Urea compounds antagonizing LPA1 receptor

Abstract

The present invention provides a compound represented by formula [I] having an effect of antagonizing an LPA1 receptor, or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

This application is a divisional application of PCT application with an international filing date of July 29, 2020, international application number PCT / JP2020 / 029003, Chinese national phase application number 202080054964.8, and invention title "Urea compound antagonizing LPA1 receptor". Technical Field

[0001] This invention relates to a pharmaceutical product containing an LPA1 receptor antagonist as an active ingredient. More specifically, it relates to a pharmaceutical product containing an LPA1 receptor antagonist, i.e., a urea compound, as an active ingredient. Background Technology

[0002] Lysophosphatidyl acid (LPA, sometimes referred to as "LPA" in this specification) is a physiologically active phospholipid with a fatty acid bonded at the 1- or 2-position of its glycerol backbone and a phosphate group bonded at the 3-position. It includes 1-acyl LPA, 1-alkyl LPA, 2-acyl LPA, etc. In addition, many LPA isotypes exist, exhibiting diversity due to the types of fatty acids bonded to them, and displaying various chemical and physiological properties due to the carbon chain length and degree of unsaturation of the fatty acids.

[0003] LPA is known to be produced by various enzymes in organisms and transmits signals into the cell by binding to conjugated G protein receptors on the cell surface, exhibiting various physiological functions. There are six known LPA receptor subtypes, from LPA1 to LPA6. LPA1, LPA2, and LPA3 receptors belong to the EDG (Endothermal Differentiation Gene) family and are designated EDG2, EDG4, and EDG7, respectively. LPA4 through LPA6 receptors are not part of the EDG family and have low homology with the aforementioned EDG family. LPA receptor subtypes are distributed throughout the body, but exhibit local differences due to subtype variations; each subtype is believed to contribute to the physiological functions of different tissues.

[0004] LPA has been shown to be involved in various fibrotic diseases, and its role as a receptor specifically suggests the involvement of the EDG receptor family. Regarding pulmonary fibrosis, LPA concentrations have been reported to be elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and in mice with bleomycin-induced pulmonary fibrosis. Furthermore, in the same mouse models, the progression of fibrosis has been reported to be significantly inhibited in Lpar1-deficient mice and mice treated with LPA1 receptor antagonists (see Non-Patent Literature 1). Similarly, serum LPA concentrations have been reported to be elevated in patients with systemic scleroderma, and LPA1 receptor antagonists and LPA1 / 3 receptor antagonists have shown inhibitory effects on fibrosis in mice with bleomycin-induced cutaneous fibrosis (see Non-Patent Literatures 2-4). For renal fibrosis, LPA production has been reported to be increased in mice with unilateral ureteral ligation, and fibrosis formation has been inhibited in Lpar1-deficient mice and under the influence of LPA1 receptor antagonists (see Non-Patent Literatures 4, 5). Furthermore, in the association with liver fibrosis, elevated serum LPA concentrations have been reported in patients with chronic hepatitis C, with the degree of elevation correlated with the histological stage of fibrosis (see Non-Patent Literature 6). Additionally, autocrine motor factor, an enzyme involved in LPA production, is overexpressed in the serum of patients with non-alcoholic fatty liver disease (NAFLD), and inhibitory effects of autocrine motor factor antagonists have been observed in various mouse models of liver damage (see Non-Patent Literature 7, 8). Moreover, LPA accumulates at high concentrations within atherosclerotic plaques, resulting in increased inflammation and apoptosis induction; however, administration of LPA1 / 3 receptor antagonists has been reported to improve lesions in model mice, suggesting that LPA may also be involved in circulatory organ diseases (see Non-Patent Literature 9).

[0005] In addition, LPA is known to induce the migration and proliferation of cancer cells, and increased LPA concentration and LPA1 receptor expression have been confirmed in the tissues of various cancer patients (see Non-Patent Literature 10-12).

[0006] In addition, LPA has been reported to cause bladder smooth muscle cell contraction, promote prostate cell proliferation, and be associated with intraurethral pressure control, suggesting its involvement in lower urinary tract diseases (see Patent Document 1, Non-Patent Documents 13, 14).

[0007] In addition, LPA has been reported to cause bladder smooth muscle cell contraction, promote prostate cell proliferation, and be associated with intraurethral pressure control, suggesting its involvement in lower urinary tract diseases (see Patent Document 1, Non-Patent Documents 13, 14).

[0008] Furthermore, LPA and its receptor are expressed in the nervous system, and LPA has been shown to induce neuropathic pain expression via the LPA1 receptor. Lpar1 knockout mice have reportedly not exhibiting pain symptoms in a mouse model of nerve ligation pain (see Non-Patent Literature 15).

[0009] While compounds with cyclic alkyl acids (Patent Documents 2-4), compounds with triazole rings and cyclohexylcarboxylic acids (Patent Document 5), and carboxylic acid compounds with amide structures (Patent Documents 6-7) have been reported as substances that antagonize LPA1 receptors, the urea compound of the present invention has not been disclosed.

[0010] Existing technical documents Patent documents Patent Document 1: WO02 / 062389 Patent Document 2: WO03 / 099765 Patent Document 3: WO2004 / 031118 Patent Document 4: WO2005 / 058790 Patent Document 5: WO2017 / 223016 Patent Document 6: WO2015 / 025164 Patent Document 7: WO2017 / 177004 Non-patent literature Non-patent literature 1: Nat Med. 2008 Jan; 14(1):45-54. Non-patent literature 2: Int J Med Sci. 2009 Jun 5; 6(4): 168-76. Non-patent literature 3: Exp Dermatol. 2015 Sep; 24(9):698-702. Non-patent literature 4: Pharmacol Exp Ther. 2011 Mar; 336(3):693-700. Non-patent literature 5: J Am Soc Nephrol. 2007 Dec; 18(12):3110-8. Non-patent literature 6: J Clin Gastroenterol. 2007 Jul; 41(6): 616-23. Non-patent literature 7: Obesity (Silver Spring). 2015 May; 23(5): 965-972. Non-patent literature 8: J Pharmacol Exp Ther. 2017 Jan; 360(1):1-13. Non-patent literature 9: Sci Rep. 2016 Nov 24; 6:37585. Non-patent literature 10: JAMA. 1998 Aug 26; 280(8): 719-23. Non-patent literature 11: Endocrinology. 2006 Oct; 147(10):4883-92. Non-patent literature 12: Proc NatlAcad Sci U SA.2006 Jun 20;103(25):9643-8. Non-patent literature 13: J Urol. 1999 Nov; 162(5): 1779-84. Non-patent literature 14: J Urol. 2000 Mar; 163(3):1027-32. Non-patent literature 15: Nat Med. 2004 Jul; 10(7): 712-8. Summary of the Invention

[0011] The technical problem that the invention aims to solve The purpose of this invention is to provide novel compounds that antagonize the LPA1 receptor.

[0012] Methods for solving problems In order to achieve the above-mentioned goal, the inventors conducted repeated and in-depth research and found that the compound shown in the following formula [I] (hereinafter, sometimes also referred to as compound [I]) has the effect of antagonizing LPA1 receptor.

[0013] The present invention will now be described in detail.

[0014] That is, the embodiments of the present invention are described below.

[0015] (1) One embodiment of the present invention provides: The following formula [I] represents a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof. [Chemistry 1] In the above formula [I], X represents the carboxyl group, C 1-4 alkoxycarbonyl, carbamoyl, tetrazolium or a group selected from the following group [II] [Chemistry 2] W represents a linear C chain. 1-3 Alkyl groups or structures selected from the following group [III] [Chemistry 3] in, The linear C 1-3 Alkyl groups can be selected from C 1-6 Alkyl (the C 1-6Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, and halogenated C groups can be substituted with alkyl groups. 1-6 Alkyl, C 3-8 cycloalkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted. Moreover, the linear C 1-3 When an alkane diene is replaced by one methyl group, it can be further replaced by one methyl group, and the ring A... 1 Ring A 2 And Ring A 3 Indicate C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused aromatic hydrocarbons, 4- to 8-membered saturated heterocycles containing oxygen atoms, 4- to 8-membered saturated heterocycles containing sulfur atoms, or 4- to 8-membered saturated heterocycles containing nitrogen atoms, among which... The sulfur atom in this 4- to 8-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. The nitrogen atom in this nitrogen-containing 4- to 8-membered saturated heterocycle can be selected from C 1-4 alkyl carbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted. also, R A11 R A21 and R A31 Independently representing hydrogen atoms, hydroxyl groups, carboxyl groups, halogen atoms, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 An alkyl carbonyl group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by one carbon atom. 1-3 Alkyl substitution ； R A12 R A22 and R A32 Independently representing a hydrogen atom, a halogen atom, or a methyl group, also, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form an oxygen atom together. further, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form a carbon atom together with the carbon atom in the adjacent ring.3-6 Cycloalkanes; R 1 Indicates a hydrogen atom or a methyl group; R 2 Indicate C 6-10 Alkyl, C 6-10 alkenyl, C 6-10 The alkynyl group, or the group represented by the following formula [IV-1] or [IV-2] [Chemistry 4] in, Ring B 1 Indicate C 3-8 Cycloalkyl groups, 4- to 8-membered saturated heterocyclic groups containing nitrogen atoms, phenyl groups, or 5- to 6-membered heteroaryl groups containing nitrogen atoms. R B11 and R B12 Independently represent hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C 1-6 Alkoxy L 1 Indicate C 3-8 Alkyl Dimethyl (the C 3-8 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, as shown in formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure shown in formula [V-1] below. [Chemistry 5] in, n11 represents an integer from 0 to 3. n12 represents an integer from 0 to 5. n13 represents an integer from 0 to 3. also, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L11 - Replaced further, As C 3-8 The distance R between two consecutive carbon atoms in an alkane dimethyl group 2 The atom with one or more nitrogen atoms bonded can be expressed by the formula -C(=O)N(R) L12 - Replaced R L11 Represents a hydrogen atom or C 1-3 alkyl, R L12 Represents a hydrogen atom or C 1-3 alkyl, Ring B 2 This indicates a partially saturated aryl group with a 9- or 10-membered fused ring, or a heteroaryl group with a 9- or 10-membered fused ring containing a nitrogen atom. R B21 and R B22 Independently represent hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C 1-6 Alkoxy L 2 Indicate C 1-2 Alkyl Dimethyl (the C 1-2 Alkyl groups can be substituted with 1 to 4 fluorine atoms), C 3-6 Alkyl Dimethyl (the C 3-6 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, or the structure shown in the following formula [V-2]. [Chemistry 6] in, n21 represents an integer from 0 to 3. n22 represents an integer from 0 to 5. n23 represents an integer from 0 to 3. also, As C 3-6 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L21 - Replaced further, As C 3-6 The distance R between two consecutive carbon atoms in an alkane dimethyl group 2 The atom with one or more nitrogen atoms bonded can be expressed by the formula -C(=O)N(R) L22 - Replaced R L21 Represents a hydrogen atom or C 1-3 alkyl, R L22 Represents a hydrogen atom or C 1-3 alkyl; R 3 Represents a hydrogen atom or C 1-3 Alkyl (the C 1-3 Alkyl groups may be substituted with one group selected from hydroxyl and methoxy groups; R 4 The group represented by the following formula [VI] [Chemistry 7] in, The ring C represents a phenyl group, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered fused-ring heteroaryl group. The phenyl group can be selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, C 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be substituted with one hydroxyl group), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl (the C 3-8 cycloalkyl groups can be substituted with one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkyl thioalkyl, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 Alkoxycarbonyl, single C 1-6 Alkylaminocarbonyl and diC 1-6 Substitution of 1 to 4 identical or different groups in an alkylaminocarbonyl group; This nitrogen-containing 6-membered heteroaryl group can be substituted by a single C14 group. 1-6 Alkoxy substitution, further, It can be selected from cyano, C 1-6 Alkyl, C 1-6 The heteroaryl group of the 9- to 10-membered fused ring can be selected from C by substitution of one or two identical or different groups in the alkoxy and oxo groups. 1-6 Alkyl, C 1-6 Substitution of 1 to 4 identical or different groups in alkoxy and oxo groups; also, R 3 and R 4 They can form partially saturated 9- to 10-membered fused ring hydrocarbon aromatic rings or partially saturated 9- to 10-membered fused ring heteroaromatic rings containing oxygen atoms together with their adjacent carbon atoms. in, The partially saturated 9- to 10-membered fused ring hydrocarbon aromatic ring can be replaced by 1 to 2 halogen atoms. The heteroaromatic ring of the 9- to 10-membered fused ring containing oxygen atoms in this part can be replaced by 1 to 2 halogen atoms.

[0016] (2) As another embodiment of the present invention, the compound described in (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided, wherein, In the group of equations [III] concerning W, R A11 R A21 and R A31 Independently representing hydrogen atoms, hydroxyl groups, carboxyl groups, halogen atoms, and C atoms. 1-6 Alkyl, C 1-6 An alkoxy group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by a single carbon atom. 1-3 Alkyl substitution; R A12 R A22 and R A32 Independently representing a hydrogen atom, a halogen atom, or a methyl group, also, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form an oxygen atom together. further, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form a carbon atom together with the carbon atom in the adjacent ring. 3-6 Cycloalkanes, Regarding R 2 In formula [IV-1], L 1 Indicate C 3-8 Alkyl Dimethyl (the C 3-8 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, or the structure shown in formula [V-1]. in, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L11 - Replaced further, As C 3-8 The distance R between two consecutive carbon atoms in an alkane dimethyl group 2 The atom with one or more nitrogen atoms bonded can be expressed by the formula -C(=O)N(R) L12 - Replaced R L11 Represents a hydrogen atom or C 1-3 alkyl, R L12 Represents a hydrogen atom or C 1-3 alkyl.

[0017] (3) As another embodiment of the invention, the compound described in (1) or (2) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided, wherein, In the aforementioned formula [I], W is a linear C chain. 1-3 Alkyl groups or structures selected from the following group [III] [Chemistry 8] in, The linear C 1-3 Alkyl groups can be selected from C 1-6 Alkyl (the C 1-6 Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, and halogenated C groups can be substituted with alkyl groups. 1-6 Alkyl, C 3-8 cycloalkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted. Moreover, the linear C 1-3 When an alkane diene is replaced by one methyl group, it can be further replaced by one methyl group, and the ring A... 1 C 3-8 Cycloalkanes, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, aziridine, pyrrolidine, or piperidine. Ring A 2 C 3-8 Cycloalkanes or tetrahydropyrans, Ring A 3 C 3-8 Cycloalkanes, dihydroindene, or tetrahydropyran, in, The sulfur atom in this tetrahydrothioran can be replaced by one or two oxygen atoms. also, Each nitrogen atom in the azacyclic butane, pyrrolidine, and piperidine can be converted by one carbon atom. 1-4 Alkyl carbonyl substitution, and, RA11 Hydrogen atom, hydroxyl group, carboxyl group, halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 An alkyl carbonyl group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by one carbon atom. 1-3 Alkyl substitution; R A12 Indicates a hydrogen atom, a halogen atom, or a methyl group. In addition, R A11 and R A12 Each can form an oxygen atom together. R A21 and R A22 All are hydrogen atoms. R A31 and R A32 All are hydrogen atoms. Furthermore, R A11 and R A12 Each can form a carbon atom together with the carbon atom in the adjacent ring. 3-6 Cycloalkanes; R 2 C 6-10 Alkyl groups, or groups represented by the following formulas [IV-1] or [IV-2] [Chemistry 9] in, Ring B 1 C 3-8 Cycloalkyl, piperidinyl, phenyl, pyrazolyl, or pyridinyl R B11 and R B12 Independently, it consists of hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C 1-6 Alkoxy L 1 Any of the structures shown in the following formulas [V-3] to [V-12] and [V-14] to [V-19] [Chemistry 10] in, n4 represents an integer from 3 to 5. n12' represents an integer from 0 to 3. "n12" represents an integer from 0 to 3. also, Ring B 2 It is dihydroindole, indole, or isoindole. R B21 and R B22Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 11] in, n5 represents an integer from 1 to 2; R 4 The group represented by the following formula [VI] [Chemistry 12] in, The ring C is phenyl, pyridinyl, pyrimidinyl, dihydropyridinyl, dihydrobenzofuranyl, benzodioxane, indolyl, inzolyl, benzimidazolyl, pyrazolopyridinyl, dihydroindolyl, or dihydroquinazolinyl. The phenyl group can be selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, C 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be substituted with one hydroxyl group), C 2-6 alkenyl, C 3-8 cycloalkyl (the C 3-8 cycloalkyl groups can be substituted with one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 alkoxy carbonyl and single C 1-6 Substitution of 1 to 4 identical or different groups in an alkylaminocarbonyl group; The pyridyl group can be ionized by 1 C 1-6 Alkoxy substitution, further, It can be selected from cyano and C 1-6 One group in the alkoxy group can be substituted, and the pyrimidinyl group can be replaced by one C. 1-6 Alkoxy substitution, further, Can be 1 C 1-6 Alkoxy substitution, The dihydropyridyl group can be substituted by a 1-C bond. 1-6 Alkoxy substitution, further, Can be selected from C 1-6 The alkyl and oxo groups are substituted with one or two identical or different groups. The dihydrobenzofuranyl and benzodioxane can be converted by a 1 C 1-6 Alkoxy substitution, The indole, indazole, benzimidazole, pyrazolopyridyl, and dihydroindole groups can be selected from C. 1-6 Alkyl and C 1-6 The substitution of one or two identical or different groups in the alkoxy group, The dihydroquinazolinyl group can be selected from C. 1-6 Alkyl, C 1-6 Substitution of 1 to 4 identical or different groups in alkoxy and oxo groups; also, R 3 and R 4 The fused ring formed together with the adjacent carbon atoms is either dihydroindene or dihydrobenzofuran. The dihydroindene and dihydrobenzofuran can be substituted with 1 to 2 halogens.

[0018] (4) As another embodiment of the present invention, the compound described in (1) or (2) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided. In the aforementioned formula [I], X represents a carboxyl group, C 1-4 alkoxycarbonyl or tetrazolium; R 1 It is a hydrogen atom; R 2 The group represented by the aforementioned formula [IV-1] or [IV-2] [Chemistry 13]

[0019] (5) As another embodiment of the invention, the compound described in (1), (2), or (4) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided, wherein, In the aforementioned formula [I], W is a methanediyl group or the structure shown in formula [III-1] below. [Chemistry 14] in, The methanediyl group can be selected from C... 1-6 Alkyl (the C1-6 Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, and halogenated C groups can be substituted with alkyl groups. 1-6 Alkyl, C 3-8 cycloalkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted. Furthermore, when the methane diene is replaced by one methyl group, it can be further replaced by another methyl group. also, In the structure shown in equation [III-1], Ring A 1 C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused-ring hydrocarbons, 4- to 8-membered saturated heterocycles containing oxygen atoms, 4- to 8-membered saturated heterocycles containing sulfur atoms, or 4- to 8-membered saturated heterocycles containing nitrogen atoms. in, The sulfur atom in this 4- to 8-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. also, The nitrogen atom in this nitrogen-containing 4- to 8-membered saturated heterocycle can be selected from C 1-4 alkyl carbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted. and, R A11 Hydrogen atom, hydroxyl group, carboxyl group, halogen atom, C 1-6 Alkyl, C 1-6 An alkoxy group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by a single carbon atom. 1-3 Alkyl substitution; R A12 It can be a hydrogen atom, a halogen atom, or a methyl group. also, R A11 and R A12 Each can form an oxygen atom together. further, R A11 and R A12 Each can form a carbon atom together with the carbon atom in the adjacent ring. 3-6 Cycloalkanes.

[0020] (6) As another embodiment of the invention, a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, as described in any one of (1), (2), (4), or (5), is provided, wherein, In the aforementioned formula [I], R 4 The group represented by the following formula [VI] [Chemistry 15] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, C 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be substituted with one hydroxyl group), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl (the C 3-8 cycloalkyl groups can be substituted with one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkyl thioalkyl, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 Alkoxycarbonyl, single C 1-6 Alkylaminocarbonyl and diC 1-6 The same or different 1 to 4 groups in the alkylaminocarbonyl group are substituted.

[0021] (7) As another embodiment of the present invention, a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, as described in any one of (1), (2), (4) to (6), is provided, wherein, In the aforementioned formula [I], R 2 The group is represented by the following formula [IV-1] or [IV-2]. [Chemistry 16] in, Ring B 1 It is a phenyl group. R B11 and R B12 Independently, it consists of hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C1-6 Alkoxy L 1 For any of the structures shown in the following formulas [V-3]~[V-5], [V-7]~[V-8], [V-11]~[V-12], [V-14]~[V-16], [Chemistry 17] in, n4 represents an integer from 3 to 5. Ring B 2 It is dihydroindole, indole, or isoindole. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 18] in, n5 is an integer from 1 to 2.

[0022] (8) As another embodiment of the present invention, a compound of any one of (4) to (7) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided, wherein, In the aforementioned formula [I], X is a carboxyl group; W is any of the structures shown in equations [III-4] to [III-17] below; [Chemistry 19] R 2 The group is represented by the following formula [IV-1] or [IV-2]. [Chemistry 20] in, Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 The structure is shown in the following formulas [V-3], [V-8], [V-12], [V-14], or [V-15]. [Chemistry 21] in, n4 is an integer between 3 and 4. also, Ring B2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 22] in, n5 is 2; R 3 It is a methyl group having the stereoconfiguration shown in formula [VII]. [Chemistry 23] R 4 It is a group represented by any of the following formulas [VI-1] to [VI-21]. [Chemistry 24] [Chemistry 25] [Chemistry 26]

[0023] (9) As another embodiment of the present invention, a compound of any one of (4) to (7) or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided, wherein, In the aforementioned formula [I], X is a carboxyl group; W is the structure shown in the following formulas [III-4]~[III-11], [III-13]~[III-14], or [III-18]~[III-19]. [Chemistry 27] R 2 The group is represented by the following formula [IV-1] or [IV-2]. [Chemistry 28] in, Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 The structure shown in the following formulas [V-3], [V-8], or [V-14] [Chemistry 29] in, n4 is 4. also, Ring B 2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 30] in, n5 is 2; R 3 It is a methyl group having the stereoconfiguration shown in formula [VII]. [Chemistry 31] R 4 The group is represented by the following formulas: [VI-2], [VI-3], [VI-8], [VI-10] to [VI-12], [VI-16], [VI-19], or [VI-21]. [Chemistry 32] [Chemistry 33]

[0024] (10) As another embodiment of the invention, a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, as described in any one of (4) to (7), is provided, wherein, In the aforementioned formula [I], X is a carboxyl group or a tetrazolium group; W is the structure shown in the following formulas [III-5], [III-8] to [III-11], or [III-13]. [Chemistry 34] R 2 The group is represented by the following formula [IV-1] or [IV-2]. [Chemistry 35] in, Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1The structure shown in the following formulas [V-3], [V-12], or [V-14] [Chemistry 36] in, n4 is an integer of 4. also, Ring B 2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 37] in, n5 is 2; R 3 It is a methyl group having the stereoconfiguration shown in formula [VII]. [Chemistry 38] R 4 The group is represented by the following formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11], or [VI-12]. [Chemistry 39]

[0025] (11) As another embodiment of the present invention, the compound described in (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the compound is any of the following: [Chemistry 40] [Chemistry 41] [Chemistry 42] [Chemistry 43] [Chemistry 44]

[0026] (12) As another embodiment of the present invention, it is the compound described in (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the compound is any of the following: [Chemistry 45] [Chemistry 46] [Chemistry 47]

[0027] (13) As another embodiment of the present invention, a medicine is provided which contains, as an active ingredient, any one of (1) to (12) of the compound or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0028] (14) As another embodiment of the present invention, an LPA1 receptor antagonist is provided, which contains any one of (1) to (12) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

[0029] (15) As another embodiment of the present invention, a preventive or therapeutic agent for systemic scleroderma is provided, which contains any one of (1) to (12) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

[0030] (16) As another embodiment of the present invention, an LPA1 receptor antagonist is provided, which contains a compound represented by the following formula [Ia] or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. [Chemistry 48] In the above formula [Ia], X represents the carboxyl group, C 1-4 alkoxycarbonyl, carbamoyl, tetrazolium, or a structure selected from the following group of formulas [IIa]. [Chemistry 49] W represents a linear C chain. 1-3 Alkyl groups or structures selected from the following group [IIIa] [Transformation 50] in, The linear C 1-3 Alkyl groups can be selected from C 1-6 Alkyl (the C 1-6 Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, and halogenated C groups can be substituted with alkyl groups. 1-6 Alkyl, C 3-8 cycloalkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted. Moreover, the linear C 1-3When an alkane diene is replaced by one methyl group, it can be further replaced by one methyl group, and the ring A... 1 Ring A 2 And Ring A 3 Indicate C 3-8 Cycloalkanes, partially saturated 9-10 membered fused ring aromatic hydrocarbons, 4-8 membered saturated heterocycles containing oxygen atoms, partially saturated 9-10 membered fused ring heterocycles containing oxygen atoms, 4-8 membered saturated heterocycles containing sulfur atoms, partially saturated 9-10 membered fused ring heterocycles containing nitrogen atoms, 4-8 membered saturated heterocycles containing nitrogen atoms, or partially saturated 9-10 membered fused ring heterocycles containing sulfur atoms. in, In the saturated heterocycles containing sulfur atoms in the 4-8 membered saturated heterocycles and the partially saturated heterocycles containing sulfur atoms in the 9-10 membered fused rings, each sulfur atom can be replaced by 1-2 oxygen atoms. also, The nitrogen atoms in the 4-8 member saturated heterocycles containing nitrogen atoms and the partially saturated 9-10 member fused heterocycles containing nitrogen atoms can be selected from C 1-4 alkyl carbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted. R A11 R A21 and R A31 Independently representing hydrogen atoms, hydroxyl groups, carboxyl groups, halogen atoms, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 An alkyl carbonyl group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by one carbon atom. 1-3 Alkyl substitution ； R A12 R A22 and R A32 Independently representing a hydrogen atom, a halogen atom, or a methyl group, In addition, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form an oxygen atom together. Furthermore, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form a carbon atom together with the carbon atom in the adjacent ring A to form a carbon atom. 3-6 Cycloalkanes; R1 Indicates a hydrogen atom or a methyl group; R 2 Indicate C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or a group represented by the following formula [IVa] [Chemistry 51] in, Ring B represents C 3-8 Cycloalkyl, 4-8 membered saturated heterocyclic groups, phenyl, 9-10 membered fused-ring aryl, 5-6 membered heteroaryl or 9-10 membered fused-ring heteroaryl, R B1 and R B2 Independently represent hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy L represents C 1-2 Alkyl Dimethyl (the C 1-2 Alkyl groups can be substituted with 1 to 4 fluorine atoms), C 3-8 Alkyl Dimethyl (the C 3-8 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, the structure shown in formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure shown in formula [V-1a] below. [Chemistry 52] in, n1 represents an integer from 0 to 3. n2 represents an integer from 0 to 5. n3 represents an integer from 0 to 3. also, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L1 - Replaced further, As C 3-8 The distance R between two consecutive carbon atoms in an alkane dimethyl group 2 The atom with one or more nitrogen atoms bonded can be expressed by the formula -C(=O)N(R) L2 - Replaced R L1 Represents a hydrogen atom or C 1-3 alkyl, R L2 Represents a hydrogen atom or C 1-3 alkyl; R 3 Represents a hydrogen atom or C 1-3 Alkyl (the C 1-3 Alkyl groups may be substituted with one group selected from hydroxyl and methoxy groups; R 4 Represents the group shown in the following formula [VIa] [Chemistry 53] in, The ring C represents a phenyl group, a 9-10 membered fused-ring aryl group, a 5-6 membered heteroaryl group, or a 9-10 membered fused-ring heteroaryl group. The phenyl group can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, or C. 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl (the C 3-8 Cycloalkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy (the C 1-6 Alkoxy and halogenated C 1-6 Alkoxy groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy), C 3-8 Cycloalkoxy (the C 3-8 Cycloalkoxy groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy), C 1-6 Alkyl thioalkyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl (the C 1-6 Alkyl thioalkyl, C 1-6 alkyl sulfinyl and C 1-6 Alkyl sulfonyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy group), single carbon 1-6 Alkylamino, diC 1-6 Alkylamino (the single C 1-6 Alkylamino and diC 1-6 Alkylamino groups can be selected from hydroxyl and C. 1-6 (substitution of one group in alkoxy), C 1-6 Alkyl carbonyl, halogenated C1-6 alkyl carbonyl, C 1-6 Alkoxycarbonyl, single C 1-6 alkylaminocarbonyl and diC 1-6 alkylaminocarbonyl (the C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 Alkoxycarbonyl, single C 1-6 alkylaminocarbonyl and diC 1-6 Alkylaminocarbonyl groups can be selected from hydroxyl and C. 1-6 The substitution of one group in the alkoxy group with one or more of the same or different groups. The aryl group of this 9- to 10-membered fused ring can be selected from halogen atoms, C... 1-6 Alkyl and C 1-6 The substitution of 1 to 3 identical or different groups in the alkoxy group, The 5-6 membered heteroaryl group can be selected from halogen atoms, cyano groups, C... 1-6 Alkyl, C 1-6 The alkoxy and oxo groups are substituted with 1 to 3 identical or different groups, and the heteroaryl group of the 9- to 10-membered fused ring can be selected from C. 1-6 Alkyl, C 1-6 Substitution of 1 to 4 identical or different groups in alkoxy and oxo groups; In addition, R 3 and R 4 Each can be together with its neighboring carbon atom Forming partially saturated 9- to 10-membered fused ring hydrocarbon aromatic rings or partially saturated 9- to 10-membered fused ring heteroaromatic rings, wherein, The partially saturated 9- to 10-membered fused ring hydrocarbon aromatic ring can be replaced by 1 to 2 halogen atoms. The partially saturated 9- to 10-membered fused ring heteroaromatic ring can be replaced by 1 to 2 halogen atoms.

[0031] (17) As another embodiment of the present invention, an LPA1 receptor antagonist as described in (16) is provided, wherein, in formula group [IIIa] concerning W, R A11 R A21 and R A31 Independently representing hydrogen atoms, hydroxyl groups, carboxyl groups, halogen atoms, and C atoms. 1-6 Alkyl, C 1-6 An alkoxy group or a nitrogen-containing 4- to 6-membered saturated heterocyclic group, wherein the nitrogen-containing 4- to 6-membered saturated heterocyclic group can be substituted by a single carbon atom. 1-3 Alkyl substitution; ； R A12 R A22 and R A32Independently representing a hydrogen atom, a halogen atom, or a methyl group, also, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form an oxygen atom together. further, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form a carbon atom together with the carbon atom in the adjacent ring A to form a carbon atom. 3-6 Cycloalkanes, Regarding R 2 In formula [IVa], L represents C 1-2 Alkyl Dimethyl (the C 1-2 Alkyl groups can be substituted with 1 to 4 fluorine atoms), C 3-8 Alkyl Dimethyl (the C 3-8 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms), or the structure shown in formula [V-1a], wherein, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L1 - Replaced further, As C 3-8 The distance R between two consecutive carbon atoms in an alkane dimethyl group 2 The atom with one or more nitrogen atoms bonded can be expressed by the formula -C(=O)N(R) L2 - Replaced R L1 Represents a hydrogen atom or C 1-3 alkyl, R L2 Represents a hydrogen atom or C 1-3 alkyl.

[0032] (18) As another embodiment of the invention, a preventive or therapeutic agent for systemic scleroderma is provided, which contains a compound of formula [Ia] as described in (16) or (17) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

[0033] (19) As another embodiment of the invention, a method for treating or preventing systemic scleroderma is provided, comprising administering to a patient in need a therapeutically effective amount of the compound represented by formula [Ia] of (16) or (17) or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0034] (20) As another embodiment of the invention, a medicine is provided which contains a compound of formula [Ia] as described in (16) or (17) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

[0035] Invention Effects The compounds of the present invention (hereinafter, sometimes referred to as "compounds of the present invention") have the effect of antagonizing LPA1 receptors. Detailed Implementation

[0036] The present invention provides compounds of the aforementioned formula [I] that have the effect of antagonizing LPA1 receptors, or pharmaceutically acceptable salts thereof or hydrates thereof.

[0037] The compounds of the present invention will be described in further detail below, but the present invention is not limited to those illustrated.

[0038] "Halogen atom" refers to fluorine, chlorine, bromine, and iodine atoms.

[0039] “C 1-3 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, and isopropyl.

[0040] “C 1-4 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0041] “C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0042] “C 1-10 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isoheptyl, and isooctyl.

[0043] “C 6-10"Alkyl" refers to a straight-chain or branched alkyl group having 6 to 10 carbon atoms. Examples include n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isoheptyl, and isooctyl.

[0044] “C 5-9 "Alkyl" refers to a straight-chain or branched alkyl group having 5 to 9 carbon atoms. Examples include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, isoheptyl, and isooctyl.

[0045] Halogenated C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms substituted with halogen atoms. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0046] Hydroxy C 1-6 "alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms that has been substituted with a hydroxyl group. The preferred number of hydroxyl substitutions is one. Examples include monohydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl.

[0047] “C 2-3 "Alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 3 carbon atoms. Examples include vinyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-1-en-2-yl, and prop-2-en-1-yl.

[0048] “C 2-6 "Alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms. Examples include vinyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-2-en-1-yl, but-3-en-1-yl, pent-4-en-1-yl, hex-5-en-1-yl, and 1-methyl vinyl.

[0049] “C 2-10 "Alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 10 carbon atoms. Examples include vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl, etc.

[0050] “C 5-9"Alkenyl" refers to an alkenyl group that has 5 to 9 carbon atoms and is either straight-chain or branched. Examples include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, and n-nonenyl.

[0051] “C 6-10 "Alkenyl" refers to an alkenyl group that has 6 to 10 carbon atoms and is either straight-chain or branched. Examples include n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, and n-decenyl.

[0052] “C 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms. Examples include ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-3-yn-1-yl, pent-4-yn-1-yl, and hex-5-yn-1-yl.

[0053] “C 2-10 "Alynyl" refers to a straight-chain or branched alkynyl group having 2 to 10 carbon atoms. Examples include ethynyl, n-propynyl, n-butynyl, n-pentynyl, n-hexynyl, n-heptynyl, n-octyynyl, n-nonynyl, and n-decynyl.

[0054] “C 5-9 "Alynyl" refers to a straight-chain or branched alkynyl group having 5 to 9 carbon atoms. Examples include n-pentynyl, n-hexynyl, n-heptynyl, n-octyynyl, and n-nonynyl.

[0055] “C 6-10 "Alynyl" refers to a straight-chain or branched alkynyl group having 6 to 10 carbon atoms. Examples include n-hexynyl, n-heptynyl, n-octyynyl, n-nonynyl, and n-decynyl.

[0056] “C 3-6 "Cycloalkanes" refers to hydrocarbon rings having 3 to 6 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0057] “C 3-8 "Cycloalkanes" refers to hydrocarbon rings having 3 to 8 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0058] “C 3-8 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0059] "Aromatic group with 9-10 fused rings" refers to an aromatic ring group of a 9-10 fused polycyclic hydrocarbon having 9-10 carbon atoms. Examples include naphthyl groups.

[0060] Furthermore, for aryl groups with 9- to 10-membered fused rings, partially saturated groups are also included in "aryl groups with 9- to 10-membered fused rings". Examples include dihydroindenyl, dihydronaphthyl, and tetrahydronaphthyl.

[0061] "Partially saturated 9- to 10-membered fused aromatic hydrocarbon rings" refers to partially saturated 9- to 10-membered fused polycyclic aromatic hydrocarbon rings with 9 to 10 carbon atoms. Examples include dihydroindene, dihydronaphthalene, and tetrahydronaphthalene.

[0062] "Partially saturated 9- to 10-membered fused-ring aryl" refers to a partially saturated 9- to 10-membered fused-ring aromatic cyclic group of a polycyclic hydrocarbon having 9 to 10 carbon atoms. Examples include dihydroindenyl, dihydronaphthyl, and tetrahydronaphthyl.

[0063] "4- to 8-membered saturated heterocyclic groups" refers to 4- to 8-membered monocyclic saturated heterocyclic groups composed of one atom selected from oxygen, sulfur, and nitrogen and 3 to 7 carbon atoms. In addition to the aforementioned oxygen, sulfur, or nitrogen atoms, it may further include one atom selected from oxygen, sulfur, and nitrogen. Examples include oxoheterocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiaranyl, azacyclic butyl, pyrrolidinyl, piperidinyl, oxazolyl, thiazolyl, imidazolyl, morpholinyl, thiomorpholinyl, and piperazineyl.

[0064] "4- to 8-membered saturated heterocycles containing oxygen atoms" refers to 4- to 8-membered monocyclic saturated heterocycles composed of one oxygen atom and three to seven carbon atoms. Examples include oxoheterocyclic butane, tetrahydrofuran, and tetrahydropyran.

[0065] "4- to 8-membered saturated heterocycles containing sulfur atoms" refers to 4- to 8-membered monocyclic saturated heterocycles composed of one sulfur atom and three to seven carbon atoms. Examples include thiocyclic butane, tetrahydrothiophene, and tetrahydrothioran.

[0066] "A 4- to 8-membered saturated heterocycle containing a nitrogen atom" refers to a 4- to 8-membered monocyclic saturated heterocycle composed of one nitrogen atom and three to seven carbon atoms, wherein, in addition to the aforementioned nitrogen atom, it may further contain one atom selected from oxygen, sulfur, and nitrogen atoms. Examples include azaheptanane, pyrrolidine, piperidine, azaheptanane, morpholine, thiomorpholine, and piperazine.

[0067] "A 4- to 6-membered saturated heterocyclic group containing a nitrogen atom" refers to a 4- to 6-membered monocyclic saturated heterocyclic group composed of one nitrogen atom and three to five carbon atoms, wherein, in addition to the aforementioned nitrogen atom, it may further contain one atom selected from oxygen, sulfur, and nitrogen atoms. Examples include nitrogen-containing heterocyclic butyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine.

[0068] "A 4- to 8-membered saturated heterocyclic group containing a nitrogen atom" refers to a 4- to 8-membered monocyclic saturated heterocyclic group composed of one nitrogen atom and three to seven carbon atoms. In addition to the aforementioned nitrogen atom, it may further include one atom selected from oxygen, sulfur, and nitrogen. Examples include azircyclic butyl, pyrrolidinyl, piperidinyl, azircyclic heptyl, morpholinyl, thiomorpholinyl, and piperazineyl.

[0069] "5-6 membered heteroaryl" refers to a 5-6 membered monocyclic aromatic heterocyclic group composed of one or more identical or different atoms selected from oxygen, sulfur, and nitrogen atoms, and 1 to 5 carbon atoms. Examples include furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl, and triazinyl.

[0070] Furthermore, in the 5- to 6-membered heteroaryl group, partially saturated groups are also included in "5- to 6-membered heteroaryl". Examples include dihydrothiazolyl, dihydropyridyl, and tetrahydropyridyl.

[0071] "5- to 6-membered heteroaryl groups containing nitrogen atoms" refers to a 5- to 6-membered monocyclic aromatic heterocyclic group composed of 1 to 4 nitrogen atoms and 1 to 5 carbon atoms, wherein, in addition to the nitrogen atom, it may further include one atom selected from oxygen and sulfur atoms. Examples include pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrazinyl, and triazinyl.

[0072] Furthermore, in the 5- to 6-membered heteroaryl groups containing nitrogen atoms, partially saturated groups are also included in the category of "5- to 6-membered heteroaryl groups containing nitrogen atoms". Examples include dihydrothiazolyl, dihydropyridyl, and tetrahydropyridyl.

[0073] "A 6-membered heteroaryl group containing nitrogen atoms" refers to a 6-membered monocyclic aromatic heterocyclic group composed of 1 to 3 nitrogen atoms and 3 to 5 carbon atoms. Examples include pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0074] Furthermore, in this nitrogen-containing 6-membered heteroaryl group, partially saturated groups are also included in "nitrogen-containing 6-membered heteroaryl group". Examples include dihydropyridyl and tetrahydropyridyl.

[0075] "A 9- to 10-membered fused-ring heteroaryl group" refers to a 9- to 10-membered fused polycyclic aromatic heterocyclic group composed of one atom selected from oxygen, sulfur, and nitrogen and 5 to 9 carbon atoms. In addition to the aforementioned oxygen, sulfur, or nitrogen atoms, it may further include 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, either the same or different. Examples include benzofuranyl, benzothiophenyl, indoleyl, indazoleyl, benzimidazolyl, and pyrazolopyridyl.

[0076] Furthermore, in the 9- to 10-membered fused-ring heteroaryl group, partially saturated groups are also included in "9- to 10-membered fused-ring heteroaryl". Examples include dihydrobenzofuranyl, dihydrobenzothiopheneyl, dihydroindolyl, dihydrobenzodioxinyl, dihydroquinazolinyl, and isoindolyl.

[0077] "Partially saturated 9- to 10-membered fused-ring heteroaromatic ring" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle composed of one atom selected from oxygen, sulfur, and nitrogen and 5 to 9 carbon atoms. In addition to the aforementioned oxygen, sulfur, or nitrogen atom, it may further contain 1 to 3 atoms selected from oxygen, sulfur, and nitrogen, either the same or different. Examples include dihydrobenzofuran, dihydrobenzothiophene, dihydroindole, dihydrobenzodioxin, and dihydroquinazoline.

[0078] "A 9- to 10-membered fused-ring heteroaryl group containing a nitrogen atom" refers to a 9- to 10-membered fused polycyclic aromatic heterocyclic group composed of one nitrogen atom and 5 to 9 carbon atoms. In addition to the nitrogen atom, it may further contain 1 to 3 atoms selected from the same or different oxygen, sulfur, and nitrogen atoms. Examples include indole, indazole, benzimidazole, and pyrazolopyridyl.

[0079] Furthermore, in the 9- to 10-membered fused ring heteroaryl group containing a nitrogen atom, partially saturated groups are also included in "9- to 10-membered fused ring heteroaryl group containing a nitrogen atom". Examples include dihydroindolyl and dihydroquinazolinyl.

[0080] "Partially saturated 9- to 10-membered fused-ring heterocycle containing oxygen atoms" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle composed of one oxygen atom and five to nine carbon atoms, wherein, in addition to the oxygen atom, it may further contain one to three identical or different atoms selected from oxygen, sulfur, and nitrogen atoms. An example is dihydrobenzofuran.

[0081] "Partially saturated 9- to 10-membered fused-ring heterocycle containing sulfur atoms" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle composed of one sulfur atom and five to nine carbon atoms, wherein, in addition to the sulfur atom, it may further contain one to three identical or different atoms selected from oxygen, sulfur, and nitrogen atoms. An example is dihydrobenzothiophene.

[0082] "Partially saturated 9- to 10-membered fused-ring heterocycle containing nitrogen atoms" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle composed of one nitrogen atom and five to nine carbon atoms, wherein, in addition to the nitrogen atom, it may further contain one to three identical or different atoms selected from oxygen, sulfur, and nitrogen atoms. An example is dihydroindole.

[0083] "Phenyl C" 1-3 "alkyl" indicates the aforementioned "C" group having one phenyl substituent. 1-3 Alkyl groups, for example, benzyl, phenethyl, 3-phenylpropyl, etc.

[0084] “Pyridyl C 1-3 "alkyl" indicates the aforementioned "C" having one pyridyl group as a substituent. 1-3 Alkyl group. Examples of alkyl groups include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 2-(pyridin-2-yl)ethyl, and 3-(pyridin-2-yl)propyl.

[0085] “C 1-4 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0086] “C 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0087] Halogenated C 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms substituted with halogen atoms. The preferred number of halogen atoms substituted is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentoxy, and 6,6,6-trifluorohexyloxy.

[0088] “C 3-8 "Cycloalkoxy" refers to a cyclic alkoxy group having 3 to 8 carbon atoms. Examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptoxy, and cyclooctoxy.

[0089] “C 1-6 "alkyl thioalkyl" indicates the aforementioned "C" 1-6 An alkyl group formed by combining an alkyl group with a thioalkyl group. Examples include methyl thioalkyl, ethyl thioalkyl, n-propyl thioalkyl, isopropyl thioalkyl, n-butyl thioalkyl, isobutyl thioalkyl, sec-butyl thioalkyl, tert-butyl thioalkyl, n-pentyl thioalkyl, and n-hexyl thioalkyl.

[0090] “C 1-6 "alkylsulfinyl" indicates the aforementioned "C" 1-6 An alkyl group is formed by combining an alkyl group with a sulfinyl group. Examples include methyl sulfinyl, ethyl sulfinyl, n-propyl sulfinyl, isopropyl sulfinyl, n-butyl sulfinyl, isobutyl sulfinyl, sec-butyl sulfinyl, tert-butyl sulfinyl, n-pentyl sulfinyl, and n-hexyl sulfinyl.

[0091] “C 1-6 "alkylsulfonyl" indicates the aforementioned "C" 1-6 An alkyl group is formed by combining an alkyl group with a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, and n-hexylsulfonyl.

[0092] “C 1-4 "alkylsulfonyloxy" indicates the aforementioned "C" 1-4 An alkyl group formed by combining with a sulfonyloxy group. Examples include methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, and tert-butylsulfonyloxy.

[0093] "Single C" 1-6 "alkylamino" indicates the presence of one of the aforementioned "C" groups. 1-6 "alkyl" is an amino group with substituents. Examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, and n-hexylamino.

[0094] "2C" 1-6 "alkylamino" indicates the presence of two identical or different C atoms. 1-6 "alkyl" is an amino group with substituents. Examples include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0095] “C 1-4 "alkyl carbonyl" indicates the aforementioned "C" 1-4 An alkyl group is a group formed by the combination of an alkyl group and a carbonyl group. Examples include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, and tert-butyl carbonyl.

[0096] “C 1-6 "alkyl carbonyl" indicates the aforementioned "C" 1-6 An alkyl group is a group formed by combining an alkyl group with a carbonyl group. Examples include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, n-pentyl carbonyl, and n-hexyl carbonyl.

[0097] Halogenated C 1-6 "alkyl carbonyl" indicates the aforementioned "halogenated C" 1-6 An alkyl group formed by combining an alkyl group with a carbonyl group. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples include monofluoromethyl carbonyl, difluoromethyl carbonyl, trifluoromethyl carbonyl, 1-fluoroethyl carbonyl, 1,1-difluoroethyl carbonyl, 2-fluoroethyl carbonyl, 2,2,2-trifluoroethyl carbonyl, 1,1,2,2,2-pentafluoroethyl carbonyl, 3,3,3-trifluoropropyl carbonyl, 4,4,4-trifluorobutyl carbonyl, 5,5,5-trifluoropentyl carbonyl, and 6,6,6-trifluorohexyl carbonyl.

[0098] “C 1-4 "alkoxycarbonyl" indicates the aforementioned "C" 1-4 An alkoxy group is formed by the combination of an alkoxy group and a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, and tert-butoxycarbonyl.

[0099] “C 1-6 "alkoxycarbonyl" indicates the aforementioned "C" 1-6 An alkoxy group is formed by the combination of an alkoxy group and a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, and n-hexyloxycarbonyl.

[0100] "Single C" 1-6 "alkylaminocarbonyl" indicates the aforementioned "single C" 1-6 An alkylamino group is a group formed by combining an alkylamino group with a carbonyl group. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, and n-hexylaminocarbonyl.

[0101] "2C" 1-6 "alkylaminocarbonyl" indicates the aforementioned "diC" 1-6 An alkylamino group is a group formed by combining an alkylamino group with a carbonyl group. Examples include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, and methyl(n-propyl)aminocarbonyl.

[0102] "Oxidation" refers to a substituent (=O) in which an oxygen atom is substituted via a double bond. Therefore, when an oxygen atom is substituted on a carbon atom, it forms a carbonyl group together with that carbon atom; when one oxygen atom is substituted on one sulfur atom, it forms a sulfinyl group together with that sulfur atom; and when two oxygen atoms are substituted on one sulfur atom, they form a sulfonyl group together with that sulfur atom.

[0103] Examples of saturated heterocyclic groups that are substituted with oxo groups include, for example, 2-oxopyrrolyl, 2-oxopyridinyl, 2-oxopyridinyl, 1,1-tetrahydrothiopheneyl, 1-tetrahydro-2H-thiaranyl, 1,1-tetrahydro-2H-thiaranyl, 1,1-isothiazolyl, 2-oxo-1,3-oxazolidinyl, and 2-oxo-1,3-oxazinyl.

[0104] In addition, examples of partially saturated heteroaryl groups that are oxysubstituted include, for example, 6-oxo-1,6-dihydropyridinyl, 6-oxo-1,1-dihydropyridazinyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-1,2-dihydroquinazolinyl, and 1-oxo-1,2,3,4-tetrahydroisoquinolinyl.

[0105] "Straight-chain C" 1-3 "Alkyl" refers to a divalent, straight-chain hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms. Examples include methanediyl, ethane-1,2-diyl, and propane-1,3-diyl.

[0106] “C 1-2 "Alkyl" refers to a divalent, straight-chain hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 2 carbon atoms. Examples include methanediyl, ethane-1,1-diyl, and ethane-1,2-diyl.

[0107] “C 1-8"Alkyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 8 carbon atoms. Examples include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, 2-methylbutane-1,4-diyl, 2-methylpentane-2,5-diyl, and 4-methylpentane-1,4-diyl.

[0108] “C 2-7 "Alkyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 2 to 7 carbon atoms. Examples include ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, 2-methylbutane-1,4-diyl, 2-methylpentane-2,5-diyl, and 4-methylpentane-1,4-diyl. 3-6 "Alkyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 3 to 6 carbon atoms. Examples include propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, 2-methylbutane-1,4-diyl, 2-methylpentane-2,5-diyl, and 4-methylpentane-1,4-diyl.

[0109] “C 3-8 "Alkyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 3 to 8 carbon atoms. Examples include propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, 2-methylbutane-1,4-diyl, 2-methylpentane-2,5-diyl, and 4-methylpentane-1,4-diyl.

[0110] "C4 alkane diel" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having four carbon atoms. An example is butane-1,4-diel.

[0111] A preferred embodiment of the compound of the present invention is the following embodiment (A).

[0112] Implementation method (A): The compound represented by the aforementioned formula [I] [Chemistry 54] In or in its pharmaceutically acceptable salts; X is a carboxyl group, C 1-4 alkoxycarbonyl, tetrazolium, or groups represented by formulas [II-2] to [II-5] below. [Chemistry 55]

[0113] In this embodiment, W is a linear C chain. 1-3 Alkyl groups, or structures selected from the following group [III] [Chemistry 56] in, The linear C 1-3 Alkyl groups can be selected from C 1-6 Alkyl, Halogenated C 1-6 Alkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted, and the straight-chain C 1-3 When an alkane diene is replaced by one methyl group, it can be further replaced by one methyl group, and the ring A... 1 Ring A 2 And Ring A 3 It is C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused aromatic hydrocarbons, 4- to 8-membered saturated heterocycles containing oxygen atoms, 4- to 8-membered saturated heterocycles containing sulfur atoms, or 4- to 8-membered saturated heterocycles containing nitrogen atoms, among which... The sulfur atom in this 4- to 8-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. The nitrogen atom in this nitrogen-containing 4- to 8-membered saturated heterocycle can be ionized by one carbon atom. 1-4 Alkyl carbonyl substitution, also, R A11 R A21 and R A31 Independently, it consists of hydrogen atoms, hydroxyl groups, halogen atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy or nitrogen-containing 4- to 6-membered saturated heterocyclic groups, R A12 R A22 and R A32 Independently, it can be a hydrogen atom, a halogen atom, or a methyl group. also, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form an oxygen atom together. further, R A11 and R A12 R A21 and R A22 and R A31 and R A32 Each can form a carbon atom together with the carbon atom in the adjacent ring. 3-6 Cycloalkanes.

[0114] More preferably, W is a linear C. 1-3 Alkyl groups, or structures selected from the following group [III] [Chemistry 57] in, The linear C 1-3 Alkyl groups can be selected from C 1-4 Alkyl, halo-C2 alkyl, phenyl C 1-2 One group in the alkyl and pyridyl C1 alkyl groups is substituted, and the straight-chain C 1-3 When an alkane diene is replaced by one methyl group, it can be further replaced by one methyl group, and the ring A... 1 It is C 3-7 Cycloalkanes, partially saturated 9-membered fused ring hydrocarbons, 4- to 6-membered saturated heterocycles containing oxygen atoms, 6-membered saturated heterocycles containing sulfur atoms, or 4- to 6-membered saturated heterocycles containing nitrogen atoms. in, The sulfur atom in this 6-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. The nitrogen atom in this nitrogen-containing 4- to 6-membered saturated heterocycle can be replaced by a C1 alkyl carbonyl group. also, R A11 It is a hydrogen atom, a hydroxyl group, a halogen atom, a C1 alkyl group, and a C1 alkyl group. 1-3 Alkoxy or a 6-membered saturated heterocyclic group containing a nitrogen atom, R A12 It can be a hydrogen atom, a halogen atom, or a methyl group. also, R A11 and R A12 They can form oxygen together. further, R A11 and RA12 Each can combine with carbon atoms in an adjacent ring to form a C4 cycloalkanes. Ring A 2 It is a C3 cycloalkanes or a 6-membered saturated heterocycle containing oxygen atoms. in, R A21 It is a hydrogen atom. R A22 It is a hydrogen atom. Ring A 3 It is C 3-5 Cycloalkanes, partially saturated 9-membered fused ring hydrocarbons, aromatic rings, or 6-membered saturated heterocycles containing oxygen atoms. in, R A31 It is a hydrogen atom. R A32 It is a hydrogen atom.

[0115] Further preferred forms of W are methanediyl, propane-1,3-diyl, or structures shown in formulas [III-1] to [III-3] below. [Chem.58] in, The methane diel can be substituted with one group selected from methyl, n-butyl, haloethyl, benzyl, phenethyl, and pyridylmethyl. Furthermore, when the methane diene is replaced by one methyl group, it can be further replaced by another methyl group. Ring A 1 The compounds are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxacyclobutane, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, aziridine, pyrrolidine, or piperidine. in, The sulfur atom in this tetrahydrothioran can be replaced by two oxygen atoms. The nitrogen atom in these azacyclic butanes, pyrrolidines, and piperidines can be replaced by a methyl carbonyl group. also, R A11 It can be a hydrogen atom, hydroxyl group, fluorine atom, methyl group, methoxy group, ethoxy group, isopropoxy group, or morpholino group. R A12 It can be a hydrogen atom, a fluorine atom, or a methyl group. also, R A11 and R A12 They can form oxygen together. further, R A11 and R A12 Each can combine with carbon atoms in an adjacent ring to form cyclobutane. Ring A 2 It is cyclopropane or tetrahydropyran. in, R A21 It is a hydrogen atom. R A22 It is a hydrogen atom. Ring A 3 It can be cyclopropane, cyclobutane, cyclopentane, dihydroindene, or tetrahydropyran. in, R A31 It is a hydrogen atom. R A32 It is a hydrogen atom.

[0116] R 1 It is a hydrogen atom.

[0117] R 2 C 6-10 Alkyl groups, or groups represented by the following formulas [IV-1] or [IV-2] [Chemistry 59] in, Ring B 1 C 3-8 Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl groups containing nitrogen atoms, R B11 and R B12 Independently, it consists of hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C 1-6 Alkoxy L 1 C 3-8 Alkyl Dimethyl (the C 3-8 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, as shown in formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure shown in formula [V-1] below. [Transformation 60] in, n11 is an integer from 0 to 3. n12 is an integer from 0 to 5. n13 is an integer between 0 and 3. also, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L11 - Replaced R L1 C1-3 alkyl, Ring B 2 It is a partially saturated aryl group with a 9-10 membered fused ring, or a partially saturated heteroaryl group with a nitrogen atom containing a 9-10 membered fused ring. R B1 and R B2 Independently, it consists of hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl, or C 1-6 Alkoxy L 2 C 1-2 Alkyl Dimethyl (the C 1-2 Alkyl groups can be replaced by 1 to 4 fluorine atoms.

[0118] More preferred R 2 C 7-8 Alkyl groups or groups represented by the following formulas [IV-1] or [IV-2] [Chemistry 61] in, Ring B 1 It is a C6 cycloalkyl, phenyl, or a 6-membered heteroaryl group containing a nitrogen atom. R B11 and R B12 Independently constitutes a hydrogen atom, a halogen atom, a C1 alkyl group, or a C1 alkoxy group. L 1 C 3-5 Alkyl Dimethyl (the C 3-5 The alkane dimethyl group can be substituted with 1 to 2 fluorine atoms, as shown in formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure shown in formula [V-1] below. [Chemistry 62] in, n1 is an integer between 0 and 1. n2 is 1, n3 is an integer between 0 and 1. also, As C 3-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 The atom bonded to two or more nitrogen atoms can be represented by the formula -O-, -S-, or -N(R). L1 - Replaced R L1 It is a C1 alkyl group. Ring B 2 It is either a partially saturated 9-membered fused ring aryl group or a partially saturated nitrogen-containing 9-membered fused ring heteroaryl group. RB1 and R B2 Both are hydrogen atoms. L 2 It is a C2 alkane dimethyl group.

[0119] Further optimized R 2 It is isoheptyl, isooctyl, or a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 63] in, Ring B 1 It is cyclohexyl, phenyl, or pyridyl. R B11 and R B12 Independently, it consists of a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group, L 1 Any of the structures shown in the following formulas [V-3] to [V-12] and [V-14] to [V-19] [Chemistry 64] [Chemistry 65] in, n4 is an integer between 3 and 5. n12' is 1, n12” is 1, Ring B 2 It is dihydroindole or isoindolyl. R B1 and R B2 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 66] in, n5 is 2.

[0120] R 3 Represents a hydrogen atom or C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one group selected from hydroxyl and methoxy. More preferred R 3 It is a hydrogen atom or a carbon atom. 1-2 Alkyl (the C 1-2 The alkyl group may be substituted with one group selected from hydroxyl and methoxy. Further optimized R 3 It can be a hydrogen atom, a methyl group (which can be substituted by one group selected from hydroxyl and methoxy), or an ethyl group.

[0121] R 4 The group represented by the following formula [VI] [Chemistry 67] in, The ring carbon is phenyl, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered fused-ring heteroaryl group. The phenyl group can be selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carbamoyl, cyano, halogen atom, C 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be substituted with one hydroxyl group), C 2-6 alkenyl, C 3-8 cycloalkyl (the C 3-8 cycloalkyl groups can be substituted with one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 alkoxy carbonyl and single C 1-6 Substitution of 1 to 4 identical or different groups in an alkylaminocarbonyl group; This nitrogen-containing 6-membered heteroaryl group can be substituted by a single C14 group. 1-6 Alkoxy substitution, further, It can be selected from cyano and C 1-6 The alkoxy group is substituted, and the heteroaryl group of the 9- to 10-membered fused ring can be selected from C. 1-6 Alkyl or C 1-6 The alkoxy group is substituted with one or two identical or different groups.

[0122] More preferred R 4 It is the group represented by the following formula [VI]. [Chemistry 68] in, The ring carbon is phenyl, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered fused-ring heteroaryl group. The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-3 Alkoxy and C 1-2 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carbamoyl, cyano, halogen atom, C 1-3 Alkyl (the C 1-3 Alkyl groups may be substituted with one group selected from hydroxyl and C1 alkoxy groups), halo-C2 alkyl groups (which may be substituted with one hydroxyl group), C 2-3 alkenyl, C3 cycloalkyl (the C3 cycloalkyl group can be substituted with one hydroxyl group), C 1-3 Alkoxy, halogenated C2 alkoxy, C3 cycloalkoxy, C1 alkyl sulfinyl, C1 alkyl sulfonyl, mono-C2 alkylamino, di-C 1-2 Alkylamino, C 1-2 Substitution of 1 to 3 identical or different groups in alkyl carbonyl, halogenated C1 alkyl carbonyl, C1 alkoxy carbonyl, and mono-C1 alkylamino carbonyl This nitrogen-containing 6-membered heteroaryl group can be substituted by a single C14 group. 1-2 Alkoxy substitution, further, It can be selected from cyano and C 1-2 The alkoxy group is substituted with one of its groups, and the heteroaryl group of the 9- to 10-membered fused ring can be selected from C. 2-3 The same or different 1 to 2 groups of alkyl or C2 alkoxy are substituted.

[0123] Further optimized R 4 It is the group represented by the following formula [VI]. [Chemistry 69] in, The ring C is phenyl, pyridinyl, pyrimidinyl, indoleyl, indazole, benzimidazolyl, pyrazolopyridinyl, dihydrobenzofuranyl, or dihydroindoleyl. The phenyl group may be substituted with one group selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl carbonyl, and ethyl carbonyl. It can be substituted by 1 to 4 groups selected from hydroxyl, carbamoyl, cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl (where the methyl, ethyl, n-propyl, and isopropyl groups can be substituted by one group selected from hydroxyl and methoxy), haloethyl (where the haloethyl group can be substituted by one hydroxyl group), vinyl, isopropenyl, cyclopropyl (where the cyclopropyl group can be substituted by one hydroxyl group), methoxy, ethoxy, n-propoxy, isopropoxy, haloethoxy, cyclopropoxy, methylsulfinyl, methylsulfonyl, ethylamino, ethylmethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl, and methylaminocarbonyl, both the same and different groups. The pyridyl or pyrimidinyl group can be substituted with one methoxy or ethoxy group. Furthermore... It can be substituted by one group selected from cyano and ethoxy. The pyrimidinyl group can be substituted with one methoxy group, and further, it can be substituted with one methoxy group. The indolyl, inzolyl, benzimidazolyl, pyrazolopyridyl, dihydrobenzofuranyl, or dihydroindolyl can be substituted by one or two identical or different groups selected from ethyl, n-propyl, or ethoxy.

[0124] In addition, R 3 and R 4 When it forms a fused ring with adjacent carbon atoms, The preferred fused ring is a partially saturated 9-10 membered fused ring hydrocarbon aromatic ring (the partially saturated 9-10 membered fused ring hydrocarbon aromatic ring can be replaced by 1-2 halogen atoms) or a partially saturated 9-10 membered fused ring heteroaromatic ring containing oxygen atoms (the partially saturated 9-10 membered fused ring heteroaromatic ring containing oxygen atoms can be replaced by 1-2 halogen atoms). More preferably, the fused ring is a partially saturated 9-membered fused ring hydrocarbon aromatic ring (the partially saturated 9-membered fused ring hydrocarbon aromatic ring can be replaced by 1 to 2 halogen atoms) or a partially saturated 9-membered fused ring heteroaromatic ring containing oxygen atoms (the partially saturated 9-membered fused ring heteroaromatic ring containing oxygen atoms can be replaced by 1 to 2 halogen atoms). Further preferred fused rings are dihydroindene (which can be substituted by 1 to 2 halogen atoms) or dihydrobenzofuran (which can be substituted by 1 to 2 halogen atoms).

[0125] Other preferred embodiments of the compound of the present invention are the following embodiments (B).

[0126] Implementation method (B): In the compounds represented by the aforementioned formula [I] or their pharmaceutically acceptable salts or hydrates thereon The compound represented by formula [I] is the same as the compound represented by formula [I-1] below. [Chemistry 70] in, R 2 It is a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 71] In this embodiment, X represents a carboxyl group, C 1-4 alkoxycarbonyl or tetrazolium, A more preferred form of X is a carboxyl group or a tetrazolium group. At this point, a further preferred X is a carboxyl group. At this point, another further preferred form of X is tetrazolium. Another, more preferred X is C. 1-4 alkoxycarbonyl, At this point, a further preferred X is a C1 alkoxycarbonyl group. At this point, another further preferred X is a C2 alkoxycarbonyl group. At this point, another further preferred X is a C4 alkoxycarbonyl group.

[0127] W is a methanediyl or the structure shown in formula [III-1] below. [Chemistry 72] in, The methanediyl group can be selected from C... 1-6 Alkyl (the C 1-6 Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, and halogenated C groups can be substituted with alkyl groups. 1-6 Alkyl, C 3-8 cycloalkyl, phenyl C 1-3 Alkyl and pyridyl C 1-3 One group in the alkyl group is substituted. Furthermore, when the methane diene is replaced by one methyl group, it can be further replaced by another methyl group. also, In the structure shown in formula [III-1], the preferred ring A 1 It is C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused aromatic hydrocarbons, 4- to 8-membered saturated heterocycles containing oxygen atoms, 4- to 8-membered saturated heterocycles containing sulfur atoms, or 4- to 8-membered saturated heterocycles containing nitrogen atoms. in, The sulfur atom in this 4- to 8-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. also, The nitrogen atom in this nitrogen-containing 4- to 8-membered saturated heterocycle can be selected from C 1-4 alkyl carbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted. Preferred R A11 It consists of hydrogen atoms, hydroxyl groups, carboxyl groups, halogen atoms, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy groups, or nitrogen-containing 4- to 6-membered saturated heterocyclic groups (these nitrogen-containing 4- to 6-membered saturated heterocyclic groups can be substituted by one carbon atom). 1-3 Alkyl substitution), Preferred R A12 It is a hydrogen atom, a halogen atom, or a methyl group. also, R A11 and R A12 They can form oxygen together. further, R A11 and R A12 Each can form a carbon atom together with the carbon atom in the adjacent ring. 3-6 Cycloalkanes.

[0128] More preferably, W is a methanediyl or the structure shown in the following formula [III-1]. [Chemistry 73] in, The methanediyl group can be selected from C... 1-4 Alkyl (the C 1-4 Alkyl groups can be substituted with one group selected from hydroxyl and carboxyl groups, halo-C2 alkyl groups, phenyl C2 alkyl groups, etc. 1-2 Substitution of one group in alkyl and pyridyl C1 alkyl groups, Furthermore, when the methane diene is replaced by one methyl group, it can be further replaced by another methyl group. also, In the structure shown in formula [III-1], the preferred ring A 1 It is C 3-7 Cycloalkanes, partially saturated 9-membered fused ring hydrocarbons, 4- to 6-membered saturated heterocycles containing oxygen atoms, 6-membered saturated heterocycles containing sulfur atoms, or 4- to 6-membered saturated heterocycles containing nitrogen atoms. in, The sulfur atom in this 6-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. also, The nitrogen atom in the nitrogen-containing 4- to 6-membered saturated heterocycle can be replaced by one group selected from C1 alkyl carbonyl groups, preferably R. A11 yes Hydrogen atom, hydroxyl group, carboxyl group, halogen atom, C1 alkyl group, C 1-3 Alkoxy groups, or 5- to 6-membered saturated heterocyclic groups containing nitrogen atoms (the 5- to 6-membered saturated heterocyclic group containing nitrogen atoms can be substituted by one C1 alkyl group), Preferred R A12 It is a hydrogen atom, a halogen atom, or a methyl group. also, R A11 and R A12 They can form oxygen together. further, R A11 and R A12 Each can combine with carbon atoms in an adjacent ring to form a C4 cycloalkane.

[0129] A further preferred form of W is a methanediyl or a structure represented by the following formula [III-1]. [Chemistry 74] in, The methane diel group can be substituted with one group selected from methyl (which can be substituted with one group selected from hydroxyl and carboxyl), ethyl, n-butyl, isobutyl, haloethyl, benzyl, phenethyl and pyridylmethyl. Furthermore, when the methane diene is replaced by one methyl group, it can be further replaced by another methyl group. also, In the structure shown in formula [III-1], the preferred ring A 1 It is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxacyclobutane, tetrahydrofuran, tetrahydropyran, tetrahydrothiaran, aziridine, pyrrolidine, or piperidine. in, The sulfur atom in this tetrahydrothioran can be replaced by two oxygen atoms. also, The nitrogen atom in these azacyclic butanes, pyrrolidines, and piperidines can be replaced by a methyl carbonyl group. Preferred R A11 yes Hydrogen atom, hydroxyl group, carboxyl group, fluorine atom, methyl group, methoxy group, ethoxy group, isopropoxy group, pyrrolyl group, morpholinyl group, or piperazine group (which may be substituted by one methyl group), Preferred R A12 It is a hydrogen atom, a fluorine atom, or a methyl group. also, R A11 and R A12 They can form oxygen together. further, RA11 and R A12 Each can combine with carbon atoms in an adjacent ring to form cyclobutane.

[0130] Ring B 1 It is a phenyl group. R B11 and R B12 Independently, it consists of hydrogen atoms, halogen atoms, and carbon atoms. 1-6 Alkyl or C 1-6 Alkoxy L 1 C 3-8 Alkyl Dimethyl (the C 3-8 Alkyl groups can be replaced by 1 to 5 fluorine atoms. also, As C 3-8 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms that are bonded can be replaced by the formula -O-.

[0131] Ring B 2 It is a partially saturated 9- to 10-membered fused-ring aryl group, or a nitrogen-containing 9- to 10-membered fused-ring heteroaryl group. R B21 and R B22 Both are hydrogen atoms. L 2 C 1-2 Alkyl Dimethyl (the C 1-2 Alkyl groups can be replaced by 1 to 4 fluorine atoms.

[0132] More preferably, ring B 1 It is phenyl. R B11 and R B12 Independently constitutes a hydrogen atom, a halogen atom, a C1 alkyl group, or a C1 alkoxy group. L 1 C 3-6 Alkyl Dimethyl (the C 3-6 Alkyl groups can be replaced by 1 to 2 fluorine atoms. also, As C 3-6 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms that are bonded can be replaced by the formula -O-.

[0133] More preferably, ring B 2 It is a partially saturated 9-membered fused ring aryl group, or a nitrogen-containing 9-membered fused ring heteroaryl group. R B21 and R B22 Both are hydrogen atoms. L 2 It is C 1-2 Alkyl dimethyl

[0134] Further optimized ring B 1 It is phenyl. R B11 and R B12 Independently, it can be a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group. L 1 For any of the structures shown in the following formulas [V-3]~[V-5], [V-7]~[V-8], [V-11]~[V-12], [V-14]~[V-16], [Chemistry 75] [Chemistry 76] in, n4 is an integer between 3 and 5.

[0135] Further optimized ring B 2 It is dihydroindole, indole, or isoindole. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 77] in, n5 is an integer from 1 to 2.

[0136] R 3 It is C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one group selected from hydroxyl and methoxy groups, more preferably R 3 It is methyl (which may be substituted with one group selected from hydroxyl and methoxy) or ethyl, with R being more preferred. 3 It is methyl. Specially selected R 3 It is a methyl group having the stereoconfiguration shown in formula [VII]. [Chemistry 78]

[0137] R 4 The group represented by the following formula [VI] [Chemistry 79] in, The ring C is phenyl. in, The phenyl group can be selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, C 1-6 Alkyl (the C 1-6 Alkyl groups can be selected from hydroxyl and C. 1-6 (substitution of one group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C) 1-6 Alkyl groups can be substituted with one hydroxyl group), C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl (the C 3-8 cycloalkyl groups can be substituted with one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkyl thioalkyl, C 1-6 alkylsulfinyl, C 1-6 Alkyl sulfonyl, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 Alkoxycarbonyl, single C 1-6 Alkylaminocarbonyl and diC 1-6 The same or different 1 to 4 groups in the alkylaminocarbonyl group are substituted.

[0138] More preferred R 4 It is the group represented by the following formula [VI]. [Chemistry 80] in, The ring C is phenyl. in, The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-3 Alkoxy and C 1-2 Substitution of one group in the alkyl carbonyl group, further, It can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atom, C 1-3 Alkyl (the C 1-3 Alkyl groups can be substituted with one group selected from hydroxyl and C1 alkoxy groups, and halogenated C1 alkoxy groups can be substituted with one group selected from hydroxyl and C1 alkoxy groups. 1-2Alkyl (the halogenated C) 1-2 Alkyl groups can be substituted with one hydroxyl group), C 2-3 alkenyl, C3 cycloalkyl (the C3 cycloalkyl group can be substituted with one hydroxyl group), C 1-3 Alkoxy, halogenated C2 alkoxy, C3 cycloalkoxy, C1 alkyl sulfinyl, C1 alkyl sulfonyl, mono-C2 alkylamino, di-C2 alkylamino, C 1-2 Substitution of 1 to 4 groups of the same or different in alkyl carbonyl, halogenated C1 alkyl carbonyl, C1 alkoxy carbonyl, and mono-C1 alkylamino carbonyl.

[0139] Further optimized R 4 It is the group represented by the following formula [VI]. [Chemistry 81] in, The ring C is phenyl. in, The phenyl group can be substituted by one group selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl carbonyl, and ethyl carbonyl. Further, It can be substituted by 1 to 4 groups selected from hydroxyl, carboxyl, carbamoyl, cyano, fluorine, chlorine, bromine, methyl (which can be substituted by one group selected from hydroxyl and methoxy), ethyl, n-propyl, isopropyl (which can be substituted by one hydroxyl), halomethyl, haloethyl (which can be substituted by one hydroxyl), vinyl, isopropenyl, cyclopropyl (which can be substituted by one hydroxyl), methoxy, ethoxy, n-propoxy, isopropoxy, haloethoxy, cyclopropoxy, methylsulfinyl, methylsulfonyl, monoethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl, and methylaminocarbonyl, either the same or different groups.

[0140] Other preferred embodiments of the compounds of the present invention are the following embodiments (C).

[0141] Implementation method (C): In this embodiment (C), the preferred embodiment is as follows.

[0142] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates, the compound represented by formula [I-1] is the compound represented by formula [I-2] below. [Chemistry 82] in, R 2It is a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 83] in, W, Ring B 1 R B11 R B12 L 1 Ring B 2 R B21 R B22 L 2 and R 4 As stated above.

[0143] In this embodiment (C), a more preferred embodiment is described below.

[0144] In the aforementioned formula [I-2], W is a methanediyl or the structure shown in the aforementioned formula [III-1]. [Chemistry 84] in, This methane dielet can be replaced by one methyl group. Furthermore, it can be further substituted with one methyl group. also, In the structure shown in equation [III-1], Ring A 1 It is C 3-4 Cycloalkanes or 4- to 5-membered saturated heterocycles containing oxygen atoms. R A11 It is a hydrogen atom, hydroxyl group, halogen atom, C1 alkyl group, or C2 alkyl group. 1-2 Alkoxy R A12 It is a hydrogen atom, a halogen atom, or a methyl group; Ring B 1 It is a phenyl group. R B11 and R B12 It is also a hydrogen atom. L 1 C 3-5 Alkyl Dimethyl (the C 3-5 Alkyl groups can be replaced by 1 to 2 fluorine atoms. in, As C 3-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms in the bonded structure can be replaced by the formula -O-. Ring B 2 It is a partially saturated 9-membered fused ring aryl group. R B21 and R B22 It is also a hydrogen atom; L 2 It is a C2 alkane dimethyl group; R 4 The group represented by the following formula [VI] [Chemistry 85] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-2 Substitution of one group in the alkoxy and C1 alkyl carbonyl groups, further, It can be selected from cyano, halogen atom, C 1-3 Alkyl (the C 1-3 Alkyl groups can be substituted with one hydroxyl group, C2 alkenyl, C3 cycloalkyl, C 1-2 The same or different 1 to 4 groups in alkoxy, mono-C2 alkylamino and C1 alkylcarbonyl are substituted.

[0145] In this embodiment (C), a further preferred embodiment is described below.

[0146] In the aforementioned formula [I-2], W is any of the structures shown in equations [III-4] to [III-17] below. [Chemistry 86] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is the structure shown in the following formulas [V-3], [V-8], [V-12], [V-14], or [V-15]. [Chemistry 87] in, n4 is an integer between 3 and 4. Ring B 2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 88] in, n5 is 2; R 4 It is any one of the groups shown in the following formulas [VI-1] to [VI-21]. [Chemistry 89] [Chemistry 90] [Chemistry 91]

[0147] Other preferred embodiments of the compounds of the present invention are the following embodiments (D).

[0148] Implementation method (D): In this embodiment (D), the preferred embodiment is as follows.

[0149] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-3] below. [Chemistry 92] in, R 2 It is a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 93] in, W, Ring B 1 R B11 R B12 L 1 Ring B 2 R B21 R B22 L 2 and R 4 As stated above.

[0150] In this embodiment (D), a more preferred embodiment is described below.

[0151] In the aforementioned formula [I-3], W is a methanediyl or the structure shown in the aforementioned formula [III-1]. [Chemistry 94] in, This methane dielet can be replaced by one methyl group. Furthermore, it can be further substituted with one methyl group. also, In the structure shown in equation [III-1], Ring A 1 It is C 3-4 Cycloalkanes, R A11 It is a hydrogen atom, a halogen atom, a C1 alkyl group, or a C1 alkyl group. 1-2 Alkoxy R A12 It is a hydrogen atom, a halogen atom, or a methyl group; Ring B 1 It is a phenyl group. R B11 and R B12 It is also a hydrogen atom. L 1 It is C 4-5 Alkyl Dimethyl (the C 4-5 (The alkane dimethyl group can be replaced by two fluorine atoms.) also, As C 4-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms in the bonded structure can be replaced by the formula -O-. Ring B 2 It is a partially saturated 9-membered fused ring aryl group. R B21 and R B22 It is also a hydrogen atom. L 2 It is a C2 alkane dimethyl group; R 4 The group represented by the following formula [VI] [Chem. 95] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-2 Substitution of one group in the alkoxy and C1 alkyl carbonyl groups, further, It can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 Alkyl groups can be substituted with one hydroxyl group), C 1-2 The same or different 1 to 4 groups in alkoxy, mono-C2 alkylamino and C1 alkylcarbonyl are substituted.

[0152] In this embodiment (D), a further preferred embodiment is described below.

[0153] In the aforementioned formula [I-3], W is the structure shown in the following formulas [III-4]~[III-11], [III-13]~[III-14], or [III-18]~[III-19]. [Chemistry 96] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is the structure shown in the following formulas [V-3], [V-8], or [V-14]. [Chemistry 97] in, n4 is 4. Ring B 2 It is dihydroindenyl. R B21 and R B22 It is also a hydrogen atom. L 2 The structure shown in the following formula [V-20] [Chem. 98] in, n5 is 2; R 4 It is any one of the groups represented by the following formulas: [VI-2], [VI-3], [VI-8], [VI-10] to [VI-12], [VI-16], [VI-19], or [VI-21]. [Chemistry 99] [Chemistry 100]

[0154] Other preferred embodiments of the compounds of the present invention are the following embodiments (E).

[0155] Implementation method (E): In this embodiment (E), the preferred embodiment is described below.

[0156] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-4] below. [Chemistry 101] in, R 4 It is a group represented by the following formula [VI-22]. [Chemistry 102] The group represented by formula [VI-22] is surrounded by 1 to 2 C atoms. 1-6 Alkyl substitution; Preferred W and ring B 1 R B11 R B12 and L 1 As stated above.

[0157] In this embodiment (E), a more preferred embodiment is described below.

[0158] In the aforementioned formula [I-4], W is the structure shown in the following formula [III-1]. [Chemistry 103] in, In the structure shown in equation [III-1], Ring A 1 It is a C4 cycloalkane. R A11 It is C 1-2 Alkoxy R A12 It is a hydrogen atom; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is a C5 alkane diester, and the distance R of one of the carbon atoms in this C5 alkane diester is... 2 Two or more nitrogen atoms that are bonded can be replaced by the formula -O-; R 4 It is the group represented by the aforementioned formula [VI-22]. [Chemistry 104] in, The group shown in formula [VI-22] is replaced by two C2 alkoxy groups.

[0159] In this embodiment (E), a further preferred embodiment is described below.

[0160] In the aforementioned formula [I-4], W is the structure shown in the following formulas [III-8] to [III-11]. [Chemistry 105] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 The structure shown in the following formula [V-14] [Chemistry 106] R 4 It is a group represented by the following formula [VI-6]. [Chemistry 107]

[0161] Furthermore, in this embodiment (E), a particularly preferred embodiment is described below.

[0162] The compound represented by the aforementioned formula [I-4] is any of the following: [Chemistry 108]

[0163] Furthermore, other particularly preferred embodiments of this embodiment (E) are described below.

[0164] The compounds represented by the aforementioned formula [I-4] are as follows: [Chemistry 109]

[0165] Furthermore, other particularly preferred embodiments of this embodiment (E) are described below.

[0166] The compounds represented by the aforementioned formula [I-4] are as follows: [Chemical 110]

[0167] Furthermore, other particularly preferred embodiments of this embodiment (E) are described below.

[0168] The compounds represented by the aforementioned formula [I-4] are as follows: [Chemistry 111]

[0169] Furthermore, other particularly preferred embodiments of this embodiment (E) are described below.

[0170] The compounds represented by the aforementioned formula [I-4] are as follows: [Chemistry 112]

[0171] Other preferred embodiments of the compounds of the present invention are the following embodiments (F).

[0172] Implementation method (F): In this embodiment (F), the preferred embodiment is described below.

[0173] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-5] below. [Chemistry 113] in, W, L 2 and R 4 As stated above.

[0174] In this embodiment (F), a more preferred embodiment is described below.

[0175] In the aforementioned formula [I-5], W is the structure shown in the following formula [III-1]. [Chemistry 114] in, In the structure shown in equation [III-1], Ring A 1 It is a C4 cycloalkane. R A11 It is a C1 alkoxy group. R A12 It is a hydrogen atom; L 2 It is a C2 alkane dimethyl group; R 4 The group represented by the following formula [VI] [Chemistry 115] in, The ring C is a phenyl group, which can be substituted by three identical or different groups selected from C2 alkoxy and C1 alkyl carbonyl groups, and further, can be substituted by one C1 alkyl group.

[0176] In this embodiment (F), a further preferred embodiment is described below.

[0177] In the aforementioned formula [I-5], W is the structure shown in equation [III-8] or [III-9] below. [Chemistry 116] L 2 The structure shown in the following formula [V-20] [Chemistry 117] in, n5 is 2; R 4 It is a group represented by the following formula [VI-10] or [VI-12]. [Chemistry 118]

[0178] Furthermore, in this embodiment (F), a particularly preferred embodiment is described below.

[0179] The compound represented by the aforementioned formula [I-5] is any of the following: [Chemistry 119]

[0180] Furthermore, other particularly preferred embodiments of this embodiment (F) are described below.

[0181] The compounds represented by the aforementioned formula [I-5] are as follows: [Chemistry 120]

[0182] Furthermore, other particularly preferred embodiments of this embodiment (F) are described below.

[0183] The compounds represented by the aforementioned formula [I-5] are as follows: [Chemistry 121]

[0184] Furthermore, other particularly preferred embodiments of this embodiment (F) are described below.

[0185] The compounds represented by the aforementioned formula [I-5] are as follows: [Chemistry 122]

[0186] Furthermore, other particularly preferred embodiments of this embodiment (F) are described below.

[0187] The compounds represented by the aforementioned formula [I-5] are as follows: [Chemistry 123]

[0188] Other preferred embodiments of the compounds of the present invention are the following embodiments (F-2).

[0189] Implementation method (F-2): In this embodiment (F-2), the preferred embodiment is as follows.

[0190] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-5-2] below. [Chemistry 124] in, R 4 It is a group represented by the following formula [VI-26]. [Chemistry 125] The group represented by formula [VI-26] can be selected from C 1-6 Alkyl, C 3-8 cycloalkyl and C 1-6 Substitution of one group in the alkyl carbonyl group, further, It can be selected from halogen atoms and C 1-6 One group in the alkyl group is substituted; W is as described above.

[0191] In this embodiment (F-2), a more preferred embodiment is described below.

[0192] In the aforementioned formula [I-5-2], W is the structure shown in the following formula [III-1]. [Chemistry 126] in, In the structure shown in equation [III-1], Ring A 1 It is a C4 cycloalkane. R A11 It is C 1-2 Alkoxy R A12 It is a hydrogen atom; R 4 It is the group represented by the aforementioned formula [VI-26]. [Chemistry 127] in, The group shown in formula [VI-26] can be substituted by one group selected from C1 alkyl, C3 cycloalkyl, and C1 alkylcarbonyl groups. Furthermore, It can be substituted by one group selected from halogen atoms and C1 alkyl groups.

[0193] In this embodiment (F-2), a further preferred embodiment is described below.

[0194] In the aforementioned formula [I-5-2], W is the structure shown in formula [III-8] or [III-10] below. [Chemistry 128] R 4 It is a group represented by the following formulas: [VI-2], [VI-6], [VI-10] to [VI-12], [VI-27], or [VI-28]. [Chemistry 129]

[0195] Furthermore, in this embodiment (F-2), a particularly preferred embodiment is described below.

[0196] The compounds represented by the aforementioned formula [I-5-2] are as follows: [Chemistry 130]

[0197] Other preferred embodiments of the compounds of the present invention are the following embodiments (G).

[0198] Implementation method (G): In this embodiment (G), the preferred embodiment is described below.

[0199] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates, the compound represented by formula [I-1] is the compound represented by formula [I-6] below. [Chemistry 131] in, R 4 It is a group represented by the following formula [VI-23]. [Chemistry 132] The group shown in formula [VI-23] can be substituted by one carbon atom. 1-6 Alkyl carbonyl substitution, further, It can be replaced by one halogen atom; W, Ring B1 R B11 R B12 and L 1 As stated above.

[0200] In this embodiment (G), a more preferred embodiment is described below.

[0201] In the aforementioned formula [I-6], W is the structure shown in the following formula [III-1]. [Chemistry 133] in, In the structure shown in equation [III-1], Ring A 1 It is a C4 cycloalkane. R A11 It is C 1-2 Alkoxy R A12 It is a hydrogen atom; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 C 4-5 Alkyl Dimethyl As the C 4-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms that are bonded can be replaced by the formula -O-; R 4 It is the group represented by the aforementioned formula [VI-23]. [Chemistry 134] in, The group shown in formula [VI-23] can be replaced by one C1 alkyl carbonyl group, and further, it can be replaced by one halogen atom.

[0202] In this embodiment (G), a further preferred embodiment is described below.

[0203] In the aforementioned formula [I-6], W is the structure shown in formula [III-8] or [III-10] below. [Chemistry 135] Ring B 1 It is a phenyl group. R B11 and R B12Both are hydrogen atoms. L 1 It is the structure shown in the following formula [V-12] or [V-14]. [Chemistry 136] R 4 It is a group represented by the following formula [VI-24] or [VI-25]. [Chemistry 137]

[0204] Furthermore, in this embodiment (G), a particularly preferred embodiment is described below.

[0205] The compound represented by the aforementioned formula [I-6] is any of the following: [Chemistry 138] [Chemistry 139]

[0206] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0207] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 140]

[0208] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0209] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 141]

[0210] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0211] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 142] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0212] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 143]

[0213] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0214] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 144]

[0215] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0216] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 145]

[0217] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0218] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 146]

[0219] Furthermore, other particularly preferred embodiments of this embodiment (G) are described below.

[0220] The compounds represented by the aforementioned formula [I-6] are as follows: [Chemistry 147]

[0221] Other preferred embodiments of the compounds of the present invention are the following embodiments (G-2).

[0222] Implementation method (G-2): In this embodiment (G-2), the preferred embodiment is as follows.

[0223] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-6-2] below. [Chemistry 148] in, R 4 It is a group represented by the following formula [VI-29]. [Chemistry 149] The group shown in formula [VI-29] is selected from halogen atoms and C. 1-6 One group in the alkyl group is substituted; W is as described above.

[0224] In this embodiment (G-2), a more preferred embodiment is described below.

[0225] In the aforementioned formula [I-6-2], W is the structure shown in the following formula [III-1]. [Chemistry 150] in, In the structure shown in equation [III-1], Ring A 1 It is a C4 cycloalkane. R A11 It is a hydrogen atom, a halogen atom, or a carbon atom. 1-2 Alkoxy R A12 It is a hydrogen atom or a halogen atom; R 4 It is the group represented by the aforementioned formula [VI-29]. [Chemistry 151] in, The group shown in formula [VI-29] is replaced by one group selected from halogen atoms and C1 alkyl groups.

[0226] In this embodiment (G-2), a further preferred embodiment is described below.

[0227] In the aforementioned formula [I-6-2], W is the structure shown in the following formulas [III-6], [III-8] to [III-11], or [III-13]. [Chemistry 152] R 4 It is a group represented by the following formula [VI-30] or [VI-31]. [Chemistry 153]

[0228] Furthermore, in this embodiment (G-2), a particularly preferred embodiment is described below.

[0229] The compound represented by the aforementioned formula [I-6-2] is any of the following: [Chemistry 154]

[0230] [Chemistry 155]

[0231] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0232] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 156]

[0233] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0234] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 157]

[0235] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0236] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 158]

[0237] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0238] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 159]

[0239] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0240] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 160]

[0241] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0242] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 161]

[0243] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0244] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 162]

[0245] Furthermore, other particularly preferred embodiments of this embodiment (G-2) are described below.

[0246] The compounds represented by the aforementioned formula [I-6-2] are as follows: [Chemistry 163]

[0247] Other preferred embodiments of the compounds of the present invention are the following embodiments (H).

[0248] Implementation method (H): In this embodiment (H), the preferred embodiment is as follows.

[0249] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-7] below. [Chemistry 164] in, R 2 It is a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 165] X, W, Ring B 1 R B11 R B12 L 1 Ring B 2 R B21 R B22 L 2 and R 4 As stated above.

[0250] In this embodiment (H), a more preferred embodiment is described below.

[0251] In the aforementioned formula [I-7], X is a carboxyl group or a tetrazolium group; W is the structure shown in the following formula [III-1]. [Chemistry 166] in, In the structure shown in equation [III-1], Ring A 1 yes C 3-4Cycloalkanes, R A11 yes Hydrogen atom, halogen atom, or C 1-2 Alkoxy R A12 yes Hydrogen atoms or halogen atoms; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is C 4-5 Alkyl Dimethyl (the C 4-5 (The alkane dimethyl group can be replaced by two fluorine atoms.) also, As C 4-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms in the bonded structure can be replaced by the formula -O-. Ring B 2 It is a partially saturated 9-membered fused ring aryl group. R B21 and R B22 Both are hydrogen atoms. L 2 It is a C2 alkane dimethyl group; R 4 The group represented by the following formula [VI] [Chemistry 167] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-2 Substitution of one group in the alkoxy and C1 alkyl carbonyl groups, further, It can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 Alkyl groups can be substituted with one hydroxyl group), C 1-2 The same or different 1 to 3 groups in the alkoxy or C1 alkyl carbonyl groups are substituted.

[0252] In this embodiment (H), a further preferred embodiment is described below.

[0253] In the aforementioned formula [I-7], X is a carboxyl group or a tetrazolium group; W is the structure shown in the following formulas [III-5], [III-8] to [III-11], or [III-13]. [Chemistry 168] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is the structure shown in the following formulas [V-3], [V-12], or [V-14]. [Chemistry 169] in, n4 is an integer of 4. Ring B 2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 170] in, n5 is 2; R 4 It is a group represented by the following formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11], or [VI-12]. [Chemistry 171]

[0254] Furthermore, in this embodiment (H), A particularly preferred embodiment is that the compound represented by the aforementioned formula [I-7] is The following are all possible scenarios: [Chemistry 172] [Chemistry 173] [Chemistry 174] [Chemistry 175] [Chemistry 176]

[0255] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0256] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 177]

[0257] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0258] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 178]

[0259] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0260] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 179]

[0261] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0262] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 180]

[0263] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0264] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 181]

[0265] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0266] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 182]

[0267] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0268] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 183]

[0269] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0270] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 184]

[0271] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0272] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 185]

[0273] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0274] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 186]

[0275] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0276] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 187]

[0277] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0278] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 188]

[0279] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0280] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 189]

[0281] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0282] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 190]

[0283] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0284] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 191]

[0285] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0286] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 192]

[0287] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0288] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 193]

[0289] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0290] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 194]

[0291] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0292] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 195]

[0293] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0294] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 196]

[0295] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0296] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 197]

[0297] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0298] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 198]

[0299] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0300] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 199]

[0301] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0302] The compounds represented by the aforementioned formula [I-7] are as follows: [Chem.200] Furthermore, other particularly preferred embodiments of this embodiment (H) are described below.

[0303] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemical Engineering 201]

[0304] Other preferred embodiments of the compounds of the present invention are the following embodiments (H-2).

[0305] Implementation method (H-2): In this embodiment (H-2), the preferred embodiment is as follows.

[0306] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-7] below. [Chemical Engineering 202] in, R 2 It is a group represented by the following formula [IV-1]. [Chemical Engineering 203] X, W, Ring B1 R B11 R B12 L 1 and R 4 As stated above.

[0307] In this embodiment (H-2), a more preferred embodiment is described below.

[0308] In the aforementioned formula [I-7], X is a carboxyl group; W is the structure shown in the following formula [III-1]. [Chemical 204] in, In the structure shown in equation [III-1], Ring A 1 yes C 3-4 Cycloalkanes, R A11 yes Hydrogen atom, halogen atom, or C 1-2 Alkoxy R A12 yes Hydrogen atoms or halogen atoms; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 C 4-5 Alkyl Dimethyl also, As C 4-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms in the bonded structure can be replaced by the formula -O-. R 4 The group represented by the following formula [VI] [Chemical Engineering 205] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, C4 alkyl groups, C5 alkyl groups, C6 ... 1-2 Substitution of one group in the alkoxy and C1 alkyl carbonyl groups, further, It can be selected from halogen atoms, C1 alkyl, C3 cycloalkyl, C 1-2 The same or different 1 to 3 groups are substituted in the alkoxy and C1 alkyl carbonyl groups.

[0309] In this embodiment (H-2), a further preferred embodiment is described below.

[0310] In the aforementioned formula [I-7], X is a carboxyl group; W is the structure shown in the following formulas [III-5], [III-6], [III-8] to [III-11], or [III-13]. [Chemical Engineering 206] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is the structure shown in the following formula [V-12] or [V-14]. [Chemical 207] R 4 It is a group represented by the following formulas: [VI-2], [VI-6], [VI-12], [VI-25], [VI-27], [VI-28], [VI-30], or [VI-31]. [Chemical Engineering 208]

[0311] Furthermore, in this embodiment (H-2), A particularly preferred embodiment is when the compound represented by the aforementioned formula [I-7] is any of the following: [Chemical Engineering 209] [Chemical 210] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0312] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 211]

[0313] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0314] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 212]

[0315] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0316] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 213]

[0317] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0318] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 214]

[0319] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0320] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemical 215]

[0321] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0322] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 216]

[0323] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0324] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 217]

[0325] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0326] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 218]

[0327] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0328] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 219]

[0329] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0330] The compounds represented by the aforementioned formula [I-7] are as follows: [Chem.220]

[0331] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0332] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 221]

[0333] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0334] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 222]

[0335] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0336] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 223]

[0337] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0338] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 224]

[0339] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0340] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 225]

[0341] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0342] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 226]

[0343] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0344] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 227]

[0345] Furthermore, other particularly preferred embodiments of this embodiment (H-2) are described below.

[0346] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 228]

[0347] Other preferred embodiments of the compounds of the present invention are the following embodiments (H-3).

[0348] Implementation method (H-3): In this embodiment (H-3), the preferred embodiment is as follows.

[0349] Among the compounds represented by formula [I-1] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I-1] is the compound represented by formula [I-7] below. [Chemistry 229] in, R 2 It is a group represented by the following formula [IV-1] or [IV-2]. [Chemistry 230] X, W, Ring B 1 R B11 R B12 L 1 Ring B 2 R B21 R B22 L 2 and R 4 As stated above.

[0350] In this embodiment (H-3), a more preferred embodiment is described below.

[0351] In the aforementioned formula [I-7], X is a carboxyl group or a tetrazolium group; W is the structure shown in the following formula [III-1]. [Chemistry 231] in, In the structure shown in equation [III-1], Ring A 1 yes C 3-4 Cycloalkanes, R A11 yes Hydrogen atom, halogen atom, or C 1-2 Alkoxy R A12 yes Hydrogen atoms or halogen atoms; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is C 4-5 Alkyl Dimethyl (the C 4-5 (The alkane dimethyl group can be replaced by two fluorine atoms.) also, As C 4-5 The distance R of one of the carbon atoms in an alkane dimethyl group 2 Two or more nitrogen atoms in the bonded structure can be replaced by the formula -O-. Ring B 2 It is a partially saturated 9-membered fused ring aryl group. R B21 and R B22 Both are hydrogen atoms. L 2 It is a C2 alkane dimethyl group; R 4 The group represented by the following formula [VI] [Chemistry 232] in, The ring C is phenyl. The phenyl group can be selected from halogen atoms, C... 1-3 Alkyl, C 1-2 Substitution of one group in the alkoxy and C1 alkyl carbonyl groups, further, It can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 Alkyl groups can be substituted with one hydroxyl group), C 1-2The same or different 1 to 3 groups in the alkoxy or C1 alkyl carbonyl groups are substituted.

[0352] In this embodiment (H-3), a further preferred embodiment is described below.

[0353] In the aforementioned formula [I-7], A further preferred form of X is a carboxyl group or a tetrazolium group; W is the structure shown in the following formulas [III-5], [III-6], [III-8] to [III-11], or [III-13]. [Chemistry 233] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is the structure shown in the following formulas [V-3], [V-12], or [V-14]. [Chemistry 234] in, n4 is an integer of 4. Ring B 2 It is dihydroindenyl. R B21 and R B22 Both are hydrogen atoms. L 2 The structure shown in the following formula [V-20] [Chemistry 235] in, n5 is 2; R 4 It is a group represented by the following formulas: [VI-2], [VI-6], [VI-7], [VI-8], [VI-10], [VI-11], [VI-12], [VI-25], [VI-27], [VI-28], [VI-30], or [VI-31]. [Chemistry 236]

[0354] Furthermore, in this embodiment (H-3), A particularly preferred embodiment is when the compound represented by the aforementioned formula [I-7] is any of the following: [Chemistry 237] [Chemistry 238] [Chemistry 239] [Chemistry 240] [Chemistry 241] [Chemistry 242] [Chemistry 243] [Chemistry 244]

[0355] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0356] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 245]

[0357] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0358] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 246]

[0359] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0360] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 247]

[0361] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0362] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 248]

[0363] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0364] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 249]

[0365] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0366] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 250]

[0367] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0368] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 251]

[0369] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0370] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 252]

[0371] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0372] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 253]

[0373] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0374] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 254]

[0375] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0376] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 255]

[0377] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0378] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 256]

[0379] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0380] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 257]

[0381] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0382] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 258]

[0383] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0384] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 259]

[0385] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0386] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 260]

[0387] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0388] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 261]

[0389] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0390] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 262]

[0391] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0392] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 263]

[0393] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0394] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 264]

[0395] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0396] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 265]

[0397] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0398] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 266]

[0399] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0400] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 267]

[0401] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0402] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 268]

[0403] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0404] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 269]

[0405] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0406] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 270]

[0407] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0408] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 271]

[0409] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0410] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 272]

[0411] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0412] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 273]

[0413] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0414] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 274]

[0415] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0416] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 275]

[0417] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0418] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 276]

[0419] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0420] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 277]

[0421] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0422] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 278]

[0423] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0424] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 279]

[0425] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0426] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 280]

[0427] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0428] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 281]

[0429] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0430] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 282]

[0431] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0432] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 283]

[0433] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0434] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 284]

[0435] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0436] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 285]

[0437] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0438] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 286]

[0439] Furthermore, other particularly preferred embodiments of this embodiment (H-3) are described below.

[0440] The compounds represented by the aforementioned formula [I-7] are as follows: [Chemistry 287]

[0441] Other preferred embodiments of the compounds of the present invention are the following embodiments (J).

[0442] Implementation method (J): In this embodiment (J), the preferred embodiment is described below.

[0443] Among the compounds represented by formula [I] above, or their pharmaceutically acceptable salts or hydrates thereof, the compound represented by formula [I] is the compound represented by formula [I-8] below. [Chemistry 288] in, R X It is C 1-4 alkyl; W, Ring B 1 R B11 R B12 L 1 and R 4 As stated above.

[0444] In this embodiment (J), a more preferred embodiment is described below.

[0445] In the aforementioned formula [I-8], R X It is a C1 alkyl, C2 alkyl, or C4 alkyl; W is the structure shown in the following formula [III-1]. [Chemistry 289] in, In the structure shown in equation [III-1], Ring A 1 It is C 3-4 Cycloalkanes, R A11 It is a hydrogen atom, a halogen atom, or a C2 alkoxy group. R A12 It is a hydrogen atom or a halogen atom; Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 It is a C5 alkane dimethyl group. The distance R, which is one of the carbon atoms in this C5 alkane dimethyl group, is... 2 Two or more nitrogen atoms that are bonded can be replaced by the formula -O-; R 4 The group represented by the following formula [VI] [Chemistry 290] in, The ring C is phenyl. The phenyl group can be substituted by three identical or different groups selected from C2 alkoxy and C1 alkyl carbonyl groups, and further, it can be substituted by one halogen atom.

[0446] In this embodiment (J), a further preferred embodiment is described below.

[0447] In the aforementioned formula [I-8], R X It is methyl, ethyl, or tert-butyl; W is the structure shown in the following formulas [III-5], [III-10], or [III-13]. [Chemistry 291] Ring B 1 It is a phenyl group. R B11 and R B12 Both are hydrogen atoms. L 1 The structure shown in the following formula [V-14] [Chemistry 292] R 4 It is a group represented by the following formula [VI-10] or [VI-11]. [Chemistry 293]

[0448] Furthermore, a particularly preferred embodiment of this embodiment (J) is described below.

[0449] The compound represented by the aforementioned formula [I-8] is any of the following: [Chemistry 294] [Chemistry 295] [Chemistry 296]

[0450] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0451] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemistry 297]

[0452] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0453] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemistry 298]

[0454] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0455] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemistry 299]

[0456] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0457] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 300]

[0458] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0459] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical Engineering 301]

[0460] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0461] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 302]

[0462] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0463] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 303]

[0464] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0465] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 304]

[0466] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0467] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 305]

[0468] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0469] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 306]

[0470] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0471] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 307]

[0472] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0473] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 308]

[0474] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0475] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 309]

[0476] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0477] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemical 310]

[0478] Furthermore, other particularly preferred embodiments of this embodiment (J) are described below.

[0479] The compounds represented by the aforementioned formula [I-8] are as follows: [Chemistry 311]

[0480] The compounds of the present invention are compounds having a urea structure as their basic skeleton, or pharmaceutically acceptable salts thereof, or their hydrates.

[0481] Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; acid addition salts of organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate; or inorganic salts such as lithium, sodium, potassium, calcium, and magnesium salts, or salts of ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts, and N-methyl-D-glucosamine salts with organic bases. It should be noted that salts include hydrated salts.

[0482] The compounds of the present invention sometimes have asymmetric centers, in which case various optical isomers exist. Therefore, the compounds of the present invention can exist as individual optically active (R) and (S) isomers, as well as as racemic mixtures or mixtures of (RS). Furthermore, in the case of compounds having two or more asymmetric centers, diastereomers resulting from their respective optical isomers are further present. The compounds of the present invention also include mixtures containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and the optically active isomers can be obtained by well-known organic chemical methods for this purpose. Furthermore, geometric isomers such as cis isomers and trans isomers sometimes exist in the compounds of the present invention. Further, the compounds of the present invention have tautomers, and various tautomers exist. The compounds of the present invention also include their isomers, and mixtures containing these isomers in any proportion.

[0483] Furthermore, when the compounds of the present invention or their salts form hydrates or solvates, they are also included within the scope of the present invention.

[0484] As mentioned above, LPA1 receptors, LPA3 receptors, and others play a variety of roles in living organisms.

[0485] Examples of diseases caused by LPA receptors include fibrotic diseases (idiopathic pulmonary fibrosis, systemic scleroderma, chronic kidney disease, chronic hepatitis, chronic rejection after organ transplantation, etc.), inflammatory diseases (rheumatoid arthritis, osteoarthritis of the knee, etc.), circulatory system diseases (arteriosclerosis, etc.), cancer-related diseases (prostate cancer, breast cancer, ovarian cancer, etc.), urinary system diseases (benign prostatic hyperplasia, overactive bladder, etc.), and neurological diseases (neuralgic pain, diabetic neuropathy, etc.).

[0486] Drugs that inhibit the physiological activity of LPA receptors, especially antagonists of the EDG family such as LPA1 and LPA3 receptors, are considered to be used for the prevention or treatment of diseases such as idiopathic pulmonary fibrosis, systemic scleroderma, chronic kidney disease, chronic hepatitis and other diseases accompanied by organ fibrosis, circulatory organ diseases such as arteriosclerosis, proliferative diseases including various cancers, urinary system diseases such as benign prostatic hyperplasia, or central and peripheral nervous system diseases.

[0487] It should be noted that the evaluation of the antagonistic effect of the compounds of the present invention on LPA receptors can be carried out in accordance with known methods, such as those described in the test examples described later in this specification.

[0488] For the medicaments described in this invention, the compounds contained therein, namely compounds antagonizing LPA1 receptors or their pharmaceutically acceptable salts or hydrates, may be administered alone or in combination with pharmaceutically or pharmacologically acceptable additives.

[0489] As additives, commonly used excipients or diluents, as well as binders, disintegrants, lubricants, coating agents, sugar coatings, pH adjusters, solvents, or aqueous or non-aqueous solvents may be used as needed. Specifically, examples include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low-viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), and other commonly used additives.

[0490] The drug described in this invention can be any form of solid composition, liquid composition, or other composition, with the optimal form selected as needed.

[0491] The drugs described in this invention can be prepared into tablets, pills, capsules, granules, powders, granules, solutions, emulsions, suspensions, injections, etc., by adding the aforementioned additives to the compounds of this invention and using common formulation techniques.

[0492] Furthermore, the drug described in this invention can be formulated by forming inclusion complexes between the compound of this invention and α, β or γ-cyclodextrin or methylated cyclodextrin.

[0493] The drug described in this invention and compounds that can be used in combination with the compounds of this invention can be formulated as a single formulation (combination agent) or as two or more formulations obtained by separate formulation (combination agents).

[0494] When these compounds are formulated into two or more formulations, each formulation can be administered simultaneously or at intervals. In this case, any one can be administered first. The two or more formulations can be administered at different frequencies throughout the day. Furthermore, the two or more formulations can be administered via different routes.

[0495] When these compounds are formulated into two separate formulations, they are sometimes administered simultaneously or at very short intervals. For example, it is preferable to state in the instructions accompanying the commercially available drug, sales brochure, or other instructions that they are intended to be used together.

[0496] Furthermore, it is preferable to formulate these active ingredients separately into a kit containing two formulations.

[0497] When the compounds of the present invention are used as LPA1 receptor antagonists, they can be administered orally directly. Furthermore, they can be formulated into pharmaceutical preparations containing the compounds of the present invention as active ingredients for oral administration.

[0498] When the compounds of the present invention are used as a preventive or therapeutic agent for systemic scleroderma, they can be administered orally directly. Alternatively, they can be formulated as pharmaceutical preparations containing the compounds of the present invention as active ingredients for oral administration.

[0499] The dosage of the compounds of the present invention varies depending on the target population, route of administration, disease, symptoms, etc. For example, when administered orally to adult patients, the usual single dose is 0.1 mg to 1000 mg, preferably 1 mg to 200 mg. Ideally, this dose is administered once to three times a day, or once every two to three days.

[0500] The following describes in detail the method for manufacturing the compound [I] of the present invention, but the manufacturing method is not particularly limited to those illustrated.

[0501] It should be noted that in the manufacture of compound [I] of the present invention, the order of each step in each manufacturing method can be appropriately changed.

[0502] Furthermore, the solvents used in the reaction can be any solvent that does not hinder the reaction, and are not particularly limited to those described below.

[0503] Furthermore, in the following manufacturing methods, the raw material compound can be used in the form of a salt. Additionally, the target compound can be prepared as a salt.

[0504] Among the usable salts, examples include, for instance, the aforementioned "pharmaceutically acceptable salts".

[0505] It should be noted that the compound [Ia] described in this invention can be manufactured by the method for manufacturing compound [I] or by a method based thereon.

[0506] The compound [I] of the present invention can be manufactured by methods known to them, such as manufacturing methods 1 to 6 shown below or methods based thereon.

[0507] In detail, in compound [I] of the present invention, X is a carboxyl group or C. 1-4 The method for manufacturing the alkoxycarbonyl compound is shown in manufacturing method 1, and the method for manufacturing the intermediate is shown in manufacturing methods 2 to 8.

[0508] Furthermore, manufacturing methods for compounds in which X is a tetrazolium group, compounds in which X is a group represented by the following formula [II-1] (hereinafter, sometimes also referred to as compound [II-1]), compounds in which X is a carbamoyl group, compounds in which X is a group represented by the following formula [II-2], [II-3] or [II-4] (hereinafter, sometimes also referred to as compound [II-2], compound [II-3], compound [II-4] respectively), and compounds in which X is a group represented by the following formula [II-5] (hereinafter, sometimes also referred to as compound [II-5]) are shown in manufacturing method 9.

[0509] [Chemistry 312] In this general manufacturing method, "reductive amination reaction" refers to a reaction in which an aldehyde or ketone compound forms a corresponding imine compound with an amine compound, for example, in an inert solvent or under solvent-free conditions, at ice-cold to reflux temperature, in the presence or absence of acids such as formic acid or acetic acid, and then a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-methylpyridineborane, or iridium (III) chloro(pentamethylcyclopentadienyl)(8-quinolinoyl)iridium (as described, for example, in Advanced Synthesis and Catalysis, Vol. 360, p. 322, 2018) is used to produce an amine compound.

[0510] Furthermore, in this general manufacturing method, "condensation reaction" means, for example, in an inert solvent, at room temperature to reflux temperature, in the presence or absence of a base and additives, a reaction in which a carboxylic acid compound reacts with an amine compound to produce an amide compound.

[0511] Examples of condensing agents used in "condensation reactions" include, for instance, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'-tetramethylureon hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,1'-carbonyldiimidazolium (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidine-1-yl)phosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM).

[0512] Examples of additives used in "condensation reactions" include, for example, N-hydroxybenzotriazole monohydrate (HOBt) and N-hydroxysuccinimide.

[0513] Examples of bases used in "condensation reactions" include, for example, aliphatic tertiary amines such as N,N-diisopropylethylamine and triethylamine, and pyridine.

[0514] Furthermore, in this general manufacturing method, "hydrolysis reaction" means, for example, in an inert solvent, at a temperature ranging from ice-cold to reflux, the reaction of an ester compound to produce a carboxylic acid compound and an alcohol compound using a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0515] In compound [I] of the present invention, X is a carboxyl group and R 1 Compounds containing hydrogen atoms [1-d] and R 1 Compounds of the methyl group [1-f] can be manufactured, for example, by the following manufacturing method 1 or a method based thereon.

[0516] Manufacturing method 1: Scheme 1 (Method for preparing compounds [1-d] and [1-f] from compound [1-a]): [Chemistry 313] In the plan, R 2 R 3 R 4 And W is the same as the definition above, Alk 1 Indicate C 1-4 alkyl.

[0517] Step 1-1: Method for producing compound [1-c]: Using compound [1-a] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine, and ureating agents such as 4-nitrophenyl chloroformate, CDI, and triphosgene, compound [1-b] is reacted to produce compound [1-c].

[0518] Steps 1-2: Method for producing compound [1-d]: Using compound [1-c] as the starting material, a "hydrolysis reaction" is carried out, thereby producing compound [1-d].

[0519] Steps 1-3: Method for producing compound [1-e]: Using compound [1-c] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of a base such as sodium hydride, a methylating agent such as iodomethane is reacted to produce compound [1-e].

[0520] Steps 1-4: Method for producing compound [1-f]: Using compound [1-e] as the starting material, a "hydrolysis reaction" is carried out using the method described in steps 1-2 above or a method based thereon, thereby producing compound [1-f].

[0521] The compounds [1-d] and [1-f] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0522] It should be noted that in compound [I] of the present invention, X is C 1-4 Alkoxycarbonyl compounds can be manufactured, for example, as compounds [1-c] or [1-e] by this manufacturing method 1 or a method based thereon.

[0523] Furthermore, in the manufacturing intermediates of compound [I] of the present invention, compounds [1-a] and [1-b] described in Scheme 1 can be manufactured by known methods or obtained by purchasing commercially available products.

[0524] Furthermore, compound [1-a] can also be manufactured by, for example, manufacturing method 2 described later or a method based thereon.

[0525] Similarly, compound [1-b] can also be manufactured by, for example, the manufacturing method 8 described later or a method based thereon.

[0526] The manufacture of compound [1-a], which is a manufacturing intermediate of compound [I] of the present invention, is exemplified in scheme 2-1 of manufacturing method 2 described below.

[0527] Manufacturing method 2: Scheme 2-1 (Method for producing compound [1-a] from compound [2-a]): [Chemical 314] In the plan, R 2 R 3 R 4 n12, n13, n22, n23, ring B 1 R B11 R B12 Ring B 2 R B21 and R B22 Same as the definition above; Ring B 1 C is represented in the same way as above. 3-8 Cycloalkyl groups, 4- to 8-membered saturated heterocyclic groups containing nitrogen atoms, phenyl groups, or 5- to 6-membered heteroaryl groups containing nitrogen atoms. Ring B 2 It also refers to partially saturated aryl groups of 9-10 membered fused rings, or heteroaryl groups of 9-10 membered fused rings containing nitrogen atoms, as described above. LG 1 Indicates the leaving group. in, LG 1 The "leaving group" shown represents, for example, halogen atoms such as chlorine atoms and bromine atoms; C atoms such as methanesulfonyloxy groups. 1-4 alkylsulfonyloxy; or arylsulfonyloxy such as p-toluenesulfonyloxy; R 2 'Indicates C 5-9 Alkyl, C 5-9 alkenyl, C 5-9 Acynyl group, or a group represented by the following formula [IV-1'] or [IV-2'], [Chemical 315] in, Ring B 1 Ring B 2 R B11 R B12 R B21 and R B22 Same as the definition above, L 1 'Indicates C 2-7 Alkyl Dimethyl (the C 2-7 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, or the structure shown in the following formula [V-1']. [Chemistry 316] in, n12 and n13 are the same as defined above. n11' represents an integer from 1 to 2. also, L 1 'For C 2-7 Alkyl Dimethyl (the C 2-7 When the alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, it serves as the C... 2-7 The distance R of one of the carbon atoms in an alkane dimethyl group 2’ The carbon atom of the carboxyl or formyl group bonded thereto, which is one or more atoms, can be of the formula -O-, -S-, or -N(R) L11 - Replaced in, R L11 Same as the definition above, also, L 1 'For C 2-7 Alkyl Dimethyl (the C 2-7 When the alkane dimethyl group can be replaced by 1 to 5 fluorine atoms, the C 2-7 The two consecutive carbon atoms in an alkane dimethyl group can be represented by the formula -C(=O)N(R). L12 - Replaced in, R L12 Same as the definition above, L 2 'Indicates C 2-7 Alkyl Dimethyl (the C 2-7 The alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, or the structure shown in the following formula [V-2']. [Chemistry 317] in, n22 and n23 are the same as defined above. n21' represents an integer from 1 to 2. also, L 2 'For C 2-7 Alkyl Dimethyl (the C 2-7 When the alkane dimethyl group can be substituted with 1 to 5 fluorine atoms, it serves as the C... 2-7 The distance R of one of the carbon atoms in an alkane dimethyl group 2’ The carbon atom of the carboxyl or formyl group bonded thereto, which is one or more atoms, can be of the formula -O-, -S-, or -N(R) L21 - Replaced in, R L21The same as above, representing a hydrogen atom or C. 1-3 alkyl, also, The C 2-7 The two consecutive carbon atoms in an alkane dimethyl group can be represented by the formula -C(=O)N(R). L22 - Replaced, where, R L22 The same as above, representing a hydrogen atom or C. 1-3 alkyl.

[0528] Step 2-1: Method for producing compound [1-a]: Using compound [2-a] as the starting material, in an inert solvent, at room temperature to reflux temperature, in the presence of a base, compound [2-b] is reacted to produce compound [1-a].

[0529] Examples of bases used in this reaction include, for example, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[4,3,0]undec-7-ene amine compounds, alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, and sodium carbonate, and alkoxy alkali metals such as potassium tert-butoxide.

[0530] Step 2-2: Another method for producing compound [1-a]: Compound [1-a] can also be produced by carrying out a "reductive amination reaction" of compound [2-a] with compounds [2-c], [2-c'] or [2-c”].

[0531] Steps 2-3: Method for producing compound [2-e]: Compound [2-e] can also be produced by carrying out a "condensation reaction" between compound [2-a] and compound [2-d].

[0532] Steps 2-4: Another method for producing compound [1-a] is as follows: starting with compound [2-e], in an inert solvent, at a temperature ranging from ice-cold to reflux, a reducing agent such as a borane-tetrahydrofuran complex or a borane-dimethyl sulfide complex is applied to produce compound [1-a].

[0533] Furthermore, compound [1-a] can also be manufactured by, for example, the manufacturing method shown in scheme 2-2 below, or a method based thereon.

[0534] Scheme 2-2 (Method for preparing compound [1-a] from compound [2-f]): [Chemistry 318] In the plan, R 2 R 3 and R 4 Same as the definition above.

[0535] Steps 2-5: Another method for producing compound [1-a]: Compound [1-a] can be produced by carrying out a "reductive amination reaction" between compound [2-f] and compound [2-g].

[0536] Furthermore, in compound [1-a], R 3 C 1-3 Alkyl compounds [1-a'] can also be manufactured by, for example, the manufacturing methods shown in schemes 2-3 below, or methods based thereon.

[0537] Scheme 2-3 (Method for producing compound [1-a'] from compound [2-h]): [Chemistry 319] In the plan, R 2 and R 4 Same as the definition above, R 3 'Indicates C 1-3 alkyl.

[0538] Steps 2-6: Method for producing compound [2-j]: Using compound [2-h] as the starting material, in the presence or absence of acids such as formic acid and acetic acid, in an inert solvent or under solvent-free conditions, at a temperature ranging from ice-cold to reflux, compound [2-j] can be produced.

[0539] Steps 2-7: Method for producing compound [1-a']: Using compound [2-j] as the starting material, compound [2-k] is reacted in an inert solvent at a temperature ranging from ice-cold to room temperature, thereby producing compound [1-a'].

[0540] Furthermore, steps 2-6 and 2-7 can also be carried out continuously without removing the compound [2-j] generated in step 2-6 as an imine (without post-processing the reaction in step 2-6).

[0541] The compounds [1-a] and [1-a'] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0542] It should be noted that R in compound [1-a] can also be produced by reacting the compound [2-j] obtained in steps 2-6 with the reducing agent used in the "reductive amination reaction". 3 Compounds containing hydrogen atoms.

[0543] Furthermore, in the manufacturing intermediates of compound [I] of the present invention, compounds [2-a], [2-b], [2-c], [2-c'], [2-c”], [2-d] of scheme 2-1, compounds [2-f], [2-g] of scheme 2-2, and compounds [2-g], [2-h], [2-k] of scheme 2-3 can be manufactured by methods known to them or obtained by purchasing commercially available products.

[0544] Furthermore, in these compounds, compound [2-a] whose structure is derived from the compound shown below [2-a'] (hereinafter, sometimes also referred to as compound [2-a']) can be manufactured, for example, by manufacturing method 3 described below or a method based thereon, and compound [2-f] whose structure is derived from the compound shown below [2-f'] (hereinafter, sometimes also referred to as compound [2-f']) and [2-h] can be manufactured, for example, by manufacturing method 6 described below or a method based thereon.

[0545] [Chem.320] Similarly, compounds [2-b], [2-c], and [2-d] whose structures are shown in [5-e] (hereinafter, sometimes also referred to as compound [5-e]), compounds [2-d] whose structures are shown in [5-e'] (hereinafter, sometimes also referred to as compound [5-e']), and [2-g] can be manufactured, for example, by manufacturing methods 4, 5, or 7 described below, or by methods based thereon.

[0546] [Chemistry 321] The manufacture of compound [2-a'], which is a manufacturing intermediate of compound [I] of the present invention, is exemplified in scheme 3-1 of the manufacturing method 3 described below.

[0547] Manufacturing method 3: Scheme 3-1 (Method for producing compound [2-a'] from compound [2-h]): [Chemistry 322] In the plan, R 3 'and R 4 Same as the definition above, M represents a lithium atom or the formula -MgX M, X M Indicates a chlorine atom, bromine atom, or iodine atom. Compound [2-k'](R) 3 '-M) indicates an alkyl metal reagent. Alk 2 It refers to tert-butyl, etc.

[0548] Step 3-1: Method for producing compound [3-b]: Using compound [2-h] as the starting material, in an inert solvent, at room temperature to 160°C, in the presence of Lewis acids such as tetraethyl orthotitanate, compound [3-a] is reacted to produce compound [3-b].

[0549] Step 3-2: Method for producing compound [3-c]: Using compound [3-b] as the starting material, compound [2-k'] is reacted in an inert solvent at -20°C to room temperature, thereby producing compound [3-c].

[0550] Step 3-3: Method for manufacturing compound [2-a']: Using compound [3-c] as the starting material, in an inert solvent, at a temperature from ice-cold to room temperature, acid such as hydrochloric acid is reacted to produce compound [2-a'].

[0551] Furthermore, steps 3-1, 3-2, and 3-3 can be performed by reference, for example, the methods described in Journal of Combinatorial Chemistry, Vol. 5, p. 590, 2003; Organic Letters, Vol. 3, p. 3707, 2001.

[0552] Furthermore, in this scheme 3-1, compound [2-a'] can be stereoselectively produced by reacting the optically active compound [3-a] in step 3-1.

[0553] In addition, in compound [2-a], R 4 The substituted phenyl group is C-substituted at the para position. 1-6 Compounds with alkyl carbonyl substituted [3-e] and C-substituted with hydroxyl groups 1-6 Alkyl-substituted compounds [3-f] can also be manufactured by, for example, the methods described in Scheme 3-2 below or methods based thereon.

[0554] Scheme 3-2 (Method for producing compounds [3-e] and [3-f] from compound [3-c']): [Chemistry 323] In the plan, R 3 and Alk 2 Same as the definition above, Alk 3 and Alk 4 Each represents C independently. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, R α1 Indicate C 1-6 Alkyl (the C 1-6 Alkyl groups can be substituted with one hydroxyl group, and halogenated C... 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Alkyl carbonyl and halogenated C 1-6 Alkyl carbonyl, Alk 5 Indicate C 1-6 Alkyl or hydroxyl-substituted C 1-6 alkyl, LG 2 Indicates a leaving group.

[0555] Among them, LG 2 The “leaving group” shown represents halogen atoms such as chlorine, bromine, and iodine atoms.

[0556] Steps 3-4: Method for producing compound [3-d]: Using compound [3-c'] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of palladium catalysts such as palladium(II) acetate, phosphine ligands such as 1,3-bis(diphenylphosphine)propane and 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene, potassium carbonate, triethylamine, etc., ethylene glycol monovinyl ether, butyl vinyl ether, etc., are reacted to produce compound [3-d].

[0557] This step can be performed by referring to, for example, the methods described in The Journal of Organic Chemistry, Vol. 66, p. 4340, 2001; and The Journal of Organic Chemistry, Vol. 72, p. 6390, 2007.

[0558] Steps 3-5: Method for manufacturing compound [3-e]: Using compound [3-d] as the starting material, in an inert solvent, at a temperature from ice-cold to room temperature, acid such as hydrochloric acid is reacted to produce compound [3-e].

[0559] It should be noted that steps 3-4 and 3-5 can also be carried out continuously as a one-pot reaction. Furthermore, this step can also be carried out in subsequent steps.

[0560] Steps 3-6: Method for manufacturing compound [3-f]: Using compound [3-e] as the starting material, in an inert solvent, at -78°C to room temperature, a reducing agent such as lithium aluminum hydride (LiAlH4) or lithium borohydride (LiBH4) is used to produce compound [3-f].

[0561] The compounds [2-a'], [3-e], and [3-f] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0562] Furthermore, in the manufacturing intermediates of compound [I] of the present invention, compounds [2-h] and [3-a] described in scheme 3-1 and compound [3-c'] described in scheme 3-2 can be manufactured by methods known to them or obtained by purchasing commercially available products.

[0563] Furthermore, among these compounds, compound [3-c'] can also be manufactured by, for example, the method described in step 3-2 above or a method based thereon.

[0564] In the manufacturing intermediate of compound [I] of the present invention, the compound [2-b] described in manufacturing method 2 can also be manufactured, for example, by manufacturing method 4 or a method based thereon.

[0565] [Chemistry 324] The manufacture of compound [2-b], which is a manufacturing intermediate of compound [I] of the present invention, is exemplified in the following scheme 4-1.

[0566] Manufacturing method 4: Scheme 4-1: A method for producing compound [2-b] from compound [4-a]. [Chemistry 325] In the plan, R 2 and LG 1 Same as the definition above.

[0567] Step 4-1: Method for manufacturing compound [2-b]: Using compound [4-a] as the starting material, (i) in an inert solvent, at a temperature from ice-cold to room temperature, in the presence of a base such as triethylamine, and in the presence or absence of additives such as trimethylamine hydrochloride, aryl sulfonyl chlorides such as p-toluenesulfonyl chloride, and C-type methyl sulfonyl chlorides such as methanesulfonyl chloride are reacted. 1-4 The compound [2-b] can be produced by reacting alkyl sulfonyl chlorides or by reacting a brominating agent such as lithium bromide in an inert solvent at room temperature to reflux temperature.

[0568] This step can be performed by referring to, for example, the method described in Tetrahedron, Volume 55, page 2183, 1999.

[0569] It should be noted that the compound [4-a] used as a raw material in step 4-1 above can be manufactured by its own known methods or obtained by purchasing commercially available products.

[0570] Furthermore, in compound [4-a], the compound whose structure is shown in the following formula [5-b] (hereinafter, sometimes also referred to as compound [5-b]) can be manufactured by, for example, the method described in scheme 5-1 of manufacturing method 5 described below, or a method based thereon.

[0571] [Chemistry 326] Furthermore, in compound [2-b], R 2 The group is shown in the aforementioned formula [IV-1], and L 1 Compounds of C4 alkane dimethyl groups substituted with one fluorine atom [4-m], and L 1 The compound [4-h], which is a C4 alkane dimethyl group substituted with two fluorine atoms, can also be manufactured by, for example, the manufacturing methods described in Schemes 4-5 below or methods based thereon.

[0572] [Chemistry 327] The manufacture of the aforementioned compounds [4-m] and [4-h] is illustrated in Scheme 4-2.

[0573] Among them, the compound [4-m] substituted with one fluorine atom can be produced by fluorinating the corresponding hydroxyl compound [4-d] with compound [4-b] as the starting material to generate compound [4-j], and the compound [4-h] substituted with two fluorine atoms can be produced by fluorinating the corresponding ketone compound [4-e] to generate compound [4-f].

[0574] It should be noted that in functional group transformation, the protection and deprotection of hydroxyl groups, etc., can be appropriately carried out.

[0575] Scheme 4-2 (Method for producing compound [4-h] or compound [4-m] from compound [4-b]): [Chemistry 328] In the plan, Ring B 1 LG 1 R B11 and R B12 Same as the definition above, PG 1 This indicates a protecting group for hydroxyl groups such as acetyl groups. LG 3 Indicates a leaving group.

[0576] Among them, LG 3 The "leaving group" shown represents, for example, C 1-6 Alkyl group.

[0577] Step 4-2: Method for producing compound [4-c]: Using compound [4-b] as the starting material, in an inert solvent, at a temperature from ice-cold to room temperature, a reducing agent is applied to produce compound [4-c].

[0578] As a reducing agent, LG 3 C 1-6 When alkoxy is involved, lithium aluminum hydride or lithium borohydride can be used, for example.

[0579] Step 4-3: Method for producing compound [4-d]: Using compound [4-c] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to room temperature, in the presence of a base such as N,N-diisopropylethylamine, acetic anhydride is reacted to selectively protect the primary hydroxyl group, thereby producing compound [4-d].

[0580] Step 4-4: Method for manufacturing compound [4-e]: Using compound [4-d] as the starting material, in an inert solvent, at a temperature from ice to room temperature, manganese dioxide and oxidants such as Des Martin periodine are used to react, thereby manufacturing compound [4-e].

[0581] Steps 4-5: Method for manufacturing compound [4-f]: Using compound [4-e] as the starting material, under inert solvent or solvent-free conditions, and at a temperature of ice-cold to 50°C, fluorinating agents such as bis(2-methoxyethyl)aminosulfur trifluoride and (diethylamino)sulfur trifluoride are applied to produce compound [4-f].

[0582] Steps 4-6: Method for manufacturing compound [4-g]: Using compound [4-f] as the starting material, in an inert solvent, at a temperature from ice to room temperature, an alkaline aqueous solution such as sodium hydroxide solution is used to remove the protecting group of the hydroxyl group, thereby manufacturing compound [4-g].

[0583] Steps 4-7: Method for manufacturing compound [4-h]: Using compound [4-g] as the starting material, compound [4-h] can be manufactured by the method described in step 4-1 above or by a method based thereon.

[0584] Steps 4-8: Method for manufacturing compound [4-j]: Using compound [4-d] as the starting material, compound [4-j] can be manufactured by the method described in steps 4-5 above or by a method based thereon.

[0585] Steps 4-9: Method for manufacturing compound [4-k]: Using compound [4-j] as the starting material, compound [4-k] can be manufactured by the methods described in steps 4-6 above or by methods based thereon.

[0586] Steps 4-10: Method for manufacturing compound [4-m]: Using compound [4-k] as the starting material, compound [4-m] can be manufactured by the methods described in steps 4-7 above or by methods based thereon.

[0587] In scheme 4-2, by using compound [4-b'] instead of compound [4-b] as the starting material, R can be manufactured using the same methods as those described above for compounds [4-h] and [4-m]. 2 The group is shown in the aforementioned formula [IV-2], and L 2 Compounds consisting of a C4 alkane dimethyl group substituted with one fluorine atom [4-m'] and L 2 [4-h'] is a compound of C4 alkane dimethyl groups substituted with two fluorine atoms. It should be noted that compound [4-b'] can be manufactured by methods known to the public or obtained by purchasing commercially available products.

[0588] [Chemistry 329] In the formula, Ring B 2 R B21 R B22 LG 1 and LG 3 Same as the definition above.

[0589] Furthermore, in compound [2-b], R2 The group is shown in the aforementioned formula [IV-1], and L 1 [4-x], a compound of C4 alkane dimethyl groups substituted with one fluorine atom, and L 1 The compound [4-u], which is a C4 alkane dimethyl group substituted with two fluorine atoms, can also be manufactured by, for example, the manufacturing method described in Scheme 4-3 below or a method based thereon.

[0590] [Chemistry 330] Examples of the manufacture of the aforementioned compounds [4-x] and [4-u] are shown in Scheme 4-3.

[0591] Among them, the compound [4-x] substituted with one fluorine atom can be produced by fluorinating the corresponding hydroxyl compound [4-q] with compound [4-n] as the starting material to generate compound [4-v], and the compound [4-u] substituted with two fluorine atoms can be produced by fluorinating the corresponding ketone compound [4-r] to generate compound [4-s].

[0592] It should be noted that in functional group transformation, the protection and deprotection of hydroxyl groups, etc., can be appropriately carried out.

[0593] Scheme 4-3 (Method for producing compound [4-u] or compound [4-x] from compound [4-n]): [Chemistry 331] In the plan, Ring B 1 R B11 R B12 PG 1 LG 1 and LG 3 Same as the definition above.

[0594] Steps 4-11: Method for manufacturing compound [4-p]: Using compound [4-n] as the starting material, compound [4-p] can be manufactured by the method described in step 4-2 above or a method based thereon.

[0595] Steps 4-12: Method for manufacturing compound [4-q]: Using compound [4-p] as the starting material, compound [4-q] can be manufactured by the method described in or based on steps 4-3 above.

[0596] Step 4-13: Method for manufacturing compound [4-r]: Using compound [4-q] as the starting material, compound [4-r] can be manufactured by the method described in or based on steps 4-4 above.

[0597] Steps 4-14: Method for manufacturing compound [4-s]: Using compound [4-r] as the starting material, compound [4-s] can be manufactured by the method described in steps 4-5 above or by a method based thereon.

[0598] Steps 4-15: Method for manufacturing compound [4-t]: Using compound [4-s] as the starting material, compound [4-t] can be manufactured by the methods described in steps 4-6 above or by methods based thereon.

[0599] Steps 4-16: Method for manufacturing compound [4-u]: Using compound [4-t] as the starting material, compound [4-u] can be manufactured by the methods described in steps 4-7 above or by methods based thereon.

[0600] Step 4-17: Method for manufacturing compound [4-v]: Using compound [4-q] as the starting material, compound [4-v] can be manufactured by the methods described in steps 4-8 above or by methods based thereon.

[0601] Step 4-18: Method for manufacturing compound [4-w]: Using compound [4-v] as the starting material, compound [4-w] can be manufactured by the methods described in steps 4-9 above or by methods based thereon.

[0602] Step 4-19: Method for manufacturing compound [4-x]: Using compound [4-w] as the starting material, compound [4-x] can be manufactured by the method described in steps 4-10 above or by a method based thereon.

[0603] In scheme 4-3, by using compound [4-n'] instead of compound [4-n] as the starting material, R can be manufactured using the same methods as those described above for compounds [4-x] and [4-u]. 2 The group is shown in the aforementioned formula [IV-2], and L 2 Compounds consisting of a C4 alkane dimethyl group substituted with one fluorine atom [4-x'] and L 2 [4-u'] is a compound of C4 alkane dimethyl groups substituted with two fluorine atoms. It should be noted that compound [4-n'] can be manufactured by methods known to the public or obtained by purchasing commercially available products.

[0604] [Chemistry 332] In the formula, Ring B 2 R B21 R B22 LG 1 and LG 3 Same as the definition above.

[0605] The compounds [2-b], [4-h], [4-h'], [4-m], [4-m'], [4-u], [4-u'], [4-x], and [4-x'] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0606] In the manufacturing intermediates of the compound [I] of the present invention, the compound [4-a] described in Scheme 4-1, the compound [4-b] described in Scheme 4-2, and the compound [4-n] described in Scheme 4-3 can be manufactured by methods known to them or obtained by purchasing commercially available products.

[0607] In the manufacturing intermediates of compound [I] of the present invention, the compounds [2-c] and [5-e] described in manufacturing method 2 can also be manufactured, for example, by manufacturing method 5 or a method based thereon.

[0608] [Chemistry 333] Manufacturing method 5: The manufacture of compound [2-c], which is a manufacturing intermediate of compound [I] of the present invention, is exemplified in the following scheme 5-1.

[0609] Scheme 5-1 (Method for producing compound [2-c] from compound [2-d]): [Chemistry 334] In the plan, R 2 Same as the definition above, LG 4 Indicates a leaving group.

[0610] Among them, LG 4 The "leaving group" shown represents, for example, C 1-6 Alkyl group.

[0611] Step 5-1: Method for manufacturing compound [5-a]: Using compound [2-d] as the starting material, in an alcohol solvent such as methanol or ethanol, under a temperature ranging from ice-cold to reflux, an acid such as sulfuric acid is reacted to produce compound [5-a].

[0612] Step 5-2: Method for manufacturing compound [5-b]: Using compound [5-a] as the starting material, compound [5-b] can be manufactured by the method described in step 4-2 above or a method based thereon.

[0613] Step 5-3: Another method for producing compound [5-b] is as follows: starting with compound [2-d], in an inert solvent, at a temperature from ice to room temperature, a reducing agent such as a borane-tetrahydrofuran complex is used to produce compound [5-b].

[0614] Step 5-4: Method for manufacturing compound [2-c]: Using compound [5-b] as the starting material, compound [2-c] can be manufactured by the method described in or based on steps 4-4 above.

[0615] It should be noted that the compound [2-d] used as a raw material in steps 5-1 and 5-3 above can be manufactured by its own known methods or obtained by purchasing commercially available products.

[0616] The preparation of compound [5-e] is illustrated in scheme 5-2 below.

[0617] Scheme 5-2 (Method for producing compound [5-e] from compound [5-c]): [Chemistry 335] In the plan, Ring B 1 R B11 and R B12 Same as the definition above, LG 5 Indicates the leaving group. Among them, LG 5 The "leaving group" shown represents, for example, halogen atoms such as chlorine atoms and bromine atoms; C atoms such as methanesulfonyloxy groups. 1-4 alkylsulfonyloxy; or arylsulfonyloxy such as p-toluenesulfonyloxy, Y 1 The expression is represented by -O-, -S-, or -N(R). L11 )-, Among them, R L11 Same as the definition above, L X11Indicate C 1-5 Alkyl Dimethyl L X12 This indicates a single bond or a C bond that can be substituted by 1 to 5 fluorine atoms. 1-5 Alkyl dimethyl

[0618] Step 5-5: Method for producing compound [5-e]: Using compound [5-c] as the starting material, in an inert solvent such as tetrahydrofuran or N-methylpyrrolidone, at a temperature ranging from ice-cold to reflux, in the presence of an alkali such as sodium hydride, compound [5-d] is reacted to produce compound [5-e].

[0619] In Scheme 5-2, compound [5-c'] is used instead of compound [5-c] and compound [5-d'] is used instead of compound [5-d] as starting materials, thereby allowing compound [5-e'] to be manufactured by the same method as that used for compound [5-e]. It should be noted that compounds [5-c'] and [5-d'] can be manufactured by methods known to them or obtained by purchasing commercially available products.

[0620] [Chemistry 336] In the formula, Ring B 2 R B21 R B22 and LG 5 Same as the definition above, Y 2 The expression is represented by -O-, -S-, or -N(R). L21 )-, Among them, R L21 Same as the definition above, L X21 Indicate C 1-5 Alkyl Dimethyl L X22 This indicates a single bond or a C bond that can be substituted by 1 to 5 fluorine atoms. 1-5 Alkyl dimethyl

[0621] The compounds [2-c], [5-e], and [5-e'] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0622] In the manufacturing intermediates of compound [I] of the present invention, compound [2-d] described in scheme 5-1 and compounds [5-c] and [5-d] described in scheme 5-2 can be manufactured by methods known to them or obtained by purchasing commercially available products.

[0623] In the manufacturing intermediate of compound [I] of the present invention, the compound [2-f'] described in manufacturing method 2 can also be manufactured, for example, by manufacturing method 6 or a method based thereon.

[0624] [Chemistry 337] Manufacturing method 6: The manufacture of compound [2-f'], which is a manufacturing intermediate for compound [I] of the present invention, is exemplified in the following scheme 6-1.

[0625] Scheme 6-1 (Method for producing compound [2-f'] from compound [6-a]): [Chemistry 338] In the plan, R 3 '、R 4 And M is the same as the previous definition, LG 6 Indicates a leaving group.

[0626] in, LG 6 The “leaving group” shown refers to, for example, the group represented by the formula -N(CH3)OCH3.

[0627] Step 6-1: Method for producing compound [2-f']: Starting with compound [6-a], alkyllithium [2-k] is reacted in an inert solvent at -78°C to room temperature, thereby producing compound [2-f'].

[0628] This step can be performed by referring to, for example, the method described in Synlett, Volume 26, page 1395, 2015.

[0629] Step 6-2: Method for manufacturing compound [6-a']: Compound [6-a'] can be manufactured by performing a "condensation reaction" of compound [6-a] with amine compounds such as N,O-dimethylhydroxylamine hydrochloride.

[0630] Step 6-3: Another method for producing compound [2-f']: starting with compound [6-a'], compound [2-k'] is reacted in an inert solvent at a temperature ranging from ice-cold to room temperature, thereby producing compound [2-f'].

[0631] Scheme 6-2 (Method for producing compound [2-h] from compound [6-b]): [Chemistry 339] In the plan, R 4 Same as the definition above, LG 7 Indicates a leaving group.

[0632] Among them, LG 7 The "leaving group" shown represents, for example, hydroxyl, C 1-6 Alkyl group.

[0633] Step 6-4: Method for producing compound [6-c]: Using compound [6-b] as the starting material, in an inert solvent, at a temperature from ice-cold to room temperature, a reducing agent is applied to produce compound [6-c].

[0634] As a reducing agent, (i)LG 7 When the hydroxyl group is used, for example, a borane-tetrahydrofuran complex can be used in the same manner as in steps 5-3 above; (ii) LG 7 C 1-6 When alkoxy is involved, lithium aluminum hydride or lithium borohydride can be used, for example, in the same way as in steps 4-2 above.

[0635] Step 6-5: Method for manufacturing compound [2-h]: Using compound [6-c] as the starting material, compound [2-h] can be manufactured by the method described in or based on steps 4-4 above.

[0636] In addition, in compound [2-h], R 4 Compounds [6-g] consisting of a substituted phenyl group and a chlorine atom substituted at the ortho position of the phenyl group can be manufactured by, for example, the methods described in schemes 6-3 below or methods based thereon.

[0637] Scheme 6-3 (Method for producing compound [6-g] from compound [6-d]): [Transformation 340] In the plan, Alk 3 and Alk 4 Same as the definition above, Alk 6 Indicate C 1-6 alkyl, R α2 Indicate C 1-6 Alkyl (the C 1-6 Alkyl groups can be substituted with one hydroxyl group, and halogenated C... 1-6 Alkyl, C3-8 cycloalkyl, C 1-6 Alkyl carbonyl and halogenated C 1-6 Alkyl carbonyl group.

[0638] Step 6-6: Method for manufacturing compound [6-e]: Using compound [6-d] as the starting material, in an inert solvent, at a temperature of -60°C to 100°C, chlorinating agents such as sulfonyl chloride and N-chlorosuccinimide (NCS) are used to react, thereby manufacturing compound [6-e].

[0639] It should be noted that this chlorination reaction can also be carried out in a separate step.

[0640] Furthermore, in this step, by using 2 equivalents of chlorinating agent relative to compound [6-d], the following compound [6-e'], in which both ortho positions are substituted with chlorine atoms, can be produced.

[0641] [Chemistry 341] Steps 6-7: Method for manufacturing compound [6-f]: Using compound [6-e] as the starting material, compound [6-f] can be manufactured by the method described in step 4-2 above or a method based thereon.

[0642] Steps 6-8: Method for manufacturing compound [6-g]: Using compound [6-f] as the starting material, compound [6-g] can be manufactured by the method described in steps 4-4 above or by a method based thereon.

[0643] Furthermore, in compound [2-h], R 4 Compounds [6-m] consisting of a substituted phenyl group and a methyl group at the ortho position of the phenyl group can be manufactured by, for example, the methods described in schemes 6-4 below or methods based thereon.

[0644] Scheme 6-4 (Method for preparing compound [6-m] from compound [6-d]): [Chemistry 342] In the plan, Alk 3 Alk 4 Alk 6 and R α2 Same as the definition above.

[0645] Steps 6-9: Method for manufacturing compound [6-h]: Using compound [6-d] as the starting material, in an inert solvent, at a temperature from ice to room temperature, in the presence of silver compounds such as silver trifluoroacetate, an iodizing agent such as iodine is applied to produce compound [6-h].

[0646] It should be noted that this iodination reaction can also be carried out in a separate step.

[0647] Steps 6-10: Method for producing compound [6-j]: Starting with compound [6-h], in an inert solvent, at room temperature to 160°C, a methylating agent such as methylboronic acid is reacted with a palladium catalyst such as tetra(triphenylphosphine)palladium(0) and a base such as tripotassium phosphate, thereby producing compound [6-j]. It should be noted that this methylation reaction can also be carried out in a separate step.

[0648] Steps 6-11: Method for manufacturing compound [6-k]: Using compound [6-j] as the starting material, compound [6-k] can be manufactured by the method described in steps 6-7 above or by a method based thereon.

[0649] Steps 6-12: Method for manufacturing compound [6-m]: Using compound [6-k] as the starting material, compound [6-m] can be manufactured by the method described in steps 6-8 above or a method based thereon.

[0650] Scheme 6-5 (another method for producing compound [6-j] from compound [6-d]): [Chemistry 343] In the plan, Alk 3 Alk 4 Alk 6 and R α2 Same as the definition above.

[0651] Steps 6-13: Method for producing compound [6-n]: Starting with compound [6-d], compound [6-n] can be produced by reacting dichloromethyl methyl ether in an inert solvent at a temperature ranging from ice-cold to room temperature in the presence of Lewis acids such as titanium(IV) chloride.

[0652] It should be noted that this formylation reaction can also be carried out in a separate step.

[0653] Steps 6-14: Another method for producing compound [6-j]: Starting with compound [6-n], compound [6-j] can be produced by reacting a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid at a temperature ranging from ice-cold to room temperature. It should be noted that this methylation reaction can also be carried out in a separate step.

[0654] In the manufacturing intermediate of compound [I] of the present invention, the following compound [2-g] described in manufacturing method 2 can be manufactured by a known method or obtained by purchasing a commercially available product, or can be manufactured by, for example, manufacturing method 7 or a method based thereon.

[0655] [Chemistry 344] Manufacturing method 7: The manufacture of compound [2-g], which is a manufacturing intermediate for compound [I] of the present invention, is exemplified in the following scheme 7.

[0656] Scheme 7 (Method for producing compound [2-g] from compound [2-b]): [Chemistry 345] In the plan, R 2 and LG 1 Same as the definition above, PG 2 This indicates a protecting group for amino groups such as tert-butoxycarbonyl. PG 3 A protecting group representing a hydrogen atom or an amino group such as a tert-butoxycarbonyl group. also, PG 2 and PG 3 It can also form phthalimides, etc., with adjacent nitrogen atoms to protect amino groups.

[0657] Step 7-1: Method for manufacturing compound [7-a]: Using compound [2-b] as the starting material, in an inert solvent, at room temperature to 120°C, in the presence or absence of a base such as potassium carbonate, potassium phthalimide, di-tert-butyl iminodiacetic acid, etc., are reacted to produce compound [7-a].

[0658] Step 7-2: Method for producing compound [2-g]: Starting with compound [7-a], compound [2-g] can be produced under any of the reaction conditions described in (i) to (ii) below.

[0659] (i) conditions for reacting acids such as hydrochloric acid in an inert solvent at a temperature of ice-cold to 100°C, or (ii) conditions for reacting hydrazine monohydrate, etc. in an inert solvent at a temperature of room temperature to reflux. The compound used as a starting material in step 7-1 above [2-b] can be manufactured by a method known to them, by the method shown in the aforementioned scheme 4-1, or obtained by purchasing commercially available products.

[0660] The compound [2-g] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0661] In the manufacturing intermediate of compound [I] of the present invention, compound [2-b] described in scheme 7 can be manufactured by a known method or obtained by purchasing a commercially available product.

[0662] In the manufacturing intermediates of the compound [I] of the present invention, the compound whose structure is represented by formula [1-b] (hereinafter, sometimes also referred to as compound [1-b]) can also be manufactured by, for example, the manufacturing method 8 described below or a method based thereon.

[0663] [Chemistry 346] Manufacturing method 8: The compound [1-b], which is a manufacturing intermediate of the compound [I] of the present invention, can be manufactured by its own known methods or obtained by purchasing commercially available products, or can be manufactured by, for example, the methods described in or based on Scheme 8-1 below.

[0664] Scheme 8-1 (Method for producing compound [1-b] from compound [8-a]): [Chemistry 347] In the plan, W and Alk 1 Same as the definition above, PG 4 It represents the protecting group of amino groups such as benzyloxycarbonyl, tert-butoxycarbonyl, and allyloxycarbonyl.

[0665] Step 8-1: Method for producing compound [8-b]: Starting with compound [8-a], compound [8-b] can be produced under any of the reaction conditions described in (i) to (iii) below.

[0666] (i) The conditions under which an alkylating agent such as iodomethane reacts in an inert solvent, at room temperature to reflux temperature, in the presence or absence of a base such as potassium carbonate. (i) Conditions under which alcohols such as methanol and ethanol are reacted in the presence or absence of an inert solvent, at room temperature to reflux temperature, in the presence of p-toluenesulfonic acid, thionyl chloride, etc.; or (iii) Conditions under which alkylating agents such as iodomethane are reacted in an inert solvent, at room temperature to reflux temperature, in the presence of silver compounds such as silver oxide. Step 8-2: Method for manufacturing compound [1-b]: Using compound [8-b] as the starting material, compound [1-b] can be manufactured in an inert solvent through the following deprotection reactions (i) to (iii).

[0667] (i) Deprotection reactions using acids such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid at temperatures cooled to 80°C. (ii) Deprotection reactions using palladium on carbon, etc., at ice-cold temperatures to room temperature, under a hydrogen atmosphere and under pressure or without pressure, in the presence or absence of acid, or (iii) In the deprotection reaction of compounds [1-b] using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in the presence of an allyl scavenger such as 1,3-dimethylbarbituric acid at a temperature of ice-cold to 80°C, the compounds [8-f] in which W has the structure shown in the aforementioned formula [III-1] can be manufactured by methods known to the public or obtained by purchasing commercially available products.

[0668] Furthermore, the compound can also be manufactured by, for example, the method described in Scheme 8-2 below or a method based thereon.

[0669] [Chemistry 348] Scheme 8-2 (Method for producing compound [8-f] from compound [8-c]): [Chemistry 349] In the plan, Ring A 1 R A11 R A12 Alk 1 and PG 4 Same as the definition above.

[0670] Step 8-3: Method for producing compound [8-d]: Using compound [8-c] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to room temperature, tetramethylammonium hydroxide, tetraethylammonium hydroxide, etc. are reacted to selectively hydrolyze only one of the two esters of compound [8-c], thereby producing compound [8-d].

[0671] This step can be performed by referring to, for example, the method described in The Journal of Organic Chemistry, Vol. 82, p. 12863, 2017.

[0672] Step 8-4: Method for manufacturing compound [8-e]: Using compound [8-d] as the starting material, in an inert solvent, at a temperature of ice-cold to 100°C, in the presence of a base such as triethylamine, an azide agent such as diphenylphosphohydride is reacted to form the corresponding isocyanate, and then benzyl alcohol, tert-butanol, allyl alcohol, etc. are reacted to produce compound [8-e].

[0673] Step 8-5: Method for manufacturing compound [8-f]: Using compound [8-e] as the starting material, compound [8-f] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0674] Furthermore, in compound [1-b], compounds [8-f'] and [8-f”] with W having the structure shown in the aforementioned formula [III-2] or [III-3] can be manufactured by their own known methods or obtained by purchasing commercially available products.

[0675] Furthermore, these compounds can also be manufactured by, for example, the methods described in or based on Scheme 8-2 above.

[0676] [Chemical 350] In the formula, Ring A 2 Ring A 3 R A21 R A22 R A31 R A32 and Alk 1 Same as the definition above.

[0677] In compound [1-b], W has the structure shown in the aforementioned formula [III-1], and in this structure, ring A 1 For being selected from "hydroxyl, C 1-6 The C group substituted by one of the following groups: alkoxy group, and nitrogen-containing 4-6 membered saturated heterocyclic group. 3-8 Cycloalkanes [8-p] can be manufactured by known methods or obtained by purchasing commercially available products.

[0678] Furthermore, the compound can also be expressed, for example, with C substituted by oxygen. 3-8The cycloalkane compound, i.e., compound [8-g], is used as the starting material and is manufactured by the method described in or based on Scheme 8-3 below.

[0679] [Chemistry 351] Scheme 8-3 (Method for producing compound [8-p] from compound [8-g]): [Chemistry 352] In the plan, Alk 1 and PG 4 Same as the definition above, Ring A 1 'For C 3-8 Cycloalkanes, PG 5 Indicate C 1-3 alkyl, in, 2 PGs 5 It can form a 5-6 membered ring with the bonded oxygen and carbon atoms (this 5-6 membered ring can be substituted by 1-2 groups selected from methyl and phenyl) to protect the carbonyl group. R A11 'Indicates hydroxyl group, C 1-6 Alkoxy groups, or nitrogen-containing 4- to 6-membered saturated heterocyclic groups (these nitrogen-containing 4- to 6-membered saturated heterocyclic groups can be substituted by one carbon atom). 1-3 Alkyl substitution).

[0680] Step 8-6: Method for producing compound [8-h]: Using compound [8-g] as the starting material, in an inert solvent, at room temperature to reflux temperature, in the presence of an acid such as p-toluenesulfonic acid, methanol, ethylene glycol, diphenylethylene glycol or an orthoester such as triethyl orthoformate are reacted to produce compound [8-h].

[0681] Steps 8-7: Method for manufacturing compound [8-j]: Using compound [8-h] as the starting material, compound [8-j] can be manufactured by the method described in or based on the aforementioned steps 8-3.

[0682] Step 8-8: Method for manufacturing compound [8-k]: Using compound [8-j] as the starting material, compound [8-k] can be manufactured by the method described in or based on steps 8-4 above.

[0683] Steps 8-9: Method for manufacturing compound [8-m]: Using compound [8-k] as the starting material, compound [8-m] can be manufactured in an inert solvent at room temperature to reflux temperature by using a deprotection reaction with acids such as hydrochloric acid and trifluoroacetic acid.

[0684] Steps 8-10: Method for producing compound [8-n]: Compound [8-n] can be produced by taking compound [8-m] as the starting material and carrying out any of the reactions described in (i) to (iv) below.

[0685] (i) Reduction reactions using sodium borohydride, lithium borohydride, diisobutylaluminum hydride, triethyllithium borohydride, trisec-butyllithium borohydride, borane-tetrahydrofuran, etc., in an inert solvent, at -80°C to reflux temperature, in the presence or absence of additives such as zinc chloride. (ii) After performing steps 8-10(i), in an inert solvent, at an ice-cold temperature to reflux temperature, in the presence of phosphorus compounds such as triphenylphosphine and azodicarboxylic acid diesters such as bis(2-methoxyethyl) ester, the "hydrolysis reaction" following the reaction of 4-nitrobenzoic acid, etc., is carried out. (iii) After performing steps 8-10(i) or 8-10(ii), in an inert solvent, at room temperature to reflux temperature, in the presence of silver compounds such as silver oxide, react with alkyl halides such as iodomethane or iodoethane, or (iv) react with the corresponding R A11 The "reductive amination reaction" of amines Steps 8-10(i) above can be performed with reference to, for example, the methods described in Bioorganic & Medicinal Chemistry, Vol. 17, p. 1982, 2009.

[0686] Furthermore, in steps 8-10(i), compounds can be stereoselectively produced by selecting a suitable reducing agent [8-n].

[0687] Steps 8-11: Method for manufacturing compound [8-p]: Using compound [8-n] as the starting material, compound [8-p] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0688] Furthermore, this compound [8-p] can also be, for example, the oxygen-substituted C obtained in scheme 8-3. 3-8 Cycloalkane compounds, i.e., compounds [8-m], are used as starting materials and are manufactured by the methods described in or based on Schemes 8-4 below.

[0689] Scheme 8-4 (Method for preparing compound [8-p] from compound [8-m]): [Chemistry 353] In the plan, Alk 1 PG 4 Ring A 1 'and R A11 Same as the definition above.

[0690] Steps 8-12: Method for manufacturing compound [1-b']: Using compound [8-m] as the starting material, compound [1-b'] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0691] Steps 8-13: Method for manufacturing compound [8-q]: Using compound [1-b'] as the starting material, in an inert solvent, at room temperature to reflux temperature, in the presence of a base such as triethylamine, phthalic anhydride is reacted to produce compound [8-q].

[0692] Steps 8-14: Method for manufacturing compound [8-r]: Using compound [8-q] as the starting material, compound [8-r] can be manufactured by the method described in steps 8-10 above or by a method based thereon.

[0693] Steps 8-15: Method for manufacturing compound [8-p]: Using compound [8-r] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, the compound [8-p] is reacted with acids such as hydrochloric acid and hydrazine, thereby producing compound [8-p].

[0694] Furthermore, in compound [1-b], W has the structure shown in the aforementioned formula [III-2] or [III-3], and in this structure, ring A 2 Ring A 3 They are respectively selected from "hydroxyl, C 1-6 The C group substituted by one of the following groups: alkoxy group, and nitrogen-containing 4-6 membered saturated heterocyclic group. 3-8 The cycloalkanes [8-p'] and [8-p”] can be manufactured by known methods or obtained by purchasing commercially available products.

[0695] Furthermore, these compounds can also be manufactured by methods described in, for example, those described in schemes 8-3 and 8-4 above, or methods based thereon.

[0696] [Chemistry 354] In the formula, Alk 1Same as the definition above, Ring A 2 'and Ring A' 3 'With ring A 1 The definition of ' is the same as C 3-8 Cycloalkanes, R A21 'and R A31 'With R A11 The definition of ' is the same as that of hydroxyl group, C 1-6 Alkoxy groups, or nitrogen-containing 4- to 6-membered saturated heterocyclic groups (these nitrogen-containing 4- to 6-membered saturated heterocyclic groups can be substituted by one carbon atom). 1-3 Alkyl substitution).

[0697] In compound [1-b], W has the structure shown in the aforementioned formula [III-1] and the ring A in this structure 1 C is replaced by one hydroxyl group 3-8 Cycloalkanes [8-w] and cycloalkanes 1 For 1 C 1-6 Alkoxy-substituted C 3-8 Cycloalkanes [8-z] can be manufactured by known methods or obtained by purchasing commercially available products.

[0698] Furthermore, these compounds can also be, for example, with C substituted by oxygen. 3-8 The cycloalkane compound, i.e., compound [8-g], is used as the starting material and is manufactured by the method described in or based on the schemes 8-5 below.

[0699] It should be noted that when corresponding enantiomers or diastereomers are present in compounds [8-w] and [8-z], the enantiomers or diastereomers can also be produced by their own known methods, by the methods shown in schemes 8-5, or obtained by purchasing commercially available products.

[0700] [Chemistry 355] Scheme 8-5 (Method for producing compounds [8-w] and [8-z] from compound [8-g]): [Chemistry 356] In the plan, Alk 1 Ring A 1 'and PG 4 Same as the definition above, R A11a Indicate C 1-6 Alkyl group.

[0701] Steps 8-16: Method for manufacturing compound [8-s]: Using compound [8-g] as the starting material, compound [8-s] can be manufactured by the method described in or based on steps 8-10(i) above.

[0702] Steps 8-17: Method for manufacturing compound [8-t]: Using compound [8-s] as the starting material, compound [8-t] can be manufactured by the method described in or based on steps 8-3 above.

[0703] Steps 8-18: Method for manufacturing compound [8-u]: Using compound [8-t] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of a base such as triethylamine, diphenyl azidophosphate and other azides are reacted to produce compound [8-u].

[0704] Steps 8-18 above can be performed by referring to, for example, the method described in the Journal of the Organic Chemistry, Vol. 82, p. 12863, 2017.

[0705] Steps 8-19: Method for manufacturing compound [8-v]: Using compound [8-u] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, an alkali such as potassium hydroxide is reacted with water to produce compound [8-v].

[0706] Steps 8-20: Method for manufacturing compound [8-w]: Compound [8-w] can also be manufactured by using compound [8-v] as the starting material, or by the method described in step 8-1(ii) above or a method based thereon.

[0707] Steps 8-21: Method for manufacturing compound [8-x]: Using compound [8-w] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of alkalis such as triethylamine, sodium hydroxide, and sodium carbonate, di-tert-butyl dicarbonate, allyl chloroformate, and benzyl chloroformate are reacted to produce compound [8-x].

[0708] Step 8-22: Method for producing compound [8-y]: Using compound [8-x] as the starting material, in an inert solvent, at room temperature to reflux temperature, in the presence of silver compounds such as silver oxide, alkyl halides such as iodomethane and iodoethane are reacted to produce compound [8-y].

[0709] Step 8-23: Method for manufacturing compound [8-z]: Compound [8-z] can also be manufactured by using compound [8-y] as the starting material, or by the method described in step 8-2 above or a method based thereon.

[0710] In compound [1-b], W has the structure shown in the aforementioned formula [III-1] and the ring A in this structure 1 For being selected from "C" 1-4 alkyl carbonyl and C 1-4 Compounds of 4- to 8-membered saturated heterocycles containing nitrogen atoms, in which one group of "alkoxycarbonyl" is substituted, can be manufactured by known methods or obtained by purchasing commercially available products.

[0711] In addition, the compound can be manufactured, for example, from a nitrogen-containing 4- to 8-membered saturated heterocyclic compound, namely compound [8-aa], by the methods described in or based thereon in schemes 8-6 below.

[0712] [Chemistry 357] Scheme 8-6 (Method for producing compound [8-ac] from compound [8-aa]): [Chemistry 358] In the plan, Alk 1 and PG 4 Same as the definition above, Ring A 1 "It is a 4- to 8-membered saturated heterocycle containing nitrogen atoms." R A11 " indicates C 1-4 alkyl carbonyl or C 1-4 Alkoxycarbonyl group.

[0713] Steps 8-24: Method for manufacturing compound [8-ac]: Starting with compound [8-aa], compound [8-ab] can be manufactured by carrying out the reaction described in (i) or (ii) below.

[0714] (i) In an inert solvent, at an ice-cold temperature up to 50°C, in the presence of a base, using acetyl chloride or the equivalent of R A11″ Acyl chlorides or acetic anhydrides, etc., correspond to R A11″ The reaction of the acid anhydride, or (ii) in an inert solvent, at an ice-cold temperature up to 50°C, in the presence or absence of a base, using ethyl chloroformate or the like corresponding to R A11″ The reaction of chloroformate Step 8-25: Method for manufacturing compound [8-ac]: Using compound [8-ab] as the starting material, compound [8-ac] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0715] Furthermore, in compound [1-b], W has the structure shown in the aforementioned formula [III-2] or [III-3], and in this structure, ring A 2 Ring A 3 They were selected from "C" respectively 1-4 alkyl carbonyl and C 1-4 Compounds of 4- to 8-membered saturated heterocycles containing nitrogen atoms, substituted with one group in the alkoxycarbonyl group, such as [8-ac'] and [8-ac”], can be manufactured by known methods or obtained by purchasing commercially available products.

[0716] Furthermore, these compounds can also be manufactured by, for example, the methods described in or based thereon in Schemes 8-6 above.

[0717] [Chemistry 359] In the formula, Alk 1 Same as the definition above, Ring A 2” And Ring A 3” With ring A 1” The definition is the same: a 4- to 8-membered saturated heterocycle containing nitrogen atoms. R A21 "and R A31 "With R" A11 The definition of " is the same as C" 1-4 alkyl carbonyl or C 1-4 Alkoxycarbonyl group.

[0718] The compounds [1-b], [8-f], [8-f'], [8-f”], [8-p], [8-p'], [8-p”], [8-w], [8-z], [8-ac], [8-ac'], and [8-ac”] obtained in this way can be separated and purified by known separation and purification methods, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization, and chromatography.

[0719] In the manufacturing intermediates of compound [I] of the present invention, compound [8-a] described in scheme 8-1, compound [8-c] described in scheme 8-2, compound [8-g] described in schemes 8-3 and 8-5, and compound [8-aa] described in scheme 8-6 can be manufactured by known methods or obtained by purchasing commercially available products.

[0720] In the compounds [I] of the present invention, compounds in which X is carbamoyl, compounds in which X is a group represented by the following formulas [II-2], [II-3], [II-4], [II-5], or [II-1], and compounds in which X is tetrazolium can be manufactured, for example, by the manufacturing method 9 described below or by a method based thereon.

[0721] [Hua360] The manufacture of compound [9-a] in which X is a carbamoyl group or a group represented by formula [II-2], [II-3], or [II-4] is exemplified in the following scheme 9-1.

[0722] Manufacturing method 9: Scheme 9-1 (Method for preparing compound [9-a] from compound [1-d]): [Chemistry 361] In the plan, R 1 R 2 R 3 R 4 The definitions of , and W are the same as those previously mentioned. EQ 1 Represents a hydrogen atom or a group selected from the following group of formulas [II']. [Chemistry 362]

[0723] Step 9-1: [9-a] Manufacturing method: Using compound [1-d] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence or absence of a base such as N,N-diisopropylethylamine, in the presence or absence of additives such as 4-dimethylaminopyridine and HOBt, and in the presence of condensing agents such as EDC and CDI, amine compounds such as methanesulfonamide, sulfonamide, N,N-dimethylsulfonamide, or ammonium chloride are reacted to produce compound [9-a].

[0724] The manufacture of compounds [9-h] in which X is a group represented by formula [II-5] in the compound [I] of the present invention is illustrated in the following scheme 9-2.

[0725] Scheme 9-2 (Method for producing compound [9-h] from compound [9-b]): [Chem.363] In the plan, R 2 R3 R 4 R A11 and R A12 Same as the definition above, Ring D represents C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused aromatic hydrocarbons, 4- to 8-membered saturated heterocycles containing oxygen atoms, 4- to 8-membered saturated heterocycles containing sulfur atoms, or 4- to 8-membered saturated heterocycles containing nitrogen atoms. in, The sulfur atom in this 4- to 8-membered saturated heterocycle containing sulfur atoms can be replaced by 1 to 2 oxygen atoms. The nitrogen atom in this nitrogen-containing 4- to 8-membered saturated heterocycle can be selected from C 1-4 alkyl carbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted. PG 5 Indicates a protecting group for benzyl or other phosphate groups. PG 6 This indicates a protecting group for amino groups such as diphenylmethyl.

[0726] Step 9-2: Method for preparing compound [9-e]: Starting with compounds [9-b], [9-c] and [9-d], in an inert solvent, bismuth(III) chloride and other Lewis acids are reacted to obtain compound [9-e].

[0727] This step can be performed by referring, for example, the method described in Organic Letters, Vol. 1, p. 1395, 1999.

[0728] Furthermore, this reaction can also be carried out under microwave irradiation.

[0729] Step 9-3: Method for manufacturing compound [9-f]: Using compound [9-e] as the starting material, in an inert solvent at room temperature to 100°C, oxidizing agents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are reacted to form the corresponding imine. Then, in an inert solvent at room temperature to 60°C, acidic aqueous solutions such as hydrochloric acid are reacted to form compound [9-f].

[0730] This step can be performed by referring, for example, the method described in Organic Letters, Vol. 1, p. 1395, 1999.

[0731] Step 9-4: Method for producing compound [9-g]: Using compound [9-f] as the starting material, in an inert solvent, at a temperature ranging from ice-cold to reflux, in the presence of bases such as triethylamine, pyridine, 4-dimethylaminopyridine, and N,N-diisopropylethylamine, and ureating agents such as 4-nitrophenyl chloroformate, CDI, and triphosgene, compound [1-a] is reacted to produce compound [9-g].

[0732] Step 9-5: Method for producing compound [9-h]: Starting with compound [9-g], compound [9-h] can be produced in an inert solvent, at a temperature from ice to room temperature, in a hydrogen atmosphere and under pressure or without pressure, in the presence or absence of acid, by using a deprotection reaction of palladium on carbon or the like.

[0733] The manufacture of compound [9-r] in which X is a group represented by formula [II-1] of the present invention is illustrated in the following scheme 9-3.

[0734] Scheme 9-3 (Method for producing compound [9-q] from compound [8-a]): [Chem.364] In the plan, PG 4 R 2 R 3 R 4 W is defined the same as above.

[0735] Step 9-6: Method for producing compound [9-j]: Compound [9-j] can be produced by performing a "condensation reaction" of compound [8-a] with amine compounds such as ammonium chloride.

[0736] Step 9-7: Method for preparing compound [9-k]: Using compound [9-j] as the starting material, in an inert solvent, at an ice-cold temperature of up to 50°C, in the presence of a base such as pyridine, aryl sulfonyl chloride such as p-toluenesulfonyl chloride or C-type sulfonyl chloride such as methanesulfonyl chloride are reacted. 1-4 Alkyl sulfonyl chlorides are used to produce compounds [9-k].

[0737] Steps 9-8: Method for manufacturing compound [9-m]: Using compound [9-k] as the starting material, compound [9-m] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0738] Step 9-9: Method for manufacturing compound [9-n]: Using compound [9-m] as the starting material, compound [9-n] can be manufactured by the method described in or based on steps 9-4 above.

[0739] Steps 9-10: Method for producing compound [9-p]: Using compound [9-n] as the starting material, hydroxylamine hydrochloride is reacted in an inert solvent at a temperature of ice-cold up to 90°C in the presence or absence of a base such as sodium carbonate and N,N-diisopropylethylamine, thereby producing compound [9-p].

[0740] Steps 9-11: Method for producing compound [9-q]: Starting with compound [9-p], in an inert solvent, at a temperature ranging from ice-cold to room temperature, in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene, CDI and other substances are reacted to produce compound [9-q].

[0741] Examples of the manufacture of compounds [9-v] in which X is a tetrazolium group in the compound [I] of the present invention are illustrated in schemes 9-4 below.

[0742] Scheme 9-4 (Method for producing compound [9-v] from compound [9-k]): [Chem365] In the plan, PG 4 R 2 R 3 R 4 The definitions of , and W are the same as those previously mentioned. PG 7 This indicates a protecting group for tetrazolium groups such as triphenylmethyl and benzyl.

[0743] Steps 9-12: Method for producing compound [9-r]: Starting with compound [9-k], in an inert solvent, at room temperature to 150°C, in the presence of inorganic acid salts of amine compounds such as ammonium chloride and trimethylamine hydrochloride, and in the presence or absence of a copper catalyst, sodium azide or other azides are reacted to produce compound [9-r]. Furthermore, this reaction can also be carried out under microwave irradiation.

[0744] Steps 9-13: Method for manufacturing compound [9-s]: Using compound [9-r] as the starting material, in an inert solvent, at a temperature from ice to room temperature, in the presence of a base such as triethylamine or potassium carbonate, triphenylmethyl chloride, benzyl bromide, etc. are reacted to produce compound [9-s].

[0745] Steps 9-14: Method for manufacturing compound [9-t]: Using compound [9-s] as the starting material, compound [9-t] can be manufactured by the method described in step 8-2 above or a method based thereon.

[0746] Steps 9-15: Method for manufacturing compound [9-u]: Using compound [9-t] as the starting material, compound [9-u] can be manufactured by the method described in or based on steps 9-4 above.

[0747] Steps 9-16: Method for manufacturing compound [9-v]: Starting with compound [9-u], in an inert solvent at a temperature ranging from ice-cold to room temperature, compound [9-v] can be manufactured by (i) reacting with an acid such as hydrochloric acid; or (ii) in a hydrogen atmosphere under pressure or without pressure, in the presence or absence of an acid, by using a deprotection reaction of palladium on carbon or the like.

[0748] The compounds [9-a], [9-h], [9-q] and [9-v] obtained in this way can be separated and purified by means of separation and purification, such as concentration, vacuum concentration, reprecipitation, solvent extraction, crystallization and chromatography.

[0749] In the manufacturing intermediates of compound [I] of the present invention, compounds [9-b], [9-c], [9-d] described in scheme 9-2 and compound [8-a] described in scheme 9-3 can be manufactured by known methods or obtained by purchasing commercially available products.

[0750] The present invention will be further described in detail by way of the following reference examples, embodiments and test examples, but they do not limit the present invention. Furthermore, changes can be made without departing from the scope of the present invention.

[0751] Furthermore, in the following reference examples and embodiments, the yield sometimes exceeds the theoretical amount due to the influence of residual solvents, etc.

[0752] In the following reference examples and embodiments, silica gel column chromatography used a packed column (Reveleris Flash Cartridges Silica, manufactured by Glaser Co., Ltd., or Biotage SNAP Cartridge HP-Sphere, manufactured by Biotage Co., Ltd.). NH silica gel column chromatography used a packed column (Reveleris Flash Cartridges Amino, manufactured by Glaser Co., Ltd., or Biotage SNAP Cartridge KP-NH, manufactured by Biotage Co., Ltd.). Preparative separation thin-layer chromatography used Merck PLC plates, 20×20cm silica gel 60F254, 2mm. Unless otherwise specified, the ratio of elution solvents indicates the volume ratio. The phase separator used was an ISOLUTE Phase Separator, manufactured by Biotage Co., Ltd.

[0753] The abbreviations used in this specification have the following meanings. s: singlet d: doublet t: triplet q: quartet quin: five peaks (quintet) sxt: Six Peaks (sextet) SPT: Seven Peaks (Septet) dd: double doublet dt: double triplet td: Triple doublet tt: triple triplet qd: Quarter doublet m: multiplet br: broad J: Coupling constant Hz: Hertz CHLOROFORM-d: Deuterated chloroform DMSO-d6: Deuterated dimethyl sulfoxide METHANOL-d4: Deuterated methanol ACETONE-d6: Deuterated acetone D2O: Heavy water HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride CDI: 1,1'-carbonyldiimidazole DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride HOBt: N-hydroxybenzotriazole monohydrate DBU: 1,8-diazabicyclo[5.4.0]-7-undecene Rf: retardation factor posi: positive (pattern) nega: negative (pattern) 1 H-NMR (proton nuclear magnetic resonance spectroscopy) uses tetramethylsilane as an internal standard and is measured by Fourier transform NMR as described below. The total δ value is expressed in ppm.

[0754] 200MHz: Gemini2000 (Agilent Technologies) 300MHz: Inova300 (Agilent Technologies) 400MHz:AVANCE III HD400(Bruker) 500MHz: JNM-ECA500(JEOL) 600MHz: JNM-ECA600(JEOL) The analysis used ACD / Spectrus Processor 2015 and ACD / Labs 2015 Release (File Version S30S41, Build 76327, 28 Feb 2015) (trade name), etc. Sometimes, very flat peaks for protons such as hydroxyl, amino, amide, pyrazole, urea, and carboxyl groups were not recorded.

[0755] It should be noted that in the analysis of compounds, there are sometimes protons that overlap with the peaks of water or solvent and cannot be identified.

[0756] MS (mass spectrometry) is performed using the following apparatus.

[0757] PlatformLC(Waters) LCMS-2010EV (Shimadzu) LCMS-IT-TOF (Shimadzu) Agilent 6130 (Agilent) Agilent 6150 (Agilent).

[0758] As ionization methods, ESI (Electrospray Ionization), EI (Electron Ionization), or a dual ionization method combining ESI and APCI (Atmospheric Pressure Chemical Ionization) were used. The data recorded are the found values. Typically, although a molecular ion peak is observed, in the case of compounds containing a tert-butoxycarbonyl (-Boc) group, peaks indicating the removal of the tert-butoxycarbonyl or tert-butyl group are sometimes observed as fragment ions. Furthermore, in the case of compounds containing a tetrahydropyranyl (THP) group, peaks indicating the removal of the tetrahydropyranyl group are sometimes observed as fragment ions. Additionally, in the case of compounds containing a hydroxyl (-OH) group, peaks indicating the removal of H₂O or OH radicals are sometimes observed as fragment peaks. In the case of salts, peaks of the free molecular ion or fragment ion are usually observed.

[0759] The determination conditions for the analytical data are recorded as mode M under the following conditions.

[0760] Device: LCMS-IT-TOF (Shimadzu) Ionization method: ESI / APCI multimode The LC-MS measurements in the examples and reference examples were performed under the following conditions.

[0761] HPLC: Agilent 1290 InfinityMS: Agilent 6130 or 6150 [HPLC conditions] Column: Acquity UPLC CSH C18, 1.7μm, 2.1X50mm (WATERS) Solvents: Solution A: water containing 0.1% formic acid; Solution B: acetonitrile containing 0.1% formic acid. (Method A, Normal Mode) Gradients: 0.00 minutes (A solution / B solution = 80 / 20), 1.20 minutes (A solution / B solution = 1 / 99), 1.40 minutes (A solution / B solution = 1 / 99), 1.41 minutes (A solution / B solution = 80 / 20), 1.50 minutes (A solution / B solution = 80 / 20) (Method B, HP mode) Gradient: 0.00 minutes (A solution / B solution = 95 / 5), 0.80 minutes (A solution / B solution = 60 / 40), 1.08 minutes (A solution / B solution = 1 / 99), 1.38 minutes (A solution / B solution = 1 / 99), 1.41 minutes (A solution / B solution = 95 / 5), 1.50 minutes (A solution / B solution = 80 / 20) (Method C, LP pattern) Gradient: 0.00 minutes (A solution / B solution = 70 / 30), 0.80 minutes (A solution / B solution = 1 / 99), 1.40 minutes (A solution / B solution = 1 / 99), 1.42 minutes (A solution / B solution = 70 / 30), 1.50 minutes (A solution / B solution = 70 / 30) Injection volume: 0.5 μL, flow rate: 0.8 mL / min Detection methods: UV 210nm, 254nm Agilent 385-ELSD with added evaporative light scattering detector (ELSD) MS conditions Ionization method: ESI or ESI / APCI multimode The measurement conditions for analyzing the data are as follows.

[0762] [Table 1-1]

[0763] The purification using preparative HPLC in the examples and reference examples was carried out under the following conditions.

[0764] Instrumentation: Gilson high-throughput purification system; column: Triart C18, 5μm, 30×50mm (YMC), or X-Bridge Prep C18 5um OBD, 30x50 (Waters). Solvents: Solution A; water containing 0.1% formic acid; Solution B; acetonitrile containing 0.1% formic acid; or Solution A; water containing 0.1% trifluoroacetic acid; Solution B; acetonitrile containing 0.1% trifluoroacetic acid. (Method A) Gradient: 0.00 minutes (A solution / B solution = 90 / 10), 2.00 minutes (A solution / B solution = 90 / 10), 11.0 minutes (A solution / B solution = 20 / 80), 12.0 minutes (A solution / B solution = 5 / 95), 13.52 minutes (A solution / B solution = 5 / 95), 15.0 minutes (A solution / B solution = 90 / 10) (Method B) Gradients: 0.00 minutes (A / B = 95 / 5), 3.00 minutes (A / B = 95 / 5), 8.53 minutes (A / B = 80 / 20), 10.0 minutes (A / B = 80 / 20), 11.0 minutes (A / B = 50 / 50), 12.02 minutes (A / B = 5 / 95), 13.5 minutes (A / B = 5 / 95), 13.65 minutes (A / B = 95 / 5), 15.0 minutes (A / B = 95 / 5) (Method C) Gradients: 0.00 minutes (A solution / B solution = 80 / 20), 2.00 minutes (A solution / B solution = 80 / 20), 10.0 minutes (A solution / B solution = 5 / 95), 11.0 minutes (A solution / B solution = 1 / 99), 13.5 minutes (A solution / B solution = 1 / 99), 13.55 minutes (A solution / B solution = 80 / 20), 15.0 minutes (A solution / B solution = 80 / 20) Flow rate: 40 mL / min Detection methods: UV210nm, UV254nm SofTAMODEL 300S ELSD with ELSD attached In the following examples, diastereomer separation was performed using preparative HPLC.

[0765] [HPLC conditions] [Table 2-1] Detection methods: UV 210nm, 254nm The chiral HPLC preparations in the examples were carried out under the following conditions.

[0766] HPLC: Gilson high-throughput purification system or Waters preparative LC system [HPLC conditions] [Table 3-1] [Table 3-2] [Table 3-3] Detection methods: UV 210nm, 254nm The chiral supercritical fluid chromatography (SFC) preparation in the examples was carried out under the following conditions.

[0767] SFC: WATERS Corporation SFC30 [SFC Conditions] [Table 4-1] Detection methods: UV 210nm, 254nm The optical rotation measurement apparatus used was the Autopol V manufactured by Rudolph Research Analytical, which used sodium D line (589 nm) as the light source.

[0768] X-ray crystal structure analysis was performed using the R-AXIS RAPIDII (manufacturer: Rigaku) ​​apparatus.

[0769] The microwave reaction apparatus used either the Biotage Initiator or the Anton-Paar MONOWAVE300.

[0770] Differential thermal analysis / thermal mass determination (TG / DTA) was performed using a Thermo Plus Evo TG8120 (Rigaku).

[0771] Compound names are derived from ACD / Name (ACD / Name 2017.1.3 and ACD / Name 2019.1.2, Advanced Chemistry Development, Inc.) and LexiChem (version 0.95), a component of PipelinePilot 9.1 manufactured by OpenEye.

[0772] For the asymmetric carbons in the compounds of the reference examples and embodiments, the stereostructures shown in this specification represent absolute configurations. It should be noted that racemates show relative configurations.

[0773] For asymmetric carbons, compounds labeled with absolute configurations are optically active.

[0774] Furthermore, in compounds where an asterisk (*) is marked on the asymmetric carbon in the structural formula, the asterisk indicates a large ratio of an absolute configuration with respect to the stereoisomers on the marked asymmetric carbon. It should be noted that the compound preferably has a substantially single absolute configuration. However, the absolute configuration of the asymmetric carbon may also be unclear.

[0775] In this instruction manual, "room temperature" refers to 20–30°C unless otherwise specified. "Cold temperature" refers to 0–5°C unless otherwise specified.

[0776] The present invention will be further described in detail by the following reference examples, examples and test examples, but they do not limit the present invention. In addition, changes can be made without departing from the scope of the present invention.

[0777] Reference Example 1-1-1 Methyl 3-methoxy-5-(methoxymethyl)benzoate [Chemical Formula 366] Potassium carbonate (168 mg) was added to a mixed solution of methanol - tetrahydrofuran (2.9 mL - 2.9 mL) of methyl 3-(bromomethyl)-5-methoxybenzoate (150 mg), and the mixture was stirred at 55 °C for 3 hours and then stirred overnight at room temperature. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated to obtain a mixture (327 mg) containing the title compound as a colorless solid.

[0778] MS ESI posi: 211 [M + H] + .

[0779] Retention time: 0.912 min (Method B) Reference Example 1-1-2 Ethyl 6-ethoxy-1-ethyl-2,3-dihydro-1H-indole-4-carboxylate [Chemical Formula 367] (1) A solution of ethyl 6-ethoxy-1H-indole-4-carboxylate (0.488 g) in N,N-dimethylformamide (4.2 mL) was cooled in ice, and sodium hydride (60% mineral oil dispersion, 92.0 mg) was added. The mixture was stirred at the same temperature for 30 minutes. A solution of iodoethane (0.254 mL) in N,N-dimethylformamide (3 mL) was added dropwise, and the mixture was stirred for 30 minutes while warming to room temperature. The reaction solution was cooled in ice, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and after filtering out the desiccant, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (from n-hexane only to ethyl acetate only) to obtain ethyl 6-ethoxy-1-ethyl-1H-indole-4-carboxylate (0.402 g) as a colorless powder.

[0780] (2) Sodium cyanoborohydride (0.144 g) was slowly added to a 1 mL solution of acetic acid containing 0.2 g of the compound obtained in (1) above, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane only – hexane: ethyl acetate = 80:20) to give the title compound (0.142 g) as a pale yellow oil.

[0781] MS ESI posi:264[M+H] + .

[0782] Retention time: 1.264 min (Method B) Refer to Example 1-2-1 Methyl 3,5-diethoxy-2,4-dimethylbenzoate [Chem.368] (1) Potassium carbonate (3.79 g) and iodoethane (2.66 mL) were added to a solution of methyl 3,5-dihydroxy-4-methylbenzoate (5 g) in N,N-dimethylformamide (55 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (2:1). The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane only ~ hexane: ethyl acetate = 70:30) to obtain methyl 3,5-diethoxy-4-methylbenzoate (2.16 g) and methyl 3-ethoxy-5-hydroxy-4-methylbenzoate (2.02 g) as colorless powders, respectively.

[0783] (2) Under a nitrogen atmosphere, the chloroform (0.8 mL) solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) obtained in (1) was chilled, and titanium(IV) chloride (0.506 mL) was added dropwise. The mixture was stirred for 30 minutes at the same temperature, and dichloromethyl methyl ether (0.187 mL) was added dropwise. Chloroform (0.8 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes while being brought back to room temperature. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was stirred for 1 hour. Water was added, and the mixture was extracted with chloroform. The organic layer was washed successively with 0.1 mol / L hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine. It was dried with anhydrous magnesium sulfate, and after filtering out the desiccant, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane only – hexane: ethyl acetate = 85:15) to give methyl 3,5-diethoxy-2-formyl-4-methylbenzoate (0.527 g) as a yellow oil.

[0784] (3) Add triethylsilane (0.72 mL) to a trifluoroacetic acid (0.1 g) solution of the compound obtained in (2) above, and stir for 1 hour at room temperature. Add water to the reaction solution and extract with chloroform. Wash the organic layer with saturated brine, dry with anhydrous magnesium sulfate, filter out the drying agent, and concentrate the filtrate. Purify the residue by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 only) to give the title compound (0.062 g) as a colorless oil.

[0785] MS ESI posi:253[M+H] + .

[0786] Retention time: 1.057 min (Method A) See Example 1-2-2 Methyl 3,5-diethoxy-2-fluoro-4-methylbenzoate [Chemistry 369] Under a nitrogen atmosphere, a solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) in acetonitrile (1.0 mL) was chilled, and a solution of N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (1.12 g) in acetonitrile (21 mL) was added. The mixture was stirred at room temperature for 23 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90:10 only) to give the title compound (0.32 g) as a yellow oil.

[0787] MS ESI posi:257[M+H] + 279[M+Na] + .

[0788] Retention time: 0.953 min (Method A) See Example 1-2-3 ethyl 2-chloro-3,5-diethoxy-4-methylbenzoate [Transformation 370] (1) N-chlorosuccinimide (1.75 g) was added to a methanol (30 mL) solution of 2 g of 3,5-dihydroxy-4-methylbenzoic acid. The mixture was stirred at 60 °C for 4 hours and then at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to obtain 2-chloro-3,5-dihydroxy-4-methylbenzoic acid (2.55 g) as a pale yellow powder.

[0789] (2) Iodoethane (4.81 mL) was added to a solution of the compound (2.41 g) obtained in (1) above and potassium carbonate (8.22 g) in N,N-dimethylformamide (24 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of n-hexane and ethyl acetate (2:1). The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane only ~ n-hexane:ethyl acetate = 90:10) to give the title compound (2.99 g) as a colorless oil.

[0790] MS ESI posi:287[M+H] + 309[M+Na] + .

[0791] Retention time: 1.023 min (Method A) See Example 1-3-1 3-Ethoxy-5-(methoxymethyl)-4-methylbenzoic acid [Chemistry 371] (1) Under a nitrogen atmosphere, pyridine (0.23 mL) and trifluoromethanesulfonic anhydride (0.288 mL) were added to a chloroform (5.7 mL) solution of methyl 3-ethoxy-5-hydroxy-4-methylbenzoate (300 mg) obtained in Reference Example 1-2-1(1), and the mixture was stirred at room temperature for 3 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 20:80) to obtain methyl 3-ethoxy-4-methyl-5-[(trifluoromethanesulfonyl)oxy]benzoate (450 mg) as a colorless oil.

[0792] (2) This reaction was carried out by the method described in the reference (Organic Letters, Vol. 14, p. 1278, 2012). Under a nitrogen atmosphere, sodium carbonate (0.186 g), potassium trifluoroborate (0.316 g), and palladium(II) methanesulfonate (RuPhosPdG3, Sigma-Aldrich, 97.7 mg) of a 1,4-dioxane-water mixture (2 mL - 0.2 mL) of the compound (400 mg) obtained in (1) above were added to a solution of 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate were stirred at 100 °C for 5 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95:5~20:80) to give methyl 3-ethoxy-5-(hydroxymethyl)-4-methylbenzoate (250 mg) as a colorless oil.

[0793] (3) Add sodium hydride (60% mineral oil dispersion, 67 mg) to a tetrahydrofuran (11 mL) solution of the compound (250 mg) obtained in (2) above, and stir for 1 hour under ice. Add iodomethane (0.1 mL) and stir overnight at room temperature. Add water to the reaction solution, extract with ethyl acetate, wash the organic layer successively with water and saturated brine, and add anhydrous magnesium sulfate. Filter out the drying agent and concentrate. Purify the residue by silica gel column chromatography (hexane only to ethyl acetate only) to give methyl 3-ethoxy-5-(methoxymethyl)-4-methylbenzoate (84 mg) as a brown oil.

[0794] (4) To a tetrahydrofuran (3.5 mL) solution of the compound (84 mg) obtained in (3) above, add 3.5 mL of 1 mol / L sodium hydroxide aqueous solution and 1.8 mL of methanol, and stir at 60 °C for 30 minutes. Concentrate the reaction solution, add 1 mol / L hydrochloric acid to adjust to acidity, and extract with chloroform. Filter the organic layer using a phase separator and concentrate to obtain the title compound (85 mg) as a colorless powder.

[0795] MS ESI posi:225[M+H] + .

[0796] MS ESI nega:223[MH] - .

[0797] Retention time: 1.128 min (Method B) See Example 1-4-1 4-Bromo-3,5-dimethoxybenzaldehyde [Chemistry 372] (1) A solution of 3.0 g of 4-bromo-3,5-dimethoxybenzoic acid in 7.7 mL of tetrahydrofuran was chilled, and a borane-tetrahydrofuran complex (0.9 mol / L tetrahydrofuran solution, 20 mL) was slowly added. The mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 2 hours. The reaction mixture was chilled, and a saturated sodium bicarbonate aqueous solution was added. The mixture was then extracted with ethyl acetate. The organic layer was filtered using a phase separator and concentrated to obtain (4-bromo-3,5-dimethoxyphenyl)methanol (2.8 g) as a colorless powder.

[0798] (2) Add manganese dioxide (8.1 g) to a toluene (62 mL) solution of the compound (2.3 g) obtained in (1) above, and stir at room temperature for 16 hours. Filter the reaction solution through Celite (registered trademark), concentrate the filtrate, and obtain the title compound (2.18 g) as a pale yellow powder.

[0799] MS ESI posi:254[M+H] + .

[0800] Retention time: 0.996 min (Method B) See Example 1-4-2 3,5-Diethoxy-4-methylbenzaldehyde [Chemistry 373] (1) A solution of methyl 3,5-diethoxy-4-methylbenzoate (1.1 g) in tetrahydrofuran (18 mL) obtained in Reference Example 1-2-1(1) was chilled, and lithium aluminum hydride (0.26 g) was added. The mixture was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (3 g) was added, and the mixture was stirred for 2 hours. The reaction solution was filtered through a Celite (registered trademark) filter, and the filtrate was concentrated to give (3,5-diethoxy-4-methylphenyl)methanol (0.98 g) as a pale yellow solid.

[0801] (2) Using the compound (0.98 g) obtained in (1) above, the reaction and post-treatment were carried out in accordance with the method described in Reference Example 1-4-1 (2), and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95:5 to 60:40) to give the title compound (205 mg) as a yellow solid.

[0802] MS ESI posi:209[M+H] + .

[0803] Retention time: 1.196 min (Method B) The following Reference Examples 1-4-3 to 1-4-6 used commercially available compounds or compounds synthesized according to methods described in the literature or based thereon, and were synthesized by methods described in or based thereon in Reference Examples 1-4-1 or 1-4-2. The structures and LCMS data of the compounds are shown in Table 5-1.

[0804] [Table 5-1]

[0805] Refer to Example 1-5-1 1-(4-bromo-3,5-diethoxyphenyl)ethane-1-one [Chemistry 374] (1) Using 4-bromo-3,5-dihydroxybenzoic acid (4 g), the reaction and post-treatment were carried out according to the method described in Reference Example 1-2-3 (2). A mixture of n-hexane and ethyl acetate (4:3, 7 mL) was added to the resulting residue to dissolve it, followed by the addition of n-hexane (12 mL). The precipitated solid was filtered off, and the filtrate was concentrated. Ethyl acetate (3 mL) was added to the resulting residue to dissolve it, followed by the addition of n-hexane (16 mL), and the precipitated solid was filtered off. The resulting solids were combined to give ethyl 4-bromo-3,5-diethoxybenzoate (5.11 g) as a colorless solid.

[0806] (2) Using the compound (5.11 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-3-1 (4) to give 4-bromo-3,5-diethoxybenzoic acid (4.68 g) in the form of a colorless solid.

[0807] (3) To a solution of the compound (4.68 g) obtained in (2) above in N,N-dimethylformamide (26 mL), N,O-dimethylhydroxylamine hydrochloride (1.65 g), HATU (9.19 g), and N,N-diisopropylethylamine (11.2 mL) were added, and the mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution (150 mL) was added to the reaction solution, and the mixture was extracted twice with a mixed solvent of n-hexane and ethyl acetate (2:1, 100 mL). The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The residue was purified by NH silica gel column chromatography (n-hexane only ~ n-hexane:ethyl acetate = 60:40) to give 4-bromo-3,5-diethoxy-N-methoxy-N-methylbenzamide (6.2 g) as a pale yellow oil.

[0808] (4) Under a nitrogen atmosphere, a tetrahydrofuran (54 mL) solution of the compound (5.36 g) obtained in (3) was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 16.1 mL) was added. The mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 4.5 hours. The reaction solution was chilled, and a saturated ammonium chloride aqueous solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. A mixed solvent of n-hexane and ethyl acetate (2:1, 60 mL) was added to the residue, and the precipitated solid was filtered off to obtain the title compound (3.18 g) as a colorless solid.

[0809] MS ESI posi:287,289[M+H] + .

[0810] Retention time: 1.149 min (Method B) See Example 1-5-2 1-(3,5-diethoxy-4-methylphenyl)ethane-1-one [Chemistry 375] (1) Using 3,5-dihydroxy-4-methylbenzoic acid (3 g), the reaction was carried out according to the method described in Reference Example 1-2-3 (2) to obtain ethyl 3,5-diethoxy-4-methylbenzoate (4.45 g) as a light brown solid.

[0811] (2) Using the compound (4.2 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-3-1 (4) to obtain 3,5-diethoxy-4-methylbenzoic acid (3.74 g) in the form of a colorless powder.

[0812] (3) The reaction was carried out according to the method described in the reference (Synlett, Vol. 26, p. 1395, 2015). Under a nitrogen atmosphere, a solution of the compound (3.7 g) obtained in (2) above in diethyl ether (130 mL) was chilled, and methyllithium (1 mol / L diethyl ether solution, 50 mL) was added. The mixture was stirred at the same temperature for 10 minutes and then stirred overnight at room temperature. The reaction solution was chilled, water was slowly added, and the solution was adjusted to acidity with 2 mol / L hydrochloric acid. The mixture was stirred for 30 minutes and extracted three times with diethyl ether. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution (60 mL) and saturated brine (60 mL), filtered and concentrated using a phase separator. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 88:12 ~ ethyl acetate only) to give the title compound (2.0 g) as a colorless powder.

[0813] MS ESI posi:223[M+H] +.

[0814] Retention time: 0.931 min (Method A) The following Reference Examples 1-5-3 to 1-5-30 use compounds obtained in Reference Examples 1-1-1 to 1-1-2, Reference Examples 1-2-1 to 1-2-3, and Reference Example 1-3-1, commercially available compounds, or compounds synthesized according to or based on methods described in the literature, and are synthesized by or based on the methods described in Reference Example 1-5-1 or Reference Example 1-5-2. The structures and LCMS data of the compounds are shown in Tables 6-1 to 6-6.

[0815] [Table 6-1]

[0816] [Table 6-2]

[0817] [Table 6-3]

[0818] [Table 6-4]

[0819] [Table 6-5]

[0820] [Table 6-6]

[0821] See Example 1-6-1 1-(4-bromo-3,5-dimethoxyphenyl)ethane-1-one [Chemistry 376] (1) A tetrahydrofuran (4.1 mL) solution of the compound (506 mg) obtained in Reference Example 1-4-1 was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 688 μL) was added. The mixture was stirred at room temperature for 2.5 hours. The reaction solution was chilled, and saturated ammonium chloride aqueous solution (5 mL) was added. The mixture was extracted with chloroform, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 35:65) to give 1-(4-bromo-3,5-dimethoxyphenyl)ethane-1-ol (443 mg) as a colorless solid.

[0822] (2) Using the compound (443 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-4-1 (2) to obtain the title compound (394 mg) in the form of a colorless powder.

[0823] MS ESI posi:259[M+H] + .

[0824] Retention time: 1.012 min (Method B) Reference Example 1-6-2 below uses the compound obtained in Reference Example 1-4-3, a commercially available compound, or a compound synthesized according to or based on the methods described in the literature, and is synthesized by or based on the methods described in Reference Example 1-6-1. The structures and LCMS data of the compounds are shown in Table 7-1.

[0825] [Table 7-1]

[0826] See Example 1-7-1 1-(3-ethoxy-5-propylphenyl)ethane-1-one [Chemistry 377] This reaction was carried out according to the method described in the reference (The Journal of Organic Chemistry, Vol. 74, p. 3626, 2009). Toluene (2.1 mL) and water (0.206 mL) were added to the compound obtained in Reference Examples 1-5-8 (0.05 g), ethylboric acid (22.8 mg), potassium carbonate (85.3 mg), palladium(II) acetate (9.23 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 38.4 mg). The mixture was stirred at 120 °C for 70 min under microwave irradiation. The insoluble matter in the reaction solution was filtered off, and the filtrate was concentrated. The resulting residue was purified by NH4 silica gel column chromatography (n-hexane: ethyl acetate = 80:20 only) to give the title compound (32.3 mg) as a colorless oil.

[0827] MS ESI posi:207[M+H] + .

[0828] Retention time: 1.265 min (Method B) See Example 1-7-2 3-Acetyl-5-ethoxybenzamide [Chemistry 378] To a dimethyl sulfoxide (1 mL) solution of the compound (53.6 mg) obtained in Reference Examples 1-5-6, 2.83 mL of 1 mol / L sodium hydroxide aqueous solution, 86.8 μL of hydrogen peroxide (30% aqueous solution), and 1 mL of ethanol were added, and the mixture was stirred at room temperature for 4 hours. A saturated sodium thiosulfate aqueous-water mixture (1:1) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 70:30 to ethyl acetate only) to give the title compound (66.1 mg) as a colorless solid.

[0829] MS ESI posi:208[M+H] + .

[0830] Retention time: 0.741 min (Method B) See Example 1-7-3 3-Acetyl-5-ethoxy-N-methylbenzamide [Chemistry 379] A 23 mL solution of tetrahydrofuran containing 1.5 g of the compound obtained in Reference Examples 1-5-9 was chilled, and 25 mL of methylamine (2 mol / L tetrahydrofuran solution), 2.8 g of EDC, and 2.2 g of HOBt were added. The mixture was stirred at room temperature for 17 hours. The reaction solution was chilled, and saturated sodium bicarbonate solution and water were added. The mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The residue was purified by preparative HPLC to give the title compound (35 mg) as a pale yellow oil.

[0831] MS ESI / APCI Multi posi:222[M+H] + .

[0832] Retention time: 0.965 min (Method F) See Example 1-7-4 1,1'-(2-ethoxy-6-fluoro-1,4-phenylene)bis(ethane-1-one) [Chemistry 380] (1) This reaction was carried out according to the method described in reference (WO2014 / 191535). Potassium carbonate (3.38 g) and water (1.2 mL) were added to a solution of 3 g of 4-bromo-2,6-difluorobenzaldehyde in 14 mL of N,N-dimethylformamide. The mixture was stirred at 90 °C for 11 hours and then overnight at room temperature. Potassium carbonate (1.78 g) and iodoethane (3.91 mL) were added to the reaction mixture, and the mixture was stirred at 65 °C for 7 hours. The reaction mixture was filtered through a Celite (registered trademark) filter, and water was added to the filtrate. The filtrate was extracted twice with ethyl acetate. The organic layer was washed three times with 0.5 mol / L hydrochloric acid and once with saturated brine. The mixture was then filtered and concentrated using a phase separator. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20) to give 0.752 g of 4-bromo-2-ethoxy-6-fluorobenzaldehyde as a colorless solid.

[0833] (2) Using the compound (0.2 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1) to give 1-(4-bromo-2-ethoxy-6-fluorophenyl)ethane-1-ol (218 mg) as a pale pink oily substance.

[0834] (3) Add manganese dioxide (0.8 g) to a hexane (10 mL) solution of the compound (218 mg) obtained in (2) above, and stir overnight at room temperature. Filter the reaction solution using a Celite (registered trademark) filter and concentrate the filtrate. Purify the residue by silica gel column chromatography (hexane only – hexane: ethyl acetate = 70:30) to obtain 1-(4-bromo-2-ethoxy-6-fluorophenyl)ethane-1-one (81.3 mg) as a colorless oil.

[0835] (4) To a mixed solution (1.56 mL - 0.156 mL) of the compound (81.3 mg) obtained in (3) above, N,N-dimethylformamide-water, butyl vinyl ether (200 μL), palladium(II) acetate (2.10 mg), 1,3-bis(diphenylphosphine)propane (7.70 mg), and potassium carbonate (0.129 g) were added, and the mixture was stirred at 120 °C for 1 hour under microwave irradiation. Butyl vinyl ether (200 μL), palladium(II) acetate (6.99 mg), and 1,3-bis(diphenylphosphine)propane (25.7 mg) were added, and the mixture was stirred at 120 °C for 1 hour under microwave irradiation. 1 mol / L hydrochloric acid (3 mL) and ethyl acetate were added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was added to a 10% potassium carbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only – n-hexane: ethyl acetate = 70:30) to give the title compound (18.3 mg) as a pale yellow oil.

[0836] MS ESI posi:225[M+H] + .

[0837] Retention time: 0.879 min (Method B) See Example 1-7-5 1-[3-ethoxy-5-fluoro-4-(1-hydroxyethyl)phenyl]ethane-1-one [Chemistry 381] Using the compound (95.3 mg) obtained in Reference Example 1-7-4(2), the reaction was carried out according to the method described in Reference Example 1-7-4(4) to give the title compound (22.4 mg) in the form of a colorless solid.

[0838] MS ESI posi:209[M-OH] + .

[0839] Retention time: 0.773 min (Method B) See Example 1-7-6 4-Ethoxy-1-ethyl-1H-indazole-6-carboxaldehyde [Chemistry 382] (1) Add 3.9 g of ethylhydrazine oxalate to a solution of N-methylpyrrolidone (8.7 mL) of the compound (5.8 g) obtained in Reference Example 1-7-4(1) and stir for 24 hours at room temperature. Add 78 mL of N-methylpyrrolidone to the reaction solution and stir for 2.5 hours at 200 °C. Add n-hexane, ethyl acetate, water, and saturated brine to the reaction solution and separate into two layers. Extract the aqueous layer with a mixed solvent of n-hexane and ethyl acetate. Combine the organic layers, wash successively with water and saturated brine, dry with anhydrous magnesium sulfate, filter out the drying agent, and concentrate the filtrate. Purify the residue by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 60:40). Add n-hexane to the residue, filter out the insoluble matter, and concentrate. The residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate = 98:2 to 60:40) to give 6-bromo-4-ethoxy-1-ethylindazole (2.48 g) as a pale green oil.

[0840] (2) Under a nitrogen atmosphere, the compound (2.48 g) obtained in (1) above, copper cyanide (I) (1.57 g) in N,N-dimethylacetamide (31 mL) solution was stirred at 150 °C for 30 hours. After cooling to room temperature, 10% ammonia, saturated brine, and water were added to the reaction solution, and the mixture was extracted with ethyl acetate and concentrated. The residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate = 95:5 ~ ethyl acetate only). A mixed solvent of n-hexane and ethyl acetate was added to the residue. The organic layer was washed successively with water and saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated the filtrate to obtain 4-ethoxy-1-ethylindazole-6-carboxynitrile (800 mg) as a pale yellow powder.

[0841] (3) Under a nitrogen atmosphere, a toluene (36 mL) solution of the compound (1.54 g) obtained in (2) above was cooled to -40 °C, and diisobutylaluminum hydride (1.0 mol / L toluene solution, 8.6 mL) was added. The mixture was stirred at the same temperature for 1 hour. Diisobutylaluminum hydride (1.0 mol / L toluene solution, 3.0 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Isopropanol (6 mL) was added dropwise to the reaction solution, silica gel was added, and the mixture was stirred for 5 minutes. The reaction solution was brought to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated to obtain the title compound (1.37 g) as a pale yellow oily substance.

[0842] MS ESI / APCI Multi posi:219[M+H] + .

[0843] Retention time: 0.980 min (Method E) See Example 1-7-7 1-[3,5-bis(cyclopropyloxy)-4-methylphenyl]ethane-1-one [Chemistry 383] (1) N-methylpyrrolidone (15 mL) was added to methyl 3,5-dihydroxy-4-methylbenzoate (700 mg), cesium carbonate (3.76 g), potassium iodide (32 mg), and cyclopropyl bromide (1.86 g). The mixture was stirred at 200 °C for 2 hours under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted and concentrated with a mixed solvent of n-hexane and ethyl acetate. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 98:2 to 80:20) to obtain a mixture (540 mg) containing methyl 3,5-bis(cyclopropoxy)-4-methylbenzoate as a colorless solid.

[0844] (2) Add 21 mL of 1 mol / L sodium hydroxide aqueous solution and 10 mL of methanol to a tetrahydrofuran solution (540 mg) of the mixture obtained in (1) above, and stir for 5 days at room temperature. Concentrate the reaction solution and wash the aqueous layer with n-hexane. Add 3 mol / L hydrochloric acid dropwise to the aqueous layer to adjust the pH to 5-6, and filter out the insoluble matter. Purify the obtained residue by preparative HPLC to obtain 3,5-bis(cyclopropoxy)-4-methylbenzoic acid (75 mg) as a colorless powder.

[0845] (3) The tetrahydrofuran (1.5 mL) solution of the compound (72 mg) obtained in (2) above was chilled, and methyllithium (1 mol / L diethyl ether solution, 0.87 mL) was added dropwise. The mixture was stirred at room temperature for 5 hours. The reaction solution was chilled, isopropanol was added dropwise, and 1 mol / L hydrochloric acid was added to adjust the pH to acidity. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane ~ n-hexane: ethyl acetate ~ 70:30) to give the title compound (92 mg) as a colorless oil.

[0846] MS ESI posi:247[M+H] + .

[0847] Retention time: 0.942 min (Method A) See Example 1-7-8 5-Acetyl-3-ethoxy-1-ethylpyridine-2(1H)-one [Chem. 384] (1) Under a nitrogen atmosphere, a solution of 2 g of 5-bromopyridine-2,3-diol in N,N-dimethylformamide (35 mL) was chilled, and sodium hydride (60% mineral oil dispersion, 1.0 g) was added. The mixture was stirred at the same temperature for 45 minutes. Iodine ethane (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 92:8~34:66) to give 2.31 g of 5-bromo-3-ethoxy-1-ethylpyridine-2-one as a pale yellow oil.

[0848] (2) Using the compound obtained in (1) above (0.512 g), the reaction was carried out according to the method described in Example 1-7-6 (2). N-methylpyrrolidone was used instead of N,N-dimethylacetamide, and the reaction was carried out at 180 °C. 5-ethoxy-1-ethyl-6-oxopyridine-3-carboxynitrile (0.3 g) was obtained as a colorless oil.

[0849] (3) This reaction was carried out according to the method described in the reference (Journal of Medicinal Chemistry, Vol. 59, p. 1556, 2016). Under a nitrogen atmosphere, a solution of the compound (0.439 g) obtained in (2) above in diethyl ether (23 mL) was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 1.5 mL) was added dropwise. The mixture was stirred at the same temperature for 3 hours, and then slowly restored to room temperature while stirring for 12 hours. Toluene (10 mL) was added to the reaction solution, and the mixture was stirred at 65 °C for 2 hours. The reaction solution was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 0.53 mL) was added. The mixture was stirred at room temperature for 40 minutes and then at 60 °C for 50 minutes. The reaction solution was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 0.53 mL) was added. The mixture was stirred at room temperature for 10 minutes and then at 60 °C for 80 minutes, and then restored to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Add 2 mol / L hydrochloric acid and 1 mol / L sodium hydroxide aqueous solution to the aqueous layer to adjust the pH to 6–7, and extract with ethyl acetate. Combine the organic layers, wash with saturated brine, dry with anhydrous magnesium sulfate, filter out the drying agent, and concentrate the filtrate. Purify the obtained residue by silica gel column chromatography (n-hexane:ethyl acetate = 85:15 to ethyl acetate only) to give the title compound (0.069 g) as a colorless powder.

[0850] MS ESI / APCI Multi posi:210[M+H] + .

[0851] Retention time: 1.156 min (Method F) See Example 1-7-9 1-(4-ethoxy-1-ethyl-1H-benzimidazol-6-yl)ethane-1-one [Chem.385] (1) Add potassium hydroxide (0.38 g) to an ethanol (20 mL) solution of 1.5 g of 5-bromo-1,3-difluoro-2-nitrobenzene and stir at room temperature for 2.5 days, then stir at 90 °C for 45 minutes. Concentrate the reaction solution, add ethyl acetate, wash successively with water and saturated brine, dry with anhydrous magnesium sulfate, filter out the drying agent, concentrate the filtrate, and obtain 1.63 g of 5-bromo-1-ethoxy-3-fluoro-2-nitrobenzene as an orange oil.

[0852] (2) The tetrahydrofuran (12 mL) solution of the compound (1.63 g) obtained in (1) above was chilled, and 2.1 mL of 12 mol / L ethylamine aqueous solution was added. The mixture was stirred at room temperature for 23 hours. The reaction solution was concentrated, diethyl ether was added, and the mixture was washed successively with water and saturated brine. The solution was dried with anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to obtain 5-bromo-3-ethoxy-N-ethyl-2-nitroaniline (1.79 g) as an orange powder.

[0853] (3) Using the compound (1.62 g) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-7-8 (2) to obtain 3-ethoxy-5-(ethylamino)-4-nitrobenzene (1.0 g) as a red powder.

[0854] (4) The mixture of the compound (0.5 g) obtained in (3) above, iron powder (0.593 g), saturated ammonium chloride aqueous solution (5 mL), and ethanol (16 mL) was stirred at room temperature for 11 hours and then stirred at 65°C for 80 minutes. A 1 mol / L sodium hydroxide aqueous solution was added to the reaction solution to adjust the pH to 9-10. The mixture was filtered through Celite (registered trademark) and the filtrate was concentrated. Water and ethyl acetate were added to the residue, and the mixture was separated into two layers. A 1 mol / L sodium hydroxide aqueous solution was added to the aqueous layer to adjust the pH to 9-10, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried with anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was then concentrated. The resulting residue was purified by silica gel column chromatography (hexane only – hexane: ethyl acetate = 50:50) to obtain 4-amino-3-ethoxy-5-(ethoxyamino)benzonitrile (222 mg) as a beige powder.

[0855] (5) To the compound (0.1 g) obtained in (4) above and the triethyl orthoformate (2.4 mL) solution, p-toluenesulfonic acid monohydrate (9 mg) was added, and the mixture was stirred at room temperature for 17 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate and concentrated. The residue was purified by preparative HPLC to obtain 7-ethoxy-3-ethylbenzimidazole-5-carboxynitrile (82 mg) as a colorless resinous substance.

[0856] (6) The compound (82 mg) obtained in (5) above was chilled in a diethyl ether solution (3.8 mL), and methyl magnesium bromide (3 mol / L diethyl ether solution, 0.254 mL) was added dropwise. The mixture was stirred at the same temperature for 25 minutes, and then at room temperature for 20 hours. Tetrahydrofuran (3.8 mL) was added to the reaction solution and chilled. Methyl magnesium bromide (3 mol / L diethyl ether solution, 0.254 mL) was added, and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for 90 minutes. The reaction solution was chilled, and methyl magnesium bromide (3 mol / L diethyl ether solution, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. This operation was repeated twice. Water was added to the reaction solution and the mixture was concentrated. The resulting residue was purified by preparative HPLC to give the title compound (35 mg) as a colorless solid.

[0857] MS ESI posi:233[M+H] + .

[0858] Retention time: 0.752 min (Method C) Refer to Example 1-8-1 4-Acetyl-2,6-diethoxybenzonitrile [Chemistry 386] Copper cyanide (I) (217 mg) was added to a solution of the compound (232 mg) obtained in Reference Example 1-5-1 in N,N-dimethylacetamide (3.2 mL), and the mixture was stirred at 150 °C for 1 hour under microwave irradiation. Ethyl acetate was added to the reaction mixture, followed by extraction with ethyl acetate in a 10% ammonium aqueous solution. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50:50 only) to give the title compound (31.7 mg) as a colorless solid.

[0859] MS ESI posi:234[M+H] + .

[0860] Retention time: 1.004 min (Method B) See Example 1-8-2 1-(4-Cyclopropyl-3,5-Diethoxyphenyl)ethane-1-one [Chemistry 387] Using the compound (50 mg) obtained in Reference Example 1-5-1 and cyclopropylboronic acid (22.4 mg), the reaction was carried out according to the method described in Reference Example 1-7-1 to give the title compound (34 mg) in the form of a colorless solid.

[0861] MS ESI posi:249[M+H] + .

[0862] Retention time: 1.199 min (Method B) The following Reference Examples 1-8-3 to 1-8-4 use the compounds obtained in Reference Example 1-5-1, commercially available compounds, or compounds synthesized according to or based on the methods described in the literature, and are synthesized by or based on the methods described in Reference Example 1-8-2. The structures and LCMS data of the compounds are shown in Table 8-1.

[0863] [Table 8-1]

[0864] See Example 1-8-5 1,1'-(2,6-diethoxy-1,4-phenylene)bis(ethane-1-one) [Chem.388] This reaction was carried out according to the method described in the reference (The Journal of Organic Chemistry, Vol. 66, p. 4340, 2001). Under a nitrogen atmosphere, butyl vinyl ether (1.12 mL), palladium(II) acetate (11.7 mg), 1,3-bis(diphenylphosphine)propane (43.1 mg), potassium carbonate (722 mg), and water (0.87 mL) were added to a solution of the compound (0.5 g) obtained in Reference Example 1-5-1 in N,N-dimethylformamide (8.7 mL). The mixture was stirred at 120 °C for 1 hour under microwave irradiation. 1 mol / L hydrochloric acid (10 mL) was added to the reaction solution, and the mixture was gently stirred at room temperature for 3 hours. A 10% potassium carbonate aqueous solution (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the filtrate was concentrated after filtering out the drying agent. The resulting residue was purified by silica gel column chromatography (n-hexane only – n-hexane: ethyl acetate = 60:40) to give the title compound (407 mg) as a colorless solid.

[0865] MS ESI posi:251[M+H] + .

[0866] Retention time: 0.994 min (Method B) See Example 1-8-6 1-[3,5-diethoxy-4-(propane-2-yl)phenyl]ethane-1-one [Chemistry 389] Palladium on carbon (19 mg) was added to a methanol (3 mL) solution of the compound (37 mg) obtained in Reference Example 1-8-3, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble matter was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75:25 only) to give the title compound (29 mg) as a colorless solid.

[0867] MS ESI posi:251[M+H] + .

[0868] Retention time: 1.338 min (Method B) The following Reference Example 1-8-7 uses the compound obtained in Reference Example 1-14-6 and cyclopropylboronic acid, synthesized by the method described in or based on Reference Example 1-8-2. The structures and LCMS data of the compounds are shown in Table 8-2.

[0869] [Table 8-2]

[0870] See Example 1-9-1 1-[3,5-diethoxy-4-(1-hydroxycyclopropyl)phenyl]ethane-1-one [Chemistry 390] (1) Ethylene glycol (8.42 mL) and p-toluenesulfonic acid monohydrate (40.0 mg) were added to a toluene (21 mL) solution of the compound (0.604 g) obtained in Reference Example 1-5-1, and the mixture was heated under reflux and stirred for 3 hours. The reaction solution was cooled, and a saturated aqueous solution of sodium bicarbonate was added. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 90:10) to give 2-(4-bromo-3,5-diethoxyphenyl)-2-methyl-1,3-dioxolane (0.633 g) as a colorless solid.

[0871] (2) This reaction was carried out according to the method described in reference (WO2015 / 159233). Under a nitrogen atmosphere, a mixed solution of diethyl ether-tetrahydrofuran (1:1, 1.8 mL) of the compound obtained in (1) above (900 mg) and tetrahydrofuran (3.6 mL) was added to a suspension of magnesium (66 mg) and iodine (14 mg) in diethyl ether (3.6 mL), and the mixture was slowly heated and stirred under reflux for 5 hours. The reaction mixture was then chilled, and a solution of 1,3-dichloroacetone (345 mg) in tetrahydrofuran (3.6 mL) was added, and the mixture was stirred at room temperature for 80 minutes. The reaction mixture was then chilled, and a solution of ferric chloride (III) (9 mg) in tetrahydrofuran (1.8 mL) and ethyl magnesium bromide (3 mol / L diethyl ether solution, 4.5 mL) were added over 5 minutes, and the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled, and 18 mL of saturated ammonium chloride aqueous solution was added. The solution was adjusted to acidity with 1 mol / L hydrochloric acid, and ethyl acetate was added to separate the layers. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was then concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 94:6–60:40) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]cyclopropane-1-ol (220 mg) as a pale yellow solid.

[0872] (3) The tetrahydrofuran (2.5 mL) solution of the compound (0.11 g) obtained in (2) above was chilled, and 1 mol / L hydrochloric acid (2.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solution was filtered and concentrated using a phase separator to give the title compound (0.088 g) as a pale yellow oil.

[0873] MS ESI posi:247[M-OH] + .

[0874] Retention time: 0.742 min (Method A) See Example 1-9-2 1-[3,5-diethoxy-4-(methanesulfinyl)phenyl]ethane-1-one [Chemistry 391] (1) This reaction was carried out according to the method described in the reference (Journal of Medicinal Chemistry, Vol. 59, p. 6772, 2016). Under a nitrogen atmosphere, a mixed solution (2 mL - 1 mL) of the compound (0.1 g) obtained in Reference Example 1-9-1(1) in diethyl ether-tetrahydrofuran was cooled to -78°C, and n-butyllithium (1.60 mol / L n-hexane solution, 0.38 mL) was added. The reaction solution was stirred under ice for 30 minutes, cooled to -78°C, and dimethyl disulfide (68.0 μL) was added. The mixture was stirred at the same temperature for 1 hour. The reaction solution was cooled under ice, and a saturated aqueous solution of ammonium chloride was added for diethyl ether extraction. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 only) to give 2-[3,5-diethoxy-4-(methylthioalkyl)phenyl]-2-methyl-1,3-dioxolane (75.8 mg) as a colorless solid.

[0875] (2) Under a nitrogen atmosphere, a methanol (1.4 mL) solution of the compound (40.8 mg) obtained in (1) above was chilled, and a water (1.4 mL) solution of sodium periodate (29.2 mg) was added. The mixture was stirred for 1 hour at the same temperature, and then stirred for 7 hours at room temperature. Saturated brine was added to the reaction solution, and the mixture was extracted with chloroform, filtered and concentrated using a phase separator. The residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate = 70:30 ~ ethyl acetate only) to give 2-[3,5-diethoxy-4-(methanesulfinyl)phenyl]-2-methyl-1,3-dioxolane (33.8 mg) as a colorless solid.

[0876] (3) Using the compound (33.8 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (34.0 mg) in the form of a colorless solid.

[0877] MS ESI posi:271[M+H] + .

[0878] Retention time: 0.636 min (Method B) See Example 1-9-3 1-[3,5-diethoxy-4-(methanesulfonyl)phenyl]ethane-1-one [Chemistry 392] (1) A chloroform (1.2 mL) solution of the compound (35 mg) obtained in Reference Example 1-9-2(1) was chilled, and m-chloroperbenzoic acid (64.8 mg) was added. The mixture was stirred for 10 minutes at the same temperature and then for 20 minutes at room temperature. The reaction mixture was chilled, and a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, filtered using a phase separator, and concentrated. The residue was purified by silica gel column chromatography (hexane only to ethyl acetate only) to give 2-[3,5-diethoxy-4-(methanesulfonyl)phenyl]-2-methyl-1,3-dioxolane (37.6 mg) as a colorless solid.

[0879] (2) Using the compound (37.6 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (35.6 mg) in the form of a colorless solid.

[0880] MS ESI posi:287[M+H] + .

[0881] Retention time: 0.696 min (Method B) See Example 1-10-1 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]ethane-1-ol [Chemistry 393] (1) Under a nitrogen atmosphere, a mixed solution (20 mL - 10 mL) of the compound (1 g) obtained in Reference Example 1-9-1(1) in diethyl ether-tetrahydrofuran was cooled to -78 °C, and 2.5 mL of n-butyllithium (1.60 mol / L n-hexane solution) was added. The mixture was stirred at ice temperature for 30 minutes. The mixture was cooled to -78 °C, and 0.35 mL of N,N-dimethylformamide was added. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was brought back to ice temperature, and 30 mL of saturated ammonium chloride aqueous solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The residue was purified by silica gel column chromatography (n-hexane only - n-hexane:ethyl acetate = 75:25) to give 0.602 g of 2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)benzaldehyde as a colorless solid.

[0882] (2) Using the compound (0.1 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1) to obtain 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]ethane-1-ol (83.3 mg) in the form of a colorless solid.

[0883] (3) Using the compound (83.3 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (68.0 mg) in the form of a colorless solid.

[0884] MS ESI posi:235 [M-OH] + .

[0885] Retention time: 0.965 min (Method B) See Example 1-10-2 1-[4-(difluoromethyl)-3,5-diethoxyphenyl]ethane-1-one [Chemistry 394] (1) To a chloroform (1.7 mL) solution of the compound (0.07 g) obtained in Reference Example 1-10-1(1), bis(2-methoxyethyl)aminosulfonyl fluoride (138 μ L) was added, and the mixture was stirred at room temperature for 1 hour. Another bis(2-methoxyethyl)aminosulfonyl fluoride (138 μ L) was added, and the mixture was stirred at 60 °C for 10 hours and then at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:hexane:ethyl acetate = 50:50 only) to give 2-[4-(difluoromethyl)-3,5-diethoxyphenyl]-2-methyl-1,3-dioxolane (31.3 mg) as a pale yellow solid.

[0886] (2) Using the compound (31.3 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (60.6 mg) in the form of a colorless solid.

[0887] MS ESI posi:259[M+H] + .

[0888] Retention time: 1.115 min (Method B) See Example 1-10-3 (4-Acetyl-2,6-diethoxyphenyl)methyl acetate [Chemistry 395] (1) A methanol (2 mL) solution of the compound (50.0 mg) obtained in Reference Example 1-10-1(1) was chilled, and sodium borohydride (10.1 mg) was added. The mixture was stirred at the same temperature for 40 minutes. After chilling, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The residue was purified by silica gel column chromatography (hexane:hexane:ethyl acetate = 60:40 only) to give [2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]methanol (43.4 mg) as a colorless solid.

[0889] (2) Add triethylamine (64.3 μL) and acetyl chloride (66.0 μL) to a chloroform (1.5 mL) solution of the compound (43.4 mg) obtained in (1) above, and stir at room temperature for 4 hours. Cool the reaction solution, add a saturated sodium bicarbonate aqueous solution, extract with chloroform, filter and concentrate using a phase separator to obtain [2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]methyl acetate (59.7 mg) as a pale yellow oil.

[0890] (3) Using the compound (59.7 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (30.7 mg) in the form of a colorless solid.

[0891] MS ESI posi:303[M+Na] + .

[0892] Retention time: 0.975 min (Method B) See Example 1-10-4 1-[3,5-diethoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]ethane-1-one [Chemistry 396] (1) This reaction was carried out according to the method described in the reference (Journal of the American Chemical Society, Vol. 111, p. 393, 1989). Under a nitrogen atmosphere, a solution of 70 mg of the compound obtained in Reference Example 1-10-1(1) in tetrahydrofuran (2.5 mL) was chilled, and (trifluoromethyl)trimethylsilane (55.4 μL) and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 25.0 μL) were added. The mixture was stirred at room temperature for 1.5 hours, and then 1 mol / L hydrochloric acid (1 mL) was added. The mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50:50 only) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]-2,2,2-trifluoroethane-1-ol (42 mg) as a colorless oil.

[0893] (2) Using the compound (90 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (61 mg) in the form of a colorless solid.

[0894] MS ESI posi:307[M+H] + .

[0895] Retention time: 1.053 min (Method B) See Example 1-10-5 1-(4-acetyl-2,6-diethoxyphenyl)-2,2,2-trifluoroethane-1-one [Chemistry 397] (1) To a solution of the compound (42 mg) obtained in Reference Example 1-10-4(1) in n-hexane (3 mL), manganese dioxide (0.8 g) was added, and the mixture was stirred at room temperature for 3.5 hours and then at 60°C for 2 hours. The reaction mixture was filtered through a Celite (registered trademark) filter, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane only: n-hexane: ethyl acetate = 50:50) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]-2,2,2-trifluoroethane-1-one (31 mg) as a colorless solid.

[0896] (2) Using the compound (31 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (34 mg) in the form of a colorless solid.

[0897] MS ESI posi:305[M+H] + .

[0898] Retention time: 1.145 min (Method B) See Example 1-10-6 Methyl 4-acetyl-2,6-diethoxybenzoate [Chem.398] (1) To a solution of 2-methyl-2-butene (0.81 mL) of the compound (266 mg) obtained in Reference Example 1-10-1(1), sodium dihydrogen phosphate (456 mg), tert-butyl alcohol (3.8 mL), water (1.3 mL), and tetrahydrofuran (3.8 mL) were added. The mixture was cooled, and sodium chlorite (344 mg) was slowly added. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled, and water (50 mL) and citric acid (1 g) were added to adjust the pH to 1-2. The solution was extracted twice with ethyl acetate. The organic layer was extracted twice with a saturated sodium bicarbonate aqueous solution (30 mL). Citric acid (4 g) was added to the aqueous layer to adjust the pH to 5. The solution was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, filtered and concentrated using a phase separator to obtain 2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)benzoic acid (205 mg) as a colorless solid.

[0899] (2) Under a nitrogen atmosphere, a chloroform-methanol mixture (2 mL - 1 mL) of the compound (32 mg) obtained in (1) was chilled, and then stirred at room temperature for 2 hours with 162 μ mL of 2 mol / L diethyl ether solution. The reaction mixture was chilled, water was added, and the mixture was extracted with chloroform. The solution was filtered and concentrated using a phase separator. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 only) to give methyl 2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)benzoate (28.6 mg) as a colorless solid.

[0900] (3) To a 920 μL-920 μL acetone-water mixture of the compound (28.6 mg) obtained in (2) above, p-toluenesulfonic acid monohydrate (17.5 mg) was added, and the mixture was stirred for 2.5 hours. Further p-toluenesulfonic acid monohydrate (17.5 mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50:50 only) to give the title compound (24.2 mg) as a colorless solid.

[0901] MS ESI posi:267[M+H] + 289[M+Na] + .

[0902] Retention time: 0.995 min (Method B) See Example 1-11-1 1-[3,5-diethoxy-4-(2-hydroxypropane-2-yl)phenyl]ethane-1-one [Chemistry 399] (1) Using the compound (111 mg) obtained in Reference Example 1-8-5, the reaction was carried out in accordance with the method described in Reference Example 1-9-1(1) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]ethane-1-one (110 mg) as a colorless solid.

[0903] (2) Using the compound (45.5 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1) to obtain 2-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]propane-2-ol (41.9 mg) as a colorless oil.

[0904] (3) Using the compound (41.9 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3) to obtain the title compound (19.7 mg) in the form of a colorless solid.

[0905] MS ESI posi:249 [M-OH] + .

[0906] Retention time: 1.037 min (Method B) See Example 1-11-2 1-[3,5-diethoxy-4-(1-hydroxypropyl)phenyl]ethane-1-one [Chemical 400] (1) Using the compound (80 mg) obtained in Reference Example 1-10-1(1) and ethyl magnesium bromide (3 mol / L diethyl ether solution, 143 μL), the reaction was carried out according to the method described in Reference Example 1-6-1(1) to obtain 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolane-2-yl)phenyl]propane-1-ol (85.0 mg) as a colorless oily substance.

[0907] (2) Using the compound (85.0 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-10-6 (3) to obtain the title compound (71.4 mg) in the form of a colorless oily substance.

[0908] MS ESI posi:249 [M-OH] + .

[0909] Retention time: 0.994 min (Method B) See Example 1-11-3 1-(4-acetyl-2,6-diethoxyphenyl)propane-1-one [Chemical Engineering 401] Using the compound (34.6 mg) obtained in Reference Example 1-11-2, the reaction was carried out according to the method described in Reference Example 1-10-5 (1) to give the title compound (19.2 mg) in the form of a colorless solid.

[0910] MS ESI posi:265[M+H] + .

[0911] Retention time: 1.018 min (Method B) See Example 1-12-1 4-Acetyl-2,6-diethoxybenzamide [Chemical 402] (1) To a tetrahydrofuran-methanol mixture (1.1 mL - 0.22 mL) of the compound (50.0 mg) obtained in Reference Example 1-10-6(1), ammonium chloride (13.5 mg), triethylamine (70.6 μL), and DMT-MM (93.4 mg) were added. The mixture was stirred at room temperature for 6 hours, at 40°C for 3 hours, and at room temperature overnight. Ammonium chloride (13.5 mg), triethylamine (70.6 μL), and DMT-MM (93.4 mg) were added again, and the mixture was stirred at 40°C for 4 hours. 0.5 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform, filtered using a phase separator, and concentrated...

Claims

1. A compound represented by formula [I-2] or a pharmaceutically acceptable salt or hydrate thereof, In the above formula [I-2], W is any one of the structures represented by the following formulas [III-4] to [III-17] R 2 It is a group represented by the following formula [IV-1] or [IV-2] in, Ring B 1 is phenyl, R B11 and R B12 Similarly for hydrogen atoms, L 1 The structure represented by the following formula [V-3], [V-8], [V-12], [V-14], or [V-15] -(CH2) n4 -[V-3], -CH2CH2CH2CF2-[V-8], in, n4 is an integer from 3 to 4, Ring B 2 is dihydroindanyl, R B21 and R B22 Similarly for hydrogen atoms, L 2 The structure shown in the following formula [V-20] (CH2) nS -[V-20], in, n5 is 2; R 4 represents a group represented by the following formula [VI] Ring C is phenyl, The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-2 substituted with one of alkoxy and C1 alkylcarbonyl, further, can be selected from cyano, halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one hydroxyl group), C2 alkenyl, C3 cycloalkyl, C 1-2 The alkoxy group, the mono-C2 alkylamino group and the C1 alkylcarbonyl group may be substituted by 1 to 4 groups which may be the same or different.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein: R 4 Any one of the groups represented by the following formulas [VI-1] to [VI-21] 3. A compound represented by the following formula [Ia] or a pharmaceutically acceptable salt or hydrate thereof, 4. A compound represented by the following formula [Ib] or a pharmaceutically acceptable salt or hydrate thereof, 5. A compound represented by the following formula [Ic] or a pharmaceutically acceptable salt or hydrate thereof, 6. A compound represented by the following formula [Id] or a pharmaceutically acceptable salt or hydrate thereof, 7. A compound represented by the following formula [Ie] or a pharmaceutically acceptable salt or hydrate thereof, 8. A medicine comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

9. An LPA1 receptor antagonist comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

10. A preventive or therapeutic agent for systemic scleroderma, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

11. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of an LPA1 receptor antagonist.

12. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a hydrate thereof for preparing a preventive or therapeutic agent for systemic scleroderma.

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