Step 7] Production of compound RE-1 A mixture of intermediate RE-1F (78 mg) and methanol (1 mL) was mixed with hydrogen chloride (2 M methanol solution, 1 mL) and stirred overnight at room temperature. The solvent was removed by distillation under reduced pressure to obtain the title compound (72 mg). MS (m / z): 365.5 [M + H] +

[0118] Reference Example 2: 2-[3-(azetidine-3-yl)-4,6-difluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound RE-2) [ka] [Step 1] Production of intermediate RE-2A [ka] Following the method described in Step 1 of Reference Example 1, 1,3,5-trifluorobenzene (7.49 g) was used instead of 2-chloro-1,4-difluorobenzene to obtain the title compound (9.74 g).

[0119] [Step 2] Production of intermediate RE-2B [ka] Following the method described in Step 2 of Reference Example 1, the title compound (9.49 g) was obtained by using intermediate RE-2A (9.74 g) instead of intermediate RE-1A.

[0120] [Step 3] Production of intermediate RE-2C [ka] Following the procedure in step 3 of Reference Example 1, intermediate RE-2B (9.49 g) was used instead of intermediate RE-1B to obtain the title compound (8.25 g). MS (m / z): 308.3 [MH] -

[0121] [Step 4] Manufacturing of intermediate RE-2D [ka] Following the procedure in step 4 of Reference Example 1, the title compound (6.2g) was obtained by using intermediate RE-2C (5.0g) instead of intermediate RE-1C. MS(m / z): 296.0[M-Boc+2H] +

[0122] [Process 5] Manufacturing of intermediate RE-2E [ka] Following the method described in Step 5 of Reference Example 1, the title compound (1.89 g) was obtained by using intermediate RE-2D (2.23 g) instead of intermediate RE-1D. MS (m / z): 366.4 [MH] -

[0123] [Step 6] Production of intermediate RE-2F [ka] Following the procedure in step 6 of Reference Example 1, 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 obtain the title compound (1.32 g). MS (m / z): 511.2 [M+Na] +

[0124] [Step 7] Production of compound RE-2 Following the method described in Step 7 of Reference Example 1, the title compound (117 mg) was obtained by using intermediate RE-2F (125 mg) instead of intermediate RE-1F. MS (m / z): 389.1 [M+H] +

[0125] Reference Example 3: 2-[3-(azetidine-3-yl)-4,6-difluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-3) [ka] A mixture of intermediate RE-2F (100 mg) and dichloromethane (1 mL) was mixed with trifluoroacetic acid (0.25 mL) and stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure to obtain the title compound (103 mg). MS (m / z): 389.1 [M + H] +

[0126] Reference Example 4: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-4) [ka] [Step 1] Production 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 sequentially added under ice bath. After stirring under ice bath for 30 minutes, the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (12.69 g). MS (m / z): 317.0 [M+H] +

[0127] [Step 2] Production 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 reaching room temperature, DMA (40 mL) was added, and after argon degassing, 1,2-dibromoethane (0.341 mL) and chloro(trimethyl)silane (0.602 mL) were added and the mixture was stirred at room temperature for 15 minutes. To this mixture, a DMA solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.2 g) was added dropwise using a dropping funnel. The mixture was stirred at room temperature for 1 hour to prepare a DMA solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc(II) iodide. Next, to a mixture of intermediate RE-4A (5.00 g) and DMA (16 mL), argon-degassed Pd(dppf)Cl2·CH2Cl2 (1.29 g) and copper(I) iodide (392 mg) were added. The previously prepared DMA solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc(II) iodide was added at room temperature, and the mixture was stirred at 85°C for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.05 g). MS (m / z): 368.1 [M+Na] +

[0128] [Step 3] Production of intermediate RE-4C [ka] Following the procedure in step 5 of Reference Example 1, intermediate RE-4B (5.08 g) was used instead of intermediate RE-1D to obtain the title compound (4.99 g). MS (m / z): 330.4 [MH] -

[0129] [Step 4] Manufacturing of intermediate RE-4D [ka] A mixture of intermediate RE-4C (150 mg), DMF (1.5 mL), DIPEA (0.235 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (95 mg) was mixed with HBTU (206 mg) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m / z): 353.1 [M-Boc+2H] +

[0130] [Step 5] Preparation of compound RE-4 A mixture of intermediate RE-4D (200 mg) and dichloromethane (4 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure to obtain the title compound (211 mg). MS (m / z): 353.1 [M + H] +

[0131] Reference Example 5: 2-[3-(azetidine-3-yl)-5-chloro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-5) [ka] [Step 1] Production of intermediate RE-5A [ka] To a mixture of 2-bromo-4-chloro-1-fluorobenzene (2.57 g) and THF (20 mL), n-butyllithium (7.82 mL in a 1.57 M solution of n-hexane) 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, e.g., 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 ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.21 g). MS (m / z): 214.0 [M-Boc+2H]+

[0132] [Step 2] Production of intermediate RE-5B 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 extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (635 mg). MS (m / z): 208.0 [M-Boc+2H] +

[0133] [Step 3] Production of intermediate RE-5C [ka] Following the procedure described in Step 1 of Reference Example 4, the title compound (246 mg) was obtained by using intermediate RE-5B (200 mg) instead of 3-iodo-2H-indazole. MS (m / z): 402.3 [M + Na] +

[0134] [Step 4] Manufacturing of intermediate RE-5D Following the procedure in step 5 of Reference Example 1 (TIFF2026086800000038.tif44169), the title compound (184 mg) was obtained by using intermediate RE-5C (246 mg) instead of intermediate RE-1D. MS (m / z): 364.3 [MH] -

[0135] [Step 5] Production of intermediate RE-5E [ka] A mixture of intermediate RE-5D (100 mg), acetonitrile (2 mL), 1-hydroxybenzotriazole monohydrate (50 mg), NMM (0.090 mL), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (49 mg) was mixed with EDCI·HCl (63 mg) and stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the title compound (123 mg). MS (m / z): 483.2 [M + Na] +

[0136] [Step 6] Preparation of compound RE-5 Following the method described in Reference Example 3, the title compound (127 mg) was obtained by using intermediate RE-5E (123 mg) instead of intermediate RE-2F. MS (m / z): 361.2 [M+H] +

[0137] Reference Example 6: 2-[3-(azetidine-3-yl)-6-fluoro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-6) [ka] [Step 1] Production of intermediate RE-6A [ka] 6-fluoro-3-iodo-1H-indazole (e.g., synthesized according to the method described in Bioorganic Med. Chem. Lett., 2010, 20, 6998-7003) (897 mg) and DMF (7 mL) were mixed and, under ice bath, cesium carbonate (1.34 g) and methyl 2-bromoacetate (0.39 mL) were sequentially added. After stirring under ice bath for 10 minutes, the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.17 g). MS (m / z): 335.0 [M+H] +

[0138] [Step 2] Production 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 then purged with argon. After reaching room temperature, DMA (5.25 mL) was added, and after argon degassing, 1,2-dibromoethane (0.045 mL) and chloro(trimethyl)silane (0.080 mL) were added and the mixture was stirred at room temperature for 15 minutes. To this mixture, a DMA (5.25 mL) solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.49 g) was added dropwise using a dropping funnel. The mixture was stirred at room temperature for 1 hour to prepare a DMA solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc(II) iodide. Next, to a mixture of intermediate RE-6A (1.17 g) and DMA (3.5 mL), argon-degassed Pd(dppf)Cl2·CH2Cl2 (286 mg) and copper(I) iodide (87 mg) were added. The previously prepared DMA solution of [1-(tert-butoxycarbonyl)azetidine-3-yl]zinc(II) iodide was added at room temperature, and the mixture was stirred at 85°C for 1 hour. Water was added to the reaction mixture, and it was extracted with a mixed solvent of ethyl acetate and hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.54 g). MS (m / z): 386.3 [M+Na] +

[0139] [Step 3] Production of intermediate RE-6C [ka] A mixture of intermediate RE-6B (1.54 g), methanol (6 mL), and THF (6 mL) was mixed with 6.36 mL of 2 M sodium hydroxide aqueous solution 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 under an ice bath. The precipitated material was filtered off to obtain the title compound (1.03 g). MS (m / z): 348.2 [MH] -

[0140] [Step 4] Manufacturing of intermediate RE-6D [ka] A mixture of intermediate RE-6C (350 mg), acetonitrile (3 mL), 1-hydroxybenzotriazole monohydrate (184 mg), NMM (0.330 mL), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (180 mg) was mixed with EDCI·HCl (231 mg) and stirred overnight at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and 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 compound was purified by silica gel column chromatography to obtain the title compound (318 mg). MS (m / z): 467.3 [M + Na] +

[0141] [Step 5] Preparation of compound RE-6 Following the method described in Reference Example 3, the title compound (285 mg) was obtained by using intermediate RE-6D (318 mg) instead of intermediate RE-2F. MS (m / z): 345.2 [M+H] +

[0142] Reference Example 7: 2-[3-(3-methylazetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-7) [ka] [Step 1] Production of intermediate RE-7A [ka] A mixture of 3-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]azetidine-3-carboxylic acid (747 mg), acetonitrile (10 mL), HOBt (797 mg), NMM (2.30 mL), and N,O-dimethylhydroxylamine hydrochloride (677 mg) was mixed with EDCI·HCl (1.13 g) and stirred overnight at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate. Next, following the method in accordance with Step 1 of Reference Example 5, 1-fluoro-2-iodobenzene (1.16 g) was used instead of 2-bromo-4-chloro-1-fluorobenzene, and the tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate obtained above was used instead of tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methylazetidine-1-carboxylate, to obtain the title compound (688 mg). MS(m / z): 194.2[M-Boc+2H] +

[0143] [Step 2] Production 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 ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-(1H-indazole-3-yl)-3-methylazetidine-1-carboxylate. Next, following the method in step 1 of Reference Example 4, the title compound (629 mg) was obtained by using the above-mentioned tert-butyl 3-(1H-indazole-3-yl)-3-methylazetidine-1-carboxylate instead of 3-iodo-2H-indazole. MS(m / z):260.3[M-Boc+2H] +

[0144] [Step 3] Production of intermediate RE-7C [ka] Following the method described in Step 5 of Reference Example 1, the title compound (466 mg) was obtained by using intermediate RE-7B (629 mg) instead of intermediate RE-1D. MS (m / z): 344.3 [MH] -

[0145] [Step 4] Manufacturing of intermediate RE-7D [ka] A mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), DIPEA (0.150 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (61 mg) was mixed with HBTU (132 mg) and stirred overnight at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (108 mg). MS (m / z): 489.4 [M + Na] +

[0146] [Step 5] Preparation of compound RE-7 Following the method described in Reference Example 3, the title compound (111 mg) was obtained by using intermediate RE-7D (108 mg) instead of intermediate RE-2F. MS (m / z): 367.3 [M+H] +

[0147] Reference Example 8: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one trifluoroacetate (compound RE-8) [ka] [Step 1] Manufacturing of intermediate RE-8A [ka] Following the procedure in step 4 of Reference Example 7, the title compound (100 mg) was obtained by using intermediate RE-4C (100 mg) instead of intermediate RE-7C, and 3,3-dimethylmorpholine (45 mg) instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m / z): 329.2 [M-Boc+2H] +

[0148] [Step 2] Preparation of compound RE-8 Following the method described in Reference Example 3, the title compound (96 mg) was obtained by using intermediate RE-8A (100 mg) instead of intermediate RE-2F. MS (m / z): 329.2 [M+H] +

[0149] Reference Example 9: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one trifluoroacetate (compound RE-9) [ka] [Step 1] Production of intermediate RE-9A [ka] Following the procedure in step 4 of Reference Example 7, intermediate RE-4C (100 mg) was used instead of intermediate RE-7C, and (2R)-2-(trifluoromethyl)morpholine hydrochloride (69 mg) was used instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride to obtain the title compound (135 mg). MS (m / z): 369.1 [M-Boc+2H] +

[0150] [Step 2] Preparation of compound RE-9 Following the method described in Reference Example 3, the title compound (145 mg) was obtained by using intermediate RE-9A (135 mg) instead of intermediate RE-2F. MS (m / z): 369.1 [M+H] +

[0151] Reference Example 10: 4-Fluoro-3-(piperidine-4-yl)-1-{[5-(trifluoromethyl)pyridine-2-yl]methyl}-1H-indazole trifluoroacetate (compound RE-10) [ka] [Step 1] Manufacturing of intermediate RE-10A [ka] Following the method described in Step 1 of Reference Example 1, 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 obtain the title compound (3.98 g).

[0152] [Step 2] Manufacturing of intermediate RE-10B [ka] Following the method described in Step 2 of Reference Example 1, the title compound (3.48 g) was obtained by using intermediate RE-10A (3.98 g) instead of intermediate RE-1A.

[0153] [Step 3] Production of intermediate RE-10C [ka] Following the method described in Step 3 of Reference Example 1, the title compound (3.31 g) was obtained by using intermediate RE-10B (3.48 g) instead of intermediate RE-1B. MS (m / z): 318.3 [MH] -

[0154] [Step 4] Manufacturing of intermediate RE-10D TIFF2026086800000058.tif41167 Intermediate RE-10C (50 mg) and acetonitrile (0.5 mL) were mixed and cesium carbonate (77 mg) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (56 mg) were added sequentially, 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] Production of compound RE-10 Following the method described in Reference Example 3, the title compound (35 mg) was obtained by using intermediate RE-10D (34 mg) instead of intermediate RE-2F. MS (m / z): 379.2 [M + H] +

[0156] Reference Example 11: 2-[4-fluoro-3-(piperidine-4-yl)-1H-indole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound RE-11) [ka] [Step 1] Manufacturing 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 overnight at 80°C. Water was added to the reaction mixture, and after extraction with ethyl acetate, the mixture was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the compound was purified by silica gel column chromatography to obtain the title compound (660 mg). MS (m / z): 317.1 [M+H] +

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

[0158] [Step 3] Production of intermediate RE-11C [ka] Following the procedure in step 4 of Reference Example 1, the title compound (450 mg) was obtained by using intermediate RE-11B (480 mg) instead of intermediate RE-1C. MS (m / z): 305.2 [M-Boc+2H] +

[0159] [Step 4] Manufacturing of intermediate RE-11D [ka] Following the method described in Step 5 of Reference Example 1, the title compound (350 mg) was obtained by using intermediate RE-11C (450 mg) instead of intermediate RE-1D. MS (m / z): 375.2 [MH] -

[0160] [Step 5] Production 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. (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (56 mg) was added, and the mixture was 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] Production of compound RE-11 Following the method described in Step 7 of Reference Example 1, the title compound (85 mg) was obtained by using intermediate RE-11E (120 mg) 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)pyrrolidine-1-yl]ethyl}-1H-indole-3-yl)azetidine-1-carboxylate (compound RE-12) [ka] [Step 1] Manufacturing of intermediate RE-12A [ka] A mixture of indole (1 g), potassium hydroxide (527 mg), and methanol (11 mL) was mixed with tert-butyl 3-oxoazetidine-1-carboxylate (1.61 g) and stirred overnight at 50°C. Water was added to the reaction mixture, and after extraction with ethyl acetate, the mixture was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain the title compound (920 mg). MS (m / z): 287.2 [MH] -

[0163] [Step 2] Production 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 under an ice bath, followed by the slow addition of trifluoroacetic acid (0.811 mL). The mixture was stirred under an ice bath for 10 minutes. Saturated sodium bicarbonate solution was added to the reaction mixture, and after extraction with dichloromethane, the mixture was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the compound was purified by silica gel column chromatography to obtain the title compound (370 mg). MS (m / z): 271.4 [MH] -

[0164] [Step 3] Production of intermediate RE-12C [ka] Following the procedure in step 4 of Reference Example 1, the title compound (400 mg) was obtained by using intermediate RE-12B (370 mg) instead of intermediate RE-1C. MS (m / z): 259.1 [M-Boc+2H] +

[0165] [Step 4] Manufacturing of intermediate RE-12D [ka] A mixture of intermediate RE-12C (400 mg), methanol (10 mL), and THF (10 mL) was mixed with 2.79 mL of 2 M sodium hydroxide aqueous solution at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, and then acidified with 2 M hydrochloric acid under an ice bath. The solvent was removed by distillation under reduced pressure, and the compound (350 mg) was purified by silica gel column chromatography. MS (m / z): 329.1 [MH] -

[0166] [Step 5] Production of compound RE-12 Following the method described in Step 5 of Reference Example 11, the title compound (50 mg) was obtained by using intermediate RE-12D (50 mg) 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)pyrrolidine-1-yl]ethyl}-1H-pyrazolo[4,3-b]pyridine-3-yl)azetidine-1-carboxylate (compound RE-13) [ka] [Step 1] Production of intermediate RE-13A [ka] Following the procedure in Step 1 of Reference Example 5, 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 obtain the title compound (608 mg). MS(m / z): 297.1[M+H] +

[0168] [Step 2] Production 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 sequentially added and the mixture was stirred at room temperature for 2 hours. Another AZADOL® (16 mg) was added and the mixture was stirred for another 2 hours at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (542 mg). MS (m / z): 295.1 [M+H] +

[0169] [Step 3] Production of intermediate RE-13C [ka] Following the procedure in Step 2 of Reference Example 5, intermediate RE-13B (542 mg) was used instead of intermediate RE-5A to obtain the title compound (363 mg). MS (m / z): 289.2 [M + H] +

[0170] [Step 4] Manufacturing of intermediate RE-13D [ka] Following the method described in Step 4 of Reference Example 1, the title compound (359 mg) was obtained by using intermediate RE-13C (290 mg) instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0171] [Step 5] Production of intermediate RE-13E [ka] Following the method described in Step 5 of Reference Example 1, the title compound (187 mg) was obtained by using intermediate RE-13D (359 mg) instead of intermediate RE-1D. MS(m / z): 347.1[M+H] +

[0172] [Step 6] Preparation of compound RE-13 Following the method described in Step 5 of Reference Example 11, the title compound (100 mg) was obtained by using intermediate RE-13E (90 mg) instead of intermediate RE-11D. MS (m / z): 468.3 [M+H] +

[0173] Reference Example 14: 2-[3-(azetidine-3-yl)-1H-pyrazolo[4,3-c]pyridine-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one 2-trifluoroacetate (compound RE-14) [ka] [Step 1] Production of intermediate RE-14A [ka] Following the method described in Step 1 of Reference Example 1, 2-chloro-4-fluoropyridine (1.07 g) was used instead of 2-chloro-1,4-difluorobenzene to obtain the title compound (1.62 g).

[0174] [Step 2] Production of intermediate RE-14B [ka] Following the method described in Step 2 of Reference Example 1, the title compound (1.47 g) was obtained by using intermediate RE-14A (1.62 g) instead of intermediate RE-1A.

[0175] [Step 3] Production of intermediate RE-14C TIFF2026086800000079.tif39169 A mixture of intermediate RE-14B (1.37 g), 1,4-dioxane (28 mL), and hydrazine monohydrate (0.65 mL) was stirred overnight at 100°C. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.79 g). MS (m / z): 309.1 [M+H] +

[0176] [Step 4] Manufacturing of intermediate RE-14D [ka] Following the procedure in step 4 of Reference Example 1, the title compound (1.04 g) was obtained by using intermediate RE-14C (0.79 g) instead of intermediate RE-1C. MS (m / z): 395.2 [M+H] +

[0177] [Step 5] Production 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 separated by Celite® filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (249 mg). MS (m / z): 361.2 [M+H] +

[0178] [Step 6] Production of intermediate RE-14F [ka] Following the method described in Step 5 of Reference Example 1, the title compound (210 mg) was obtained by using intermediate RE-14E (249 mg) instead of intermediate RE-1D. MS (m / z): 333.2 [M+H] +

[0179] [Step 7] Production of intermediate RE-14G [ka] Following the procedure in step 5 of Reference Example 11, the title compound (92 mg) was obtained by using intermediate RE-14F (100 mg) instead of intermediate RE-11D. MS (m / z): 454.3 [M+H] +

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

[0181] Reference Example 15: 3-{[3-(azetidine-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl]methyl}-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole trifluoroacetate (compound RE-15) [ka] [Step 1] Manufacturing of intermediate RE-15A [ka] Following the method described in Step 1 of Reference Example 1, 3,5-difluoropyridine (2.80 g) was used instead of 2-chloro-1,4-difluorobenzene to obtain the title compound (4.92 g).

[0182] [Step 2] Manufacturing of intermediate RE-15B [ka] Following the method described in Step 2 of Reference Example 1, the title compound (4.64 g) was obtained by using intermediate RE-15A (4.86 g) instead of intermediate RE-1A.

[0183] [Step 3] Production 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 overnight at 100°C. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.9 g). MS (m / z): 291.2 [MH] -

[0184] [Step 4] Manufacturing of intermediate RE-15D [ka] Following the method described in Step 4 of Reference Example 10, 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 obtain the title compound (1.22 g).

[0185] [Step 5] Production 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 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 removing the solvent under reduced pressure, ethyl acetate was added to the residue and suspended. The mixture was filtered through Celite®, and insoluble matter was separated 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] Production of intermediate RE-15F [ka] 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) was mixed with HATU (41 mg) and 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 (27 mg). MS (m / z): 483.2 [M+H] +

[0187] [Step 7] Production of compound RE-15 Following the method described in Reference Example 3, the title compound (28 mg) was obtained by using intermediate RE-15F (27 mg) instead of intermediate RE-2F. MS (m / z): 383.1 [M + H] +

[0188] Reference Example 16: 2-[3-(azetidine-3-yl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one 2-trifluoroacetate (compound RE-16) [ka] [Step 1] Manufacturing of intermediate RE-16A [ka] Following the procedure in Step 1 of Reference Example 5, 3-bromo-2-fluoromethylpyridine (0.63 g) was used instead of 2-bromo-4-chloro-1-fluorobenzene, and tert-butyl 3-formylazetidine-1-carboxylate (0.74 g) was used instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate to obtain the title compound (0.57 g). MS(m / z): 197.1[M-Boc+2H] +

[0189] [Step 2] Production of intermediate RE-16B [ka] Following the procedure described in Step 2 of Reference Example 1, the title compound (241 mg) was obtained by using intermediate RE-16A (0.57 g) instead of intermediate RE-1A. MS (m / z): 195.0 [M-Boc+2H] +

[0190] [Step 3] Production of intermediate RE-16C [ka] Following the method described in Step 3 of Reference Example 1, the title compound (148 mg) was obtained by using intermediate RE-16B (241 mg) instead of intermediate RE-1B. MS (m / z): 289.1 [M+H] +

[0191] [Step 4] Manufacturing of intermediate RE-16D [ka] Following the method described in Step 4 of Reference Example 1, the title compound (166 mg) was obtained by using intermediate RE-16C (148 mg) instead of intermediate RE-1C. MS (m / z): 375.1 [M+H] +

[0192] [Step 5] Production of intermediate RE-16E [ka] Following the method described in Step 5 of Reference Example 1, the title compound (139 mg) was obtained by using intermediate RE-16D (166 mg) instead of intermediate RE-1D. MS (m / z): 347.1 [M+H] +

[0193] [Step 6] Production of intermediate RE-16F [ka] Following the method described in Step 5 of Reference Example 11, the title compound (88 mg) was obtained by using intermediate RE-16E (70 mg) instead of intermediate RE-11D. MS (m / z): 412.1 [M-(tBu+2H)] +

[0194] [Step 7] Preparation of compound RE-16 Following the method described in Reference Example 3, the title compound (130 mg) was obtained by using intermediate RE-16F (88 mg) instead of intermediate RE-2F. MS (m / z): 368.0 [M+H] +

[0195] Reference Example 17: 3-(azetidine-3-yl)-1-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole trifluoroacetate (compound RE-17) [ka] [Step 1] Production of intermediate RE-17A [ka] To a mixture of 1-fluoro-2-iodobenzene (8.31 g) and THF (62 mL), n-butyllithium (23.8 mL in a 1.57 M solution of n-hexane) 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 ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-carboxylate. To the above mixture of tert-butyl 3-[(2-fluorophenyl)(hydroxy)methyl]azetidine-1-carboxylate and dichloromethane (124 mL), iodobenzene diacetate (9.6 g) and AZADOL® (190 mg) were sequentially added and the mixture was 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 sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, 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] Production 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 extracted with ethyl acetate / n-hexane (1 / 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (4.39 g). MS (m / z): 274.1 [M+H] +

[0197] [Step 3] Production 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 sequentially added and the mixture was stirred at room temperature for 4 hours, followed by stirring overnight at 60°C. 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 obtain the title compound (94 mg). MS (m / z): 422.2 [MH] -

[0198] [Step 4] Production of compound RE-17 Following the method described in Reference Example 3, the title compound (98 mg) was obtained by using intermediate RE-17C (94 mg) 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-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-18) [ka] [Step 1] Manufacturing of intermediate RE-18A [ka] Following the same method as in Step 1 of Reference Example 1, 1,3-difluorobenzene (1.85 g) was used instead of 2-chloro-1,4-difluorobenzene to obtain the title compound (2.72 g).

[0200] [Step 2] Production of intermediate RE-18B [ka] Following the procedure described in Step 2 of Reference Example 1, the title compound (2.39 g) was obtained by using intermediate RE-18A (2.72 g) instead of intermediate RE-1A. MS (m / z): 298.0 [M+H] +

[0201] [Step 3] Production of intermediate RE-18C [ka] Following the method described in Step 3 of Reference Example 1, intermediate RE-18B (2.39 g) was used instead of intermediate RE-1B to obtain the title compound (2.15 g). MS (m / z): 290.3 [MH] -

[0202] [Step 4] Manufacturing 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. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.01 g). MS (m / z): 230.1 [M-Boc+2H] +

[0203] [Step 5] Production of compound RE-18 (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate (e.g., synthesized according to the method described in WO2014205234) (300 mg) and DMF (3 mL) were mixed with sodium azide (84.7 mg) and stirred overnight at 120°C to prepare a DMF solution of 3-(azidomethyl)-1,1-difluorocyclobutane (approximately 0.36 mol / L). After cooling, 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) were mixed with copper(I) iodide (2.9 mg) and 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 removed 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-(azetidine-3-yl)-4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl]methyl}-1H-indazole trifluoroacetate (compound RE-19) [ka] [Step 1] Production of intermediate RE-19A [ka] Following the method described in Step 4 of Reference Example 10, 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 obtain the title compound (65 mg). MS (m / z): 368.1 [M-Boc+2H] +

[0205] [Step 2] Preparation of compound RE-19 Following the method described in Reference Example 3, the title compound (67 mg) was obtained by using intermediate RE-19A (65 mg) instead of intermediate RE-2F. MS (m / z): 368.1 [M+H] +

[0206] Reference Example 20: 2-[3-(azetidine-3-yl)-4-fluoro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-20) [ka] [Step 1] Manufacturing of intermediate RE-20A [ka] Following the method described in Step 4 of Reference Example 1, the title compound (638 mg) was obtained by using intermediate RE-18C (500 mg) instead of intermediate RE-1C. MS(m / z):278.0[M-Boc+2H] +

[0207] [Step 2] Manufacturing of intermediate RE-20B [ka] Following the method described in Step 5 of Reference Example 1, the title compound (476 mg) was obtained by using intermediate RE-20A (638 mg) instead of intermediate RE-1D. MS (m / z): 348.4 [MH] -

[0208] [Step 3] Production of intermediate RE-20C [ka] Following the method described in Step 5 of Reference Example 5, the title compound (81 mg) was obtained by using intermediate RE-20B (64 mg) instead of intermediate RE-5D. MS (m / z): 468.3 [M + Na] +

[0209] [Step 4] Production of compound RE-20 Following the method described in Reference Example 3, the title compound (84 mg) was obtained by using intermediate RE-20C (81 mg) instead of intermediate RE-2F. MS (m / z): 345.2 [M + H] +

[0210] Reference Example 21: 2-[3-(azetidine-3-yl)-4,5,6,7-tetrahydro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-21) [ka] [Step 1] Manufacturing of intermediate RE-21A [ka] Following the procedure described in Step 1 of Reference Example 4, 3-iodo-4,5,6,7-tetrahydro-1H-indazole (e.g., synthesized according to the method described in US2014171432) (1.63 g) was used instead of 3-iodo-2H-indazole to obtain a mixture of the title compound and approximately 10% positional isomers (2.14 g). MS(m / z): 321.1[M+H] +

[0211] [Step 2] Manufacturing of intermediate RE-21B [ka] Following the procedure in Step 2 of Reference Example 4, the title compound (0.39 g) was obtained by using intermediate RE-21A (2.14 g) obtained in Step 1 of Reference Example 21 instead of intermediate RE-4A. MS (m / z): 372.3 [M + Na] +

[0212] [Step 3] Production of intermediate RE-21C [ka] Following the procedure in step 5 of Reference Example 1, the title compound (34 mg) was obtained by using intermediate RE-21B (0.39 g) instead of intermediate RE-1D. MS (m / z): 334.2 [MH] -

[0213] [Step 4] Manufacturing of intermediate RE-21D [ka] Following the method described in Step 5 of Reference Example 11, the title compound (16 mg) was obtained by using intermediate RE-21C (34 mg) instead of intermediate RE-11D. MS (m / z): 457.3 [M+H] +

[0214] [Step 5] Production of compound RE-21 Following the method described in Reference Example 3, the title compound (16 mg) was obtained by using intermediate RE-21D (16 mg) instead of intermediate RE-2F. MS (m / z): 357.2 [M + H] +

[0215] Reference Example 22: 2-[3-(azetidine-3-yl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-22) [ka] [Step 1] Manufacturing of intermediate RE-22A [ka] A reaction vessel containing 30 mL of diethyl ether was cooled with ice, and 596 mg of 60% sodium hydride was added. Next, 0.087 mL of ethanol was added and the mixture was stirred under ice for 20 minutes. To this, a solution of 2.0 g of 4,4-difluorocyclohexane-1-one and 1.80 mL of ethyl formate in 10 mL of diethyl ether was added dropwise over 10 minutes using a dropping funnel. The mixture was gradually allowed to rise to room temperature and stirred overnight. After stirring, 0.3 mL of ethanol was added to the reaction mixture and stirred at room temperature for 1 hour. Water was added to the reaction mixture and 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 dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain the title compound (1.35 g). MS (m / z): 163.1 [M + H] +

[0216] [Step 2] Manufacturing 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 overnight at room temperature. The solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.65 g). MS (m / z): 159.1 [M+H] +

[0217] [Step 3] Production 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 sequentially added under an ice bath, and the mixture was stirred overnight at room temperature. A saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (468 mg). MS (m / z): 284.8 [M+H] +

[0218] [Step 4] Manufacturing of intermediate RE-22D [ka] Following the procedure described in Step 1 of Reference Example 4, intermediate RE-22C (468 mg) was used instead of 3-iodo-2H-indazole to obtain a mixture (582 mg) of the title compound with approximately 24% positional isomers. MS(m / z):356.8[M+H] +

[0219] [Step 5] Production of intermediate RE-22E [ka] Following the procedure in Step 2 of Reference Example 4, the title compound (360 mg) was obtained by using intermediate RE-22D (582 mg) instead of intermediate RE-4A. MS (m / z): 408.3 [M + Na] +

[0220] [Step 6] Production of intermediate RE-22F [ka] Following the procedure in step 5 of Reference Example 1, the title compound (103 mg) was obtained by using intermediate RE-22E (360 mg) instead of intermediate RE-1D. MS (m / z): 370.2 [MH]-

[0221] [Step 7] Production of intermediate RE-22G [ka] Following the method described in Step 5 of Reference Example 11, the title compound (60 mg) was obtained by using intermediate RE-22F (50 mg) instead of intermediate RE-11D. MS (m / z): 515.3 [M + Na] +

[0222] [Step 8] Preparation of compound RE-22 Following the method described in Reference Example 3, the title compound (62 mg) was obtained by using intermediate RE-22G (60 mg) 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] Manufacturing of intermediate RE-23A [ka] A mixture of 2-fluoropyridine-4-carbonitride (500 mg), NMP (4.0 mL), and DIPEA (2.1 mL) was mixed with cyclopropanamine (0.57 mL) and stirred overnight at 80°C. Water was added to the reaction mixture and extracted with ethyl acetate / n-hexane (1 / 1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (550 mg).

[0224] [Step 2] Preparation of compound RE-23 A mixture of intermediate RE-23A (550 mg), ethanol (2 mL), and water (2 mL) was mixed with potassium hydroxide (970 mg) and stirred overnight at 80°C. The solvent was removed by reduced pressure, and 2 M hydrochloric acid was added to the residue to adjust the pH to 7-8. The precipitated material was filtered to obtain 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 (e.g., synthesized according to the method described in WO202186879) (2.00 g), tert-butyl carbonate (1.02 g), Xantphos (168 mg), cesium carbonate (3.30 g), and 1,4-dioxane (24 mL) was degassed with argon, and Pd(OAc)2 (33 mg) was added and the mixture was stirred overnight at 90°C. The insoluble material was filtered off with Celite®, and the mother liquor was washed sequentially with water and saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain tert-butyl 2-{[(tert-butoxy)carbonyl]amino}-5-fluoropyridine-4-carboxylate. Next, the obtained tert-butyl 2-{[(tert-butoxy)carbonyl]amino}-5-fluoropyridine-4-carboxylate was mixed with hydrogen chloride (4M 1,4-dioxane solution, 9 mL) and stirred at 70°C for 6 hours. After cooling, the resulting precipitate was filtered to obtain 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] Manufacturing of intermediate RE-25A [ka] A mixture of methyl 2-chloro-3-methylpyridine-4-carboxylate (2.50 g), (4-methoxyphenyl)methaneamine (2.63 mL), rac-BINAP (839 mg), cesium carbonate (13.2 g), and 1,4-dioxane (45 mL) was degassed with argon, and Pd(OAc)2 (151 mg) was added. The mixture was stirred overnight at 100°C. Insoluble matter was filtered off with Celite®, the mother liquor was washed with saturated saline solution, and the mixture was dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (4.07 g). MS (m / z): 287.1 [M+H] +

[0227] [Step 2] Manufacturing of intermediate RE-25B [ka] Following the method described in Step 5 of Reference Example 1, the title compound (4.02 g) was obtained by using intermediate RE-25A (4.07 g) instead of intermediate RE-1D. MS (m / z): 273.0 [M+H] +

[0228] [Step 3] Production of compound RE-25 A mixture of intermediate RE-25B (1.64 g) and trifluoroacetic acid (20 mL) was stirred overnight at 70°C. The mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate slurry to obtain 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] Manufacturing of intermediate RE-26A [ka] A mixture of 4-chloro-5-fluoropyrimidine-2-amine (1.36 g), tributyl(1-ethoxyvinyl)tin (3.66 g), and DMF (18 mL) was degassed with argon, and PdCl2(PPh3)2 (129 mg) was added. The mixture was stirred overnight at 90°C. Water was added to the reaction mixture, and it was extracted with ethyl acetate / n-hexane (1 / 4). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.46 g). MS (m / z): 184.2 [M+H] +

[0230] [Step 2] Manufacturing of intermediate RE-26B [ka] To a mixture of intermediate RE-26A (1.46 g) and 1,4-dioxane (24 mL), 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 more times at 2-hour intervals, and the mixture was stirred for another 2 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, diluted with ethyl acetate, and filtered through Celite® to separate insoluble matter. The mother liquor was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the title compound (400 mg). MS (m / z): 186.2 [M+H] +

[0231] [Step 3] Preparation of compound RE-26 Following the method described in Step 5 of Reference Example 1, the title compound (140 mg) was obtained by using intermediate RE-26B (400 mg) 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] A mixture of tert-butyl 6-chloropyrimidine-4-carboxylate (e.g., synthesized according to the method described in US9598419, 2017, B1) (58 mg), DIPEA (0.01 mL), and ethanol (1 mL) was mixed with cyclopropylamine (77 mg) and reacted in a microwave reactor at 140°C for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (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] Manufacturing of intermediate RE-28A [ka] A mixture of 2-fluoropyridine-4-carbonitrile (200 mg), DIPEA (0.85 mL), and NMP (1.6 mL) was mixed with 1-methylcyclopropane-1-amine hydrochloride (77 mg) and reacted overnight at 80°C. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (110 mg). 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 A mixture of intermediate RE-28A (110 mg), ethanol (2 mL), and water (2 mL) was mixed with potassium hydroxide (0.2 g) and reacted overnight at 80°C. The solvent was removed by distillation under reduced pressure, and the residue was diluted with 2 M hydrochloric acid to pH 7-8. The precipitate was filtered and washed with water. After drying, the title compound (63 mg) was obtained. 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 using 4,4-difluorocyclohexane-1-amine hydrochloride, following a synthetic route similar to that described for compound RE-28. 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-(azetidine-3-yl)-4-chloro-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound RE-30) [ka]

[0236] [Step 1] Manufacturing of intermediate RE-30A [ka] The title compound was obtained by using 1-chloro-3-fluorobenzene instead of 2-chloro-1,4-difluorobenzene, following the same method as in Step 1 of Reference Example 1. MS(m / z):316.1[M+H] +

[0237] [Step 2] Manufacturing 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 stirred overnight at room temperature. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (557 mg). 1 H-NMR(400MHz,CDCl3)δ7.39-7.33(m,1H),7.24(d,1H),7.07(t,1H),4.23-4.20(m,2H),4.09(t,2H),3.97-3.88(m,1H),1.45(s,9H)

[0238] [Step 3] Production of intermediate RE-30 Compound RE-30 was synthesized starting from intermediate RE-30B, following a procedure similar to that described in steps 3 through 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-(azetidine-3-yl)-4,7-difluoro-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound RE-31) [ka]

[0240] [Step 1] Manufacturing 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 it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (218 mg). MS (m / z): 310.5 [M+H]+

[0241] [Step 2] Manufacturing 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 sequentially added under ice bath and stirred at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (238 mg). 1 H-NMR(400MHz,CDCl3)δ7.00-6.90(m,1H),6.70-6.60(m,1H),5.22(s,2H),4.40-4.27(m ,4H),4.25-4.17(m,1H),4.16-4.11(m,2H),1.70-1.59(m,2H),1.46(s,9H),0.89(t,3H)

[0242] [Step 3] Production of compound RE-31 Compound RE-31 was synthesized starting from intermediate RE-31A, following a procedure similar to that described in steps 5 through 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-(azetidine-3-yl)-4-bromo-5-fluoro-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound RE-32) [ka]

[0244] [Step 1] Manufacturing of intermediate RE-32A [ka] The title compound was obtained by using 2-bromo-1,3-difluorobenzene instead of 2-chloro-1,4-difluorobenzene, following the same method as in Step 1 of Reference Example 1.1 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] Manufacturing of intermediate RE-32B [ka] The title compound was obtained by using intermediate RE-32A instead of intermediate RE-30A, following the method described in Step 2 of Reference Example 30. 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] Manufacturing 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 and 2 of Reference Example 31 for the production 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] Production of compound RE-32 Compound RE-32 was synthesized starting from intermediate RE-32C, following a procedure similar to that described in steps 5 through 7 of Reference Example 1 for the preparation of compound RE-1. MS(m / z):407.1[MH] -

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

[0249] [Step 1] Manufacturing of intermediate RE-33A [ka] A mixture of compound RE-14D (200 mg), trimethylboroxine (70 mg), potassium carbonate (280 mg), Pd(dppf)Cl2·CH2Cl2 (41 mg), and 1,4-dioxane (2.5 mL) was degassed and stirred at 110°C for 5 hours under an argon atmosphere. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (98 mg). MS(m / z): 375.1[M+H] +

[0250] [Step 2] Preparation of compound RE-33 A mixture of intermediate RE-33A (98 mg), methanol (1 mL), and THF (1 mL) was mixed with 1 mL of 2 M aqueous sodium hydroxide solution at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water, and acidified with 2 M hydrochloric acid under an ice bath. Saturated sodium bicarbonate solution was added to neutralize the mixture, 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 solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (97 mg). MS (m / z): 468.2 [M + H] +

[0251] Reference Example 34: tert-butyl 3-(1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-pyrazolo[4,3-b]pyridine-3-yl)azetidine-1-carboxylate (compound RE-34) [ka]

[0252] [Step 1] Manufacturing of intermediate RE-34A [ka] To a mixture of 3-fluoropyridine (674 mg) and THF (9 mL), lithium diisopropylamide (1.08 M n-hexane / tetrahydrofuran solution, 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) (e.g., synthesized 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 ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (490 mg). MS (m / z): 281.0 [M+H] +

[0253] [Step 2] Manufacturing of intermediate RE-34B [ka] The title compound was obtained by using intermediate RE-34A instead of intermediate RE-1B, following the method described in Step 1 of Reference Example 31. MS(m / z):275.1[M+H] +

[0254] [Step 3] Production of compound RE-34 Compound RE-34 was synthesized starting from intermediate RE-34B, following a procedure similar to that described in steps 1 and 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]pyridine-3-yl)azetidine-1-carboxylate (compound RE-35) [ka]

[0256] [Step 1] Manufacturing of intermediate RE-35A [ka] The title compound was obtained by using 2-chloro-5-fluoropyridine instead of 3-fluoropyridine, following the method described in Step 1 of Reference Example 34. 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] Manufacturing of intermediate RE-35B [ka] The title compound was obtained by using intermediate RE-35A instead of intermediate RE-1B, following the method described in Step 1 of Reference Example 31. MS(m / z): 309.1[M+H] +

[0258] [Step 3] Production of intermediate RE-35C [ka] A mixture of intermediate RE-35B (100 mg) and DMF (2 mL) was mixed with cesium carbonate (211 mg) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (116 mg) under ice cooling, and the mixture was stirred for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (134 mg). MS (m / z): 467.2 [M+H] +

[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·CH2Cl2 (23 mg), and 1,4-dioxane (1.4 mL) was degassed and stirred at 110°C for 5 hours under an argon atmosphere. Pd(dppf)Cl2·CH2Cl2 (23 mg) was added and stirred overnight at 90°C. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (58 mg). MS(m / z): 447.3[M+H] +

[0260] Reference Example 36: tert-butyl 3-(5-methyl-1-{2-oxo-2-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carboxylate (compound RE-36) [ka]

[0261] [Step 1] Manufacturing of intermediate RE-36A [ka] A mixture of intermediate RE-35B (280 mg), trimethylboroxine (171 mg), potassium carbonate (376 mg), Pd(dppf)Cl2·CH2Cl2 (148 mg), and 1,4-dioxane (3 mL) was reacted in a microwave reactor at 130 °C for 1 hour, followed by stirring at 150 °C for 1 hour. Trimethylboroxine (0.8 mL) was added, and the mixture was reacted in a microwave reactor at 180 °C for 5 minutes. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (66 mg). MS (m / z): 289.2 [M+H] +

[0262] [Step 2] Manufacturing of intermediate RE-36B [ka] Intermediate RE-36B was synthesized starting from intermediate RE-36A, following a procedure similar to that described in steps 4 to 5 of Reference Example 1 for the production 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 overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (40 mg). MS (m / z): 484.3 [M+H] +

[0264] Reference Example 37: 2-[3-(azetidine-3-yl)-5-methyl-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-37) [ka]

[0265] [Step 1] Manufacturing of intermediate RE-37A [ka] The title compound was obtained by using 2-bromo-1-fluoro-4-methylbenzene instead of 2-bromo-4-chloro-1-fluorobenzene, following the method described in Step 1 of Reference Example 5. MS(m / z):294.0[M+H] +

[0266] [Step 2] Manufacturing 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 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-(5-methyl-1H-indazole-3-yl)azetidine-1-carboxylate. To a mixture of the obtained tert-butyl 3-(5-methyl-1H-indazole-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 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazole-3-yl]azetidine-1-carboxylate. A mixture of the obtained tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazole-3-yl]azetidine-1-carboxylate (467 mg), methanol (2 mL), and THF (2 mL) was mixed with 1.9 mL of 2 M aqueous sodium hydroxide solution at room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, diluted with water, and then acidified with 2 M hydrochloric acid under an ice bath. The precipitated sediment was filtered to obtain the title compound (383 mg). MS (m / z): 344.2 [MH] -

[0267] [Step 3] Production of intermediate RE-37C [ka] The title compound was obtained by using intermediate RE-37B instead of intermediate RE-4C, following the same method as in step 4 of Reference Example 4. MS(m / z):467.3[M+H]

[0268] [Step 4] Preparation of compound RE-37 A mixture of intermediate RE-37C (171 mg) and dichloromethane (4 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added and the solvent was removed by vacuum distillation to obtain the title compound (145 mg). MS (m / z): 367.2 [M + H] +

[0269] Reference Example 38: 2-[3-(azetidine-3-yl)-5-fluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-38) [ka]

[0270] [Step 1] Manufacturing of intermediate RE-38A [ka] The title compound was obtained by using 1,4-difluoro-2-iodobenzene instead of 2-bromo-4-chloro-1-fluorobenzene, following the method described in Step 1 of Reference Example 5. MS(m / z):298.1[M+H] +

[0271] [Step 2] Manufacturing of intermediate RE-38B [ka] The title compound was obtained by using intermediate RE-38A instead of intermediate RE-1B, following the method described in step 3 of Reference Example 1. MS(m / z):290.1[MH] -

[0272] [Step 3] Production of intermediate RE-38C [ka] A mixture of intermediate RE-38B (176 mg) and DMF (3 mL) was mixed with cesium carbonate (236 mg) and methyl bromoacetate (111 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (183 mg). 1 H-NMR(400MHz,CDCl3)δ7.37(d,1H),7.25-7.15(m,2H),5.10(s,2H),4.41(t,2H),4.29(t,2H),4.13-4.03(m,1H),3.77(s,3H),1.48(s,9H)

[0273] [Step 4] Manufacturing of intermediate RE-38D [ka] The title compound was obtained by using intermediate RE-38C instead of intermediate RE-1D, following the method described in step 5 of Reference Example 1. MS(m / z):348.4[MH] -

[0274] [Step 5] Manufacturing of intermediate RE-38E [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-38D instead of intermediate RE-1E, and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS(m / z):471.3[M+H] +

[0275] [Step 6] Preparation of compound RE-38 The title compound was obtained by using intermediate RE-38E instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):371.2[M+H] +

[0276] Reference Example 39: tert-butyl 2-[3-(1-{2-[3-(azetidine-3-yl)-1H-indazole-1-yl]acetyl}azetidine-3-yl)-1H-indazole-1-yl]acetate (compound RE-39) [ka]

[0277] [Step 1] Manufacturing of intermediate RE-39A [ka] A mixture of 1-benzyloxycarbonylazetidine-3-carboxylic acid (120 mg), di(pyridine-2-yl)carbonate (100 mg), DMAP (6 mg), and dichloromethane (1.2 mL) was stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (94 mg). MS (m / z): 313.1 [M+H] +

[0278] [Step 2] Manufacturing 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 Pd(OAc)2 (45 mg) was added. The mixture was stirred overnight at 50°C under an argon atmosphere. The solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (207 mg). MS (m / z): 314.0 [M+H] +

[0279] [Step 3] Production 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 overnight at 150°C. Ice water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.26 g). MS (m / z): 308.1 [M+H] +

[0280] [Step 4] Manufacturing 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 stirred for 30 minutes. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (875 mg). MS (m / z): 444.2 [M + Na] +

[0281] [Step 5] Preparation of compound RE-39 A mixture of intermediate RE-39D (875 mg) and methanol (21 mL) was mixed with 5% Pd-C (440 mg) and stirred overnight at room temperature under a hydrogen atmosphere (0.1 MPa). Insoluble matter was separated by Celite® filtration, and the filtrate was concentrated under reduced pressure to obtain 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)pyrrolidine-1-yl]ethyl}-1H-indazole-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (compound RE-40) [ka]

[0283] [Step 1] Manufacturing 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. Then, the mixture was stirred at room temperature for 30 minutes. Saturated ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.88 g). 1 H-NMR(400MHz,CDCl3)δ7.64(d,1H),7.50-7.44(m,1H),7.32(d,1H),7.27(t,1H),5.13(s,2H),3.75(s,3H)

[0284] [Step 2] Manufacturing of intermediate RE-40B [ka] Intermediate RE-40A (200 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (345 mg), sodium carbonate (236 mg), Pd(dppf)Cl2·CH2Cl2 (91 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) were degassed and stirred overnight at 95°C under an argon atmosphere. Insoluble matter was separated by Celite® filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (255 mg). MS (m / z): 356.3 [MH] ―

[0285] [Step 3] Production of compound RE-40 A mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (75 mg) was mixed with HBTU (162 mg) and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to obtain 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-indazole-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (compound RE-41) [ka] A mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and 2,2,2-trifluoroethanamine hydrochloride (64 mg) was mixed with HBTU (162 mg) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (104 mg). MS (m / z): 475.2 [M + Na] +

[0287] Reference Example 42: 2-[3-(azetidine-3-yl)-5-fluoro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-42) [ka]

[0288] [Step 1] Manufacturing of intermediate RE-42A [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-38D instead of intermediate RE-1E, and using 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride. MS(m / z):467.2[M+Na] +

[0289] [Step 2] Preparation of compound RE-42 The title compound was obtained by using intermediate RE-42A instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):345.1[M+H] +

[0290] Reference Example 43: 2-[3-(azetidine-3-yl)-5,6-difluoro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-43) [ka]

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

[0292] [Step 2] Production of intermediate RE-43B [ka] Intermediate RE-43B was synthesized starting from intermediate RE-43A, following 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[MH] -

[0293] [Step 3] Production of intermediate RE-43C [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-43B instead of intermediate RE-1E, and using 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS(m / z):485.2[M+Na] +

[0294] [Step 4] Preparation of compound RE-43 The title compound was obtained by using intermediate RE-43C instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):363.1[M+H] +

[0295] Reference Example 44: 2-[3-(azetidine-3-yl)-5,6-difluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-44) [ka] Compound RE-44 was synthesized starting from intermediate RE-43B, following 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-hydroxyazetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-45) [ka]

[0297] [Step 1] Manufacturing of intermediate RE-45A [ka] A mixture of 1-(tert-butyl)3-methyl3-hydroxyazetidine-1,3-dicarboxylate (1.0 g) and DMF (14 mL) was mixed with 60% sodium hydride (260 mg) under ice cooling and stirred for 50 minutes. Then, benzyl bromide (1.10 g) was added and the mixture was stirred at room temperature for 5 hours. Saturated ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.07 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] Manufacturing of intermediate RE-45B [ka] A mixture of intermediate RE-45A (1.07 g), methanol (8 mL), and THF (8 mL) was mixed with 2 M aqueous sodium hydroxide and stirred at room temperature. The solvent was removed by vacuum distillation, neutralized with 2 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, the residue was washed with hexane, and the title compound (866 mg) was obtained by drying. MS (m / z): 306.1 [MH] ―

[0299] [Step 3] Production 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 overnight at room temperature. Saturated baking soda water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (961 mg). MS (m / z): 373.0 [M+H] +

[0300] [Step 4] Manufacturing of intermediate RE-45D [ka] The title compound was obtained by following the method in step 1 of Reference Example 5, using 1-fluoro-2-iodobenzene instead of 2-bromo-4-chloro-1-fluorobenzene, and using intermediate RE-45C instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate. MS(m / z): 286.2[M-Boc+2H] + , 1 H-NMR(400MHz,DMSO-d6)δ7.75-7.68(m,2H),7.35(dd,2H),7.22-7.20(m, 3H),6.93-6.90(m,2H),4.36(d,2H),4.23(s,2H),4.13(d,2H),1.41(s,9H)

[0301] [Step 5] Production 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 ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was mixed with cesium carbonate (1.99 g) and DMA (7 mL). Methyl bromoacetate (467 mg) was added under ice cooling and stirred overnight at room temperature. Saturated ammonium chloride solution was added to the reaction mixture and 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 by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain the title compound (709 mg). MS (m / z): 474.3 [M + Na] +

[0302] [Step 6] Manufacturing of intermediate RE-45F [ka] A mixture of intermediate RE-45E (709 mg) and THF (20 mL) was mixed with 5% Pd-C (600 mg) and stirred under a hydrogen atmosphere (0.3 MPa) at 40°C for 6 hours. The mixture was then stirred at 50°C for 11 hours. Insoluble matter was separated by Celite® filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (425 mg). MS (m / z): 384.2 [M + Na] +

[0303] [Step 7] Production of intermediate RE-45G [ka] The title compound was obtained by using intermediate RE-45F instead of intermediate RE-1D, following the method described in step 5 of Reference Example 1. MS(m / z):346.1[MH] -

[0304] [Step 8] Production of intermediate RE-45H [ka] A mixture of intermediate RE-45G (159 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (121 mg), HOBt (93 mg), DIPEA (0.24 mL), and DMF (0.3 mL) was mixed with EDCI·HCl (132 mg) and stirred overnight at room temperature. Saturated baking soda water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (193 mg). MS (m / z): 491.3 [M + Na] +

[0305] [Step 9] Preparation of compound RE-45 The title compound was obtained by using intermediate RE-45H instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):369.2[M+H] +

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

[0307] Reference Example 47: 2-[3-(azetidine-3-yl)-5-methyl-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-47) [ka]

[0308] [Step 1] Manufacturing of intermediate RE-47A [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-37B instead of intermediate RE-1E, and using 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS(m / z):463.3[M+Na] +

[0309] [Step 2] Preparation of compound RE-47 The title compound was obtained by using intermediate RE-47A instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):341.0[M+H] + Reference Example 48: tert-butyl 3-(5-methoxy-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-48) [ka]

[0310] [Step 1] Manufacturing 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[MH] ― [Step 2] Preparation of compound RE-48 The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-48A instead of intermediate RE-1E, and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS(m / z): 505.2[M+Na] +

[0311] Reference Example 49: 2-[3-(azetidine-3-yl)-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-49) [ka]

[0312] [Step 1] Manufacturing of intermediate RE-49A [ka] Intermediate RE-49A was synthesized starting from 3-iodo-5,5-dimethyl-1,4,6,7-tetrahydroindazole (e.g., synthesized according to the method described in Journal of Medicinal Chemistry 2013, 56(4), 1677-1692) and 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] Production of intermediate RE-49B [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-49A instead of intermediate RE-1E, and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride. MS(m / z):485.4[M+H] +

[0314] [Step 3] Preparation of compound RE-49 The title compound was obtained by using intermediate RE-49B instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):385.4[M+H] +

[0315] Reference Example 50: 2-[3-(azetidine-3-yl)-4-chloro-5-fluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-50) [ka] A mixture of intermediate RE-1E (200 mg), HATU (258 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (119 mg), and DMF (1.7 mL) was mixed with DIPEA (0.3 mL) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain tert-butyl 3-(4-chloro-5-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-indazole-3-yl)azetidine-1-carboxylate (250 mg). A mixture of tert-butyl 3-(4-chloro-5-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-indazole-3-yl)azetidine-1-carboxylate (250 mg) and dichloromethane (0.5 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 4 hours. The solvent was removed by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added and the solvent was removed by vacuum distillation to obtain the title compound (260 mg). MS(m / z):405.1[M+H] +

[0316] Reference Example 51: 2-[3-(azetidine-3-yl)-4-chloro-5-fluoro-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-51) [ka]

[0317] [Step 1] Manufacturing of intermediate RE-51A [ka] The title compound was obtained by using 2,2,2-trifluoro-N-methylethaneamine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride, following the method described in Step 6 of Reference Example 1. MS(m / z): 501.2[M+Na] +

[0318] [Step 2] Production of compound RE-51 The title compound was obtained by using intermediate RE-51A instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-52) [ka] The title compound was obtained by using intermediate RE-2E instead of intermediate RE-1E, following the method described in step 6 of Reference Example 1. 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-(azetidine-3-yl)-4,6-difluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-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 through 7 of Reference Example 2 for the preparation of compound RE-2, but 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)pyrrolidine-1-yl]ethyl}-1H-indazole-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, but 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-indazole-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 overnight at room temperature. Saturated ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (80 mg). MS (m / z): 342.1 [M-Boc+2H] +

[0323] Reference Example 56: tert-butyl 3-[4,6-difluoro-1-(3-phenylpropane-2-in-1-yl)-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-56) [ka] The title compound was obtained by using 3-phenylprop-2-in-1-yl 4-methylbenzenesulfonate instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate, following the method described in Reference Example 55. MS(m / z): 342.1[M-Boc+2H] +

[0324] Reference Example 57: tert-butyl 3-[1-(3-cyclopropylpropane-2-in-1-yl)-4,6-difluoro-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-57) [ka] The title compound was obtained by using 3-cyclopropylprop-2-in-1-yl 4-methylbenzenesulfonate instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate, following the method described in Reference Example 55. MS(m / z):288.2[M-Boc+2H] +

[0325] Reference Example 58: tert-butyl 3-{4,6-difluoro-1-[(1-phenylazetidine-3-yl)methyl]-1H-indazole-3-yl}azetidine-1-carboxylate (compound RE-58) [ka]

[0326] [Step 1] Manufacturing 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 and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-[1-({1-[(benzyloxy)carbonyl]azetidine-3-yl}methyl)-4,6-difluoro-1H-indazole-3-yl]azetidine-1-carboxylate. This mixture was then stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was separated by Celite® filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (270 mg). MS (m / z): 379.2 [M+H] +

[0327] [Step 2] Preparation of compound RE-58 A mixture of intermediate RE-58A (30 mg), bromobenzene (15 mg), Pd(OAc)2 (2 mg), Xantphos (9 mg), cesium carbonate (52 mg), and 1,4-dioxane (0.3 mL) was stirred at 90°C for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain 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)azetidine-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-59) [ka] A mixture of intermediate RE-58A (30 mg), DIPEA (0.04 mL), and THF (0.3 mL) was mixed with (2,2,2-trifluoroethyl)trifluoromethanesulfonate (37 mg) and stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain 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-indazole-3-yl}azetidine-1-carboxylate (compound RE-60) [ka] The title compound was obtained by using indan-2-ylmethyl 4-methylbenzenesulfonate instead of (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate, following the method described in Reference Example 55. MS(m / z): 340.1[M-Boc+2H] +

[0330] Reference Example 61: 2-[3-(azetidine-3-yl)-4,6-difluoro-1H-indazole-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one trifluoroacetate (compound RE-61) [ka]

[0331] [Step 1] Manufacturing of intermediate RE-61A [ka] A mixture of intermediate RE-2E (100 mg), DMF (0.9 mL), DIPEA (0.14 mL), and (2R)-2-(trifluoromethyl)morpholine hydrochloride (63 mg) was mixed with HBTU (124 mg) and stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain 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 using intermediate RE-61A instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):405.1[M+H] +

[0333] Reference Example 62: 2-[3-(azetidine-3-yl)-4,6-difluoro-1H-indazole-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, following a procedure similar to that described in steps 1 and 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-(azetidine-3-yl)-1H-indazole-1-yl]-N-tert-butylacetamide trifluoroacetate (compound RE-63) [ka] Compound RE-63 was synthesized starting 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, but using 2-methylpropan-2-amine instead of (2R)-2-(trifluoromethyl)morpholine hydrochloride. MS(m / z):287.2[M+H] +

[0335] Reference Example 64: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-N,N-bis(propan-2-yl)acetamide trifluoroacetate (compound RE-64) [ka] Compound RE-64 was synthesized starting 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, but using diisopropylamine instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride. MS(m / z):315.3[M+H] +

[0336] Reference Example 65: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-N-tert-butyl-N-methylacetamide trifluoroacetate (compound RE-65) [ka] Compound RE-65 was synthesized starting 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, but using N,2-dimethylpropane-2-amine instead of 2,2,2-trifluoro-N-methylethaneamine hydrochloride. MS(m / z):301.2[M+H] +

[0337] Reference Example 66: 2-[3-(azetidine-3-yl)-1H-indazole-1-yl]-N-methyl-N-(2,2,2-trifluoroethyl)acetamide trifluoroacetate (compound RE-66) [ka]

[0338] [Step 1] Manufacturing of intermediate RE-66A [ka] A mixture of intermediate RE-4C (350 mg), 2,2,2-trifluoro-N-methylethaneamine hydrochloride (190 mg), 1-hydroxybenzotriazole monohydrate (194 mg), NMM (0.35 mL), and acetonitrile (3 mL) was mixed with EDCI·HCl (243 mg) and stirred overnight at room temperature. Saturated baking soda water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (280 mg). MS (m / z): 449.3 [M + Na] +

[0339] [Step 2] Preparation of compound RE-66 The title compound was obtained by using intermediate RE-66A instead of intermediate RE-37C, following the method described in Step 4 of Reference Example 37. MS(m / z):327.2[M+H] +

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

[0341] Reference Example 68: 2-[3-(azetidine-3-yl)-5-chloro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-68) [ka] A mixture of intermediate RE-5D (115 mg), DMF (0.6 mL), DIPEA (0.16 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (66 mg) was mixed with HATU (143 mg) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the compound (116 mg). A mixture of the obtained compound (116 mg) and dichloromethane (2 mL) was mixed with trifluoroacetic acid (0.5 mL) and stirred at room temperature. The solvent was removed by distillation under reduced pressure to obtain the title compound (119 mg). MS (m / z): 387.1 [M+H] +

[0342] Reference Example 69: 2-[3-(azetidine-3-yl)-6-fluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one trifluoroacetate (compound RE-69) [ka] Compound RE-69 was synthesized starting from intermediate RE-6C, following a procedure similar to that described in steps 1 and 2 of Reference Example 66 for the preparation of compound RE-66, but using (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoro-N-methylethaneamine 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-70) [ka] A mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), HBTU (132 mg), and 2,2,2-trifluoro-N-methylethaneamine hydrochloride (52 mg) was mixed with DIPEA (0.15 mL) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (109 mg). MS (m / z): 463.4 [M + Na] +

[0344] Reference Example 71: 2-[4-fluoro-3-(piperidine-4-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound RE-71) [ka]

[0345] [Step 1] Manufacturing 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[MH] ―

[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 overnight at room temperature. Saturated baking soda water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and ethyl acetate (5 mL) and hydrogen chloride (4 M ethyl acetate solution, 0.4 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography to obtain 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)morpholine-4-yl]ethyl}-1H-indazole-3-yl)piperidine-1-carboxylate (compound RE-72) [ka] A mixture of intermediates 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 obtain 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)morpholine-4-yl]ethyl}-1H-indazole-3-yl)piperidine-1-carboxylate (compound RE-73) [ka] The title compound was obtained by using (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)morpholine hydrochloride, following the method described in Reference Example 72. MS(m / z): 537.1[M+Na] +

[0349] Reference Example 74: tert-butyl 4-(4-fluoro-1-{[6-(trifluoromethyl)pyridine-3-yl]methyl}-1H-indazole-3-yl)piperidine-1-carboxylate (compound RE-74) [ka] The title compound was obtained by using 5-(chloromethyl)-2-(trifluoromethyl)pyridine instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine, following the method described in Step 4 of Reference Example 10. MS(m / z): 501.2[M+Na] +

[0350] Reference Example 75: tert-butyl 4-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-indole-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (compound RE-75) [ka] Compound RE-75 was synthesized starting from intermediate RE-11A, following 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)morpholine-4-yl]ethyl}-1H-indole-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, but using (2R)-2-(trifluoromethyl)morpholine hydrochloride 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)morpholine-4-yl]ethyl}-1H-indole-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, but using (2S)-2-(trifluoromethyl)morpholine hydrochloride instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS(m / z): 536.2[M+Na] +

[0353] Reference Example 78: 2-[3-(azetidine-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one dihydrochloride (compound RE-78) [ka]

[0354] [Step 1] Manufacturing of intermediate RE-78A [ka] The title compound was obtained using the method described in Reference Example 67, with intermediate RE-13D 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 using intermediate RE-78A instead of intermediate RE-1F, following the method described in step 7 of Reference Example 1. MS(m / z):384.2[M+H] +

[0356] Reference Example 79: 2-[3-(azetidine-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl]-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one dihydrochloride (compound RE-79) [ka]

[0357] [Step 1] Manufacturing of intermediate RE-79A [ka] A mixture of intermediate RE-13D (52 mg), DMF (1.0 mL), HBTU (74 mg), and 3,3-dimethylmorpholine (22 mg) was mixed with DIPEA (0.08 mL) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain 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 using intermediate RE-79A instead of intermediate RE-1F, following the method described in step 7 of Reference Example 1. MS(m / z):344.2[M+H] +

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

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

[0361] [Step 2] Manufacturing of compound RE-80 The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-80A instead of intermediate RE-1E, and (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of 2,2,2-trifluoroethaneamine hydrochloride. MS(m / z):488.2[M+H] +

[0362] Reference Example 81: tert-butyl 3-(4-fluoro-1-{2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carboxylate (compound RE-81) [ka] The title compound was obtained by following the method in step 6 of Reference Example 1, using intermediate RE-80A instead of intermediate RE-1E, and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride. MS(m / z):472.2[M+H] +

[0363] Reference Example 82: tert-butyl 3-(4-fluoro-1-{[5-(trifluoromethyl)pyridine-2-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carboxylate (compound RE-82) [ka] The title compound was obtained by using intermediate RE-15C instead of intermediate RE-10C, following the method described in step 4 of Reference Example 10. 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]pyridine-3-yl)azetidine-1-carboxylate (compound RE-83) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-15C instead of intermediate RE-10C, and using 1-(bromomethyl)-4-(trifluoromethyl)benzene 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-oxadiazole-3-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carboxylate (compound RE-84) [ka] The title compound was obtained by using 2-fluorobenzoic acid instead of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid, following the method described in Step 6 of Reference Example 15. MS(m / z): 469.2[M+H] +

[0366] Reference Example 85: tert-butyl 3-(4-fluoro-1-{[3-(3-fluoropyridine-4-yl)-1,2,4-oxadiazole-5-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carboxylate (compound RE-85) [ka] Intermediate RE-80A (40 mg), 3-fluoro-N'-hydroxypyridine-4-carboxamide (e.g., synthesized 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) were mixed with HATU (48 mg) and 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-(azetidine-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl]-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one dihydrochloride (compound RE-86) [ka] The title compound was obtained by using compound RE-80 instead of intermediate RE-1F, following the method described in step 7 of Reference Example 1. MS(m / z):388.1[M+H] +

[0368] Reference Example 87: 2-[3-(azetidine-3-yl)-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl]-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one dihydrochloride (compound RE-87) [ka]

[0369] [Step 1] Manufacturing of intermediate RE-87A [ka] A mixture of intermediate RE-80A (80 mg), DMF (0.8 mL), HBTU (130 mg), and (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (56 mg) was mixed with DIPEA (0.2 mL) and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain 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 using intermediate RE-87A instead of intermediate RE-1F, following the method described in step 7 of Reference Example 1. MS(m / z):402.2[M+H] +

[0371] Reference example 88: 3-(azetidine-3-yl)-1-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole (compound RE-88) [ka]

[0372] [Step 1] Manufacturing 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 overnight at 60°C. The reaction mixture was purified by silica gel column chromatography to obtain 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-triazole-4-yl)methyl]-1H-indazole-3-yl}azetidine-1-carboxylate (compound RE-89) [ka] A mixture of intermediate RE-18D (74 mg), azidobenzene (54 mg), DMF (2 mL), and methanol (0.2 mL) was mixed with copper(I) iodide (4 mg) and stirred at 60°C for 3 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (62 mg). 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-triazole-4-yl)methyl]-4-fluoro-1H-indazole-3-yl}azetidine-1-carboxylate (compound RE-90) [ka] The title compound was obtained by using azidomethylbenzene instead of azidobenzene, following a method similar to Reference Example 89. 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-triazole-4-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-91) [ka] The title compound was obtained by using 2-azido-1,1,1-trifluoroethane instead of azidobenzene, following the method described in Reference Example 89. MS(m / z):355.0[M-Boc+2H] +

[0377] Reference Example 92: tert-butyl 3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-92) [ka] The title compound was obtained by using azidomethylcyclobutane instead of azidobenzene, following the method described in Reference Example 89. MS(m / z): 341.1[M-Boc+2H] +

[0378] Reference Example 93: tert-butyl 3-{4-fluoro-1-[(3-methyl-1,2,4-oxadiazole-5-yl)methyl]-1H-indazole-3-yl}azetidine-1-carboxylate (compound RE-93) [ka] A mixture of intermediate RE-18C (50 mg) and THF (0.6 mL) was mixed with 60% sodium hydride (5 mg) 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 baking soda water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-94) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-18C instead of intermediate RE-10C, and using 1-(bromomethyl)-4-(trifluoromethyl)benzene 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-95) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-18C instead of intermediate RE-10C, and using 1-(bromomethyl)-3-(trifluoromethyl)benzene 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-96) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-18C instead of intermediate RE-10C, and using 1-(bromomethyl)-2-(trifluoromethyl)benzene 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-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-97) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-18C instead of intermediate RE-10C, and 5-(chloromethyl)-3-trifluoromethyl-1,2,4-oxadiazole instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine. MS(m / z): 342.1[M-Boc+2H] +

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

[0384] [Step 1] Manufacturing 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 production 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 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 (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-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-99) [ka] The title compound was obtained by using 3-trifluoromethylbenzoic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. MS(m / z): 418.1[M-Boc+2H] +

[0387] Reference Example 100: tert-butyl 3-(4-fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-100) [ka] The title compound was obtained by following the method in step 4 of Reference Example 10, using intermediate RE-18C instead of intermediate RE-10C, and using 2-(chloromethyl)-5-trifluoromethyl-1,3,4-oxadiazole 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-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-101) [ka] The title compound was obtained by using tetrahydropyran-4-carboxylic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. 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-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-103) (compound RE-102) [ka] The title compound was obtained by using 1-(trifluoromethyl)cyclobutanecarboxylic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. MS(m / z): 518.2[M+Na] +

[0390] Reference Example 103: tert-butyl 3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carboxylate (compound RE-103) [ka] The title compound was obtained by using 1-(trifluoromethyl)cyclopropanecarboxylic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. MS(m / z): 504.2[M+Na] +

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

[0392] Reference Example 105: tert-butyl 3-(4-fluoro-1-{[5-(5-fluoropyridine-2-yl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-105) [ka] The title compound was obtained by using 5-fluoropyridine-2-carboxylic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. 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-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-106) [ka] The title compound was obtained by using 6-methylpyridazine-3-carboxylic acid instead of 4-fluorobenzoic acid, following the method described in Reference Example 98. MS(m / z): 366.1[M-Boc+2H] +

[0394] Reference Example 107: 3-(azetidine-3-yl)-4-fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazole-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 overnight at 60°C. Trifluoroacetic anhydride (81 mg) was added and the mixture was stirred at 60°C for 2 hours. The reaction mixture was then purified by silica gel column chromatography to obtain the title compound (13 mg). MS (m / z): 342.1 [M+H] +

[0395] Reference Example 108: 2-[3-(azetidine-3-yl)-4-fluoro-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound RE-108) [ka] Compound RE-108 was synthesized starting from intermediate RE-20B, following 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-oxadiazole-5-yl}methyl)-1H-indazole-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 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 (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-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-110) [ka] The title compound was obtained by using 4-fluoro-N'-hydroxybenzamidine instead of N'-hydroxy-3-(trifluoromethyl)benzamidine, following the method described in Reference Example 109. MS(m / z): 368.1[M-Boc+2H] +

[0398] Reference Example 111: tert-butyl 3-(4-fluoro-1-{[3-(pyridine-4-yl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carboxylate (compound RE-111) [ka] The title compound was obtained by using N'-hydroxypyridine-4-carboxamidine instead of N'-hydroxy-3-(trifluoromethyl)benzamidine, following the method described in Reference Example 109. 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-indazole-3-yl}azetidine-1-carboxylate (compound RE-112) [ka] The title compound was obtained by following the method in step 1 of Reference Example 87, using intermediate RE-20B instead of intermediate RE-80A, and norbornane-2-amine hydrochloride 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-indazole-3-yl}azetidine-1-carboxylate (compound RE-113) [ka] The title compound was obtained by following the procedure in step 1 of Reference Example 87, using intermediate RE-20B instead of intermediate RE-80A, and using bicyclo[1.1.1]pentan-1-amine 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-indazole-3-yl)azetidine-1-carboxylate (compound RE-114) [ka] The title compound was obtained by following the method in step 1 of Reference Example 87, using intermediate RE-20B instead of intermediate RE-80A, and using 2,2-difluoroethaneamine instead of (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride. MS(m / z): 313.1[M-Boc+2H] +

[0402] Reference Example 115: 4-{4-[4-Fluoro-1-(propa-2-in-1-yl)-1H-indazole-3-yl]piperidine-1-carbonyl}pyridine-2-amine (compound RE-115) [ka] A mixture of intermediate RE-10C (70 mg) and DMF (0.7 mL) was mixed with potassium carbonate (45 mg) and propagyl bromide (29 mg) and stirred overnight at room temperature. Saturated ammonium chloride water was added to the reaction mixture, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and the resulting residue (78 mg) was mixed with dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 3 hours. The solvent was removed by vacuum distillation, 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, and then the separately prepared residue DMF solution was added and stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (65 mg). MS (m / z): 378.2 [M+H] +

[0403] Reference Example 116: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}acetic acid (compound RE-116) [ka]

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

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

[0406] Reference Example 117: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}acetic acid trifluoroacetate (compound RE-117) [ka]

[0407] [Step 1] Manufacturing of intermediate RE-117A [ka] A mixture of compound RE-39 (473 mg), compound RE-24 (349 mg), HOBt (289 mg), EDCI·HCl (410 mg), and DMF (5.5 mL) was mixed with DIPEA (0.85 mL) and stirred at room temperature for 2 hours. Saturated baking soda water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (409 mg). MS (m / z): 426.2 [M+H] +

[0408] [Step 2] Preparation of compound RE-117 A mixture of intermediate RE-117A (389 mg) and dichloromethane (2 mL) was mixed with trifluoroacetic acid (0.5 mL) and stirred at room temperature for 1 hour. Another 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred overnight at room temperature. The solvent was removed by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added, and the solvent was removed by vacuum distillation. The residue was washed with diethyl ether and dried to obtain the title compound (396 mg). MS (m / z): 370.2 [M+H] +

[0409] Reference Example 118: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}acetic acid (compound RE-118) [ka]

[0410] [Step 1] Manufacturing 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 removed 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. Then, the separately prepared residue in DMF was added, and the mixture was stirred overnight at room temperature. Saturated water bicarbonate was added to the reaction mixture, and it 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 removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (83 mg). MS (m / z): 397.8 [M + H] +

[0411] [Step 2] Preparation of compound RE-118 A mixture of intermediate RE-118A (83 mg) and methanol (2 mL) was mixed with 0.1 mL of 2 M aqueous sodium hydroxide solution under ice cooling and stirred overnight at room temperature. Neutralization was achieved by adding 2 M hydrochloric acid, and the solvent was removed under reduced pressure to obtain 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)azetidine-3-yl]-4,6-difluoro-1H-indazole-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, but using 2-amino-3-methylpyridine-4-carboxylic acid 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)azetidine-3-yl]-4,6-difluoro-1H-indazole-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, but 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)azetidine-3-yl]-1H-indazole-1-yl}acetic acid (compound RE-121) [ka] Compound RE-121 was synthesized starting from intermediate RE-4B, following a procedure similar to that described in steps 1 and 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-(propa-2-in-1-yl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (compound RE-122) [ka] A mixture of intermediate RE-18D (100 mg) and hydrogen chloride (4M 1,4-dioxane solution, 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 container, a mixture of 2-aminopyridine-4-carboxylic acid (32 mg), DMF (2.3 mL), DIPEA (0.4 mL), and HBTU (114 mg) was stirred at room temperature for 2 hours. Then, the separately prepared residue in DMF solution was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to obtain 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]azetidine-3-yl}-5-fluoro-1H-indazole-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]azetidine-3-yl}-5-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (compound E-1A) [ka] 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) were mixed with HATU (37 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (15 mg).

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

[0418] Example 2: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound E-2) [ka] [Step 1] Preparation of 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-2A) [ka] A mixture of 2-aminopyridine-4-carboxylic acid (13 mg), HBTU (35 mg), and DMF (1 mL) was mixed with DIPEA (0.098 mL) 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 obtain the title compound (34 mg).

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

[0420] Example 3: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-3) [ka] A mixture of compound RE-4 (20 mg) obtained in step 5 of Reference Example 4, compound RE-24 (9.1 mg) obtained in Reference Example 24, HOBt (7.5 mg), EDCI·HCl (10.7 mg), and DMF (0.5 mL) was mixed with DIPEA (0.022 mL) 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): 491.1 [M+H] +

[0421] Example 4: 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-4) [ka] Following the method of Example 3, compound RE-5 (43 mg), obtained in step 6 of Reference Example 5, was used instead of compound RE-4, and 2-aminopyrimidine-4-carboxylic acid (15 mg) was used instead of compound RE-24 to obtain the title compound (24 mg). MS (m / z): 482.3 [M+H] +

[0422] Example 5: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-5) [ka] Following the method described in Example 3, compound RE-6 (40 mg), obtained in step 5 of Reference Example 6, was used instead of compound RE-4 to obtain the title compound (32 mg). MS(m / z):483.3[M+H] +

[0423] Example 6: 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-6) [ka] The title compound (7 mg) was obtained by using a method similar to Step 1 of Example 2, but instead of compound RE-2, compound RE-7 (55 mg) obtained in Step 5 of Reference Example 7 was used. MS(m / z):487.4[M+H] +

[0424] Example 7: 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (compound E-7) [ka] Following the method of Example 3, 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 obtain the title compound (12 mg). MS (m / z): 469.2 [M+H] +

[0425] Example 8: 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (compound E-8) [ka] Following the same procedure as in Step 1 of Example 2, 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 obtain the title compound (15 mg). MS (m / z): 503.2 [M+H] +

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

[0427] Example 10: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-10) [ka] Following the method described in Example 3, compound RE-11 (46 mg), obtained in step 6 of Reference Example 11, was used instead of compound RE-4 to obtain the title compound (17 mg). MS(m / z): 536.3[M+H] +

[0428] Example 11: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-11) [ka] A mixture of compound RE-12 (50 mg) obtained in step 5 of Reference Example 12 and ethyl acetate (0.4 mL) was mixed with hydrogen chloride (4 M ethyl acetate solution, 0.14 mL) and stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure to obtain 2-[3-(azetidine-3-yl)-1H-indole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride. Next, following the same procedure as in Step 1 of Example 2, the title compound (14 mg) was obtained by using 2-[3-(azetidine-3-yl)-1H-indole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride, obtained above, instead of compound RE-2. MS(m / z):472.3[M+H] +

[0429] Example 12: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 the mixture was stirred overnight at room temperature. To remove remaining raw materials, hydrogen chloride (2 M methanol solution, 0.53 mL) was added 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 overnight at room temperature. The solvent was removed by distillation under reduced pressure to obtain 2-[3-(azetidine-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride. Next, following the same procedure as in Step 1 of Example 2, 2-[3-(azetidine-3-yl)-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (33 mg) obtained above was used instead of compound RE-2 to obtain the title compound (12 mg). MS(m / z):488.2[M+H] +

[0430] Example 13: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound E-13) [ka] [Step 1] Preparation of 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-13A) [ka] The title compound (22 mg) was obtained by using a method similar to Step 1 of Example 2, but instead of compound RE-2, compound RE-14 (30 mg) obtained in Step 8 of Reference Example 14 was used.

[0431] [Step 2] Preparation of Compound E-13 The title compound (18 mg) was obtained by using compound E-13A (22 mg) instead of compound E-2A, following the same procedure as in Step 2 of Example 2. MS (m / z): 474.2 [M+H] +

[0432] Example 14: 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-pyrazolo[3,4-c]pyridine-3-yl]azetidine-1-carbonyl}pyridine-2-amine (Compound E-14) [ka] Following the same procedure as in Step 1 of Example 2, compound RE-15 (27.5 mg), obtained in Step 7 of Reference Example 15, was used instead of compound RE-2 to obtain the title compound (22.3 mg). MS (m / z): 503.2 [M+H] +

[0433] Example 15: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-15) [ka] Following the same procedure as in Step 1 of Example 2, compound RE-16 (43 mg), obtained in Step 7 of Reference Example 16, was used instead of compound RE-2 to obtain the title compound (27 mg). MS(m / z):488.1[M+H] +

[0434] Example 16: 2-{3-[1-(6-aminopyridazine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-16) [ka] Following the same procedure as in Step 1 of Example 2, compound RE-3 (20 mg) obtained in Reference Example 3 was used instead of compound RE-2, and 6-aminopyridazine-4-carboxylic acid (8.3 mg) was used instead of 2-aminopyridine-4-carboxylic acid to obtain the title compound (5 mg). MS (m / z): 510.3 [M+H] +

[0435] Example 17: 2-[4,6-difluoro-3-(1-{1H-pyrazolo[3,4-b]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-17) [ka] A mixture of 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (7.8 mg), EDCI·HCl (9.2 mg), HOBt (6.5 mg), and DMF (0.5 mL) was mixed with DIPEA (0.021 mL) 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 obtain 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-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (Compound E-18) [ka] Following the same procedure as in Step 1 of Example 2, 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 obtain 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-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine hydrochloride (compound E-19) [ka] [Step 1] Preparation of 4-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (Compound E-19A) [ka] Following the method described in step 7 of Reference Example 1, compound RE-18 (56 mg) was used instead of intermediate RE-1F to obtain 3-(azetidine-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride. Next, following the same procedure as in Step 1 of Example 2, the title compound (14 mg) was obtained by using 3-(azetidine-3-yl)-1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole hydrochloride, obtained above, instead of compound RE-2.

[0438] [Step 2] Preparation of Compound E-19 Following the same procedure as in Step 2 of Example 2, compound E-19A (14 mg) was used instead of compound E-2A to obtain the title compound (5.4 mg). MS (m / z): 497.1 [M+H] +

[0439] Example 20: 4-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (Compound E-20) [ka] Following the same procedure as in Step 1 of Example 2, compound RE-19 (67 mg), obtained in Step 2 of Reference Example 19, was used instead of compound RE-2 to obtain the title compound (53 mg). MS(m / z): 488.2[M+H] +

[0440] Example 21: 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-21) [ka] Using a method similar to that of Example 3, compound RE-5 (43 mg), obtained in step 6 of Reference Example 5, was used instead of compound RE-4, and compound RE-26 (17 mg), obtained in step 3 of Reference Example 26, was used instead of compound RE-24 to obtain the title compound (6 mg). MS (m / z): 500.3 [M+H] +

[0441] Example 22: 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-22) [ka] Following the method described in Example 3, compound RE-26 (16 mg), obtained in step 3 of Reference Example 26, was used instead of compound RE-24 to obtain the title compound (22 mg). MS(m / z): 492.2[M+H] +

[0442] Example 23: 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-23) [ka] Using a method similar to that of Example 3, 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 obtain the title compound (19 mg). MS(m / z):484.3[M+H] +

[0443] Example 24: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-24) [ka] Following the method described in Example 3, compound RE-21 (16 mg), obtained in step 6 of Reference Example 21, was used instead of compound RE-4 to obtain the title compound (9 mg). MS (m / z): 495.3 [M+H] +

[0444] Example 25: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-25) [ka] Following the method described in Example 3, compound RE-22 (62 mg), obtained in step 8 of Reference Example 22, was used instead of compound RE-4 to obtain the title compound (40 mg). MS(m / z): 531.3[M+H] +

[0445] Example 26: 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-5-fluoro-1H-indazole-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. The mixture was stirred at room temperature for 5 minutes. The solvent was removed by vacuum distillation, 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 values ​​(C 23 H 21 (As ClF4N6O2·C7H8O3S+2.7H2O) Calculated values ​​(%) C: 48.32, H: 4.65, N: 11.27 Measured values ​​(%) C: 48.35, H: 4.44, N: 10.95

[0446] Example 27: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 removed by distillation under reduced pressure, and the residue was dissolved in acetonitrile by heating. After cooling, the precipitated solid was filtered and dried to obtain 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 values ​​(C 23 H 21 (As F5N6O2·CH4O3S+0.5H2O) Calculated values ​​(%) C: 46.98, H: 4.27, N: 13.70 Measured values ​​(%) C: 46.73, H: 3.89, N: 13.62

[0447] Example 28: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound E-28) [ka] The title compound was obtained using compound E-3 instead of compound E-2A, following the same procedure as in Step 2 of Example 2. MS(m / z):474.2[M+H] + optical rotation [α] 589 25 = -2.78° (0.01g methanol, 1mL, 50mm) Elemental analysis values ​​(C 23 H 22 (As F4N6O2·HCl+0.9H2O) Calculated values ​​(%) C: 50.86, H: 4.60, N: 15.47 Measured values ​​(%) C: 51.13, H: 4.75, N: 15.14

[0448] Example 29: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 by vacuum distillation, and the residue was washed with a mixture of methanol and diethyl ether. The resulting mixture was dissolved in methanol, the solvent was removed by vacuum distillation, and the residue was washed with a mixed solvent of 2-propanol and hexane. The mixture was dried to obtain 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 values ​​(C 23 H 22 (As F4N6O2·CH4O3S) Calculated values ​​(%) C: 49.14, H: 4.47, N: 14.33 Measured values ​​(%) C: 49.10, H: 4.50, N: 14.36

[0449] Example 30: 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-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]azetidine-3-yl}-4,6-difluoro-1H-indazole-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 overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the resulting residue (50 mg), compound RE-23 (28 mg), DIPEA (0.16 mL), and DMF (1 mL) were mixed with HATU (59 mg) at room temperature, and the mixture was stirred overnight at room temperature. 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 using compound E-30A instead of compound E-2A, following the same method as in Step 2 of Example 2. MS(m / z): 509.5[M+H] +

[0451] Example 31: 2-(3-{1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (compound E-31) [ka] [Step 1] Production 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 overnight at room temperature. The solvent was removed by distillation under reduced pressure to obtain 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 overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the resulting residue (20 mg) was mixed with 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate (23 mg), DIPEA (0.04 mL), and DMF (1 mL). HBTU (30 mg) was added at room temperature, and the mixture was stirred for 3 hours at room temperature. 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}azetidine-3-yl)-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (compound E-32) [ka]

[0453] [Step 1] Preparation of 2-{3-[1-(2-bromopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-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 overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the resulting residue (84 mg) was dissolved in DMF (2 mL). In a separate container, a mixture of 2-bromopyridine-4-carboxylic acid (57 mg), HBTU (108 mg), and DMF (3 mL) was mixed with DIPEA (0.1 mL) and stirred at room temperature for 15 minutes. The separately prepared residue in DMF solution was added, and the mixture was stirred overnight at room temperature. 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-oxethanamine (10 mg), and 1,4-dioxane (2 mL) was degassed with argon, and Pd(OAc)2 (2 mg) was added and the mixture was stirred at 100°C for 3 hours. Insoluble matter was filtered off with Celite®, the solvent was removed by reduced pressure distillation, and the residue was purified by silica gel column chromatography to obtain 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}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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. Compound RE-2 (30 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (37 mg).

[0457] [Step 2] Preparation of Compound E-33 The title compound was obtained by using compound E-33A instead of compound E-2A, following the same procedure as in Step 2 of Example 2. MS(m / z): 533.2[M+H] +

[0458] Example 34: 4-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazole-4-yl)methyl]-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-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-triazole-4-yl)methyl]-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-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 overnight at room temperature. The solvent was removed by distillation under reduced pressure, and the resulting residue (49 mg) was dissolved in a small amount of DMF. In a separate container, a mixture of 2-(tert-butoxycarbonylamino)pyridine-4-carboxylic acid (39 mg), DMF (5.4 mL), DIPEA (0.2 mL), and HATU (62 mg) was mixed with the separately prepared DMF solution of the residue, and the mixture was stirred overnight at room temperature. 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 1,4-dioxane solution, 2 mL) was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (14 mg). MS (m / z): 469.2 [M + H] +

[0461] Example 35: 4-(3-{1-[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]-4-fluoro-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine hydrochloride (compound E-35) [ka]

[0462] [Step 1] Preparation of tert-butyl N-[4-(3-{1-[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]-4-fluoro-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-yl]carbamate (compound E-35A) [ka] The title compound was obtained by using compound RE-90 instead of compound RE-89, following the same procedure as in Step 1 of Example 34. 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 (4M 1,4-dioxane solution, 2 mL), and 1,4-dioxane (2 mL) was stirred overnight at room temperature. After adding 4M hydrochloric acid (3 mL) and stirring, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (64 mg). MS (m / z): 483.2 [M+H] +

[0464] Example 36: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(hydroxymethyl)pyrrolidine-1-yl]ethane-1-one (compound E-36) [ka] A mixture of compound RE-116 (20 mg), D-prolinol (8 mg), DIPEA (0.03 mL), and methanol (0.5 mL) was mixed with DMTMM (21 mg) 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-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (compound E-37) [ka]

[0466] [Step 1] Preparation of 4-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (compound E-37A) [ka] A mixture of compound RE-122 (120 mg), azidomethylcyclopropane (83 mg), DMF (2 mL), and methanol (0.2 mL) was mixed with copper(I) iodide (7 mg) and stirred overnight at 60°C under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 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), 4M hydrochloric acid (0.02 mL), and 1,4-dioxane (2 mL) was stirred at room temperature for 20 minutes. The solvent was removed by distillation under reduced pressure, and the mixture was dried to obtain 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-triazole-4-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (Compound E-38) [ka] The title compound was obtained by using 3-(azidomethyl)oxetane instead of azidomethylcyclopropane, following the same procedure as in Step 1 of Example 37. MS(m / z):463.2[M+H] +

[0469] Example 39: 4-{4-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]piperidine-1-carbonyl}pyridine-2-amine (Compound E-39) [ka] The title compound was obtained by following the method described in Step 1 of Example 37, using compound RE-115 instead of compound RE-122, and using 3-(azidomethyl)-1,1-difluorocyclobutane instead of azidomethylcyclopropane. MS(m / z): 525.3[M+H] +

[0470] Example 40: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-40) [ka] The title compound was obtained by using compound RE-4 instead of compound RE-2, following the same procedure as in Step 1 of Example 2. MS(m / z):473.2[M+H] +

[0471] Example 41: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound E-41) [ka] Compound E-40 (3.2 g) was dissolved in methanol (23 mL), and 2 M hydrochloric acid (3.6 mL) was added. The mixture was stirred at room temperature for 10 minutes. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 2-propanol. Hexane was added, and the precipitated solid was filtered off. 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 values ​​(C 23 H 23 (As F3N6O2·HCl+3H2O) Calculated values ​​(%) C: 49.07, H: 5.37, N: 14.93 Measured values ​​(%) C: 49.54, H: 5.81, N: 14.51

[0472] Example 42: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (compound E-42) [ka] The title compound was obtained using compound RE-61 instead of compound RE-4, following the same method as in Example 3. MS(m / z): 543.2[M+H] +

[0473] Example 43: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one p-toluenesulfonate (compound E-43) [ka] Compound E-42 (32 mg) was dissolved in THF (2 mL), and p-toluenesulfonic acid monohydrate (13 mg) was added. The mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (36 mg). MS (m / z): 543.2 [M + H] + [α]589 25 = +7.42° (0.001g methanol, 1mL, 100mm) Elemental analysis values ​​(C 23 H 20 (As F6N6O3·C7H8O3S+1.4H2O) Calculated values ​​(%) C: 48.70, H: 4.20, N: 11.36 Measured values ​​(%) C: 49.01, H: 4.05, N: 10.89

[0474] Example 44: 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one dip-toluenesulfonate (compound E-44) [ka]

[0475] [Step 1] Preparation of 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-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. Compound RE-87 (19 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (17 mg). [Step 2] Preparation of compound E-44 Compound E-44A (17 mg) was dissolved in ethyl acetate (2 mL), and p-toluenesulfonic acid monohydrate (13 mg) was added. The mixture was stirred at room temperature. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (19 mg). MS (m / z): 536.2 [M + H] +

[0476] Example 45: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-45) [ka] Compound RE-121 (20 mg), 2,2,2-trifluoro-N-methylethaneamine hydrochloride (13 mg), HBTU (33 mg), and DMF (0.3 mL) were mixed with DIPEA (0.05 mL) 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)azetidine-3-yl]-1H-indazole-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), and p-toluenesulfonic acid monohydrate (23 mg) was added. The mixture was stirred at room temperature for 10 minutes. The solvent was removed by distillation under reduced pressure, the residue was dissolved in methanol, and diethyl ether was added. The precipitated solid was filtered off. The mixture was dried under reduced pressure to obtain the title compound (69 mg). MS (m / z): 447.2 [M + H] + Elemental analysis values ​​(C 21 H 21 (As F3N6O2·C7H8O3S+3.5H2O) Calculated values ​​(%) C: 49.33, H: 5.32, N: 12.33 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-tetrahydropyridine-4-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added and the solvent was removed by vacuum distillation. In a separate container, a mixture of compound RE-24 (51 mg), DIPEA (0.1 mL), HOBt (35 mg), and DMF (0.5 mL) was mixed with EDCI·HCl (50 mg), stirred at room temperature for 30 minutes, and 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)piperidine-4-yl]-1H-indazole-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-tetrahydropyridine-4-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (compound E-48A) [ka] The title compound was obtained using compound RE-41 instead of compound RE-40 by a method similar to that of Example 47. 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 removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (24 mg). MS (m / z): 493.3 [M+H] +

[0482] Example 49: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (compound E-49) [ka] The title compound was obtained by using compound E-47 instead of compound E-48A, following the same procedure as in Step 2 of Example 48. MS(m / z): 519.3[M+H] +

[0483] Example 50: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 obtain the title compound (21 mg). MS (m / z): 509.1 [M+H]+

[0484] Example 51: 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one hydrochloride (compound E-51) [ka]

[0485] [Step 1] Preparation of 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-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 obtain the title compound (31 mg).

[0486] [Step 2] Manufacturing of (Compound E-51) Compound E-51A (31 mg) was dissolved in methanol (2 mL), and 1 M hydrochloric acid (0.06 mL) was added and the mixture was stirred at room temperature for 5 minutes. The solvent was removed by vacuum distillation, 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-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (compound E-52) [ka]

[0488] [Step 1] Preparation of 4-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-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 removed by distillation 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 the separately prepared residue in DMF solution was added, and the mixture was stirred overnight at room temperature. 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 1,4-dioxane solution, 0.02 mL) was stirred at room temperature. The solvent was removed by distillation under reduced pressure, and the residue was washed with a mixture of methanol and diethyl ether. The mixture was then dried to obtain the title compound (8 mg). MS (m / z): 475.1 [M + H] +

[0489] Example 53: 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added and the solvent was removed by vacuum distillation 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. The previously obtained residue (44 mg) was added, and the mixture was stirred overnight at room temperature. 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)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (compound E-54) [ka]

[0491] [Step 1] Preparation of 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 overnight at room temperature. The solvent was removed by distillation 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 the separately prepared residue in DMF solution was added, and the mixture was stirred overnight at room temperature. 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 1,4-dioxane solution, 2 mL) was stirred at room temperature for 30 minutes. The solvent was removed by distillation under reduced pressure, the residue was washed with a mixture of methanol and diethyl ether, and dried to obtain 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-oxadiazole-5-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-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 removed by distillation 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 the separately prepared residue in DMF solution was added. The mixture was stirred overnight at room temperature. 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)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one (compound E-56) TIFF2026086800000357.tif41169 A mixture of compound RE-116 (30 mg), HBTU (38 mg), and DMF (0.5 mL) was mixed with DIPEA (0.1 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-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (Compound E-57) [ka] Compound RE-55 (80 mg) was dissolved in methanol (0.7 mL), hydrogen chloride (4 M ethyl acetate solution, 0.03 mL) was added, and the mixture was stirred at room temperature for a total of 4 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in DMF (0.5 mL). In a separate container, 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 the separately prepared residue in DMF solution was added, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (48 mg). MS (m / z): 462.3 [M + H] +

[0496] Example 58: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one dip-toluenesulfonate (compound E-58) [ka] [Step 1] Preparation of 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one (compound E-58A) 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) was mixed with EDCI·HCl (12 mg) and stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (11 mg). [Step 2] Preparation of Compound E-58 Compound E-58A (11 mg) was dissolved in ethyl acetate (2 mL), and p-toluenesulfonic acid monohydrate (8 mg) was added. The mixture was stirred at room temperature. The precipitated solid was filtered 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 values ​​(C 23 H 22 F5N7O3.C 14 H 16 (As O6S2 + 3.0H2O) Calculated values ​​(%) C: 47.38, H: 4.73, N: 10.45 Measured values ​​(%) C: 47.14, H: 4.72, N: 10.36

[0497] Example 59: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-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 by vacuum distillation, and toluene was added to the resulting residue and removed by vacuum distillation. Then ethyl acetate and hexane were added and the solvent was removed by vacuum distillation. 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 obtain the title compound (18 mg). MS (m / z): 483.2 [M+H] +

[0498] Example 60: 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-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 overnight at room temperature. The reaction mixture was purified by silica gel column chromatography to obtain the title compound (20 mg). MS (m / z): 491.0 [M+H] +

[0499] The compounds in each example shown in Tables 1 to 32 below (where "XXX" in "E-XXX" indicates the example number) were prepared by condensation reactions, and, if necessary, deprotection and chlorination reactions, using a combination of the reference example compound and reaction fragment, following a procedure similar to that described in the aforementioned examples. In the table, "Reference Example" indicates that the compound was produced by the method described in the example number, or by a method similar to that method using the corresponding raw materials. 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, "data" refers to instrumental analysis data of the compound in question, 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 (where "XXX" in "E-XXX" indicates the example) were prepared by condensation reactions, and, if necessary, deprotection and chlorination reactions, using combinations of reference example compounds and reaction fragments, following procedures similar to those described in the aforementioned 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] Tables 49 to 72 below show the numbers and chemical names of the example compounds. In the tables, the chemical name refers to the name of the compound corresponding to the compound number.

[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 the test substance The test substances were prepared in dimethyl sulfoxide (DMSO, Nacalai Tesque, 13445-74) to a concentration of 10 mM. Six concentrations were selected for each compound, and each was 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% Tween20 (Tokyo Chemical Industries, T0543), selecting six concentrations for each compound to achieve concentrations of 330000, 33000, 330, 33, 3, 0.3, and 0.03 nM, and these were prepared as test substance solutions. 2. Measurement of inhibitory effect on the kinase activity of DDR1 kinase Six concentrations were selected for each compound, and the prepared test substance solutions were added at a rate of 3 μL / well to a 384-well plate (Corning, 4512) to final concentrations of 10,000, 1,000, 10, 1, 0.1, and 0.01 nM, respectively. DDR1 protein (Carnabio Sciences, 08-113) was added at a rate of 2 μL / well to 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 a rate of 5 μL / well. After incubation at room temperature for 2 hours, 10 μL / well of LANCE Detection Buffer (PerkinElmer, CR97-100) containing EDTA (DOJINDO, K001) at a final concentration of 10 mM and Europium (PerkinElmer, AD0068) at a final concentration of 1 nM was added. After incubation at room temperature for 1 hour, fluorescence intensity at 615 nm and 665 nm was measured using Envision (PerkinElmer) or SpectraMax iD5 (molecular device). The tests were performed using duplicates. 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 for each test substance. The maximum inhibition rate for each test substance was set to 100%, and the minimum inhibition rate to 0%, to calculate the inhibition rate for each test substance. IC of the test substances... 50 The values ​​(50% inhibitory concentration) were calculated using logistic regression analysis. The results for each example compound are shown in Tables 73 to 78 below.

[0576] [Table 73]

[0577] [Table 74]

[0578] [Table 75]

[0579] [Table 76]

[0580] [Table 77]

[0581] [Table 78]

[0582] <Test Example 2: Evaluation of DDR1 kinase inhibitory effect in DDR1-expressing U2OS cells> 1. Preparation of the test substance The test substances were prepared to 10 mM with DMSO, and then diluted with DMSO to final concentrations of 1000, 100, 10, 1, and 0.1 μM, respectively. Furthermore, these solutions were diluted with 10% fetal bovine serum (FBS, Gibco, 10270106) in E-MEM medium (Fujifilm Wako Pure Chemical Industries, 051-07615) to concentrations of 60000, 6000, 600, 60, 60, 6, and 0.6 nM, respectively, to prepare the test substance solutions. 2. Measurement of DDR1 kinase inhibitory effect in DDR1-expressing U2OS cells DDR1-expressing U2OS cells (DiscoverX, 93-0894C3) suspended at 2.5 × 10^5 cells / mL in 10% FBS + E-MEM medium were seeded in 20 μL portions into 384-well plates (DiscoverX, 92-0013) and cultured overnight at 37°C in 5% CO2. The following day, the prepared test substance solutions were added at a rate of 5 μL / well to achieve final concentrations of 10,000, 1,000, 100, 10, 1, and 0.1 nM, respectively. After incubation at 37°C and 5% CO2 for 1 hour, type I collagen (Nitta Gelatin, 631-00771) was added at a rate of 5 μL / well to achieve a final concentration of 50 μg / mL, and the mixture was inc...

Claims

1. Equation (I) 【Chemistry 1】 [During the ceremony, A is, 【Chemistry 2】 (In the formula, Y １ , Y ２ , Y ３ and Y ４ Each of these is independently N or C-R ５ And, Here, the above Y １ , Y ２ , Y ３ and Y ４ Among them, at most two are N, and the others are C-R ５ and R ５ C may be substituted with hydrogen, halogen, cyano, alkoxy, or optionally C １ -C ６ It is alkyl, (The dashed lines indicate connection points.) is, or 【Transformation 3】 (In the formula, R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , R ６ｅ , R ６ｆ , R ６ｇ and R ６ｈ Each of these C atoms may be independently substituted with hydrogen, halogen, cyano, or optionally. １ -C ６ It is alkyl, (The dashed lines indicate connection points.) And, B is a 3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle, which may be substituted depending on the circumstances. X is N or CR ７ And here R ７ C may be substituted with hydrogen, halogen, cyano, or optionally C １ -C ６ It is alkyl, R １ These are, independently, hydrogen, halogen, cyano, oxo, and C. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C ３ -C １０ Cycloalkyl, C ３ -C ６ Selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be substituted as needed. R ２ and R ３ Each of these C atoms may be independently substituted with hydrogen, halogen, or optionally substituted. １ -C ６ It is alkyl, R ４ These are hydrogen, halogen, cyano, and C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Selected from the group consisting of alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, monocyclic or bicyclic saturated carbocyclic, monocyclic or bicyclic unsaturated carbocyclic, monocyclic or bicyclic saturated heterocyclic, and monocyclic or bicyclic unsaturated heterocyclic, each of which may be substituted as such, or R ４ is, -CONR ８ R ９ And, Here, R ８ and R ９ Each of them independently consists of hydrogen and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ３ -C ６ Selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be substituted, R ８ and R ９ These atoms, together with the atoms to which they are bonded, may be substituted in some cases, and form a 5-10 member monocyclic or bicyclic saturated heterocycle or a 5-10 member monocyclic or bicyclic unsaturated heterocycle. m is an integer between 0 and 3. n is an integer between 0 and 3. Het is a 5- to 10-membered monocyclic or bicyclic saturated heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle. A compound thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The compound of formula (I) is, formula (II): 【Chemistry 4】 [In the formula, B, R １ , R ２ , R ３ , R ４ , Het, X, Y １ , Y ２ , Y ３ , Y ４ m and n are defined as shown in equation (I). The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The compound of formula (I) is the compound of formula (III) 【Transformation 5】 [wherein, B, R １ , R ２ , R ３ , R ４ , R ６ａ , R ６ｂ , R ６ｃ , R ６ｄ , R ６ｅ , R ６ｆ , R ６ｇ , R ６ｈ , Het, X, m and n are as defined in formula (I)] The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. R １ is, independently of each other, hydrogen, halogen, oxo, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C ３ -C １０ -cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may optionally be substituted, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, or a solvate thereof.

5. R ４ However, hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C ３ -C １０ Cycloalkyl, C ３ -C ６ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted.

6. R ４ ga-CONR ８ R ９ And, Here, R ８ and R ９ Each of them independently consists of hydrogen and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C ３ -C １０ Cycloalkyl, C ３ -C ６ Selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be substituted as needed, or R ８ and R ９ These atoms, together with the atoms to which they are bonded, form a 5-10 member monocyclic or bicyclic saturated heterocycle or a 5-10 member monocyclic or bicyclic unsaturated heterocycle, which may be substituted in some cases. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is N.

8. X is CR ７ And here R ７ However, C may be substituted with hydrogen, halogen, cyano, or optionally. １ -C ６ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is alkyl.

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]azetidine-3-yl}-5-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (2) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (3) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (4) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (5) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (6) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (7) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (8) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (9) 4-[4-(4-fluoro-1-{[5-(trifluoromethyl)pyridine-2-yl]methyl}-1H-indazole-3-yl)piperidine-1-carbonyl]pyridine-2-amine (10) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (11) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (12) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (13) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (14) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-pyrazolo[3,4-c]pyridine-3-yl]azetidine-1-carbonyl}pyridine-2-amine (15) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-methyl-1H-pyrazolo[3,4-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (16) 2-{3-[1-(6-aminopyridazine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (17) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[3,4-b]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (18) 5-Fluoro-4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (19) 4-{3-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine hydrochloride (20) 4-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,3,4-oxadiazole-2-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (21) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (22) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (23) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (24) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (25) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (26) 2-(4-chloro-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-5-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (27) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one methanesulfonate (28) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (29) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one methanesulfonate (30) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (31) 2-(3-{1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (32) 2-[4,6-difluoro-3-(1-{2-[(oxetan-3-yl)amino]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (33) 2-[4,6-difluoro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (34) 4-(3-{4-fluoro-1-[(1-phenyl-1H-1,2,3-triazole-4-yl)methyl]-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (35) 4-(3-{1-[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]-4-fluoro-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine hydrochloride (36) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(hydroxymethyl)pyrrolidine-1-yl]ethane-1-one (37) 4-[3-(1-{[1-(cyclopropylmethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (38) 4-{3-[4-fluoro-1-({1-[(oxetan-3-yl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (39) 4-{4-[1-({1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazole-4-yl}methyl)-4-fluoro-1H-indazole-3-yl]piperidine-1-carbonyl}pyridine-2-amine (40) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (41) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (42) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (43) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one p-toluenesulfonate (44) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one dip-toluenesulfonate (45) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (46) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-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-tetrahydropyridine-4-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (48) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (49) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (50) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (51) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one hydrochloride (52) 4-[3-(1-{[1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (53) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (54) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (55) 4-{3-[4-fluoro-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole-5-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (56) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one (57) 4-(3-{1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (58) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one dip-toluenesulfonate (59) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (60) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (61) 2-[4-chloro-3-(1-{1H-pyrrolo[2,3-b]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide (62) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-chloro-1H-indazole-1-yl}-N-(2,2,2-trifluoroethyl)acetamide (63) 2-(4-chloro-3-{1-[2-(methylamino)pyridine-4-carbonyl]azetidine-3-yl}-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (64) 2-(4-chloro-3-{1-[2-(ethylamino)pyridine-4-carbonyl]azetidine-3-yl}-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (65) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (66) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4,7-difluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (67) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-chloro-5-fluoro-1H-indazole-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (68) 2-(3-{1-[2-(cyclobutylamino)pyridine-4-carbonyl]azetidine-3-yl}-4-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (69) 2-(4-bromo-3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-5-fluoro-1H-indazole-1-yl)-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (70) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-bromo-5-fluoro-1H-indazole-1-yl}-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (71) 2-[4-fluoro-3-(1-{2-[(oxan-4-yl)amino]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (72) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (73) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one hydrochloride (74) 2-[4,6-difluoro-3-(1-{2-[(1-methylcyclopropyl)amino]pyridine-4-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (75) 2-[3-(1-{2-[(4,4-difluorocyclohexyl)amino]pyridine-4-carbonyl}azetidine-3-yl)-4,6-difluoro-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (76) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(pyrrolidine-1-yl)ethane-1-one (77) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (78) 2-{3-[1-(2-amino-5-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride (79) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-methylmorpholine-4-yl]ethane-1-one hydrochloride (80) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3R)-3-methylmorpholine-4-yl]ethane-1-one hydrochloride (81) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (82) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (83) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3R)-3-(propan-2-yl)morpholine-4-yl]ethane-1-one (84) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R,6S)-2,6-dimethylmorpholine-4-yl]ethane-1-one (85) 2-{3-[1-(6-aminopyridine-3-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (86) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]piperidine-4-yl}-4-fluoro-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (87) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-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}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (89) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one hydrochloride (90) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (91) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (92) 4-[3-(1-{[1-(cyclobutylmethyl)-1H-1,2,3-triazole-4-yl]methyl}-4-fluoro-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (93) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-4-methyl-1H-pyrazolo[4,3-c]pyridine-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (94) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (95) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one hydrochloride (96) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (97) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (98) 2-(3-{1-[2-(cyclopropylamino)-1,3-thiazole-5-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (99) 2-(3-{1-[2-(cyclopropylamino)-4-methyl-1,3-thiazole-5-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (100) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (101) 2-[4,6-difluoro-3-(1-{imidazo[1,2-a]pyridine-3-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (102) 2-[4,6-difluoro-3-(1-{pyrazolo[3,2-b][1,3]thiazole-7-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (103) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]propan-1-one hydrochloride (104) 4-[3-(4-fluoro-1-{[3-(4-fluorophenyl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (105) 2-{3-[1-(2-amino-1,3-oxazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (106) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (107) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-2-fluoro-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (108) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (109) 4-(3-{4-fluoro-1-[(3-methyl-1,2,4-oxadiazole-5-yl)methyl]-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (110) 2-{3-[1-(2-amino-4-methyl-1,3-oxazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (111) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidine-1-yl]ethane-1-one (112) 4-[3-(4-fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (113) 4-[3-(4-fluoro-1-{[3-(trifluoromethyl)phenyl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (114) 4-[3-(4-fluoro-1-{[2-(trifluoromethyl)phenyl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (115) 4-[3-(4-fluoro-1-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine hydrochloride (116) 4-[3-(4-fluoro-1-{[5-(4-fluorophenyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (117) 4-{3-[4-fluoro-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (118) 2-{3-[1-(2-amino-1,3-thiazole-5-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (119) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (120) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (121) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-1H-pyrazolo[4,3-b]pyridine-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (122) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (123) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3S)-3-(trifluoromethyl)morpholine-4-yl]ethane-1-one (124) 2-{3-[1-(2-aminopyridine-4-carbonyl)-1,2,3,6-tetrahydropyridine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (125) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3S)-3-(difluoromethoxy)pyrrolidine-1-yl]ethane-1-one (126) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3R)-3-(difluoromethoxy)pyrrolidine-1-yl]ethane-1-one (127) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(2,2-dimethylpyrrolidine-1-yl)ethane-1-one (128) 4-[3-(4-fluoro-1-{[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (129) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (130) 2-(3-{1-[2-(cyclopropylamino)pyridine-4-carbonyl]azetidine-3-yl}-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (131) 2-{3-[1-(6-aminopyrimidine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (132) 2-{4,6-difluoro-3-[1-(pyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (133) 2-{4,6-difluoro-3-[1-(3-methoxypyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (134) 4-[4-(4-fluoro-1-{[6-(trifluoromethyl)pyridine-3-yl]methyl}-1H-indazole-3-yl)piperidine-1-carbonyl]pyridine-2-amine (135) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (136) 2-{3-[1-(2-aminopyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indole-1-yl}-1-[(2S)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (137) 4-[3-(4-fluoro-1-{[5-(oxan-4-yl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (138) 4-[3-(4-fluoro-1-{[3-(pyridine-4-yl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (139) 2-(3-{1-[2-amino-4-(trifluoromethyl)-1,3-thiazole-5-carbonyl]azetidine-3-yl}-4,6-difluoro-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (140) 2-{4,6-difluoro-3-[1-(1H-indazole-5-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (141) 2-[4,6-difluoro-3-(1-{1H-pyrazolo[4,3-b]pyridine-5-carbonyl}azetidine-3-yl)-1H-indazole-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (142) 2-{4,6-difluoro-3-[1-(3-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (143) 2-{3-[1-(3-chloropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (144) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-chloro-5-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (145) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (146) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclobutyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine hydrochloride (147) 4-{3-[4-fluoro-1-({5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl}methyl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (148) 4-[3-(4-fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (149) 2-{3-[1-(2-amino-4-chloro-1,3-thiazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (150) 4-[3-(4-fluoro-1-{[5-(trifluoromethyl)pyridine-2-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carbonyl]pyridine-2-amine (151) 4-[3-(4-fluoro-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carbonyl]pyridine-2-amine (152) 4-{3-[4,6-difluoro-1-(3-phenylpropane-2-in-1-yl)-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (153) 4-[3-(4-fluoro-1-{[5-(5-fluoropyridine-2-yl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (154) 4-[3-(4-fluoro-1-{[5-(6-methylpyridazin-3-yl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (155) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (156) 4-{3-[1-(3-cyclopropylpropane-2-in-1-yl)-4,6-difluoro-1H-indazole-3-yl]azetidine-1-carbonyl}pyridine-2-amine (157) 4-(3-{4,6-difluoro-1-[(1-phenylazetidine-3-yl)methyl]-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (158) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(1,2,3,4-tetrahydroquinoline-1-yl)ethane-1-one (159) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(3,4-dihydro-2H-1,4-benzoxazine-4-yl)ethane-1-one (160) 4-[3-(4-fluoro-1-{[5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carbonyl]pyridine-2-amine (161) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(6-bromo-2,3-dihydro-1H-indole-1-yl)ethane-1-one (162) 2-{4,6-difluoro-3-[1-(oxan-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (163) 2-{4,6-difluoro-3-[1-(2-hydroxypyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (164) 2-{4,6-difluoro-3-[1-(1H-pyrazole-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (165) 2-{4,6-difluoro-3-[1-(5-methyl-1H-pyrazole-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (166) 2-(4,6-difluoro-3-{1-[5-(trifluoromethyl)-1H-pyrazole-4-carbonyl]azetidine-3-yl}-1H-indazole-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (167) 4-[3-(4,6-difluoro-1-{[1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (168) 4-[3-(5-methyl-1-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carbonyl]pyridine-2-amine (169) 2-{3-[1-(1H-1,2,3-benzotriazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (170) 4-[3-(4-fluoro-1-{[3-(3-fluoropyridine-4-yl)-1,2,4-oxadiazole-5-yl]methyl}-1H-pyrazolo[3,4-c]pyridine-3-yl)azetidine-1-carbonyl]pyridine-2-amine (171) 4-(3-{1-[(2,3-dihydro-1H-inden-2-yl)methyl]-4,6-difluoro-1H-indazole-3-yl}azetidine-1-carbonyl)pyridine-2-amine (172) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(6-cyclopropyl-2,3-dihydro-1H-indole-1-yl)ethane-1-one (173) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (174) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidine-4-yl]-4-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (175) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one (176) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(2,2-dimethylmorpholine-4-yl)ethane-1-one (177) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (178) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one dihydrochloride (179) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidine-1-yl]ethane-1-one (180) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (181) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethane-1-one (182) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(3S,5S)-3,5-dimethylmorpholine-4-yl]ethane-1-one (183) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-4-fluoro-1H-pyrazolo[3,4-c]pyridine-1-yl}-1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidine-1-yl]ethane-1-one p-toluenesulfonate (184) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one p-toluenesulfonate (185) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one p-toluenesulfonate (186) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one p-toluenesulfonate (187) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (188) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (189) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-N-tert-butylacetamide (190) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (191) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(3,3-dimethylmorpholine-4-yl)ethane-1-one (192) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (193) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (194) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (195) 2-{3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (196) 2-{3-[1-(2-amino-3-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (197) 2-{3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (198) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-tert-butylacetamide (199) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-tert-butylacetamide (200) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (201) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (202) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (203) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (204) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (205) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (206) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (207) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (208) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(1-methoxy-2-methylpropane-2-yl)acetamide (209) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(4-methyloxan-4-yl)acetamide (210) 2-{3-[1-(2-amino-5-chloropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (211) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2,2,2-trifluoroethyl)acetamide (212) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[(2R)-1,1,1-trifluoropropane-2-yl]acetamide (213) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[(2S)-1,1,1-trifluoropropane-2-yl]acetamide (214) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(3,3-difluorocyclobutyl)acetamide (215) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-(trifluoromethyl)morpholine-4-yl]ethane-1-one (216) 4-[3-(4-fluoro-1-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (217) 4-[3-(1-{[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (218) 4-[3-(1-{[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]methyl}-1H-indazole-3-yl)azetidine-1-carbonyl]pyridine-2-amine (219) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]ethane-1-one (220) tert-butyl 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}acetate (221) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(2,2-dimethylpyrrolidine-1-yl)ethane-1-one (222) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R)-2-ethylpyrrolidine-1-yl]ethane-1-one (223) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-{2-azabicyclo[3.1.0]hexane-2-yl}ethane-1-one (224) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(dicyclopropylmethyl)acetamide (225) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2,2-difluorocyclopentyl)acetamide (226) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(4-fluorophenyl)acetamide (227) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[2-(trifluoromethoxy)ethyl]acetamide (228) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(methoxymethyl)pyrrolidine-1-yl]ethane-1-one (229) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(cyclopropylmethyl)-N-methylacetamide (230) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(3S)-3-methoxypyrrolidine-1-yl]ethane-1-one (231) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(3R)-3-methoxypyrrolidine-1-yl]ethane-1-one (232) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-{2-oxa-6-azaspiro[3,4]octan-6-yl}ethane-1-one (233) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(oxan-4-yl)acetamide (234) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2-cyclopropylpropane-2-yl)acetamide (235) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(4,4-difluorocyclohexyl)acetamide (236) (2S)-1-(2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}acetyl)pyrrolidine-2-carbonitrile (237) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-4,4-difluoro-2-(fluoromethyl)pyrrolidine-1-yl]ethane-1-one (238) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-{bicyclo[2.2.1]heptan-2-yl}acetamide (239) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-{bicyclo[1.1.1]pentan-1-yl}acetamide (240) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (241) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (242) 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4-fluoro-1H-indazole-1-yl}-N-(2,2-difluoroethyl)acetamide (243) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[trans-2-fluorocyclopropyl]acetamide (244) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(1-cyanocyclopropyl)acetamide (245) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[(1R,2S)-2-fluorocyclopropyl]acetamide (246) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[(1S,2R)-2-fluorocyclopropyl]acetamide (247) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(1-methyl-1H-pyrazole-5-yl)acetamide (248) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2,2-difluorocyclopropyl)acetamide (249) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide (250) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(3,3-difluorocyclobutyl)-N-methylacetamide (251) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-cyclopropyl-N-(2,2,2-trifluoroethyl)acetamide (252) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-cyclopropyl-N-methylacetamide (253) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(propan-2-yl)acetamide (254) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(oxetan-3-yl)acetamide (255) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(oxan-4-yl)acetamide (256) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-[(3,3-difluorocyclobutyl)methyl]-N-methylacetamide (257) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(4,4-difluoropiperidine-1-yl)ethane-1-one (258) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}ethane-1-one (259) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[3-(trifluoromethyl)piperidine-1-yl]ethane-1-one (260) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-(4-methylpiperazine-1-yl)ethane-1-one (261) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-[(2S)-1,1,1-trifluoropropane-2-yl]acetamide (262) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-[(2R)-1,1,1-trifluoropropane-2-yl]acetamide (263) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N,N-diethylacetamide (264) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-[2-(morpholine-4-yl)ethyl]acetamide (265) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2-methoxyethyl)-N-methylacetamide (266) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2R,6S)-2,6-dimethylpiperidine-1-yl]ethane-1-one (267) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N,N-bis(propan-2-yl)acetamide (268) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-tert-butyl-N-methylacetamide (269) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-(2,2-difluoroethyl)-N-methylacetamide (270) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (271) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (272) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(difluoromethyl)pyrrolidine-1-yl]ethane-1-one (273) 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (274) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (275) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (276) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (277) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (278) 2-{3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (279) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5,6-difluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (280) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (281) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-hydroxyazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (282) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5,6-difluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (283) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (284) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (285) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-3-fluoroazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (286) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (287) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-4-chloro-5-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (288) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (289) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (290) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-chloro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (291) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5-methoxy-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (292) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-methyl-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one (293) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide (294) 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one, and (295) 2-{3-[1-(2-aminopyrimidine-4-carbonyl)azetidine-3-yl]-5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one.

10. 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

11. 2-{3-[1-(2-aminopyridine-4-carbonyl)azetidine-3-yl]-4,6-difluoro-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one hydrochloride, or its solvate.

12. 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-6-fluoro-1H-indazole-1-yl}-N-methyl-N-(2,2,2-trifluoroethyl)acetamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. 2-{3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

14. 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. 2-{3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidine-3-yl]-1H-indazole-1-yl}-1-[(2S)-2-(trifluoromethyl)pyrrolidine-1-yl]ethane-1-one methanesulfonate, or its solvate.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. A DDR1 kinase inhibitor containing the compound described in any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

18. A method for inhibiting DDR1 kinase, comprising administering a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject requiring such action.

19. A preventive or therapeutic agent for diseases involving DDR1 kinase, comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. A therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, Henoch-Schönlein 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 lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis, comprising a compound described in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.

21. A method for preventing or treating a disease involving DDR1 kinase, comprising administering a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof, to a subject in need thereof.

22. A method for preventing or treating Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, Henoch-Schönlein 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 lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis, comprising administering the compound described in any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject in need.

23. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the prevention or treatment of diseases involving DDR1 kinase.

24. A compound according to any one of claims 1 to 15, 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, Henoch-Schönlein 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 lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

25. Use of a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a preventive or therapeutic agent for a disease involving DDR1 kinase.

26. Use of a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a prophylactic or therapeutic agent for Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, Henoch-Schönlein 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 lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, glioma, non-small cell lung cancer, small cell lung cancer, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, or osteoarthritis.

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