1,4,5,6-Tetrahydropyrimidin-2-amine derivatives

Abstract

The present invention provides a compound, or a pharmaceutically-acceptable salt thereof, represented by general formula (I) or (II) below [wherein A is a C6 to C10 aryl group or heteroaryl group (at least one hydrogen atom of the aryl group or the heteroaryl group may be substituted with a substituent selected from a prescribed group), R is a hydrogen atom or C1 to C6 alkyl group, R1 is a hydrogen atom or halogen atom, and Y is a hydrogen atom, a fluorine atom, or a hydroxy group].

Description

[Technical field]

[0001] The present invention relates to 1,4,5,6-tetrahydropyrimidin-2-amine derivatives and pharmaceutical compositions containing the same, in particular to 1,4,5,6-tetrahydropyrimidin-2-amine derivatives and pharmaceutical compositions containing the same for the prevention, alleviation and / or treatment of diseases associated with integrin αv. [Background technology]

[0002] In recent years, integrins have been attracting attention for their cell adhesion and intracellular signal transduction functions in response to information from the extracellular matrix. Integrins are proteins expressed on the cell surface and are composed of a heterodimer of two subunits, an α chain and a β chain. 24 types of integrins are formed into several subfamilies by combining 18 types of α chains and 8 types of β chains. RGD integrins, one of the major subfamilies, recognize ligands that contain an RGD (arginine-glycine-aspartic acid) motif in the protein sequence. There are eight subtypes of RGD integrins: αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, αIIbβ3, α5β1, and α8β1 (Non-Patent Document 1).

[0003] Integrin αv is known to be involved in various diseases, and its inhibition is expected to be effective in treating, for example, cardiovascular diseases, diabetic diseases, neurodegenerative diseases, cancer diseases, tumor metastasis, eye diseases, autoimmune diseases, bone diseases, and various fibroses (Non-Patent Documents 2 to 6).

[0004] Transforming growth factor β (TGF-β) is known to control cell proliferation and differentiation, and is involved in diseases such as fibrosis, autoimmune diseases, and cancer, and is secreted in an inactive form in a complex with latency-associated protein (LAP) (Non-Patent Document 7). In cell studies, it has been reported that RGD integrins such as integrins αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8 activate latent TGF-β (Non-Patent Documents 8 and 9).

[0005] Fibrosis, a pathological feature of many diseases, is caused by a malfunction of the body's natural ability to repair damaged tissue. Fibrosis can result in excessive scarring that exceeds the wound healing response of vital organs, potentially causing irreparable damage and eventual organ failure (Non-Patent Document 10). In fibrosis, extracellular matrix is ​​primarily produced by activated fibroblasts (myofibroblasts), and it is known that TGF-β is involved in the activation of these fibroblasts (Non-Patent Document 11).

[0006] Integrin expression is also involved in fibrosis; for example, the expression levels of integrin β5 and β6 are significantly increased after tissue injury and play an important role in tissue fibrosis in vivo (Non-Patent Documents 12 and 13). Increased expression levels of integrin β6 are also associated with increased mortality in fibrosis patients (Non-Patent Document 14).

[0007] Inhibition of integrins is known to confer resistance to various fibrotic diseases. For example, integrin β6 knockout mice inhibit TGF-β activation and are resistant to various fibrotic diseases (Non-Patent Documents 15 and 16). It has also been reported that fibroblast-specific deletion of integrin αv similarly confer resistance to various fibrotic diseases (Non-Patent Documents 17 and 18).

[0008] For example, pirfenidone and nintedanib are used as therapeutic agents for fibrosis in idiopathic pulmonary fibrosis (IPF), but no safe and established therapeutic agent has yet been found for fibrosis in various organs. Therefore, there is a need for a therapeutic agent for fibrosis that has minimal side effects and is effective for various organs.

[0009] Research has been conducted on integrins involved in the control of various cell functions and their inhibitors (Patent Documents 1 to 8, Non-Patent Document 19). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 1997 / 008145 [Patent Document 2] International Publication No. 1999 / 044994 [Patent Document 3] International Publication No. 1999 / 052896 [Patent Document 4] International Publication No. 2000 / 051686 [Patent Document 5] International Publication No. 2004 / 060376 [Patent Document 6] International Publication No. 2014 / 015054 [Patent Document 7] US Patent Application Publication No. 2014 / 0051715 [Patent Document 8] International Publication No. 2017 / 117538 [Non-patent literature]

[0011] [Non-Patent Document 1] Cell, 2002, 110(6), 673-687. [Non-Patent Document 2] Cellular and Molecular Life Sciences, 2017, 74(12), 2263-2282. [Non-Patent Document 3] Pharmacology Research and Perspectives, 2017, 5(5), e00354. [Non-Patent Document 4] Neurobiology of Aging, 2008, 29(10), 1485-1493. [Non-Patent Document 5] Angewandte Chemie International Edition in English, 2018, 57(13), 3298-3321. [Non-Patent Document 6] Clinical & Experimental Metastasis, 2003, 20, 203-213. [Non-Patent Document 7] Cold Spring Harbor Perspectives in Biology, 2016, 8(5), a021873.

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

[0012] The present invention relates to providing novel compounds and pharmaceutical compositions containing the same that are useful for the prevention, alleviation and / or treatment of diseases associated with integrin αv. [Means for solving the problem]

[0013] As a result of extensive research into compounds having integrin αv inhibitory activity, the present inventors have found that a series of 1,4,5,6-tetrahydropyrimidin-2-amine derivatives or pharma- ceutical acceptable salts thereof having an indazole structure in the molecule have excellent integrin αv (αvβ1, αvβ6, etc.) inhibitory activity, excellent pharmacokinetic properties, or excellent safety. The 1,4,5,6-tetrahydropyrimidin-2-amine derivatives or pharma- ceutical acceptable salts thereof according to the present invention may be useful for the prevention, alleviation, and / or treatment of diseases associated with integrin αv, preferably for the prevention, alleviation, and / or treatment of fibrosis.

[0014] That is, the present invention is as follows. [1] The following general formula (I) or (II): [ka] [During the ceremony, A is C6-C 10 is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group), R is a hydrogen atom or a C1-C6 alkyl group; R 1 is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom, or a hydroxy group. or a pharma- ceutically acceptable salt thereof. [2] The following general formula (I) [ka] [During the ceremony, A is C6-C 10 is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group), R is a hydrogen atom or a C1-C6 alkyl group; R1 is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom, or a hydroxy group. or a pharma- ceutically acceptable salt thereof. [3] The following general formula (II) [ka] [During the ceremony, A is C6-C 10 is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group), R is a hydrogen atom or a C1-C6 alkyl group; R 1 is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom, or a hydroxy group. or a pharma- ceutically acceptable salt thereof. [4] A is a phenyl group; at least one hydrogen atom of the phenyl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group; The compound according to any one of the above [1] to [3] or a pharma- ceutically acceptable salt thereof. [5] A is a phenyl group; at least one hydrogen atom of the phenyl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group; The compound according to any one of the above [1] to [4] or a pharma- ceutically acceptable salt thereof. [6] A is a phenyl group; At least one hydrogen atom of the phenyl group may be substituted with a substituent selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted with a C1-C6 alkyl group; The compound according to any one of the above [1] to [5] or a pharma- ceutically acceptable salt thereof. [7] The compound or a pharma- ceutically acceptable salt thereof according to any one of the above [1] to [6], wherein Y is a fluorine atom. [8] A is represented by the following formula (i): [ka] [During the ceremony, R 2 is a hydrogen atom or a halogen atom, R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group; R 4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, R 5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group, R 6 is a hydrogen atom or a halogen atom. The compound according to any one of the above [1] to [7], wherein the compound is a group represented by the following formula: [9] R 2 is a hydrogen atom, R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group; R 4 is a hydrogen atom or a halogen atom, R 5is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group; R 6 is a hydrogen atom or a halogen atom; The compound according to the above [8] or a pharma- ceutically acceptable salt thereof.

[10] (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methyl-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methoxy-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-morpholinophenyl)propanoic acid, (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, and (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid The compound according to the above-mentioned [1], or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0015] In another embodiment, the present invention relates to a pharmaceutical composition comprising the compound according to any one of the above [1] to

[10] or a pharma- ceutical acceptable salt thereof, As an embodiment of the pharmaceutical composition, A pharmaceutical composition for preventing, alleviating and / or treating a disease associated with integrin αv or a disease ameliorated by inhibiting integrin αv, or A pharmaceutical composition for the treatment of fibrosis.

[0016] In another embodiment, the present invention relates to a pharmaceutical composition comprising the compound according to any one of the above [1] to

[10] or a pharma- ceutical salt thereof, more preferably a pharmaceutical composition for the treatment of fibrosis, i.e., the prevention, alleviation and / or cure of fibrosis.

[0017] In another embodiment, the present invention relates to a method for treating a disease associated with integrin αv or a disease that is ameliorated by inhibiting integrin αv, such as fibrosis, comprising administering to a subject a compound according to any one of the above [1] to

[10] or a pharma- ceutical acceptable salt thereof.

[0018] In another embodiment, the present invention relates to the use of a compound according to any one of the above [1] to

[10] or a pharma- ceutical acceptable salt thereof in the treatment of a disease associated with integrin αv or a disease ameliorated by inhibiting integrin αv, such as fibrosis.

[0019] In another embodiment, the present invention relates to a compound or a pharma- ceutical ly acceptable salt thereof according to any one of the above [1] to

[10] for use in the treatment of a disease associated with integrin αv or a disease ameliorated by inhibiting integrin αv, such as fibrosis.

[0020] In another embodiment, the present invention relates to the use of a compound described in any one of the above [1] to

[10] or a pharma- ceutical ly acceptable salt thereof in the manufacture of a medicament for treating a disease associated with integrin αv or a disease ameliorated by inhibiting integrin αv, such as fibrosis.

[0021] In another embodiment, the present invention relates to an intermediate of the compound according to any one of the above [1] to

[10] or a pharma- ceutically acceptable salt thereof.

[0022] In another embodiment, the present invention relates to a method for producing the compound or a pharma- ceutically acceptable salt thereof according to any one of the above [1] to

[10] . Effect of the Invention

[0023] The present invention provides a novel compound and a method for synthesizing the compound. In another aspect of the present invention, a pharmaceutical composition for preventing, alleviating and / or treating a disease (e.g., fibrosis) associated with at least one integrin αv, comprising the compound, the compound for preventing, alleviating and / or treating the disease, or a method for preventing, alleviating and / or treating the disease by the compound, is provided. In another aspect of the present invention, a novel intermediate for synthesizing the compound is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] <Definition> In this specification, various substituents are as follows: "C6-C 10 The term "aryl group" refers to a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 ring carbon atoms. Examples of the aryl group include phenyl and naphthyl.

[0025] The term "heteroaryl group" refers to a monovalent aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is preferably a monovalent aromatic heterocyclic group having 5 to 10 ring atoms. Examples of the heteroaryl group include monocyclic heteroaryl groups such as pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl; and bicyclic heteroaryl groups such as indolyl, indazolyl, benzotriazolyl, benzofuranyl, benzimidazolyl, benzothiophenyl, benzoisoxazolyl, benzopyranyl, benzothienyl, quinolyl, and isoquinolyl.

[0026] "Halogen" or "halo" refers to halogen atoms, including, for example, fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0027] "C1-C6 alkyl group" means an alkyl group having 1 to 6 carbon atoms, and the alkyl group may be a straight chain alkyl group or a branched chain alkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, neohexyl, and tert-hexyl. The alkyl group may be a C1-C4 alkyl group.

[0028] The term "C1-C6 haloalkyl group" refers to a group in which at least one hydrogen of the "C1-C6 alkyl group" is replaced with a halogen atom. The haloalkyl group may be a straight-chain haloalkyl group or a branched-chain haloalkyl group. Examples of the haloalkyl group include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2-diiodoethyl, 2,2,2-trifluoro ... Examples of the haloalkyl group include ethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-triiodoethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 3-iodopropyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-iodobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, and 6-iodohexyl. The haloalkyl group may be a C1-C4 haloalkyl group.

[0029] The term "C2-C6 alkenyl group" refers to an alkenyl group having 2 to 6 carbon atoms, and the alkenyl group may be a straight-chain alkenyl group or a branched-chain alkenyl group. Examples of the alkenyl group include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 3-methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, and 3-methyl-1-pentenyl. The alkenyl group may be a C2-C4 alkenyl group.

[0030] "C2-C6 alkynyl group" means an alkynyl group having 2 to 6 carbon atoms, and the alkynyl group may be a straight-chain alkynyl group or a branched-chain alkynyl group. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1,1-dimethyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, and 3-methyl-1-pentynyl. The alkynyl group may be a C2-C4 alkynyl group.

[0031] The term "C1-C6 alkoxy group" refers to a group to which the "C1-C6 alkyl group" is bonded via an oxygen atom. The alkoxy group may be a straight-chain alkoxy group or a branched-chain alkoxy group. Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy, neohexoxy, and tert-hexoxy. The alkoxy group may be a C1-C4 alkoxy group.

[0032] The term "C1-C6 haloalkoxy group" refers to a group in which at least one hydrogen of the "C1-C6 alkoxy group" is replaced by a halogen atom. The haloalkoxy group may be a straight-chain haloalkoxy group or a branched-chain haloalkoxy group. Examples of the haloalkoxy group include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, diiodomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2-dibromoethoxy, 2,2-diiodoethoxy, 2,2,2-trifluoro ... Examples of the haloalkoxy group include ethoxy, 2,2,2-trichloroethoxy, 2,2,2-tribromoethoxy, 2,2,2-triiodoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 3-bromopropoxy, 3-iodopropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 4-iodobutoxy, 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy, etc. The haloalkoxy group may be a C1-C4 haloalkoxy group.

[0033] The term "C3-C6 cycloalkyl group" refers to an alicyclic saturated hydrocarbon group having 3 to 6 ring carbon atoms. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] The term "C3-C6 cycloalkenyl group" refers to an alicyclic unsaturated hydrocarbon group having 3 to 6 ring carbon atoms and at least one carbon-carbon double bond in the ring. Examples of the cycloalkenyl group include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl (2-cyclohexenyl, 3-cyclohexenyl), etc.

[0035] The term "C3-C6 cycloalkoxy group" refers to a group in which the "C3-C6 cycloalkyl group" is bonded via an oxygen atom. Examples of the cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0036] The term "heterocyclyl group" refers to a saturated monovalent heterocyclic group or a non-aromatic unsaturated monovalent heterocyclic group containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is preferably a saturated monovalent heterocyclic group having 5 to 10 ring atoms. Examples of the heterocyclyl group include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl (i.e., thiolanyl), piperazinyl, and morpholinyl.

[0037] The term "C1-C6 alkoxycarbonyl group" refers to a group to which the "C1-C6 alkoxy group" is bonded via a carbonyl group. The alkoxycarbonyl group may be a straight-chain alkoxycarbonyl group or a branched-chain alkoxycarbonyl group. Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, tert-pentoxycarbonyl, n-hexoxycarbonyl, isohexoxycarbonyl, neohexoxycarbonyl, and tert-hexoxycarbonyl. The alkoxycarbonyl group may be a C1-C4 alkoxycarbonyl group.

[0038] The term "C1-C6 alkylsulfanyl group" refers to a group to which the "C1-C6 alkyl group" is bonded via a sulfur atom. The alkylsulfanyl group may be a straight-chain alkylsulfanyl group or a branched-chain alkylsulfanyl group. Examples of the alkylsulfanyl group include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, tert-pentylsulfanyl, n-hexylsulfanyl, isohexylsulfanyl, neohexylsulfanyl, and tert-hexylsulfanyl. The alkylsulfanyl group may be a C1-C4 alkylsulfanyl group.

[0039] The term "C1-C6 alkylsulfonyl group" refers to a group to which the "C1-C6 alkyl group" is bonded via a sulfonyl group. The alkylsulfonyl group may be a straight-chain alkylsulfonyl group or a branched-chain alkylsulfonyl group. Examples of the alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, neohexylsulfonyl, and tert-hexylsulfonyl. The alkylsulfonyl group may be a C1-C4 alkylsulfonyl group.

[0040] In this specification, "pharmaceutical acceptable salts" includes pharmaceutical acceptable acid addition salts and salts with pharmaceutical acceptable acids (hereinafter, these are also collectively referred to as "acid addition salts, etc."), as well as pharmaceutical acceptable base addition salts and salts with pharmaceutical acceptable bases (hereinafter, these are also collectively referred to as "base addition salts, etc.").

[0041] In this specification, examples of "acid addition salts" or "salts with acids" (acid addition salts, etc.) include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, acetates, oxalates, malonates, fumarates, maleates, phthalates, trifluoroacetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, 2,4-dimethylbenzenesulfonates, 2,4,6-trimethylbenzenesulfonates, 4-ethylbenzenesulfonates, and naphthalenesulfonates.

[0042] In the present specification, the term "base addition salt" or "salt with a base" (base addition salt, etc.) includes, for example, metal salts, inorganic amine salts, organic amine salts, or amino acid salts. Metal salts can be, for example, alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; iron salts; zinc salts; copper salts; nickel salts; or cobalt salts. Inorganic amine salts can be, for example, ammonium salts. Organic amine salts can be, for example, morpholine salts, glucosamine salts, ethylenediamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, diethanolamine salts, piperazine salts, or tetramethylammonium salts. Amino acid salts can be, for example, glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts.

[0043] In the present specification, the term "diseases associated with integrin αv" refers to diseases involving integrin αv, and is not particularly limited as long as the symptoms can be alleviated, improved, suppressed, or prevented by inhibiting integrin αv. Integrins are heterodimers composed of an α chain and a β chain. Integrin αv is a type of α chain, and integrins containing integrin αv include integrins αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8. "Diseases associated with integrin αv" may include diseases associated with integrin αvβ1, αvβ3, αvβ5, αvβ6, or αvβ8, in the sense that they include integrin αv. In addition, "diseases associated with integrin αv" include, for example, "diseases associated with integrin αvβ1" or "diseases associated with integrin αvβ6". Examples of diseases associated with integrin αv include inflammatory diseases, fibrosis, cancer, neurodegenerative diseases, eye diseases, osteoporosis, osteogenesis imperfecta, etc. Inhibiting integrin αv includes a decrease in the level of a signal mediated by integrin αv compared to a control, or a decrease in the binding ability of integrin αv to a ligand compared to a control.

[0044] As used herein, the term "inflammatory disease" refers to a disease, disorder, or condition associated with inflammation, including, but not limited to, arthritis, rheumatoid arthritis, Crohn's disease, irritable bowel disease, inflammatory bowel disease (IBD), systemic lupus erythematosus, periodontal disease, psoriasis, acute hepatitis, chronic hepatitis, Alport syndrome, diabetes-induced inflammation, articular arterial inflammation, large cell arterial inflammation, Kawasaki disease, Takayasu's arteritis, Churg-Strauss syndrome, and Henoch-Schonlein purpura.

[0045] As used herein, "fibrosis" includes, but is not limited to, fibrosis in the lung, liver, kidney, heart, blood vessel, skin, pancreas, bone marrow, and other organs or tissues. In the present invention, fibrosis is preferably pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, vascular fibrosis, skin fibrosis, pancreatic fibrosis, bone marrow fibrosis, and skeletal muscle fibrosis. More preferably, fibrosis is pulmonary fibrosis, liver fibrosis, renal fibrosis, or cardiac fibrosis. Pulmonary fibrosis also includes idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP), acute interstitial pneumonia (AIP), interstitial lung disease, peribronchiolar fibrosis, small airway disease (e.g., bronchiolitis obliterans), emphysema, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), post-infectious pulmonary fibrosis, drug-induced pulmonary fibrosis, airway fibrosis, diffuse alveolar damage, collagen vascular disease-associated pulmonary fibrosis, silicosis, radiation-induced fibrosis, bleomycin-induced fibrosis, influenza-induced fibrosis, asbestos-related pulmonary fibrosis, desquamative interstitial fibrosis, and chronic hypersensitivity pneumonitis. Liver fibrosis also includes primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), infectious liver fibrosis (due to HCV, HCV or parasites such as schistosomiasis), alcoholic liver disease (ASH), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis of all etiologies, congenital hepatic fibrosis, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and α1-antitrypsin deficiency. Renal fibrosis also includes chronic kidney disease (CKD), glomerulonephritis (GN) of all etiologies, mesangial proliferative GN, immune-mediated GN, crescentic GN, tubulointerstitial injury, renal interstitial fibrosis, renal fibrosis resulting from complications of drug exposure (including cyclosporine treatment of transplant recipients), nephrogenic systemic fibrosis, HIV-associated nephropathy, transplant nephropathy, diabetic kidney disease (diabetic nephropathy), focal segmental glomerulosclerosis (FSGS), idiopathic retroperitoneal fibrosis, hypertensive nephrosclerosis and IgA nephropathy. In addition, cardiac fibrosis and vascular fibrosis include cardiac fibrosis associated with myocardial infarction, vascular injury-induced fibrosis, cardiac stenosis, aortic stenosis, atherosclerosis, thrombosis, arteriosclerosis, myocardial infarction, angina pectoris, valvular heart disease, renal arteriosclerosis, congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, myocarditis, vascular stenosis cardiac fibrosis, post-infarction cardiac fibrosis, left ventricular hypertrophy, venous occlusion disease, restenosis, restenosis after angioplasty, arteriovenous graft failure, atherosclerosis, hypertension, hypertensive heart disease, cardiac hypertrophy, heart failure, aortic disease, hereditary hemorrhagic telangiectasia (HHT), arterial tortuosity syndrome, Raynaud's syndrome and hypertriglyceridemia. Dermatofibrosis also includes systemic sclerosis, polymyositis, systemic lupus erythematosus, dermatomyositis, Dupuytren's contracture, post-operative adhesions, fibrosis resulting from surgical incision or mechanical trauma, excessive or hypertrophic scar or keloid formation in the dermis that occurs during wound healing resulting from trauma or surgical wounds. Pancreatic fibrosis also includes cystic fibrosis (CF), chronic pancreatitis, and autoimmune pancreatitis. In addition, myelofibrosis includes primary myelofibrosis, idiopathic myelofibrosis, secondary myelofibrosis, and myeloproliferative neoplasms. Fibrosis in other organs or tissues includes skeletal muscle fibrosis, intestinal fibrosis, fibrosis occurring after organ transplantation, penile sclerosis (Peyronie's disease), bladder fibrosis, Kamuracchi-Engelmann disease, Loeys-Dietz syndrome, Marfan syndrome, premature menopause, preeclampsia, mediastinal fibrosis, and intestinal stenosis.

[0046] As used herein, "cancer" includes tumor angiogenesis, carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, seminoma, or tumor metastasis. Exemplary tumor sites that may be treated according to the present invention include the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gallbladder, reproductive organs, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.

[0047] As used herein, "neurodegenerative disease" includes peripheral neuropathy, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and the like.

[0048] As used herein, "ocular disease" refers to age-related macular degeneration (AMD), glaucoma, ocular fibrosis, scarring of the retina or cornea, diabetic retinopathy, proliferative vitreoretinopathy (PVR), vitreous retinopathy of any etiology, fibrosis associated with ophthalmic surgery, retinal reattachment surgery, lens extraction, or any type of drainage procedure, etc., scarring in the cornea and conjunctiva, fibrosis in the corneal endothelium, alkali burns (e.g., alkali burns to the cornea), fibrosis of the lens capsule after cataract surgery, excessive scarring of the tissues around the extraocular muscles in strabismus surgery, anterior subcapsular cataract and posterior capsular congestion. These include: opacities, anterior segment fibrosis, fibrosis of the corneal stroma, fibrosis associated with corneal opacities, fibrosis of the trabecular meshwork, fibrosis associated with glaucoma, posterior segment fibrosis, fibrovascular scarring, fibrosis in the retinal or choroidal vessels of the eye, retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis, age-related macular degeneration, fibrosis associated with retinal surgery and post-glaucoma surgery, tractional retinal detachment associated with tissue contraction in diabetic retinopathy, cicatricial pemphigoid glaucoma filtration surgery scarring, retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR).

[0049] As used herein, a "subject" is a human, monkey, cow, horse, sheep, goat, rabbit, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. As used herein, a subject is an individual in need of treatment for the above-mentioned disease.

[0050] As used herein, "treatment" includes at least one of prevention, alleviation, and cure, and also includes alleviating disease symptoms, inhibiting the progression of disease symptoms, removing disease symptoms, improving disease prognosis, preventing disease recurrence, and preventing disease. In one embodiment of the present invention, the treatment is a therapy.

[0051] <Compound of the Present Invention> In one embodiment, the present invention relates to a compound represented by the following general formula (I) or (II): [ka] [During the ceremony, A is C6-C 10 is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group), R is a hydrogen atom or a C1-C6 alkyl group; R 1 is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom, or a hydroxy group. or a pharma- ceutically acceptable salt thereof. In this specification, the compound represented by general formula (I) may be simply referred to as "compound (I)", and the compound represented by general formula (II) may be simply referred to as "compound (II)".

[0052] In one embodiment of the present invention, A in compound (I) or (II) is preferably a phenyl group. At least one hydrogen atom of the phenyl group which may be selected as A may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group.

[0053] At least one hydrogen atom of the phenyl group that can be selected as A may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group.

[0054] In another embodiment of the present invention, at least one hydrogen atom of the phenyl group that may be selected as A may be substituted with a substituent selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0055] Furthermore, in another embodiment of the present invention, A in compound (I) or (II) may be a group represented by the following formula (i): [ka]

[0056] In the above formula (i), R 2 is a hydrogen atom or a halogen atom. In another embodiment, R 2 is a hydrogen atom, a fluorine atom or a chlorine atom. In another embodiment, R 2 is a hydrogen atom.

[0057] R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group. In another embodiment, R 3 is a hydrogen atom, a halogen atom, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C4 alkyl group. In another embodiment, R 3 is a hydrogen atom, a halogen atom, a C1-C4 haloalkyl group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group. In another embodiment, R 3 is a hydrogen atom, a halogen atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclopropoxy group, a morpholyl group, or a pyrazolyl group. In another embodiment, R 3is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group. In another embodiment, R 3 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C4 alkyl group. In another embodiment, R 3 represents a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, or a pyrazolyl group optionally substituted with a methyl group. In another embodiment, R 3 is a halogen atom, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, or a pyrazolyl group.

[0058] R 4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group. In another embodiment, R 4 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group. In another embodiment, R 4 is a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, or a difluoromethoxy group. In another embodiment, R 4 is a hydrogen atom or a halogen atom. In another embodiment, R 4 is a hydrogen atom or a fluorine atom.

[0059] R 5is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group. In another embodiment, R 5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or a pyrazolyl group. In another embodiment, R 5 is a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a pyrazolyl group. In another embodiment, R 5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group. In another embodiment, R 5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group. In another embodiment, R 5 is a hydrogen atom, a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group. In another embodiment, R 5 is a halogen atom, a methyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group.

[0060] R 6 is a hydrogen atom or a halogen atom. In another embodiment, R 6 is a hydrogen atom, a fluorine atom or a chlorine atom. In another embodiment, R 6 is a hydrogen atom or a fluorine atom.

[0061] For example, in another embodiment, in formula (i), R 2is a hydrogen atom, R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group, R 4 is a hydrogen atom or a halogen atom, R 5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, R 6 is a hydrogen atom or a halogen atom, It is also possible to use the following.

[0062] In another embodiment, in the formula (i), R 2 is a hydrogen atom, R 3 is a hydrogen atom, a halogen atom, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C4 alkyl group; R 4 is a hydrogen atom or a halogen atom, R 5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, R 6 is a hydrogen atom or a halogen atom, It is also possible to use the following.

[0063] In another embodiment of the present invention, A in compound (I) or (II) may be a group represented by any one of the following formulas (i)-a to (i)-g. [ka] [In the above formula, * indicates a bond position, Ra1 ~R a13 are each independently a substituent selected from the group consisting of a halogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group.

[0064] In the above embodiment, R a1 ~R a13 may each independently be a substituent selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0065] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-a, R a1 and R a2 one of the groups is a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group; The other may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0066] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-a, R a1 and Ra2 one of the groups is a halogen atom, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group, The other may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0067] Furthermore, in another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-a, R a1 and R a2 one of the groups is a halogen atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group, The other may be a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclopropoxy group, a morpholyl group, or a pyrazolyl group.

[0068] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-b, R a3 is a halogen atom, R a4 may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0069] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-b, R a3 is a halogen atom, R a4may be a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group.

[0070] Furthermore, in another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-b, R a3 is a halogen atom, R a4 However, it may also be a C1-C6 haloalkyl group.

[0071] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by formula (i)-c above, R a5 is a halogen atom, R a6 may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0072] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-c, R a5 is a halogen atom, R a6 may be a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group.

[0073] Furthermore, in another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-c, R a5 is a halogen atom, R a6 may be a halogen atom, a trifluoromethyl group, or a trifluoromethoxy group.

[0074] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-d, R a7 and R a8 one of the groups is a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group; The other may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0075] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-d, R a7 and R a8 one of the groups is a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group; The other may be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group.

[0076] Furthermore, in another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-d, R a7 and R a8 one of the groups is a halogen atom, a trifluoromethyl group, or a trifluoromethoxy group, The other may be a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0077] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-e, R a9 , R a10 and R a11At least one of is a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group; The remainder may each independently be a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group.

[0078] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-e, R a9 , R a10 and R a11 may each independently be a halogen atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy group.

[0079] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-f, R a12 may be a heteroaryl group optionally substituted with a halogen atom, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a C1-C6 alkyl group.

[0080] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-f, R a12 may be a pyrazolyl group optionally substituted with a halogen atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclopropoxy group, a morpholinyl group, or a methyl group.

[0081] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-g, R a13may be a heteroaryl group optionally substituted with a halogen atom, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a C1-C6 alkyl group.

[0082] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-f, R a13 may be a pyrazolyl group optionally substituted with a halogen atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, a cyclopropyl group, a cyclopropoxy group, a morpholinyl group, or a methyl group.

[0083] In another embodiment of the present invention, when A of compound (I) or (II) is a group represented by the above formula (i)-f, R a13 may be a C1-C6 haloalkyl group or a C1-C6 haloalkoxy group. Also, R a13 may be a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group.

[0084] In one embodiment, R of compound (I) or (II) is a hydrogen atom or a C1-C6 alkyl group. In another embodiment, R of compound (I) or (II) is a hydrogen atom or a C1-C4 alkyl group. In another embodiment, R of compound (I) or (II) is a hydrogen atom or a methyl group. In another embodiment, R of compound (I) or (II) is a hydrogen atom.

[0085] In one embodiment, R of compound (I) or (II) 1 is a hydrogen atom or a halogen atom. In another embodiment, R of compound (I) or (II) 1is a hydrogen atom, a fluorine atom or a chlorine atom. In another embodiment, R of compound (I) or (II) 1 is a hydrogen atom.

[0086] In one embodiment, Y in compound (I) or (II) is a hydrogen atom, a fluorine atom or a hydroxy group. In another embodiment, Y in compound (I) or (II) is a fluorine atom.

[0087] In another embodiment, the present invention provides a compound selected from the group consisting of: (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methyl-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methoxy-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-morpholinophenyl)propanoic acid, (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid.

[0088] Furthermore, the compound represented by general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof can form a hydrate or solvate, each of which or a mixture thereof is included in the present invention.

[0089] When the compound of the present invention represented by general formula (I) or (II) or a pharma- ceutically acceptable salt thereof has one or more asymmetric centers, carbon-carbon double bonds, axial asymmetry, etc., optical isomers (including enantiomers and diastereomers), geometric isomers, tautomers, and rotational isomers may exist, and these isomers and mixtures thereof are described by a single formula such as formula (I) or (II). The present invention includes each of these isomers and mixtures thereof in any ratio (including racemates).

[0090] In certain embodiments, compound (I) of the present invention has both of the following absolute configurations: [ka]

[0091] In certain embodiments, compound (I) of the present invention has the following absolute configuration: [ka]

[0092] In certain embodiments, compound (I) of the present invention has the following absolute configuration: [ka]

[0093] Similarly, in certain embodiments, compound (II) of the present invention has both of the following absolute configurations: [ka]

[0094] In certain embodiments, compound (II) of the present invention has the following absolute configuration: [ka]

[0095] In certain embodiments, compound (II) of the present invention has the following absolute configuration: [ka]

[0096] Racemates can be resolved into their optical antipodes by known methods, for example by separation of their diastereoisomeric salts with optically active acids and liberation of optically active amine compounds by treatment with bases. Another method for resolving racemates into their optical antipodes is based on chromatography on optically active matrices. Compounds of the present invention can also be resolved by the formation of diastereoisomeric derivatives. Additional methods for resolving optical isomers known to those skilled in the art can be used, such as J. Jaques, A. Collet and S. Wilen et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

[0097] The compounds of the present invention represented by general formula (I) or (II) can form acid addition salts, etc., and these acid addition salts, etc. are included in the pharma- ceutical acceptable salts of the present invention. The compounds represented by the general formula (I) or (II) of the present invention can form acid addition salts with acids in any ratio, and each of them (e.g., monohydrochloride, dihydrochloride, etc.) or a mixture thereof is included in the present invention. In addition, for example, when R in the general formula (I) or (II) is a hydrogen atom, the compounds can form base addition salts, etc., and these base addition salts, etc. are also included in the pharma- ceutically acceptable salts of the present invention.

[0098] When the compound represented by the general formula (I) or (II) of the present invention has a group capable of forming an ester group, such as a hydroxy group or a carboxy group, it can be converted into a pharma- ceutical acceptable ester, and such a pharma-ceutical acceptable ester is included in the present invention. The pharma-ceutical acceptable ester of the compound represented by the general formula (I) or (II) can be a prodrug of the compound represented by the general formula (I) or (II), and when administered to the living body of a subject, it can be decomposed in a metabolic process (e.g., hydrolysis) to generate the compound represented by the general formula (I) or (II).

[0099] The compound represented by the general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof can form an isotopic compound in which one or more atoms constituting the compound are replaced with an isotope atom at a non-natural ratio. The isotope atom can be radioactive or non-radioactive, and for example, deuterium ( 2 H;D), tritium ( 3 H;T), carbon-14( 14 C), iodine-125( 125 I) and the like. Radioactive or non-radioactive isotope compounds can be used as medicines for treating or preventing diseases, research reagents (e.g., assay reagents), diagnostic agents (e.g., imaging diagnostic agents), and the like. The present invention encompasses radioactive or non-radioactive isotope compounds.

[0100] The compounds of the present invention represented by the general formula (I) or (II) or pharma- ceutical acceptable salts thereof can inhibit the binding of integrin αv to its ligand. In another embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharma- ceutical acceptable salt thereof can inhibit the activation of TGF-β. TGF-β is involved in cell differentiation, survival, proliferation, etc., and plays an important role in development, immunity, wound healing, etc., and is therefore deeply involved in diseases such as inflammation, fibrosis, and cancer. Three types of isoforms of TGF-β are known in mammals, and TGF-β1 is known as a master regulator of tissue repair, inflammation, and fibrosis (Seminars in Cell and Developmental Biology, 2020,101,123-139.). TGF-β is secreted as an inactive (latent) form and is activated in various ways to exhibit physiological activity. It is known that RGD integrins including αvβ1 and αvβ6 play an important role in the activation of TGF-β1, and for example, αvβ1 integrin inhibitors (Non-Patent Document 8: Science Translational Medicine, 2015,7(288),288ra79.) and αvβ6 integrin inhibitors (Cancer Research,2008,68(2),561-570.) inhibit the activation of TGF-β1. Therefore, the compound represented by the general formula (I) or (II) of the present invention or a pharmacologic acceptable salt thereof may be useful for the prevention, alleviation and / or treatment of diseases such as inflammatory diseases, fibrosis, cancer, neurodegenerative diseases, eye diseases, osteoporosis and osteogenesis imperfecta. In another embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharma- ceutical acceptable salt thereof can induce dedifferentiation of activated human hepatic stellate cells. Stellate cells and fibroblasts are differentiated into activated stellate cells and myofibroblasts expressing α-smooth muscle actin (α-SMA, ACTA2) by TGF-β1 and the like, and enhance collagen production and the like. For example, it has been reported that in stellate cells in which integrin αv is knocked out, TGF-β1 is not activated, so that the expression of α-SMA is suppressed, and further the production of collagen and the like is also suppressed (Non-Patent Document 16: Nature Medicine, 2013, 19(12), 1617-1624.). Such enhanced collagen production is seen in diseases such as inflammation, fibrosis, and cancer. Therefore, the compound represented by general formula (I) or (II) of the present invention or a pharma- ceutical acceptable salt thereof may be useful for the prevention, alleviation and / or treatment of diseases such as inflammatory diseases, fibrosis, cancer, neurodegenerative diseases, eye diseases, osteoporosis and osteogenesis imperfecta. In another embodiment, the compound represented by general formula (I) or (II) of the present invention or its pharmacologic acceptable salt can suppress the increase in hydroxyproline (HYP), which is an index of fibrosis, in nonalcoholic steatohepatitis (NASH) model animals.Therefore, the compound represented by general formula (I) or (II) of the present invention or its pharmacologic acceptable salt can be useful for the prevention, alleviation and / or treatment of nonalcoholic steatohepatitis (NASH). In another embodiment, the compound represented by general formula (I) or (II) of the present invention or a pharmacokinetically acceptable salt thereof has excellent pharmacokinetic properties.For example, the compound represented by general formula (I) or (II) of the present invention or a pharmacokinetically acceptable salt thereof can show excellent transcellular permeability in a membrane permeability test using Caco2 cells.It is said that the transcellular permeability in a membrane permeability test using Caco2 cells correlates with the absorption rate in the intestinal tract. Furthermore, in another embodiment, the compound represented by general formula (I) or (II) of the present invention or a pharma- ceutical acceptable salt thereof has excellent safety. For example, it is shown that the compound represented by general formula (I) or (II) of the present invention or a pharma-ceutical acceptable salt thereof does not generate or is difficult to generate reactive metabolites by metabolism in liver microsomes.

[0101] <Pharmaceutical composition of the present invention> In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound represented by general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof.

[0102] In one embodiment, the pharmaceutical compositions of the present invention can be used for the treatment of diseases associated with integrin αv.

[0103] In one embodiment, the present invention relates to the use of a compound represented by general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof in diseases associated with integrin αv.

[0104] In one embodiment, the present invention relates to a compound represented by general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease associated with integrin αv.

[0105] In one embodiment, the present invention relates to the use of a compound represented by general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with integrin αv.

[0106] In one embodiment, the present invention relates to a method for treating a disease associated with integrin αv, comprising administering to a subject a prophylactically, alleviatively and / or therapeutically effective amount of a compound represented by general formula (I) or (II) of the present invention or a pharma- ceutical acceptable salt thereof.

[0107] In one embodiment, the present invention relates to a disease associated with integrin αv, and examples thereof include inflammatory diseases, fibrosis, cancer, neurodegenerative diseases, eye diseases, osteoporosis, and osteogenesis imperfecta. In another embodiment, the disease associated with integrin αv is fibrosis.

[0108] In one embodiment, the fibrosis can be selected from fibrosis in the lung, liver, kidney, heart, blood vessels, skin, pancreas, bone marrow, and other organs or tissues. In another embodiment, the fibrosis may be selected from pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, vascular fibrosis, skin fibrosis, pancreatic fibrosis, bone marrow fibrosis and musculoskeletal fibrosis. In another embodiment, the fibrosis can be selected from pulmonary fibrosis, hepatic fibrosis, renal fibrosis or cardiac fibrosis.

[0109] In one embodiment, the disease associated with integrin αv is idiopathic pulmonary fibrosis (IPF). In another embodiment, the disease associated with integrin αv is non-alcoholic fatty liver disease (NAFLD). In another embodiment, the disease associated with integrin αv is non-alcoholic steatohepatitis (NASH). In another embodiment, the disease associated with integrin αv is primary biliary cholangitis (PBC). In another embodiment, the disease associated with integrin αv is primary sclerosing cholangitis (PSC). In another embodiment, the disease associated with integrin α v is alcoholic liver disease. In another embodiment, the disease associated with integrin αv is chronic kidney disease (CKD). In another embodiment, the disease associated with integrin αv is diabetic kidney disease (diabetic nephropathy). In another embodiment, the disease associated with integrin α v is cardiac fibrosis associated with myocardial infarction.

[0110] The subject to which the compound represented by the general formula (I) or (II) of the present invention or its pharma- ceutically acceptable salt, or the pharmaceutical composition of the present invention is administered is a mammal. Mammals include, for example, humans, monkeys, cows, horses, sheep, goats, rabbits, dogs, cats, mice, rats, guinea pigs, or transgenic species thereof. The compound represented by the general formula (I) or (II) of the present invention or its pharma- ceutical acceptable salt, or the pharmaceutical composition of the present invention is preferably administered to humans.

[0111] The dosage of the compound represented by the general formula (I) or (II) of the present invention or a pharma- ceutically acceptable salt thereof, i.e., an effective amount for prevention, alleviation and / or treatment, may vary depending on the frequency and method of administration, the species of the animal to be treated, sex, age, body weight and general condition, the degree of disease, etc., but can be appropriately set by a person skilled in the art. In the case of oral administration to an adult (60 kg), the daily dosage of the compound of the present invention is appropriately 0.01 to 3000 mg, preferably 0.1 to 600 mg, etc., which can be administered once to several times a day, for example, 1, 2, 3 or 4 times in divided doses. In the case of parenteral administration to an adult, the dosage of the compound of the present invention is appropriately 0.001 to 1000 mg, preferably 0.01 to 300 mg, etc., which can be administered once to several times a day, for example, 1, 2, 3 or 4 times in divided doses. In the case of parenteral administration, for example, a concentration of 0.00001% (w / v) to 10% (w / v), preferably 0.001% (w / v) to 5% (w / v) can be used.

[0112] For parenteral routes, such as intravenous, intrathecal, intramuscular and the like administration, dosages are typically lower than those used for oral administration.

[0113] The compound of the present invention represented by general formula (I) or (II) or its pharma- ceutically acceptable salt can be administered as a single dose or multiple doses as a pure compound alone or in combination with a pharma- ceutical acceptable carrier. The pharmaceutical composition formed by combining the compound of the present invention with a pharma- ceutical acceptable carrier can be administered in various dosage forms suitable for the administration route. The pharmaceutical composition according to the present invention can be formulated with a pharma- ceutical acceptable carrier according to conventional methods, for example, as disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

[0114] The pharmaceutical composition of the present invention can be administered orally or parenterally. Parenteral administration can include rectal, nasal, pulmonary, transdermal, intracerebral, intraperitoneal, vaginal, subcutaneous, intramuscular, intrathecal, intravenous and intradermal routes. The pharmaceutical composition of the present invention can be specifically formulated for administration by any suitable route. The preferred route can be selected depending on the general condition and age of the subject to be treated, the nature of the condition to be treated, and the active ingredient selected.

[0115] Pharmaceutical compositions for oral administration include solid preparations such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with a coating. Non-solid preparations for oral administration include solutions (including inhalables), emulsions, suspensions, syrups and elixirs.

[0116] Pharmaceutical compositions for parenteral administration include injections, suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc. Injections are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

[0117] When preparing a solid preparation for oral administration, a carrier, for example, an excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, etc., are added to the main drug, and then the main drug can be made into tablets, coated tablets, granules, fine granules, powders, capsules, etc. by a conventional method. In addition, non-solid preparations for oral administration such as syrups can also be appropriately prepared.

[0118] Examples of excipients include lactose, sucrose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., examples of binders include polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc., examples of lubricants include magnesium stearate, talc, silica, etc., examples of colorants include those permitted for addition to pharmaceuticals, and examples of flavoring agents include cocoa powder, peppermint, aromatic acid, peppermint oil, bornoleum, cinnamon powder, etc. These tablets and granules may of course be coated with sugar, gelatin, or other appropriate coatings as necessary.

[0119] When preparing an injection, a carrier such as a pH adjuster, a buffer, a suspending agent, a solubilizing agent, a stabilizer, an isotonicity agent, a preservative, etc. may be added to the main drug as necessary to prepare an intravenous, subcutaneous, or intramuscular injection or a drip infusion in a conventional manner. In this case, it may be lyophilized in a conventional manner as necessary.

[0120] Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, powdered tragacanth, sodium carboxymethylcellulose, and polyoxyethylene sorbitan monolaurate.

[0121] Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester, cyclodextrin, and the like.

[0122] Examples of stabilizers include sodium sulfite and sodium metasulfite, and examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0123] <Synthesis method> The compounds of the present invention represented by general formula (I) or (II) can be prepared by the methods outlined in the following reaction schemes 1 to 5 as well as in Example B. In the methods described below, it is possible to make use of variations or modifications which are themselves known to chemists of ordinary skill in the art or which may be apparent to those skilled in the art.

[0124] In the following description of the manufacturing method, unless otherwise specified, A, R, R 1 and Y is as defined above.

[0125] <Recipe 1> Of the compounds (I) and (II), the compounds in which R is a C1-C6 alkyl group can be produced via step 1 of the following Production Method 1. [ka]

[0126] Step 1 of Preparation Method 1 is a step of producing compound (I) or (II) of the present invention by condensing compound (1A) or (2A) with compound (3) in a solvent using a dehydrating condensing agent. Compounds (1A) and (2A) can be produced in accordance with the following Synthesis 1-2 and the description of the Examples of this specification. Compounds (1A) and (2A) may be in the form of an acid addition salt, etc. Examples of the acid addition salt include hydrochloride, sulfate, acetate, etc.

[0127] Compound (3) can also be produced in accordance with the procedure described later in Synthesis 6 and in the Examples section of this specification. Compound (3) may be in the form of an acid addition salt, etc. Examples of the acid addition salt include hydrochloride, sulfate, acetate, etc.

[0128] Examples of the dehydration condensation agent used in step 1 of Production Method 1 include dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride salt (EDC, EDAC), N,N-dicyclohexylamide, carbonyldiimidazole, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and the like, and N,N'-diisopropylcarbodiimide or dicyclohexylcarbodiimide is preferred.

[0129] Step 1 of Production Method 1 may be carried out, if necessary, in the presence of an activating agent such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), or 4-dimethylaminopyridine. Furthermore, step 1 of production method 1 may be carried out in the presence of a base such as N,N-diisopropylethylamine, N-methylmorpholine, or triethylamine, if necessary.

[0130] The solvent used in step 1 of Production Method 1 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane (DCM), etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; sulfur-based solvents such as dimethyl sulfoxide (DMSO), etc.; or any mixed solvents of these, and the like. Preferably, it is an aprotic polar solvent, and more preferably, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent obtained by mixing these.

[0131] The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C.

[0132] The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 120 hours, and preferably from 30 minutes to 48 hours.

[0133] <Recipe 2> Compound (I') or (II'), which is compound (I) or (II) in which R is a hydrogen atom, can be produced by subjecting compound (I) or (II) produced by the above-mentioned Production Method 1 to step 2 of the following Production Method 2. [ka]

[0134] Step 2 of Preparation Method 2 is a step of producing compound (I') or (II') by hydrolyzing the ester moiety of compound (I) or compound (II) or an acid addition salt thereof, for example, by reacting with a base in a solvent.

[0135] Examples of the base used in step 2 of production method 2 include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and are preferably alkali metal hydroxides, and more preferably lithium hydroxide or sodium hydroxide. These bases may be used alone or in combination of two or more. The base may be added in the form of a solution in which the base is dissolved in a solvent described below.

[0136] The solvent used in step 2 of production method 2 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably water, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, or a mixed solvent of two or more of these.

[0137] The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C.

[0138] The reaction time varies depending on the reaction temperature and the like, but is usually from 1 minute to 48 hours, and preferably from 10 minutes to 30 hours.

[0139] <Synthesis 1> The compounds (1A) and (2A) used as starting materials in the above-mentioned Preparation Method 1 can be produced through each step of Synthesis 1 below. [ka]

[0140] In the above formula, P 1 indicates a protecting group such as a tetrahydropyranyl (THP) group. In addition, in the above formula, R x is a hydrocarbon group having 1 to 6 carbon atoms, and specifically, a C1-C6 alkyl group is preferred. In the following description of the manufacturing method, unless otherwise specified, 1 and R x is as defined above.

[0141] Step 3 of Synthesis 1 is a step of reacting compound (1A)-1 or (2A)-1 with methyl isothiocyanate in a solvent to obtain compound (1A)-2 or (2A)-2. Compounds (1A)-1 and (2A)-1 are known compounds or can be produced from other known compounds, for example, according to the synthesis 3-4 described below and the examples of this specification.

[0142] The solvent used in step 3 of Synthesis 1 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably N,N-dimethylformamide, N-methylpyrrolidone, or methanol. Step 3 of Synthesis 1 may be carried out in the presence of acetic acid, if necessary. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, and preferably 20°C to 120°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 72 hours, and preferably from 30 minutes to 48 hours.

[0143] In step 4 of synthesis 1, a protecting group P in compound (1A)-2 or (2A)-2 is reacted in a solvent. 1 and the substituent R x to obtain compound (1A)-3 or (2A)-3. In step 4 of synthesis 1, a protecting group P 1 may be eliminated from the substituent R x It may be desorbed from.

[0144] Protecting group P 1 When is, for example, a tetrahydropyranyl group, it can be removed by adding an acid to a solution containing compound (1A)-2 or (2A)-2 to form an acidic solution. Protecting group P in step 4 of synthesis 1 1 The acid used in the elimination of is not particularly limited, and examples thereof include hydrochloric acid (hydrochloric acid), sulfuric acid, nitric acid, trifluoroacetic acid (TFA), etc. These acids may be used alone or in combination of two or more. As a method for adding the acid, the acid may be added in the form of a solution dissolved in a solvent described below.

[0145] Protecting group P in step 4 of synthesis 1 1The solvent used in the elimination of is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferred are water; tetrahydrofuran, dichloromethane, 1,4-dioxane, methanol, or a mixed solvent of two or more of these. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 150°C, and preferably from 0°C to 100°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 24 hours, and preferably from 30 minutes to 10 hours.

[0146] In addition, the substituent R x can be removed by adding a base to a solution containing compound (1A)-2 or (2A)-2. Substituent R in Step 4 of Synthesis 1 x Examples of the base used in the elimination of include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and are preferably alkali metal hydroxides, and more preferably lithium hydroxide or sodium hydroxide. These bases may be used alone or in combination of two or more. The base may be added in the form of a solution in which the base is dissolved in a solvent described below.

[0147] Substituent R in Step 4 of Synthesis 1 xThe solvent used in the elimination of is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent, and examples thereof include water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably water, tetrahydrofuran, methanol, or a mixed solvent of two or more of these. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 24 hours, and preferably from 30 minutes to 10 hours.

[0148] Step 5 of Synthesis 1 is a step in which compound (1A)-3 or (2A)-3 is reacted with methyl iodide (iodomethane), which is a methylating agent, in a first-step reaction in a solvent, and then reacted with a diamine of compound (a1) or an acid addition salt thereof, or the like, in a second-step reaction to obtain compound (1A) or (2A). The solvent used in the first stage of step 5 of Synthesis 1 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent. Examples of the solvent include amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; or any mixed solvents of these, and preferably N,N-dimethylformamide or N-methylpyrrolidone. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, preferably 10°C to 120°C, and more preferably 20°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 1 minute to 48 hours, and preferably from 10 minutes to 24 hours.

[0149] In the second step of step 5 of synthesis 1, compound (1A) or (2A) is produced by reacting compound (a1) with a diamine or an acid addition salt thereof in the presence or absence of water. Compound (a1) may be an acid addition salt, and examples of the acid addition salt include hydrochloride, sulfate, acetate, and the like. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, and preferably 20°C to 120°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0150] In step 4 of synthesis 1, the protecting group P in compound (1A)-2 or (2A)-2 is 1 and the substituent R x After removing both of the substituents, compound (1A) or (2A) is produced through step 5. In addition, as shown below, the substituent R in compound (1A)-2 is x is removed to give compound (1A)-3' (step 4a), which is then passed through step 5 to give compound (1A)-4, after which the protecting group P 1 Compound (1A) may be produced by removing the aryl group (step 4b). Compound (2A) can also be produced by the same scheme as below.

[0151] [ka]

[0152] In the above scheme, the substituent R in step 4a x and the method for removing the protecting group P in step 4b. 1The method for removing the group can be the same as that in step 4.

[0153] <Synthesis 2> In synthesis 1, the amino group of the five-membered heterocyclic ring is protected by a protecting group P 1 Compounds (1A) and (2A) are produced using compound (1A)-1 or (2A)-1 protected by the protecting group P 1 The compound may be prepared using a compound that is not protected by the formula (I). For example, compound (1A) can be produced by using compound (1A)-1' through each step of the following Synthesis 2. Compound (2A) can also be produced by the same scheme as in the following Synthesis 2. [ka]

[0154] Steps 3 and 5 of Synthesis 2 are the same as steps 3 and 5 of Synthesis 1. In addition, in step 4a of Synthesis 2, the substituent R x In step 4a of Synthesis 2, unlike step 4 of Synthesis 1, the substituent R x Only the operation of desorbing is performed. Substituent R x is the substituent R in step 4 of Synthesis 1 above. x The type of base used in step 4a of synthesis 2 and the method of adding the base can be determined by the same method as that for removing the substituent R x This is the same as the method for removing the

[0155] <Synthesis 3> Compound (1A)-1 used as a raw material in the above-mentioned Synthesis 1 can be produced through steps 6 to 8 of the following Synthesis 3. Compound (2A)-1 can also be produced by the same scheme as in the following Synthesis 3. [ka]

[0156] In the above formula, Z is a chlorine atom, a bromine atom, or an iodine atom.

[0157] In step 6 of synthesis 3, a protecting group P is added to the amino structure of the five-membered heterocyclic ring of compound (1A)-1-1 in a solvent. 1 to obtain compound (1A)-1-2. Compound (1A)-1-1 is either known or can be produced from another known compound. Protecting group P 1 The method for introducing the protecting group can be a known method, for example, the method described in Org. Biomol. Chem., 2017, 15, 8614-8626 and J. Org. Chem., 2015, 80, 7713-7726 can be used. That is, a protecting group can be introduced into the amino structure portion of a compound corresponding to the protecting group to be introduced. For example, the protecting group P 1 When is a tetrahydropyranyl group, a tetrahydropyranyl group can be introduced into the amino structure portion of the five-membered heterocyclic ring by reacting with dihydropyran (DHP) in the presence of an acid catalyst (eg, p-toluenesulfonic acid).

[0158] The solvent used in step 6 of Synthesis 3 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent, and examples thereof include amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; or any mixed solvents of these, and preferably dichloromethane, toluene, xylene, or tetrahydrofuran. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, and preferably 0°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0159] Step 7 of Synthesis 3 is a step of reacting compound (1A)-1-2 with benzophenone imine in a solvent under an inert gas stream in the presence of a catalyst to obtain compound (1A)-1-3. Examples of the catalyst used in step 7 of synthesis 3 include organopalladium complexes such as tris(dibenzylideneacetone)dipalladium and palladium acetate.

[0160] In step 7 of synthesis 3, the reaction may be carried out in the presence or absence of a ligand. Examples of the ligand used in step 7 of synthesis 3 include 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene (Xantphos) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP).

[0161] In step 7 of synthesis 3, the reaction may be carried out in the presence or absence of a base. Examples of the base used in step 7 of synthesis 3 include alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, and sodium hydrogen carbonate; alkali metal phosphates such as tribasic potassium phosphate, sodium phosphate, and sodium hydrogen phosphate; alkali metal fluorides such as cesium fluoride and potassium fluoride; alkylamines such as triethylamine and N,N-diisopropylethylamine; pyridines such as pyridine and 4-dimethylaminopyridine; and 1,8-diazabicyclo[5.4.0]-7-undecene. These bases may be used alone or in combination of two or more. The base may be added in the form of a solution in which the base is dissolved in a solvent described below.

[0162] The solvent used in step 7 of Synthesis 3 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; or any mixed solvents of these, and preferably toluene, xylene, or 1,4-dioxane. Examples of the inert gas that can be used include nitrogen gas and argon gas. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 50°C to 250°C, and preferably 70°C to 200°C. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 48 hours, and preferably 3 to 24 hours.

[0163] Step 8 of Synthesis 3 is a step for obtaining compound (1A)-1 from compound (1A)-1-3. In step 8, compound (1A)-1 can be obtained by subjecting compound (1A)-1-3 to a reduction reaction in the presence of a metal catalyst in a solvent in the presence of hydrogen gas. Metal catalysts used in step 8 of synthesis 3 include heterogeneous catalysts such as Pd-C catalysts, palladium hydroxide catalysts, Pt-C catalysts, and platinum oxide catalysts. The solvent used in step 8 of Synthesis 3 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; acetic acid; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably ethyl acetate, tetrahydrofuran, or methanol. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 150°C, and preferably 20°C to 100°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 120 hours, and preferably from 30 minutes to 48 hours.

[0164] In step 8, a solution of an acid such as citric acid may be added to the solution containing compound (1A)-1-3 to hydrolyze compound (1A)-1-3, thereby obtaining compound (1A)-1. The solvent used in step 8 of Synthesis 3 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably tetrahydrofuran. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 200°C, and preferably 0°C to 100°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 120 hours, and preferably from 30 minutes to 48 hours.

[0165] <Synthesis 4> Compound (1A)-1 used as a raw material in the above-mentioned Synthesis 1 can also be produced by the steps of the following Synthesis 3 using the following compound (1A)-1-4, in addition to the above-mentioned Synthesis 3. Compound (2A)-1 can also be produced by the same scheme as the following Synthesis 4. [ka]

[0166] In step 9 of synthesis 4, a protecting group P is added to the amino structure of the five-membered heterocyclic ring of compound (1A)-1-4 in a solvent. 1 In step 9, a protecting group P is introduced to obtain a compound (1A)-1-5. The compound (1A)-1-4 is either known or can be prepared from another known compound. 1 The method for introducing can be the same as that used in step 6 of Synthesis 3 above, and the solvent used is also the same as that used in step 6 of Synthesis 3.

[0167] Step 10 of Synthesis 4 is a step in which the nitro group of compound (1A)-1-5 is reduced to an amino group to obtain compound (1A)-1. In step 10 of Synthesis 4, the nitro group of compound (1A)-1-5 can be reduced to an amino group to obtain compound (1A)-1 by subjecting compound (1A)-1-5 to a reduction reaction in a solvent in the presence of a reducing agent such as sodium dithionite to reduce the nitro group of compound (1A)-1-5 to an amino group, thereby obtaining compound (1A)-1. The solvent used in step 10 of Synthesis 4 using a reducing agent is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent, and examples thereof include water; acetic acid; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; esters such as ethyl acetate, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably water or ethanol. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 200°C, and preferably 50°C to 150°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0168] In step 10, compound (1A)-1-5 can also be subjected to a reduction reaction in the presence of a metal catalyst in a solvent in the presence of hydrogen gas to reduce the nitro group of compound (1A)-1-5 to an amino group to obtain compound (1A)-1. Examples of the metal catalyst used in this case include heterogeneous catalysts such as Pd-C catalyst, palladium hydroxide catalyst, Pt-C catalyst, and platinum oxide catalyst. The solvent used in step 10 of synthesis 4 using a metal catalyst is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent. Examples of the solvent include water; acetic acid; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; esters such as ethyl acetate, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; alcohols such as methanol, ethanol, n-propanol, isopropanol, etc.; nitriles such as acetonitrile, propionitrile, etc.; or any mixed solvents of these, and preferably acetic acid or tetrahydrofuran. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually 0°C to 200°C, and preferably 20°C to 100°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0169] <Synthesis 5> Among the compounds (4) used as raw materials in the above-mentioned Production Method 1, compound (4)-S, which is an S-configuration compound in which R is a C1-C6 alkyl group, can be produced via steps 11 to 13 in the following Synthesis 5. Compound (4)-S is included in compound (4). [ka]

[0170] Step 11 of Synthesis 5 is a step of reacting compound (4)-1 with (R)-2-methylpropane-2-sulfinamide (a4) in a solvent in the presence of pyrrolidine and molecular sieves (4 Å) to obtain compound (4)-S-1. The solvent used in step 11 of Synthesis 5 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent. Examples of the solvent include halogenated hydrocarbons such as dichloromethane (DCM) and the like; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane and tert-butyl methyl ether; and the like; or any mixed solvents of these, and preferably toluene or tetrahydrofuran. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 150°C, and preferably from 0°C to 120°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0171] Step 12 of Synthesis 5 is a step of reacting compound (4)-S-1 with compound (a5) in a solvent to obtain compound (4)-S-2. Compound (a5) is a compound corresponding to R in the target compound (4)-S. Compound (a5) is either known or can be produced from a known compound in accordance with the description in the Examples section of this specification below. Specific examples of compound (a5) include (2-methoxy-2-oxoethyl)zinc(II) bromide, (2-ethoxy-2-oxoethyl)zinc(II) bromide, (2-isopropoxy-2-oxoethyl)zinc(II) bromide, and [2-(tert-butoxy)-2-oxoethyl]zinc(II) bromide.

[0172] The solvent used in step 12 of Synthesis 5 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent. Examples of the solvent include halogenated hydrocarbons such as dichloromethane (DCM) and the like; aromatic hydrocarbons such as toluene and the like; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether and the like; or any mixed solvents thereof, and preferably tetrahydrofuran. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -78°C to 100°C, and preferably from -20°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, and preferably 30 minutes to 24 hours.

[0173] Step 13 of Synthesis 5 is a step of reacting compound (4)-S-2 with an acid in a solvent to obtain compound (4)-S. Examples of the acid used in step 13 of synthesis 5 include organic acids such as acetic acid, formic acid, trifluoroacetic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid (hydrochloric acid), hydrobromic acid, and sulfuric acid, with hydrochloric acid being preferred. These acids may be used alone or in combination of two or more. The acid may be added in the form of a solution in which the acid is dissolved in a solvent as described below.

[0174] The solvent used in step 13 of Synthesis 5 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent. Examples of the solvent include water; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane (DCM); aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; or any mixed solvents of these, and preferably ethers, alcohols, or any mixed solvents of these. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 1 minute to 48 hours, and preferably from 10 minutes to 24 hours. The compound (4)-S thus obtained may be an acid addition salt, etc. Examples of the acid addition salt include hydrochloride, sulfate, acetate, etc.

[0175] As described above, compound 4-(S) can be synthesized through steps 11 to 13 of synthesis 5. Also, by using, for example, (S)-2-methylpropane-2-sulfinamide instead of compound (a4) and going through steps 11 to 13, a compound having the opposite chirality to compound (4)-S can be synthesized. Furthermore, by using, for example, racemic 2-methylpropane-2-sulfinamide instead of compound (a4) and going through steps 11 to 13, a racemic mixture of compound (4)-S can be synthesized.

[0176] <Synthesis 6> Among the compounds (3) used as raw materials in the above-mentioned Preparation Method 1, the compound (3) in which R is a C1-C6 alkyl group can be produced via steps 14 and 15 of the following Synthesis 6. [ka]

[0177] Step 14 of Synthesis 6 is a step in which compound (3)-1 is obtained by reacting compound (4) or an acid addition salt thereof obtained by a method such as Synthesis 5 with compound (a6) in a solvent in the presence of a dehydrating condensation agent. In the above formula, P 2 indicates a protecting group such as t-butoxycarbonyl (Boc) group.

[0178] Examples of the dehydration condensation agent used in step 14 of synthesis 6 include dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (EDC, EDAC), N,N-dicyclohexylamide, 1-hydroxybenzotriazole, carbonyldiimidazole, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, and the like, and preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (EDC, EDAC).

[0179] In addition, step 14 of synthesis 6 may be carried out in the presence or absence of a base. Examples of the base used in step 14 of synthesis 6 include N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4-(N,N-dimethylamino)pyridine, N-ethyl-N-isopropylpropan-2-amine, and the like, and N,N-diisopropylethylamine or triethylamine is preferred. These bases may be used alone or in combination of two or more. The base may be added in the form of a solution in which the base is dissolved in a solvent as described below.

[0180] The solvent used in step 14 of Synthesis 6 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to some extent. Examples of the solvent include amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone, etc.; halogenated hydrocarbons such as dichloromethane (DCM), etc.; esters such as ethyl acetate, etc.; hydrocarbons such as dichlorohexane, n-hexane, etc.; aromatic hydrocarbons such as toluene, etc.; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, tert-butyl methyl ether, etc.; or any mixed solvents of these, and preferably dichloromethane. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 72 hours, and preferably from 30 minutes to 48 hours.

[0181] In step 15 of synthesis 6, a protecting group P is removed from compound (3)-1 using an acid in a solvent. 2 is deprotected to obtain compound (3). Examples of the acid used in step 15 of synthesis 6 include organic acids such as acetic acid, formic acid, trifluoroacetic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid (hydrochloric acid), hydrobromic acid, and sulfuric acid, with hydrochloric acid being preferred. These acids may be used alone or in combination of two or more. The acid may be added in the form of a solution in which the acid is dissolved in a solvent as described below.

[0182] The solvent used in step 15 of Synthesis 6 is not particularly limited as long as it does not inhibit the reaction and dissolves the raw materials to a certain extent, and examples thereof include water; alcohols such as methanol and ethanol; halogenated hydrocarbons such as dichloromethane (DCM); aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; nitriles such as acetonitrile and propionitrile; or any mixed solvents of these, and preferably ethers, alcohols, or any mixed solvents of these. The reaction temperature varies depending on the types and amounts of raw materials and solvents used, but is usually from -20°C to 100°C, and preferably from 0°C to 50°C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 72 hours, and preferably from 30 minutes to 48 hours. The compound (3) thus obtained may be an acid addition salt, etc. Examples of the acid addition salt include hydrochloride, sulfate, acetate, etc.

[0183] In the present specification, the compounds obtained in each step may be isolated and purified by known means, or may be directly subjected to the next step. Isolation and purification may be carried out using conventional operations, such as filtration, extraction, crystallization, various column chromatography, etc.

[0184] <Intermediate of the Invention> In one embodiment of the present invention, the following compound, which is an intermediate of compound (I) or (II) or a pharma- ceutical acceptable salt thereof, is also included in the present invention. One embodiment of the intermediate of the present invention includes a compound represented by the following general formula (X-1) or (X-2) or a salt thereof. [ka] In the above formulas (X-1) and (X-2), R Y is a group represented by the following formula (x)-i or (x)-ii. [ka] (In the above formula, Y is a hydrogen atom, a fluorine atom, or a hydroxyl group, as in the above general formulas (I) and (II). 7 is a C1-C6 alkyl group. * indicates the bond position. R 1 is a hydrogen atom or a halogen atom, as in the above general formulas (I) and (II). R XA is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and is preferably a hydrogen atom or a C1-C6 alkyl group. R Z is a hydrogen atom or P 1 (P 1 represents a protecting group such as a tetrahydropyranyl (THP) group, as described above.

[0185] In one embodiment, in the above general formula (X-1), R Y is a group represented by the above formula (x)-i. In one embodiment, in the above general formula (X-1), R Y is a group represented by the above formula (x)-ii. In one embodiment, in the above general formula (X-2), R Y is a group represented by the above formula (x)-i. In one embodiment, in the above general formula (X-2), R Yis a group represented by the above formula (x)-ii.

[0186] One embodiment of the intermediate of the present invention is a compound represented by the following general formula (X-1-1) or (X-2-1) or a salt thereof. [ka] In the above formulas (X-1-1) and (X-2-1), R YA is a group represented by the following formula (x)-i-1, (x)-i-2, (x)-i-3, or (x)-ii-1. [ka] (In the above formula, * indicates the bond position.) R 1A is a hydrogen atom, a fluorine atom, or a chlorine atom. R XA1 is a hydrogen atom or a methyl group. R ZA is a hydrogen atom or a tetrahydropyranyl (THP) group.

[0187] In one embodiment, in the above general formula (X-1-1), R YA is a group represented by the above formula (x)-i-1, (x)-i-2, or (x)-i-3. In one embodiment, in the above general formula (X-1-1), R YA is a group represented by the above formula (x)-ii-1. In one embodiment, in the above general formula (X-2-1), R YA is a group represented by the above formula (x)-i-1, (x)-i-2, or (x)-i-3. In one embodiment, in the above general formula (X-2-1), R YA is a group represented by the above formula (x)-ii-1.

[0188] Furthermore, one embodiment of the intermediate of the present invention includes a compound selected from the following group or a salt thereof. [ka]

[0189] One embodiment of the intermediate of the present invention is a compound selected from the following group or a salt thereof: [ka]

[0190] One embodiment of the intermediate of the present invention is a compound selected from the following group or a salt thereof: [ka]

[0191] One embodiment of the intermediate of the present invention is a compound selected from the following group or a salt thereof: [ka]

[0192] Another embodiment of the intermediate of the present invention includes a compound represented by the following general formula (X-3) and a salt thereof. [ka] In the above formula (X-3), A is, as in the above general formulas (I) and (II), a C6-C 10It is an aryl group or a heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group may be substituted with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted with a C1-C6 alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a C1-C6 alkylsulfonyl group). As in general formulas (I) and (II) above, R is a hydrogen atom or a C1-C6 alkyl group. R W is a hydrogen atom or P 2 (P 2 As described above, represents a protecting group such as t-butoxycarbonyl (Boc) group.

[0193] Moreover, one embodiment of the intermediate of the present invention includes a compound represented by the following general formula (X-3-1) and a salt thereof. [ka] In the above formula (X-3-1), R 2 is a hydrogen atom or a halogen atom, R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group; R 4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group, R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or a heteroaryl group optionally substituted with a C1-C6 alkyl group, R 6 is a hydrogen atom or a halogen atom, R is a hydrogen atom or a C1-C6 alkyl group, as in the general formulas (I) and (II) above. R W is a hydrogen atom or P 2 (P 2 As described above, represents a protecting group such as t-butoxycarbonyl (Boc) group.

[0194] Furthermore, one embodiment of the intermediate of the present invention is a compound represented by the following general formula (X-3-2) or a salt thereof. [ka] As in general formulas (I) and (II) above, R is a hydrogen atom or a C1-C6 alkyl group. R W is a hydrogen atom or P 2 (P 2 As described above, represents a protecting group such as t-butoxycarbonyl (Boc) group. A 1 is a group selected from the group below: In the following formula, * indicates the bonding position. [ka]

[0195] One embodiment of the intermediate of the present invention may be a salt of a compound represented by any one of the above formulas (X-1) to (X-3), (X-1-1), (X-2-1), (X-3-1) and (X-2-3). The salt is not particularly limited, and examples thereof include "acid addition salts, etc." and "base addition salts, etc." exemplified above as "pharmaceutical acceptable salts."

[0196] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety. EXAMPLES

[0197] The present invention will be described in more detail below with reference to examples, examples, and test examples, but the scope of the present invention is not limited to these. The names of reference examples, examples, and test examples are merely given for convenience to distinguish experimental examples, and do not mean that any of them is not included in the present invention.

[0198] The mass spectrum ionization mode DUIS is a mixed mode of ESI and APCI.

[0199] In this specification, 1 Unless otherwise specified, H-NMR is expressed as chemical shifts (δ) with tetramethylsilane as the internal standard (0 ppm), and coupling constants (J values) are expressed in Hz. The abbreviations for the splitting patterns of each peak have the following meanings: s: singlet, d: doublet, dd: double doublet, ddd: double double doublet, t: triplet, tt: triple triplet, quin: quintet, m: multiplet.

[0200] The abbreviations used in the Reference Examples, Examples, Test Examples, and chemical structural formulae are generally used in the sense commonly used in the fields of organic chemistry and pharmacology, and specifically, are understood by those skilled in the art as abbreviations for the terms shown below. Me: Methyl group DMSO: Dimethyl sulfoxide tert: tertiary N: Regulation M: Molar concentration ESI: electrospray ionization APCI: Atmospheric Pressure Ionization EI: Electron ionization CI: Chemical ionization

[0201] Reference example 1-(a) Preparation of (R,E)-N-(3-chloro-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide [ka]

[0202] To a solution of 3.82 g of 3-chloro-5-(trifluoromethyl)benzaldehyde in toluene (20 ml), 2.35 g of (R)-2-methylpropane-2-sulfinamide (Combi-Blocks), 0.079 ml of pyrrolidine, and 4 g of molecular sieves (4 Å) were added at room temperature under an argon stream, and the mixture was stirred at 70° C. for 2.5 hours. After the reaction was completed, the reaction solution was filtered through Celite and concentrated under reduced pressure. Hexane was added to the concentrated residue and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure at 60°C to obtain 2.22 g of the title compound as a white solid. Mass spectrum (ESI, m / z): 312 [M+H] + .

[0203] Reference example 2-(a) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(a) to obtain the compounds shown in the following Tables 1-1 to 1-8.

[0204] [Table 1-1]

[0205] [Table 1-2]

[0206] [Table 1-3]

[0207] [Table 1-4]

[0208] [Table 1-5]

[0209] [Table 1-6]

[0210] [Table 1-7]

[0211] [Table 1-8]

[0212] Reference example 1-(b) Preparation of methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate [ka]

[0213] 5.05 g of copper chloride (I) was added to 33.3 g of zinc under argon flow while stirring, and then the mixture was degassed under reduced pressure at a bath temperature of 70°C for 15 minutes. The mixture was replaced with argon, and 45 ml of tetrahydrofuran was added under argon flow, and the mixture was stirred at 70°C for 1 hour. The bath temperature was then lowered to 40°C, and 10.4 ml of methyl bromoacetate was added dropwise at an internal temperature of 30°C to 37°C. After the addition was completed, the mixture was stirred at a bath temperature of 50°C for 1 hour. After returning to room temperature, the mixture was cooled in an ice-salt bath, and a solution of 5.00 g of (R,E)-N-(3-chloro-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide synthesized in the same manner as in Reference Example 1-(a) in tetrahydrofuran (22.5 ml) was added dropwise under argon flow at an internal temperature of -5°C or less, and further washed in with 7.50 ml of tetrahydrofuran. After the dropwise addition was completed, the mixture was cooled in an ice bath and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered through Celite (545) and washed with ethyl acetate, and then a saturated aqueous solution of ammonium chloride was added to the filtrate and stirred. This mixture was filtered, and the filtrate was separated. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 4.82 g of the title compound as a slightly yellow oil. Mass spectrum (ESI, m / z): 386 [M+H] + .

[0214] Reference example 2-(b) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(b) to obtain the compounds shown in the following Tables 2-1 to 2-8.

[0215] [Table 2-1]

[0216] [Table 2-2]

[0217] [Table 2-3]

[0218] [Table 2-4]

[0219] [Table 2-5]

[0220] [Table 2-6]

[0221] [Table 2-7]

[0222] [Table 2-8]

[0223] Reference example 1-(c) Preparation of methyl (S)-3-amino-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate hydrochloride [ka]

[0224] To a solution of 24.6 g of methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate synthesized in the same manner as in Reference Example 1-(b) in cyclopentyl methyl ether (270 ml), 2.52 ml of methanol and 34.2 ml of a 4 M hydrogen chloride / cyclopentyl methyl ether solution were added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. 50 ml of cyclopentyl methyl ether and 600 ml of hexane were added to the concentrated residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with hexane, and then dried under reduced pressure at 50°C to obtain 17.5 g of the title compound as a white solid. Mass spectrum (ESI, m / z): 282 [M+H] + .

[0225] Reference example 2-(c) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(c) to obtain the compounds shown in the following Tables 3-1 to 3-7.

[0226] [Table 3-1]

[0227] [Table 3-2]

[0228] [Table 3-3]

[0229] [Table 3-4]

[0230] [Table 3-5]

[0231] [Table 3-6]

[0232] [Table 3-7]

[0233] Reference example 1-(d) Preparation of methyl (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate [ka]

[0234] To a dichloromethane (20 ml) solution of 2.23 g of methyl (S)-3-amino-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate hydrochloride synthesized in Reference Example 1-(c) and 0.977 ml of triethylamine, 1.36 g of (tert-butoxycarbonyl)glycine and 1.61 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 2.92 g of the title compound as a colorless oil. Mass spectrum (ESI, m / z): 439 [M+H] + .

[0235] Reference example 2-(d) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(d) to obtain the compounds shown in the following Tables 4-1 to 4-8.

[0236] [Table 4-1]

[0237] [Table 4-2]

[0238] [Table 4-3]

[0239] [Table 4-4]

[0240] [Table 4-5]

[0241] [Table 4-6]

[0242] [Table 4-7]

[0243] [Table 4-8]

[0244] Reference example 1-(e) Preparation of methyl (S)-3-(2-aminoacetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate hydrochloride [ka]

[0245] To a solution of 27.8 g of methyl (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate synthesized in the same manner as in Reference Example 1-(d) in cyclopentyl methyl ether (190 ml), 60 ml of a 4 M hydrogen chloride / cyclopentyl methyl ether solution was added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 21.5 g of the title compound as a pale yellow oil. Mass spectrum (ESI, m / z): 339 [M+H] + .

[0246] Reference example 2-(e) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(e) to obtain the compounds shown in the following Tables 5-1 to 5-8.

[0247] [Table 5-1]

[0248] [Table 5-2]

[0249] [Table 5-3]

[0250] [Table 5-4]

[0251] [Table 5-5]

[0252] [Table 5-6]

[0253] [Table 5-7]

[0254] [Table 5-8]

[0255] Reference example 18-(c) Preparation of methyl (S)-3-amino-3-(3-bromo-5-chlorophenyl)propanoate hydrochloride [ka]

[0256] To a solution of 2.26 g of methyl (S)-3-(3-bromo-5-chlorophenyl)-3-(((R)-tert-butylsulfinyl)amino)propanoate synthesized in Reference Example 18-(b) in 1,4-dioxane (20 ml), 0.23 ml of methanol and 4.1 ml of a 4 M hydrogen chloride / 1,4-dioxane solution were added at room temperature under an argon stream, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, 60 ml of hexane was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and 10 ml of tert-butyl methyl ether was added to the concentrated residue, and the mixture was stirred at room temperature for 3 hours. The solid was collected by filtration and dried under reduced pressure to obtain 1.07 g of the title compound as a white solid. Mass spectrum (ESI, m / z): 292, 294 [M+H] + .

[0257] Reference example 7-(c) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 18-(c) to give the compounds listed in Table 6 below.

[0258] [Table 6]

[0259] Reference example 8-(a) Preparation of methyl (S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-((tert-butoxycarbonyl)amino)acetamido)propanoate [ka]

[0260] To a solution of 300 mg of methyl (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(3-bromo-5-(trifluoromethyl)phenyl)propanoate synthesized in the same manner as in Reference Example 2-(d) in N,N-dimethylformamide (3 ml), 51 mg of pyrazole, 392 μl of trans-N,N'-dimethylcyclohexane-1,2-diamine, and 345 mg of potassium carbonate were added at room temperature under an argon stream, and the mixture was stirred at room temperature for 10 minutes under argon bubbling. Then, 236 mg of copper iodide (I) was added at room temperature, and the mixture was stirred at 90°C for 3 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 81 mg of the title compound as a colorless oil. Mass spectrum (ESI, m / z): 471 [M+H] + .

[0261] Reference example 29-(a): The corresponding starting compounds were treated in the same manner as in Reference Example 8-(a) to give the compounds shown in Table 7 below.

[0262] [Table 7]

[0263] Reference example 14-(e) Preparation of methyl (S)-3-(2-aminoacetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoate hydrochloride [ka]

[0264] To 293 mg of methyl (S)-3-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoate synthesized in Reference Example 14-(d), 3.2 ml of tert-butyl methyl ether and 0.657 ml of 4 M hydrogen chloride / 1,4-dioxane solution were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. 0.657 ml of 4 M hydrogen chloride / 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 3 hours. 0.657 ml of 4 M hydrogen chloride / 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 259 mg of the title compound. Mass spectrum (ESI, m / z): 319 [M+H] + .

[0265] Reference example 15-(a) Preparation of (3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)methanol [ka]

[0266] To a solution of 1.00 g of 3-chloro-4-fluoro-5-(trifluoromethyl)benzoic acid in tetrahydrofuran (20 ml) was added 9.16 ml of 0.9 M borane-tetrahydrofuran complex / tetrahydrofuran solution in an ice bath under an argon atmosphere, and the mixture was stirred at room temperature for 20 hours. After the reaction was completed, 2M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 1.06 g of the title compound as a colorless oil. Mass spectrum (EI, m / z): 228[M] + .

[0267] Reference example 21-(a) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 15-(a) to give the compounds shown in Table 8 below.

[0268] [Table 8]

[0269] Reference example 21-(b) Manufacturing of 3-chloro-5-iodobenzaldehyde [ka]

[0270] To a dichloromethane (40 ml) solution of 2.04 g of (3-chloro-5-iodophenyl)methanol synthesized in Reference Example 21-(a), 4.83 g of Dess-Martin periodinane was added at room temperature with stirring under an argon stream, and the mixture was stirred at room temperature for 10 minutes. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate containing sodium thiosulfate was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 1.66 g of the title compound as a colorless oil. Mass spectrum (EI, m / z): 266[M] + .

[0271] Reference example 15-(b) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 21-(b) to give the compounds shown in Table 9 below.

[0272] [Table 9]

[0273] Reference example 24-(a) Preparation of 3-(difluoromethoxy)-5-(trifluoromethyl)benzaldehyde [ka]

[0274] To a suspension of 4.36 g of potassium carbonate in N,N-dimethylformamide (16 ml) was added dropwise a solution of 6.42 g of sodium chlorodifluoroacetate and 4.00 g of 3-hydroxy-5-(trifluoromethyl)benzaldehyde in N,N-dimethylformamide (20 ml) at 95° C. under an argon stream, and the mixture was stirred at 95° C. for 30 minutes. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with tert-butyl methyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 1.48 g of the title compound as a colorless oil. Mass spectrum (EI, m / z): 240 [M] + .

[0275] Reference example 25-(a) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 24-(a) to give the compounds shown in Table 10 below.

[0276] [Table 10]

[0277] Reference example 1-(f) Preparation of 2-fluoromalonamide [ka]

[0278] To a solution of 25.0 g of diethyl 2-fluoromalonate in methanol (100 ml) was added 80 ml of 7N ammonia / methanol solution at room temperature under an argon stream, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solid was collected by filtration, washed with methanol, and then dried under reduced pressure at 50° C. to obtain 15.91 g of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, DMSO-d6) δ: 7.78 - 7.48 (m, 4H), 5.16 (d, J = 48.9 Hz, 1H).

[0279] Reference example 1-(g) Preparation of 2-fluoropropane-1,3-diamine hydrochloride [ka]

[0280] To 400 ml of a 0.9 M borane-tetrahydrofuran complex / tetrahydrofuran solution, 7.20 g of 2-fluoromalonamide synthesized in Reference Example 1-(f) was added in portions at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 20 hours. After the reaction was completed, the reaction solution was cooled to 0°C, and 73 ml of methanol was added dropwise at 20°C or less. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. 40 ml of ethanol was added to the concentrated residue, and 60 ml of 2M hydrogen chloride / ethanol solution was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, dissolved in methanol, and concentrated under reduced pressure. 70 g of Amberlite (IRA478RF CL) washed with 200 ml of water and 200 ml of methanol in sequence was added to a methanol (200 ml) solution of 6.91 g of the obtained solid at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 4.55 g of the title compound as a white solid. 1 H-NMR spectrum (400 MHz, DMSO-d6 + D2O) δ: 4.77 - 4.53 (m, 1H), 3.01 - 2.79 (m, 4H).

[0281] Reference example 48-(a) Preparation of methyl 4-bromo-3-fluoro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0282] To a suspension of 200 mg of methyl 4-bromo-1H-indazole-6-carboxylate in acetonitrile (8 ml) was added 333 mg of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) at room temperature under an argon stream, and the mixture was stirred at 100° C. for 4 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To a suspension of the resulting concentrated residue in dichloromethane (8 ml) were added 3,4-dihydro-2H-pyran (143 μl) and p-toluenesulfonic acid monohydrate (15 mg) at room temperature under an argon stream, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate), and the fraction containing the target product was concentrated under reduced pressure. The resulting residue was purified by gel permeation chromatography (column: YMC-GPC T30000, YMC-GPC T4000, YMC-GPC T2000, elution solvent: ethyl acetate) to obtain 32 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 357, 359 [M+H] + .

[0283] Reference example 49-(a) Preparation of methyl 3-chloro-4-nitro-1H-indazole-6-carboxylate [ka]

[0284] To a suspension of 300 mg of methyl 4-nitro-1H-indazole-6-carboxylate in acetonitrile (8 ml), 217 mg of N-chlorosuccinimide was added at room temperature under an argon stream, and the mixture was stirred for 2 hours at 80° C. Next, 145 mg of N-chlorosuccinimide was added at 80° C., and the mixture was stirred for 2 hours at 80° C. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 347 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 254 [MH] - .

[0285] Reference example 1-(h) Preparation of methyl 4-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0286] To a suspension of 1.00 g of methyl 4-bromo-1H-indazole-6-carboxylate in dichloromethane (10 ml) were added 717 μl of 3,4-dihydro-2H-pyran and 82 mg of p-toluenesulfonic acid monohydrate at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 1.13 g of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 339, 341 [M+H] + .

[0287] Reference example 49-(b): The corresponding starting compounds were treated in the same manner as in Reference Example 1-(h) to give the compounds shown in Table 11 below.

[0288] [Table 11]

[0289] Reference example 1-(i) Preparation of methyl 4-((diphenylmethylene)amino)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0290] To a xylene (20 ml) solution of 1.13 g of methyl 4-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in Reference Example 1-(h), 1.11 ml of benzophenone imine, 305 mg of tris(dibenzylideneacetone)dipalladium(0), 771 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 3.26 g of cesium carbonate were added at room temperature under an argon atmosphere, and the mixture was stirred at 150° C. for 6 hours under an argon atmosphere. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with toluene. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate), and the fraction containing the target product was concentrated under reduced pressure. 20 mL of tert-butyl methyl ether was added to the resulting residue at room temperature, stirred at room temperature for 1 hour, and the solid was filtered to obtain 1.09 g of the title compound as a yellow solid. 1 H-NMR spectrum (400MHz,DMSO-d6)δ:8.09 (d, J = 0.8 Hz, 1H), 7.90 - 7.87 (m, 1H), 7.78 - 7.70 (m, 2H), 7.62 - 7.46 (m, 3H), 7.28 - 7.17 (m, 5H), 6.91 (d, J = 1.1 Hz, 1H), 5.91 (dd, J = 2.3, 9.5 Hz, 1H), 3.89 - 3.72 (m, 5H), 2.40 - 2.29 (m, 1H), 2.04 - 1.92 (m, 2H), 1.80 - 1.68 (m, 1H), 1.61 - 1.49 (m, 2H).

[0291] Reference example 48-(b): The corresponding starting compounds were treated in the same manner as in Reference Example 1-(i) to give the compounds shown in Table 12 below.

[0292] [Table 12]

[0293] Reference example 1-(j) Preparation of methyl 4-amino-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0294] To a solution of 890 mg of methyl 4-((diphenylmethylene)amino)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in Reference Example 1-(i) in tetrahydrofuran (30 ml), 970 mg of 5% palladium carbon (50.57% water content, AER-type manufactured by N.E. Chemcat Corporation) was added at room temperature under an argon stream, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was filtered through Celite and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to give 523 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 276 [M+H] + .

[0295] Reference example 48-(c) Preparation of methyl 4-amino-3-fluoro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0296] To a solution of 100 mg of methyl 4-((diphenylmethylene)amino)-3-fluoro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in Reference Example 48-(b) in tetrahydrofuran (0.4 ml), 0.8 ml of 10% aqueous citric acid solution was added at room temperature under an argon stream, and the mixture was stirred at 70° C. for 18 hours. After the reaction was completed, saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 53 mg of the title compound as a yellow solid. Mass spectrum (ESI, m / z): 294 [M+H] + .

[0297] Reference example 49-(c) Preparation of methyl 4-amino-3-chloro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0298] To a suspension of 304 mg of methyl 3-chloro-4-nitro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in Reference Example 49-(b) in ethanol (3 ml) / water (1.5 ml), 779 mg of sodium dithionite was added at room temperature under an argon stream, and the mixture was stirred at 90° C. for 1 hour. After the reaction was completed, the reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 131 mg of the title compound as a slightly yellow solid. Mass spectrum (ESI, m / z): 310 [M+H] + .

[0299] Reference example 1-(k) Preparation of methyl 4-(3-methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate [ka]

[0300] To a solution of 200 mg of methyl 4-amino-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in the same manner as in Reference Example 1-(j) in N-methylpyrrolidone (2 ml), 133 mg of methyl isothiocyanate and 200 μl of acetic acid were added at room temperature under an argon stream, and the mixture was stirred at 100° C. for 9 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 184 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 349 [M+H] + .

[0301] Reference example 48-(d) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(k) to give the compounds shown in Table 13 below.

[0302] [Table 13]

[0303] Reference example 52-(a) Preparation of methyl 6-(3-methylthioureido)-1H-indazole-4-carboxylate [ka]

[0304] To a solution of 500 mg of methyl 6-amino-1H-indazole-4-carboxylate in N-methylpyrrolidone (2.5 ml) was added 233 mg of methyl isothiocyanate at room temperature under an argon atmosphere, the mixture was stirred at room temperature for 2 hours, allowed to stand at room temperature for 84 hours, and stirred at 70°C for 7 hours. After the reaction was completed, water was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 408 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 265 [M+H] + .

[0305] Reference example 1-(l) Preparation of 4-(3-methylthioureido)-1H-indazole-6-carboxylic acid [ka]

[0306] To a suspension of 4.81 g of methyl 4-(3-methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate (synthesized in the same manner as in Reference Example 1-(k)) in methanol (69.2 ml), 17.3 ml of a 4 M hydrogen chloride / 1,4-dioxane solution was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, azeotroped with 30 ml of tert-butyl methyl ether, and dried at 50°C under reduced pressure. To a suspension of the resulting residue in methanol (41.4 ml) was added 1M aqueous sodium hydroxide solution (41.4 ml) at room temperature under an argon stream, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, 2M hydrochloric acid was added to the reaction solution to adjust the pH to 4.0 and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 2.80 g of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 251 [M+H] + .

[0307] Reference example 49-(e) Preparation of methyl 3-chloro-4-(3-methylthioureido)-1H-indazole-6-carboxylate [ka]

[0308] To a suspension of 840 mg of methyl 3-chloro-4-(3-methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate (synthesized in the same manner as in Reference Example 49-(d)) in dichloromethane (5 ml), 2.52 ml of trifluoroacetic acid was added dropwise at room temperature under an argon stream, and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by medium pressure preparative chromatography (silica gel, elution solvent: hexane:ethyl acetate) to obtain 375 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 299 [M+H] + .

[0309] Reference example 48-(e) Preparation of 3-fluoro-4-(3-methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylic acid [ka]

[0310] To a suspension of 245 mg of methyl 3-fluoro-4-(3-methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate (synthesized in the same manner as in Reference Example 48-(d)) in methanol (2 ml), 2 ml of 1M aqueous sodium hydroxide solution and 3 ml of tetrahydrofuran were added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1M hydrochloric acid was added to the reaction solution to adjust the pH to 4.0, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, tetrahydrofuran was distilled off under reduced pressure, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 202 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 353 [M+H] + .

[0311] Reference example 49-(f) Preparation of 3-chloro-4-(3-methylthioureido)-1H-indazole-6-carboxylic acid [ka]

[0312] To a suspension of 337 mg of methyl 3-chloro-4-(3-methylthioureido)-1H-indazole-6-carboxylate synthesized in Reference Example 49-(e) in methanol (4.2 ml), 1.69 ml of 2M aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, 2M hydrochloric acid was added to the reaction solution to adjust the pH to 4, and the mixture was stirred at room temperature for 0.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 110 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 285 [M+H] + .

[0313] Reference example 52-(b): The corresponding starting compounds were treated in the same manner as in Reference Example 49-(f) to give the compounds shown in Table 14 below.

[0314] [Table 14]

[0315] Reference example 1-(m) Preparation of 4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic acid [ka]

[0316] To a solution of 10.00 g of 4-(3-methylthioureido)-1H-indazole-6-carboxylic acid synthesized in the same manner as in Reference Example 1-(l) in N-methylpyrrolidone (100 ml), 3.00 ml of iodomethane was added at room temperature under argon gas flow, and the mixture was stirred at room temperature for 16 hours. The reaction solution was decompressed to remove excess iodomethane, and 10.27 g of 2-fluoropropane-1,3-diamine hydrochloride synthesized in the same manner as in Reference Example 1-(g) and 17 ml of water were added at room temperature, and the mixture was stirred at 110°C for 8 hours, at room temperature for 13 hours, at 110°C for 11 hours, at room temperature for 13 hours, and at 110°C for 9 hours. After the reaction was completed, 283 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 7.40 g of the title compound as a white solid. Mass spectrum (ESI, m / z): 278 [M+H] + .

[0317] Reference example 48-(f) etc.: The corresponding starting compounds were treated in the same manner as in Reference Example 1-(m) to give the compounds shown in Table 15 below.

[0318] [Table 15]

[0319] Reference example 50-(a) Preparation of 4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic acid [ka]

[0320] To a solution of 1.00 g of 4-(3-methylthioureido)-1H-indazole-6-carboxylic acid synthesized in the same manner as in Reference Example 1-(l) in N-methylpyrrolidone (10 ml), 0.30 ml of iodomethane was added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction solution was decompressed to remove excess iodomethane, and 1.08 g of 1,3-diaminopropan-2-ol was added at room temperature to the resulting solution, and the mixture was stirred at 110° C. for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and stirred at room temperature for 17 hours. 10 ml of water was added, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 915 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 276 [M+H] + .

[0321] Reference example 51-(a): The corresponding starting compounds were treated in the same manner as in Reference Example 50-(a) to give the compounds shown in Table 16 below.

[0322] [Table 16]

[0323] Reference example 48-(g) Preparation of 3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic acid [ka]

[0324] 1M hydrochloric acid 2.9ml was added to 3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylic acid 110mg synthesized in the same manner as in Reference Example 48-(f) at room temperature under argon atmosphere, stirred at 60°C for 11 hours, and stirred at room temperature for 13 hours. Then, 1M hydrochloric acid 1.45ml was added at room temperature, stirred at 70°C for 9 hours, and stirred at room temperature for 18 hours. After completion of the reaction, the solid was collected by filtration, washed with water, and then dried under reduced pressure at 60° C. to obtain 74 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 296 [M+H] + .

[0325] Example 1-(a) Preparation of methyl (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate [ka]

[0326] To a suspension of 80 mg of methyl (S)-3-(2-aminoacetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate hydrochloride synthesized in the same manner as in Reference Example 1-(e) and 65 mg of 4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic acid synthesized in the same manner as in Reference Example 1-(m) in N,N-dimethylformamide (1 ml), 38 mg of 1-hydroxybenzotriazole was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 10 minutes. Next, 0.043 ml of N,N'-diisopropylcarbodiimide was added at room temperature, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was purified by medium pressure preparative chromatography (ODS, elution solvent: 0.1% aqueous trifluoroacetic acid: 0.1% solution of trifluoroacetic acid in acetonitrile) to obtain 132 mg of the title compound as a slightly yellow solid. Mass spectrum (ESI, m / z): 598 [M+H] + .

[0327] Example 2-(a) etc.: The corresponding starting compounds were treated in the same manner as in Example 1-(a) to obtain the compounds shown in the following Tables 17-1 to 17-7.

[0328] [Table 17-1]

[0329] [Table 17-2]

[0330] [Table 17-3]

[0331] [Table 17-4]

[0332] [Table 17-5]

[0333] [Table 17-6]

[0334] [Table 17-7]

[0335] Example 1-(b) Preparation of (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0336] To a suspension of 130 mg of methyl (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 1-(a) in acetonitrile (1.5 ml) / water (1.5 ml), 22 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.2, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 58 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.06 (m, 2H), 7.70 - 7.67 (m, 1H), 7.66 - 7.63 (m, 1H), 7.54 - 7.50 (m, 2H), 5.30 - 5.13 (m, 2H), 4.18 - 4.05 (m, 2H), 3.72 - 3.45 (m, 4H), 2.74 - 2.60 (m, 2H).

[0337] Example 2-(b) Preparation of (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0338] To a solution of 193 mg of methyl (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamide)propanoate trifluoroacetate synthesized in Example 2-(a) in acetonitrile (3 ml) / water (3 ml), 31 mg of lithium hydroxide was added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 3 hours. Next, 36 mg of lithium hydroxide was added at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.8, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 107 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 628, 630 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.05 (m, 2H), 7.86 - 7.81 (m, 1H), 7.71 - 7.64 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 5.31 - 5.12 (m, 2H), 4.18 - 4.05 (m, 2H), 3.73 - 3.43 (m, 4H), 2.73 - 2.60 (m, 2H).

[0339] Example 3-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0340] To a solution of 79 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 3-(a) in acetonitrile (1.5 ml) / water (1.5 ml), 12 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.4, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 35 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 676 [M+H] + . 1 H-NMR spectrum (400 MHz, CD3OD) δ: 8.09 - 8.05 (m, 2H), 8.03 - 8.00 (m, 1H), 7.84 - 7.81 (m, 1H), 7.72 - 7.69 (m, 1H), 7.52 - 7.49 (m, 1H), 5.29 - 5.13 (m, 2H), 4.18 - 4.04 (m, 2H), 3.71 - 3.44 (m, 4H), 2.73 - 2.57 (m, 2H).

[0341] Example 4-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methyl-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0342] To a solution of 97 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methyl-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 4-(a) in acetonitrile (1 ml) / water (1 ml), 17 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.8, and the solution was filtered. The filtrate was stirred at room temperature for 17 hours, and the precipitated solid was collected by filtration, washed with water, and dried at 60° C. under reduced pressure to obtain 46 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 564 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 (d, J = 0.9 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.33 - 7.30 (m, 1H), 5.30 - 5.14 (m, 2H), 4.19 - 4.04 (m, 2H), 3.73 - 3.45 (m, 4H), 2.75 - 2.63 (m, 2H), 2.39 (s, 3H).

[0343] Example 5-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methoxy-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0344] To a solution of 183 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methoxy-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 5-(a) in acetonitrile (1 ml) / water (1 ml), 24 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 44 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 580 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.00 (m, 2H), 7.51 - 7.45 (m, 1H), 7.28 - 7.17 (m, 2H), 7.02 - 6.96 (m, 1H), 5.29 - 5.10 (m, 2H), 4.18 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.83 (s, 3H), 3.70 - 3.40 (m, 4H), 2.77 - 2.57 (m, 2H).

[0345] Example 6-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0346] To a solution of 163 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 6-(a) in acetonitrile (1 ml) / water (1 ml), 28 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, 1 ml of water was added to the reaction solution. 1N hydrochloric acid was added to adjust the pH to 5.6, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 66 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 568 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.05 (m, 2H), 7.56 - 7.53 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.29 - 7.24 (m, 1H), 5.30 - 5.12 (m, 2H), 4.18 - 4.05 (m, 2H), 3.70 - 3.45 (m, 4H), 2.75 - 2.60 (m, 2H).

[0347] Example 7-(b) Preparation of (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0348] To a solution of 130 mg of methyl (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 7-(a) in acetonitrile (1 ml) / water (1 ml), 21 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, 1 ml of water was added to the reaction solution. 1N hydrochloric acid was added to adjust the pH to 5.6, and the mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60°C under reduced pressure to obtain 87 mg of the title compound as a gray solid. Mass spectrum (ESI, m / z): 618 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.05 (m, 2H), 8.01 - 7.98 (m, 2H), 7.81 - 7.78 (m, 1H), 7.52 - 7.49 (m, 1H), 5.35 (t, J = 5.3 Hz, 1H), 5.30 - 5.12 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.07 (d, J = 16.8 Hz, 1H), 3.70 - 3.45 (m, 4H), 2.78 - 2.63 (m, 2H).

[0349] Example 8-(b) Preparation of (3S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0350] To a solution of 150 mg of methyl (3S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 8-(a) in acetonitrile (1 ml) / water (1 ml), 34 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 45 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 616 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.48 (d, J = 2.4 Hz, 1H), 8.12 - 8.06 (m, 2H), 8.04 - 8.00 (m, 1H), 8.00 - 7.95 (m, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.66 - 7.62 (m, 1H), 7.54 (d, J = 1.0 Hz, 1H), 6.56 - 6.52 (m, 1H), 5.39 - 5.34 (m, 1H), 5.29 - 5.10 (m, 1H), 4.20 - 4.05 (m, 2H), 3.72 - 3.40 (m, 4H), 2.84 - 2.66 (m, 2H).

[0351] Example 9-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0352] To a suspension of 88 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 9-(a) in acetonitrile (1 ml) / water (1 ml), 16 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the mixture was stirred at room temperature for 7.5 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60°C under reduced pressure to obtain 46 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 568 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 (d, J = 1.0 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.74 - 7.69 (m, 1H), 7.56 - 7.51 (m, 2H), 7.27 - 7.22 (m, 1H), 5.49 (t, J = 5.2 Hz, 1H), 5.30 - 5.13 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.70 - 3.45 (m, 4H), 2.76 - 2.58 (m, 2H).

[0353] Example 10-(b) Preparation of (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0354] To a suspension of 79 mg of methyl (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 10-(a) in acetonitrile (1 ml) / water (1 ml), 14 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 58 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 (d, J = 0.9 Hz, 1H), 8.10 - 8.07 (m, 1H), 7.77 - 7.73 (m, 1H), 7.66 - 7.62 (m, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.42 - 7.36 (m, 1H), 5.61 (t, J = 5.1 Hz, 1H), 5.29 - 5.13 (m, 1H), 4.17 - 4.03 (m, 2H), 3.70 - 3.45 (m, 4H), 2.75 - 2.58 (m, 2H).

[0355] Example 11-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0356] To a solution of 85 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 11-(a) in acetonitrile (1 ml) / water (1 ml), 15 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the mixture was stirred at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 23 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 568 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.06 (m, 2H), 7.80 - 7.76 (m, 1H), 7.61 - 7.55 (m, 1H), 7.52 (d, J = 1.0 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.50 (t, J = 5.4 Hz, 1H), 5.30 - 5.14 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.71 - 3.45 (m, 4H), 2.78 - 2.61 (m, 2H).

[0357] Example 12-(b) Preparation of (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0358] To a solution of 127 mg of methyl (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 12-(a) in acetonitrile (1 ml) / water (1 ml), 22 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.3, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 58 mg of the title compound as a gray solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.12 - 8.06 (m, 2H), 7.80 (d, J = 1.6 Hz, 1H), 7.59 - 7.50 (m, 3H), 5.58 (t, J = 5.3 Hz, 1H), 5.30 - 5.14 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.07 (d, J = 16.8 Hz, 1H), 3.72 - 3.45 (m, 4H), 2.76 - 2.62 (m, 2H).

[0359] Example 13-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0360] To a solution of 114 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 1-(a) in acetonitrile (1 ml) / water (1 ml), 20 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.3, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60°C under reduced pressure to obtain 62 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 568 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.05 (m, 2H), 7.72 - 7.64 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.26 - 7.20 (m, 1H), 5.31 - 5.14 (m, 2H), 4.17 - 4.02 (m, 2H), 3.73 - 3.46 (m, 4H), 2.73 - 2.60 (m, 2H).

[0361] Example 14-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0362] To a solution of 115 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 14-(a) in acetonitrile (1 ml) / water (1 ml), 20 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 46 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 564 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.03 (m, 2H), 7.66 - 7.62 (m, 1H), 7.51 - 7.46 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 5.28 - 5.12 (m, 2H), 4.16 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.71 - 3.43 (m, 4H), 2.72 - 2.59 (m, 2H), 2.43 - 2.38 (m, 3H).

[0363] Example 15-(b) Preparation of (3S)-3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0364] To a solution of 90 mg of methyl (3S)-3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 15-(a) in acetonitrile (1 ml) / water (1 ml), 15 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1 ml of water was added to the reaction solution and filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and 1 ml of water and 1 ml of acetonitrile were added and stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 51 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 602 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.07 (m, 2H), 7.80 (dd, J = 2.2, 6.6 Hz, 1H), 7.66 (dd, J = 2.2, 6.0 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 5.30 - 5.16 (m, 2H), 4.17 - 4.02 (m, 2H), 3.73 - 3.46 (m, 4H), 2.74 - 2.60 (m, 2H).

[0365] Example 16-(b) Preparation of (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0366] To a solution of 110 mg of methyl (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 16-(a) in acetonitrile (1 ml) / water (1 ml), 19 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.2, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 62 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 590, 592 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.06 - 8.01 (m, 2H), 7.55 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 1.1 Hz, 1H), 7.30 (dd, J = 2.1, 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 5.29 - 5.11 (m, 2H), 4.16 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.80 (s, 3H), 3.67 - 3.42 (m, 4H), 2.70 - 2.57 (m, 2H).

[0367] Example 17-(b) Preparation of (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0368] To a suspension of 120 mg of methyl (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 17-(a) in acetonitrile (1 ml) / water (1 ml), 22 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.3, and the mixture was stirred at room temperature for 2.5 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 76 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 550 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 - 8.05 (m, 2H), 7.51 - 7.47 (m, 1H), 7.37 - 7.34 (m, 2H), 7.25 (t, J = 1.9 Hz, 1H), 5.30 - 5.13 (m, 2H), 4.17 - 4.05 (m, 2H), 3.71 - 3.44 (m, 4H), 2.70 - 2.57 (m, 2H).

[0369] Example 18-(b) Preparation of (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0370] To a solution of 125 mg of methyl (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 18-(a) in acetonitrile (1 ml) / water (1 ml), 21 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, 2 ml of water and 0.5 ml of acetonitrile were added to the reaction solution, and the mixture was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.8, and the mixture was stirred at room temperature for 22 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 85 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 594, 596 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 - 8.05 (m, 2H), 7.52 - 7.48 (m, 2H), 7.41 - 7.38 (m, 2H), 5.30 - 5.13 (m, 2H), 4.17 - 4.05 (m, 2H), 3.71 - 3.45 (m, 4H), 2.70 - 2.56 (m, 2H).

[0371] Example 19-(b) Preparation of (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0372] To a suspension of 48 mg of methyl (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 19-(a) in acetonitrile (0.5 ml) / water (0.5 ml), 13 mg of lithium hydroxide monohydrate was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1M hydrochloric acid was added to the reaction solution to adjust the pH to 5.9, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. to obtain 34 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 640 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.07 (m, 2H), 7.56 - 7.53 (m, 3H), 7.52 (d, J = 1.1 Hz, 1H), 5.31 - 5.10 (m, 2H), 4.18 - 4.03 (m, 2H), 3.71 - 3.45 (m, 4H), 2.71 - 2.54 (m, 2H).

[0373] Example 20-(b) Preparation of (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0374] To a suspension of 140 mg of methyl (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 20-(a) in acetonitrile (1 ml) / water (1 ml), 21 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 88 mg of the title compound as a light brown solid. Mass spectrum (ESI, m / z): 686, 688 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.05 (m, 2H), 7.74 - 7.70 (m, 2H), 7.57 - 7.54 (m, 1H), 7.52 (d, J = 1.1 Hz, 1H), 5.33 - 5.15 (m, 1H), 5.13 (t, J = 5.3 Hz, 1H), 4.17 - 4.04 (m, 2H), 3.72 - 3.45 (m, 4H), 2.69 - 2.55 (m, 2H).

[0375] Example 21-(b) Preparation of (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0376] To a suspension of 48 mg of methyl (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 21-(a) in acetonitrile (0.5 ml) / water (0.5 ml), 13 mg of lithium hydroxide monohydrate was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1M hydrochloric acid was added to the reaction solution to adjust the pH to 5.9, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. to obtain 38 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 642 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.13 - 8.05 (m, 2H), 7.71 - 7.65 (m, 1H), 7.61 - 7.56 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.44 - 7.39 (m, 1H), 5.31 - 5.11 (m, 2H), 4.18 - 4.03 (m, 2H), 3.73 - 3.45 (m, 4H), 2.71 - 2.54 (m, 2H).

[0377] Example 22-(b) Preparation of (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0378] To a solution of 203 mg of methyl (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 22-(a) in acetonitrile (1 ml) / water (1 ml), 49 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours, and the precipitated solid was collected by filtration. Acetonitrile / methanol = 1 / 9 (v / v) (0.74 ml) was added to the obtained solid, and the mixture was stirred at 80 ° C. Acetonitrile / methanol = 1 / 9 (v / v) (0.74 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60 ° C. to obtain 46 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 534 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.04 (m, 2H), 7.51 (d, J = 1.0 Hz, 1H), 7.44 (dd, J = 2.7, 6.5 Hz, 1H), 7.22 (ddd, J = 2.7, 4.3, 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 9.9 Hz, 1H), 5.45 - 5.40 (m, 1H), 5.28 - 5.10 (m, 1H), 4.19 - 4.05 (m, 2H), 3.71 - 3.41 (m, 4H), 2.75 - 2.57 (m, 2H).

[0379] Example 23-(b) Preparation of (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0380] To a solution of 145 mg of methyl (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 23-(a) in acetonitrile (1 ml) / water (1 ml), 48 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 50 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 578, 580 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.06 (m, 2H), 7.58 (dd, J = 2.6, 6.7 Hz, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.37 (ddd, J = 2.6, 4.5, 8.7 Hz, 1H), 7.00 (dd, J = 8.7, 10.1 Hz, 1H), 5.45 - 5.40 (m, 1H), 5.30 - 5.11 (m, 1H), 4.18 - 4.05 (m, 2H), 3.73 - 3.43 (m, 4H), 2.76 - 2.57 (m, 2H).

[0381] Example 24-(b) Preparation of (3S)-3-(3-(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0382] To a solution of 118 mg of methyl (3S)-3-(3-(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 24-(a) in acetonitrile (1 ml) / water (1 ml), 19 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 77 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 616 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.05 (m, 2H), 7.59 - 7.56 (m, 1H), 7.51 (d, J = 0.9 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.27 - 7.24 (m, 1H), 6.97 (t, J = 73.5 Hz, 1H), 5.32 - 5.11 (m, 2H), 4.15 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.71 - 3.42 (m, 4H), 2.75 - 2.60 (m, 2H).

[0383] Example 25-(b) Preparation of (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0384] To a solution of 135 mg of methyl (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 25-(a) in acetonitrile (1 ml) / water (1 ml), 23 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 55 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 582 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.06 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.14 - 7.10 (m, 1H), 7.06 - 7.04 (m, 1H), 6.90 (t, J = 73.5 Hz, 1H), 5.32 - 5.13 (m, 2H), 4.15 - 4.06 (m, 2H), 3.74 - 3.45 (m, 4H), 2.78 - 2.70 (m, 2H).

[0385] Example 26-(b) Preparation of (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0386] To a solution of 177 mg of methyl (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 26-(a) in acetonitrile (1 ml) / water (1 ml), 25 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 88 mg of the title compound as a slightly brown solid. Mass spectrum (ESI, m / z): 626, 628 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.05 (m, 2H), 7.52 (d, J = 1.1 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.20 - 7.14 (m, 2H), 6.90 (t, J = 73.5 Hz, 1H), 5.32 - 5.15 (m, 2H), 4.16 - 4.04 (m, 2H), 3.73 - 3.44 (m, 4H), 2.76 - 2.61 (m, 2H).

[0387] Example 27-(b) Preparation of (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0388] To a solution of 150 mg of methyl (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 27-(a) in acetonitrile (1 ml) / water (1 ml), 49 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 40 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 566 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.04 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.31 (dd, J = 2.1, 7.4 Hz, 1H), 7.25 (ddd, J = 2.1, 4.4, 8.6 Hz, 1H), 7.14 (dd, J = 8.6, 10.4 Hz, 1H), 6.86 (t, J = 73.8 Hz, 1H), 5.30 - 5.14 (m, 2H), 4.14 (d, J = 16.8 Hz, 1H), 4.04 (d, J = 16.8 Hz, 1H), 3.73 - 3.42 (m, 4H), 2.72 - 2.58 (m, 2H).

[0389] Example 28-(b) Preparation of (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0390] To a solution of 152 mg of methyl (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 28-(a) in acetonitrile (1 ml) / water (1 ml), 49 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 70 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 566 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.11 - 8.06 (m, 2H), 7.53 (d, J = 1.1 Hz, 1H), 7.22 (dd, J = 2.9, 6.1 Hz, 1H), 7.11 - 6.98 (m, 2H), 6.81 (t, J = 74.3 Hz, 1H), 5.47 - 5.42 (m, 1H), 5.30 - 5.12 (m, 1H), 4.17 - 4.03 (m, 2H), 3.71 - 3.43 (m, 4H), 2.76 - 2.61 (m, 2H).

[0391] Example 29-(b) Preparation of (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0392] To a solution of 162 mg of methyl (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 29-(a) in acetonitrile (1 ml) / water (1 ml), 48 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, 3 ml of water was added, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 65 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 614 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.38 (d, J = 2.4 Hz, 1H), 8.11 - 8.06 (m, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.13 - 7.10 (m, 1H), 6.95 (t, J = 73.9 Hz, 1H), 6.53 - 6.49 (m, 1H), 5.30 - 5.10 (m, 2H), 4.17 (d, J = 16.7 Hz, 1H), 4.08 (d, J = 16.7 Hz, 1H), 3.70 - 3.40 (m, 4H), 2.81 - 2.64 (m, 2H).

[0393] Example 30-(b) Preparation of (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0394] To a suspension of 51 mg of methyl (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 30-(a) in acetonitrile (0.5 ml) / water (0.5 ml), 15 mg of lithium hydroxide monohydrate was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1M hydrochloric acid was added to the reaction solution to adjust the pH to 5.9, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. to obtain 44 mg of the title compound as a brown solid. Mass spectrum (ESI, m / z): 614 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.03 (m, 2H), 7.54 - 7.48 (m, 1H), 7.06 - 7.00 (m, 2H), 6.90 (t, J = 73.9 Hz, 2H), 6.77 - 6.74 (m, 1H), 5.30 - 5.12 (m, 2H), 4.19 - 3.99 (m, 2H), 3.72 - 3.43 (m, 4H), 2.71 - 2.57 (m, 2H).

[0395] Example 31-(b) Preparation of (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0396] To a suspension of 70 mg of methyl (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 31-(a) in acetonitrile (0.5 ml) / water (0.5 ml), 21 mg of lithium hydroxide monohydrate was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1M hydrochloric acid was added to the reaction solution to adjust the pH to 5.9, and the mixture was stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. to obtain 52 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 600 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.13 - 8.05 (m, 2H), 7.52 (d, J = 1.3 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.29 - 7.25 (m, 1H), 7.21 - 7.18 (m, 1H), 5.34 -5.13 (m, 2H), 4.17 - 4.05 (m, 2H), 3.78 - 3.45 (m, 4H), 2.77 - 2.65 (m, 2H).

[0397] Example 32-(b) Preparation of (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0398] To a solution of 321 mg of methyl (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 32-(a) in acetonitrile (2.5 ml) / water (2.5 ml), 50 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, 2.5 ml of water was added to the reaction solution, 1N hydrochloric acid was added to adjust the pH to 5.0, and the mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 244 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 644, 646 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.12 - 8.06 (m, 2H), 7.61 - 7.58 (m, 1H), 7.51 (d, J = 1.1 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.33 - 7.30 (m, 1H), 5.33 - 5.16 (m, 2H), 4.16 - 4.05 (m, 2H), 3.73 - 3.49 (m, 4H), 2.76 (d, J = 6.4 Hz, 2H).

[0399] Example 33-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)propanoic acid [ka]

[0400] To a solution of 270 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)propanoate trifluoroacetate synthesized in Example 33-(a) in acetonitrile (2 ml) / water (2 ml), 45 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.2, 4 ml of water was added, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 169 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400 MHz, CD3OD) δ: 8.08 - 8.05 (m, 2H), 7.50 - 7.48 (m, 1H), 7.38 - 7.34 (m, 1H), 7.20 - 7.12 (m, 2H), 5.49 - 5.44 (m, 1H), 5.30 - 5.14 (m, 1H), 4.18 - 4.04 (m, 2H), 3.73 - 3.41 (m, 4H), 2.78 - 2.61 (m, 2H).

[0401] Example 34-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)propanoic acid [ka]

[0402] To a solution of 93 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)propanoate trifluoroacetate synthesized in Example 34-(a) in acetonitrile (1 ml) / water (1 ml), 16 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, 1 ml of water was added to the reaction solution, and the solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.6, and the solution was stirred at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60°C under reduced pressure to obtain 63 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 (d, J = 1.0 Hz, 1H), 8.07 - 8.05 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.22 (dd, J = 8.6, 10.1 Hz, 1H), 5.31 - 5.14 (m, 2H), 4.15 (d, J = 16.8 Hz, 1H), 4.05 (d, J = 16.8 Hz, 1H), 3.72 - 3.46 (m, 4H), 2.71 - 2.58 (m, 2H).

[0403] Example 35-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0404] To a solution of 142 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 35-(a) in acetonitrile (1.5 ml) / water (1.5 ml), 26 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, acetonitrile was distilled off under reduced pressure, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 63 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 550 [M+H] + . 1 H-NMR spectrum (400 MHz, CD3OD) δ: 8.10 - 8.04 (m, 2H), 7.73 - 7.67 (m, 1H), 7.67 - 7.61 (m, 1H), 7.53 - 7.45 (m, 3H), 5.31 (t, J = 5.5 Hz, 1H), 5.29 - 5.13 (m, 1H), 4.20 - 4.04 (m, 2H), 3.72 - 3.44 (m, 4H), 2.77 - 2.64 (m, 2H).

[0405] Example 36-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethoxy)phenyl)propanoic acid [ka]

[0406] To a solution of 104 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethoxy)phenyl)propanoate trifluoroacetate synthesized in Example 36-(a) in acetonitrile (1 ml) / water (1 ml), 18 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.2. The reaction solution was concentrated under reduced pressure, acetonitrile was distilled off under reduced pressure, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 50 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 566 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 (d, J = 0.9 Hz, 1H), 8.06 - 8.04 (m, 1H), 7.48 (d, J = 1.1 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.32 - 7.28 (m, 1H), 7.15 - 7.09 (m, 1H), 5.33 - 5.14 (m, 2H), 4.18 - 4.04 (m, 2H), 3.71 - 3.45 (m, 4H), 2.78 - 2.66 (m, 2H).

[0407] Example 37-(b) Preparation of (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0408] To a solution of 110 mg of methyl (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 37-(a) in acetonitrile (1 ml) / water (1 ml), 20 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5. The reaction solution was concentrated under reduced pressure, acetonitrile was distilled off under reduced pressure, and the mixture was stirred at room temperature for 2.5 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 50 mg of the title compound as a beige solid. Mass spectrum (ESI, m / z): 548 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.10 - 8.03 (m, 2H), 7.50 (d, J = 1.1 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.26 - 7.21 (m, 1H), 7.18 - 7.15 (m, 1H), 6.98 - 6.93 (m, 1H), 6.83 (t, J = 74.3 Hz, 1H), 5.29 - 5.12 (m, 2H), 4.19 - 4.02 (m, 2H), 3.70 - 3.43 (m, 4H), 2.72 - 2.60 (m, 2H).

[0409] Example 38-(b) Preparation of (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0410] To a solution of 150 mg of methyl (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 38-(a) in acetonitrile (1 ml) / water (1 ml), 28 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.3, and the mixture was stirred at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 60 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 532 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.06 (d, J = 1.0 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.57 - 7.51 (m, 2H), 7.47 (d, J = 1.3 Hz, 1H), 7.42 - 7.35 (m, 2H), 6.71 (t, J = 56.2 Hz, 1H), 5.30 - 5.11 (m, 2H), 4.17 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.68 - 3.41 (m, 4H), 2.75 - 2.63 (m, 2H).

[0411] Example 39-(b) Preparation of (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0412] To a solution of 149 mg of methyl (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 39-(a) in acetonitrile (1 ml) / water (1 ml), 25 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 19 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 66 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 522 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.06 (d, J = 1.0 Hz, 1H), 8.03 (dd, J = 1.0, 1.1 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.14 - 7.07 (m, 3H), 6.89 - 6.85 (m, 1H), 5.27 - 5.11 (m, 2H), 4.19 (d, J = 16.7 Hz, 1H), 4.03 (d, J = 16.7 Hz, 1H), 3.70 - 3.38 (m, 4H), 2.71 - 2.58 (m, 2H), 1.88 - 1.79 (m, 1H), 0.93 - 0.83 (m, 2H), 0.70 - 0.59 (m, 2H).

[0413] Example 40-(b) Preparation of (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0414] To a solution of 155 mg of methyl (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 40-(a) in acetonitrile (1 ml) / water (1 ml), 25 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 51 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 538 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.06 (d, J = 0.9 Hz, 1H), 8.02 (dd, J = 0.9, 1.1 Hz, 1H), 7.45 (d, J = 1.1 Hz, 1H), 7.16 (dd, J = 7.7, 7.8 Hz, 1H), 7.06 (dd, J = 1.9, 2.1 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.87 (dd, J = 2.1, 7.8 Hz, 1H), 5.27 - 5.11 (m, 2H), 4.19 (d, J = 16.8 Hz, 1H), 4.04 (d, J = 16.8 Hz, 1H), 3.73 (tt, J = 3.0, 6.0 Hz, 1H), 3.68 - 3.40 (m, 4H), 2.72 - 2.60 (m, 2H), 0.79 - 0.55 (m, 4H).

[0415] Example 41-(b) Preparation of (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0416] To a solution of 99 mg of methyl (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 41-(a) in acetonitrile (1 ml) / water (1 ml), 19 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 1 ml of water was added to the reaction solution, and the solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the solution was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 33 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 516 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 (d, J = 1.0 Hz, 1H), 8.07 - 8.06 (m, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.42 - 7.39 (m, 1H), 7.32 - 7.28 (m, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.21 - 7.17 (m, 1H), 5.29 - 5.13 (m, 2H), 4.18 - 4.04 (m, 2H), 3.71 - 3.44 (m, 4H), 2.71 - 2.59 (m, 2H).

[0417] Example 42-(b) Preparation of (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0418] To a suspension of 122 mg of methyl (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 42-(a) in acetonitrile (1 ml) / water (1 ml), 22 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 1 ml of water was added to the reaction solution, and the solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.3, and the solution was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 66 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 560, 562 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 - 8.06 (m, 2H), 7.56 (t, J = 1.7 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.36 - 7.32 (m, 2H), 7.22 - 7.17 (m, 1H), 5.30 - 5.14 (m, 2H), 4.18 - 4.04 (m, 2H), 3.71 - 3.45 (m, 4H), 2.70 - 2.57 (m, 2H).

[0419] Example 43-(b) Preparation of (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0420] To a solution of 123 mg of methyl (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 43-(a) in acetonitrile (1 ml) / water (1 ml), 25 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5 and stirred at room temperature for 19 hours. The reaction solution was purified with BondElut (elution solvent: water:acetonitrile:methanol) to obtain 49 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 548 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.30 (dd, J = 0.5, 2.5 Hz, 1H), 8.08 (d, J = 0.8 Hz, 1H), 8.06 (dd, J = 0.8, 1.3 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.67 (m, 1H), 7.61 - 7.55 (m, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.44 - 7.31 (m, 2H), 6.49 (dd, J = 1.9, 2.5 Hz, 1H), 5.33 - 5.28 (m, 1H), 5.25 - 5.07 (m, 1H), 4.21 - 4.06 (m, 2H), 3.66 - 3.37 (m, 4H), 2.84 - 2.65 (m, 2H).

[0421] Example 44-(b) Preparation of (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0422] To a solution of 120 mg of methyl (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 44-(a) in acetonitrile (1 ml) / water (1 ml), 41 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.0, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile was distilled off under reduced pressure, 300 μl of acetonitrile was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60° C. to obtain 35 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 576 [M+H] + . 1 H-NMR spectrum (400MHz, CD3OD) δ:8.03 (d, J = 0.9 Hz, 1H), 8.00 - 7.98 (m, 1H), 7.47 - 7.39 (m, 4H), 7.29 - 7.22 (m, 1H), 6.00 (s, 1H), 5.33 - 5.28 (m, 1H), 5.26 - 5.08 (m, 1H), 4.17 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.66 - 3.38 (m, 4H), 2.82 - 2.60 (m, 2H), 2.23 (s, 3H), 2.19 (s, 3H).

[0423] Example 45-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-morpholinophenyl)propanoic acid [ka]

[0424] To a solution of 78 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-morpholinophenyl)propanoate trifluoroacetate synthesized in Example 45-(a) in acetonitrile (1 ml) / water (1 ml), 27 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.5 and stirred at room temperature for 19 hours. The reaction solution was purified with BondElut (elution solvent: water:acetonitrile:methanol) to obtain 44 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 567 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.08 (d, J = 0.9 Hz, 1H), 8.03 (dd, J = 0.9, 1.1 Hz, 1H), 7.48 (d, J = 1.1 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.99 - 6.96 (m, 1H), 6.89 - 6.85 (m, 1H), 6.80 - 6.76 (m, 1H), 5.28 - 5.11 (m, 2H), 4.20 (d, J = 16.7 Hz, 1H), 4.01 (d, J = 16.7 Hz, 1H), 3.80 - 3.74 (m, 4H), 3.69 - 3.39 (m, 4H), 3.14 - 3.06 (m, 4H), 2.79 - 2.57 (m, 2H).

[0425] Example 46-(b) Preparation of (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0426] To a solution of 126 mg of methyl (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 46-(a) in acetonitrile (1 ml) / water (1 ml), 23 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1 ml of water was added to the reaction solution, and the solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the solution was stirred at room temperature for 17 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 69 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 548 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 (d, J = 1.0 Hz, 1H), 8.06 - 8.04 (m, 1H), 7.50 (d, J = 1.3 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.06 - 7.02 (m, 2H), 6.73 (t, J = 74.3 Hz, 1H), 5.28 - 5.13 (m, 2H), 4.19 - 4.01 (m, 2H), 3.70 - 3.42 (m, 4H), 2.71 - 2.59 (m, 2H).

[0427] Example 47-(b) Preparation of (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid [ka]

[0428] To a solution of 125 mg of methyl (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 47-(a) in acetonitrile (1 ml) / water (1 ml), 23 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, 1 ml of water was added to the reaction solution, and the solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.4, and the solution was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 70 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 550 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.09 (d, J = 1.0 Hz, 1H), 8.07 - 8.05 (m, 1H), 7.56 (s, 4H), 7.52 (d, J = 1.1 Hz, 1H), 5.30 - 5.13 (m, 2H), 4.17 (d, J = 16.8 Hz, 1H), 4.07 (d, J = 16.8 Hz, 1H), 3.71 - 3.43 (m, 4H), 2.74 - 2.62 (m, 2H).

[0429] Example 48-(b) Preparation of (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0430] To a solution of 65 mg of methyl (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamide)propanoate trifluoroacetate synthesized in Example 48-(a) in acetonitrile (0.8 ml) / water (0.8 ml), 10 mg of lithium hydroxide was added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Next, 10 mg of lithium hydroxide was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.6, 1.6 ml of water was added, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 38 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 602 [M+H] + . 1 H-NMR spectrum (400 MHz, CD3OD) δ: 8.01 - 7.94 (m, 1H), 7.70 - 7.61 (m, 2H), 7.55 - 7.49 (m, 1H), 7.46 - 7.41 (m, 1H), 5.31 - 5.08 (m, 2H), 4.18 - 4.03 (m, 2H), 3.70 - 3.41 (m, 4H), 2.79 - 2.56 (m, 2H).

[0431] Example 49-(b) Preparation of (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0432] To a solution of 54 mg of methyl (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 49-(a) in acetonitrile (0.5 ml) / water (0.5 ml), 10 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1 ml of water was added to the reaction solution, and 1N hydrochloric acid was added to adjust the pH to 5.6, followed by stirring at room temperature for 22 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60° C. to obtain 36 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 618 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.14 (d, J = 1.3 Hz, 1H), 7.69 - 7.67 (m, 1H), 7.65 - 7.62 (m, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.54 - 7.51 (m, 1H), 5.27 - 5.10 (m, 2H), 4.17 - 4.04 (m, 2H), 3.68 - 3.44 (m, 4H), 2.73 - 2.59 (m, 2H).

[0433] Example 50-(b) Preparation of (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0434] To a solution of 115 mg of methyl (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 50-(a) in acetonitrile (1 ml) / water (1 ml), 20 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.6, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 72 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 582 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.16 (d, J = 1.0 Hz, 1H), 8.06 - 8.04 (m, 1H), 7.70 - 7.67 (m, 1H), 7.66 - 7.63 (m, 1H), 7.53 - 7.51 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H), 5.26 (t, J = 5.3 Hz, 1H), 4.24 (quin, J = 3.1 Hz, 1H), 4.18 - 4.05 (m, 2H), 3.49 - 3.38 (m, 2H), 3.36 - 3.29 (m, 2H), 2.74 - 2.60 (m, 2H).

[0435] Example 51-(b) Preparation of (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid [ka]

[0436] To a suspension of 117 mg of methyl (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 51-(a) in acetonitrile (1 ml) / water (1 ml), 21 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.6, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 47 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 566 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.12 (d, J = 1.0 Hz, 1H), 8.04 - 8.02 (m, 1H), 7.71 - 7.68 (m, 1H), 7.67 - 7.64 (m, 1H), 7.54 - 7.51 (m, 1H), 7.49 (d, J = 1.1 Hz, 1H), 5.26 (t, J = 5.2 Hz, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.06 (d, J = 16.8 Hz, 1H), 3.40 - 3.26 (m, 4H), 2.75 - 2.59 (m, 2H), 2.00 - 1.90 (m, 2H).

[0437] Example 52-(b) Preparation of (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid [ka]

[0438] To a suspension of 152 mg of methyl (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 52-(a) in acetonitrile (2 ml) / water (2 ml), 26 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.8, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 86 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.48 - 8.45 (m, 1H), 7.71 - 7.68 (m, 1H), 7.66 - 7.64 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.54 - 7.51 (m, 1H), 5.29 - 5.12 (m, 2H), 4.19 - 4.10 (m, 2H), 3.72 - 3.46 (m, 4H), 2.72 - 2.59 (m, 2H).

[0439] Example 53-(b) Preparation of (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid [ka]

[0440] To a solution of 192 mg of methyl (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoate trifluoroacetate synthesized in Example 53-(a) in acetonitrile (3 ml) / water (3 ml), 30 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.8, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried at 60° C. under reduced pressure to obtain 84 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 628, 630 [M+H] + . 1 H-NMR spectrum (400MHz,DMSO-d6+D2O)δ:8.35 - 8.31 (m, 1H), 7.86 - 7.83 (m, 1H), 7.79 - 7.67 (m, 2H), 7.54 - 7.49 (m, 1H), 7.44 - 7.40 (m, 1H), 5.32 - 5.06 (m, 2H), 4.07 - 3.89 (m, 2H), 3.60 - 3.29 (m, 4H), 2.62 - 2.40 (m, 2H).

[0441] Example 54-(b) Preparation of (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid [ka]

[0442] To a solution of 85 mg of methyl (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 54-(a) in acetonitrile (1 ml) / water (1 ml), 13 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5.4, and the solution was filtered. The filtrate was concentrated under reduced pressure, and acetonitrile was removed under reduced pressure, followed by stirring at room temperature for 5 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 38 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 676 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.48 - 8.47 (m, 1H), 8.03 - 8.01 (m, 1H), 7.84 - 7.82 (m, 1H), 7.72 - 7.69 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.60 - 7.58 (m, 1H), 5.27 - 5.12 (m, 2H), 4.20 - 4.08 (m, 2H), 3.72 - 3.46 (m, 4H), 2.71 - 2.57 (m, 2H).

[0443] Example 55-(b) Preparation of (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0444] To a suspension of 142 mg of methyl (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 55-(a) in acetonitrile (1.5 ml) / water (1.5 ml), 25 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.5, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 77 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 568 [M+H] + . 1 H-NMR spectrum (400MHz, CD3OD) δ:8.45 - 8.43 (m, 1H), 7.73 - 7.64 (m, 2H), 7.62 - 7.59 (m, 2H), 7.27 - 7.20 (m, 1H), 5.28 - 5.13 (m, 2H), 4.20 - 4.08 (m, 2H), 3.72 - 3.46 (m, 4H), 2.71 - 2.57 (m, 2H).

[0445] Example 56-(b) Preparation of (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid [ka]

[0446] To a suspension of 161 mg of methyl (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoate trifluoroacetate synthesized in Example 56-(a) in acetonitrile (1.5 ml) / water (1.5 ml), 28 mg of lithium hydroxide was added at room temperature under an argon stream, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered. 1N hydrochloric acid was added to the filtrate to adjust the pH to 5.8, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 96 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 550 [M+H] + . 1 H-NMR spectrum (400MHz,CD3OD)δ:8.45 - 8.43 (m, 1H), 7.72 - 7.68 (m, 1H), 7.67 - 7.63 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.60 - 7.58 (m, 1H), 7.50 - 7.46 (m, 2H), 5.32 - 5.27 (m, 1H), 5.27 - 5.11 (m, 1H), 4.21 - 4.09 (m, 2H), 3.71 - 3.46 (m, 4H), 2.73 - 2.60 (m, 2H).

[0447] (Test Example 1) αvβ1 cell adhesion inhibition test Test Example 1 was performed with some modifications to the method of Reed et al. (Sci Transl Med., 7(288), 288ra79, 2015). Human fibronectin (Sigma-Aldrich, F0895) was prepared at 1.25μg / mL with phosphate buffered saline (PBS), and 100μL of this was dispensed into a 96-well plate and left to stand overnight. After washing with Hanks' Balanced Salt Solution (HBSS), blocking was performed with Dulbecco's modified Eagle medium (DMEM) containing 1% bovine serum albumin (BSA) (Fujifilm Wako Pure Chemical Corporation, cell culture grade, 017-22231), and this was used as a coating plate for the adhesion test.

[0448] αv-transfected cells (CHO cells lacking the α5 gene and transfected with the αv gene) cultured in Ham's F-12 Medium (Fujifilm Wako Pure Chemical Industries, Ltd., 087-08335) containing 10% Fetal Bovine Serum (FBS), 1% penicillin / streptomycin / amphotericin B (Thermo Fisher Scientific, 15240), 1 mM GlutaMAX Supplement (Thermo Fisher Scientific, 35050), and 400 μg / mL Hygromycin B (Fujifilm Wako Pure Chemical Industries, Ltd., 080-07683) were collected and suspended in DMEM containing 1 mM MnCl2 (Sigma-Aldrich, M1787) to prepare a cell suspension. A test compound dissolved in DMSO was added to the cell suspension.

[0449] Coat the plate with 1x10 6 A cell suspension of 100 cells / mL was added to each well and allowed to stand for 1 hour in a 5% carbon dioxide incubator (37°C). After 1 hour, the supernatant was removed and the plate was washed with HBSS. The cells attached to the plate were stained with crystal violet, lysed, and the absorbance was measured. The inhibition rate of cell adhesion by the test compound was calculated using the following formula, with 100% inhibition in the absence of substrate coating and 0% inhibition in the case of adding DMSO instead of the test compound. Cell adhesion inhibition rate (%) = [1-{(absorbance when test compound was added)-(absorbance without substrate coating)} ÷ {(absorbance when DMSO was added)-(absorbance without substrate coating)}] x 100

[0450] IC from the cell adhesion inhibition rate by the test compound 50 The results of each test compound in this test are shown in Table 18 below. A: IC 50 <3nM, B:3nM≦IC 50 <10nM, C:10nM≦IC 50 <30nM, D:30nM≦IC 50 <100nM, or E:IC 50 ≧100 nM. [Table 18]

[0451] (Test Example 2) αvβ6 cell adhesion inhibition test Test Example 2 was performed with some modifications to the method of Henderson et al. (Nat Med., 19(12), 1617-24, 2013). In Test Example 2, the same reagents as in Test Example 1 were used unless otherwise specified. Recombinant Human LAP Protein (R&D, 246-LP-025) was diluted to 0.2 μg / mL with PBS, dispensed into a 96-well plate at 100 μL / well, and left to stand overnight. After washing with HBSS, blocking was performed with DMEM containing 1% BSA, and this was used as a coating plate for the adhesion test.

[0452] HT-29 cells were cultured in McCoy's 5A Medium (Thermo Fisher Scientific, 16600) containing 10% FBS and 1% penicillin / streptomycin / amphotericin B, and were then collected and suspended in DMEM containing 0.1% BSA and 200 μM MnCl2 to prepare a cell suspension. A test compound was added to the cell suspension.

[0453] Coat the plate with 5 x 10 5 A cell suspension of 100 cells / mL was added to each well and allowed to stand for 1 hour in a 5% carbon dioxide incubator (37℃). After 1 hour, the supernatant was removed and the plate was washed with HBSS containing 200μM MnCl2. The cells attached to the plate were stained with crystal violet, lysed, and the absorbance was measured. The cell adhesion inhibition rate by the test compound was calculated from the following formula, with 100% inhibition in the absence of substrate coating and 0% inhibition in the case of adding DMSO instead of the test compound. Cell adhesion inhibition rate (%) = [1-{(absorbance when test compound was added)-(absorbance without substrate coating)} ÷ {(absorbance when DMSO was added)-(absorbance without substrate coating)}] x 100

[0454] IC from the cell adhesion inhibition rate by the test compound 50 The results of each test compound in this test are shown in Table 19 below. A: IC 50 <3nM, B:3nM≦IC 50 <10nM, C:10nM≦IC 50 <30nM, D:30nM≦IC 50 <100nM, or E:IC 50 ≧100 nM. [Table 19]

[0455] (Test Example 3) TGF-β activation inhibition test In Test Example 3, the inhibition of TGF-β activation by a compound was detected using the inhibition of phosphorylation of SMAD3 as an indicator. In Test Example 3, the same reagents as in Test Example 1 were used unless otherwise specified. Human fibronectin was adjusted to 14 μg / mL with PBS and dispensed at 50 μL / well into a 96-well plate. After standing at room temperature for 1 hour or more, the fibronectin solution was removed and the plate was washed with PBS and used as a coating plate.

[0456] The test compound dissolved in DMSO was added to RPMI Medium 1640 (Thermo Fisher Scientific, 11875) containing 1% FBS and 1% penicillin / streptomycin / amphotericin B to prepare a medium containing the test compound at a concentration twice the final concentration, which was added to the coating plate at 100 μL / well. TFK-1 cells (Medical Cell Resource Center, Institute of Development, Aging, Tohoku University) cultured in RPMI Medium 1640 containing 10% FBS, 1% penicillin / streptomycin / amphotericin B were suspended in RPMI Medium 1640 containing 1% FBS, 1% penicillin / streptomycin / amphotericin B to 1 × 10 6 A cell suspension of 100 cells / mL was prepared. The prepared cell suspension was further added at 100 μL / well and cultured in a 5% carbon dioxide incubator (37°C) for 2 days.

[0457] After 2 days of culture, phosphorylated SMAD3 in the cells was measured using the Phospho-SMAD3 (Ser423 / 425) cellular kit (cisbio, 63ADK025), and the DeltaF value was calculated according to the kit's calculation formula. The phosphorylated SMAD3 inhibition rate by the test compound was calculated using the following formula, with 100% inhibition when 10 μM of LY364947 (FUJIFILM Wako Pure Chemical Industries, Ltd., 123-05981) was added instead of the test compound, and 0% inhibition when DMSO was added. Phosphorylated SMAD3 inhibition rate (%) = [1-{(DeltaF value when test compound was added)-(DeltaF value when LY364947 was added at 10 μM)} ÷ {(DeltaF value when DMSO was added)-(DeltaF value when LY364947 was added at 10 μM)}] x 100

[0458] IC from the phosphorylated SMAD3 inhibition rate by the test compound 50 The results of each test compound in this test are shown in Table 20 below. A: IC 50 <10nM, B:10nM≦IC 50 <50nM, C: 50nM ≤ IC 50<100nM, or D:IC 50 ≧100 nM. [Table 20]

[0459] (Test Example 4) Activated human hepatic stellate cell dedifferentiation test Human hepatic stellate cells (Scien Cell Research Laboratories, 5300) were suspended in DMEM containing 10% FBS and 1% penicillin / streptomycin / amphotericin B, and 0.5 × 10 5 A cell suspension of 100 cells / mL was prepared as the cells at the initiation of differentiation. The cells at the initiation of differentiation were dispensed into a 12-well plate at 1 mL / well, and cultured in a 5% carbon dioxide incubator (37°C) for 3 days to allow differentiation. The culture medium was removed from each well, and 1 mL / well of DMEM containing 10% FBS, 1% penicillin / streptomycin / amphotericin B (DMSO final concentration 0.1%), to which a test compound dissolved in DMSO had been added, was added. This was further cultured for 2 days in a 5% carbon dioxide incubator (37°C). In Test Example 4, the same reagents as in Test Example 1 were used unless otherwise specified.

[0460] RNA in the cultured cells was extracted using NucleoSpin® RNA (Takara, U0955C), and the extracted RNA was subjected to Prime Script PCR. TM cDNA was synthesized using RT Reagent Kit with gDNA Eraser (Takara, RR047A). The synthesized cDNA, various primers, and TB Green® Premix Ex Taq TMReal-time PCR was performed using a PCR Thermal Cycler Dice Real Time (Takara, System Code TP910, Model Code TP900) and actin alpha2, smooth muscle (ACTA2) primer (Takara, HA136273) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) primer (Takara, HA067812).

[0461] The PCR amplification curve was analyzed by the comparative Ct method. The expression level of ACTA2mRNA was corrected using the expression level of GAPDHmRNA. The ACTA2mRNA expression level when DMSO was added instead of the test compound was set to 100%, and the ACTA2mRNA expression level of cells at the start of differentiation was set to 0%, and the reduction rate of ACTA2mRNA expression by the test compound was calculated from the following formula. ACTA2 mRNA expression reduction rate (%) = [1-{(ACTA2 mRNA expression level when test compound was added)-(ACTA2 mRNA expression level in cells at the start of differentiation)} ÷ {(ACTA2 mRNA expression level when DMSO was added)-(ACTA2 mRNA expression level in cells at the start of differentiation)}] x 100

[0462] IC from the rate of decrease in ACTA2 mRNA expression by the test compound 50 The results of each test compound in this test are shown in Table 21 below. A: IC 50 <10nM, B:10nM≦IC 50 <50nM, C: 50nM ≤ IC 50 <100nM, or D:IC 50 ≧100 nM. [Table 21]

[0463] (Test Example 5) Liver fibrosis inhibition test in a liver fibrosis (nonalcoholic steatohepatitis; NASH) model Test Example 5 was carried out with some modifications to the method of Matsumoto et al. (Int J Exp Pathol., 94(2), 93-103(2013)). A liver fibrosis model was created by feeding CDAHFD (choline-deficient diet, high-fat diet, 0.1% methionine added, 60 kcal% fat, ResearchDiets, A06071302) to C57BL / 6J mice (male, Japan SLC Co., Ltd.) for 8 weeks. The start of CDAHFD feeding was designated as week 0, and the test compound or vehicle was administered once a day during the period from week 0 to week 8. The group administered the test compound was designated the test compound administration group, and the group administered the vehicle was designated the vehicle group. Mice fed CE-2 (CLEA Japan, Inc.) instead of CDAHFD were designated as the non-fibrotic group. After 8 weeks, the mice were sacrificed by exsanguination from the abdomen under isoflurane inhalation anesthesia, and the liver was removed. Hydroxyproline (HYP) was quantified using a portion of the liver, and the amount of hepatic HYP per unit weight was calculated. The increase in the amount of hepatic HYP per unit weight of the vehicle group relative to the amount of hepatic HYP in the non-fibrotic group was set as 100%, and the HYP increase inhibition rate of the test compound administration group was calculated. When the Example compounds were tested, they suppressed the increase in HYP.

[0464] (Test Example 6) Transcellular transport test using Caco2 cells Caco2 cells (purchased from ATCC) were cultured in DMEM medium (ThermoFisher Scientific, 11965) containing 10% FBS (ThermoFisher Scientific, 10082) and 1% penicillin / streptomycin / amphotericin B (ThermoFisher Scientific, 15240). Transcellular transport assays were performed according to the MultiScreen Caco2 Drug Transport Assembly in a 96-well system (Application Note AN1727EN, MultiScreen Caco-2 Assay System, Merck) with some modifications. Caco2 cells were cultured at 4 × 10 4At a cell density of cells / well, the cells were seeded onto the polycarbonate inserts of the micropores of a 96-well plate (Merck, Millcell-96 culture insert plate 0.4μm pore size, well membrane area = 0.11cm 2 , PSHT004S5), and the monolayers cultured for 20 - 22 days were used for the transcellular transport assay. The medium of the seeded cells was changed every 3 - 4 days.

[0465] For the transport from apical to basolateral (AtoB) across the Caco2 cell monolayer membrane, HBSS medium (ThermoFisher Scientific, 14025) containing 20 mM HEPES (ThermoFisher Scientific, 15630) (pH = 7.4) was used. A HEPES-containing HBSS medium containing 10 μM of the compound (added such that a 1000-fold dilution of a 10 mM DMSO solution of the compound was achieved, with a final DMSO concentration of 0.1%) was added at 75 μL / well to the apical side, and a HEPES-containing HBSS medium without the compound was added at 250 μL / well to the basolateral side, and the cells were cultured at 37°C for 90 minutes. After the culture, 100 μL was collected from the basolateral side, and the concentration of the permeated compound was measured by LC-MS / MS under the measurement conditions described below. From the obtained concentration, Papp (Apparent Permeability; cm / sec) was calculated. Papp was calculated from the slope (dA / dt; nmol / sec) of the straight line drawn between two points, 0 minutes and the amount of compound 0, on a graph with the assay time (90 minutes) on the x-axis and the amount of compound in the solution on the permeated side on the y-axis, according to the following formula. The assay concentration was measured by UV-HPLC under the measurement conditions described below for the concentration of the compound in the HEPES-containing HBSS medium containing the added compound. ·Papp (cm / sec) = C0 × S × (dA / dt) C0; assay concentration, S; plate membrane area = 0.11cm 2

[0466] <Measurement Conditions for LC-MS / MS Analysis> LC: LC20 or LC30 HPLC system manufactured by Shimadzu Corporation Column: Phenomenex Kinetex C18 (50 mm × 2.1 mm, 2.6 μm) Column temperature: 40 °C Flow rate: 0.3 mL / min Mobile phase A: 0.1% aqueous formic acid solution Mobile phase B: 0.1% formic acid, 50% acetonitrile / methanol mixture Gradient: 0 - 2 min; A / B = 90 / 10 ~ 10 / 90, 2 - 3 min; A / B = 10 / 90, 3 - 3.01 min; A / B = 10 / 90 ~ 90 / 10 MS: SCIEX Q-Trap 3200 Ionization: ESI Mode: Positive

[0467] <Measurement conditions for UV-HPLC analysis> LC: Shimadzu Corporation's LC20 or LC30 HPLC system Column: Phenomenex Kinetex C18 (100 mm × 2.1 mm, 2.6 μm) Column temperature: 40 °C Flow rate: 0.25 mL / min Mobile phase A: 0.1% aqueous formic acid solution Mobile phase B: 0.1% formic acid, 50% acetonitrile / methanol mixture Gradient: 0 - 3 min; A / B = 90 / 10, 3 - 11 min; A / B = 90 / 10 ~ 5 / 95, 11 - 15 min; A / B = 5 / 95, 15 - 15.1 min; A / B = 5 / 95 ~ 90 / 10 UV detector: Photodiode array detector

[0468] In this test, the results of each test compound are shown in Table 22 below. A: Papp > 1×10 -6 (cm / sec), B: 1×10 -6 (cm / sec) ≥ Papp > 5×10 -7 (cm / sec), C: 5×10 -7 (cm / sec) ≥ Papp > 1×10 -7 (cm / sec), or D: Papp ≤ 1×10 -7 (cm / sec). [Table 22]

[0469] (Test Example 7) Dansylated glutathione (dGSH) trapping assay To detect reactive metabolites, metabolites generated from the test compound by metabolism in liver microsomes that react with dansylated glutathione (dGSH) were detected and quantified. The concentration of metabolite-dGSH conjugates was measured using a fluorescence detection UPLC system (Shimadzu Corporation). When the example compounds were tested, they did not produce dGSH adducts or produced them with little difficulty. This proves that the compounds represented by the general formula (I) or (II) of the present invention or their pharma- ceutically acceptable salts are excellent in safety and do not produce or produce reactive metabolites with little difficulty.

[0470] (Test Example 8) Liver fibrosis inhibition test in carbon tetrachloride-induced liver fibrosis model Under isoflurane inhalation anesthesia, carbon tetrachloride diluted 2-fold with olive oil was administered subcutaneously at 2mL / kg twice a week to C57BL / 6J mice (Charles River Japan, Inc.) to create a carbon tetrachloride-induced liver fibrosis model. After orally administering the test compound once a day for 56 days from the start of model creation, the liver was harvested and HYP in the left lateral lobe was quantified. When the Example compounds were tested, they suppressed the increase in HYP.

[0471] (Test Example 9) Pulmonary fibrosis inhibition test in a bleomycin-induced idiopathic pulmonary fibrosis model Under triple anesthesia (medetomidine hydrochloride / mitazolam / butorphanol tartrate), bleomycin (Nippon Kayaku Co., Ltd.) diluted with saline was administered once at 3.0 mg / kg (50 μL / mouse) via the trachea using a Microsprayer (Penn-Century Co., Ltd.) to create a bleomycin-induced idiopathic pulmonary fibrosis model. After administering the test compound for 14 days starting 7 days after bleomycin administration, the lungs were harvested and HYP was quantified using the left lung lobe. When the Example compounds were tested, they suppressed the increase in HYP.

[0472] (Test Example 10) Renal fibrosis inhibition test in a unilateral ureteral ligation renal fibrosis model Test Example 10 was performed with reference to the method of Swaney et al. (The Journal of Pharmacology and Experimental Therapeutics 336(3): 693-700(2011)). Under isoflurane inhalation anesthesia, the left ureter of a C57BL / 6J mouse (male, Japan SLC Co., Ltd.) was ligated with a suture to prepare a unilateral ureteral ligation renal fibrosis model. After administering the test compound for 10 days after the model preparation, the left kidney was harvested and HYP was quantified. When the Example compounds were tested, they suppressed the increase in HYP.

Claims

1. The following general formula (I) or (II): 【Chemistry 1】 [During the ceremony, A is C ６ -C １０ is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group is replaced with a halogen atom, a hydroxyl group, １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ Cycloalkenyl group, C ３ -C ６ Cycloalkoxy group, heterocyclyl group, C １ -C ６ A heteroaryl group which may be substituted with an alkyl group, a cyano group, a carboxyl group, a carbamoyl group, １ -C ６ Alkoxycarbonyl group, C １ -C ６ Alkylsulfanyl group, and C １ -C ６ and optionally substituted with a substituent selected from the group consisting of alkylsulfonyl groups. R is a hydrogen atom or C １ -C ６ is an alkyl group, R １ is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom or a hydroxy group. or a pharma- ceutically acceptable salt thereof.

2. The following general formula (I) 【Chemistry 2】 [During the ceremony, A is C ６ -C １０ is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group is replaced with a halogen atom, a hydroxyl group, １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ Cycloalkenyl group, C ３ -C ６ Cycloalkoxy group, heterocyclyl group, C １ -C ６ A heteroaryl group which may be substituted with an alkyl group, a cyano group, a carboxyl group, a carbamoyl group, １ -C ６ Alkoxycarbonyl group, C １ -C ６ Alkylsulfanyl group, and C １ -C ６ and optionally substituted with a substituent selected from the group consisting of alkylsulfonyl groups. R is a hydrogen atom or C １ -C ６ is an alkyl group, R １ is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom or a hydroxy group. or a pharma- ceutically acceptable salt thereof.

3. The following general formula (II) 【Chemistry 3】 [During the ceremony, A is C ６ -C １０ is an aryl or heteroaryl group (wherein at least one hydrogen atom of the aryl group and the heteroaryl group is replaced with a halogen atom, a hydroxyl group, １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ Cycloalkenyl group, C ３ -C ６ Cycloalkoxy group, heterocyclyl group, C １ -C ６ A heteroaryl group which may be substituted with an alkyl group, a cyano group, a carboxyl group, a carbamoyl group, １ -C ６ Alkoxycarbonyl group, C １ -C ６ Alkylsulfanyl group, and C １ -C ６ and optionally substituted with a substituent selected from the group consisting of alkylsulfonyl groups. R is a hydrogen atom or C １ -C ６ is an alkyl group, R １ is a hydrogen atom or a halogen atom, Y is a hydrogen atom, a fluorine atom or a hydroxy group. or a pharma- ceutically acceptable salt thereof.

4. A is a phenyl group, At least one hydrogen atom of the phenyl group is replaced by a halogen atom, a hydroxyl group, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ Cycloalkenyl group, C ３ -C ６ Cycloalkoxy group, heterocyclyl group, C １ -C ６ A heteroaryl group which may be substituted with an alkyl group, a cyano group, a carboxyl group, a carbamoyl group, １ -C ６ Alkoxycarbonyl group, C １ -C ６ Alkylsulfanyl group, and C １ -C ６ optionally substituted with a substituent selected from the group consisting of alkylsulfonyl groups; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. A is a phenyl group, At least one hydrogen atom of the phenyl group is a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ Cycloalkoxy groups, heterocyclyl groups, and C １ -C ６ Heteroaryl groups optionally substituted with alkyl groups, The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein Y is a fluorine atom.

7. A is represented by the following formula (i): 【Chemistry 4】 [During the ceremony, R ２ is a hydrogen atom or a halogen atom, R ３ is a hydrogen atom, a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ A cycloalkoxy group, a heterocyclyl group, or C １ -C ６ a heteroaryl group optionally substituted with an alkyl group, R ４ is a hydrogen atom, a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, or C １ -C ６ is a haloalkoxy group, R ５ is a hydrogen atom, a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ haloalkoxy group, or C １ -C ６ a heteroaryl group optionally substituted with an alkyl group, R ６ is a hydrogen atom or a halogen atom. is a group represented by The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

8. R ２ is a hydrogen atom, R ３ is a hydrogen atom, a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ haloalkoxy group, or C １ -C ６ a heteroaryl group optionally substituted with an alkyl group, R ４ is a hydrogen atom or a halogen atom, R ５ is a hydrogen atom, a halogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, or C １ -C ６ is a haloalkoxy group, R ６ is a hydrogen atom or a halogen atom; 8. The compound according to claim 7 or a pharma- ceutically acceptable salt thereof.

9. (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methyl-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-methoxy-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-methyl-3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2-fluoro-5-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-(trifluoromethoxy)phenyl)propanoic acid, (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-morpholinophenyl)propanoic acid, (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamide)acetamido)propanoic acid, (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3-chloro-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic acid, (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid, (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-iodo-5-(trifluoromethyl)phenyl)propanoic acid, (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4-fluoro-3-(trifluoromethyl)phenyl)propanoic acid, and (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3-(trifluoromethyl)phenyl)propanoic acid Selected from the group consisting of:

2. The compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10 for preventing, alleviating and / or treating a disease associated with integrin αv or a disease which is ameliorated by inhibiting integrin αv.

12. A pharmaceutical composition according to claim 9 or 10 for the treatment of fibrosis.

13. 10. The compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof for use in the prevention, alleviation and / or treatment of a disease associated with integrin αv or a disease that is ameliorated by inhibiting integrin αv.

14. 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, for use in the treatment of fibrosis.

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