1, 4, 5, 6-tetrahydropyrimidine-2-amine derivative

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

221102_G2572WO English Translation (Final) clean copy Description Title of Invention: 1,4,5, 6-TETRAHYDROPYRIMIDIN-2-AMINE DERIVATIVE Technical Field

[0001] The present invention relates to a 1,4,5,6- tetrahydropyrimidin-2-amine derivative and a pharmaceutical composition containing the same and particularly relates to a 1,4,5,6-tetrahydropyrimidin-2- amine derivative for the prevention, alleviation and / or remedy of a disease related to integrin av and a pharmaceutical composition containing the same. Background Art

[0002] In recent years, integrins have received attention in terms of possessing cell adhesion or intracellular signal transduction functions in response to extracellular matrix information. The integrins are proteins that are expressed on cell surface, and are composed of a heterodimer of two subunits a and B chains. 24 integrins form some subfamilies by combinations of 18 a chains and 8 PB chains. RGD integrin, one of the major subfamilies, recognizes a ligand containing a RGD (arginine-glycine-aspartic acid) motif in a protein sequence. The RGD integrin includes 8 subtypes avfl, 221102_G2572WO English Translation (Final) clean copy avB3, avB5, avB6, avs, aIIbB3, a5Bl, and a8Bl (Non Patent Literature 1).

[0003] Integrin av is known to participate in various diseases, and its inhibition is expected to have a therapeutic effect on, for example, cardiovascular disease, diabetic disease, neurodegenerative disease, cancer disease, tumor metastasis, eye disease, autoimmune disease, bone disease, and various fibroses (Non Patent Literatures 2 to 6).

[0004] Transforming growth factor B (TGF-B) is known to control cell proliferation, differentiation, or the like and to participate in diseases such as fibrosis, autoimmune disease, and cancer, and is secreted as an inactive complex with latency-associated protein (LAP) (Non Patent Literature 7). In research using cell, it has been reported that RGD integrin such as integrin avBl, avB3, avp5, avB6 and avp8 activates latent TGF-B (Non Patent Literatures 8 and 9).

[0005] Fibrosis, a pathological feature of many diseases, is caused by the dysfunction of body's original ability to repair injured tissues. Fibrosis brings about excessive scarring that surpasses the wound healing response of an important organ, and might cause unrecoverable injury and final organ failure (Non Patent Literature 10). In fibrosis, extracellular matrix is mainly produced by activated fibroblasts (myofibroblasts), and TGF-B is known to participate in 221102_G2572WO English Translation (Final) clean copy the activation of the fibroblasts (Non Patent Literature 1X)

[0006] The expression of integrins also participates in fibrosis. For example, the expression level of integrin B5 or B6 markedly increases after tissue injury and plays an important in vivo role in tissue fibrosis (Non Patent Literatures 12 and 13). The increased expression level of integrin B6 is also related to increase in the death rate of fibrosis patients (Non Patent Literature 14).

[0007] The inhibition of integrins is known to exhibit resistance to various fibroses. For example, integrin B6-knockout mice inhibit the activation of TGF-B and exhibit resistance to various fibroses (Non Patent Literatures 15 and 16). It has also been reported that fibroblast-specific deficiency in integrin av similarly exhibits resistance to various fibroses (Non Patent Literatures 17 and 18).

[0008] For example, pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) are used as therapeutic drugs for fibrosis. However, any safe and established therapeutic drug for various organ fibroses has not yet been found. Thus, there is a demand for a therapeutic drug for fibrosis that is effective for various organs with reduced adverse reactions. [000%] Research has been made so far on integrins involved in the functional control of various cells or 221102_G2572WO English Translation (Final) clean copy their inhibitors (Patent Literatures 1 to 8 and Non Patent Literature 19). Citation List Patent Literature

[0010] Patent Literature 1: WO 1997 / 008145 Patent Literature 2: WO 1999 / 044994 Patent Literature 3: WO 1999 / 052896 Patent Literature 4: WO 2000 / 051686 Patent Literature 5: WO 2004 / 060376 Patent Literature 6: WO 2014 / 015054 Patent Literature 7: US 2014 / 0051715 Patent Literature 8: WO 2017 / 117538 Non Patent Literature

[0011] Non Patent Literature 1: Cell, 2002, 110 (6), 673-687 Non Patent Literature 2: Cellular and Molecular Life Sciences, 2017, 74 (12), 2263-2282 Non Patent Literature 3: Pharmacology Research and Perspectives, 2017, 5 (5), e00354 Non Patent Literature 4: Neurobiology of Aging, 2008, 28 (10), 1485-1493 Non Patent Literature 5: Angewandte Chemie International Edition in English, 2018, 57 (13), 3298-3321 Non Patent Literature 6: Clinical & Experimental Metastasis, 2003, 20, 203-213 221102_G2572WO English Translation (Final) clean copy Non Patent Literature 7: Cold Spring Harbor Perspectives in Biology, 2016, 8 (5), a021873 Non Patent Literature 8: Cold Spring Harbor Perspectives in Biology, 2011, 3 (11), a005017 Non Patent Literature 9: Science Translational Medicine, 2015, 7 (288), 288ra7% Non Patent Literature 10: Molecular Aspects of Medicine, 2019, 65, 2-15 Non Patent Literature 11: Nature Reviews Nephrology, 2016, 12 (6), 325-338 Non Patent Literature 12: Journal of Hepatology, 2008, 48 (3), 453-464 Non Patent Literature 13: The American Journal of Pathology, 2004, 164 (4), 1275-1292 Non Patent Literature 14: European Respiratory Journal, 2015, 46 (2), 486-494 Non Patent Literature 15: The American Journal of Pathology, 2003, 163 (4), 1261-1273 Non Patent Literature 16: Cell, 1999, 96 (3), 319-328 Non Patent Literature 17: Nature Medicine, 2013, 19 (12), 1617-1624 Non Patent Literature 18: Nature Communications, 2017, 8 (1), 1118 Non Patent Literature 19: Biochemical Pharmacology, 2016, 117, 88-96 Summary of Invention 221102_G2572WO English Translation (Final) clean copy Technical Problem

[0012] The present invention relates to the provision of a novel compound useful in the prevention, alleviation and / or remedy of a disease related to integrin av and a pharmaceutical composition containing the same. Solution to Problem

[0013] The present inventors have conducted diligent studies on compounds having integrin av inhibitory activity and consequently found that a series of 1,4,5,6- tetrahydropyrimidin-2-amine derivatives having an intramolecular indazole structure, or pharmaceutically acceptable salts thereof have excellent integrin av (avBl, avB6, etc.) inhibitory activity, excellent pharmacokinetic characteristics or excellent safety. The 1,4,5,6-tetrahydropyrimidin-2-amine derivative according to the present invention or a pharmaceutically acceptable salt thereof can be useful in the prevention, alleviation and / or remedy of a disease related to integrin av, preferably the prevention, alleviation and / or remedy of fibrosis.

[0014] Specifically, the present invention is as follows. [1] A compound represented by the following general formula (I) or (II) or a pharmaceutically acceptable salt thereof: 221102_G2572WO English Translation (Final) clean copy Y Y A A H I i Ce 85 A LAH 5 A HN-N N-NH C0 C0 HN ZN HNN NS WN AH OY eo Cry Yoon RY 1 \ JR N-NH HN-N om ny wherein A is a C¢-Cjp aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-C¢ alkyl group, a C;- Cs haloalkyl group, a C,-Cs alkenyl group, a C,-Cg¢ alkynyl group, a C;-Cs alkoxy group, a Ci:-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkenyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C1-Ce alkylsulfanyl group, and a C1-C¢ alkylsulfonyl group, R is a hydrogen atom or a Ci;-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group. [2] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: 221102_G2572WO English Translation (Final) clean copy Y: AN H I oOo A cD eto HN N Yr R! \ N—-NH N-NH 1) wherein A is a C¢-Cjp aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-C¢ alkyl group, a C;- Cs haloalkyl group, a C,-Cs alkenyl group, a C,-Cg¢ alkynyl group, a C;-Cs alkoxy group, a Ci:-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkenyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C1-Ce alkylsulfanyl group, and a C1-C¢ alkylsulfonyl group, R is a hydrogen atom or a Ci;-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group. [3] A compound represented by the following general formula (II) or a pharmaceutically acceptable salt thereof: 221102_G2572WO English Translation (Final) clean copy Y A oO A HN-N lle et ° ; ry JR HN=N (n wherein A is a C¢-Cjp aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-C¢ alkyl group, a C;- Cs haloalkyl group, a C,-Cs alkenyl group, a C,-Cg¢ alkynyl group, a C;-Cs alkoxy group, a Ci:-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkenyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C1-Ce alkylsulfanyl group, and a C1-C¢ alkylsulfonyl group, R is a hydrogen atom or a Ci;-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group. [4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, wherein 221102_G2572WO English Translation (Final) clean copy at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-C¢ alkyl group, a C;-C¢ haloalkyl group, a C,-C¢ alkenyl group, a C»-Cs alkynyl group, a C;-Cs alkoxy group, a C;-Csg haloalkoxy group, a C3;-Cs cycloalkyl group, a C3;-Cs cycloalkenyl group, a C3;-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a Ci1-Cs alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C;-Cs alkylsulfonyl group. [5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, wherein at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-Cs alkyl group, a Ci:-Cs haloalkyl group, a C-Cs alkenyl group, a C;-Cs alkoxy group, a Ci-Cs haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-Cg cycloalkenyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-Cs alkoxycarbonyl group, a C1-Cs alkylsulfanyl group, and a C;-Cg¢ alkylsulfonyl group. 221102_G2572WO English Translation (Final) clean copy [6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, wherein at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a C;-Cs alkyl group, a C;-C¢ haloalkyl group, a C;-C¢ alkoxy group, a C;-Cs haloalkoxy group, a C3-Cg cycloalkyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted by a C;-C¢ alkyl group. [7] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein Y is a fluorine atom. [8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the following formula (i): RS | RS R4 Re (i) wherein R2 is a hydrogen atom or a halogen atom, R3? is a hydrogen atom, a halogen atom, a C1-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, a C1-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs 221102_G2572WO English Translation (Final) clean copy cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group, R? is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cg¢ haloalkyl group, a C;-Ce¢ alkoxy group, or a C1-Cs haloalkoxy group, R5 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs¢ haloalkyl group, a C;-Cg¢ alkoxy group, a C1-C¢ haloalkoxy group, or a heteroaryl group optionally substituted by a C1-Cs alkyl group, and Rf is a hydrogen atom or a halogen atom. [9] The compound according to [8] or a pharmaceutically acceptable salt thereof, wherein R? is a hydrogen atom, R3 is a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, a C1-Cs haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group, R¢ is a hydrogen atom or a halogen atom, R5 is a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, or a C1-Cs haloalkoxy group, and Rf is a hydrogen atom or a halogen atom.

[10] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 221102_G2572WO English Translation (Final) clean copy (35) -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, (35) -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, (35) -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, 221102_G2572WO English Translation (Final) clean copy (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, (35) -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, (35) -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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (35) -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, (35) -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, (35) -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- v1)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, (35) -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, 221102_G2572WO English Translation (Final) clean copy (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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (35) -3- (3-bromophenyl) -3- (2- (4- ( (5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid, (38) -3-(3- (1H-pyrazol-1l-yl) phenyl) -3-(2- (4- ((5- fluoro-1,4,5,6-tetrahydropyrimidin-2-yl) amino) -1H- indazole-6-carboxamido) acetamido) propanoic acid, (35) -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-carboxamido) acetamido)propancic acid, (38)-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, 221102_G2572WO English Translation (Final) clean copy (35) -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 (35) -3-(2-(6-((5-fluoro-1,4,5, 6-tetrahydropyrimidin- 2-yl)amino) -1H-indazole-4-carboxamido)acetamido) -3- (3- (trifluoromethyl) phenyl) propancic acid.

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

[10] or a pharmaceutically acceptable salt thereof, and in an embodiment of the pharmaceutical composition, 221102_G2572WO English Translation (Final) clean copy relates to a pharmaceutical composition for preventing, alleviating and / or treating a disease related to integrin av or a disease that is improved by inhibiting integrin av, or a pharmaceutical composition for treating fibrosis.

[0016] In an alternative embodiment, the present invention relates to a pharmaceutical composition, more preferably a pharmaceutical composition for the treatment of fibrosis, i.e., the prevention, alleviation and / or remedy of fibrosis, comprising a compound according to any one of [1] to

[10] or a pharmaceutically acceptable salt thereof.

[0017] In an alternative embodiment, the present invention relates to a method for the treatment of a disease related to integrin av or a disease that is improved by inhibiting integrin av, for example, fibrosis, comprising administering a compound according to any one of [1] to

[10] or a pharmaceutically acceptable salt thereof to a subject.

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

[10] or a pharmaceutically acceptable salt thereof in the treatment of a disease related to integrin av or a disease that is improved by inhibiting integrin av, for example, fibrosis. [001%] In an alternative embodiment, the present invention relates to the compound according to any one of 221102_G2572WO English Translation (Final) clean copy [1] to

[10] or a pharmaceutically acceptable salt thereof for use in the treatment of a disease related to integrin av or a disease that is improved by inhibiting integrin av, for example, fibrosis.

[0020] In an alternative embodiment, the present invention relates to use of a compound according to any one of [1] to

[10] or a pharmaceutically acceptable salt thereof in the production of a medicament for the treatment of a disease related to integrin av or a disease that is improved by inhibiting integrin av, for example, fibrosis.

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

[10] or a pharmaceutically acceptable salt thereof.

[0022] In an alternative embodiment, the present invention relates to a method for producing a compound according to any one of [1] to

[10] or a pharmaceutically acceptable salt thereof. Advantageous Effects of Invention

[0023] The present invention provides a novel compound and a method for synthesizing the compound. Another aspect of the present invention provides a pharmaceutical composition for the prevention, alleviation and / or remedy of a disease related to at least any integrin av (e.g., fibrosis), comprising the compound, the compound for 221102_G2572WO English Translation (Final) clean copy preventing, alleviating and / or treating the disease, or a method for preventing, alleviating and / or treating the disease with the compound. An alternative aspect of the present invention provides a novel intermediate for synthesizing the compound. Description of Embodiments

[0024] <Definition> In the present specification, various substituents are as follows. The "Cg-Cio aryl group" means a monocyclic or dicyclic monovalent aromatic hydrocarbon group having 6 to 10 ring-forming carbon atoms. Examples of the aryl group include phenyl and naphthyl.

[0025] The "heteroaryl group" means 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-forming 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 dicyclic heteroaryl groups such as indolyl, indazolyl, benzotriazolyl, benzofuranyl, 221102_G2572WO English Translation (Final) clean copy benzimidazolyl, benzothiophenyl, benzisoxazolyl, benzopyranyl, benzothienyl, quinolyl, and isoquinolyl.

[0026] The "halogen" or the "halo" means a halogen atom. Examples thereof include a fluorine atom (fluoro), a chlorine atom (chloro), a bromine atom (bromo) and an iodine atom (iodo).

[0027] The "C;-C¢ alkyl group" means an alkyl group having to 6 carbon atoms, and the alkyl group may be a linear alkyl group or may be a branched 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 Ci1-C4 alkyl group.

[0028] The "C;-Cs haloalkyl group" means a group in which at least one hydrogen of the "C;-C¢ alkyl group" is replaced with a halogen atom. The haloalkyl group may be a linear haloalkyl group or may be a branched haloalkyl group. Examples of the haloalkyl group include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 2-fluorocethyl, 2- chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2- difluorocethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2- diiodoethyl, 2,2,2-trifluorcethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-triiodoethyl, 3-fluoropropyl, 221102_G2572WO English Translation (Final) clean copy 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-Cg haloalkyl group.

[0028] The "C,-Cs alkenyl group" means an alkenyl group having 2 to 6 carbon atoms, and the alkenyl group may be a linear alkenyl group or may be a branched alkenyl group. Examples of the alkenyl group include vinyl, allyl, l-propenyl, 2-propenyl, l-butenyl, 2-butenyl, 3- butenyl, l-methyl-l-propenyl, l-methyl-2-propenyl, 2- methyl-l-propenyl, 2-methyl-2-propenyl, l-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, l-methyl-2-butenyl, 3- methyl-1-butenyl, l-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, l-methyl-2-pentenyl, and 3-methyl-1- pentenyl. The alkenyl group may be a C,-C; alkenyl group.

[0030] The "C,-Cs alkynyl group" means an alkynyl group having 2 to 6 carbon atoms, and the alkynyl group may be a linear alkynyl group or may be a branched alkynyl group. Examples of the alkynyl group include ethynyl, propynyl, 2-propynyl, l-butynyl, 2-butynyl, 3-butynyl, methyl-2-propynyl, 1,1-dimethyl-2-propynyl, l-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-methyl-2-butynyl, 3-methyl-1l-butynyl, l-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl, l-methyl-2-pentynyl, and 3-methyl-1- pentynyl. The alkynyl group may be a C,-C; alkynyl group. 221102_G2572WO English Translation (Final) clean copy

[0031] The "C;-Cs alkoxy group" means a group in which the "C;-Cs alkyl group" is bonded via an oxygen atom. The alkoxy group may be a linear alkoxy group or may be a branched 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 C;-C; alkoxy group.

[0032] The "C;-Cs haloalkoxy group" means a group in which at least one hydrogen of the "C;-C¢ alkoxy group" is replaced with a halogen atom. The haloalkoxy group may be a linear haloalkoxy group or may be a branched haloalkoxy group. Examples of the haloalkoxy group include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, diiodomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, 2- fluorocethoxy, 2-chloroethoxy, 2-bromoethoxy, 2- iodoethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2- dibromoethoxy, 2,2-diiodoethoxy, 2,2,2-trifluorcethoxy, 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- 221102_G2572WO English Translation (Final) clean copy bromohexoxy, and 6-iodohexoxy. The haloalkoxy group may be a C;-C; haloalkoxy group.

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

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

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

[0036] The "heterocyclyl group" means a saturated monovalent heterocyclic group or a nonaromatic 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-forming atoms. Examples of the heterocyclyl group include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl (i.e., thiolanyl), piperazinyl, and morpholinyl. 221102_G2572WO English Translation (Final) clean copy

[0037] The "C;-Cs alkoxycarbonyl group" means a group in which the "C;-Cs alkoxy group" is bonded via a carbonyl group. The alkoxycarbonyl group may be a linear alkoxycarbonyl group or may be a branched 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 C;-C4 alkoxycarbonyl group.

[0038] The "C;-Cs alkylsulfanyl group" means a group in which the "C;-Cs alkyl group" is bonded via a sulfur atom. The alkylsulfanyl group may be a linear alkylsulfanyl group or may be a branched 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 C;-C; alkylsulfanyl group.

[0038] The "C;-C¢ alkylsulfonyl group" means a group in which the "C;-Cg alkyl group" is bonded via a sulfonyl 221102_G2572WO English Translation (Final) clean copy group. The alkylsulfonyl group may be a linear alkylsulfonyl group or may be a branched 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 C;-C; alkylsulfonyl group.

[0040] In the present specification, the "pharmaceutically acceptable salt" includes a pharmaceutically acceptable acid-addition salt and a salt with a pharmaceutically acceptable acid (hereinafter, these are also collectively referred to as an "acid- addition salt, etc."), and a pharmaceutically acceptable base-addition salt and a salt with a pharmaceutically acceptable base (hereinafter, these are also collectively referred to as a "base-addition salt, etc.").

[0041] In the present specification, examples of the "acid-addition salt" or the "salt with an acid" (acid- addition salt, etc.) include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, oxalate, malonate, fumarate, maleate, phthalate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, 2,4-dimethylbenzenesul fonate, 2,4, 6- 221102_G2572WO English Translation (Final) clean copy trimethylbenzenesulfonate, 4-ethylbenzenesulfonate, and naphthalenesulfonate.

[0042] In the present specification, the "base-addition salt" or the "salt with a base" (base-addition salt, etc.) includes, for example, a metal salt, an inorganic amine salt, an organic amine salt, and an amino acid salt. The metal salt may be, for example, an alkali metal salt such as sodium salt, potassium salt, or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; aluminum salt; iron salt; zinc salt; copper salt; nickel salt; or cobalt salt. The inorganic amine salt may be, for example, ammonium salt. The organic amine salt may be, for example, morpholine salt, glucosamine salt, ethylenediamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, diethanolamine salt, piperazine salt, or tetramethylammonium salt. Examples of the amino acid salt include glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0043] In the present specification, the "disease related to integrin av" is a disease involving integrin av and is not particularly limited as long as its symptom is alleviated, improved, suppressed, or prevented by inhibiting integrin av. Integrins are heterodimers composed of a and PB chains. The integrin av is an a chain. Integrins comprising integrin av include integrins avBl, avB3, avB5, avp6 and avB8. The "disease 221102_G2572WO English Translation (Final) clean copy related to integrin av" may include a disease related to integrin avfl, avf3, avB5, avpé or avp8 because these integrins comprise integrin av. The "disease related to integrin av" includes, for example, a "disease related to integrin avpl" or a "disease related to integrin avpé". Examples of the disease related to integrin av include inflammatory disease, fibrosis, cancer, neurodegenerative disease, eye disease, osteoporosis, and osteogenesis imperfecta. The inhibition of integrin av includes decrease in the degree of signals mediated by integrin av, as compared with a control, or decrease in the ability of integrin av to bind to a ligand, as compared with a control.

[0044] In the present specification, the "inflammatory disease" refers to a disease, disorder, or a condition related to inflammation. Examples thereof include, but are not limited to, arthritis, rheumatoid arthritis, Crohn disease, irritable bowel disease, inflammatory bowel disease (IBD), systemic erythematosus, gum disease, psoriasis, acute hepatitis, chronic hepatitis, Alport's syndrome, inflammation caused by diabetes mellitus, joint arterial inflammation, large-cell arterial inflammation, Kawasaki disease, Takayasu arteritis, Churg-Strauss syndrome and Henoch-Schonlein purpura.

[0045] In the present specification, examples of the "fibrosis" include, but are not particularly limited to, fibroses in the lung, the liver, the kidney, the heart, 221102_G2572WO English Translation (Final) clean copy vascular vessels, the skin, the pancreas, the bone marrow, and other organs or tissues. In the present invention, the fibrosis is preferably pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis, vascular fibrosis, dermatofibrosis, pancreatic fibrosis, myelofibrosis or skeletal myofibrosis, more preferably pulmonary fibrosis, hepatic fibrosis, renal fibrosis or cardiac fibrosis. The pulmonary fibrosis includes idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), interstitial lung disease, peribronchiolar fibrosis, peripheral airway disease (e.g., bronchiolitis obliterans), pulmonary emphysema, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), postinfectious pulmonary fibrosis, drug- induced pulmonary fibrosis, airway fibrosis, diffuse alveolar damage, collagen-vascular disease-related pulmonary fibrosis, silicosis, radiation-induced fibrosis, bleomycin-induced fibrosis, influenza-induced fibrosis, asbestos-induced pulmonary fibrosis, desquamative interstitial pneumonia and chronic hypersensitivity pneumonitis. The hepatic fibrosis includes primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), infectious hepatic fibrosis (caused by HCV or a parasite such as blood fluke), alcoholic steatohepatitis (ASH), 221102_G2572WO English Translation (Final) clean copy non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis caused by every etiology, congenital hepatic fibrosis, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and al-antitrypsin deficiency. The renal fibrosis includes chronic kidney disease (CKD), glomerulonephritis (GN) of every etiology, mesangial proliferative GN, immune GN, crescentic GN, tubulointerstitial injury, renal interstitial fibrosis, renal fibrosis brought about by complications of drug exposure (including the cyclosporine treatment of transplantation recipients), nephrogenic systemic fibrosis, HIV-related nephropathy, graft nephropathy, diabetic kidney disease (diabetic nephropathy), focal segmental glomerulosclerosis (FSGS), idiopathic retroperitoneal fibrosis, hypertensive nephrosclerosis and IgA nephropathy. The cardiac fibrosis and the vascular fibrosis include cardiac fibrosis associated with myocardial infarction, vascular injury-induced fibrosis, cardiac stenosis, aortostenosis, atherosclerosis, thrombosis, arteriosclerosis, myocardial infarction, angina pectoris, cardiac valvular disease, renal arteriosclerosis, congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, myocarditis, vascular stenosis cardiac fibrosis, post- infarction cardiac fibrosis, left ventricular 221102_G2572WO English Translation (Final) clean copy hypertrophy, venous occlusion, restenosis, restenosis after angiogenesis, arteriovenous transplantation failure, hypertension, hypertensive heart disease, cardiomegaly, heart failure, aortic disease, hereditary hemorrhagic telangiectasia (HHT), arterial tortuosity syndrome, Raynaud syndrome and hypertriglyceridemia. The dermatofibrosis includes generalized scleroderma, polymyositis, systemic lupus erythematosus, dermatomyositis, Dupuytren's contracture, postoperative adhesion, fibrosis caused by surgical incision or mechanical trauma, and excessive or hypertrophic scarring or keloid formation in the dermis during wound healing brought about from trauma or surgical wound. The pancreatic fibrosis includes cystic fibrosis (CF), chronic pancreatitis, and autoimmune pancreatitis. The myelofibrosis includes primary myelofibrosis, idiopathic myelofibrosis, secondary myelofibrosis, and myeloproliferative tumor. The fibrosis in other organs or tissues includes skeletal myofibrosis, intestinal fibrosis, fibrosis after organ transplantation, induratio penis plastica (Peyronie disease), bladder fibrosis, Camurati-Engelmann disease, Loeys-Dietz syndrome, Marfan syndrome, premature ovarian failure, preeclampsia, mediastinal fibrosis, and intestinal stenosis.

[0046] In the present specification, the "cancer" includes tumor angiogenesis, carcinoma, sarcoma, 221102_G2572WO English Translation (Final) clean copy lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, seminoma, and tumor metastasis. Examples of the tumor site that may be treated according to the present invention include the bladder, blood, bone, the brain, the breast, the central nervous system, the uterine cervix, the colon, the endometrium, the esophagus, the gallbladder, the genital organ, the genitourinary tract, the head, the kidney, the larynx, the liver, the lung, muscular tissues, the neck, oral or nasal mucosa, the ovary, the pancreas, the prostate, the skin, the spleen, the small intestine, the large intestine, the stomach, the testis, and the thyroid gland.

[0047] In the present specification, the "neurodegenerative disease" includes peripheral nerve disorder, Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

[0048] In the present specification, the "eye disease" includes age-related macular degeneration (AMD), glaucoma, ocular fibrosis, retinal or corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), vitreoretinopathy of arbitrary etiology, fibrosis related to ophthalmic surgery, retinal reattachment surgery, cataract extraction, or an arbitrary type of drainage treatment, scarring in the cornea and the conjunctiva, corneal endothelial fibrosis, alkaline burn (e.g., alkaline burn in the cornea), capsulolenticular fibrosis after cataract operation, excessive scarring in 221102_G2572WO English Translation (Final) clean copy tissues surrounding extraocular muscle in strabismus operation, anterior subcapsular cataract and posterior capsule opacification, anterior eye fibrosis, corneal stromal fibrosis, fibrosis related to corneal clouding, trabecular meshwork fibrosis, fibrosis related to glaucoma, posterior eye fibrosis, fibrovascular scarring, fibrosis in the retinal blood vessel or choroid blood vessel of the eye, retinal fibrosis, epiretinal fibrosis, retinal gliosis, subretinal fibrosis, fibrosis related to retinal operation and glaucoma operation, retinal traction detachment related to tissue contraction in diabetic retinopathy, scarring of cicatricial pemphigoid glaucoma filtration surgery, retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR).

[0048] In the present specification, the "subject" is a human, a monkey, a bovine, a horse, sheep, a goat, a rabbit, a dog, a cat, a mouse, a rat, a guinea pig or a transgenic species thereof. In the present specification, the subject is an individual in need of the treatment of the disease.

[0050] In the present specification, the "treatment" includes at least one of prevention, alleviation and remedy and also encompasses reduction of a symptom of the disease, suppression of the progression of a symptom of the disease, removal of a symptom of the disease, improvement in the prognosis of the disease, prevention of the recurrence of the disease, and prevention of the 221102_G2572WO English Translation (Final) clean copy disease. In one aspect of the present invention, the treatment is remedy.

[0051] <Compound of present invention> In one embodiment, the present invention relates to a compound represented by the following general formula (I) or (II) or a pharmaceutically acceptable salt thereof: Y Y A A H | H Lo TT H on | oF Tea Nw © A j— | / N—NH HN=-N 3 ill HNN HNN NY cor NY cor ” 0 A , 0 A A JR N—NH HN-N ny (in wherein A 1s a Cg-Cio aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Cs alkyl group, a Ci- Cs haloalkyl group, a C,-Cs alkenyl group, a C-Cs alkynyl group, a C;-Ce¢ alkoxy group, a C;-C¢ haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkenyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C;-Cg¢ alkylsulfonyl group, 221102_G2572WO English Translation (Final) clean copy R is a hydrogen atom or a Ci1-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group. In the present specification, the compound represented by the general formula (I) is also simply referred to as a "compound (I)" and the compound represented by the general formula (II) is also simply referred to as a "compound (II)".

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

[0053] At least one hydrogen atom of the phenyl group that may be selected as A is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-C¢ alkyl group, a Ci- 221102_G2572WO English Translation (Final) clean copy Cs haloalkyl group, a C,-Cs alkenyl group, a C;-Cs alkoxy group, a C;-Cs¢ haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-C¢ cycloalkenyl group, a C3-Cg¢ cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a Ci1-Cs alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C;-Cs 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 is optionally replaced with a substituent selected from the group consisting of a halogen atom, a C1-C¢ alkyl group, a C;-C¢ haloalkyl group, a C;-C¢ alkoxy group, a C;-Cs haloalkoxy group, a C3-Cgs cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted by a C;-Cs alkyl group.

[0055] In an alternative embodiment of the present invention, A in the compound (I) or (II) may be a group represented by the following formula (i): RS 1 RS Rr? R4 Re (i)

[0056] In the formula (i), R? is a hydrogen atom or a halogen atom. 221102_G2572WO English Translation (Final) clean copy In another embodiment, R? is a hydrogen atom, a fluorine atom or a chlorine atom. In an alternative embodiment, R? is a hydrogen atom.

[0057] R® is a hydrogen atom, a halogen atom, a C;-Cg alkyl group, a Ci1-Cs haloalkyl group, a Ci:-Cs alkoxy group, a C;-Cs haloalkoxy group, a C3;-Cg¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group. In another embodiment, R® is a hydrogen atom, a halogen atom, a C;-Cs haloalkyl group, a C;-Cs haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-Cg¢ cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C:-Cs; alkyl group. In an alternative embodiment, R3® is a hydrogen atom, a halogen atom, a C;-C; haloalkyl group, a C1-C4 haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, or a heteroaryl group. In an alternative embodiment, R3® 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 morpholinyl group, Or a pyrazolinyl group. In an alternative embodiment, R3® is a hydrogen atom, a halogen atom, a C;-Cs¢ alkyl group, a C;-Cg¢ haloalkyl group, a C;-Cg¢ alkoxy group, a Ci;-C¢ haloalkoxy group, or 221102_G2572WO English Translation (Final) clean copy a heteroaryl group optionally substituted by a C1-Cg alkyl group. In an alternative embodiment, R3® is a hydrogen atom, a halogen atom, a C;-C; alkyl group, a C;-C; haloalkyl group, a C;-C4 alkoxy group, a Ci:-C; haloalkoxy group, or a heteroaryl group optionally substituted by a C;-C4 alkyl group. In an alternative embodiment, R3® is a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, a trifluoromethoxy group, or a pyrazolinyl group optionally substituted by a methyl group. In an alternative embodiment, R3® is a halogen atom, a trifluoromethyl group, a difluoromethoxy group, a trifluoromethoxy group, or a pyrazolinyl group.

[0058] R¢ is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-C¢ haloalkyl group, a C;-C¢ alkoxy group, or a C;-Cg¢ haloalkoxy group. In another embodiment, R%¢ is a hydrogen atom, a halogen atom, a Ci:-C; alkyl group, a Ci-C4; haloalkyl group, a C;-C; alkoxy group, or a C;-C; haloalkoxy group. In an alternative embodiment, R% is a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, or a difluoromethoxy group. In an alternative embodiment, R* is a hydrogen atom or a halogen atom. 221102_G2572WO English Translation (Final) clean copy In an alternative embodiment, R* is a hydrogen atom or a fluorine atom.

[0059] R®> is a hydrogen atom, a halogen atom, a C;-Cg alkyl group, a C;-Cg¢ haloalkyl group, a C;-C¢ alkoxy group, a C;-Cs haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cgs alkyl group. In another embodiment, R5 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs; haloalkyl group, a C;-C4 alkoxy group, a Ci:-C; haloalkoxy group, or a pyrazolinyl group. In an alternative embodiment, R® is a hydrogen atom, a halogen atom, a methyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a pyrazolinyl group. In an alternative embodiment, RS is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cgs alkoxy group, or a C;-C¢ haloalkoxy group. In an alternative embodiment, R5 is a hydrogen atom, a halogen atom, a C;-Cs4 alkyl group, a C;-Cs; haloalkyl group, a C;-Cs alkoxy group, or a C;-C; haloalkoxy group. In an alternative embodiment, R® 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 an alternative embodiment, RS is a halogen atom, a methyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group. 221102_G2572WO English Translation (Final) clean copy

[0060] R® is a hydrogen atom or a halogen atom. In another embodiment, Rf is a hydrogen atom, a fluorine atom or a chlorine atom. In an alternative embodiment, RS is a hydrogen atom or a fluorine atom.

[0061] In an alternative embodiment, for example, in the formula (i), R?2 may be a hydrogen atom, R3 may be a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a Ci:-Cs haloalkyl group, a Ci:-Cs alkoxy group, a C;-Cs haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group, R% may be a hydrogen atom or a halogen atom, R5 may be a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a Ci:-Cs haloalkyl group, a Ci:-Cs alkoxy group, or a C;-Cs haloalkoxy group, and Rf may be a hydrogen atom or a halogen atom.

[0062] In an alternative embodiment, in the formula (i), R2 may be a hydrogen atom, R?® may be a hydrogen atom, a halogen atom, a Ci-Cg haloalkyl group, a C;-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cg¢ cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C1-Cs4 alkyl group, R% may be a hydrogen atom or a halogen atom, 221102_G2572WO English Translation (Final) clean copy R® may be a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a C;-C¢ haloalkyl group, a C;-C¢ alkoxy group, or a C;-Cg¢ haloalkoxy group, and Ré may be a hydrogen atom or a halogen atom.

[0063] In an alternative embodiment of the present invention, A in the compound (I) or (II) may be a group represented by any of the following formulas (i)-a to (i) -g: * * * TE Ra Re 1 Ra! a2 R R%4 a6 RET 9 I. Re Ra Ra10 R212 (ira (i)-b (irc (id (ire (if (ig wherein * represents a binding position, and Ral to Ral3 are each independently a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Cs alkyl group, a C;-C¢ haloalkyl group, a C,-Cs¢ alkenyl group, a C,-Cs alkynyl group, a C;- Cs alkoxy group, a C;-Ce¢ haloalkoxy group, a C3-Cg cycloalkyl group, a C3-Cs cycloalkenyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C1-Cs alkylsulfonyl group.

[0064] In the embodiment, R23! to R213 may each independently be a substituent selected from the group consisting of a halogen atom, a C;-Cs alkyl group, a C;-Cg 221102_G2572WO English Translation (Final) clean copy haloalkyl group, a C;-Cs alkoxy group, a Ci-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cg¢ cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted by a C;-C¢ alkyl group.

[0065] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-a, one of Ral and R22 may be a halogen atom, a C;-Cg haloalkyl group, or a Ci;-Cgs halocalkoxy group, and the other moiety may be a halogen atom, a C;-Cg alkyl group, a C;-Cs haloalkyl group, a C;-C¢ alkoxy group, a C1-C¢ haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group.

[0066] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-a, one of Ral and R22 may be a halogen atom, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group, and the other moiety may be a halogen atom, a C;-Cs alkyl group, a C;-Cg¢ haloalkyl group, a C;-Cg¢ alkoxy group, a C1-C¢ haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a Ci-Cs alkyl group. 221102_G2572WO English Translation (Final) clean copy

[0067] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-a, one of Ral and R22 may be a halogen atom, a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group, and the other moiety 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 morpholinyl group, or a pyrazolinyl group.

[0068] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-b, R23 may be a halogen atom, and R34 may be a halogen atom, a C;-Cs alkyl group, a Ci- Cs haloalkyl group, a C;-Cs alkoxy group, a C;-Cg haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group. [006%] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-b, R33 may be a halogen atom, and R#¢ may be a halogen atom, a C;-C¢ haloalkyl group, or a C;-C¢ haloalkoxy group. 221102_G2572WO English Translation (Final) clean copy

[0070] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-b, Ra3 may be a halogen atom, and R24 may be a C;-Cs haloalkyl group.

[0071] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-c, R35 may be a halogen atom, and R2¢ may be a halogen atom, a Ci1-Cs alkyl group, a Ci- Cs haloalkyl group, a C;-Cs alkoxy group, a C;-Csg haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group.

[0072] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-c, R35 may be a halogen atom, and R26 may be a halogen atom, a Ci:-Cs haloalkyl group, or a C;-Cs haloalkoxy group.

[0073] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-c, R25 may be a halogen atom, and R26 may be a halogen atom, a trifluoromethyl group, or a trifluoromethoxy group. 221102_G2572WO English Translation (Final) clean copy

[0074] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-d, one of R27 and R2® may be a halogen atom, a C;-Cg haloalkyl group, or a Ci-C¢ haloalkoxy group, and the other moiety may be a halogen atom, a C;-Cs alkyl group, a C;-Cg¢ haloalkyl group, a C;-Cg¢ alkoxy group, a C1-C¢ haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group.

[0075] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-d, one of R27 and R2® may be a halogen atom, a C1-Cg haloalkyl group, or a Ci-C¢ haloalkoxy group, and the other moiety may be a halogen atom, a C;-Cs alkyl group, a C;-Ce¢ haloalkyl group, a C;-Ce¢ alkoxy group, or a C;-C¢ haloalkoxy group.

[0076] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-d, one of R27 and R2® may be a halogen atom, a trifluoromethyl group, or a trifluoromethoxy group, and the other moiety may be a halogen atom, a methyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group. 221102_G2572WO English Translation (Final) clean copy

[0077] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-e, at least one of Ra? Ral® and Rall may be a halogen atom, a C;-Cs haloalkyl group, or a Ci-Cs haloalkoxy group, and the remaining moieties may each individually be a halogen atom, a C;-Cs¢ alkyl group, a C;-Cg¢ haloalkyl group, a C;-Cs alkoxy group, a Ci:-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group.

[0078] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-e, R29, Ral0 and Rall! may each individually be a halogen atom, a C;-Cs haloalkyl group, or a C;-Cg haloalkoxy group.

[00728] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-f, R312 may be a halogen atom, a C;-Cs haloalkyl group, a C1-C¢ haloalkoxy group, a C3-Cg¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a Ci-Cs alkyl group. 221102_G2572WO English Translation (Final) clean copy

[0080] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-f, R312 may be 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 pyrazolinyl group optionally substituted by a methyl group.

[0081] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-g, R313 may be a halogen atom, a C;-Cs haloalkyl group, a C1-C¢ haloalkoxy group, a C3—-Cg cycloalkyl group, a C3-Cs cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C1-C¢ alkyl group.

[0082] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-f, Ral3 may be 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 pyrazolinyl group optionally substituted by a methyl group.

[0083] In an alternative embodiment of the present invention, when A in the compound (I) or (II) is a group represented by the formula (i)-f, 221102_G2572WO English Translation (Final) clean copy R213 may be a Ci1-C¢ haloalkyl group or a Ci-Cg haloalkoxy group. Alternatively, R213 may be a difluoromethyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group.

[0084] In one embodiment, R in the compound (I) or (II) is a hydrogen atom or a Ci;-C¢ alkyl group. In another embodiment, R in the compound (I) or (II) is a hydrogen atom or a Ci;-Cs alkyl group. In an alternative embodiment, R in the compound (I) or (II) is a hydrogen atom or a methyl group. In an alternative embodiment, R in the compound (I) or (II) is a hydrogen atom.

[0085] In one embodiment, R! in the compound (I) or (II) is a hydrogen atom or a halogen atom. In another embodiment, R! in the compound (I) or (II) is a hydrogen atom, a fluorine atom or a chlorine atom. In an alternative embodiment, R! in the compound (I) or (II) is a hydrogen atom.

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

[0087] In an alternative embodiment, the present invention provides a compound selected from the following group or a pharmaceutically acceptable salt thereof: 221102_G2572WO English Translation (Final) clean copy (35) -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, (35) -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, (35) -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, 221102_G2572WO English Translation (Final) clean copy (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, (35) -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, (35) -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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (35) -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, (35) -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, (35) -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- v1)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, (35) -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, 221102_G2572WO English Translation (Final) clean copy (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, (38) -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, 221102_G2572WO English Translation (Final) clean copy (35) -3- (3-bromophenyl) -3- (2- (4- ( (5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid, (38) -3-(3- (1H-pyrazol-1l-yl) phenyl) -3-(2- (4- ((5- fluoro-1,4,5,6-tetrahydropyrimidin-2-yl) amino) -1H- indazole-6-carboxamido) acetamido) propanoic acid, (35) -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-carboxamido) acetamido)propancic acid, (38)-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, 221102_G2572WO English Translation (Final) clean copy (35) -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 (35) -3-(2-(6-((5-fluoro-1,4,5, 6-tetrahydropyrimidin- 2-yl)amino) -1H-indazole-4-carboxamido)acetamido) -3- (3- (trifluoromethyl) phenyl) propancic acid.

[0088] The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof can form a hydrate or a solvate, and each individual or a mixture thereof is encompassed by the present invention. 221102_G2572WO English Translation (Final) clean copy [008%] When the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof has one or more asymmetric centers, carbon-carbon double bonds, axial chirality, or the like, optical isomers (including enantiomers and diastereomers), geometrical isomers, tautomers, and rotational isomers may exist. These isomers and mixtures thereof are represented by a single formula such as the formula (I) or (II). The present invention encompasses each of these isomers and mixtures (including racemates) thereof at arbitrary ratios.

[0090] In an embodiment, the compound (I) of the present invention has both the following absolute configurations: Y Y AN AN HL 2 oo mB (3 o HN. __N HN. _N mot and HH ni LN NYY oor NY) oR RL oO A R! oO A \ \ N-NH N—-NH ey Ae N—-NH N-NH

[0091] In an embodiment, the compound (I) of the present invention has the following absolute configuration: Y A H I H § a OY iho ° ] HN N NY cor Rr’ 0 A < N—-NH N-NH

[0092] In an embodiment, the compound (I) of the present invention has the following absolute configuration: 221102_G2572WO English Translation (Final) clean copy Y A H IL oO A C0 HH ° . HN Ne NY x oR R! \ N—NH N-NH

[0093] Likewise, in an embodiment, the compound (II) of the present invention has both the following absolute configurations: Y PRIN o ” . kid o H B..8 H H 4 = LL HH 5 a | 1 H ! 1 H HN N and HN No, $Y eR Yee o A o A »—R' rR HN~N Rant HN~-N

[0094] In an embodiment, the compound (II) of the present invention has the following absolute configuration: Y PN oO A HN-N OO Np ° " HN N NYY ee Oo A JR HN-N

[0095] In an embodiment, the compound (II) of the present invention has the following absolute configuration: Y PN HN=N ON A } HN Neos NYY cor 0 A rR HNN 221102_G2572WO English Translation (Final) clean copy

[0096] A racemate can be resolved into optical enantiomers by a method known in the art, for example, separation of a diastereoisomeric salt thereof with an optically active acid, and release of an optically active amine compound by treatment with a base. Another method for resolving a racemic compound into optical enantiomers is based on chromatography of optically active matrix. The compound of the present invention may also be resolved by the formation of a diastereoisomeric derivative. A further method for resolving optical isomers known to those skilled in the art, such as J. Jaques, A. Collet and S. Wilen et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981) can be used. An optically active compound can also be produced from an optically active starting material.

[0097] The compound represented by the general formula (I) or (II) of the present invention can form an acid- addition salt, etc., and such an acid-addition salt, etc. is encompassed by the pharmaceutically acceptable salt of the present invention. The compound represented by the general formula (I) or (II) of the present invention can form an acid- addition salt with an acid at an arbitrary ratio, and each individual (e.g., monohydrochloride or dihydrochloride) or a mixture thereof is encompassed by the present invention. When R in the general formula (I) 221102_G2572WO English Translation (Final) clean copy or (II) is, for example, a hydrogen atom, such a compound can form a base-addition salt, etc., and such a base- addition salt, etc. is also encompassed by the pharmaceutically acceptable salt of the present invention.

[0098] The compound represented by the general formula (I) or (II) of the present invention, when having a group capable of forming an ester group, such as a hydroxy group or a carboxy group, can be converted to a pharmaceutically acceptable ester, and such a pharmaceutically acceptable ester is encompassed by the present invention. The pharmaceutically acceptable ester of the compound represented by the general formula (I) or (II) is capable of serving as a prodrug of the compound represented by the general formula (I) or (II) and can be hydrolyzed in a metabolic process (e.g., hydrolysis), when administered in vivo to a subject, to form the compound represented by the general formula (I) or (II).

[0098] The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof can form an isotope compound in which one or more atoms constituting the compound or the salt are replaced with isotope atoms at a non-natural ratio. The isotope atom may be radioactive or nonradioactive and includes, for example, heavy hydrogen (2H; D), tritium (3H; T), carbon-14 (14C), and iodine-125 (125I). The radioactive or nonradioactive 221102_G2572WO English Translation (Final) clean copy isotope compound may be used as a medicament for the remedy or prevention of a disease, a reagent for research (e.g., a reagent for assay), a diagnostic drug (e.g., a diagnostic imaging drug), or the like. The present invention encompasses such a radioactive or nonradioactive isotope compound.

[0100] The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is capable of inhibiting the binding of integrin av to its ligand. In an alternative embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is capable of inhibiting the activation of TGF-B. TGF-B participates in the differentiation, survival, proliferation, and the like of cells and plays an important role in development, immunity, wound healing, and the like and therefore, is deeply involved in diseases such as inflammation, fibrosis and cancer. TGF- B is known to have three types of isoforms in mammals, and TGF-P1l is known as a master regulator for tissue repair, inflammation, and fibrosis (Seminars in Cell and Developmental Biology, 2020, 101, 123-139). TGF-B is secreted as an inactive form (latent form) and activated by various methods so as to exhibit physiological activity. RGD integrin including avBl and avBé6 is known to play an important role in the activation of TGF-B1. 221102_G2572WO English Translation (Final) clean copy For example, an avBfl integrin inhibitor (Non Patent Literature 8: Science Translational Medicine, 2015, 7 (288), 288ra79) or an avB6 integrin inhibitor (Cancer Research, 2008, 68 (2), 561-570) inhibits the activation of TGF-Bl. Thus, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof can be useful in the prevention, alleviation and / or remedy of diseases such as inflammatory disease, fibrosis, cancer, neurodegenerative disease, eye disease, osteoporosis and osteogenesis imperfecta. In an alternative embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is capable of inducing the dedifferentiation of activated human hepatic stellate cells. Stellate cells or fibroblasts differentiate into active stellate cells or myofibroblasts expressing a-smooth muscle actin (a- SMA, ACTA2) through TGF-Bl or the like, and enhance collagen production, etc. For example, it has been reported that in integrin av-knockout stellate cells, the expression of a-SMA was suppressed and further the production of collagen or the like was also suppressed, because TGF-Bl is not activated (Non Patent Literature 16: Nature Medicine, 2013, 19% (12), 1617-1624). Such enhanced collagen production is seen in diseases such as inflammation, fibrosis and cancer. Thus, the compound 221102_G2572WO English Translation (Final) clean copy represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof can be useful in the prevention, alleviation and / or remedy of diseases such as inflammatory disease, fibrosis, cancer, neurodegenerative disease, eye disease, osteoporosis and osteogenesis imperfecta. In an alternative embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is capable of suppressing increase in hydroxyproline (HYP) level which is an index for fibrosis in non-alcoholic steatohepatitis (NASH) model animals. Thus, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof can be useful in the prevention, alleviation and / or remedy of non-alcoholic steatohepatitis (NASH). In an alternative embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof has excellent pharmacokinetic characteristics. The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is capable of exhibiting excellent transcellular permeability, for example, in a membrane permeability test using Caco2 cells. The transcellular permeability in a membrane permeability 221102_G2572WO English Translation (Final) clean copy test using Caco2 cells reportedly correlates with the rate of intestinal absorption. In an alternative embodiment, the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof has excellent safety. The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof is shown to form no or few reactive metabolites through metabolism in liver microsomes, for example.

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

[0102] In one embodiment, the pharmaceutical composition of the present invention can be used for the treatment of a disease related to integrin av.

[0103] In one embodiment, the present invention relates to use of the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof for a disease related to integrin av.

[0104] In one embodiment, the present invention relates to the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically 221102_G2572WO English Translation (Final) clean copy acceptable salt thereof for use in the treatment of a disease related to integrin av.

[0105] In one embodiment, the present invention relates to use of the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof for producing a medicament for the treatment of a disease related to integrin av.

[0106] In one embodiment, the present invention relates to a method for the treatment of a disease related to integrin av, comprising administering the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof in an amount effective for prevention, alleviation and / or remedy to a subject.

[0107] In one embodiment of the present invention, examples of the disease related to integrin av can include inflammatory disease, fibrosis, cancer, neurodegenerative disease, eye disease, osteoporosis, and osteogenesis imperfecta. In an alternative embodiment, the disease related to integrin av is fibrosis.

[0108] In one embodiment, the fibrosis can be selected from fibroses in the lung, the liver, the kidney, the heart, vascular vessels, the skin, the pancreas, the bone marrow, and other organs or tissues. 221102_G2572WO English Translation (Final) clean copy In another embodiment, the fibrosis can be selected from pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis, vascular fibrosis, dermatofibrosis, pancreatic fibrosis, myelofibrosis and skeletal myofibrosis. In an alternative embodiment, the fibrosis can be selected from pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis.

[0108] In one embodiment, the disease related to integrin av is idiopathic pulmonary fibrosis (IPF). In another embodiment, the disease related to integrin av is non-alcoholic fatty liver disease (NAFLD). In an alternative embodiment, the disease related to integrin av is non-alcoholic steatohepatitis (NASH). In an alternative embodiment, the disease related to integrin av is primary biliary cholangitis (PBC). In an alternative embodiment, the disease related to integrin av is primary sclerosing cholangitis (PSC). In an alternative embodiment, the disease related to integrin av is alcoholic steatohepatitis. In an alternative embodiment, the disease related to integrin av is chronic kidney disease (CKD). In an alternative embodiment, the disease related to integrin av is diabetic kidney disease (diabetic nephropathy) . 221102_G2572WO English Translation (Final) clean copy In an alternative embodiment, the disease related to integrin av 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 a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is administered is a mammal. The mammal includes, for example, a human, a monkey, a bovine, a horse, sheep, a goat, a rabbit, a dog, a cat, a mouse, a rat, a guinea pig or a transgenic species thereof. The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is preferably administered to a human.

[0111] The dose, i.e., the amount effective for prevention, alleviation and / or remedy, of the compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof may vary depending on the frequency and method of administration, the animal species, sex, age, body weight and general condition of a recipient, the severity of the disease, etc., and can be appropriately set by those skilled in the art. For oral administration as to an adult human (60 kg), for example, 0.01 to 3000 mg, preferably 0.1 to 600 mg, is appropriate as the dose per day of the compound of the present invention and can be 221102_G2572WO English Translation (Final) clean copy administered once to several times a day, for example, in one portion or two, three or four divided portions. For parenteral administration to an adult human, for example, 0.001 to 1000 mg, preferably 0.01 to 300 mg, is appropriate as the dose of the compound of the present invention and can be administered once to several times a day, for example, in one portion or two, three or four divided portions. For parenteral administration, the compound of the present invention can be used at a concentration of, for example, 0.00001% (w / v) to 10% (w / v), preferably 0.001% (w / v) to 5% (w / v).

[0112] As for a parenteral route of intravenous, intrathecal, intramuscular or similar administration, etc., the dosage is typically smaller than an amount that is used for oral administration.

[0113] The compound represented by the general formula (I) or (II) of the present invention or a pharmaceutically acceptable salt thereof may be administered by single administration or multiple administration, either singly as a pure compound or in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition formed by combining the compound of the present invention with a pharmaceutically acceptable carrier may be administered in various dosage forms suitable for administration routes. The pharmaceutical composition according to the present invention may be formulated together with a 221102_G2572WO English Translation (Final) clean copy pharmaceutically acceptable carrier in accordance with a conventional approach disclosed in, for example, Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995,

[0114] The pharmaceutical composition of the present invention can be administered orally or parenterally. The parenteral route may include, for example, rectal, transnasal, pulmonary, transdermal, intracerebral, intraperitoneal, vaginal, subcutaneous, intramuscular, intrathecal, intravenous and intradermal routes. The pharmaceutical composition of the present invention may be specified and formulated for administration through an arbitrary appropriate route. A preferred route may be selected depending on the general condition and age of a recipient, the properties of a condition to receive a treatment, and an active ingredient selected.

[0115] The pharmaceutical composition for oral administration includes solid preparations such as capsules, tablets, sugar-coated tablets, pills, lozenges, powders and granules. Such solid preparations can be prepared in a coated form, if appropriate. Nonsolid preparations for oral administrations include solutions (including solutions for inhalations), emulsions, suspensions, syrups and elixirs.

[0116] The pharmaceutical composition for parenteral administration includes, for example, injections, 221102_G2572WO English Translation (Final) clean copy suppositories, sprays, ointments, creams, gels, inhalants, skin patches, and implants. The injection is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. Every sterile aqueous medium used is readily available by a standard approach known to those skilled in the art.

[0117] In the case of preparing an oral solid preparation, a carrier, for example, an excipient, and optionally a binder, a disintegrant, a lubricant, a colorant, a corrigent, and the like can be added to a principal agent, followed by a routine method to prepare tablets, coated tablets, granules, fine granules, powders, capsules, or the like. An oral nonsolid preparation such as a syrup can also be appropriately prepared.

[0118] For example, lactose, sucrose, corn starch, saccharose, glucose, sorbitol, crystalline cellulose, or silicon dioxide is used as the excipient. For example, polyvinyl alcohol, ethylcellulose, methylcellulose, gum arabic, hydroxypropylcellulose, or hydroxypropylmethylcellulose is used as the binder. For example, magnesium stearate, talc, or silica is used as the lubricant. An agent that is acceptable for addition to medicaments is used as the colorant. For example, cacao powder, menthol, aromatic acid, mint oil, kapur, or powdered cinnamon bark is used as the corrigent. Such tablets or granules may be appropriately coated, if 221102_G2572WO English Translation (Final) clean copy necessary, with sugar, gelatin, or the like as a matter of course.

[0118] In the case of preparing an injection, a carrier, for example, a pH adjuster, a buffer, a suspending agent, a solubilizer, a stabilizer, a tonicity agent, or a preservative can be added, if necessary, to a principal agent, followed by a routine method to prepare an intravenous injection, a subcutaneous injection, an intramuscular injection, or an intravenous drip infusion agent. In this respect, a freeze-dried product may be prepared by a routine method, if necessary.

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

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

[0122] Examples of the stabilizer can include sodium sulfite and sodium metasulfite. Examples of the preservative can include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0123] <Synthesis method> 221102_G2572WO English Translation (Final) clean copy The compound represented by the general formula (I) or (II) of the present invention can be produced by a method summarized in any of reaction processes 1 to 2 given below. A modification or an alteration that is known per se to chemists in the art or can be obvious to those skilled in the art may be used in the methods described below.

[0124] In the following description about production methods, A, R, R! and Y are as defined above, unless otherwise specified.

[0125] <Process 1> A compound (I) or (II) wherein R is a Ci1-Cs alkyl group can be produced through step 1 of the following process 1. Y H NE 0 ng SN SAGE HNN o + 0 A —— H yy Step1 _, AJ H oo a (3) I ki HN OH R' \ N-NH A ht HN. N. > YY eR a \ N-NH 0 an () ¥ Y AN AN 0 H HN cor oOo A + 0 A —- (3) HN h 0 “OUT : 2 R’ HN~N A a ° u HN. N —— NY cor 1 , 0 A JR HN-N (n (2A) (In

[0126] Step 1 of process 1 is the step of condensing a compound (1A) or (2A) and a compound (3) in a solvent 221102_G2572WO English Translation (Final) clean copy using a dehydration-condensation agent to produce the compound (I) or (II) of the present invention. The compound (1A) or (2A) can be produced in accordance with syntheses 1 and 2 mentioned later and the description of Examples of the present specification. The compound (lA) or (2A) may be an acid-addition salt, etc. Examples of the acid-addition salt, etc. include hydrochloride, sulfate, and acetate.

[0127] The compound (3) can also be produced in accordance with synthesis 6 mentioned later and the description of Examples of the present specification. The compound (3) may be an acid-addition salt, etc. Examples of the acid-addition salt, etc. include hydrochloride, sulfate, and acetate.

[0128] Examples of the dehydration-condensation agent for use in step 1 of process 1 include dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide or hydrochloride thereof (EDC, EDAC), N,N-dicyclohexylamide, carbonyldiimidazole, 1H- benzotriazol-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate, and O-(7-azabenzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate. N,N'- Diisopropylcarbodiimide or dicyclohexylcarbodiimide is preferred.

[0129] Step 1 of process 1 may be performed, if necessary, in the presence of an activator such as 1 221102_G2572WO English Translation (Final) clean copy hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), or 4- dimethylaminopyridine. Step 1 of process 1 may be performed, if necessary, in the presence of a base such as N,N- diisopropylethylamine, N-methylmorpholine, or triethylamine.

[0130] The solvent for use in step 1 of process 1 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: amides such as N,N- dimethylformamide (DMF), N,N-dimethylacetamide, and N- methylpyrrolidone; halogenated hydrocarbons such as dichloromethane (DCM); esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; sulfur solvents such as dimethyl sulfoxide (DMSO); and arbitrary mixed solvents thereof. An aprotic polar solvent is preferred, and N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent prepared by mixing them is more preferred.

[0131] The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C. 221102_G2572WO English Translation (Final) clean copy

[0132] The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 120 hours, preferably 30 minutes to 48 hours.

[0133] <Process 2> A compound (I') or (II') which is a compound (I) or (II) wherein R is a hydrogen atom can be produced by subjecting the compound (I) or (II) produced by the process 1 to step 2 of the following process 2. Y Y AN AN —- H § A» °° Step2 A J H 45 4 od ; Y 8 H yes YY eon i o A \ N-NH NY cor > NYY co Ho a Step 2 Hoo a RY. Si N—NH I) (I Y Y AN AN Hp H HN. ZN HNN Y o H hd 9 H —— A Step2 ba. B28 A | 1 H | 1 H HN N. HN N. NY cor > NY ~coH oO A Step 2 , 0 A rR rR HN=N HN=N (n ay

[0134] Step 2 of process 2 is the step of hydrolyzing the ester moiety of the compound (I) or (II) or an acid- addition salt, etc. thereof in a solvent, for example, through reaction with a base to produce a compound (I') or (I1').

[0135] Examples of the base for use in step 2 of process 2 include alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and 221102_G2572WO English Translation (Final) clean copy alkaline earth metal hydroxide such as calcium hydroxide and magnesium hydroxide. Alkali metal hydroxide is preferred, and lithium hydroxide or sodium hydroxide is more preferred. These bases may each be used singly or may be used in combination of two or more thereof. A method for adding the base may involve adding the base in the form of a solution containing the base dissolved in a solvent mentioned later.

[0136] The solvent for use in step 2 of process 2 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Water, acetonitrile, tetrahydrofuran, N,N- dimethylformamide, methanol, ethanol, or a mixed solvent prepared by mixing two or more of them is preferred.

[0137] The reaction temperature differs depending on the types, usages, etc. of the starting materials, the 221102_G2572WO English Translation (Final) clean copy solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C.

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

[0139] «Synthesis 1> The compounds (1A) and (2A) for use as starting materials in the process 1 mentioned above can be produced through each step of the following synthesis 1. 221102_G2572WO English Translation (Final) clean copy HN. __S 9 To I > — Step 3 R~% 7 Step 4 Av T L HN . HN OR* CH3NCS OR I R! R! \ Step 3 \ 7 N -N, pi RE ~ ~ x N-N os (1A)-1 1) Mel v NH 2) HN.___S oo > ANH: 0 (a1) ~ I I hd HN OH R! \ a N-NH Step 5 a ° ye u R CY N—-NH (1A)-3 (1A) o oo o CH3NCS HN OR* CH3NCS NR 1 3! ~ he ORX R! >» S 1 \ 7 Step 3 { )R ; a | B —— rT ses © EO 7 R' Step4 NN Step 3 J p N-N ) pt of (2A)-1 (2A)-2 1) Mel v NH, o 2) AN H H 3 ANH: Oo (a1) — - H H nn OC S 1 7 R LA Step 5 HN-N HN~N YU oo > “oy 1 ) R HN~-N (2A)-3 (2A)

[0140] In the formulas, P! represents a protective group such as a tetrahydropyranyl (THP) group. 221102_G2572WO English Translation (Final) clean copy In the formulas, R* is a hydrocarbon group having 1 to 6 carbon atoms, specifically, preferably a C;-Cs alkyl group. In the following description about production methods, P! and R* are as defined above unless otherwise specified.

[0141] Step 3 of synthesis 1 is the step of reacting a compound (1lA)-1 or (2A)-1 with methyl isothiocyanate in a solvent to obtain a compound (1lA)-2 or (2A)-2. The compound (1A)-1 or (2A)-1 is known in the art or may be produced from another compound known in the art. The compound can be produced, for example, in accordance with syntheses 3 and 4 mentioned later and the description of Examples of the present specification.

[0142] The solvent for use in step 3 of synthesis 1 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and 221102_G2572WO English Translation (Final) clean copy arbitrary mixed solvents thereof. N,N-Dimethylformamide, N-methylpyrrolidone, or methanol is preferred. Step 3 of synthesis 1 may be performed, if necessary, in the presence of acetic acid. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 150°C, preferably 20°C to 120°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0143] Step 4 of synthesis 1 is the step of eliminating the protective group P! and the substituent R* in the compound (1lA)-2 or (2A)-2 in a solvent to obtain a compound (1A)-3 or (2A)-3. In step 4 of synthesis 1, the protective group P! may be eliminated first, or the substituent R* may be eliminated first.

[0144] When the protective group P! is, for example, a tetrahydropyranyl group, this group can be eliminated by preparing an acidic solution by the addition of an acid to a solution containing the compound (1A)-2 or (2A)-2. Examples of the acid for use in the elimination of the protective group P! in step 4 of synthesis 1 include, but are not particularly limited to, hydrochloric acid, sulfuric acid, nitric acid, and trifluoroacetic acid (TFA). These acids may each be used singly or may be 221102_G2572WO English Translation (Final) clean copy used in combination of two or more thereof. A method for adding the acid may involve adding the acid in the form of a solution containing the acid dissolved in a solvent mentioned later.

[0145] The solvent for use in the elimination of the protective group P! in step 4 of synthesis 1 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n- propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Water, tetrahydrofuran, dichloromethane, 1,4-dioxane, methanol, or a mixed solvent prepared by mixing two or more of them is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -20°C to 150°C, preferably 0°C to 100°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 24 hours, preferably 30 minutes to 10 hours. 221102_G2572WO English Translation (Final) clean copy

[0146] The substituent R* can be eliminated by adding a base to a solution containing the compound (1lA)-2 or (2A) -2. Examples of the base for use in the elimination of the substituent R* in step 4 of synthesis 1 include alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and alkaline earth metal hydroxide such as calcium hydroxide and magnesium hydroxide. Alkali metal hydroxide is preferred, and lithium hydroxide or sodium hydroxide is more preferred. These bases may each be used singly or may be used in combination of two or more thereof. A method for adding the base may involve adding the base in the form of a solution containing the base dissolved in a solvent mentioned later.

[0147] The solvent for use in the elimination of the substituent R* in step 4 of synthesis 1 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Water, tetrahydrofuran, methanol, or a 221102_G2572WO English Translation (Final) clean copy mixed solvent prepared by mixing two or more of them is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 24 hours, preferably 30 minutes to 10 hours.

[0148] Step 5 of synthesis 1 is the step of reacting the compound (1lA)-3 or (2A)-3 with methyl iodide (iodomethane) which is a methylating agent in reaction of the first stage and with diamine of the compound (al) or an acid-addition salt, etc. thereof in reaction of the second stage in a solvent to obtain a compound (1A) or (2A) . The solvent for use at the first stage in step 5 of synthesis 1 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: amides such as N,N-dimethylformamide, N,N- dimethylacetamide, and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n- hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; 221102_G2572WO English Translation (Final) clean copy and arbitrary mixed solvents thereof. N,N- Dimethylformamide or N-methylpyrrolidone is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 150°C, preferably 10°C to 120°C, more preferably 20°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 1 minute to 48 hours, preferably 10 minutes to 24 hours.

[0149] At the second stage in step 5 of synthesis 1, a compound (lA) or (2A) is produced through reaction with diamine of the compound (al) or an acid-addition salt, etc. thereof in the presence or absence of water. The compound (al) may be an acid-addition salt, etc. Examples of the acid-addition salt, etc. include hydrochloride, sulfate, and acetate. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 150°C, preferably 20°C to 120°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0150] Both the protective group P! and the substituent R* in the compound (1A)-2 or (2A)-2 are eliminated in a solvent in step 4 of synthesis 1, and then, step 5 is performed to produce a compound (lA) or (2A). 221102_G2572WO English Translation (Final) clean copy Alternatively, as shown below, the substituent R* in the compound (1A)-2 may be eliminated to prepare a compound (1A) -3' (step 4a), followed by the step 5 mentioned above to prepare a compound (1lA)-4, and then, the protective group P! can be eliminated to produce a compound (1A) (step 4b). The compound (2A) can also be produced by the same scheme as described below.

[0151] 1) Mel ~NH2 HN___S a HN. __S hd I oJ -—e AN 2° PHAN SY fo) oO 2) hg a ANH ORX OH (at) R! >» R' § 7 Step 4a \ JT Step 5 <7 Step 4a RT Step 5 NN ' NN (1A)-2 (1A)-3' Y Y AL AL oO HNN 0 HNN NF . Step 4b 1 AM DoS 1 R \ nt 1 4 DS 1 R \ Ww ob N-NH N-N oi (1A)-4 (1A)

[0152] In the scheme, the same methods as in step 4 can be applied to a method for eliminating the substituent Rx in step 4a, and a method for eliminating the protective group P! in step 4b.

[0153] <Synthesis 2> In synthesis 1, the compound (lA) or (2A) is produced using the compound (lA)-1 or (2A)-1 in which the 221102_G2572WO English Translation (Final) clean copy amino group of the 5-membered heterocyclic ring is protected with the protective group P!. This compound may be produced using a compound that is not protected with the protective group Pl. For example, the compound (lA) may be produced through each step of synthesis 2 given below using a compound (1lA)-1'. The compound (2A) can also be produced by the same scheme as in the following synthesis 2. 0 HN.__S ¥ CH3NCS 3p od) pe. I wv DOS 1, R \ NT Step3 I Step 4a HN R? : ) o —NH ’ N-NH olep o N-N N-NH (1A)-1" (1A)-2' 1) Mel v ~NHz 2) ) yANNH: 0 | HN. __S ¥ INT (a1) —_— Step 5 I 4 DOR 1 R \ IT HN Na: Da . R \ N-NH N-NH hn oN N-NH (1A)-3 (1A)

[0154] Step 3 and step 5 of synthesis 2 are the same as step 3 and step 5 of synthesis 1. Step 4a of synthesis 2 is the step of eliminating the substituent R* in the compound (1A)=-2' or (2A)-2' in a solvent to obtain a compound (1A)-3 or (2A)-3. Unlike step 4 of synthesis 1, only the operation of eliminating the substituent R* is performed in step 4a of synthesis 3 221102_G2572WO English Translation (Final) clean copy The substituent R* can be eliminated by adding a base, as in the method for eliminating the substituent Rx in step 4 of the synthesis 1 mentioned above. The type of the base for use in step 4a of synthesis 2 and a method for adding the base are the same as in the method for eliminating the substituent R* in step 4 of the synthesis 1 mentioned above.

[0155] <Synthesis 3> The compound (1A)-1 for use as a starting material in the synthesis 1 mentioned above can be produced through steps 6 to 8 of synthesis 3 given below. The compound (2A)-1 can also be produced by the same scheme as in the following synthesis 3. 0 fe] Ph NH “ Ph >», AH —_— Step 6 RC 7 Step 7 wv hed or or > R! R! Nf Step 6 \ XX ND N-NH N-N hs 1A)-1- (1A)-1-1 (1A)-1-2 Ph__Ph hd 0 0 mm mt Aik ov oO N OR* HaN ORX R! > Rt \ Sten 8 \ Step 8 N-| N, on olep © xX N: —N. ot (1A)-1-3 (1A)-1

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

[0157] Step 6 of synthesis 3 is the step of introducing the protective group P! to the amino structure moiety of the 5-membered heterocyclic ring of a compound (1A)-1-1 221102_G2572WO English Translation (Final) clean copy in a solvent to obtain a compound (1lA)-1-2. The compound (1A)-1-1 is known in the art or may be produced from another compound known in the art. A method known in the art can be used as a method for introducing the protective group P!. The method can be performed in accordance with, for example, a method described in Org. Biomol. Chem., 2017, 15, 8614-8626, or J. Org. Chem., 2015, 80, 7713-7726. Specifically, the protective group can be introduced to the amino structure moiety using a compound corresponding to the protective group to be introduced. When the protective group P! is, for example, a tetrahydropyranyl group, the tetrahydropyranyl group can be introduced to the amino structure moiety of the 5- membered heterocyclic ring through reaction with dihydropyran (DHP) in the presence of an acid catalyst (p-toluenesulfonic acid, etc.).

[0158] The solvent for use in step 6 of synthesis 3 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl 221102_G2572WO English Translation (Final) clean copy methyl ether, 1,4-dioxane, and tert-butyl methyl ether; and arbitrary mixed solvents thereof. Dichloromethane, toluene, xylene, or tetrahydrofuran is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 150°C, preferably 0°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

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

[0160] In step 7 of synthesis 3, the reaction may be performed in the presence of a ligand or may be performed in the absence of a ligand. Examples of the ligand for use in step 7 of synthesis 3 include 4,5'-bis(diphenylphosphino)-9,9'- dimethylxanthene (Xantphos) and 2,2'- bis (diphenylphosphino)-1,1'-binaphthyl (BINAP). 221102_G2572WO English Translation (Final) clean copy

[0161] In step 7 of synthesis 3, the reaction may be performed in the presence of a base or may be performed in the absence of a base. Examples of the base for use in step 7 of synthesis 3 include: alkali metal carbonate such as cesium carbonate, potassium carbonate, sodium carbonate, and sodium bicarbonate; alkali metal phosphate such as tribasic potassium phosphate, sodium phosphate, and sodium biphosphate; alkali metal fluoride 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. Alkali metal carbonate is preferred, and cesium carbonate is more preferred. These bases may each be used singly or may be used in combination of two or more thereof. A method for adding the base may involve adding the base in the form of a solution containing the base dissolved in a solvent mentioned later.

[0162] The solvent for use in step 7 of synthesis 3 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; 221102_G2572WO English Translation (Final) clean copy 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 arbitrary mixed solvents thereof. Toluene, xylene, or 1,4-dioxane is preferred. Examples of the inert gas used include nitrogen gas and argon gas. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 50°C to 250°C, preferably 70°C to 200°C. The reaction time differs depending on the reaction temperature, etc., and is usually 1 hour to 48 hours, preferably 3 hours to 24 hours.

[0163] Step 8 of synthesis 3 is the step of obtaining a compound (1lA)-1 from the compound (1lA)-1-3. A method for obtaining the compound (1A)-1 in step 8 can involve obtaining the compound (1A)-1 through the reductive reaction of the compound (1A)-1-3 in the presence of a metal catalyst and in the presence of hydrogen gas in a solvent. Examples of the metal catalyst for use in step 8 of synthesis 3 include inhomogeneous catalysts such as Pd-C catalysts, palladium hydroxide catalysts, Pt-C catalysts, and platinum oxide catalysts. The solvent for use in step 8 of synthesis 3 is not particularly limited as long as the solvent dissolves the 221102_G2572WO English Translation (Final) clean copy starting materials to some extent without inhibiting the reaction. Examples thereof include: water; acetic acid; amides such as N,N-dimethylformamide, N,N- dimethylacetamide, and N-methylpyrrolidone; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n- propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Ethyl acetate, tetrahydrofuran, or methanol is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 150°C, preferably 20°C to 100°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 120 hours, preferably 30 minutes to 48 hours.

[0164] In step 8, the compound (1A)-1 may be obtained by hydrolyzing the compound (1A)-1-3 by the addition of an acid (e.g., citric acid) solution to a solution containing the compound (1A)-1-3. The solvent for use in step 8 of synthesis 3 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; amides such 221102_G2572WO English Translation (Final) clean copy as N,N-dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene and xylene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Tetrahydrofuran is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 200°C, preferably 0°C to 100°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 120 hours, preferably 30 minutes to 48 hours.

[0165] <Synthesis 4> The compound (1A)-1 for use as a starting material in the synthesis 1 mentioned above may be produced through each step of synthesis 4 given below using a compound (1lA)-1-4 given below, in addition to the synthesis 3 mentioned above. The compound (2A)-1 can also be produced by the same scheme as in the following synthesis 4. 221102_G2572WO English Translation (Final) clean copy o o o HN a 1 \ R™ R R C NS Step 9 Nf Step 10 \_ Step9 Non Step 10 N NI H olep J » N -N 1 viep tw N -N ot (1A)-1-4 (1A)-1-5 (1A)-1

[0166] Step 9 of synthesis 4 is the step of introducing the protective group P! to the amino structure moiety of the 5-membered heterocyclic ring of a compound (1A)-1-4 in a solvent to obtain a compound (1A)-1-5. The compound (1A)-1-4 is known in the art or may be produced from another compound known in the art. The same method as in step 6 of the synthesis 3 mentioned above can be adopted as a method for introducing the protective group P! in step 9. The solvent used is also the same as that used in step 6 of synthesis 3.

[0167] Step 10 of synthesis 4 is the step of reducing the nitro group of the compound (1lA)-1-5 into an amino group to obtain a compound (1A)-1. In step 10 of synthesis 4, a method for reducing the nitro group of the compound (1A)-1-5 into an amino group to obtain a compound (1A)-1 can involve reducing the nitro group of the compound (1A)-1-5 into an amino group through the reductive reaction of the compound (1A)-1-5 in the presence of a reducing agent such as sodium dithionite in a solvent to obtain a compound (1A)-1. The solvent for use in step 10 of synthesis 4 using a reducing agent is not particularly limited as long as 221102_G2572WO English Translation (Final) clean copy the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; acetic acid; amides such as N,N- dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; esters such as ethyl acetate; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Water or ethanol is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 200°C, preferably 50°C to 150°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0168] In step 10, the compound (1A)-1 may be obtained by reducing the nitro group of compound (1lA)-1-5 into an amino group through the reductive reaction of the compound (1A)-1-5 in the presence of a metal catalyst and in the presence of hydrogen gas in a solvent. In this case, examples of the metal catalyst used include inhomogeneous catalysts such as Pd-C catalysts, palladium hydroxide catalysts, Pt-C catalysts, and platinum oxide catalysts. 221102_G2572WO English Translation (Final) clean copy The solvent for use in step 10 of synthesis 4 using a metal catalyst is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; acetic acid; amides such as N,N- dimethylformamide, N,N-dimethylacetamide, and N- methylpyrrolidone; esters such as ethyl acetate; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; alcohols such as methanol, ethanol, n-propanol, and isopropanol; nitriles such as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. Acetic acid or tetrahydrofuran is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually 0°C to 200°C, preferably 20°C to 100°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0169] <Synthesis 5> A compound (4)-S which is an S form of the compound (4) for use as a starting material in the process I mentioned above, wherein R is a C1-Cs alkyl group can be produced through steps 11 to 13 of synthesis 5 given below. The compound (4)-S is included in the compound (4). 221102_G2572WO English Translation (Final) clean copy oO Oo Brzn._co,RStep 10 ji NS 2 < Step 9 (ab) (ad) A-CHO = ——» ¥ N\ RN NS Step 11 ~~ Step 12 (4)-1 H -— HaN cor 8 A ~ 7 Step13 A H Sh eNom 0 A (4)-8-2 (4)

[0170] Step 11 of synthesis 5 is the step of reacting a compound (4)-1 with (R)-2-methylpropane-2-sulfinamide of a compound (a4) in the presence of pyrrolidine and a molecular sieve (4 angstroms) in a solvent to obtain a compound (4)-S-1. The solvent for use in step 11 of synthesis 5 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: halogenated hydrocarbons such as dichloromethane (DCM); 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 arbitrary mixed solvents thereof. Toluene or tetrahydrofuran is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the 221102_G2572WO English Translation (Final) clean copy solvent, and the like, and is usually -20°C to 150°C, preferably 0°C to 120°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0171] Step 12 of synthesis 5 is the step of reacting the compound (4)-S-1 with a compound (a5) in a solvent to obtain a compound (4)-S-2. The compound (a5) used is a compound corresponding to R of the compound (4)-S of interest. The compound (a5) is known in the art, or can be produced from a compound known in the art in accordance with the description of Examples of the present specification mentioned later. Specific examples of the 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 for use in step 12 of synthesis 5 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: halogenated hydrocarbons such as dichloromethane (DCM); aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 221102_G2572WO English Translation (Final) clean copy 1,4-dioxane, and tert-butyl methyl ether; and arbitrary mixed solvents thereof. Tetrahydrofuran is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -78°C to 100°C, preferably -20°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0173] Step 13 of synthesis 5 is the step of reacting the compound (4)-S-2 with an acid in a solvent to obtain a compound (4) -S. Examples of the acid for use 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, hydrobromic acid, and sulfuric acid. Hydrochloric acid is preferred. These acids may each be used singly or may be used in combination of two or more thereof. A method for adding the acid may involve adding the acid in the form of a solution containing the acid dissolved in a solvent mentioned later.

[0174] The solvent for use in step 13 of synthesis 5 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: water; alcohols such as methanol and ethanol; halogenated hydrocarbons 221102_G2572WO English Translation (Final) clean copy 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; and arbitrary mixed solvents thereof. An ether, an alcohol or an arbitrary mixed solvent thereof is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 1 minute to 48 hours, preferably 10 minutes to 24 hours. The compound (4)-S thus obtained may be an acid- addition salt, etc. Examples of the acid-addition salt, etc. include hydrochloride, sulfate, and acetate.

[0175] As described above, the compound (4)-S can be synthesized through steps 11 to 13 of synthesis 5. An asymmetric compound opposite to the compound (4)-S can be synthesized through steps 11 to 13 using, for example, (S)-2-methylpropane-2-sulfinamide, instead of the compound (a4). Further, a racemate of the compound (4)-S can be synthesized through steps 11 to 13 using, for example, racemic 2-methylpropane-2-sulfinamide, instead of the compound (a4).

[0176] <Synthesis 6> 221102_G2572WO English Translation (Final) clean copy The compound (3) for use as a starting material in the process 1 mentioned above, wherein R is a C;-Cs alkyl group can be produced through steps 14 and 15 of the following synthesis 6. Hw © Regi, H (a6) HNScor —_— = nr eR H HNN cor 0 A P2 f NY cor _ co A St A Step14 ~~ © A Step 15 ¢ a “) 3)1 3)

[0177] Step 14 of synthesis 6 is the step of reacting the compound (4) obtained by a method such as synthesis 5 or an acid-addition salt, etc. thereof with a compound (a6) in the presence of a dehydration-condensation agent in a solvent to obtain a compound (3)-1. In the formulas, P2 represents a protective group such as a t-butoxycarbonyl group (Boc).

[0178] Examples of the dehydration-condensation agent for use in step 14 of synthesis 6 include dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide or hydrochloride thereof (EDC, EDAC), N,N-dicyclohexylamide, l-hydroxybenzotriazole, carbonyldiimidazole, 1H-benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate, and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. 1-(3-Dimethylaminopropyl)=-3- ethylcarbodiimide or hydrochloride thereof (EDC, EDAC) is preferred. 221102_G2572WO English Translation (Final) clean copy

[0179] In step 14 of synthesis 6, the reaction may be performed in the presence of a base or may be performed in the absence of a base. Examples of the base for use in step 14 of synthesis 6 include N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, 4-(N,N-dimethylamino)pyridine, and N- ethyl-N-isopropylpropan-2-amine. N,N- Diisopropylethylamine or triethylamine is preferred. These bases may each be used singly or may be used in combination of two or more thereof. A method for adding the base may involve adding the base in the form of a solution containing the base dissolved in a solvent mentioned later.

[0180] The solvent for use in step 14 of synthesis 6 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. Examples thereof include: amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane (DCM); esters such as ethyl acetate; hydrocarbons such as dichlorohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl methyl ether; and arbitrary mixed solvents thereof. Dichloromethane is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the 221102_G2572WO English Translation (Final) clean copy solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 72 hours, preferably 30 minutes to 48 hours.

[0181] Step 15 of synthesis 6 is the step of deprotecting the protective group P? from the compound (3)-1 using an acid in a solvent to obtain a compound (3). Examples of the acid for use 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, hydrobromic acid, and sulfuric acid. Hydrochloric acid is preferred. These acids may each be used singly or may be used in combination of two or more thereof. A method for adding the acid may involve adding the acid in the form of a solution containing the acid dissolved in a solvent mentioned later.

[0182] The solvent for use in step 15 of synthesis 6 is not particularly limited as long as the solvent dissolves the starting materials to some extent without inhibiting the reaction. 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 221102_G2572WO English Translation (Final) clean copy as acetonitrile and propionitrile; and arbitrary mixed solvents thereof. An ether, an alcohol or an arbitrary mixed solvent thereof is preferred. The reaction temperature differs depending on the types, usages, etc. of the starting materials, the solvent, and the like, and is usually -20°C to 100°C, preferably 0°C to 50°C. The reaction time differs depending on the reaction temperature, etc., and is usually 10 minutes to 72 hours, preferably 30 minutes to 48 hours. The compound (3) thus obtained may be an acid- addition salt, etc. Examples of the acid-addition salt, etc. include hydrochloride, sulfate, and acetate.

[0183] In the present specification, the obtained compound in each step may be isolated or purified by an approach known in the art or may be subjected directly to a subsequent step. The isolation or the purification can be carried out by use of a usual operation, for example, filtration, extraction, crystallization, or each column chromatography.

[0184] <Intermediate of present invention> In one embodiment of the present invention, compounds given below which are intermediates of the compound (I) or (II) or a pharmaceutically acceptable salt thereof are also included in the present invention. In one embodiment, examples of the intermediate of the present invention include compounds represented by 221102_G2572WO English Translation (Final) clean copy the following general formula (X-1) or (X-2) and salts thereof: Y 9 oO Y R R o oh ow T ow ORXA HN ny or \ Cre N~—nI 3 ! -N i RZ A NN (X-1) (X-2) In the formulas (X-1) and (X-2), RY is a group represented by the following formula (x)-1i or (x)-ii: Y A R7 \ N \ S Hp LW * * (x)-i (x)-ii wherein Y is a hydrogen atom, a fluorine atom or a hydroxy group, as in the general formulas (I) and (II), R7 is a C1-Cs alkyl group, and * represents a binding position. R! is a hydrogen atom or a halogen atom, as in the general formulas (I) and (II). RX** is a hydrogen atom or a hydrocarbon group having to 6 carbon atoms and is preferably a hydrogen atom or a C1-Cgs alkyl group. 221102_G2572WO English Translation (Final) clean copy R? is a hydrogen atom or P! (wherein P! represents, as mentioned above, a protective group such as a tetrahydropyranyl (THP) group).

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

[0186] In one embodiment, examples of the intermediate of the present invention include compounds represented by the following general formula (X-1-1) or (X-2-1) and salts thereof: RYA o RYA o rr rd he a | i | | “XR 1A NO / R 1 oO 1A Rr \ _N-N RZA NO N-N{ RZA (X-1-1) (X-2-1) In the formulas (X-1-1) and (X-2-1), RY is a group represented by the following formula (x)-i-1, (x)-i-2, (x)-1-3, or (x)-ii-1: 221102_G2572WO English Translation (Final) clean copy F OH AT ATA HNN HN__N HN__N HN__S Fh TNE Tg NF * * * * (x)-i-1 (x)-i-2 (x)-ii-1 wherein * represents a binding position. RIA is a hydrogen atom, a fluorine atom, or a chlorine atom. RX*Al is a hydrogen atom or a methyl group. RZ? is a hydrogen atom or a tetrahydropyranyl (THP) group.

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

[0188] In one embodiment, examples of the intermediate of the present invention include compounds selected from the following group and salts thereof: 221102_G2572WO English Translation (Final) clean copy | | | HN.S HN S HN > HN. HN HN. 2 oe oo xo Cg ~ < N-NH N-NH N-NH | | | HN S$ HN S$ S 7 0 Wil Hig Hs NS HN on HN HN i ~F HN on MN oH “A A $4. oe : 0 0 A | | HN. HN SS vo My : “X hr Hit] Hi

[0183] In one embodiment, the intermediate of the present invention is a compound selected from the following group or a salt thereof: | | | HN HS HN S$ YF 9 Y Y 0 wel oo MN or HN 7” Sef Bf < N-NH N-NH N-NH | | | Hs i ps | | HN S$ HN S o HN on MN on HN = TI xX Ny oH OH ci F~( < J NN, NN, NN, cr F 221102_G2572WO English Translation (Final) clean copy

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

[0191] In one embodiment, the intermediate of the present invention is a compound selected from the following group or a salt thereof: Next AM HN=-N HN=-N HN~N

[0192] In another embodiment, examples of the intermediate of the present invention include compounds represented by the following general formula (X-3) and salts thereof: H RW ~N N ‘ N N ~~ I COR . oO A (X-3) In the formula (X-3), A is a Ce¢-Cio aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the hetercaryl group is optionally 221102_G2572WO English Translation (Final) clean copy replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Cg alkyl group, a C;-C¢ haloalkyl group, a C,-Cg¢ alkenyl group, a C,-Cg¢ alkynyl group, a C;-Cs alkoxy group, a C;-Cg haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Ce cycloalkenyl group, a C;-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C;-Cs alkylsulfanyl group, and a C;-Cs alkylsulfonyl group, as in the general formulas (I) and (II). R is a hydrogen atom or a C;-Cg¢ alkyl group, as in the general formulas (I) and (II). R" is a hydrogen atom or P2, wherein P? represents, as mentioned above, a protective group such as a t- butoxycarbonyl group (Boc).

[0193] In one embodiment, examples of the intermediate of the present invention include compounds represented by the following general formula (X-3-1) and salts thereof: H RW ~ N N N N ~ 1 COR (X-3-1) oO RE = RS NN 2 R3 R4 In the formula (X-3-1), 221102_G2572WO English Translation (Final) clean copy R? is a hydrogen atom or a halogen atom, R3 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs¢ haloalkyl group, a C;-Cg¢ alkoxy group, a C1-C¢ haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group, R¢ is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Ce¢ haloalkyl group, a C;-Ce¢ alkoxy group, or a C1-Cs haloalkoxy group, RS is a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a C;-Cs haloalkyl group, a C;-C¢ alkoxy group, a C;-C¢ haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group, Rf is a hydrogen atom or a halogen atom, R is a hydrogen atom or a C;-Cs alkyl group, as in the general formulas (I) and (II), and R¥ is a hydrogen atom or P2 (wherein P? represents, as mentioned above, a protective group such as a t- butoxycarbonyl group (Boc)).

[0194] In one embodiment, examples of the intermediate of the present invention include compounds represented by the following general formula (X-3-2) and salts thereof: H RW ~ N % N N ~~ I COR al oO Al (X-3-2) 221102_G2572WO English Translation (Final) clean copy R is a hydrogen atom or a C;-Cs alkyl group, as in the general formulas (I) and (II). R¥ is a hydrogen atom or P2 (wherein P? represents, as mentioned above, a protective group such as a t- butoxycarbonyl group (Boc)). Al is a group selected from the group given below. In the following formulas, * represents a binding position. : CFs 'CF3 A a a A a 1 OMe OMe cr Br’ FaHCO’ 'CF3 CF "OCHF, Br’ "OCHF, 'OCHF, F 2 2 2. .0.70 QL F2HCO’ 0) FHC "OCHF, CI "OCF; Br OCFy "OCF; OCF; CF3 F A. O.. A.. a, 2.0, &, Quy Oy Oy DQ

[0195] In one embodiment, the intermediate of the present invention may be a salt of the compound represented by any of the formulas (X-1) to (X-3), the formula (X-1-1), the formula (X-2-1), the formula (X-3-1) and the formula 221102_G2572WO English Translation (Final) clean copy (X-2-3). Examples of the salt include, but are not particularly limited to, the "acid-addition salt, etc." and the "base-addition salt, etc." listed as examples of the "pharmaceutically acceptable salt" mentioned above.

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

[0197] Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples. However, the scope of the present invention is not limited by these examples. The names Reference Examples, Examples and Test Examples are merely given for the sake of convenience in order to discriminate among experimental examples and do not mean that any of these examples are not included in the present invention.

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

[0198] In the present specification, H-NMR is indicated by chemical shift (8) with tetramethylsilane as an internal standard (0 ppm), and a coupling constant (J value) is indicated by Hz unit, unless otherwise specified. The abbreviation of the splitting pattern of each peak means the following: s: singlet, d: doublet, dd: double doublet, ddd: double double doublet, t: 221102_G2572WO English Translation (Final) clean copy triplet, tt: triple triplet, quin: quintet, and m: multiplet.

[0200] Abbreviations described in Reference Examples, Examples, Test Examples and chemical structural formulas are typically used in meanings that are generally used in the field of organic chemistry or pharmaceuticals, and specifically, should be understood as the abbreviations of the following terms by those skilled in the art. Me: methyl group DMSO: dimethyl sulfoxide tert: tertiary N: normal M: molar concentration ESI: electrospray ionization APCI: atmospheric pressure chemical ionization EI: electronic ionization CI: chemical ionization

[0201] Reference Example 1-(a) Production of (R,E)-N-(3-chloro-5- (trifluoromethyl)benzylidene)-2-methylpropane-2- sul finamide o N.. )®! CI NCE,

[0202] To a solution of 3.82 g of 3-chloro-5- (trifluoromethyl) benzaldehyde in toluene (20 ml), 2.35 g 221102_G2572WO English Translation (Final) clean copy of (R)-2-methylpropane-2-sulfinamide (manufactured by Combi-Blocks Inc.), 0.079 ml of pyrrolidine, and 4 g of a molecular sieve (4 angstroms) were added at room temperature under a stream of argon, and the mixture was stirred at 70°C for 2.5 hours. After the completion of reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure. Hexane was added to the concentration residue, and the mixture was stirred at room temperature for 30 minutes. A deposited solid was collected by filtration, washed with hexane, and then 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(a) to obtain compounds described in the following Tables 1-1 to 1-8. 221102_G2572WO English Translation (Final) clean copy

[0204] Table 1-1 Reference Example Structural formula Mass spectrum >Lo - 9 Reference Ns (Cl, mz): 356, 358 [M+H]* | Example 2-(a) 1 ) | © Br eR So LE Roe My (ESI, mz): 404 [+H] | Example 3-(a) DR N a I Clg So cS Reference Ne | (DUIS, miz): 292 [M+H]* | Example 4-(a) 1 | N ~ Cy 0 Refurence 8 (ESI, m / z): 308 [M+H]* Example 5-(a) bY N & ~o CF So <9 Reference Ny | (ESI, m / z): 206 [M+H]* | Example 6-(a) 1 x N a r ou Slo 3 Reference Ny (ES, miz): 346 [MH] Example 7-(a) 1 N a FiC CF 7 CF, 221102_G2572WO English Translation (Final) clean copy

[0205] Table 1-2 Reference Example | Structural formula Mass spectrum So | (ESI, m / z): 296 [M+HI* Reference Example | 9-(a) N > & CF3 “CFs Lo (ESI, mz): 312 [M+H]* Reference Example | 10-(a) N Ss oc CFs 0 dd s | ES, mi: 296 11-(a) 1, oo "ow Reference Example Ng OH, ml I eile Lo 1 a (ESI, m / z): 312 [M+H] oo N, dd 7 (ESI. miz): 296 [M+H]* 13a) A Lo Reference Example | Ne (ES, m / z): 292 [M+HI* 14-(a) PN 221102_G2572WO English Translation (Final) clean copy

[0206] Table 1-3 Reference Example | Structural formula Mass spectrum 0 Reference Example | Ns Si A (ESI, m / z): 330 [+H] Loo Reference. Example | M (ESI, mfz): 318, 320 [M+H]* 16a) A 3 Ns OMe Lo Reference Example | 17-(a) (ESI, mz): 322, 324 [MH] Reference Example | NS (DUIS, m / z): 278 [M+H]* 17-(@) ' al cl Ago Refeance Example | NS | Esl mz): 322, 324 [Mt -(a) ~ J N, a Br Cl 0 | (ESI, m / z): 368 [M+H]* Reference Example | 19-(a) x N, ~ Br Br oo (ESI, mz): 414, 416 [M+H]* Reference Example | 20-(a) N a | Br 221102_G2572WO English Translation (Final) clean copy

[0207] Table 1-4 Reference Example | Structural formula Mass spectrum Lo | (ESI, m / z): 370 [M+HI* Reference Example | 21-0) N, A cl 1 Lo Reference. Example | Ms (ES, mz): 262 [M+H]* 2) 1s yo Reference Example | sy (ESI, miz): 306, 308 [M+H]* Lo oN Reference Example Ny \ . | ee | ML | (ESI, m / z): 344 [M+H] -R Ny | ES! Fo Fo CF; Soo TE Ge Reference Example | Ng (ESI, m / z): 310 [M+H]* 25-(b) No NS (ES A . ae > 0 wo Reference Example | 'R | (ESI, m / z): 354, 356 [M+H]* 26-0) DE Ng | ES! A aoe 221102_G2572WO English Translation (Final) clean copy

[0208] Table 1-5 Reference Example | Structural formula Mass spectrum Noo Reference Example | s (ESI, m / z): 294 [M+H]* 27-(b) Ry So Reference Example | 28-(b) | (Cl, miz): 342 [M+H]* Reference Example | Ny (ESI, miz): 294 [+H] 28-(b) ¥ Rare Ls Reference Example NS . +. | NE) | ; Pp } (CI, miz): 342 [M+H] - 3 e | Ny | F 2 I | i-ho~Photy | Soo Reference. Example | Ns | (ESI, m / z): 328 [M+H]* 31-(a) 1 a. A N, ’ | ESI, cl OCF; Xo oy Referance Example | Ns (ES, miz): 372, 374 [M#H]* 32-(a) 1 = N : (ES Br OCF; Loo Reference Example | Na | (ESI, m / z): 312 [M+H]* 221102_G2572WO English Translation (Final) clean copy

[0209] Table 1-6 Reference Example | Structural formula Mass spectrum Lo (ES, miz): 278 [M+H]' Reference Example | NS (ESI, mz): 312 [+H] OCF | i go Ref Exampl f Lye ample | 1 | Es! mlz): 278 [M+H]* Na So Si Reference Example | Ng (ES, mz): 204 [M#H* 3-(a) 1 OCF, >So Reference Example | Ny Es, mia): 276 [MH] 37-(a) PU OL, So Reference Example | Ns a 2, (ESI, m / z): 260 [M+H] >Lo 3 Reference Example Ns : | | hy 1 | (ESI, miz): 250 [M+H] 221102_G2572WO English Translation (Final) clean copy

[0210] Table 1-7 Reference Example | Structural formula Mass spectrum So | (ESI, m / z): 266 [M+HI* Reference Example | 40-(a) NO La oo FE Ae Reference Example | Ny (ESI, miz): 244 [M+H]* 41a) 1 PN Reference Example | Ns (ESI, miz): 288, 290 [M+H]* 4242) 1 No Reference Example | LN 38) A | (ESI, mz): 276 [M+H] So N, Ref Exampl S iif ane] A | ES, mz: 304 poad Apo N, Reference Example N ! . | 45a) | (ES, miz): 295 [M+H] 221102_G2572WO English Translation (Final) clean copy

[0211] Table 1-8 Reference Example | Structural formula Mass spectrum Ls Re Exampl | Se xample | A | Esl miz): 276 [M+H]* Ao N Reference Example "S ! . | a) ths | (ESI, m / z): 278 [M+H]

[0212] Reference Example 1-(b) Production of methyl (S)-3-(((R)-tert- butylsulfinyl)amino)-3-(3-chloro-5- (trifluoromethyl) phenyl) propanoate slo "er LL oF cE,

[0213] To 33.3 g of zinc, 5.05 g of copper(I) chloride was added with stirring under a stream of argon, followed by deaeration under reduced pressure at a bath temperature of 70°C for 15 minutes. After purging with argon, 45 ml of tetrahydrofuran was added thereto under a stream of argon, and the mixture was stirred at 70°C for . hour. Then, the bath temperature was lowered to 40°C, and 10.4 ml of methyl bromoacetate was added dropwise 221102_G2572WO English Translation (Final) clean copy thereto at an internal temperature of 30°C to 37°C. After the completion of addition, the mixture was stirred at a bath temperature of 50°C for 1 hour. The reaction mixture was brought back to room temperature and then cooled in an ice salt bath. 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 thereto at an internal temperature of -5°C or lower under a stream of argon, and the mixture was further washed repeatedly with 7.50 ml of tetrahydrofuran. After the completion of dropwise addition, the mixture was cooled in an ice bath and stirred for 2 hours. After the completion of reaction, the reaction mixture was filtered through celite (545) and washed with ethyl acetate. Then, a saturated aqueous solution of ammonium chloride was added to the filtrate, and the mixture was stirred. This mixed solution was filtered, and the filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained concentration residue was purified by medium-pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate) to obtain 4.82 g of the title compound as a pale yellow oil. 221102_G2572WO English Translation (Final) clean copy Mass spectrum (ESI, m / z): 386 [M+H]*.

[0214] Reference Example 2-(b), etc.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(b) to obtain compounds described in the following Tables 2-1 to 2-8. 221102_G2572WO English Translation (Final) clean copy

[0215] Table 2-1 Reference Example Structural formula | Mass spectrum oo Reference HN o. : . | ii Xr | (Cl, mz): 430, 432 [M#H] NO CT HN oO. & Br CFy 0 Li Reference HN Oo. ; le | iii TY | (ESI, miz): 478 [M+H] I HN o. &F I CFs Shoo Rokionge HN Bi | esl miz): 366 [M+HI" Example 4-(b) lo HN o. aE CFy 0 Reference HN I) | Example 5-(b) TY > (ESI, m / z): 382 [M+H]* Aa Yel HN o. &F “So CF Lo Reference HN o | Example 6-(b) TY - | £8, maa pt CO 7 HN o. &F F CF; Ao Bokahne = Os | (ESI, m / z): 420 [M+H]* | Example 7-(b) XY J ANS Os oo FC CF, 221102_G2572WO English Translation (Final) clean copy

[0216] Table 2-2 Reference Example | Structural formula Mass spectrum SL 0 | oe Example | i oa (ESI, m / z): 370 [+H] F Ea - 3 HN CO,Me F CF3 Slo Reference Example | HN CoMe (ES! miz): 386 [M+H]* 10-(b) [a "= HN COMe cl CF3 oo Reference Example | HN come | Esa: 370 [M+H]* 11-(b) ALF ME - ? HN co me O FiC Lo (ESI, m / z): 386 [M+H]* Reference Example | 12-(b) can ; ANS ~come or FC [R (ESI, miz): 370 [+H] i Reference Example | 13-(b) HN. Oo ° CF ¥ Soo Reference Example HN Os ” + | pe | TT | Est mis 366 [M#H] HN o. 0 Fy 221102_G2572WO English Translation (Final) clean copy

[0217] Table 2-3 Reference Example | Structural formula Mass spectrum Loo HN. 0. Reference. Example | ~ | (ESI, mz): 404 [M#H]" 16-6) As rg HN oo cl SL Lo Reference Example | come = miz): 392, 394 [M+H]* 16-(p) A ' ' LE wn 'CO;Me Br OMe eo (ESI, miz): 352 [+H] Reference Example | 17-(b) HN OL o cl Cl Slo (ESI, m / z): 396, 398 [M+H]* oO Reference Example | 18-(b) 9 V AOS 0 Br cl Ao cw Reference Example HN 0. . . | i | YY ~ | Esti: 442 [MH] Cr HN o. &F Br Br Soo Reference Example | HN OMe | (ESI, miz): 488, 490 [M+H]* 20) I I HN OMe & I Br 221102_G2572WO English Translation (Final) clean copy

[0218] Table 2-4 Reference Example | Structural formula Mass spectrum Sle (ESI, miz): 444 [+H] Reference Example | 21-(d) HN Oo. &F ci | Ao Reference Example | HN come | (ESI, mlz): 336 [M#HI" 22-(b) UF oo <2 ) hid “7 coMe or cl > 0 | Reference Example | Hoge (ESI, mz): 380, 382 [M+H]* 23-(b) iF LF hx CO,Me F Br Slo ME Reference Example HN o | ; Ls ] OY ~ | ES, mi: 418 ot HN on ! 0 ¢ pry CF So (ESI, miz): 384 [+H] Reference Example | 25-(c) po HN o. Vp of oi So (ESI, miz): 428, 430 [M+H]* Reference Example | 26-(c) L HN (Ny Op Br als 221102_G2572WO English Translation (Final) clean copy

[0219] Table 2-5 Reference Example | Structural formula Mass spectrum So Reference Example wl Os y . Ls LE | ES, mi: 38 ot >A 0 Reference Example | 28-(c) HN co ve | (ES, mlz): 368 [MH] LO F Aq Ao Reference Example | 30-(d) | HN os | ES mi: 416 iy F Se | pho Foe | SL 0 (ESI, m / z): 402 [M+HI* Oo Reference Example | 31-(b) R\ ARO Oo Ct 'OCF3 Ao : 446, 448 [M+H]* HO | Est ma: 445, Example I Reference r 1% oe: i HN NT oe Br OCF4 Ao (ESI, m / z): 386 [MH] Reference Example | 33-(b) or hy OMe E F,CO 221102_G2572WO English Translation (Final) clean copy

[0220] Table 2-6 Reference Example | Structural formula Mass spectrum Soo Reference Example IN Os | 34-0) TY (ESI, m / z): 386 [M+H]* IN oO. ° OCF; z >A 0 a Reference Example HN CN ; - | iy | TY (ESI, m / z): 352 [M+H] I HN Se. &F CFs So (ESI, m / z): 368 [V+H]* Reference Example | 36-(b) = & CO,Me OCF; A 0 (ESI, m / z): 350 [V+H]* cw Reference Example | HN ove 37-(b) A T Wwave QL F aad “| Soo Reference Example HN 4 | . | py % (ESI, miz): 334 [M+H] HN. o. yo HN o Referance Example | Tr | Est mis 304 [Me 39-0) L$ idl ! HN 0. & 221102_G2572WO English Translation (Final) clean copy

[0221] Table 2-7 Reference Example | Structural formula Mass spectrum Lo (ESI, miz): 340 [M+H]" Reference Example | HN Oo Ls Y 0 (ESI, mz): 318 [M+H] Reference Example | 41-(b) ww v ih mB, A. © oN >A 5° HJ N : 362, 364 [M+ HO (ESI, mlz): 36 Example I Reference De | 42-(b) - i Wp = oC Br Skoo Reference Example HN Os 4; + | ii | 3% | Es mi: 350 [+H a HN Oy, &F N vy So HN 0. Reference Example "> | . | i XY | (ESI, m2): 378 [M+H] 0 oO (ESI, m / z): 369 [M+H]* Reference Example | 45-(b) 3 221102_G2572WO English Translation (Final) clean copy

[0222] Table 2-8 Reference Example | Structural formula Mass spectrum Lo Reference Example | ° (ESI, miz): 350 [M+H]* 46-(b) Sy HN. oO. : ° Sy” Reference Example HN Oo ” " | is | 3 | esi mi: 352 [M+H]

[0223] Reference Example 1-(c) Production of methyl (S)-3-amino-3-(3-chloro-5- (trifluoromethyl) phenyl) propanocate hydrochloride Her H:N 2. Tr 1 . 0 CI” FCF,

[0224] To a solution of 24.6 g of methyl (S)-3-(((R)- tert-butylsulfinyl)amino)-3-(3-chloro-5- (trifluoromethyl) phenyl) propancate 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 solution of hydrogen chloride in cyclopentyl methyl ether were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture was concentrated under reduced pressure. 50 ml of cyclopentyl methyl ether and 600 ml of hexane were added to the concentration residue, and the mixture was stirred at room temperature for 1 hour. A deposited 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(c) to obtain compounds described in the following Tables 3-1 to 3-7. 221102_G2572WO English Translation (Final) clean copy

[0226] Table 3-1 Reference Example Structural formula | Mass spectrum HCI Oo. HN 0 Reference z YY > eu m / z): 326, 328 [M+H]* Example 2-(c) AN 0 r 1 Jo N Br CF, HCI Oo. HN HoN Oo Reference i di = iz): 374 [MH] Example 3-(c) AN o 1 1 oe | CF3 HCH OL HN HN 0. Reference YY | ous, mlz): 262 (MeH' Example 4-(c) AL © ki 1 oc Qn HCI HoN o Reference GH | es. mz): 278 [M+H]* Example 5-(c) A o 1 Jig oN ~o CF; HCI Oo. PN HzN O Reference ? YY ~ | Es! m / z): 266 [M+H]* Example 6-(c) A le] oO F CFs HCI HN om roa | (ESI, m / z): 266 [M+H]* Example 9-(c) ANF Lg : CF; 221102_G2572WO English Translation (Final) clean copy

[0227] Table 3-2 Reference Example | Structural formula Mass spectrum HCI HN co Me (ESI, miz): 282 [+H]* Reference Example | 10-(c) CF, HCI HN 2 come (ESI, miz): 266 [M+H]* = Reference Example | 11-(c) | Fic” HCI HN Aco me (ESI, miz): 282 [+H] Reference Example | 12-(c) FN le | co, Cl | A HCI OL HN oO (ESI, mz): 266 [M+H]* Reference Example | 13-0) FE HCI 0 (ESI, m / z): 300 [M+H]* Reference Example | 15-(e) HN OL 0 cl CFs F HCI Hon co Me (ESI, m / z): 288, 290 [M+H]* Reference Example | 16-(c) JO OMe 221102_G2572WO English Translation (Final) clean copy

[0228] Table 3-3 Reference Example | Structural formula Mass spectrum HCI HoN 0 Yr - (DUIS, m / z): 248 [M+H]* Reference Example | 17-(c) 0 Ci Cf HCI Reference Example | 19-(c) (ESI, mlz): 384, 386 [M+H]* MaiN J. Reference Example | Eh a (ES, mz): 338 [M#HI* 19-(c) > 0 ' Br Br | Hel HN OMe Reference Example | 2 as EC ma): 384, 386 [M 20-(c) oh, 0 HN “yp OMe 00 1 Br | Hl (ES, mz): 340 [M+H]* Reference Example | 21-(e) HN 0 oe cl | HCI HN come Reference Example | 22-0) (ES, mz): 276, 278 [M+H]* riety Reference Example | YY “COMe (ESI, miz): 232 [WH 22-(c) or cl HN ~~ CO;Me os Example | or | Est mlz): 276, 278 [Mh (0) AN | F Br 221102_G2572WO English Translation (Final) clean copy

[0229] Table 3-4 Reference Example | Structural formula Mass spectrum HCI (ESI, mz): 314 [M+H]* Reference Example | 24-(d) . | HN Os, 1 &F | Ao CF HCI OL HN (ESI, m / z): 280 [M#H]* Reference Example | 25-(d) 1 Cp 00s Cl , HCI SN FN (ESI, m / z): 324, 326 [M+H]* Reference Example | 26-(d) 1 Tp 0 Br - HCI (ESI, mz): 264 [+H] Yr Loi was | 2, | Est mia 204 os or E. Reference Example | HN. CO,Me (ESI, mz): 264 [M#HI* 28-(d) LAF mlz) le | AN co,me i F | Fo HCI (ES, mz): 312 [M+H]* Reference Example | 30-(e) e | FN o. ] ~ 1 | Ho oe 221102_G2572WO English Translation (Final) clean copy

[0230] Table 3-5 Reference Example | Structural formula Mass spectrum HCI Oo. HN Oo (ESI, miz): 298 [+H] Reference Example | 31-(c) 1 1 00 cl OCF, | Hel HN 0 Reference Example | 2 yO | Es. miz): 342, 344 [M+H] 32:c) A © 1 1 oe Br OCF5 (ESI, miz): 282 [+H] Reference Example | 33-(c) HN come ple | 2 Te | | F4CO~ C HC! SN FN © (ES, mz): 248 [M+H]* Reference Example | 35-(c) HCI HoN ~CoMe (ESI, mz): 264 [+H] Reference Example | 36-(c) HCI HN OMe (ESI, mz): 246 [M+H]* F Reference Example | 37-(c) OL: oF 221102_G2572WO English Translation (Final) clean copy

[0231] Table 3-6 Reference Example | Structural formula Mass spectrum HCI oO (ESI, mz): 230 [+H] Reference Example | 38-(c) HaN Oo. Oo ¢ F HCI HN Oo. YY (ESI, mz): 220 [M#H]* Reference Example | 39-(c) HCI Oo. HN oO (ESI, miz): 236 [+H] Reference Example | 40-(c) Coa HCl oO (ES, mz): 246 [M+H]* Reference Example | 43-(c) a Oo Qo HCI Refel | rence 4 Exa mj ple | Hlth ANS o NN | (ES, , mlz): 2 : 274 [M +H] HCI o (ESI, mz): 265 [M+H]* Reference Example | 45-(c) HzN 0. &F NT wood NN) 221102_G2572WO English Translation (Final) clean copy

[0232] Table 3-7 Reference Example | Structural formula Mass spectrum HCI oO (ESI, miz): 246 [M+H]* Reference Example | 46-(c) Er © oy F HCI Fan ad | Reference Example | LT (ESI, m / z): 248 [M+H]* 47-0) | HN OL : 0 CF,

[0233] Reference Example 1-(d) Production of methyl (S)-3-(2-((tert- butoxycarbonyl)amino)acetamido) -3- (3-chloro-5- (trifluoromethyl) phenyl) propanoate a i 1 i 0, N - = ~ - . hey ry ea 0 J : Fo Q oS, CFa

[0234] To a solution of 2.23 g of methyl (S)-3-amino-3- (3-chloro-5- (trifluoromethyl) phenyl) propanocate hydrochloride synthesized in Reference Example 1-(c), and 0.977 ml of triethylamine in dichloromethane (20 ml), 1.36 g of (tert-butoxycarbonyl)glycine and 1.61 g of 1 (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added at room temperature under a stream of argon, 221102_G2572WO English Translation (Final) clean copy and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixed solution was subjected to extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentration residue was purified by medium-pressure preparative chromatography (silica gel, eluting 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(d) to obtain compounds described in the following Tables 4-1 to 4-8. 221102_G2572WO English Translation (Final) clean copy

[0236] Table 4-1 Reference Example Structural formula Mass spectrum e H N 0. Roforange Shohyy i |e iz): 483, 485 [M+H]" Example 2-(d) 0 AN 0 1 1 1 oO Br CFy oO Reference Example 3-(d) 0 PN { o. >o NY TY [SEE [M#H]* L., SK N 0. Refoionce NY YY | est me tsps Example 4-(d) o AN o Ji 1 Ji ol CFs 9 A SLR N 0. Rotana NY YY stm 8 IM#HI Example 5-(d) 0 A o 1 1 il So CF, oO oO A. OO Reference Example 6-(d) QO H ° oer ~ | (ESI, mlz): 423 [+H] 0 oO 0, 0 o Lm A Reference Se N 7 coMe ; , | Example 7-() NY es (ESI, m / z): 473 [M#H] “O FaC CFs 221102_G2572WO English Translation (Final) clean copy

[0237] Table 4-2 Reference Example | Structural formula Mass spectrum o “ Reference Example | 9d) oO H SoA A come (ESI, miz): 445 [M+Na]* 0 F AN Lg CF3 o 0 Reference Example | 10-(d) Oo AK ho NY cove | (ESI, mz): 461 [M+Nal* NY CF, 0 4 £ m / z): 445 [M+Na]* Na come | (ESI, Holy Ye . | Reference Example | 11-(d) fo} Reference Example | 12-(d) : Nal* i fd Sl, m / z): 461 [M+ N CO,Me IG i Fo hy © FiC Oo Reference Example | 13-(d) 2 H Mody foo io QL (ESI, miz): 423 [M+H]* CF3 : 0 Reference Example | 14-(d) 0 H o N he; Ay Ty | (ESI, mz): 419 [M+H] C. 221102_G2572WO English Translation (Final) clean copy

[0238] Table 4-3 Reference Example | Structural formula Mass spectrum o H Oo SLL Ho YY (ESI, miz): 457 [M+H]' Reference Example | 15-(f) F 0 Reference Example | 16-(d) 0 SLL i o. 0” °N YY AF | (ESI, miz): 445, 447 [MH] Br 0 oO SUA { oL © NY XY | (ESI, miz): 427 [M+Na* Reference Example | 17-(d) x 5 A o To cl oll 0 oO SLL Ho 0” °N ~ i + NY 1X (ESI, miz): 449, 451 [M+H] Reference Example | 18-(d) Nn | A Br Ci Oo Reference Example | 19-(d) 1 H ody A ! To (DUIS, miz): 493 [M-H} 0 0 Br Br oO Reference Example | 20-(d) SA Mo o TY i ! ~. Esl miz): 541, 543 [M#H]* Br I 221102_G2572WO English Translation (Final) clean copy

[0239] Table 4-4 Reference Example | Structural formula Mass spectrum oO Reference Example | 21-(f) SL AH ol 0 NY I (ESI, miz): 497 [M+H]* Ci 1 Oo Reference Example | 22-(d) wv > oA I cou | (E51, mia: 369 eH cl 0 2 H Reference Example SLA N COM i . Li ¥Y CoiMe | (ES, miz): 433,435 [+H] Br AL He Referance. Example | 0 IY | gs) mg 71 pushy 24-(e) 0 A © 9 H Hohe yrs (ESI, mz): 471 [+H 2 LO. oO (ESI, miz): 437 [M+H]' Reference Example | 25-(e) Il CF o a o. I Oo 0 F BEE | oO J AN o Referance Example | > NY 8 | Esl mlz): 481, 483 [MH] 26-(e) o A o. 2 H Hoh X o. I X r ar oF | 221102_G2572WO English Translation (Final) clean copy

[0240] Table 4-5 Reference Example | Structural formula Mass spectrum 0 ZO N IN Vn | Reference Example | NY Lo, (ESI, m / z): 421 [M+H]* 27-(e) Ee | pe. o. 0 0 E | | a, | 1 0 Reference Example | 28-(e) ¥ H Heh NY come | (E51, mi 42 [M+H] o F v KL Ao Oo Reference Example | 30-(f) SE © yt Bu | Esl mlz): 469 [M+H]* e® Sy Fo oF | Oo Reference Example | 31-(d) Oo H Hohe res (ES, mz): 455 [M+H* “Ql | Qo Reference Example | 32-(d) © A { ° Ho EY TY > = mlz): 499, 501 [M+H]* ce | NANG Reference Example 2 NY COzMe 33-(d) o F (ESI, m / z): 439 [M+H]* FaCO 221102_G2572WO English Translation (Final) clean copy

[0241] Table 4-6 Reference Example | Structural formula Mass spectrum [eo] Reference Example | 34-(d) Shon Ho N NN © NY XY es m / z): 439 [M+H]* oo | Oo Reference Example | 35-(d) © JR o Ho EY I > | (ESI, m / z): 405 [M+H]* CF3 O Reference Example | 36-(d) SLA Ho NY YY es, mz): 443 [M+Na]* ° A © : o | OCF; | Oo Reference Example | 37-(d) Q H Hoyos (ES, m / z): 403 [M+H]" 0 AO oc, oe | 0 Reference Example | 38-(d) 0 Hedy F yo foo ° (ESI, m / z): 409 [M+Na]* F -E ; oO ai Reference Example | 39-(d) A J He 0 N je NY &F | (ESI, miz): 377 [+H] 221102_G2572WO English Translation (Final) clean copy

[0242] Table 4-7 Reference Example | Structural formula Mass spectrum oO QO A O (ESI, miz): 393 [M+H]' Reference Example | 40-(d) SE A YLT |e Cal oO > J { o Reference Example | 0 Ny oY (ESI, mia): 374 [M+HE 41d) Hoo A o we oO Reference Example | 42-(d) o JN Ho NY re Esl mlz): 415, 417 [M+H]* Q. fe) Reference Example | 43-(d) o SUL i o 0” °N = NY &F | (ESI, miz): 403 [M+H]* -N, w | wo a CONT YO OC Lo Example "oe 0° | esi m2): 431 [MH] AA. N 1 Hepes Cow | | Q H SEK N o. “YY | (ESI, m / z): 422 [M+H]* Reference Example | 45-(d) 221102_G2572WO English Translation (Final) clean copy

[0243] Table 4-8 Reference Example | Structural formula Mass spectrum 0 7H Reference Example | 6 5 ° | Esl mlz): 425 [M+Nal* 48-(d) # Qo Shy Aa oe NYY | (ESI, m / z): 427 [M+Nal* Reference Example | 47-(d)

[0244] Reference Example 1-(e) Production of methyl (S)-3-(2-aminoacetamido)-3-(3- chloro-5- (trifluoromethyl) phenyl) propanoate hydrochloride HCI f 0 Ha" YY Se oO A. 0 1 1 Ml CTF,

[0245] To a solution of 27.8 g of methyl (S)-3-(2-((tert- butoxycarbonyl) amino) acetamido) -3- (3-chloro-5- (trifluoromethyl) phenyl) propancate synthesized in the same manner as in Reference Example 1-(d) in cyclopentyl methyl ether (190 ml), 60 ml of a 4 M solution of hydrogen chloride in cyclopentyl methyl ether was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 7 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(e) to obtain compounds described in the following Tables 5-1 to 5-8. 221102_G2572WO English Translation (Final) clean copy

[0247] Table 5-1 Reference Example Structural formula Mass spectrum HCI H HoN ~r N ~~ ro N Ol Reforhte WNT | mlz): 383, 385 [MH] Example 2-(¢) o AN o 1 1 in 00 Br CFs Reference Example 3-(e) HCl i N o. HN YY | (ESI, miz): 431 [M+H]* °ry° | 1! | ~ o > o | CFq Reference Example 4-(e) Cl H N o HyN I~ hrs | (ESI, m / z): 319 [M+H]* NY | np 1 i 1 QL CF, HCI Reference Example 5-(e) HN ~ wR | (ESI, m / z): 335 [M+H]* ~N a | Nooo Ad ‘00 ~o CFs HCI Reference Example 6-(e) Cl d N o HN ~ 2 DY TY | (ES mi: 323 eH “= 1 Jig | 1 “O0 F CFs HC! Reference Example 7-(e) HN ~ Rr | (ESI, m / z): 373 [M+H]* 221102_G2572WO English Translation (Final) clean copy

[0248] Table 5-2 Reference Example | Structural formula Mass spectrum HCI Al H N o HN ~ NYY FN YT 1 | Reference Example | § N g | ES, mi: 371 ey &(b) NC FI JON HCI Spon A N Reference Example HN co Me I we | Y a F ‘ es, mlz): 323 [+H] 1 | F CF3 HCI cl i RNY ae ee N R CogMe : 339 [M+H]* Reference Example | Hd i: (ES, mz): 339 [+H] 1046) AN CF3 HCI Reference Example | 11-(e) H on " Ty come | ESI, mz): 323 (M HN re ( 0 A y Il 1 ot, oy FiC HCI Tyg ——— N COM . Reference. Example | HN T= we es mlz): 339 [M+H] i xT KCI RCl H ° HNN NSN ON oo A. O | (ESI, m / z): 323 [M+H]* Reference Example | 13) F 221102_G2572WO English Translation (Final) clean copy

[0249] Table 5-3 Reference Example | Structural formula Mass spectrum HCI i H N 0. WN errno Li Example | ° Ne Es, mz): 357 [M4H 154g) 7S HCI ou i» oy wy YT wr TIC Ly Example | o A © | Esl Miz): 345, 347 [M#H]* 16-(e) 2 OMe HCl Reference Example | 17-8) Cl H N Di, WNYC TY | (ESI, m / z): 305 [M+H]* Ql Hel H Reference Example | 18-(e) Cl H N 0. HoN ~% : Y TY es, mz): 349, 35 [M+H]* 21 NN RCI H NNN OS (ESI, m / z): 395 [M+H]* Reference Example | 19-(e) ~ ~ oO © Oo Br Br HCI H Reference Example | 20-(e) ot H N oO HN ~ 2 is Y | Esl Miz): 441, 443 [M+H]* A) “oo Br 1 221102_G2572WO English Translation (Final) clean copy

[0250] Table 5-4 Reference Example | Structural formula Mass spectrum HCI H HN NSN OS (ESI, miz): 397 [M+H]' Reference Example | 21g) CC 0 cl | HC! H | (ESI, m / z): 289 [M+H]" HCI H HN Ny come 0 ALF Reference Example | 22-(e) HCI H FN co Me | (ESI, m / z): 333, 335 [M+H]* Reference Example | 23-(e) no “OF Br HCI H Reference Example | 2) : > 371 [M+H]* " m2): 371 | ES], HoN “> Y | ~ TCT For I 1 | 1 To Fo CF3 HC! H HN" come (ESI, miz): 337 [M+H]' Reference Example | 25-(f) "Or Cl a F HCI H HNN Co Me | (ESI, m / z): 381, 383 [M+H]* F Reference Example | 26-(f) o A. or Br PL 221102_G2572WO English Translation (Final) clean copy

[0251] Table 5-5 Reference Example | Structural formula Mass spectrum HC} RH HN co Me oO F (ESI, miz): 321 [M+H]' Reference Example | 27-(f) F Hel H COM HN ye Me | (ESI, m / z): 321 [M+H]* Reference Example | 28-(f) Oy Fo HCH H HN co Me FO AN Fav lA T eae Reference Example | 7 0 by | (ESI, miz): 369 [M+H]* 20-(b) oo > JT 7 wWhie OL Fo vy HCI H HN NNO | (ESI, m / z): 369 [M+HI* Reference Example | 30-9) MQW hoy Gg HCI svg os oOo A. 0 (ESI, m / z): 355 [M+H]* Reference Example | 31-(e) oN cl OCF, HC! Co H HN Nr N NOs oo A. © | (ESI, miz): 399, 401 [M#H]* Reference Example | 32-(e) 1 1 Jig “0 Br OCF, 221102_G2572WO English Translation (Final) clean copy

[0252] Table 5-6 Reference Example | Structural formula Mass spectrum HCI H N HAN come (ESI, miz): 339 [M+H]' Reference Example | 33-(e) Or F4CO HCH Ct H Ha ~~ N os oOo J. 0 een rn ur Example | Ga al ° | Esl mlz): 339 [+H] 34-(e) 5 F HCI aul d ° HNN NSN OS oc A. OO (ESI, miz): 305 [M+H]' Reference Example | 35-(e) HCl H ol H N oO HN YS = iz): 321 [MHI oC A Oo Reference Example | 36-(¢) HCI H HN ~r N OS oO (ESI, miz): 303 [M+H]' Reference Example | 37-(e) ° FF HCI , Jo QW: “oF Ho | H HNN NON | oO A. 0 | (ESI, m / z): 287 [M+H]* Reference Example | 38-(e) F 221102_G2572WO English Translation (Final) clean copy

[0253] Table 5-7 Reference Example | Structural formula Mass spectrum HCI Hi H N o. WN ha a HN | Li Bane | 7 7 | Esl mlz): 277 [M+H] 39-(¢) Ny HCI Co H HNN OS Oo A. 0 | (ESI, m / z): 293 [M+HI" Reference Example | 40-(e) Coa HCI Reference Example | 41-(e) J H N 0 HN ~ ? J TY | Esl miz): 271 [MH] AN HC Reference Example | 42-(e) Cl H N Oo HN i z Y Y Sl mi 35,517 sk = A HCI Fill H HNO oo LA. oO HN SY yr Li Barge | "J AF | Esl ma: 303 43-(e) 7 B | NN Ww HCI oO A. O | (ESI, m / z): 331 [M+H]* Reference Example | 44-e) 221102_G2572WO English Translation (Final) clean copy

[0254] Table 5-8 Reference Example | Structural formula Mass spectrum HCI HH 8 A 0 (ES, miz): 322 [M+H]' Reference Example | 45-(e) NYY 0 o NTT Ld HCI A 0 Reference Example | ¢ (ES, m / z): 303 [M+H]* 46-(e) HCI Cl H o° HNN ~ oO AO (ESI, m / z): 305 [M+H]* Reference Example | 47-(e) CF3

[0255] Reference Example 18-(c) Production of methyl (S)-3-amino-3-(3-bromo-5- chlorophenyl)propanocate hydrochloride HCI Hoo mn On TY A © nr A L..

[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 solution of hydrogen 221102_G2572WO English Translation (Final) clean copy chloride in 1,4-dioxane were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 18 hours. After the completion of reaction, 60 ml of hexane was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. 10 ml of tert-butyl methyl ether was added to the concentration residue, and the mixture was stirred at room temperature for 3 hours. A 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 18-(c) to obtain compounds described in the following Table 6. 221102_G2572WO English Translation (Final) clean copy

[0258] Table 6 Reference Example | Structural formula Mass spectrum HCI HN O. Yr Reference Example | 7c) oe FC CF, 111 oO (ESI, mz): 262 [M+H]* Reference Example | 14-(c) HN Oo o CF HCI 0 Reference Example | 34-(c) Heo Be © OCF3 F HCl N Qo Reference Example | Min On | Esl mz: 214 #10) PR HCI Oo HN Reference Example | 42-(c) Ha Pfs Refarence Example | Tr (ESI, miz): 258, 260 [M+H]' 42-(c) OS Br

[0259] Reference Example 8- (a) Production of methyl (S)-3-(3-(lH-pyrazol-1l-yl)- (trifluoromethyl) phenyl)-3-(2-((tert- butoxycarbonyl)amino)acetamido) propanoate 221102_G2572WO English Translation (Final) clean copy 0 Sok, pod 0. 1 = [Xt RS Le

[0260] To a solution of 300 mg of methyl (S)-3-(2-((tert- butoxycarbonyl)amino)acetamido)-3- (3-bromo-5- (trifluoromethyl) phenyl)propanocate synthesized in the same manner as in Reference Example 2-(d) in N,N- dimethylformamide (3 ml), 51 mg of pyrazole, 392 pl of trans-N,N'-dimethylcyclohexane-1,2-diamine, and 345 mg of potassium carbonate were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 10 minutes under argon bubbling. Subsequently, 236 mg of copper(I) iodide was added thereto at room temperature, and the mixture was stirred at 90°C for 3 hours. After the completion of reaction, water was added to the reaction mixture, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium-pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate) to obtain 81 mg of the title compound as a colorless oil. Mass spectrum (ESI, m / z): 471 [M+H]'. 221102_G2572WO English Translation (Final) clean copy

[0261] Reference Example 29- (a): A corresponding starting compound was treated in the same manner as in Reference Example 8-(a) to obtain a compound described in the following Table 7.

[0262] Table 7 Reference Example | Structural formula Mass spectrum 0 =o bu A rn | Reference Example | KY TY (ESI, m / z): 469 [M+H]* 29-(a) | oN BN 34, y { > JC

[0263] Reference Example 14-(e) Production of methyl (S)-3-(2-aminocacetamido)-3-(4- methyl-3- (trifluoromethyl) phenyl) propanocate hydrochloride el H Hans NO o J. 0

[0264] To 293 mg of methyl (S)-3-(2-((tert- butoxycarbonyl)amino)acetamido) -3- (4-methyl-3- (trifluoromethyl) phenyl)propancate synthesized in Reference Example 14-(d), 3.2 ml of tert-butyl methyl ether and 0.657 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane were added in a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. 0.657 ml of a 4 M solution of hydrogen chloride in 1,4- dioxane was further added thereto, and the mixture was 221102_G2572WO English Translation (Final) clean copy stirred at room temperature for 3 hours. 0.657 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane was further added thereto, and the mixture was stirred at room temperature for 2 hours. After the completion of reaction, the reaction mixture 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) Production of (3-chloro-4-fluoro-5- (trifluoromethyl) phenyl)methanol Ha. al QO,

[0266] To a solution of 1.00 g of 3-chloro-4-fluoro-5- (trifluoromethyl)benzoic acid in tetrahydrofuran (20 ml), 9.16 ml of a 0.9 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added in an ice bath under a stream of argon, and the mixture was stirred at room temperature for 20 hours. After the completion of reaction, 2 M hydrochloric acid was added to the reaction mixture, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by 221102_G2572WO English Translation (Final) clean copy medium-pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate) to obtain 1.06 g of the title compound as a colorless oil. Mass spectrum (EI, m / z): 228 [M]t.

[0267] Reference Example 21-(a), etc.: Corresponding starting compounds were treated in the same manner as in Reference Example 15-(a) to obtain compounds described in the following Table 8.

[0268] Table 8 Reference Example | Structural formula Mass spectrum HO, | (EI, miz): 268 [M]* Reference Example | 21-(a) Ol Hoy F YX F (EI, miz): 240 [M]* Reference Example | 30-(a) ro! Fo AoE |

[0269] Reference Example 21-(b) Production of 3-chloro-5-iodobenzaldehyde OL

[0270] To a solution of 2.04 g of (3-chloro-5- iodophenyl)methanol synthesized in Reference Example 21- (a) in dichloromethane (40 ml), 4.83 g of Dess-Martin periodinane was added at room temperature with stirring 221102_G2572WO English Translation (Final) clean copy under a stream of argon, and the mixture was stirred at room temperature for 10 minutes. After the completion of reaction, a saturated aqueous solution of sodium bicarbonate supplemented with sodium thiosulfate was added to the reaction solution, and the mixed solution was subjected to extraction with methylene chloride. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium-pressure preparative chromatography (silica gel, eluting 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 21-(b) to obtain compounds described in the following Table 9.

[0272] Table 9 Reference Example | Structural formula Mass spectrum Reference Example | o (C1, miz): 227 [M+H]* 15-(b) Cl "CF. Reference Example | 30-(b) Os ® a ¥ Fo oF | 221102_G2572WO English Translation (Final) clean copy

[0273] Reference Example 24- (a) Production of 3-(difluoromethoxy)-5- (trifluoromethyl) benzaldehyde Ox C 2 a “CF,

[0274] To a suspension of 4.36 g of potassium carbonate in N,N-dimethylformamide (16 ml), 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) was added dropwise at 95°C under a stream of argon, and the mixture was stirred at 95°C for 30 minutes. After the completion of reaction, water was added to the reaction mixture, and the mixed solution was subjected to extraction 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 obtained residue was purified by medium-pressure preparative chromatography (silica gel, eluting 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.: 221102_G2572WO English Translation (Final) clean copy Corresponding starting compounds were treated in the same manner as in Reference Example 24-(a) to obtain compounds described in the following Table 10.

[0276] Table 10

[0277] Reference Example 1-(f) Production of 2-fluoromalonamide 0 0 HN HA

[0278] To a solution of 25.0 g of diethyl 2-fluoromalonate in methanol (100 ml), 80 ml of a 7 N solution of ammonia in methanol was added at room temperature under a stream 221102_G2572WO English Translation (Final) clean copy of argon, and the mixture was stirred at room temperature for 4 hours. After the completion of reaction, a 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. 1H-NMR spectrum (400MHz, DMSO-dg) 8: 7.78 - 7.48 (m, 4H), 5.16 (d, J =: 48.9 Hz, 1H).

[0279] Reference Example 1-(g) Production of 2-fluoropropane-1,3-diamine hydrochloride HCI HaN™ fi

[0280] To 400 ml of a 0.9 M solution of a borane- tetrahydrofuran complex in tetrahydrofuran, 7.20 g of 2- fluoromalonamide synthesized in Reference Example 1-(f) was added in divided portions at room temperature under a stream of argon, and the mixture was stirred at room temperature for 20 hours. After the completion of reaction, the reaction mixture was cooled to 0°C, and 73 ml of methanol was added dropwise thereto at 20°C or lower. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. 40 ml of ethanol was added to the concentration residue, then 60 ml of a 2 M solution of hydrogen chloride in ethanol was added thereto at 0°C, and the mixture was stirred at room temperature for 3 221102_G2572WO English Translation (Final) clean copy hours. A deposited solid was collected by filtration, and the solid was dissolved in methanol and concentrated under reduced pressure. To the obtained solution of 6.91 g of the solid in methanol (200 ml), 70 g of Amberlite (IRA478RF CL) sequentially washed with 200 ml of water and 200 ml of methanol was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 4.55 g of the title compound as a white solid. 1H-NMR spectrum (400MHz, DMSO-d¢+D,0) 8: 4.77 - 4.53 (m, 1H), 3.01 - 2.79 (m, 4H).

[0281] Reference Example 48- (a) Production of methyl 4-bromo-3-fluoro-1-(tetrahydropyran- 2-yl)-1H-indazole-6-carboxylate 0 A Ihr ~. 0 = -N_ rm. 0, Nid

[0282] To a suspension of 200 mg of methyl 4-bromo-1H- indazole-6-carboxylate in acetonitrile (8 ml), 333 mg of l-chloromethyl-4-fluoro-1, 4-diazoniabicyclo([2.2.2] octane bis (tetrafluoroborate) was added at room temperature under a stream of argon, and the mixture was stirred at 100°C for 4 hours. After the completion of reaction, water was added to the reaction mixture, and the mixed solution was 221102_G2572WO English Translation (Final) clean copy subjected to extraction 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 obtained concentration residue in dichloromethane (8 ml), 143 pl of 3,4-dihydro- 2H-pyran and 15 mg of p-toluenesulfonic acid monohydrate were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 4 hours. After the completion of reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixed solution was subjected to extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to medium- pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate), and a fraction containing the compound of interest was concentrated under reduced pressure. The obtained residue was purified by gel permeation chromatography (column: YMC-GPC T30000, YMC-GPC T4000, and YMC-GPC T2000, eluting 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) 221102_G2572WO English Translation (Final) clean copy Production of methyl 3-chloro-4-nitro-lH-indazole-6- carboxylate £3 IL CaN rs o oo Cl- CY N--NI

[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 a stream of argon, and the mixture was stirred at 80°C for 2 hours. Next, 145 mg of N-chlorosuccinimide was further added thereto at 80°C, and the mixture was stirred at 80°C for 2 hours. After the completion of reaction, the reaction mixture was poured to a saturated aqueous solution of sodium bicarbonate, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with saturated saline, 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 [M-H]-.

[0285] Reference Example 1-(h) Production of methyl 4-bromo-1-(tetrahydropyran-2-yl)-1H- indazole-6-carboxylate 221102_G2572WO English Translation (Final) clean copy 0} g-.4 Bro ag Ag pe Wn N-=N_ FE yo, od

[0286] To a suspension of 1.00 g of methyl 4-bromo-1H- indazole-6-carboxylate in dichloromethane (10 ml), 717 pl of 3,4-dihydro-2H-pyran and 82 mg of p-toluenesulfonic acid monohydrate were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixed solution was subjected to extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium- pressure preparative chromatography (silica gel, eluting 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): A corresponding starting compound was treated in the same manner as in Reference Example 1-(h) to obtain a compound described in the following Table 11. 221102_G2572WO English Translation (Final) clean copy

[0288] Table 11 Reference Example | Structural formula Mass spectrum oO Referenc Li e Example | ~ ci 7 - M: W\ = | Es ol , m / z): 340 [M+H]* MM Dea “A 0, 9 NS

[0289] Reference Example 1-(1i) Production of methyl 4-((diphenylmethylene)amino)-1- (tetrahydropyran-2-yl)-1H-indazole-6-carboxylate QO Pll No oy Ale Ph JJ fin NN 0. NS

[0290] To a solution of 1.13 g of methyl 4-bromo-1- (tetrahydropyran-2-yl)-1H-indazole-6-carboxylate synthesized in Reference Example 1-(h) in xylene (20 ml), 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 a stream of argon. After purging with an argon atmosphere, the mixture was stirred at 150°C for 6 hours under a stream of argon. After the completion of reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixed solution was subjected to 221102_G2572WO English Translation (Final) clean copy extraction with toluene. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to medium- pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate), and a fraction containing the compound of interest was concentrated under reduced pressure. 20 mL of tert-butyl methyl ether was added to the obtained residue at room temperature, and the mixture was stirred at room temperature for 1 hour. A solid was collected by filtration to obtain 1.09 g of the title compound as a yellow solid. H-NMR spectrum (400MHz, DMSO-ds) 8: 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), 3.8% - 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): A corresponding starting compound was treated in the same manner as in Reference Example 1-(i) to obtain a compound described in the following Table 12. 221102_G2572WO English Translation (Final) clean copy

[0292] Table 12 Reference Example | Structural formula Mass spectrum 0 (ESI, m / z): 458 [M+H]* Reference Example | 48-(b) Ph._Ph Q bea ” F \ -N ro WN agh LT

[0293] Reference Example 1-(j) Production of methyl 4-amino-1-(tetrahydropyran-2-yl)-1H- indazole-6-carboxylate €y 4 HN yh i or -N Tr UN oy Q ~ Nudd

[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 (containing 50.57% water, AER-type manufactured by N.E. Chemcat Corp.) was added at room temperature under a stream of argon. After purging with a hydrogen atmosphere, the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was filtered through celite and washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by medium- 221102_G2572WO English Translation (Final) clean copy pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate) to obtain 523 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 276 [M+H]*.

[0295] Reference Example 48-(c) Production of methyl 4-amino-3-fluoro-1-(tetrahydropyran- 2-yl)-1H-indazole-6-carboxylate oO 1H, Ss 5 pe M y-0 ~ No oF

[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 a 10% aqueous citric acid solution was added at room temperature under a stream of argon, and the mixture was stirred at 70°C for 18 hours. After the completion of reaction, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium- pressure preparative chromatography (silica gel, eluting 221102_G2572WO English Translation (Final) clean copy 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) Production of methyl 4-amino-3-chloro-1-(tetrahydropyran- 2-yl)-1H-indazole-6-carboxylate 0 Hen hg | re fi NN Hs Nod

[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) and water (1.5 ml), 779 mg of sodium dithionite was added at room temperature under a stream of argon, and the mixture was stirred at 90°C for 1 hour. After the completion of reaction, the reaction mixture was poured to water, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium- pressure preparative chromatography (silica gel, eluting solvent: hexane:ethyl acetate) to obtain 131 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 310 [M+H]'. 221102_G2572WO English Translation (Final) clean copy

[0299] Reference Example 1-(k) Production of methyl 4-(3-methylthioureido)-1- (tetrahydropyran-2-yl)-1H-indazole-6-carboxylate OH © eH ob a A For ~ 5 “ = N RA Fry ad

[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 pul of acetic acid were added at room temperature under a stream of argon, and the mixture was stirred at 100°C for 9 hours. After the completion of reaction, water was added to the reaction mixture, and the mixed solution was subjected to extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by medium-pressure preparative chromatography (silica gel, eluting 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.: 221102_G2572WO English Translation (Final) clean copy Corresponding starting compounds were treated in the same manner as in Reference Example 1-(k) to obtain compounds described in the following Table 13.

[0302] Table 13 Reference Example | Structural formula Mass spectrum oO | (ESI, miz): 367 [M+HI* Reference Example | 48-(d) | HN ° © BH . NN igi LE NF HN 0” Reference Example | | (ES, miz): 383 [M+H]* 49-(d) Cl—¢ 3 | NS o Dead “ 0, Foy NO 7 LW J

[0303] Reference Example 52- (a) Production of methyl 6-(3-methylthioureido)-1H-indazole- 4-carboxylate * MH [SY L_. will py Hit

[0304] To a solution of 500 mg of methyl 6-amino-1H- indazole-4-carboxylate in N-methylpyrrolidone (2.5 ml), 233 mg of methyl isothiocyanate was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours, left standing at room temperature for 84 hours, and stirred at 70°C for 7 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, water was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C 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-(1) Production of 4-(3-methylthioureido)-1H-indazole-6- carboxylic acid Q il hid . ot &

[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 solution of hydrogen chloride in 1,4-dioxane was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 6 hours. After the completion of reaction, the reaction mixture was concentrated under reduced pressure, subjected to azeotropy with 30 ml of tert-butyl methyl ether, and dried under reduced pressure at 50°C. To a suspension of the obtained residue in methanol (41.4 ml), 41.4 ml of a 1 M aqueous sodium hydroxide solution was added at room temperature under a stream of 221102_G2572WO English Translation (Final) clean copy argon, and the mixture was stirred at room temperature for 3 hours. After the completion of reaction, the reaction mixture was adjusted to pH 4.0 by the addition of 2 M hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C 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) Production of methyl 3-chloro-4-(3-methylthioureido)-1H- indazole-6-carboxylate Hil + o NN r J. Clay! ~~.

[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 a stream of argon, and the mixture was stirred at room temperature for 10 hours. After the completion of reaction, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by medium-pressure 221102_G2572WO English Translation (Final) clean copy preparative chromatography (silica gel, eluting 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) Production of 3-fluoro-4-(3-methylthioureido)-1- (tetrahydropyran-2-yl)-1H-indazole-6-carboxylic acid o Tay Nod

[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 a 1 M aqueous sodium hydroxide solution and 3 ml of tetrahydrofuran were added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours. After the completion of reaction, the reaction mixture was adjusted to pH 4.0 by the addition of 1 M hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and tetrahydrofuran was distilled off under reduced pressure. The residue was stirred at room temperature for 15 hours. A deposited solid was collected by filtration, washed with 221102_G2572WO English Translation (Final) clean copy 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) Production of 3-chloro-4-(3-methylthioureido)-1H- indazole-6-carboxylic acid oO | HN... 7° ny Ba I HI OY en 2 nif F--NH

[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 a 2 M aqueous sodium hydroxide solution was added dropwise at room temperature, and the mixture was stirred at room temperature for 5 hours. After the completion of reaction, the reaction mixture was adjusted to pH 4 by the addition of 2 M hydrochloric acid, and the mixture was stirred at room temperature for 0.5 hours. A deposited 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): 221102_G2572WO English Translation (Final) clean copy A corresponding starting compound was treated in the same manner as in Reference Example 49-(f) to obtain a compound described in the following Table 14.

[0314] Table 14 Reference Example | Structural formula Mass spectrum oO Reference Example | 52-(b) -r x es. mlz): 251 [M+H]* N=

[0315] Reference Example 1-(m) Production of 4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2- yl)amino)-1H-indazole-6-carboxylic acid no os or ; | he

[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 (1) in N-methylpyrrolidone (100 ml), 3.00 ml of iodomethane was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 16 hours. The pressure of the reaction mixture was reduced, and excess iodomethane was removed. 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 to the obtained solution at room temperature, and the mixture was stirred at 110°C for 8 221102_G2572WO English Translation (Final) clean copy hours, stirred at room temperature for 13 hours, stirred at 110°C for 11 hours, stirred at room temperature for 13 hours, and stirred at 110°C for 9 hours. After the completion of reaction, 283 ml of water was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C 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.: Corresponding starting compounds were treated in the same manner as in Reference Example 1-(m) to obtain compounds described in the following Table 15.

[0318] Table 15 Reference Example | Structural formula Mass spectrum (ESI, mlz): 380 [+H] Reference Example | Structural formula A HN ZN Reference Example | oy % 48-(f) ; C N-N, J) NA ol Li Example | ng Yoo | ES mi: 312 Oo Reference Example | 52-(c) CTY X OH | Est mi 276 shy EAN > HN-N 221102_G2572WO English Translation (Final) clean copy

[0319] Reference Example 50- (a) Production of 4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin- 2-yl)amino)-1H-indazole-6-carboxylic acid H H o ii i or Sy oH Lor § ! 1-H

[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 a stream of argon, and the mixture was stirred at room temperature for 2 hours. The pressure of the reaction mixture was reduced, and excess iodomethane was removed. 1.08 g of 1,3- diaminopropan-2-ol was added to the obtained solution at room temperature, and the mixture was stirred at 110°C for 6 hours. After the completion of reaction, the reaction mixture was cooled to room temperature and stirred at room temperature for 17 hours. 10 ml of water was added thereto, and the mixture was stirred at room temperature for 4 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain 915 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 276 [M+H]*. 221102_G2572WO English Translation (Final) clean copy

[0321] Reference Example 51-(a): A corresponding starting compound was treated in the same manner as in Reference Example 50-(a) to obtain a compound described in the following Table 16.

[0322] Table 16 Reference Example | Structural formula Mass spectrum oO Reference Example | 51-(a) REX ne OH | esi: 260 [M+H]* SN N-NH

[0323] Reference Example 48-(g) Production of 3-fluoro-4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic acid -Cl on

[0324] To 110 mg of 3-fluoro-4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1- (tetrahydropyran-2-yl)- 1H-indazole-6-carboxylic acid synthesized in the same manner as in Reference Example 48-(f), 2.9 ml of 1 M hydrochloric acid was added at room temperature under a stream of argon, and the mixture was stirred at 60°C for 11 hours and stirred at room temperature for 13 hours. Subsequently, 1.45 ml of 1 M hydrochloric acid was added 221102_G2572WO English Translation (Final) clean copy thereto at room temperature, and the mixture was stirred at 70°C for 9 hours and stirred at room temperature for 18 hours. After the completion of reaction, a 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) Production 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 0 HH jo} H x econ WooY NY YY PAN 0 A ° \ N-NH nN 1A 0 g oO Cl CF)

[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 l-hydroxybenzotriazole was added at room temperature under a stream of argon, and the mixture was stirred at 221102_G2572WO English Translation (Final) clean copy room temperature for 10 minutes. Subsequently, 0.043 ml of N,N'-diisopropylcarbodiimide was added thereto at room temperature, and the mixture was stirred at room temperature for 5 hours. After the completion of reaction, the reaction mixture was purified by medium-pressure preparative chromatography (ODS, eluting solvent: 0.1% aqueous trifluoroacetic acid solution:0.1% solution of trifluoroacetic acid in acetonitrile) to obtain 132 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 598 [M+H]*.

[0327] Example 2-(a), etc.: Corresponding starting compounds were treated in the same manner as in Example 1-(a) to obtain compounds described in the following Tables 17-1 to 17-7. 221102_G2572WO English Translation (Final) clean copy

[0328] Table 17-1 Example | Structural formula Mass spectrum o Nu o 5: seen Example 2) HH A Ano Wor ~ "LK oY . Tesi may iz 004 aor \ Ret Br CFs o ih 0 J NON NOL [Sime | re w iY Try | Esl mlz): 690 [M+H]* OY } nO NY > AN ( 0 0 N-NH I CFy o Ww 0 J NN N Oo [ae | we * LX YY | Esl mz); 578 [M+H]* Al AHH o (AN NY 0 " N-NH CFy o on o Jl NN N (Ny Example | Fic oH or YY Y (ESI, m / z): 594 [M+H]* 5a) F \ 2 o H o H i . HOR LEY Lr PT JL o © om 0 I NN NANOS Banple | rio” ox or YY | Est ma: sez hy: 6-2) F » \ 7) o HoH H NN N o. N H XY F \ N-NH F CFs o Fi 0 J NON NAO Lg | re WAX YY | Esl mlz): 632 [M+H]* CY ) Rg 1 { HO ) N A NY “a ( 0 0 N-NH FaC CFa o of lg fe] he Fe on (ESI, m / z): 630 [M+H]* Example 8a) NCA ~ oe Nr AX pos ° ° C 0 = 3 0 J NN N [Sage | Fi ® LO T YY Lo | (ESI, mlz): 582 [WH] Nn 1 HH HA no oY cone FANN ( 0 F N-NH Fy 221102_G2572WO English Translation (Final) clean copy

[0329] Table 17-2 Example | Structural formula Mass spectrum 0 RE 0 N FiC Fon Exampl J NON NSN Li | ne = 1X NY es. iz); 598 [MH] “1 | "LX you YY Le N 0 Cl F \ N-NH CF, o 4 OR 0 Erample | £0” on or WY) owe es. iz): 582 [M+H]* 11-(a) F OY ZY " LX pos ¥Y ge N 0 F F \ NM FC 0 | I RAI ~H Example FC oH CY N COM La AK NTE | fs may sa unr N-nH FC 3 0 ° o a | (a FN ! oe & (ESI, iz): 582 [M+HI* CFs I o HH Q H A NN N (oN Example | F1C7 OH LX oY I (ESI, miz): 578 [M#H]* ta) f N-NH CFs o wo Ga o oa dH Example | Fi” om Lr NY > ak AA § LE (ESI, m / z): 616 [M+H]* N-NH al Fy F o Ae ae 0 ~ Fic Aon (ESI, miz): 604, 606 [M+H]' Soa mye Example Peon N h fi | AX N-H x Br o FA 0 Bample | econ oy a ; , Lo | es A j RPE: | est mlz): 564 [M+H] Rg A H 0 My y ~ AN NY 0 \ N-NH al cl 221102_G2572WO English Translation (Final) clean copy

[0330] Table 17-3 Example | Structural formula Mass spectrum o Ou 0 Example | ron My NYS \ : Le | es LI YELLE | E51 miz: 608,610 i RR A } o “rr N ~ FSO ral] \ N-NH Br cl o BF a 0 J NN N Ny Lig | eo CF IY Y | s mlz): 654 [M+H]* a 1 HAA Mo WoO NY ~ FANN yo 0 o N-NH Br’ Br o Ou 0 J NON NO Lig | re =X YY > IG mlz): 700, 702 [M+H]* QO 1 RA A Mo Hoo NY ~ FANN yo 0 0 N-NH Br , o vou 0 J NON N AON Li | re 3 IY YY | Esl miz): 656 [M+H]* \ | N-NH RR A { o HOT N > AN oY J ° \ N-NH z ; o 2 Bg 0 |S | ton CY WY C0 | etm \ 1 gi i { HOY NY COMe FAN ( 0 F N-NH cl 0 a 4 0 Lig | ro = 1X Nye Es, mlz): 592, 504 [M+H]* 0 hl AK I f WoO NN c FAN ( NY Soe N-NH BW o win 0 A NN NN OL Lg | FC w 3 YY | Est mlz): 630 [M+H]* \ hv | BA Fm Homo wT NY ~ AN ¢ £0 0 N-NH Ao 5 o uu o J N_N N 0 |Semme | ton UXT HY LY sma soor \ 1 5 Rg 1 { o Wor N ~ LX Ly \ N-NH al oA 221102_G2572WO English Translation (Final) clean copy

[0331] Table 17-4 Example | Structural formula Mass spectrum o BR oO Hy Apel NAO Li | ee = LX YY IY, | Emi: 640, 642 MoH \ | A 1 RN SONG WY OY = EN ( 0 0. N-NH Br oA o uy me o Ad sion Example 27-(a) | (ESI, miz): 580 [M+H]* tA He " CX NY > N o o F ( F N-NH oe F 0 nm NN N Example | ricPon or NYY coe | es. iz): 580 [M+H]* 20 PD PELE PS " [X WY oe F ( F N-NH p o seen Example Fic oon ~ NY Ba Lo AX ILT HT XX | esi mlz): 628 [M+H]* 2k LL, RAI Ho H Lr NY = N o [} F C F N-=NH Ao hi o uu 0 A My NNN ON Li | re o Lr YY LY, = iz): 628 [M+H]* Nn | 1 Y ! Rg I { o GEE F ( F F NN oN oO EF aa 0 NN N (Ng Example Fc om T NY ESI, miz): 614 [M+H]* Li SI ELE [es maon 9 H H H NR N 0. N H LX NYY E \ N-NH al OCF 0 © ma 0 NN NA On Example | Fie on Lx YY | est mlz): 658, 660 [M+H]' 32-(a) ‘ OY A 0 H H H NN N o. N H * IX YY F \ N-NH Br OCF; 0 0 oR 0 A Non NA copme a Bampe | rotor (My § | (esi mi: 598 Li | LR A 7) UF RR AH \ N 0M H Lr LL Me E \ -NH FCO" 221102_G2572WO English Translation (Final) clean copy

[0332] Table 17-5 Example | Structural formula Mass spectrum o o oom NN N OL Li won OX oy pe | esi mlz): 598 [M+H NH Sy 2 tA Ae wy NY ~ N o 0 . N-NH § OCF 0 wn ware Example 35-(a) o " 5 Ih ' = ESI, m / z). 564 [M+H] ’ } H Lx oY N ( ’ Net CFs o OR o rato Example 36-(a) H ery 0. AN ( Hoo AF | (ESH, mi: 580 N-NH OCF3 o wl o Example oon AN Ny Ou ; i La | SX YY LY, | Esl Miz): 562 [M+H] HOY NY AN ( o 0. N-NH or 0 Wu 0 at sgetoon Example FiC” “OH x N. Ma 3 | or YY | est mlz): 546 [M+HI* -! F " LY : F \ N-NH F ” R,, MHA AK mple | Fc oH [CY NY Os | LR or TE | ESH, mi: 536 N-NH 0 uu 0 son Example 40-(a) H OY N ~ . . J rs I AF [= iz): 552 [MH] \ N-NH A o uu 0 he son Example 41-(a) tH ATA Woo N i SK oY I es. iz): 530 [M+H]" a . 221102_G2572WO English Translation (Final) clean copy

[0333] Table 17-6 Example | Structural formula Mass spectrum oO uu o nn wn Example 42-(a) HoT He noo NY > ESI, mz): 574, 576 [M+H]' AN or o 0 (ESI, mz): 574, 576 [M+H] N-NH Br o pre aa o 2 H H g ge | = Or 5) F N " ; Xr S SF ) |= mz): 562 [M+H]* ww 0 Wd Qo or rion FC OH (CY NY Example | SK YY (ES), mz): 590 [M+H]* 44-(a) N-NH NN I J » [X TY © Qo con |Gamme | ee X LTT LY -(a] F hb od * 2 SE (ESI, iz): 581 [M+HI" H Lr NY ~ F N ¢ o o N-NH N 0 0 ra Example ee 1 3 eel LF a .) | est mlz): 562 [M+HI* A [NS ETSY Sp o sen Example Fic” OH WY a 47a) FAN L ° 5F | Esl m / z). 564 [M+H]* gH Rats Wr NY & N o o F A N-NH CF, Il a ESI, mz): 616 [M+H]* Example Hon 0 i o. ES), Lo I sey ) A HN | on™ 9 pes N oL N xr F. £ N-NH a CFs 221102_G2572WO English Translation (Final) clean copy

[0334] Table 17-7 Example | Structural formula Mass spectrum o fh Example Ho 8 He (ESI, m / z): 632 [M+H]* | forte | sia : No wg HN. N o ir Cl: ¢ Ls a CFs. Ga a 0 ” 0 i ae 0 A ANN NANOS |e | rotor (XX HY LY | esmassoon: § TI I on (7 NY i Hor ( 0 0 ~NH N or CFs oO aw 0 3 FC Jhon Example 51-(a) DW 2 . or TY ° | (ESI, m / z): 580 [M+H]* CI CF3 oO Fa. 0 oN NN N OL Lig | oe iY TY XY | (Est mos oh X ) ) WOT NY > AN \ 0 0 ig cl CFs o va o A NN N OL |S | sem OY TY XY | (E31 mia 642,64 1 I! o H o H q RR vy X HOY T AN \ | HN=N of 3 o Fl 0 NN N OL Example | Foon Lx NY I es. mlz): 690 [M+H]* 54-(a) F AD 2 o H HOH g NN W " LY NY 0 E / Hi | CFs o 5 o - ron A, NN N. J. Example | FCToH [0 N > | 55a) | LN & Ri LF (ESI, miz): 582 [M+H]* H o H " loprens ~~ ’ =f "CFs o Goa 0 brid A) JO NUN N 0 Lig | =e 1% TY pe | (E81 mis 504 oH 1 7 I IH AIH u oy CLvY or h FANN o o HN- CFy 221102_G2572WO English Translation (Final) clean copy

[0335] Example 1-(b) Production 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)propanocic acid 0 A. O N—-NH STE mE HH AK Hm 0 r N Yr XY 1 1 1 0 JON [¢] CF;

[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) propanocate trifluorocacetate synthesized in Example 1-(a) in acetonitrile (1.5 ml) and water (1.5 ml), 22 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.2 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited 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]*. 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 A “ = NY ~eogH FN ( 7 o A NN we A N-NH Br CF

[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- carboxamido) acetamido) propanoate trifluorocacetate synthesized in Example 2-(a) in acetonitrile (3 ml) and water (3 ml), 31 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3 hours. Subsequently, 36 mg of lithium hydroxide was further added thereto at room temperature, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room 221102_G2572WO English Translation (Final) clean copy temperature for 16 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 107 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 628, 630 [M+H]". 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 0 NA 1 i oH YY XY N-NH a 1 1 go | CF,

[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) propanocate trifluoroacetate synthesized in Example 3-(a) in acetonitrile (1.5 ml) and water (1.5 ml), 12 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. A deposited 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): 676 [M+H]". 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO RHA Mn on OYECy N-NH 1 1 I QL CF3

[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)propanocate trifluoroacetate synthesized in Example 4-(a) in acetonitrile (1 ml) and 221102_G2572WO English Translation (Final) clean copy water (1 ml), 17 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was filtered. The filtrate was stirred at room temperature for 17 hours, and a deposited 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]*". H-NMR spectrum (400MHz, CD3OD) 8: 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), 4.1% - 4.04 (m, 2H), 3.73 - 3.45 (m, 4H), 2.75 - 2.63 (m, 2H), 2.39 (s, 3H).

[0343] Example 5-(b) Production of (38)-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 oY NYY ee FANN 0 2 N-NH ~o CF,

[0344] To a solution of 183 mg of methyl (3S)-3-(2-(4- ((5-fluoro-1,4,5, 6-tetrahydropyrimidin-2-yl)amino)-1H- 221102_G2572WO English Translation (Final) clean copy indazole-6-carboxamido)acetamido) -3- (3-methoxy-5- (trifluoromethyl) phenyl)propancate trifluoroacetate synthesized in Example 5-(a) in acetonitrile (1 ml) and water (1 ml), 24 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 221102_G2572WO English Translation (Final) clean copy 0 NR 1 R oH Y NYY FANA CAN i I N-NH J 1 Jil 0 g o F CF,

[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)propanocate trifluoroacetate synthesized in Example 6-(a) in acetonitrile (1 ml) and water (1 ml), 28 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3.5 hours. After the completion of reaction, . ml of water was added to the reaction mixture. The reaction mixture was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 15 hours. A deposited 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]*. H-NMR spectrum (400MHz, CD3;0D) &: 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) 221102_G2572WO English Translation (Final) clean copy Production 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 0 H H mn NN ] yr " N OH AN NY XY x f N-NH ~ 1 ~ Oo 2 Oo FC CF

[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) and water (1 ml), 21 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2.5 hours. After the completion of reaction, . ml of water was added to the reaction mixture. The reaction mixture was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 20 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 87 mg of the title compound as a gray solid. Mass spectrum (ESI, m / z): 618 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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, 221102_G2572WO English Translation (Final) clean copy 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) Production of (3S)-3-(3-(lH-pyrazol-1l-yl)-5- (trifluoromethyl) phenyl) -3-(2-(4-((5-fluoro-1,4,5, 6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid oO RR 1 i ry NY NO CoH FAN 0 A N-NH I © “2 N a Ny

[0350] To a solution of 150 mg of methyl (3S)-3-(3-(1lH- 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) and water (1 ml), 34 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 45 mg of the title compound as a white solid. 221102_G2572WO English Translation (Final) clean copy Mass spectrum (ESI, m / z): 616 [M+H]*. 1H-NMR spectrum (400MHz, CDs;OD) &: 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) Production 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 oO HR AK FODOR RPE N-NH 1 F : CFa

[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)propanocate trifluoroacetate synthesized in Example 9-(a) in acetonitrile (1 ml) and water (1 ml), 16 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the 221102_G2572WO English Translation (Final) clean copy mixture was stirred at room temperature for 7.5 hours. A deposited 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): 568 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO Ny ’ Bepesa ve 4 ANC N-NH oc CFs

[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) and water (1 ml), 14 mg of lithium hydroxide was added at 221102_G2572WO English Translation (Final) clean copy room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. 2A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO RR 1 R ~ N Srornrire od AF N-NH I | oy Fol

[0356] To a solution of 85 mg of methyl (3S)-3-(2-(4-((5- fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H- 221102_G2572WO English Translation (Final) clean copy indazole-6-carboxamido)acetamido) -3- (2-fluoro-5- (trifluoromethyl) phenyl) propancate trifluoroacetate synthesized in Example 11l-(a) in acetonitrile (1 ml) and water (1 ml), 15 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 18 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) 8: 8.10 - 8.06 (m, 2H), 7.80 - 7.76 (m, 1H), 7.61 - 7.55 (m, 1H), 7.52 (4d, 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) Production of (3S8)-3-(2-chloro-5- (trifluoromethyl) phenyl) -3-(2-(4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido)acetamido)propanocic acid 221102_G2572WO English Translation (Final) clean copy 0 RRA My NYY com AN 0 AC N-NH

[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) and water (1 ml), 22 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.3 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 16 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CDs;OD) 8: 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) 221102_G2572WO English Translation (Final) clean copy Production 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 0 oO A. 0 , A ANN RR I y oH Arne A | N-NH F

[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)propancate trifluorocacetate synthesized in Example 1-(a) in acetonitrile (1 ml) and water (1 ml), 20 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.3 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. A deposited 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 pale yellow solid. Mass spectrum (ESI, m / z): 568 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 8.10 - 8.05 (m, 2H), 7.72 - 7.64 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.26 221102_G2572WO English Translation (Final) clean copy - 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) Production of (38)-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 oO RRA HNnon Sry N-NH

[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)propanocate trifluoroacetate synthesized in Example 14-(a) in acetonitrile (1 ml) and water (1 ml), 20 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. A deposited 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]". 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO oO A. OO FAN RR Hon OTYy \ | N-NH ~ 1 rx o o cl CF3 F

[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) and water (1 ml), 15 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, . ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid. . ml of water and 1 ml of acetonitrile were added thereto, and the mixture 221102_G2572WO English Translation (Final) clean copy was stirred at room temperature for 10 minutes. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 0 NA 1 8 oH or NY TY FAN AN N-NH 0

[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) and water (1 ml), 19 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.2 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 16 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO RK 1 { oH SY Y N-NH Mu 1 14 oO oN Cl i }

[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) and 221102_G2572WO English Translation (Final) clean copy water (1 ml), 22 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3.5 hours. After the completion of reaction, the reaction mixture was adjusted to pH 5.3 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2.5 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 76 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 550 [M+H]*. H-NMR spectrum (400MHz, CD3;OD) &: 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) Production 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 oO Ml FANN RK I R oH ITNT LY \ | N-NH ~ | i~ 2 Br Cl

[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 221102_G2572WO English Translation (Final) clean copy synthesized in Example 18-(a) in acetonitrile (1 ml) and water (1 ml), 21 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2.5 hours. After the completion of reaction, 2 ml of water and 0.5 ml of acetonitrile were added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 22 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO HR AA yi Aye N 0 SO DOAR SY N-NH ~ | “2 Br Br 221102_G2572WO English Translation (Final) clean copy

[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 trifluorocacetate synthesized in Example 19-(a) in acetonitrile (0.5 ml) and water (0.5 ml), 13 mg of lithium hydroxide monohydrate was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.9 by the addition of 1 M hydrochloric acid, and the mixture was stirred overnight at room temperature. A deposited 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]*. 1H-NMR spectrum (400MHz, CD3;0D) 8: 8.10 - 8.07 (m, 2H), 7.56 = 7.53 (mn, 3H), 7.52 {¢, 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) Production 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 221102_G2572WO English Translation (Final) clean copy oO hy N N OH Be! oy YY AF ~~ ° N-NH nn | A © © 0 Br |

[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 trifluorocacetate synthesized in Example 20-(a) in acetonitrile (1 ml) and water (1 ml), 21 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3.5 hours. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 16 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 88 mg of the title compound as a light brown solid. Mass spectrum (ESI, m / z): 686, 688 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) 221102_G2572WO English Translation (Final) clean copy Production 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 oO RR KR Be OY Le N-NH el

[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) and water (0.5 ml), 13 mg of lithium hydroxide monohydrate was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.9 by the addition of 1 M hydrochloric acid, and the mixture was stirred overnight at room temperature. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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), 221102_G2572WO English Translation (Final) clean copy 4,18 - 4.03 (m, 2H), 3.73 - 3.45 (m, 4H), 2.71 -- 2.54 (m, 2H).

[0377] Example 22-(b) Production 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 oO NK I y Myr N Sep eas vei AF ANF N-NH

[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) and water (1 ml), 49 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited 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 further added thereto, and the mixture was stirred at room temperature for 30 minutes. 221102_G2572WO English Translation (Final) clean copy A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 Oo NH 1 R Bupa Reis N-NH rw oy Br

[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) and water (1 ml), 48 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited 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 white solid. Mass spectrum (ESI, m / z): 578, 580 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 lo] \g 1 { hg OY CoH AN o Z NY TL

[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 221102_G2572WO English Translation (Final) clean copy trifluoroacetate synthesized in Example 24-(a) in acetonitrile (1 ml) and water (1 ml), 19 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 15 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD3;0D) &: 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) Production 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 oO gt 1 R “™ NY co AN © A F N-NH el Cl OF 221102_G2572WO English Translation (Final) clean copy

[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) propanocate trifluorocacetate synthesized in Example 25-(a) in acetonitrile (1 ml) and water (1 ml), 23 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 15 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD3;0D) 8: 8.11 - 8.06 (m, 2H), 7.51 (4, 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) Production 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)propancic acid 221102_G2572WO English Translation (Final) clean copy oO N-NH RA I R [gag NY ~ coH EAN "L 2 N-NH Br op

[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 trifluorocacetate synthesized in Example 26-(a) in acetonitrile (1 ml) and water (1 ml), 25 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 88 mg of the title compound as a light brown solid. Mass spectrum (ESI, m / z): 626, 628 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production of (3S)-3-(3-(difluoromethoxy)-4- fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5, 6- 221102_G2572WO English Translation (Final) clean copy tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid oO “~r NY co FAN ° AN ’ Ni N-NH YY coH > E AA FE

[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) and water (1 ml), 49 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 40 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 566 [M+H]". 1H-NMR spectrum (400MHz, CD3;0D) &: 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 221102_G2572WO English Translation (Final) clean copy (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) Production 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 Oo RR I y NY ~NcoH FAN et AF N-NH H OL CT oY Fo

[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) and water (1 ml), 49 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited 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): 566 [M+H]". 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 Oo RR 1 q wy N-NH B nm TT LOR ° LQ Fo vy

[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)propanocate trifluorocacetate synthesized in Example 29-(a) in acetonitrile (1 ml) and water (1 ml), 48 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid. 3 ml of water was added thereto, and the mixture was stirred at room temperature for 15 hours. 221102_G2572WO English Translation (Final) clean copy A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 65 mg of the title compound as a pale yellow solid. Mass spectrum (ESI, m / z): 614 [M+H]*. 1H-NMR spectrum (400MHz, CD;OD) 8: 8.38 (d, J = 2.4 Hz, 1H), 8.11 - 8.06 (m, 2H), 7.6% (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) Production of (3S)-3-(3,5-bis(diflucromethoxy)phenyl)-3- (2-(4-((5-fluoro-1,4,5, 6-tetrahydropyrimidin-2-yl) amino) - 1H-indazole-6-carboxamido) acetamido) propanoic acid oO MHA Ag Rom or \ H Lt FO AN Ck N-NH mM A 1 MA FO os py op

[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) and water (0.5 ml), 15 mg of lithium hydroxide monohydrate was added at room temperature under a stream 221102_G2572WO English Translation (Final) clean copy of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.9 by the addition of 1 M hydrochloric acid, and the mixture was stirred overnight at room temperature. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO RK 1 y x WE N-NH i 1 “2 cl OCF,

[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- 221102_G2572WO English Translation (Final) clean copy carboxamido)acetamido) propanoate trifluoroacetate synthesized in Example 31-(a) in acetonitrile (0.5 ml) and water (0.5 ml), 21 mg of lithium hydroxide monohydrate was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.9 by the addition of 1 M hydrochloric acid, and the mixture was stirred overnight at room temperature. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 o H MN AN RK I 1 oH TNTY \ | N-NH i 1 I 0 Br OCF3 221102_G2572WO English Translation (Final) clean copy

[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) propanocate trifluorocacetate synthesized in Example 32-(a) in acetonitrile (2.5 ml) and water (2.5 ml), 50 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 3.5 hours. After the completion of reaction, 2.5 ml of water was added to the reaction mixture. The reaction mixture was adjusted to pH 5.0 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 20 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 244 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 644, 646 [M+H]*. 1H-NMR spectrum (400MHz, CD3;0D) 8: 8.12 - 8.06 (m, 28), 7.61 = 7.58 (m, 1H), 7.81 {&, 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) Production of (38)-3-(2-(4-((5-fluoro-1,4,5,6~ tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido)acetamido)-3-(2-fluoro-5- (trifluoromethoxy) phenyl) propancic acid 221102_G2572WO English Translation (Final) clean copy 0 AH 1 i Sordi N-NH Ho 8 JF jog F4CO

[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)propancate trifluoroacetate synthesized in Example 33-(a) in acetonitrile (2 ml) and water (2 ml), 45 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.2 by the addition of 1 N hydrochloric acid. 4 ml of water was added thereto, and the mixture was stirred at room temperature for 16 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 169 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 584 [M+H]*. 1H-NMR spectrum (400MHz, CDs;OD) 8: 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) 221102_G2572WO English Translation (Final) clean copy Production 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)propancic acid oO oO A. OO A FANN H H 1 H NN N OH Shorey \ | N-NH F

[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)propancate trifluorocacetate synthesized in Example 34-(a) in acetonitrile (1 ml) and water (1 ml), 16 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2.5 hours. After the completion of reaction, !. ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 18 hours. A deposited 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 white solid. Mass spectrum (ESI, m / z): 584 [M+H]*. 1H-NMR spectrum (400MHz, CDs;OD) &: 8.08 (d, J = 1.0 Hz, 1H), 8.07 - 8.05 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H), 221102_G2572WO English Translation (Final) clean copy 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) Production 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 oO OO AO , Lb ANN RRA Ron SOT Y \ | N-NH

[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)propancate trifluorocacetate synthesized in Example 35-(a) in acetonitrile (1.5 ml) and water (1.5 ml), 26 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and acetonitrile was distilled off under 221102_G2572WO English Translation (Final) clean copy reduced pressure. The residue was stirred at room temperature for 3 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CDs;OD) 8: 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) Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) -3-(3- (trifluoromethoxy) phenyl) propanocic acid Oo RR 1 R OH Yr NYY PAN 0 AN © N-NH

[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) propancate trifluorcacetate synthesized in Example 36-(a) in acetonitrile (1 ml) and water (1 ml), 18 mg of lithium hydroxide was added at 221102_G2572WO English Translation (Final) clean copy room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.2 by the addition of 1 N hydrochloric acid. The reaction mixture was concentrated under reduced pressure, and acetonitrile was distilled off under reduced pressure. The residue was stirred at room temperature for 2 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD3;0D) &: 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) Production of (35)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4- ((5-fluoro-1,4,5, 6-tetrahydropyrimidin-2-yl) amino) -1H- indazole-6-carboxamido)acetamido) propanoic acid oO AK I { OH Sorry N-NH > Jo Qs oF 221102_G2572WO English Translation (Final) clean copy

[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) propanocate trifluorocacetate synthesized in Example 37-(a) in acetonitrile (1 ml) and water (1 ml), 20 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid. The reaction mixture was concentrated under reduced pressure, and acetonitrile was distilled off under reduced pressure. The residue was stirred at room temperature for 2.5 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CDs;OD) &: 8.10 - 8.03 (m, 2H), 7.50 (d4, 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) 221102_G2572WO English Translation (Final) clean copy Production 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 oO AN 1 { oH Sorry N-NH

[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) and water (1 ml), 28 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.3 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 18 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) 8: 8.06 (d, J = 1.0 Hz, 1H), 8.05 - 8.02 (m, 1H}, 7.57 - 7.51 (mn, 2H), 7.47 (d, 3 = 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, 221102_G2572WO English Translation (Final) clean copy 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) Production 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 0 orgie Nn | N-NH

[0412] To a solution of 14% 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) and water (1 ml), 25 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. A deposited 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): 522 [M+H]*. 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO RR I N ? N CoH SX oY : \ | A A al N-NH QQ.

[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) and water (1 ml), 25 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 15 hours. A deposited solid was collected by filtration, washed with water, and then 221102_G2572WO English Translation (Final) clean copy dried under reduced pressure at 60°C to obtain 51 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 538 [M+H]". H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 0 NK A Homo TY N 0 0 FAN AF AS N-NH

[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) and water (1 ml), 19 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 4 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, I. ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO oO J. 0 LU AN RR AA AR on TTY i | N-NH

[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 221102_G2572WO English Translation (Final) clean copy synthesized in Example 42-(a) in acetonitrile (1 ml) and water (1 ml), 22 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours. After the completion of reaction, . ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.3 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD3;0D) &: 8.09 — 8.06 (m, 2Hy, 7.56 (£t, 3 = 1.7 Hz, 1H), 7.52 (4, + 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) Production of (38)-3-(3-(lH-pyrazol-1-yl)phenyl)-3-(2-(4- ((5-fluoro-1,4,5, 6-tetrahydropyrimidin-2-yl) amino) -1H- indazole-6-carboxamido)acetamido) propanoic acid 0 Oo Ul AN RRA ~K ag NYY oH AUN Hoo A < | N-NH { Fr dan QL -N WO 221102_G2572WO English Translation (Final) clean copy

[0420] To a solution of 123 mg of methyl (3S)-3-(3-(1H- pyrazol-1l-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido)acetamido) propanocate trifluorocacetate synthesized in Example 43-(a) in acetonitrile (1 ml) and water (1 ml), 25 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was purified by BondElut (eluting solvent: water:acetonitrile:methanol) to obtain 49 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 548 [M+H]*. H-NMR spectrum (400MHz, CD30D) 8: 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) Production of (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1- v1)phenyl)-3-(2-(4-((5-fluoro-1,4,5, 6- 221102_G2572WO English Translation (Final) clean copy tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid oO NH X y Ny N ) N Shore SOE N-NH

[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) and water (1 ml), 41 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.0 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and acetonitrile was distilled off under reduced pressure. 300 pl of acetonitrile was added to the residue, and the mixture was stirred at room temperature for 1 hour. A deposited 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]". 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 oO HoH 1 H Ny NN coum BODO RERDY N-NH TL LO

[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)propancate trifluoroacetate synthesized in Example 45-(a) in acetonitrile (1 ml) and water (1 ml), 27 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was 221102_G2572WO English Translation (Final) clean copy purified by BondElut (eluting solvent: water:acetonitrile:methanol) to obtain 44 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 567 [M+H]*. 1H-NMR spectrum (400MHz, CD3;OD) &: 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) Production 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 WAV 22UVEM Sr Tr Yr VY ERE indazole-6-carboxamido)a SS or NY FAN ¢ 0 0 N-NH OF F

[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) and water (1 ml), 23 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, I. ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 17 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido)acetamido)-3-(4- (trifluoromethyl) phenyl) propanocic acid [eo] AR I i oH OYECy N-NH

[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 trifluorocacetate 221102_G2572WO English Translation (Final) clean copy synthesized in Example 47-(a) in acetonitrile (1 ml) and water (1 ml), 23 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2.5 hours. After the completion of reaction, . ml of water was added to the reaction mixture, and the mixture was filtered. The filtrate was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD3;0D) &: 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) Production 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 Wad MH ot 2 8 ¢ bb c Fy 221102_G2572WO English Translation (Final) clean copy

[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- carboxamido)acetamido) propanocate trifluorocacetate synthesized in Example 48-(a) in acetonitrile (0.8 ml) and water (0.8 ml), 10 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 10 mg of lithium hydroxide was further added thereto at room temperature, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid. 1.6 ml of water was added thereto, and the mixture was stirred at room temperature for 16 hours. A deposited 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): 602 [M+H]*. 1H-NMR spectrum (400MHz, CDsOD) 8: 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) Production of (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- 221102_G2572WO English Translation (Final) clean copy carboxamido)acetamido)-3-(3-chloro-5- (trifluoromethyl) phenyl) propanoic acid r r NN 0 HN A OH NY cl 0 © N-NH N a CF, PSA IIT Pri wv ry mide 3 am:

[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) and water (0.5 ml), 10 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, . ml of water was added to the reaction mixture. The reaction mixture was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 22 hours. A deposited 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]*. 1H-NMR spectrum (400MHz, CD;OD) &: 8.14 (d, J = 1.3 Hz, 1H), 7.6% - 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, 221102_G2572WO English Translation (Final) clean copy 2H), 4.17 - 4.04 (m, 2H), 3.68 - 3.44 (m, 4H), 2.73 - 2.59 (m, 2H).

[0433] Example 50-(b) Production 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 HHH Hon —R Ea, HO > Ql 1 Ii N-=NH 1 1 oO JL A. © oN ox CF,

[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) and water (1 ml), 20 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. A deposited 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]'. 221102_G2572WO English Translation (Final) clean copy 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 Hu oO H Hou T Hl aN UN on XTX N-nI1 aoibics,

[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 trifluorocacetate synthesized in Example 51-(a) in acetonitrile (1 ml) and water (1 ml), 21 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.6 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited solid was collected by filtration, washed with 221102_G2572WO English Translation (Final) clean copy 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]". H-NMR spectrum (400MHz, CD;OD) &: 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), 7.4% (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) Production 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 oO H H 1 H N._N N OH CLE CY N o o EA ~N a HN-N JA H i OL cl CFs

[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) and water (2 ml), 26 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 2 hours. 221102_G2572WO English Translation (Final) clean copy After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 4 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD;OD) &: 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) Production 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 Oo Rg 1 R NY coH FANN \ o A HN-N il 1 - Br CF,

[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) and 221102_G2572WO English Translation (Final) clean copy water (3 ml), 30 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 30 minutes. After the completion of reaction, the reaction mixture was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C to obtain 84 mg of the title compound as a white solid. Mass spectrum (ESI, m / z): 628, 630 [M+H]*. H-NMR spectrum (400MHz, DMSO-ds+D;0) 8: 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) Production 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 e AN "O / / HN-N | CF.

[0442] To a solution of 85 mg of methyl (3S)-3-(2-(6-((5- fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H- 221102_G2572WO English Translation (Final) clean copy indazole-4-carboxamido)acetamido) -3- (3-iodo-5- (trifluoromethyl) phenyl) propancate trifluoroacetate synthesized in Example 54-(a) in acetonitrile (1 ml) and water (1 ml), 13 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was adjusted to pH 5.4 by the addition of 1 N hydrochloric acid, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and acetonitrile was distilled off under reduced pressure. The residue was stirred at room temperature for 5 hours. A deposited 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]*. H-NMR spectrum (400MHz, CD3OD) &: 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) Production of (38)-3-(2-(6~-((5-fluoro-1,4,5,6~ tetrahydropyrimidin-2-yl)amino)-1H-indazole-4- carboxamido)acetamido) -3-(4-fluoro-3- (trifluoromethyl) phenyl) propanocic acid 221102_G2572WO English Translation (Final) clean copy NG A. PT r HN CFs I

[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) and water (1.5 ml), 25 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.5 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD3;OD) 8: 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) Production of (3S)-3-(2-(6-((5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-4- 221102_G2572WO English Translation (Final) clean copy carboxamido)acetamido) -3-(3- (trifluoromethyl) phenyl) propanoic acid Oo NH 1 i oH SECIYY CY HN-N

[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)propancate trifluoroacetate synthesized in Example 56-(a) in acetonitrile (1.5 ml) and water (1.5 ml), 28 mg of lithium hydroxide was added at room temperature under a stream of argon, and the mixture was stirred at room temperature for 1 hour. After the completion of reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 5.8 by the addition of 1 N hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. A deposited 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]". 1H-NMR spectrum (400MHz, CD3;0D) &: 8.45 - 8.43 (m, 14), 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). 221102_G2572WO English Translation (Final) clean copy

[0447] (Test Example 1) avPfl cell adhesion inhibition test Test Example 1 was performed by partially modifying the method of Reed et al. (Sci Transl Med., 7 (288), 288ra79, 2015). Human fibronectin (manufactured by Sigma-Aldrich Co. LLC, F0895) was prepared at 1.25 pg / mL with phosphate buffered saline (PBS), dispensed at 100 pL / well to a 96- well plate, and left standing overnight. The plate was washed with Hanks' balanced salt solution (HBSS), then subjected to blocking treatment with Dulbecco's modified Eagle medium (DMEM) containing 1% bovine serum-derived albumin (BSA) (FUJIFILM Wako Pure Chemical Corp., for cell culture, 017-22231), and used as a coated plate in the adhesion test.

[0448] av-transfected cells (CHO cells deficient in a5 gene and transfected with av gene) cultured in Ham's F-12 medium (FUJIFILM Wako Pure Chemical Corp., 087-08335) containing 10% fetal bovine serum (FBS), 1% penicillin / streptomycin / amphotericin B (manufactured by Thermo Fisher Scientific, Inc., 15240), .. mM GlutaMAX Supplement (manufactured by Thermo Fisher Scientific, Inc., 35050), and 400 pg / mL hygromycin B (FUJIFILM Wako Pure Chemical Corp., 080-07683) were recovered and suspended in DMEM containing 1 mM MnCl, (manufactured by Sigma-Aldrich Co. LLC, M1787) to prepare a cell 221102_G2572WO English Translation (Final) clean copy suspension. A test compound dissolved in DMSO was added thereto.

[0449] The cell suspension of 1 x 10° cells / mL containing the test compound was added at 100 pL / well to the coated plate and left standing for 1 hour in a 5% CO; incubator (37°C). One hour later, the supernatant was removed, and the plate was washed with HBSS. The cells that adhered to each well in the plate were stained with crystal violet, and the cells were lysed, followed by absorbance measurement. Inhibition without substrate coating was defined as 100% inhibition, and inhibition when DMSO was added instead of the test compound was defined as 0% inhibition. The rate of inhibition of cell adhesion by the test compound was calculated according to the following expression. Rate of inhibition of cell adhesion (%) : [1 - { (Absorbance in the case of adding the test compound) - (Absorbance without substrate coating)} , { (Absorbance in the case of adding DMSO) : (Absorbance without substrate coating)}] x 100

[0450] An ICso value was calculated from the rate of inhibition of cell adhesion by the test compound. The results about each test compound in this test are shown in Table 18 below. A: ICso < 3 nM, B: 3 nM £ ICso< 10 nM, C: 10 nM £ ICss < 30 nM, D: 30 nM £ ICsg < 100 nM, or E: ICs0 2 100 nM. 221102_G2572WO English Translation (Final) clean copy Table 18. Results of av 1 cell adhesion inhibition test about compound of Example

[0451] (Test Example 2) avPf6 cell adhesion inhibition test Test Example 2 was performed by partially modifying 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 (manufactured by R&D Systems, Inc., 246-LP-025) was prepared at 0.2 pg / mL with 221102_G2572WO English Translation (Final) clean copy PBS, dispensed at 100 pL / well to a 96-well plate, and left standing overnight. The plate was washed with HBSS, then subjected to blocking treatment with DMEM containing 1% BSA, and used as a coated plate in the adhesion test.

[0452] HT-29 cells cultured in McCoy's 5A medium (manufactured by Thermo Fisher Scientific, Inc., 16600) containing 10% FBS and 1% penicillin / streptomycin / amphotericin B were recovered and suspended in DMEM containing 0.1% BSA and 200 pM MnCl; to prepare a cell suspension. A test compound was added thereto.

[0453] The cell suspension of 5 x 105 cells / mL containing the test compound was added at 100 pL / well to the coated plate and left standing for 1 hour in a 5% CO; incubator (37°C). One hour later, the supernatant was removed, and the plate was washed with HBSS containing 200 puM MnCl,. The cells that adhered to each well in the plate were stained with crystal violet, and the cells were lysed, followed by absorbance measurement. Inhibition without substrate coating was defined as 100% inhibition, and inhibition when DMSO was added instead of the test compound was defined as 0% inhibition. The rate of inhibition of cell adhesion by the test compound was calculated according to the following expression. Rate of inhibition of cell adhesion (%) : [1 - { (Absorbance in the case of adding the test compound) - (Absorbance without substrate coating)} , { (Absorbance in 221102_G2572WO English Translation (Final) clean copy the ca...

Claims

Claims

1. A compound represented by the following general formula (I) or (II) or a pharmaceutically acceptable salt thereof: Y Y A A 0 A E22 © OO A N-NH N—-N HN-=N il ll HNN HNN SM SM NY cor NY COR ” 0 A , 0 A \ rR N-NH HN~N on [(1)] wherein A 1s a Cg-Cio aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Ce¢ alkyl group, a C;- Cs haloalkyl group, a C,-Cs alkenyl group, a C-Cs alkynyl group, a C;-Cs alkoxy group, a Ci:-Cs haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkenyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-Cs alkoxycarbonyl group, a C1-Cs alkylsulfanyl group, and a C;-Cg¢ alkylsulfonyl group, R is a hydrogen atom or a Ci;-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group.

2. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: Y A H H Il i H § a Ca he, HN N NYY Neos Rl 0 A \ N—NH A IN} N—NH [0] wherein A 1s a Cg-Cio aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Cs alkyl group, a Ci- Cs haloalkyl group, a C,-Cs alkenyl group, a C-Cs alkynyl group, a C;-Ce¢ alkoxy group, a C;-C¢ haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkenyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C1-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C;-Cg¢ alkylsulfonyl group, R is a hydrogen atom or a Ci1-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group.

3. A compound represented by the following general formula (II) or a pharmaceutically acceptable salt thereof: Y A HNN oO A HN-N OY hot ° ; NY Yoo JR HN~N (1) wherein A is a C¢-Cip aryl group or a heteroaryl group, wherein at least one hydrogen atom of the aryl group or the heteroaryl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C;-Cs alkyl group, a Ci- Cs haloalkyl group, a C,-Cs alkenyl group, a C,-Cg¢ alkynyl group, a C;-Ce¢ alkoxy group, a C;-C¢ haloalkoxy group, a C3-C¢ cycloalkyl group, a C3-Cg cycloalkenyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a C;-C¢ alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cg alkoxycarbonyl group, a C1-Ce alkylsulfanyl group, and a C1-Cg¢ alkylsulfonyl group, R is a hydrogen atom or a Ci;-Cs alkyl group, R! is a hydrogen atom or a halogen atom, and Y is a hydrogen atom, a fluorine atom or a hydroxy group.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, wherein at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a hydroxy group, a C1-Cs alkyl group, a Ci:-Cs haloalkyl group, a C-Cs alkenyl group, a C»-Cs alkynyl group, a C;-Cs alkoxy group, a C;-Csg haloalkoxy group, a C3;-Cs cycloalkyl group, a C3;-Cs cycloalkenyl group, a C3;-Cs cycloalkoxy group, a heterocyclyl group, a heteroaryl group optionally substituted by a Ci1-Cs alkyl group, a cyano group, a carboxyl group, a carbamoyl group, a C;-Cs alkoxycarbonyl group, a C;-Cg¢ alkylsulfanyl group, and a C;-Cs alkylsulfonyl group.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, wherein at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a C;-Ce¢ alkyl group, a C;-C¢ haloalkyl group, a C;-C¢ alkoxy group, a C;-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted by a C;-Cg¢ alkyl group.

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

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the following formula (i): * RS R? R® R® R* i) wherein R2 is a hydrogen atom or a halogen atom, R3 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cg¢ haloalkyl group, a C;-Cg¢ alkoxy group, a C1-Cs haloalkoxy group, a C3-Cs cycloalkyl group, a C3-Cg cycloalkoxy group, a heterocyclyl group, or a heteroaryl group optionally substituted by a C;-C¢ alkyl group, R% is a hydrogen atom, a halogen atom, a Ci1-Cs alkyl group, a C;-Ce¢ haloalkyl group, a C;-Ce¢ alkoxy group, or a C1-Cs haloalkoxy group, R5 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, a C1-Cs haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group, and Rf is a hydrogen atom or a halogen atom.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R? is a hydrogen atom, R3 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, a C1-Cs haloalkoxy group, or a heteroaryl group optionally substituted by a C;-Cs alkyl group, R% is a hydrogen atom or a halogen atom, R5 is a hydrogen atom, a halogen atom, a C;-Cs alkyl group, a C;-Cs haloalkyl group, a C;-Cs alkoxy group, or a C1-Cs haloalkoxy group, and Rf is a hydrogen atom or a halogen atom.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of (35) -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, (35) -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, (35) -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, (35) -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, (35) -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, (38) -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, (38) -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, (35) -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, (35) -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, (35) -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- v1)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, (35) -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, (38) -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, (35) -3- (3-bromophenyl) -3- (2- (4- ( (5-fluoro-1,4,5,6- tetrahydropyrimidin-2-yl)amino)-1H-indazole-6- carboxamido) acetamido) propanoic acid, (38) -3-(3- (1H-pyrazol-1l-yl) phenyl) -3-(2- (4- ((5- fluoro-1,4,5,6-tetrahydropyrimidin-2-yl) amino) -1H- indazole-6-carboxamido) acetamido) propanoic acid, (35) -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-carboxamido) acetamido)propancic acid, (38)-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, (35) -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 (35) -3-(2-(6-((5-fluoro-1,4,5, 6-tetrahydropyrimidin- 2-yl)amino) -1H-indazole-4-carboxamido)acetamido) -3- (3- (trifluoromethyl) phenyl) propancic acid.

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

11. The pharmaceutical composition according to claim 10 for preventing, alleviating and / or treating a disease related to integrin av or a disease that is improved by inhibiting integrin av.

12. The pharmaceutical composition according to claim 9 or 10 for the remedy of fibrosis.

13. A method for preventing, alleviating and / or treating a disease related to integrin av or a disease that is improved by inhibiting integrin av, comprising administering a compound according to any one of claims I to 9 or a pharmaceutically acceptable salt thereof to a subject.

14. A method for treating fibrosis, comprising administering a compound according to any one of claims I to 9 or a pharmaceutically acceptable salt thereof to a subject.

15. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for use in the prevention, alleviation and / or remedy of a disease related to integrin av or a disease that is improved by inhibiting integrin av.

16. The compound according to any one of claims 1 or a pharmaceutically acceptable salt thereof for 1 the remedy of fibrosis.