Urea compounds that antagonize LPA1 receptors

Abstract

The present invention provides a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof which has an LPA1 receptor antagonistic effect.

Description

Technical Field

[0001] The present invention relates to a drug containing an LPA1 receptor antagonist as an active ingredient. More specifically, it relates to a drug containing a urea compound, which is an LPA1 receptor antagonist, as an active ingredient. Background Art

[0002] Lysophosphatidic acid (sometimes referred to as "LPA" in this specification) is a physiologically active phospholipid with a fatty acid bonded to the 1st or 2nd position of the glycerol backbone and a phosphate group bonded to the 3rd position. This includes 1-acyl LPA, 1-alkyl LPA, and 2-acyl LPA. There are also numerous LPA subtypes, each exhibiting diverse chemical and physiological properties depending on the type of fatty acid bonded to it and the carbon chain length and degree of unsaturation of the fatty acid.

[0003] LPA is known to be produced in vivo by various enzymes and binds to G-protein-conjugated receptors on the cell surface, transmitting signals into the cell and exhibiting various physiological effects. Six subtypes of LPA receptors are known: LPA1 through LPA6. Three receptors, LPA1, LPA2, and LPA3, belong to the EDG (Endotherial Differentiation Gene) family, designated EDG2, EDG4, and EDG7, respectively. LPA4 through LPA6 are not members of the EDG family and share little homology with the aforementioned EDG family. LPA receptor subtypes are distributed throughout the body, but their localization varies depending on the subtype, and each subtype is believed to contribute to the physiological functions of different tissues.

[0004] LPA has been implicated in various fibrotic diseases, with the involvement of the EDG receptor family as a receptor being particularly implicated. Regarding pulmonary fibrosis, LPA concentrations have been reported to be elevated in the alveolar lavage fluid of patients with idiopathic pulmonary fibrosis and mice with a bleomycin-induced pulmonary fibrosis model. Furthermore, LPA levels have been reported to be significantly inhibited in Lpar1-deficient mice and mice treated with an LPA1 receptor antagonist in these same models (see Non-Patent Document 1). Similarly, serum LPA concentrations have been reported to be elevated in patients with systemic scleroderma, and LPA1 and LPA1 / 3 receptor antagonists have been shown to inhibit fibrosis in a mouse model of bleomycin-induced skin fibrosis (see Non-Patent Documents 2-4). Regarding renal fibrosis, LPA production has been reported to be enhanced in a mouse model of unilateral ureteral ligation, but fibrosis formation has been inhibited in Lpar1-deficient mice and in mice treated with an LPA1 receptor antagonist (see Non-Patent Documents 4 and 5). Furthermore, in relation to liver fibrosis, elevated LPA concentrations in the blood of patients with chronic hepatitis C have been reported, with the degree of LPA reportedly correlating with the histological stage of fibrosis (see Non-Patent Document 6). Furthermore, expression of autotaxin, an LPA-producing enzyme, is elevated in the blood of patients with non-alcoholic fatty liver disease (NAFLD), and autotaxin inhibitors have been shown to have an inhibitory effect in various mouse models of liver damage (see Non-Patent Documents 7 and 8). Furthermore, LPA accumulates at high concentrations within atherosclerotic plaques, resulting in hyperinflammation and apoptosis induction. However, administration of LPA1 / 3 receptor antagonists has been reported to ameliorate lesions in these mouse models, suggesting that LPA may also be involved in circulatory organ diseases (see Non-Patent Document 9).

[0005] Furthermore, LPA is known to induce the migration and growth of cancer cells, and elevated LPA concentrations and LPA1 receptor expression have been observed in tissues of various cancer patients (see Non-Patent Documents 10 to 12).

[0006] Furthermore, LPA is reported to contract bladder smooth muscle cells, promote prostate cell proliferation, and be involved in the control of urethral intra-urethral pressure in vivo, suggesting its involvement in lower urinary tract diseases (see Patent Document 1, Non-Patent Documents 13 and 14).

[0007] Furthermore, LPA is reported to contract bladder smooth muscle cells, promote prostate cell proliferation, and be involved in the control of urethral intra-urethral pressure in vivo, suggesting its involvement in lower urinary tract diseases (see Patent Document 1, Non-Patent Documents 13 and 14).

[0008] LPA and LPA receptors are expressed in the nervous system, and LPA has been shown to induce neuropathic pain via the LPA1 receptor. Lpar1 knockout mice have been reported to show no pain symptoms in a mouse nerve ligation pain model (see Non-Patent Document 15).

[0009] Although reports have been made on substances that antagonize the LPA1 receptor, such as alkanoic acid compounds having a ring (Patent Documents 2 to 4), cyclohexylcarboxylic acid compounds having a triazole ring (Patent Document 5), and carboxylic acid compounds having an amide structure (Patent Documents 6 and 7), the urea compounds of the present invention are not disclosed.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: WO02 / 062389

[0013] Patent Document 2: WO03 / 099765

[0014] Patent Document 3: WO2004 / 031118

[0015] Patent Document 4: WO2005 / 058790

[0016] Patent Document 5: WO2017 / 223016

[0017] Patent Document 6: WO2015 / 025164

[0018] Patent Document 7: WO2017 / 177004

[0019] Non-patent literature

[0020] Non-patent literature 1: Nat Med. 2008 Jan;14(1):45-54.

[0021] Non-patent literature 2: Int J Med Sci. 2009 Jun 5;6(4):168-76.

[0022] Non-patent literature 3: Exp Dermatol. 2015 Sep;24(9):698-702.

[0023] Non-patent literature 4: Pharmacol Exp Ther. 2011 Mar;336(3):693-700.

[0024] Non-patent literature 5: J Am Soc Nephrol. 2007 Dec;18(12):3110-8.

[0025] Non-patent literature 6: J Clin Gastroenterol. 2007 Jul;41(6):616-23.

[0026] Non-patent literature 7: Obesity (Silver Spring). 2015 May; 23(5): 965-972.

[0027] Non-patent literature 8: J Pharmacol Exp Ther. 2017 Jan;360(1):1-13.

[0028] Non-patent literature 9: Sci Rep. 2016 Nov 24;6:37585.

[0029] Non-patent literature 10: JAMA. 1998 Aug 26;280(8):719-23.

[0030] Non-patent literature 11: Endocrinology. 2006 Oct;147(10):4883-92.

[0031] Non-patent literature 12: Proc Natl Acad Sci US A. 2006 Jun 20;103(25):9643-8.

[0032] Non-patent literature 13: J Urol. 1999 Nov;162(5):1779-84.

[0033] Non-patent literature 14: J Urol. 2000 Mar;163(3):1027-32.

[0034] Non-patent literature 15: Nat Med. 2004 Jul;10(7):712-8. Summary of the Invention

[0035] Technical problem to be solved by the invention

[0036] The object of the present invention is to provide novel compounds that antagonize LPA1 receptors.

[0037] Means for solving problems

[0038] To achieve the above-mentioned object, the present inventors have conducted intensive studies and have found that a compound represented by the following formula [I] (hereinafter sometimes referred to as compound [I]) has an LPA1 receptor antagonistic effect.

[0039] Hereinafter, the present invention will be described in detail.

[0040] That is, embodiments of the present invention are as follows.

[0041] (1) One embodiment of the present invention provides:

[0042] A compound represented by the following formula [I] or a pharmaceutically acceptable salt or hydrate thereof,

[0043] [Chemistry 1]

[0044]

[0045] In the above formula [I],

[0046] X represents carboxyl, C 1-4 Alkoxycarbonyl, carbamoyl, tetrazolyl or a group selected from the following formula group [II]

[0047] [Chemistry 2]

[0048] ;

[0049] W represents a linear C 1-3 Alkanediyl or a structure selected from the following formula group [III]

[0050] [Chemistry 3]

[0051] ;

[0052] in,

[0053] The linear C 1-3 The alkanediyl group may be selected from C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C 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,

[0054] Furthermore, the linear C 1-3 When the alkanediyl group is substituted by one methyl group, it may be further substituted by one methyl group.

[0055] Ring A 1 Ring A 2 and Ring A 3 Indicates C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 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,

[0056] in,

[0057] The sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0058] The nitrogen atom in the 4-8 membered saturated heterocyclic ring containing nitrogen atom can be selected from C 1-4 Alkylcarbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted,

[0059] also,

[0060] R A11 、R A21 and R A31 independently represent a hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl or 4-6 membered saturated heterocyclic group containing nitrogen atom, the 4-6 membered saturated heterocyclic group containing nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution ；

[0061] R A12 、R A22 and R A32 independently represent a hydrogen atom, a halogen atom or a methyl group,

[0062] also,

[0063] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form an oxo group together,

[0064] further,

[0065] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form a C 3-6 Cycloalkanes;

[0066] R 1 represents a hydrogen atom or a methyl group;

[0067] R 2 Indicates C 6-10 Alkyl, C 6-10 Alkenyl, C 6-10 Alkynyl, or a group represented by the following formula [IV-1] or [IV-2]

[0068] [Chemistry 4]

[0069] ;

[0070] in,

[0071] Ring B 1 Indicates C 3-8 Cycloalkyl, 4- to 8-membered saturated heterocyclic group containing nitrogen atoms, phenyl or 5- to 6-membered heteroaryl containing nitrogen atoms,

[0072] R B11 and R B12 independently represent a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0073] L 1 Indicates C 3-8 Alkanediyl (the C 3-8 The alkanediyl group may be substituted with 1 to 5 fluorine atoms), the structure represented by the formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure represented by the following formula [V-1]

[0074] [Chemistry 5]

[0075] ;

[0076] in,

[0077] n11 represents an integer from 0 to 3,

[0078] n12 represents an integer from 0 to 5,

[0079] n13 represents an integer from 0 to 3,

[0080] also,

[0081] As C 3-8 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L11 )-replaced,

[0082] further,

[0083] As C 3-8 The distance R between two consecutive carbon atoms in an alkanediyl group 2 The nitrogen atom to which one or more atoms are bonded may be represented by the formula -C(=O)N(R L12 )-replaced,

[0084] R L11 Represents a hydrogen atom or C 1-3 alkyl,

[0085] R L12 Represents a hydrogen atom or C 1-3 alkyl,

[0086] Ring B 2 represents a partially saturated 9- to 10-membered fused ring aryl group, or a 9- to 10-membered fused ring heteroaryl group containing a nitrogen atom,

[0087] R B21 and R B22 independently represent a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0088] L 2 Indicates C 1-2 Alkanediyl (the C 1-2 The alkanediyl group may be substituted by 1 to 4 fluorine atoms), C 3-6 Alkanediyl (the C 3-6 The alkanediyl group may be substituted with 1 to 5 fluorine atoms), or the structure shown in the following formula [V-2]

[0089] [Chemistry 6]

[0090] ;

[0091] in,

[0092] n21 represents an integer from 0 to 3,

[0093] n22 represents an integer from 0 to 5,

[0094] n23 represents an integer from 0 to 3,

[0095] also,

[0096] As C 3-6 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L21 )-replaced,

[0097] further,

[0098] As C 3-6 The distance R between two consecutive carbon atoms in an alkanediyl group 2 The nitrogen atom to which one or more atoms are bonded may be represented by the formula -C(=O)N(R L22 )-replaced,

[0099] R L21 Represents a hydrogen atom or C 1-3 alkyl,

[0100] R L22 Represents a hydrogen atom or C 1-3 alkyl;

[0101] R3 Represents a hydrogen atom or C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one group selected from hydroxy and methoxy);

[0102] R 4 represents a group represented by the following formula [VI]

[0103] [Chemistry 7]

[0104] ;

[0105] in,

[0106] Ring C represents a phenyl group, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered condensed heteroaryl group,

[0107] The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 One group in the alkylcarbonyl group is substituted, and further,

[0108] can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be substituted with one hydroxyl group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be substituted by one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, mono-C 1-6 Alkylaminocarbonyl and di-C 1-6 The alkylaminocarbonyl group is substituted by 1 to 4 identical or different groups,

[0109] The 6-membered heteroaryl group containing a nitrogen atom may be replaced by a C 1-6 Alkoxy substituted, further,

[0110] Can be selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy and oxo are substituted by 1 to 2 groups of the same or different groups,

[0111] The 9-10 membered fused ring heteroaryl group can be selected from C 1-6 Alkyl, C 1-6 Alkoxy and oxo are substituted by 1 to 4 identical or different groups;

[0112] also,

[0113] R 3 and R 4 Together with their adjacent carbon atoms, they may form a partially saturated 9- to 10-membered fused hydrocarbon aromatic ring or a partially saturated 9- to 10-membered fused heteroaromatic ring containing an oxygen atom.

[0114] in,

[0115] The partially saturated 9- to 10-membered fused hydrocarbon aromatic ring may be substituted by 1 to 2 halogen atoms.

[0116] The partially saturated oxygen-containing 9- to 10-membered condensed heteroaromatic ring may be substituted with 1 to 2 halogen atoms.

[0117] (2) As another embodiment of the present invention, there is provided the compound described in (1), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0118] In the formula group [III] about W,

[0119] R A11 、R A21 and R A31 independently represent a hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom, the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution;

[0120] R A12 、R A22 and R A32 independently represent a hydrogen atom, a halogen atom or a methyl group,

[0121] also,

[0122] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form an oxo group together,

[0123] further,

[0124] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form a C 3-6 Cycloalkanes,

[0125] In About R 2 In formula [IV-1],

[0126] L 1 Indicates C 3-8 Alkanediyl (the C 3-8 The alkanediyl group may be substituted with 1 to 5 fluorine atoms), or the structure shown in formula [V-1],

[0127] in,

[0128] As C 3-8 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L11 )-replaced,

[0129] further,

[0130] As C 3-8 The distance R between two consecutive carbon atoms in an alkanediyl group 2 The nitrogen atom to which one or more atoms are bonded may be represented by the formula -C(=O)N(R L12 )-replaced,

[0131] R L11 Represents a hydrogen atom or C 1-3 alkyl,

[0132] R L12 Represents a hydrogen atom or C 1-3 alkyl.

[0133] (3) As another embodiment of the present invention, there is provided the compound described in (1) or (2), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0134] In the aforementioned formula [I],

[0135] W is a straight chain C 1-3 Alkanediyl or a structure selected from the following formula group [III]

[0136] [Chemistry 8]

[0137] ,

[0138] in,

[0139] The linear C 1-3 The alkanediyl group may be selected from C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C 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,

[0140] Furthermore, the linear C 1-3 When the alkanediyl group is substituted by one methyl group, it may be further substituted by one methyl group.

[0141] Ring A 1 C 3-8 cycloalkane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

[0142] Ring A 2 C 3-8 Cycloalkanes or tetrahydropyrans,

[0143] Ring A 3 C 3-8 Cycloalkanes, dihydroindanes or tetrahydropyrans,

[0144] in,

[0145] The sulfur atom in the tetrahydrothiopyran may be substituted by 1 to 2 oxo groups.

[0146] also,

[0147] Each nitrogen atom in azetidine, pyrrolidine, and piperidine can be replaced by a C 1-4 Alkylcarbonyl substitution,

[0148] and,

[0149] R A11 A hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl or 4-6 membered saturated heterocyclic group containing nitrogen atom, the 4-6 membered saturated heterocyclic group containing nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution;

[0150] R A12 represents a hydrogen atom, a halogen atom or a methyl group,

[0151] In addition, R A11 and R A12 Each can form an oxo group together,

[0152] R A21 and R A22 are all hydrogen atoms,

[0153] R A31 and R A32 are all hydrogen atoms,

[0154] Further, R A11 and R A12 Each can form a C 3-6 Cycloalkanes;

[0155] R 2 C 6-10 Alkyl group, or a group represented by the following formula [IV-1] or [IV-2]

[0156] [Chemistry 9]

[0157] ,

[0158] in,

[0159] Ring B 1 C 3-8 cycloalkyl, piperidinyl, phenyl, pyrazolyl or pyridyl,

[0160] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0161] L 1 Any one of the structures represented by the following formulas [V-3] to [V-12] and [V-14] to [V-19],

[0162] [Chemistry 10]

[0163]

[0164] in,

[0165] n4 represents an integer from 3 to 5,

[0166] n12' represents an integer from 0 to 3,

[0167] n12" represents an integer from 0 to 3,

[0168] also,

[0169] Ring B 2is indanyl, indolyl or isoindolyl,

[0170] R B21 and R B22 Similarly for hydrogen atoms,

[0171] L 2 The structure shown in the following formula [V-20]

[0172] [Chemistry 11]

[0173] ,

[0174] in,

[0175] n5 represents an integer from 1 to 2;

[0176] R 4 A group represented by the following formula [VI]

[0177] [Chemistry 12]

[0178] ,

[0179] in,

[0180] Ring C is phenyl, pyridyl, pyrimidinyl, dihydropyridyl, dihydrobenzofuranyl, benzodioxanyl, indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, dihydroindolinyl or dihydroquinazolinyl,

[0181] The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 One group in the alkylcarbonyl group is substituted, and further,

[0182] can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be substituted with one hydroxyl group), C 2-6 Alkenyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be substituted by one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono C 1-6 Alkylamino, di-C 1-6 Alkylamino, C1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, and single C 1-6 The alkylaminocarbonyl group is substituted by 1 to 4 identical or different groups,

[0183] The pyridyl group may be replaced by a C 1-6 Alkoxy substituted, further,

[0184] Can be selected from cyano and C 1-6 One group in the alkoxy group is substituted,

[0185] The pyrimidine group can be replaced by a C 1-6 Alkoxy substituted, further,

[0186] Can be 1 C 1-6 Alkoxy substitution,

[0187] The dihydropyridyl group may be replaced by a C 1-6 Alkoxy substituted, further,

[0188] Can be selected from C 1-6 The alkyl group and the oxo group are substituted by 1 to 2 groups of the same or different groups,

[0189] The dihydrobenzofuranyl and benzodioxanyl groups may be replaced by 1 C 1-6 Alkoxy substitution,

[0190] The indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl and dihydroindole groups may be selected from C 1-6 Alkyl and C 1-6 The alkoxy group is substituted by 1 to 2 groups of the same or different types,

[0191] The dihydroquinazolinyl group may be selected from C 1-6 Alkyl, C 1-6 Alkoxy and oxo are substituted by 1 to 4 identical or different groups;

[0192] also,

[0193] R 3 and R 4 Together with their adjacent carbon atoms, they form a fused ring that is dihydroindene or dihydrobenzofuran.

[0194] The dihydroindene and dihydrobenzofuran may be substituted with 1 to 2 halogens.

[0195] (4) As another embodiment of the present invention, there is provided the compound described in (1) or (2), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0196] In the aforementioned formula [I],

[0197] X is carboxyl, C 1-4 an alkoxycarbonyl group or a tetrazolyl group;

[0198] R 1 is a hydrogen atom;

[0199] R 2 A group represented by the above formula [IV-1] or [IV-2]

[0200] [Chemistry 13]

[0201] .

[0202] (5) As another embodiment of the present invention, there is provided a compound according to (1), (2), or (4), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0203] In the aforementioned formula [I],

[0204] W is a methanediyl group or a structure represented by the following formula [III-1]

[0205] [Chemistry 14]

[0206] ,

[0207] in,

[0208] The methanediyl group may be selected from C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C 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,

[0209] Furthermore, when the methanediyl group is substituted with one methyl group, it may be further substituted with one methyl group.

[0210] also,

[0211] In the structure represented by formula [III-1],

[0212] Ring A 1 C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 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,

[0213] in,

[0214] The sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0215] also,

[0216] The nitrogen atom in the 4-8 membered saturated heterocyclic ring containing nitrogen atom can be selected from C 1-4 Alkylcarbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted,

[0217] and,

[0218] R A11 A hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom, the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution;

[0219] R A12 is a hydrogen atom, a halogen atom or a methyl group,

[0220] also,

[0221] R A11 and R A12 Each can form an oxo group together,

[0222] further,

[0223] R A11 and R A12 Each can form a C 3-6 Cycloalkanes.

[0224] (6) As another embodiment of the present invention, there is provided a compound according to any one of (1), (2), (4), or (5), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0225] In the aforementioned formula [I],

[0226] R 4 A group represented by the following formula [VI]

[0227] [Chemistry 15]

[0228] ,

[0229] in,

[0230] Ring C is phenyl,

[0231] The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C1-6 One group in the alkylcarbonyl group is substituted, and further,

[0232] can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be substituted with one hydroxyl group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be substituted by one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, mono-C 1-6 Alkylaminocarbonyl and di-C 1-6 The alkylaminocarbonyl group may be substituted by 1 to 4 groups which may be the same or different.

[0233] (7) As another embodiment of the present invention, there is provided a compound according to any one of (1), (2), (4) to (6), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0234] In the aforementioned formula [I],

[0235] R 2 A group represented by the following formula [IV-1] or [IV-2]

[0236] [Chemistry 16]

[0237] ,

[0238] in,

[0239] Ring B 1 is phenyl,

[0240] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0241] L 1 Any one of the structures represented by the following formulas [V-3] to [V-5], [V-7] to [V-8], [V-11] to [V-12], and [V-14] to [V-16],

[0242] [Chemistry 17]

[0243]

[0244] in,

[0245] n4 represents an integer from 3 to 5,

[0246] Ring B 2 is indanyl, indolyl or isoindolyl,

[0247] R B21 and R B22 Similarly for hydrogen atoms,

[0248] L 2 The structure shown in the following formula [V-20]

[0249] [Chemistry 18]

[0250] ,

[0251] in,

[0252] n5 is an integer from 1 to 2.

[0253] (8) As another embodiment of the present invention, there is provided a compound according to any one of (4) to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0254] In the aforementioned formula [I],

[0255] X is a carboxyl group;

[0256] W is any one of the structures represented by the following formulas [III-4] to [III-17];

[0257] [Chemistry 19]

[0258]

[0259] R 2 A group represented by the following formula [IV-1] or [IV-2]

[0260] [Chemistry 20]

[0261] ,

[0262] in,

[0263] Ring B 1 is phenyl,

[0264] R B11 and R B12 Similarly for hydrogen atoms,

[0265] L 1 The structure represented by the following formula [V-3], [V-8], [V-12], [V-14], or [V-15]

[0266] [Chemistry 21]

[0267] ,

[0268] in,

[0269] n4 is an integer from 3 to 4,

[0270] also,

[0271] Ring B 2 is dihydroindanyl,

[0272] R B21 and R B22 Similarly for hydrogen atoms,

[0273] L 2 The structure shown in the following formula [V-20]

[0274] [Chemistry 22]

[0275] ,

[0276] in,

[0277] n5 is 2;

[0278] R 3 It is a methyl group having the stereo configuration shown in the following formula [VII]

[0279] [Chemistry 23]

[0280] ;

[0281] R 4 A group represented by any one of the following formulas [VI-1] to [VI-21]

[0282] [Chemistry 24]

[0283]

[0284] [Chemistry 25]

[0285]

[0286] [Chemistry 26]

[0287] .

[0288] (9) As another embodiment of the present invention, there is provided a compound according to any one of (4) to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0289] In the aforementioned formula [I],

[0290] X is a carboxyl group;

[0291] W is a structure represented by the following formula [III-4] to [III-11], [III-13] to [III-14], or [III-18] to [III-19]

[0292] [Chemistry 27]

[0293] ;

[0294] R 2 A group represented by the following formula [IV-1] or [IV-2]

[0295] [Chemistry 28]

[0296] ,

[0297] in,

[0298] Ring B 1 is phenyl,

[0299] R B11 and R B12 Similarly for hydrogen atoms,

[0300] L 1 The structure represented by the following formula [V-3], [V-8], or [V-14]

[0301] [Chemistry 29]

[0302] ,

[0303] in,

[0304] n4 is 4,

[0305] also,

[0306] Ring B 2 is dihydroindanyl,

[0307] R B21 and R B22 Similarly for hydrogen atoms,

[0308] L 2The structure shown in the following formula [V-20]

[0309] [Chemistry 30]

[0310] ,

[0311] in,

[0312] n5 is 2;

[0313] R 3 It is a methyl group having the stereo configuration shown in the following formula [VII]

[0314] [Chemistry 31]

[0315] ;

[0316] R 4 A group represented by the following formula [VI-2], [VI-3], [VI-8], [VI-10] to [VI-12], [VI-16], [VI-19], or [VI-21]

[0317] [Chemistry 32]

[0318]

[0319] [Chemistry 33]

[0320] .

[0321] (10) As another embodiment of the present invention, there is provided a compound according to any one of (4) to (7), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein:

[0322] In the aforementioned formula [I],

[0323] X is a carboxyl group or a tetrazolyl group;

[0324] W is a structure represented by the following formula [III-5], [III-8] to [III-11], or [III-13]

[0325] [Chemistry 34]

[0326] ;

[0327] R 2 A group represented by the following formula [IV-1] or [IV-2]

[0328] [Chemistry 35]

[0329] ,

[0330] in,

[0331] Ring B 1 is phenyl,

[0332] R B11 and R B12 Same as hydrogen atoms

[0333] L 1 The structure represented by the following formula [V-3], [V-12], or [V-14]

[0334] [Chemistry 36]

[0335] ,

[0336] in,

[0337] n4 is an integer of 4,

[0338] also,

[0339] Ring B 2 is dihydroindanyl,

[0340] R B21 and R B22 Similarly for hydrogen atoms,

[0341] L 2 The structure shown in the following formula [V-20]

[0342] [Chemistry 37]

[0343] ,

[0344] in,

[0345] n5 is 2;

[0346] R 3 It is a methyl group having the stereo configuration shown in the following formula [VII]

[0347] [Chemistry 38]

[0348] ;

[0349] R 4 A group represented by the following formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11], or [VI-12]

[0350] [Chemistry 39]

[0351] .

[0352] (11) Another embodiment of the present invention is the compound described in (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the compound is any one of the following:

[0353] [Chemistry 40]

[0354]

[0355] [Chemistry 41]

[0356]

[0357] [Chemistry 42]

[0358]

[0359] [Chemistry 43]

[0360]

[0361] [Chemistry 44]

[0362] .

[0363] (12) Another embodiment of the present invention is the compound described in (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the compound is any one of the following:

[0364] [Chemistry 45]

[0365]

[0366] [Chemistry 46]

[0367]

[0368] [Chemistry 47]

[0369] .

[0370] (13) As another embodiment of the present invention, there is provided a medicine containing the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

[0371] (14) As another embodiment of the present invention, there is provided an LPA1 receptor antagonist comprising the compound according to any one of (1) to (12), or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0372] (15) As another embodiment of the present invention, there is provided a preventive or therapeutic agent for systemic scleroderma, comprising the compound according to any one of (1) to (12), or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[0373] (16) As another embodiment of the present invention, there is provided an LPA1 receptor antagonist comprising a compound represented by the following formula [Ia] or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient,

[0374] [Chemistry 48]

[0375]

[0376] In the above formula [Ia],

[0377] X represents carboxyl, C 1-4 Alkoxycarbonyl, carbamoyl, tetrazolyl or a structure selected from the following group [IIa]

[0378] [Chemistry 49]

[0379] ;

[0380] W represents a linear C 1-3 Alkanediyl or a structure selected from the following formula group [IIIa]

[0381] [Chemistry 50]

[0382] ;

[0383] in,

[0384] The linear C 1-3 The alkanediyl group may be selected from C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C 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,

[0385] Furthermore, the linear C 1-3 When the alkanediyl group is substituted by one methyl group, it may be further substituted by one methyl group.

[0386] Ring A 1 Ring A 2 and Ring A 3 Indicates C 3-8Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 4- to 8-membered saturated heterocyclic rings containing oxygen atoms, partially saturated 9- to 10-membered fused heterocyclic rings containing oxygen atoms, 4- to 8-membered saturated heterocyclic rings containing sulfur atoms, partially saturated 9- to 10-membered fused heterocyclic rings containing nitrogen atoms, 4- to 8-membered saturated heterocyclic rings containing nitrogen atoms, or partially saturated 9- to 10-membered fused heterocyclic rings containing sulfur atoms,

[0387] in,

[0388] Each sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom and the partially saturated 9- to 10-membered condensed heterocyclic ring containing a sulfur atom may be substituted with 1 to 2 oxo groups.

[0389] also,

[0390] Each nitrogen atom in the 4-8 membered saturated heterocyclic ring containing nitrogen atoms and the partially saturated 9-10 membered condensed saturated heterocyclic ring containing nitrogen atoms can be selected from C 1-4 Alkylcarbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted,

[0391] R A11 、R A21 and R A31 independently represent a hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylcarbonyl or 4-6 membered saturated heterocyclic group containing nitrogen atom, the 4-6 membered saturated heterocyclic group containing nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution ；

[0392] R A12 、R A22 and R A32 independently represent a hydrogen atom, a halogen atom or a methyl group,

[0393] In addition, R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form an oxo group together,

[0394] Further, R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form a C 3-6 Cycloalkanes;

[0395] R 1 represents a hydrogen atom or a methyl group;

[0396] R 2 Indicates C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or a group represented by the following formula [IVa]

[0397] [Chemistry 51]

[0398] ;

[0399] in,

[0400] Ring B represents C 3-8 Cycloalkyl, 4-8 membered saturated heterocyclic group, phenyl, 9-10 membered fused ring aryl, 5-6 membered heteroaryl or 9-10 membered fused ring heteroaryl,

[0401] R B1 and R B2 independently represent a hydrogen atom, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy,

[0402] L stands for C 1-2 Alkanediyl (the C 1-2 The alkanediyl group may be substituted by 1 to 4 fluorine atoms), C 3-8 Alkanediyl (the C 3-8 The alkane diyl group may be substituted with 1 to 5 fluorine atoms), the structure represented by the formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure represented by the following formula [V-1a]

[0403] [Chemistry 52]

[0404] ;

[0405] in,

[0406] n1 represents an integer from 0 to 3,

[0407] n2 represents an integer from 0 to 5,

[0408] n3 represents an integer from 0 to 3,

[0409] also,

[0410] As C 3-8 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L1 )-replaced,

[0411] further,

[0412] As C 3-8 The distance R between two consecutive carbon atoms in an alkanediyl group 2 The nitrogen atom to which one or more atoms are bonded may be represented by the formula -C(=O)N(R L2 )-replaced,

[0413] R L1 Represents a hydrogen atom or C 1-3 alkyl,

[0414] R L2 Represents a hydrogen atom or C 1-3 alkyl;

[0415] 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 hydroxy and methoxy);

[0416] R 4 represents a group represented by the following formula [VIa]

[0417] [Chemistry 53]

[0418] ;

[0419] in,

[0420] Ring C represents a phenyl group, a 9- to 10-membered fused ring aryl group, a 5- to 6-membered heteroaryl group, or a 9- to 10-membered fused ring heteroaryl group,

[0421] The phenyl group may be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be selected from hydroxy and C 1-6 1 group in the alkoxy group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy (the C 1-6 Alkoxy and halogenated C 1-6 The alkoxy group may be selected from hydroxyl and C 1-61 group in the alkoxy group), C 3-8 Cycloalkoxy (the C 3-8 The cycloalkoxy group may be selected from hydroxy and C 1-6 1 group in the alkoxy group), C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl (the C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl and C 1-6 The alkylsulfonyl group may be selected from hydroxy and C 1-6 1 group in the alkoxy group), single C 1-6 Alkylamino, di-C 1-6 Alkylamino (the single C 1-6 Alkylamino and di-C 1-6 The alkylamino group may be selected from hydroxy and C 1-6 1 group in the alkoxy group), C 1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, mono-C 1-6 Alkylaminocarbonyl, and di-C 1-6 Alkylaminocarbonyl (the C 1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, mono-C 1-6 Alkylaminocarbonyl, and di-C 1-6 The alkylaminocarbonyl group may be selected from hydroxy and C 1-6 1 group in the alkoxy group is substituted) is substituted by 1 to 4 groups of the same or different groups,

[0422] The 9-10 membered fused ring aryl group may be selected from halogen atoms, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted by 1 to 3 groups of the same or different types,

[0423] The 5- to 6-membered heteroaryl group may be selected from halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy and oxo are substituted by 1 to 3 groups of the same or different groups,

[0424] The 9-10 membered fused ring heteroaryl group can be selected from C 1-6 Alkyl, C 1-6 Alkoxy and oxo are substituted by 1 to 4 identical or different groups;

[0425] In addition, R 3 and R 4 Each can be combined with adjacent carbon atoms

[0426] forming a partially saturated 9- to 10-membered fused hydrocarbon aromatic ring or a partially saturated 9- to 10-membered fused heteroaromatic ring,

[0427] in,

[0428] The partially saturated 9- to 10-membered fused hydrocarbon aromatic ring may be substituted by 1 to 2 halogen atoms.

[0429] The partially saturated 9- to 10-membered fused heteroaromatic ring may be substituted by 1 to 2 halogen atoms.

[0430] (17) As another embodiment of the present invention, there is provided the LPA1 receptor antagonist described in (16), wherein:

[0431] In the formula group [IIIa] about W,

[0432] R A11 、R A21 and R A31 independently represent a hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom, the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 Alkyl substitution; ；

[0433] R A12 、R A22 and R A32 independently represent a hydrogen atom, a halogen atom or a methyl group,

[0434] also,

[0435] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form an oxo group together,

[0436] further,

[0437] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form a C 3-6 Cycloalkanes,

[0438] In About R 2 In formula [IVa],

[0439] L stands for C 1-2 Alkanediyl (the C 1-2 The alkanediyl group may be substituted by 1 to 4 fluorine atoms), C 3-8 Alkanediyl (the C 3-8 The alkanediyl group may be substituted with 1 to 5 fluorine atoms), or the structure represented by formula [V-1a], wherein:

[0440] As C 3-8 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L1 )-replaced,

[0441] further,

[0442] As C 3-8 The distance R between two consecutive carbon atoms in an alkanediyl group 2 The nitrogen atom to which one or more atoms are bonded may be represented by the formula -C(=O)N(R L2 )-replaced,

[0443] R L1 Represents a hydrogen atom or C 1-3 alkyl,

[0444] R L2 Represents a hydrogen atom or C 1-3 alkyl.

[0445] (18) As another embodiment of the present invention, a preventive or therapeutic drug for systemic scleroderma is provided, which contains the compound represented by formula [Ia] described in (16) or (17) or its pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

[0446] (19) As another embodiment of the present invention, a method for treating or preventing systemic scleroderma is provided, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula [Ia] described in (16) or (17), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0447] (20) As another embodiment of the present invention, a drug is provided, which contains the compound represented by formula [Ia] described in (16) or (17) or its pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

[0448] Effects of the Invention

[0449] The compound of the present invention (hereinafter, sometimes referred to as “the compound of the present invention”) has an LPA1 receptor antagonistic effect. DETAILED DESCRIPTION

[0450] The present invention provides a compound represented by the aforementioned formula [I] or a pharmaceutically acceptable salt or hydrate thereof having an LPA1 receptor antagonistic effect.

[0451] Hereinafter, the compounds of the present invention will be described in further detail, but the present invention is not limited to the exemplified compounds.

[0452] The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0453] “C 1-3 The term "alkyl" refers to a linear or branched alkyl group having 1 to 3 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, and isopropyl.

[0454] “C 1-4 The term "alkyl" refers to a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0455] “C 1-6 The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0456] “C 1-10 The term "alkyl" refers to a linear or branched alkyl group having 1 to 10 carbon atoms. Examples thereof 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.

[0457] “C 6-10 The term "alkyl" refers to a linear or branched alkyl group having 6 to 10 carbon atoms. Examples thereof include n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isoheptyl, and isooctyl.

[0458] “C 5-9 The term "alkyl" refers to a linear or branched alkyl group having 5 to 9 carbon atoms. Examples thereof include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, isoheptyl, and isooctyl.

[0459] "Halogenated C 1-6The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted by a halogen atom. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof 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.

[0460] "Hydroxy C 1-6 The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a hydroxy group. The preferred number of substitutions of the hydroxy group is 1. Examples thereof include monohydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, and 6-hydroxyhexyl.

[0461] “C 2-3 The term "alkenyl" refers to a linear or branched alkenyl group having 2 to 3 carbon atoms. Examples thereof 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.

[0462] “C 2-6 The term “alkenyl” refers to a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples thereof 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-methylvinyl.

[0463] “C 2-10 The term "alkenyl" refers to a linear or branched alkenyl group having 2 to 10 carbon atoms. Examples thereof include ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, and n-decenyl.

[0464] “C 5-9 The term "alkenyl" refers to a linear or branched alkenyl group having 5 to 9 carbon atoms. Examples thereof include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, and n-nonenyl.

[0465] “C 6-10 The term "alkenyl" refers to a linear or branched alkenyl group having 6 to 10 carbon atoms. Examples thereof include n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl, and n-decenyl.

[0466] “C 2-6The term "alkynyl" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms. Examples thereof 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.

[0467] “C 2-10 The term "alkynyl" refers to a linear or branched alkynyl group having 2 to 10 carbon atoms. Examples thereof include ethynyl, n-propynyl, n-butynyl, n-pentynyl, n-hexynyl, n-heptynyl, n-octynyl, n-nonynyl, and n-decynyl.

[0468] “C 5-9 The term "alkynyl" refers to a linear or branched alkynyl group having 5 to 9 carbon atoms. Examples thereof include n-pentynyl, n-hexynyl, n-heptynyl, n-octynyl, and n-nonynyl.

[0469] “C 6-10 The term "alkynyl" refers to a linear or branched alkynyl group having 6 to 10 carbon atoms. Examples thereof include n-hexynyl, n-heptynyl, n-octynyl, n-nonynyl and n-decynyl.

[0470] “C 3-6 "Cycloalkane" means a hydrocarbon ring having 3 to 6 carbon atoms. Examples thereof include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0471] “C 3-8 "Cycloalkane" means a hydrocarbon ring having 3 to 8 carbon atoms. Examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0472] “C 3-8 The "cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0473] The term "9- to 10-membered fused ring aryl group" refers to a 9- to 10-membered fused polycyclic hydrocarbon aromatic ring group having 9 to 10 carbon atoms, and an example thereof includes naphthyl.

[0474] Furthermore, regarding the 9- to 10-membered fused ring aryl group, partially saturated groups are also included in the "9- to 10-membered fused ring aryl group." Examples thereof include dihydroindanyl, dihydronaphthyl, and tetrahydronaphthyl.

[0475] The "partially saturated 9- to 10-membered fused hydrocarbon aromatic ring" refers to a partially saturated 9- to 10-membered fused polycyclic hydrocarbon aromatic ring having 9 to 10 carbon atoms, and examples thereof include dihydroindane, dihydronaphthalene, and tetrahydronaphthalene.

[0476] The "partially saturated 9- to 10-membered fused ring aryl group" refers to a partially saturated 9- to 10-membered fused polycyclic hydrocarbon aromatic ring group having 9 to 10 carbon atoms, and examples thereof include dihydroindanyl, dihydronaphthyl, and tetrahydronaphthyl.

[0477] A "4- to 8-membered saturated heterocyclic group" refers to a 4- to 8-membered monocyclic saturated heterocyclic group consisting of one atom selected from oxygen, sulfur, and nitrogen atoms, and 3 to 7 carbon atoms, wherein the group may further contain one atom selected from oxygen, sulfur, and nitrogen atoms in addition to the aforementioned oxygen, sulfur, or nitrogen atoms. Examples include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0478] The term "oxygen-containing 4- to 8-membered saturated heterocyclic ring" refers to a 4- to 8-membered monocyclic saturated heterocyclic ring consisting of one oxygen atom and 3 to 7 carbon atoms. Examples thereof include oxetane, tetrahydrofuran, and tetrahydropyran.

[0479] The term "sulfur-containing 4- to 8-membered saturated heterocyclic ring" refers to a 4- to 8-membered monocyclic saturated heterocyclic ring consisting of one sulfur atom and 3 to 7 carbon atoms. Examples thereof include thietane, tetrahydrothiophene, and tetrahydrothiopyran.

[0480] A "nitrogen-containing 4- to 8-membered saturated heterocycle" refers to a 4- to 8-membered monocyclic saturated heterocycle consisting of one nitrogen atom and 3-7 carbon atoms, which may further contain one atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom. Examples include azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine, and piperazine.

[0481] A "nitrogen-containing 4- to 6-membered saturated heterocyclic group" refers to a 4- to 6-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3-5 carbon atoms, which may further contain one atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom. Examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0482] A "nitrogen-containing 4- to 8-membered saturated heterocyclic group" refers to a 4- to 8-membered monocyclic saturated heterocyclic group consisting of one nitrogen atom and 3-7 carbon atoms, which may further contain one atom selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to the nitrogen atom. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0483] The term "5- to 6-membered heteroaryl group" refers to a 5- to 6-membered monocyclic aromatic heterocyclic group consisting of one or more atoms, the same or different, selected from oxygen, sulfur, and nitrogen atoms, and 1 to 5 carbon atoms. Examples thereof include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0484] Furthermore, among the 5- to 6-membered heteroaryl groups, partially saturated groups are also included in the "5- to 6-membered heteroaryl group", and examples thereof include dihydrothiazolyl, dihydropyridyl, and tetrahydropyridyl.

[0485] The term "nitrogen-containing 5- to 6-membered heteroaryl group" refers to a 5- to 6-membered monocyclic aromatic heterocyclic group composed of 1 to 4 nitrogen atoms and 1 to 5 carbon atoms, which may further contain an oxygen atom and a sulfur atom in addition to the nitrogen atom. Examples thereof include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0486] Furthermore, among the 5- to 6-membered heteroaryl groups containing a nitrogen atom, partially saturated groups are also included in the "5- to 6-membered heteroaryl groups containing a nitrogen atom", for example, dihydrothiazolyl, dihydropyridyl, and tetrahydropyridyl.

[0487] The "nitrogen-containing 6-membered heteroaryl group" refers to a 6-membered monocyclic aromatic heterocyclic group consisting of 1 to 3 nitrogen atoms and 3 to 5 carbon atoms, and examples thereof include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0488] Furthermore, among the nitrogen-containing 6-membered heteroaryl groups, partially saturated groups are also included in the "nitrogen-containing 6-membered heteroaryl group", for example, dihydropyridyl and tetrahydropyridyl.

[0489] A "9- to 10-membered fused heteroaryl group" refers to a 9- to 10-membered fused polycyclic aromatic heterocyclic group consisting of one atom selected from oxygen, sulfur, and nitrogen atoms, and 5 to 9 carbon atoms. In addition to the aforementioned oxygen, sulfur, or nitrogen atom, the group may further contain 1 to 3 atoms, the same or different, selected from oxygen, sulfur, and nitrogen atoms. Examples include benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, and pyrazolopyridinyl.

[0490] Furthermore, among the 9- to 10-membered fused-ring heteroaryl groups, partially saturated groups are also included in the "9- to 10-membered fused-ring heteroaryl groups." Examples thereof include dihydrobenzofuranyl, dihydrobenzothienyl, dihydroindole, dihydrobenzodioxinyl, dihydroquinazolinyl, and isoindolyl.

[0491] A "partially saturated 9- to 10-membered fused heteroaromatic ring" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocyclic ring composed of one atom selected from oxygen, sulfur, and nitrogen atoms and 5 to 9 carbon atoms, wherein the ring may further contain, in addition to the aforementioned oxygen, sulfur, or nitrogen atoms, 1 to 3 atoms, the same or different, selected from oxygen, sulfur, and nitrogen atoms. Examples thereof include dihydrobenzofuran, dihydrobenzothiophene, dihydroindoline, dihydrobenzodioxin, and dihydroquinazoline.

[0492] A "nitrogen-containing 9- to 10-membered fused heteroaryl group" refers to a 9- to 10-membered fused polycyclic aromatic heterocyclic group consisting of one nitrogen atom and 5 to 9 carbon atoms, which may further contain, in addition to the nitrogen atom, 1 to 3 atoms, the same or different, selected from oxygen atoms, sulfur atoms, and nitrogen atoms. Examples include indolyl, indazolyl, benzimidazolyl, and pyrazolopyridinyl.

[0493] Furthermore, among the nitrogen-containing 9- to 10-membered fused-ring heteroaryl groups, partially saturated groups are also included in the "nitrogen-containing 9- to 10-membered fused-ring heteroaryl groups," for example, indolinyl and dihydroquinazolinyl.

[0494] A "partially saturated oxygen-containing 9- to 10-membered fused heterocycle" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle consisting of one oxygen atom and 5 to 9 carbon atoms, which may further contain, in addition to the oxygen atom, 1 to 3 atoms, the same or different, selected from oxygen atoms, sulfur atoms, and nitrogen atoms. An example of such a heterocycle is dihydrobenzofuran.

[0495] A "partially saturated sulfur-containing 9- to 10-membered fused heterocycle" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle consisting of one sulfur atom and 5 to 9 carbon atoms, which may further contain, in addition to the sulfur atom, 1 to 3 atoms, the same or different, selected from oxygen atoms, sulfur atoms, and nitrogen atoms. An example of such a heterocycle is dihydrobenzothiophene.

[0496] A "partially saturated nitrogen-containing 9- to 10-membered fused heterocycle" refers to a partially saturated 9- to 10-membered fused polycyclic aromatic heterocycle consisting of one nitrogen atom and 5 to 9 carbon atoms, which may further contain, in addition to the nitrogen atom, 1 to 3 atoms, the same or different, selected from oxygen atoms, sulfur atoms, and nitrogen atoms. An example of such a heterocycle is indoline.

[0497] "Phenyl C 1-3 "Alkyl" means the aforementioned "C 1-3 Alkyl group". For example, benzyl, phenethyl, 3-phenylpropyl, etc. can be mentioned.

[0498] "Pyridyl C1-3 "Alkyl" means the aforementioned "C 1-3 Alkyl". For example, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 2-(pyridin-2-yl)ethyl, and 3-(pyridin-2-yl)propyl.

[0499] “C 1-4 The term "alkoxy" refers to a linear or branched alkoxy group having 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0500] “C 1-6 The term "alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0501] "Halogenated C 1-6 The term "alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms substituted by a halogen atom. The preferred number of halogen atoms is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof 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-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy.

[0502] “C 3-8 The term "cycloalkoxy" refers to a cyclic alkoxy group having 3 to 8 carbon atoms. Examples thereof include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0503] “C 1-6 "Alkylsulfanyl" means the aforementioned "C 1-6 A group in which an "alkyl" group is bonded to a sulfanyl group. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl, and n-hexylsulfanyl.

[0504] “C 1-6 "Alkylsulfinyl" means the aforementioned "C 1-6 A group in which an "alkyl" group is bonded to a sulfinyl group. Examples thereof include a methylsulfinyl group, an ethylsulfinyl group, an n-propylsulfinyl group, an isopropylsulfinyl group, an n-butylsulfinyl group, an isobutylsulfinyl group, a sec-butylsulfinyl group, a tert-butylsulfinyl group, an n-pentylsulfinyl group, and an n-hexylsulfinyl group.

[0505] “C 1-6 "Alkylsulfonyl" means the aforementioned "C 1-6 A group in which an "alkyl" group is bonded to a sulfonyl group. Examples thereof include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, an n-pentylsulfonyl group, and an n-hexylsulfonyl group.

[0506] “C 1-4 "Alkylsulfonyloxy" means the aforementioned "C 1-4 The term "alkyl" refers to a group formed by combining a sulfonyloxy group. Examples thereof include a methylsulfonyloxy group, an ethylsulfonyloxy group, an n-propylsulfonyloxy group, an isopropylsulfonyloxy group, an n-butylsulfonyloxy group, an isobutylsulfonyloxy group, a sec-butylsulfonyloxy group, and a tert-butylsulfonyloxy group.

[0507] "Single C 1-6 "Alkylamino" means having one of the aforementioned "C 1-6 An amino group having an "alkyl" group as a substituent. Examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.

[0508] "Two C 1-6 "Alkylamino" means having two identical or different "C 1-6 An amino group having an "alkyl" group as a substituent. Examples thereof include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, and methyl(n-propyl)amino.

[0509] “C 1-4 "Alkylcarbonyl" means the aforementioned "C 1-4 A group formed by combining an "alkyl" group with a carbonyl group. Examples thereof include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, and a tert-butylcarbonyl group.

[0510] “C 1-6 "Alkylcarbonyl" means the aforementioned "C 1-6 A group formed by combining an "alkyl" group with a carbonyl group. Examples thereof include a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonyl group, an n-pentylcarbonyl group, and an n-hexylcarbonyl group.

[0511] "Halogenated C 1-6 "Alkylcarbonyl" means the aforementioned "halogenated C 1-6The preferred number of substitutions for the halogen atom is 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include monofluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 1-fluoroethylcarbonyl, 1,1-difluoroethylcarbonyl, 2-fluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 1,1,2,2,2-pentafluoroethylcarbonyl, 3,3,3-trifluoropropylcarbonyl, 4,4,4-trifluorobutylcarbonyl, 5,5,5-trifluoropentylcarbonyl, and 6,6,6-trifluorohexylcarbonyl.

[0512] “C 1-4 "Alkoxycarbonyl" means the aforementioned "C 1-4 An "alkoxy" group is a group formed by combining a carbonyl group. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.

[0513] “C 1-6 "Alkoxycarbonyl" means the aforementioned "C 1-6 An "alkoxy" group is a group formed by combining a carbonyl group. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexyloxycarbonyl.

[0514] "Single C 1-6 "Alkylaminocarbonyl" means the aforementioned "mono-C 1-6 The term "alkylamino" refers to a group formed by combining an "alkylamino" group with a carbonyl group. Examples thereof include a methylaminocarbonyl group, an ethylaminocarbonyl group, an n-propylaminocarbonyl group, an isopropylaminocarbonyl group, an n-butylaminocarbonyl group, an isobutylaminocarbonyl group, a sec-butylaminocarbonyl group, a tert-butylaminocarbonyl group, an n-pentylaminocarbonyl group, and an n-hexylaminocarbonyl group.

[0515] "Two C 1-6 "Alkylaminocarbonyl" means the aforementioned "diC 1-6 A group in which an "alkylamino group" is bonded to a carbonyl group. Examples thereof include a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a di(n-propyl)aminocarbonyl group, a di(isopropyl)aminocarbonyl group, an ethylmethylaminocarbonyl group, and a methyl(n-propyl)aminocarbonyl group.

[0516] "Oxo" refers to a substituent (=O) in which an oxygen atom is replaced by a double bond. Thus, when an oxo group is substituted on a carbon atom, it forms a carbonyl group together with the carbon atom. When one oxo group is substituted on a sulfur atom, it forms a sulfinyl group together with the sulfur atom. When two oxo groups are substituted on a sulfur atom, they form a sulfonyl group together with the sulfur atom.

[0517] Examples of the saturated heterocyclic group substituted with oxo include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 1,1-dioxidotetrahydrothiophenyl, 1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1-dioxidisothiazolidinyl, 2-oxo-1,3-oxazolidinyl, and 2-oxo-1,3-oxazinyl.

[0518] Examples of the partially saturated heteroaryl group substituted with oxo include 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.

[0519] "Straight-chain C 1-3 The term "alkanediyl" refers to a divalent linear hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms. Examples thereof include methanediyl, ethane-1,2-diyl, and propane-1,3-diyl.

[0520] “C 1-2 The term "alkanediyl" refers to a divalent linear hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 2 carbon atoms. Examples thereof include methanediyl, ethane-1,1-diyl, and ethane-1,2-diyl.

[0521] “C 1-8 The term "alkanediyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 8 carbon atoms. Examples thereof 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.

[0522] “C 2-7 The term "alkanediyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 2 to 7 carbon atoms. Examples thereof 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. "C 3-6The term "alkanediyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 3 to 6 carbon atoms. Examples thereof 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.

[0523] “C 3-8 The term "alkanediyl" refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 3 to 8 carbon atoms. Examples thereof 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.

[0524] The "C4 alkanediyl group" refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from an alkyl group having 4 carbon atoms, and an example thereof is butane-1,4-diyl.

[0525] A preferred embodiment of the compound of the present invention is the following embodiment (A).

[0526] Implementation method (A):

[0527] The compound represented by the above formula [I]

[0528] [Chemistry 54]

[0529]

[0530] or a pharmaceutically acceptable salt thereof;

[0531] X is carboxyl, C 1-4 Alkoxycarbonyl, tetrazolyl, or a group represented by the following formulas [II-2] to [II-5]

[0532] [Chemistry 55]

[0533] .

[0534] In this embodiment, W is a linear C 1-3 Alkanediyl, or a structure selected from the following formula group [III]

[0535] [Chemistry 56]

[0536] ,

[0537] in,

[0538] The linear C 1-3 The alkanediyl group may 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,

[0539] Furthermore, the linear C 1-3 When the alkanediyl group is substituted by one methyl group, it may be further substituted by one methyl group.

[0540] Ring A 1 Ring A 2 and Ring A 3 It is C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 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,

[0541] in,

[0542] The sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0543] The nitrogen atom in the 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom may be replaced by one C 1-4 Alkylcarbonyl substitution,

[0544] also,

[0545] R A11 、R A21 and R A31 are independently a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 an alkoxy group or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom,

[0546] R A12 、R A22 and R A32 are independently a hydrogen atom, a halogen atom, or a methyl group,

[0547] also,

[0548] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form an oxo group together,

[0549] further,

[0550] R A11 and R A12 、R A21 and R A22 , and R A31 and R A32 Each can form a C 3-6 Cycloalkanes.

[0551] More preferably, W is a linear C 1-3 Alkanediyl, or a structure selected from the following formula group [III]

[0552] [Chemistry 57]

[0553] ,

[0554] in,

[0555] The linear C 1-3 The alkanediyl group may be selected from C 1-4 Alkyl, halogenated C2 alkyl, phenyl C 1-2 Alkyl and pyridyl C1 alkyl substituted with one group,

[0556] Furthermore, the linear C 1-3 When the alkanediyl group is substituted by one methyl group, it may be further substituted by one methyl group.

[0557] Ring A 1 It is C 3-7 Cycloalkanes, partially saturated 9-membered fused hydrocarbon aromatic rings, 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,

[0558] in,

[0559] The sulfur atom in the 6-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0560] The nitrogen atom in the 4- to 6-membered saturated heterocyclic ring containing a nitrogen atom may be substituted by one C1 alkylcarbonyl group.

[0561] also,

[0562] R A11 It is a hydrogen atom, a hydroxyl group, a halogen atom, a C1 alkyl group, a C 1-3 an alkoxy group or a 6-membered saturated heterocyclic group containing a nitrogen atom,

[0563] R A12 is a hydrogen atom, a halogen atom or a methyl group,

[0564] also,

[0565] RA11 and R A12 can form oxygen together,

[0566] further,

[0567] R A11 and R A12 Each can form a C4 cycloalkane together with the carbon atoms in the adjacent ring,

[0568] Ring A 2 It is a C3 cycloalkane or a 6-membered saturated heterocycle containing an oxygen atom,

[0569] in,

[0570] R A21 is a hydrogen atom,

[0571] R A22 is a hydrogen atom,

[0572] Ring A 3 It is C 3-5 Cycloalkanes, partially saturated 9-membered fused hydrocarbon aromatic rings or 6-membered saturated heterocyclic rings containing oxygen atoms,

[0573] in,

[0574] R A31 is a hydrogen atom,

[0575] R A32 A hydrogen atom.

[0576] More preferably, W is a methanediyl group, a propane-1,3-diyl group, or a structure represented by the following formulas [III-1] to [III-3]

[0577] [Chemistry 58]

[0578] ,

[0579] in,

[0580] The methanediyl group may be substituted by one group selected from methyl, n-butyl, haloethyl, benzyl, phenethyl and pyridylmethyl,

[0581] Furthermore, when the methanediyl group is substituted with one methyl group, it may be further substituted with one methyl group.

[0582] Ring A 1 is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

[0583] in,

[0584] The sulfur atom in the tetrahydrothiopyran can be substituted by two oxo groups.

[0585] The nitrogen atom in the azetidine, pyrrolidine and piperidine may be substituted by a methylcarbonyl group.

[0586] also,

[0587] R A11 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, an isopropoxy group or a morpholinyl group,

[0588] R A12 is a hydrogen atom, a fluorine atom or a methyl group,

[0589] also,

[0590] R A11 and R A12 can form oxygen together,

[0591] further,

[0592] R A11 and R A12 Each can form a cyclobutane together with the adjacent ring carbon atoms,

[0593] Ring A 2 is cyclopropane or tetrahydropyran,

[0594] in,

[0595] R A21 is a hydrogen atom,

[0596] R A22 is a hydrogen atom,

[0597] Ring A 3 is cyclopropane, cyclobutane, cyclopentane, dihydroindene, or tetrahydropyran,

[0598] in,

[0599] R A31 is a hydrogen atom,

[0600] R A32 A hydrogen atom.

[0601] R 1 A hydrogen atom.

[0602] R 2 C 6-10 Alkyl group, or a group represented by the following formula [IV-1] or [IV-2]

[0603] [Chemistry 59]

[0604] ,

[0605] in,

[0606] Ring B 1 C 3-8 Cycloalkyl, phenyl, or 5- to 6-membered heteroaryl containing a nitrogen atom,

[0607] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0608] L 1 C 3-8 Alkanediyl (the C 3-8 The alkanediyl group may be substituted with 1 to 5 fluorine atoms), the structure represented by the formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure represented by the following formula [V-1]

[0609] [Chemistry 60]

[0610] ,

[0611] in,

[0612] n11 is an integer from 0 to 3,

[0613] n12 is an integer from 0 to 5,

[0614] n13 is an integer from 0 to 3,

[0615] also,

[0616] As C 3-8 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L11 )-replaced,

[0617] R L1 C 1-3 alkyl,

[0618] Ring B 2 is a partially saturated 9- to 10-membered fused ring aryl group, or a partially saturated 9- to 10-membered fused ring heteroaryl group containing a nitrogen atom,

[0619] R B1 and R B2 are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl, or C 1-6 Alkoxy,

[0620] L 2 C 1-2 Alkanediyl (the C1-2 The alkanediyl group may be substituted by 1 to 4 fluorine atoms).

[0621] More preferably, R 2 C 7-8 Alkyl group or a group represented by the following formula [IV-1] or [IV-2]

[0622] [Chemistry 61]

[0623] ,

[0624] in,

[0625] Ring B 1 is a C6 cycloalkyl group, a phenyl group, or a 6-membered heteroaryl group containing a nitrogen atom,

[0626] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C1 alkyl group, or a C1 alkoxy group,

[0627] L 1 C 3-5 Alkanediyl (the C 3-5 The alkanediyl group may be substituted with 1 to 2 fluorine atoms), the structure represented by the formula [V-6]: -CH2CH2CH=C(CH3)-, or the structure represented by the following formula [V-1]

[0628] [Chemistry 62]

[0629] ,

[0630] in,

[0631] n1 is an integer from 0 to 1,

[0632] n2 is 1,

[0633] n3 is an integer from 0 to 1,

[0634] also,

[0635] As C 3-5 The distance R between one of the carbon atoms in the alkane diradical 2 The nitrogen atom to which the bond is bonded may be 2 or more atoms of the formula -O-, -S- or -N(R L1 )-replaced,

[0636] R L1 is a C1 alkyl group,

[0637] Ring B 2 is a partially saturated 9-membered fused ring aryl group, or a partially saturated 9-membered fused ring heteroaryl group containing a nitrogen atom,

[0638] RB1 and R B2 Similarly for hydrogen atoms,

[0639] L 2 It is a C2 alkane diyl.

[0640] More preferably, R 2 isoheptyl, isooctyl, or a group represented by the following formula [IV-1] or [IV-2]

[0641] [Chemistry 63]

[0642] ,

[0643] in,

[0644] Ring B 1 is cyclohexyl, phenyl, or pyridyl,

[0645] R B11 and R B12 are independently a hydrogen atom, a fluorine atom, a methyl group or a methoxy group, L 1 Any one of the structures represented by the following formulas [V-3] to [V-12] and [V-14] to [V-19],

[0646] [Chemistry 64]

[0647]

[0648] [Chemistry 65]

[0649]

[0650] in,

[0651] n4 is an integer from 3 to 5,

[0652] n12' is 1,

[0653] n12" is 1,

[0654] Ring B 2 is dihydroindanyl or isoindoleyl,

[0655] R B1 and R B2 Similarly for hydrogen atoms,

[0656] L 2 The structure shown in the following formula [V-20]

[0657] [Chemistry 66]

[0658] ,

[0659] in,

[0660] n5 is 2.

[0661] R 3 Represents a hydrogen atom or C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted by one group selected from hydroxyl and methoxy),

[0662] More preferably, R 3 A hydrogen atom or C 1-2 Alkyl (the C 1-2 The alkyl group may be substituted by one group selected from hydroxyl and methoxy),

[0663] More preferably, R 3 is a hydrogen atom, a methyl group (the methyl group may be substituted with one group selected from a hydroxyl group and a methoxy group), or an ethyl group.

[0664] R 4 represents a group represented by the following formula [VI]

[0665] [Chemistry 67]

[0666] ,

[0667] in,

[0668] Ring C is a phenyl group, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered fused heteroaryl group,

[0669] The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 One group in the alkylcarbonyl group is substituted, and further,

[0670] can be selected from hydroxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be substituted with one hydroxyl group), C 2-6 Alkenyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be substituted by one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, and single C 1-6 The alkylaminocarbonyl group is substituted by 1 to 4 identical or different groups,

[0671] The 6-membered heteroaryl group containing a nitrogen atom may be replaced by a C 1-6 Alkoxy substituted, further,

[0672] Can be selected from cyano and C 1-6 One group in the alkoxy group is substituted,

[0673] The 9-10 membered fused ring heteroaryl group can be selected from C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by 1 to 2 identical or different groups.

[0674] More preferably, R 4 It is a group represented by the following formula [VI]

[0675] [Chemistry 68]

[0676] ,

[0677] in,

[0678] Ring C is a phenyl group, a 6-membered heteroaryl group containing a nitrogen atom, or a 9- to 10-membered fused heteroaryl group,

[0679] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-2 One group in the alkylcarbonyl group is substituted, and further,

[0680] can be selected from hydroxyl, carbamoyl, cyano, halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted by one group selected from hydroxyl and C1 alkoxy), halogenated C2 alkyl (the halogenated C2 alkyl group may be substituted by one hydroxyl group), C 2-3 Alkenyl, C3 cycloalkyl (the C3 cycloalkyl may be substituted with one hydroxyl group), C 1-3 Alkoxy, halogenated C2 alkoxy, C3 cycloalkoxy, C1 alkylsulfinyl, C1 alkylsulfonyl, mono-C2 alkylamino, di-C 1-2 Alkylamino, C 1-2 substituted by 1 to 3 of the same or different groups selected from alkylcarbonyl, halogenated C1 alkylcarbonyl, C1 alkoxycarbonyl, and mono-C1 alkylaminocarbonyl,

[0681] The 6-membered heteroaryl group containing a nitrogen atom may be replaced by a C 1-2 Alkoxy substituted, further,

[0682] Can be selected from cyano and C 1-2 One group in the alkoxy group is substituted,

[0683] The 9-10 membered fused ring heteroaryl group can be selected from C 2-3 The alkyl group or the C2 alkoxy group may be substituted by 1 to 2 identical or different groups.

[0684] More preferably, R 4 It is a group represented by the following formula [VI]

[0685] [Chemistry 69]

[0686] ,

[0687] in,

[0688] Ring C is phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, dihydrobenzofuranyl or dihydroindolinyl,

[0689] The phenyl group may be substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a methylcarbonyl group, and an ethylcarbonyl group, and further,

[0690] may be substituted by 1 to 4 groups, which may be the same or different, selected from hydroxyl, carbamoyl, cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl (the methyl, ethyl, n-propyl and isopropyl may be substituted by one group selected from hydroxyl and methoxy), haloethyl (the haloethyl may be substituted by one hydroxyl), vinyl, isopropenyl, cyclopropyl (the cyclopropyl may be substituted by one hydroxyl), methoxy, ethoxy, n-propoxy, isopropoxy, haloethoxy, cyclopropyloxy, methylsulfinyl, methylsulfonyl, ethylamino, ethylmethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl and methylaminocarbonyl,

[0691] The pyridyl group or pyrimidyl group may be substituted by one methoxy group or ethoxy group, and further,

[0692] may be substituted by one group selected from cyano and ethoxy,

[0693] The pyrimidinyl group may be substituted by one methoxy group, and further may be substituted by one methoxy group.

[0694] The indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, dihydrobenzofuranyl or dihydroindolinyl may be substituted by 1 to 2 identical or different groups selected from ethyl, n-propyl or ethoxy.

[0695] In addition, R 3 and R 4 When it forms a fused ring with adjacent carbon atoms,

[0696] The preferred fused ring is a partially saturated 9- to 10-membered fused hydrocarbon aromatic ring (the partially saturated 9- to 10-membered fused hydrocarbon aromatic ring may be substituted by 1 to 2 halogen atoms) or a partially saturated 9- to 10-membered fused heteroaromatic ring containing oxygen atoms (the partially saturated 9- to 10-membered fused heteroaromatic ring containing oxygen atoms may be substituted by 1 to 2 halogen atoms).

[0697] More preferably, the fused ring is a partially saturated 9-membered fused hydrocarbon aromatic ring (the partially saturated 9-membered fused hydrocarbon aromatic ring may be substituted by 1 to 2 halogen atoms) or a partially saturated 9-membered fused heteroaromatic ring containing an oxygen atom (the partially saturated 9-membered fused heteroaromatic ring containing an oxygen atom may be substituted by 1 to 2 halogen atoms).

[0698] A further preferred fused ring is dihydroindene (the dihydroindene may be substituted with 1 to 2 halogen atoms) or dihydrobenzofuran (the dihydrobenzofuran may be substituted with 1 to 2 halogen atoms).

[0699] Another preferred embodiment of the compound of the present invention is the following embodiment (B).

[0700] Implementation method (B):

[0701] In the compound represented by the aforementioned formula [I] or its pharmaceutically acceptable salt or hydrate thereof,

[0702] The compound represented by formula [I] is a compound represented by the following formula [I-1]

[0703] [Chemistry 70]

[0704] ,

[0705] in,

[0706] R 2 It is a group represented by the following formula [IV-1] or [IV-2]

[0707] [Chemistry 71]

[0708]

[0709] In this embodiment,

[0710] X is carboxyl, C 1-4 an alkoxycarbonyl group or a tetrazolyl group,

[0711] A more preferred X is carboxyl or tetrazolyl,

[0712] In this case, a further preferred X is a carboxyl group,

[0713] In this case, another further preferred X is tetrazolyl,

[0714] Another more preferred X is C 1-4 Alkoxycarbonyl,

[0715] In this case, a further preferred X is a C1 alkoxycarbonyl group,

[0716] In this case, another further preferred X is a C2 alkoxycarbonyl group,

[0717] In this case, another further preferred X is a C4 alkoxycarbonyl group.

[0718] W is a methanediyl group or a structure represented by the following formula [III-1]

[0719] [Chemistry 72]

[0720] ,

[0721] in,

[0722] The methanediyl group may be selected from C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C 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,

[0723] Furthermore, when the methanediyl group is substituted with one methyl group, it may be further substituted with one methyl group.

[0724] also,

[0725] In the structure represented by formula [III-1],

[0726] Preferred Ring A 1 It is C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 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,

[0727] in,

[0728] The sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0729] also,

[0730] The nitrogen atom in the 4-8 membered saturated heterocyclic ring containing nitrogen atom can be selected from C 1-4 Alkylcarbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted,

[0731] Preferred R A11 It is a hydrogen atom, a hydroxyl group, a carboxyl group, a halogen atom, a C 1-6 Alkyl, C 1-6 Alkoxy, or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom (the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 alkyl substituted),

[0732] Preferred R A12 is a hydrogen atom, a halogen atom, or a methyl group,

[0733] also,

[0734] R A11 and R A12 can form oxygen together,

[0735] further,

[0736] R A11 and R A12 Each can form a C 3-6 Cycloalkanes.

[0737] More preferably, W is a methanediyl group or a structure represented by the following formula [III-1]

[0738] [Chemistry 73]

[0739] ,

[0740] in,

[0741] The methanediyl group may be selected from C 1-4 Alkyl (the C 1-4 The alkyl group may be substituted by one group selected from hydroxyl and carboxyl), halogenated C2 alkyl, phenyl C 1-2 Alkyl, and pyridyl C1 alkyl substituted with one group,

[0742] Furthermore, when the methanediyl group is substituted with one methyl group, it may be further substituted with one methyl group.

[0743] also,

[0744] In the structure represented by formula [III-1],

[0745] Preferred Ring A 1 It is C 3-7Cycloalkanes, partially saturated 9-membered fused hydrocarbon aromatic rings, 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,

[0746] in,

[0747] The sulfur atom in the 6-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[0748] also,

[0749] The nitrogen atom in the nitrogen-containing 4- to 6-membered saturated heterocyclic ring may be substituted by one group selected from C1 alkylcarbonyl groups.

[0750] Preferred R A11 yes

[0751] Hydrogen atom, hydroxyl group, carboxyl group, halogen atom, C1 alkyl group, C 1-3 an alkoxy group, or a 5- to 6-membered saturated heterocyclic group containing a nitrogen atom (the 5- to 6-membered saturated heterocyclic group containing a nitrogen atom may be substituted with one C1 alkyl group),

[0752] Preferred R A12 is a hydrogen atom, a halogen atom, or a methyl group,

[0753] also,

[0754] R A11 and R A12 can form oxygen together,

[0755] further,

[0756] R A11 and R A12 Each can form a C4 cycloalkane together with the adjacent ring carbon atoms.

[0757] More preferably, W is a methanediyl group or a structure represented by the following formula [III-1]

[0758] [Chemistry 74]

[0759] ,

[0760] in,

[0761] The methanediyl group may be substituted by one group selected from the group consisting of methyl (the methyl group may be substituted by one group selected from the group consisting of hydroxyl and carboxyl), ethyl, n-butyl, isobutyl, haloethyl, benzyl, phenethyl and pyridylmethyl.

[0762] Furthermore, when the methanediyl group is substituted with one methyl group, it may be further substituted with one methyl group.

[0763] also,

[0764] In the structure represented by formula [III-1],

[0765] Preferred Ring A 1 is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

[0766] in,

[0767] The sulfur atom in the tetrahydrothiopyran can be substituted by two oxo groups.

[0768] also,

[0769] The nitrogen atom in the azetidine, pyrrolidine and piperidine may be substituted by a methylcarbonyl group.

[0770] Preferred R A11 yes

[0771] a hydrogen atom, a hydroxyl group, a carboxyl group, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, an isopropoxy group, a pyrrolidinyl group, a morpholinyl group, or a piperazinyl group (the piperazinyl group may be substituted with one methyl group),

[0772] Preferred R A12 is a hydrogen atom, a fluorine atom, or a methyl group,

[0773] also,

[0774] R A11 and R A12 can form oxygen together,

[0775] further,

[0776] R A11 and R A12 Each can be taken together with adjacent ring carbon atoms to form a cyclobutane.

[0777] Ring B 1 is phenyl,

[0778] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0779] L 1 C 3-8 Alkanediyl (the C 3-8 The alkanediyl group may be substituted by 1 to 5 fluorine atoms).

[0780] also,

[0781] As C 3-8The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms to which the nitrogen atom is bonded may be replaced by atoms of the formula -O-.

[0782] Ring B 2 is a partially saturated 9- to 10-membered fused ring aryl group, or a 9- to 10-membered fused ring heteroaryl group containing a nitrogen atom,

[0783] R B21 and R B22 Similarly for hydrogen atoms,

[0784] L 2 C 1-2 Alkanediyl (the C 1-2 The alkanediyl group may be substituted by 1 to 4 fluorine atoms).

[0785] More preferred ring B 1 It is phenyl,

[0786] R B11 and R B12 are independently a hydrogen atom, a halogen atom, a C1 alkyl group, or a C1 alkoxy group,

[0787] L 1 C 3-6 Alkanediyl (the C 3-6 The alkanediyl group may be substituted by 1 to 2 fluorine atoms).

[0788] also,

[0789] As C 3-6 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms to which the nitrogen atom is bonded may be replaced by atoms of the formula -O-.

[0790] More preferred ring B 2 is a partially saturated 9-membered fused ring aryl group, or a 9-membered fused ring heteroaryl group containing a nitrogen atom,

[0791] R B21 and R B22 Similarly for hydrogen atoms,

[0792] L 2 It is C 1-2 Alkanediyl.

[0793] Further preferred ring B 1 It is phenyl,

[0794] R B11 and R B12 are independently a hydrogen atom, a fluorine atom, a methyl group, or a methoxy group,

[0795] L 1Any one of the structures represented by the following formulas [V-3] to [V-5], [V-7] to [V-8], [V-11] to [V-12], and [V-14] to [V-16],

[0796] [Chemistry 75]

[0797]

[0798] [Chemistry 76]

[0799]

[0800] in,

[0801] n4 is an integer from 3 to 5.

[0802] Further preferred ring B 2 is indanyl, indolyl, or isoindolyl,

[0803] R B21 and R B22 Similarly for hydrogen atoms,

[0804] L 2 The structure shown in the following formula [V-20]

[0805] [Chemistry 77]

[0806] ,

[0807] in,

[0808] n5 is an integer from 1 to 2.

[0809] R 3 It is C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted by one group selected from hydroxyl and methoxy),

[0810] More preferably, R 3 is a methyl group (the methyl group may be substituted with one group selected from a hydroxyl group and a methoxy group) or an ethyl group,

[0811] More preferably, R 3 It's methyl.

[0812] Particularly preferred R 3 It is a methyl group having the stereo configuration shown in the following formula [VII]

[0813] [Chemistry 78]

[0814] .

[0815] R 4 represents a group represented by the following formula [VI]

[0816] [Chemistry 79]

[0817] ,

[0818] in,

[0819] Ring C is phenyl,

[0820] in,

[0821] The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 One group in the alkylcarbonyl group is substituted, and further,

[0822] can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-6 Alkyl (the C 1-6 The alkyl group may be selected from hydroxyl and C 1-6 1 group in the alkoxy group), halogenated C 1-6 Alkyl (the halogenated C 1-6 The alkyl group may be substituted with one hydroxyl group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl (the C 3-8 The cycloalkyl group may be substituted by one hydroxyl group), C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, halogenated C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, mono-C 1-6 Alkylaminocarbonyl and di-C 1-6 The alkylaminocarbonyl group may be substituted by 1 to 4 groups which may be the same or different.

[0823] More preferably, R 4 It is a group represented by the following formula [VI]

[0824] [Chemistry 80]

[0825] ,

[0826] in,

[0827] Ring C is phenyl,

[0828] in,

[0829] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-2 One group in the alkylcarbonyl group is substituted, and further,

[0830] can be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted by one group selected from hydroxyl and C1 alkoxy), halogenated C 1-2 Alkyl (the halogenated C 1-2 The alkyl group may be substituted with one hydroxyl group), C 2-3 Alkenyl, C3 cycloalkyl (the C3 cycloalkyl may be substituted with one hydroxyl group), C 1-3 Alkoxy, halogenated C2 alkoxy, C3 cycloalkoxy, C1 alkylsulfinyl, C1 alkylsulfonyl, mono-C2 alkylamino, di-C2 alkylamino, C 1-2 The alkylcarbonyl group may be substituted with 1 to 4 of the same or different groups selected from the group consisting of an alkylcarbonyl group, a halogenated C1 alkylcarbonyl group, a C1 alkoxycarbonyl group, and a mono-C1 alkylaminocarbonyl group.

[0831] More preferably, R 4 It is a group represented by the following formula [VI]

[0832] [Chemistry 81]

[0833] ,

[0834] in,

[0835] Ring C is phenyl,

[0836] in,

[0837] The phenyl group may be substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a methylcarbonyl group, and an ethylcarbonyl group, and further,

[0838] The group may be substituted by 1 to 4 groups, which may be the same or different, selected from hydroxyl, carboxyl, carbamoyl, cyano, fluorine, chlorine, bromine, methyl (the methyl may be substituted by one group selected from hydroxyl and methoxy), ethyl, n-propyl, isopropyl (the ethyl, n-propyl and isopropyl may be substituted by one hydroxyl), halomethyl, haloethyl (the haloethyl may be substituted by one hydroxyl), vinyl, isopropenyl, cyclopropyl (the cyclopropyl may be substituted by one hydroxyl), methoxy, ethoxy, n-propoxy, isopropoxy, haloethoxy, cyclopropyloxy, methylsulfinyl, methylsulfonyl, monoethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl and methylaminocarbonyl.

[0839] Another preferred embodiment of the compound of the present invention is the following embodiment (C).

[0840] Implementation method (C):

[0841] In this embodiment (C), preferred embodiments are as follows.

[0842] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[0843] The compound represented by formula [I-1] is a compound represented by the following formula [I-2]

[0844] [Chemistry 82]

[0845] ,

[0846] in,

[0847] R 2 It is a group represented by the following formula [IV-1] or [IV-2]

[0848] [Chemistry 83]

[0849] ;

[0850] in,

[0851] W, Ring B 1 、R B11 、R B12 , L 1 , Ring B 2 、R B21 、R B22 , L 2 and R 4 As mentioned above.

[0852] In this embodiment (C), more preferred embodiments are as follows.

[0853] In the aforementioned formula [I-2],

[0854] W is a methanediyl group or a structure represented by the above formula [III-1]

[0855] [Chemistry 84]

[0856] ,

[0857] in,

[0858] The methanediyl group may be substituted with one methyl group.

[0859] Moreover, it can be further substituted with one methyl group.

[0860] also,

[0861] In the structure represented by formula [III-1],

[0862] Ring A 1 It is C 3-4 Cycloalkane or a 4-5 membered saturated heterocyclic ring containing oxygen atoms,

[0863] R A11 is a hydrogen atom, a hydroxyl group, a halogen atom, a C1 alkyl group or a C 1-2 Alkoxy,

[0864] R A12 is a hydrogen atom, a halogen atom or a methyl group;

[0865] Ring B 1 is phenyl,

[0866] R B11 and R B12 At the same time, it is a hydrogen atom,

[0867] L 1 C 3-5 Alkanediyl (the C 3-5 The alkanediyl group may be substituted by 1 to 2 fluorine atoms).

[0868] in,

[0869] As C 3-5 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-.

[0870] Ring B 2 is a partially saturated 9-membered fused ring aromatic group,

[0871] R B21 and R B22 At the same time, it is a hydrogen atom;

[0872] L 2is a C2 alkanediyl group;

[0873] R 4 represents a group represented by the following formula [VI]

[0874] [Chemistry 85]

[0875] ,

[0876] in,

[0877] Ring C is phenyl,

[0878] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-2 Alkoxy and C1 alkylcarbonyl are substituted, and further,

[0879] Can be selected from cyano, halogen atoms, C 1-3 Alkyl (the C 1-3 Alkyl may be substituted with one hydroxyl group), C2 alkenyl, C3 cycloalkyl, C 1-2 The alkyl group is substituted by 1 to 4 of the same or different groups selected from the group consisting of alkoxy, mono-C2 alkylamino and C1 alkylcarbonyl.

[0880] In this embodiment (C), further preferred embodiments are as follows.

[0881] In the aforementioned formula [I-2],

[0882] W is any one of the structures represented by the following formulas [III-4] to [III-17]

[0883] [Chemistry 86]

[0884] ;

[0885] Ring B 1 is phenyl,

[0886] R B11 and R B12 Similarly for hydrogen atoms,

[0887] L 1 The structure represented by the following formula [V-3], [V-8], [V-12], [V-14], or [V-15]

[0888] [Chemistry 87]

[0889] ,

[0890] in,

[0891] n4 is an integer from 3 to 4,

[0892] Ring B2 is dihydroindanyl,

[0893] R B21 and R B22 Similarly for hydrogen atoms,

[0894] L 2 The structure shown in the following formula [V-20]

[0895] [Chemistry 88]

[0896] ,

[0897] in,

[0898] n5 is 2;

[0899] R 4 Any one of the groups represented by the following formulas [VI-1] to [VI-21]

[0900] [Chemistry 89]

[0901]

[0902] [Chemistry 90]

[0903]

[0904] [Chemistry 91]

[0905] .

[0906] Another preferred embodiment of the compound of the present invention is the following embodiment (D).

[0907] Implementation method (D):

[0908] In this embodiment (D), preferred embodiments are as follows.

[0909] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[0910] The compound represented by formula [I-1] is a compound represented by the following formula [I-3]

[0911] [Chemistry 92]

[0912] ,

[0913] in,

[0914] R 2 It is a group represented by the following formula [IV-1] or [IV-2]

[0915] [Chemistry 93]

[0916] ;

[0917] in,

[0918] W, Ring B 1 、R B11 、R B12 , L 1 , Ring B 2 、R B21 、R B22 , L 2 and R 4 As mentioned above.

[0919] In this embodiment (D), more preferred embodiments are as follows.

[0920] In the aforementioned formula [I-3],

[0921] W is a methanediyl group or a structure represented by the above formula [III-1]

[0922] [Chemistry 94]

[0923] ,

[0924] in,

[0925] The methanediyl group may be substituted with one methyl group.

[0926] Moreover, it can be further substituted with one methyl group.

[0927] also,

[0928] In the structure represented by formula [III-1],

[0929] Ring A 1 It is C 3-4 Cycloalkanes,

[0930] R A11 is a hydrogen atom, a halogen atom, a C1 alkyl group or a C 1-2 Alkoxy,

[0931] R A12 is a hydrogen atom, a halogen atom or a methyl group;

[0932] Ring B 1 is phenyl,

[0933] R B11 and R B12 At the same time, it is a hydrogen atom,

[0934] L 1 It is C 4-5 Alkanediyl (the C 4-5 The alkanediyl group may be substituted by two fluorine atoms).

[0935] also,

[0936] As C 4-5 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-.

[0937] Ring B 2 is a partially saturated 9-membered fused ring aromatic group,

[0938] R B21 and R B22 At the same time, it is a hydrogen atom,

[0939] L 2 is a C2 alkanediyl group;

[0940] R 4 represents a group represented by the following formula [VI]

[0941] [Chemistry 95]

[0942] ,

[0943] in,

[0944] Ring C is phenyl,

[0945] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-2 Alkoxy and C1 alkylcarbonyl are substituted, and further,

[0946] Can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one hydroxyl group), C 1-2 The alkyl group is substituted by 1 to 4 of the same or different groups selected from the group consisting of alkoxy, mono-C2 alkylamino and C1 alkylcarbonyl.

[0947] In this embodiment (D), further preferred embodiments are as follows.

[0948] In the aforementioned formula [I-3],

[0949] W is a structure represented by the following formula [III-4] to [III-11], [III-13] to [III-14], or [III-18] to [III-19]

[0950] [Chemistry 96]

[0951] ;

[0952] Ring B 1 is phenyl,

[0953] R B11 and R B12 Similarly for hydrogen atoms,

[0954] L 1 The structure represented by the following formula [V-3], [V-8], or [V-14]

[0955] [Chemistry 97]

[0956] ,

[0957] in,

[0958] n4 is 4,

[0959] Ring B 2 is dihydroindanyl,

[0960] R B21 and R B22 At the same time, it is a hydrogen atom,

[0961] L 2 The structure shown in the following formula [V-20]

[0962] [Chemistry 98]

[0963] ,

[0964] in,

[0965] n5 is 2;

[0966] R 4 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]

[0967] [Chemistry 99]

[0968]

[0969] [Chemistry 100]

[0970] .

[0971] Another preferred embodiment of the compound of the present invention is the following embodiment (E).

[0972] Implementation method (E):

[0973] In this embodiment (E), preferred embodiments are as follows.

[0974] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[0975] The compound represented by formula [I-1] is a compound represented by the following formula [I-4]

[0976] [Chemistry 101]

[0977] ,

[0978] in,

[0979] R 4 It is a group represented by the following formula [VI-22]

[0980] [Chemistry 102]

[0981] ,

[0982] The group represented by the formula [VI-22] is replaced by 1 to 2 C 1-6 Alkoxy substitution;

[0983] Preferred W, Ring B 1 、R B11 、R B12 and L 1 As mentioned above.

[0984] In this embodiment (E), more preferred embodiments are as follows.

[0985] In the aforementioned formula [I-4],

[0986] W is a structure represented by the following formula [III-1]

[0987] [Chemistry 103]

[0988] ,

[0989] in,

[0990] In the structure represented by formula [III-1],

[0991] Ring A 1 It is a C4 cycloalkane,

[0992] R A11 It is C 1-2 Alkoxy,

[0993] R A12 It is a hydrogen atom;

[0994] Ring B 1 is phenyl,

[0995] R B11 and R B12Similarly for hydrogen atoms,

[0996] L 1 is a C5 alkane diyl,

[0997] As the distance R between one of the carbon atoms in the C5 alkane diyl group 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-;

[0998] R 4 is a group represented by the aforementioned formula [VI-22]

[0999] [Chemistry 104]

[1000] ,

[1001] in,

[1002] The group represented by the formula [VI-22] is substituted by two C2 alkoxy groups.

[1003] In this embodiment (E), further preferred embodiments are as follows.

[1004] In the aforementioned formula [I-4],

[1005] W is a structure represented by the following formulas [III-8] to [III-11]

[1006] [Chemistry 105]

[1007] ;

[1008] Ring B 1 is phenyl,

[1009] R B11 and R B12 Similarly for hydrogen atoms,

[1010] L 1 The structure shown in the following formula [V-14]

[1011] [Chemistry 106]

[1012] ;

[1013] R 4 It is a group represented by the following formula [VI-6]

[1014] [Chemistry 107]

[1015] .

[1016] Furthermore, in this embodiment (E), a particularly preferred embodiment is as follows.

[1017] The compound represented by the above formula [I-4] is any of the following:

[1018] [Chemistry 108]

[1019] .

[1020] In addition, in this embodiment (E), other particularly preferred embodiments are as follows.

[1021] The compound represented by the aforementioned formula [I-4] is as follows:

[1022] [Chemistry 109]

[1023] .

[1024] In addition, in this embodiment (E), other particularly preferred embodiments are as follows.

[1025] The compound represented by the aforementioned formula [I-4] is as follows:

[1026] [Chemistry 110]

[1027] .

[1028] In addition, in this embodiment (E), other particularly preferred embodiments are as follows.

[1029] The compound represented by the aforementioned formula [I-4] is as follows:

[1030] [Chemistry 111]

[1031] .

[1032] In addition, in this embodiment (E), other particularly preferred embodiments are as follows.

[1033] The compound represented by the aforementioned formula [I-4] is as follows:

[1034] [Chemistry 112]

[1035] .

[1036] Another preferred embodiment of the compound of the present invention is the following embodiment (F).

[1037] Implementation method (F):

[1038] In this embodiment (F), preferred embodiments are as follows.

[1039] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1040] The compound represented by formula [I-1] is a compound represented by the following formula [I-5]

[1041] [Chemistry 113]

[1042] ,

[1043] in,

[1044] W, L 2 and R 4 As mentioned above.

[1045] In this embodiment (F), more preferred embodiments are as follows.

[1046] In the aforementioned formula [I-5],

[1047] W is a structure represented by the following formula [III-1]

[1048] [Chemistry 114]

[1049] ,

[1050] in,

[1051] In the structure represented by formula [III-1],

[1052] Ring A 1 It is a C4 cycloalkane,

[1053] R A11 is a C1 alkoxy group,

[1054] R A12 It is a hydrogen atom;

[1055] L 2 is a C2 alkanediyl group;

[1056] R 4 represents a group represented by the following formula [VI]

[1057] [Chemistry 115]

[1058] ,

[1059] in,

[1060] Ring C is phenyl,

[1061] The phenyl group may be substituted by three identical or different groups selected from C2 alkoxy and C1 alkylcarbonyl groups, and further,

[1062] It may be substituted by 1 C1 alkyl group.

[1063] In this embodiment (F), further preferred embodiments are as follows.

[1064] In the aforementioned formula [I-5],

[1065] W is a structure represented by the following formula [III-8] or [III-9]

[1066] [Chemistry 116]

[1067] ;

[1068] L 2 The structure shown in the following formula [V-20]

[1069] [Chemistry 117]

[1070] ,

[1071] in,

[1072] n5 is 2;

[1073] R 4 It is a group represented by the following formula [VI-10] or [VI-12]

[1074] [Chemistry 118]

[1075] .

[1076] Furthermore, in this embodiment (F), a particularly preferred embodiment is as follows.

[1077] The compound represented by the aforementioned formula [I-5] is any of the following:

[1078] [Chemistry 119]

[1079] .

[1080] In addition, in this embodiment (F), other particularly preferred embodiments are as follows.

[1081] The compound represented by the aforementioned formula [I-5] is as follows:

[1082] [Chemistry 120]

[1083] .

[1084] In addition, in this embodiment (F), other particularly preferred embodiments are as follows.

[1085] The compound represented by the aforementioned formula [I-5] is as follows:

[1086] [Chemistry 121]

[1087] .

[1088] In addition, in this embodiment (F), other particularly preferred embodiments are as follows.

[1089] The compound represented by the aforementioned formula [I-5] is as follows:

[1090] [Chemistry 122]

[1091] .

[1092] In addition, in this embodiment (F), other particularly preferred embodiments are as follows.

[1093] The compound represented by the aforementioned formula [I-5] is as follows:

[1094] [Chemistry 123]

[1095] .

[1096] Another preferred embodiment of the compound of the present invention is the following embodiment (F-2).

[1097] Implementation method (F-2):

[1098] In this embodiment (F-2), preferred embodiments are as follows.

[1099] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1100] The compound represented by formula [I-1] is a compound represented by the following formula [I-5-2]

[1101] [Chemistry 124]

[1102] ,

[1103] in,

[1104] R 4 It is a group represented by the following formula [VI-26]

[1105] [Chemistry 125]

[1106] ,

[1107] The group represented by the formula [VI-26] can be selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-6 One group in the alkylcarbonyl group is substituted, and further,

[1108] can be selected from halogen atoms and C 1-6 One group in the alkyl group is substituted;

[1109] W as described above.

[1110] In this embodiment (F-2), more preferred embodiments are as follows.

[1111] In the above formula [I-5-2],

[1112] W is a structure represented by the following formula [III-1]

[1113] [Chemistry 126]

[1114] ,

[1115] in,

[1116] In the structure represented by formula [III-1],

[1117] Ring A 1 It is a C4 cycloalkane,

[1118] R A11 It is C 1-2 Alkoxy,

[1119] R A12 It is a hydrogen atom;

[1120] R 4 is a group represented by the aforementioned formula [VI-26]

[1121] [Chemistry 127]

[1122] ,

[1123] in,

[1124] The group represented by the formula [VI-26] may be substituted by one group selected from the group consisting of a C1 alkyl group, a C3 cycloalkyl group, and a C1 alkylcarbonyl group, and further,

[1125] It may be substituted by one group selected from a halogen atom and a C1 alkyl group.

[1126] In this embodiment (F-2), further preferred embodiments are as follows.

[1127] In the above formula [I-5-2],

[1128] W is a structure represented by the following formula [III-8] or [III-10]

[1129] [Chemistry 128]

[1130] ;

[1131] R 4 A group represented by the following formula [VI-2], [VI-6], [VI-10] to [VI-12], [VI-27], or [VI-28]

[1132] [Chemistry 129]

[1133] .

[1134] Furthermore, in this embodiment (F-2), particularly preferred embodiments are as follows.

[1135] The compound represented by the above formula [I-5-2] is the following:

[1136] [Chemistry 130]

[1137] .

[1138] Another preferred embodiment of the compound of the present invention is the following embodiment (G).

[1139] Implementation method (G):

[1140] In this embodiment (G), preferred embodiments are as follows.

[1141] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1142] The compound represented by formula [I-1] is a compound represented by the following formula [I-6]

[1143] [Chemistry 131]

[1144] ,

[1145] in,

[1146] R 4 It is a group represented by the following formula [VI-23]

[1147] [Chemistry 132]

[1148] ,

[1149] The group represented by the formula [VI-23] may be replaced by one C 1-6 Alkylcarbonyl substituted, further,

[1150] Can be substituted by 1 halogen atom;

[1151] W, Ring B 1 、R B11 、R B12and L 1 As mentioned above.

[1152] In this embodiment (G), more preferred embodiments are as follows.

[1153] In the aforementioned formula [I-6],

[1154] W is a structure represented by the following formula [III-1]

[1155] [Chemistry 133]

[1156] ,

[1157] in,

[1158] In the structure represented by formula [III-1],

[1159] Ring A 1 It is a C4 cycloalkane,

[1160] R A11 It is C 1-2 Alkoxy,

[1161] R A12 It is a hydrogen atom;

[1162] Ring B 1 is phenyl,

[1163] R B11 and R B12 Similarly for hydrogen atoms,

[1164] L 1 C 4-5 Alkanediyl,

[1165] As the C 4-5 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-;

[1166] R 4 is a group represented by the aforementioned formula [VI-23]

[1167] [Chemistry 134]

[1168] ,

[1169] in,

[1170] The group represented by the formula [VI-23] may be substituted with one C1 alkylcarbonyl group, and further,

[1171] It may be substituted by one halogen atom.

[1172] In this embodiment (G), further preferred embodiments are as follows.

[1173] In the aforementioned formula [I-6],

[1174] W is a structure represented by the following formula [III-8] or [III-10]

[1175] [Chemistry 135]

[1176] ;

[1177] Ring B 1 is phenyl,

[1178] R B11 and R B12 Similarly for hydrogen atoms,

[1179] L 1 The structure represented by the following formula [V-12] or [V-14]

[1180] [Chemistry 136]

[1181] ;

[1182] R 4 It is a group represented by the following formula [VI-24] or [VI-25]

[1183] [Chemistry 137]

[1184] .

[1185] Furthermore, in this embodiment (G), a particularly preferred embodiment is as follows.

[1186] The compound represented by the aforementioned formula [I-6] is any of the following:

[1187] [Chemistry 138]

[1188]

[1189] [Chemistry 139]

[1190] .

[1191] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1192] The compound represented by the aforementioned formula [I-6] is as follows:

[1193] [Chemistry 140]

[1194] .

[1195] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1196] The compound represented by the aforementioned formula [I-6] is as follows:

[1197] [Chemistry 141]

[1198] .

[1199] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1200] The compound represented by the aforementioned formula [I-6] is as follows:

[1201] [Chemistry 142]

[1202]

[1203] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1204] The compound represented by the aforementioned formula [I-6] is as follows:

[1205] [Chemistry 143]

[1206] .

[1207] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1208] The compound represented by the aforementioned formula [I-6] is as follows:

[1209] [Chemistry 144]

[1210] .

[1211] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1212] The compound represented by the aforementioned formula [I-6] is as follows:

[1213] [Chemistry 145]

[1214] .

[1215] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1216] The compound represented by the aforementioned formula [I-6] is as follows:

[1217] [Chemistry 146]

[1218] .

[1219] In addition, in this embodiment (G), other particularly preferred embodiments are as follows.

[1220] The compound represented by the aforementioned formula [I-6] is as follows:

[1221] [Chemistry 147]

[1222] .

[1223] Another preferred embodiment of the compound of the present invention is the following embodiment (G-2).

[1224] Implementation method (G-2):

[1225] In this embodiment (G-2), preferred embodiments are as follows.

[1226] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1227] The compound represented by formula [I-1] is a compound represented by the following formula [I-6-2]

[1228] [Chemistry 148]

[1229] ,

[1230] in,

[1231] R 4 It is a group represented by the following formula [VI-29]

[1232] [Chemistry 149]

[1233] ,

[1234] The group represented by the formula [VI-29] is selected from halogen atoms and C 1-6 One group in the alkyl group is substituted;

[1235] W as described above.

[1236] In this embodiment (G-2), more preferred embodiments are as follows.

[1237] In the above formula [I-6-2],

[1238] W is a structure represented by the following formula [III-1]

[1239] [Chemistry 150]

[1240] ,

[1241] in,

[1242] In the structure represented by formula [III-1],

[1243] Ring A 1 It is a C4 cycloalkane,

[1244] R A11 Is a hydrogen atom, a halogen atom or a C 1-2 Alkoxy,

[1245] R A12 is a hydrogen atom or a halogen atom;

[1246] R 4 It is a group represented by the above formula [VI-29]

[1247] [Chemistry 151]

[1248] ,

[1249] in,

[1250] The group represented by the formula [VI-29] is substituted with one group selected from a halogen atom and a C1 alkyl group.

[1251] In this embodiment (G-2), further preferred embodiments are as follows.

[1252] In the above formula [I-6-2],

[1253] W is a structure represented by the following formula [III-6], [III-8] to [III-11], or [III-13]

[1254] [Chemistry 152]

[1255] ;

[1256] R 4 It is a group represented by the following formula [VI-30] or [VI-31]

[1257] [Chemistry 153]

[1258] .

[1259] Furthermore, in this embodiment (G-2), a particularly preferred embodiment is as follows.

[1260] The compound represented by the above formula [I-6-2] is any of the following:

[1261] [Chemistry 154]

[1262] .

[1263] [Chemistry 155]

[1264] .

[1265] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1266] The compound represented by the above formula [I-6-2] is as follows:

[1267] [Chemistry 156]

[1268] .

[1269] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1270] The compound represented by the above formula [I-6-2] is as follows:

[1271] [Chemistry 157]

[1272] .

[1273] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1274] The compound represented by the above formula [I-6-2] is the following:

[1275] [Chemistry 158]

[1276] .

[1277] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1278] The compound represented by the above formula [I-6-2] is as follows:

[1279] [Chemistry 159]

[1280] .

[1281] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1282] The compound represented by the above formula [I-6-2] is the following:

[1283] [Chemistry 160]

[1284] .

[1285] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1286] The compound represented by the above formula [I-6-2] is the following:

[1287] [Chemistry 161]

[1288] .

[1289] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1290] The compound represented by the above formula [I-6-2] is the following:

[1291] [Chemistry 162]

[1292] .

[1293] In addition, in this embodiment (G-2), other particularly preferred embodiments are as follows.

[1294] The compound represented by the above formula [I-6-2] is the following:

[1295] [Chemistry 163]

[1296] .

[1297] Another preferred embodiment of the compound of the present invention is the following embodiment (H).

[1298] Implementation method (H):

[1299] In this embodiment (H), preferred embodiments are as follows.

[1300] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1301] The compound represented by formula [I-1] is a compound represented by the following formula [I-7]

[1302] [Chemistry 164]

[1303] ,

[1304] in,

[1305] R 2 It is a group represented by the following formula [IV-1] or [IV-2]

[1306] [Chemistry 165]

[1307] ;

[1308] X, W, Ring B 1 、R B11 、R B12 , L 1 , Ring B 2 、R B21 、R B22 , L 2 , and R 4 As mentioned above.

[1309] In this embodiment (H), more preferred embodiments are as follows.

[1310] In the aforementioned formula [I-7],

[1311] X is a carboxyl group or a tetrazolyl group;

[1312] W is a structure represented by the following formula [III-1]

[1313] [Chemistry 166]

[1314] ,

[1315] in,

[1316] In the structure represented by formula [III-1],

[1317] Ring A 1 yes

[1318] C 3-4 Cycloalkanes,

[1319] R A11 yes

[1320] Hydrogen atom, halogen atom, or C 1-2 Alkoxy,

[1321] R A12 yes

[1322] a hydrogen atom or a halogen atom;

[1323] Ring B 1 is phenyl,

[1324] R B11 and R B12 Similarly for hydrogen atoms,

[1325] L 1 It is C 4-5 Alkanediyl (the C 4-5 The alkanediyl group may be substituted by two fluorine atoms).

[1326] also,

[1327] As C 4-5The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-.

[1328] Ring B 2 is a partially saturated 9-membered fused ring aromatic group,

[1329] R B21 and R B22 Similarly for hydrogen atoms,

[1330] L 2 is a C2 alkanediyl group;

[1331] R 4 represents a group represented by the following formula [VI]

[1332] [Chemistry 167]

[1333] ,

[1334] in,

[1335] Ring C is phenyl,

[1336] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-2 Alkoxy and C1 alkylcarbonyl are substituted, and further,

[1337] Can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one hydroxyl group), C 1-2 The alkoxy group or C1 alkylcarbonyl group is substituted by 1 to 3 groups which are the same or different.

[1338] In this embodiment (H), further preferred embodiments are as follows.

[1339] In the aforementioned formula [I-7],

[1340] X is a carboxyl group or a tetrazolyl group;

[1341] W is a structure represented by the following formula [III-5], [III-8] to [III-11], or [III-13]

[1342] [Chemistry 168]

[1343] ;

[1344] Ring B 1 is phenyl,

[1345] R B11 and R B12 Similarly for hydrogen atoms,

[1346] L 1 The structure represented by the following formula [V-3], [V-12], or [V-14]

[1347] [Chemistry 169]

[1348] ,

[1349] in,

[1350] n4 is an integer of 4,

[1351] Ring B 2 is dihydroindanyl,

[1352] R B21 and R B22 Similarly for hydrogen atoms,

[1353] L 2 The structure shown in the following formula [V-20]

[1354] [Chemistry 170]

[1355] ,

[1356] in,

[1357] n5 is 2;

[1358] R 4 A group represented by the following formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11], or [VI-12]

[1359] [Chemistry 171]

[1360] .

[1361] Furthermore, in this embodiment (H),

[1362] A particularly preferred embodiment is that the compound represented by the aforementioned formula [I-7] is

[1363] Any of the following situations:

[1364] [Chemistry 172]

[1365]

[1366] [Chemistry 173]

[1367]

[1368] [Chemistry 174]

[1369]

[1370] [Chemistry 175]

[1371]

[1372] [Chemistry 176]

[1373] .

[1374] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1375] The compound represented by the aforementioned formula [I-7] is as follows:

[1376] [Chemistry 177]

[1377] .

[1378] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1379] The compound represented by the aforementioned formula [I-7] is as follows:

[1380] [Chemistry 178]

[1381] .

[1382] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1383] The compound represented by the aforementioned formula [I-7] is as follows:

[1384] [Chemistry 179]

[1385] .

[1386] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1387] The compound represented by the aforementioned formula [I-7] is as follows:

[1388] [Chemistry 180]

[1389] .

[1390] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1391] The compound represented by the aforementioned formula [I-7] is as follows:

[1392] [Chemistry 181]

[1393] .

[1394] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1395] The compound represented by the aforementioned formula [I-7] is as follows:

[1396] [Chemistry 182]

[1397] .

[1398] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1399] The compound represented by the aforementioned formula [I-7] is as follows:

[1400] [Chemistry 183]

[1401] .

[1402] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1403] The compound represented by the aforementioned formula [I-7] is as follows:

[1404] [Chemistry 184]

[1405] .

[1406] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1407] The compound represented by the aforementioned formula [I-7] is as follows:

[1408] [Chemistry 185]

[1409] .

[1410] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1411] The compound represented by the aforementioned formula [I-7] is as follows:

[1412] [Chemistry 186]

[1413] .

[1414] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1415] The compound represented by the aforementioned formula [I-7] is as follows:

[1416] [Chemistry 187]

[1417] .

[1418] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1419] The compound represented by the aforementioned formula [I-7] is as follows:

[1420] [Chemistry 188]

[1421] .

[1422] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1423] The compound represented by the aforementioned formula [I-7] is as follows:

[1424] [Chemistry 189]

[1425] .

[1426] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1427] The compound represented by the aforementioned formula [I-7] is as follows:

[1428] [Chemistry 190]

[1429] .

[1430] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1431] The compound represented by the aforementioned formula [I-7] is as follows:

[1432] [Chemistry 191]

[1433] .

[1434] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1435] The compound represented by the aforementioned formula [I-7] is as follows:

[1436] [Chemistry 192]

[1437] .

[1438] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1439] The compound represented by the aforementioned formula [I-7] is as follows:

[1440] [Chemistry 193]

[1441] .

[1442] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1443] The compound represented by the aforementioned formula [I-7] is as follows:

[1444] [Chemistry 194]

[1445] .

[1446] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1447] The compound represented by the aforementioned formula [I-7] is as follows:

[1448] [Chemistry 195]

[1449] .

[1450] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1451] The compound represented by the aforementioned formula [I-7] is as follows:

[1452] [Chemistry 196]

[1453] .

[1454] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1455] The compound represented by the aforementioned formula [I-7] is as follows:

[1456] [Chemistry 197]

[1457] .

[1458] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1459] The compound represented by the aforementioned formula [I-7] is as follows:

[1460] [Chemistry 198]

[1461] .

[1462] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1463] The compound represented by the aforementioned formula [I-7] is as follows:

[1464] [Chemistry 199]

[1465] .

[1466] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1467] The compound represented by the aforementioned formula [I-7] is as follows:

[1468] [Chemistry 200]

[1469]

[1470] In addition, in this embodiment (H), other particularly preferred embodiments are as follows.

[1471] The compound represented by the aforementioned formula [I-7] is as follows:

[1472] [Chemistry 201]

[1473] .

[1474] Another preferred embodiment of the compound of the present invention is the following embodiment (H-2).

[1475] Implementation method (H-2):

[1476] In this embodiment (H-2), preferred embodiments are as follows.

[1477] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1478] The compound represented by formula [I-1] is a compound represented by the following formula [I-7]

[1479] [Chemistry 202]

[1480]

[1481] in,

[1482] R 2 It is a group represented by the following formula [IV-1]

[1483] [Chemistry 203]

[1484] ,

[1485] X, W, Ring B 1 、R B11 、R B12 , L 1 , and R 4 As mentioned above.

[1486] In this embodiment (H-2), more preferred embodiments are as follows.

[1487] In the aforementioned formula [I-7],

[1488] X is a carboxyl group;

[1489] W is a structure represented by the following formula [III-1]

[1490] [Chemistry 204]

[1491] ,

[1492] in,

[1493] In the structure represented by formula [III-1],

[1494] Ring A 1 yes

[1495] C 3-4 Cycloalkanes,

[1496] R A11 yes

[1497] Hydrogen atom, halogen atom, or C 1-2 Alkoxy,

[1498] R A12 yes

[1499] a hydrogen atom or a halogen atom;

[1500] Ring B 1 is phenyl,

[1501] R B11 and R B12 Similarly for hydrogen atoms,

[1502] L 1 C 4-5 Alkanediyl,

[1503] also,

[1504] As C 4-5 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-.

[1505] R 4represents a group represented by the following formula [VI]

[1506] [Chemistry 205]

[1507] ,

[1508] in,

[1509] Ring C is phenyl,

[1510] The phenyl group may be selected from halogen atoms, C1 alkyl groups, C 1-2 Alkoxy and C1 alkylcarbonyl are substituted, and further,

[1511] Can be selected from halogen atoms, C1 alkyl, C3 cycloalkyl, C 1-2 The alkoxy group and the C1 alkylcarbonyl group are substituted by 1 to 3 groups which may be the same or different.

[1512] In this embodiment (H-2), further preferred embodiments are as follows.

[1513] In the aforementioned formula [I-7],

[1514] X is a carboxyl group;

[1515] W is a structure represented by the following formula [III-5], [III-6], [III-8] to [III-11], or [III-13]

[1516] [Chemistry 206]

[1517] ;

[1518] Ring B 1 is phenyl,

[1519] R B11 and R B12 Similarly for hydrogen atoms,

[1520] L 1 The structure represented by the following formula [V-12] or [V-14]

[1521] [Chemistry 207]

[1522] ,

[1523] R 4 A group represented by the following formula [VI-2], [VI-6], [VI-12], [VI-25], [VI-27], [VI-28], [VI-30], or [VI-31]

[1524] [Chemistry 208]

[1525] .

[1526] Furthermore, in this embodiment (H-2),

[1527] A particularly preferred embodiment is when the compound represented by the aforementioned formula [I-7] is any of the following:

[1528] [Chemistry 209]

[1529]

[1530] [Chemistry 210]

[1531]

[1532] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1533] The compound represented by the aforementioned formula [I-7] is as follows:

[1534] [Chemistry 211]

[1535] .

[1536] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1537] The compound represented by the aforementioned formula [I-7] is as follows:

[1538] [Chemistry 212]

[1539] .

[1540] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1541] The compound represented by the aforementioned formula [I-7] is as follows:

[1542] [Chemistry 213]

[1543] .

[1544] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1545] The compound represented by the aforementioned formula [I-7] is as follows:

[1546] [Chemistry 214]

[1547] .

[1548] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1549] The compound represented by the aforementioned formula [I-7] is as follows:

[1550] [Chemistry 215]

[1551] .

[1552] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1553] The compound represented by the aforementioned formula [I-7] is as follows:

[1554] [Chemistry 216]

[1555] .

[1556] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1557] The compound represented by the aforementioned formula [I-7] is as follows:

[1558] [Chemistry 217]

[1559] .

[1560] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1561] The compound represented by the aforementioned formula [I-7] is as follows:

[1562] [Chemistry 218]

[1563] .

[1564] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1565] The compound represented by the aforementioned formula [I-7] is as follows:

[1566] [Chemistry 219]

[1567] .

[1568] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1569] The compound represented by the aforementioned formula [I-7] is as follows:

[1570] [Chemistry 220]

[1571] .

[1572] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1573] The compound represented by the aforementioned formula [I-7] is as follows:

[1574] [Chemistry 221]

[1575] .

[1576] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1577] The compound represented by the aforementioned formula [I-7] is as follows:

[1578] [Chemistry 222]

[1579] .

[1580] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1581] The compound represented by the aforementioned formula [I-7] is as follows:

[1582] [Chemistry 223]

[1583] .

[1584] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1585] The compound represented by the aforementioned formula [I-7] is as follows:

[1586] [Chemistry 224]

[1587] .

[1588] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1589] The compound represented by the aforementioned formula [I-7] is as follows:

[1590] [Chemistry 225]

[1591] .

[1592] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1593] The compound represented by the aforementioned formula [I-7] is as follows:

[1594] [Chemistry 226]

[1595] .

[1596] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1597] The compound represented by the aforementioned formula [I-7] is as follows:

[1598] [Chemistry 227]

[1599] .

[1600] In addition, in this embodiment (H-2), other particularly preferred embodiments are as follows.

[1601] The compound represented by the aforementioned formula [I-7] is as follows:

[1602] [Chemistry 228]

[1603] .

[1604] Another preferred embodiment of the compound of the present invention is the following embodiment (H-3).

[1605] Implementation Method (H-3):

[1606] In this embodiment (H-3), preferred embodiments are as follows.

[1607] In the compound represented by the aforementioned formula [I-1], or a pharmaceutically acceptable salt or hydrate thereof,

[1608] The compound represented by formula [I-1] is a compound represented by the following formula [I-7]

[1609] [Chemistry 229]

[1610] ,

[1611] in,

[1612] R 2 It is a group represented by the following formula [IV-1] or [IV-2]

[1613] [Chemistry 230]

[1614] ;

[1615] X, W, Ring B 1 、R B11 、RB12 , L 1 , Ring B 2 、R B21 、R B22 , L 2 , and R 4 As mentioned above.

[1616] In this embodiment (H-3), more preferred embodiments are as follows.

[1617] In the aforementioned formula [I-7],

[1618] X is a carboxyl group or a tetrazolyl group;

[1619] W is a structure represented by the following formula [III-1]

[1620] [Chemistry 231]

[1621] ,

[1622] in,

[1623] In the structure represented by formula [III-1],

[1624] Ring A 1 yes

[1625] C 3-4 Cycloalkanes,

[1626] R A11 yes

[1627] Hydrogen atom, halogen atom, or C 1-2 Alkoxy,

[1628] R A12 yes

[1629] a hydrogen atom or a halogen atom;

[1630] Ring B 1 is phenyl,

[1631] R B11 and R B12 Similarly for hydrogen atoms,

[1632] L 1 It is C 4-5 Alkanediyl (the C 4-5 The alkanediyl group may be substituted by two fluorine atoms).

[1633] also,

[1634] As C 4-5 The distance R between one of the carbon atoms in the alkane diradical 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-.

[1635] Ring B 2 is a partially saturated 9-membered fused ring aromatic group,

[1636] R B21 and R B22 Similarly for hydrogen atoms,

[1637] L 2 is a C2 alkanediyl group;

[1638] R 4 represents a group represented by the following formula [VI]

[1639] [Chemistry 232]

[1640] ,

[1641] in,

[1642] Ring C is phenyl,

[1643] The phenyl group may be selected from halogen atoms, C 1-3 Alkyl, C 1-2 Alkoxy and C1 alkylcarbonyl are substituted, and further,

[1644] Can be selected from halogen atoms, C 1-3 Alkyl (the C 1-3 The alkyl group may be substituted with one hydroxyl group), C 1-2 The alkoxy group or C1 alkylcarbonyl group is substituted by 1 to 3 groups which are the same or different.

[1645] In this embodiment (H-3), further preferred embodiments are as follows.

[1646] In the aforementioned formula [I-7],

[1647] Further preferably, X is a carboxyl group or a tetrazolyl group;

[1648] W is a structure represented by the following formula [III-5], [III-6], [III-8] to [III-11], or [III-13]

[1649] [Chemistry 233]

[1650] ;

[1651] Ring B 1 is phenyl,

[1652] R B11 and R B12 Similarly for hydrogen atoms,

[1653] L 1The structure represented by the following formula [V-3], [V-12], or [V-14]

[1654] [Chemistry 234]

[1655] ,

[1656] in,

[1657] n4 is an integer of 4,

[1658] Ring B 2 is dihydroindanyl,

[1659] R B21 and R B22 Similarly for hydrogen atoms,

[1660] L 2 The structure shown in the following formula [V-20]

[1661] [Chemistry 235]

[1662] ,

[1663] in,

[1664] n5 is 2;

[1665] R 4 A group represented by the following formula [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]

[1666] [Chemistry 236]

[1667] .

[1668] Furthermore, in this embodiment (H-3),

[1669] A particularly preferred embodiment is when the compound represented by the aforementioned formula [I-7] is any of the following:

[1670] [Chemistry 237]

[1671]

[1672] [Chemistry 238]

[1673]

[1674] [Chemistry 239]

[1675]

[1676] [Chemistry 240]

[1677]

[1678] [Chemistry 241]

[1679] ,

[1680] [Chemistry 242]

[1681]

[1682] [Chemistry 243]

[1683]

[1684] [Chemistry 244]

[1685] .

[1686] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1687] The compound represented by the aforementioned formula [I-7] is as follows:

[1688] [Chemistry 245]

[1689] .

[1690] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1691] The compound represented by the aforementioned formula [I-7] is as follows:

[1692] [Chemistry 246]

[1693] .

[1694] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1695] The compound represented by the aforementioned formula [I-7] is as follows:

[1696] [Chemistry 247]

[1697] .

[1698] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1699] The compound represented by the aforementioned formula [I-7] is as follows:

[1700] [Chemistry 248]

[1701] .

[1702] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1703] The compound represented by the aforementioned formula [I-7] is as follows:

[1704] [Chemistry 249]

[1705] .

[1706] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1707] The compound represented by the aforementioned formula [I-7] is as follows:

[1708] [Chemistry 250]

[1709] .

[1710] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1711] The compound represented by the aforementioned formula [I-7] is as follows:

[1712] [Chemistry 251]

[1713] .

[1714] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1715] The compound represented by the aforementioned formula [I-7] is as follows:

[1716] [Chemistry 252]

[1717] .

[1718] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1719] The compound represented by the aforementioned formula [I-7] is as follows:

[1720] [Chemistry 253]

[1721] .

[1722] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1723] The compound represented by the aforementioned formula [I-7] is as follows:

[1724] [Chemistry 254]

[1725] .

[1726] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1727] The compound represented by the aforementioned formula [I-7] is as follows:

[1728] [Chemistry 255]

[1729] .

[1730] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1731] The compound represented by the aforementioned formula [I-7] is as follows:

[1732] [Chemistry 256]

[1733] .

[1734] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1735] The compound represented by the aforementioned formula [I-7] is as follows:

[1736] [Chemistry 257]

[1737] .

[1738] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1739] The compound represented by the aforementioned formula [I-7] is as follows:

[1740] [Chemistry 258]

[1741] .

[1742] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1743] The compound represented by the aforementioned formula [I-7] is as follows:

[1744] [Chemistry 259]

[1745] .

[1746] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1747] The compound represented by the aforementioned formula [I-7] is as follows:

[1748] [Chemistry 260]

[1749] .

[1750] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1751] The compound represented by the aforementioned formula [I-7] is as follows:

[1752] [Chemistry 261]

[1753] .

[1754] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1755] The compound represented by the aforementioned formula [I-7] is as follows:

[1756] [Chemistry 262]

[1757] .

[1758] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1759] The compound represented by the aforementioned formula [I-7] is as follows:

[1760] [Chemistry 263]

[1761] .

[1762] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1763] The compound represented by the aforementioned formula [I-7] is as follows:

[1764] [Chemistry 264]

[1765] .

[1766] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1767] The compound represented by the aforementioned formula [I-7] is as follows:

[1768] [Chemistry 265]

[1769] .

[1770] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1771] The compound represented by the aforementioned formula [I-7] is as follows:

[1772] [Chemistry 266]

[1773] .

[1774] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1775] The compound represented by the aforementioned formula [I-7] is as follows:

[1776] [Chemistry 267]

[1777] .

[1778] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1779] The compound represented by the aforementioned formula [I-7] is as follows:

[1780] [Chemistry 268]

[1781] .

[1782] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1783] The compound represented by the aforementioned formula [I-7] is as follows:

[1784] [Chemistry 269]

[1785] .

[1786] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1787] The compound represented by the aforementioned formula [I-7] is as follows:

[1788] [Chemistry 270]

[1789] .

[1790] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1791] The compound represented by the aforementioned formula [I-7] is as follows:

[1792] [Chemistry 271]

[1793] .

[1794] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1795] The compound represented by the aforementioned formula [I-7] is as follows:

[1796] [Chemistry 272]

[1797] .

[1798] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1799] The compound represented by the aforementioned formula [I-7] is as follows:

[1800] [Chemistry 273]

[1801] .

[1802] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1803] The compound represented by the aforementioned formula [I-7] is as follows:

[1804] [Chemistry 274]

[1805] .

[1806] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1807] The compound represented by the aforementioned formula [I-7] is as follows:

[1808] [Chemistry 275]

[1809] .

[1810] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1811] The compound represented by the aforementioned formula [I-7] is as follows:

[1812] [Chemistry 276]

[1813] .

[1814] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1815] The compound represented by the aforementioned formula [I-7] is as follows:

[1816] [Chemistry 277]

[1817] .

[1818] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1819] The compound represented by the aforementioned formula [I-7] is as follows:

[1820] [Chemistry 278]

[1821] .

[1822] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1823] The compound represented by the aforementioned formula [I-7] is as follows:

[1824] [Chemistry 279]

[1825] .

[1826] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1827] The compound represented by the aforementioned formula [I-7] is as follows:

[1828] [Chemistry 280]

[1829] .

[1830] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1831] The compound represented by the aforementioned formula [I-7] is as follows:

[1832] [Chemistry 281]

[1833] .

[1834] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1835] The compound represented by the aforementioned formula [I-7] is as follows:

[1836] [Chemistry 282]

[1837] .

[1838] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1839] The compound represented by the aforementioned formula [I-7] is as follows:

[1840] [Chemistry 283]

[1841] .

[1842] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1843] The compound represented by the aforementioned formula [I-7] is as follows:

[1844] [Chemistry 284]

[1845] .

[1846] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1847] The compound represented by the aforementioned formula [I-7] is as follows:

[1848] [Chemistry 285]

[1849] .

[1850] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1851] The compound represented by the aforementioned formula [I-7] is as follows:

[1852] [Chemistry 286]

[1853] .

[1854] In addition, in this embodiment (H-3), other particularly preferred embodiments are as follows.

[1855] The compound represented by the aforementioned formula [I-7] is as follows:

[1856] [Chemistry 287]

[1857] .

[1858] Another preferred embodiment of the compound of the present invention is the following embodiment (J).

[1859] Implementation method (J):

[1860] In this embodiment (J), preferred embodiments are as follows.

[1861] In the compound represented by the aforementioned formula [I] or its pharmaceutically acceptable salt or hydrate thereof,

[1862] The compound represented by formula [I] is a compound represented by the following formula [I-8]

[1863] [Chemistry 288]

[1864] ,

[1865] in,

[1866] R X It is C 1-4 alkyl;

[1867] W, Ring B 1 、R B11 、R B12 , L 1 and R 4 As mentioned above.

[1868] In this embodiment (J), more preferred embodiments are as follows.

[1869] In the aforementioned formula [I-8],

[1870] R X is a C1 alkyl group, a C2 alkyl group, or a C4 alkyl group;

[1871] W is a structure represented by the following formula [III-1]

[1872] [Chemistry 289]

[1873] ,

[1874] in,

[1875] In the structure represented by formula [III-1],

[1876] Ring A 1 It is C 3-4 Cycloalkanes,

[1877] R A11 is a hydrogen atom, a halogen atom, or a C2 alkoxy group,

[1878] R A12 is a hydrogen atom or a halogen atom;

[1879] Ring B 1 is phenyl,

[1880] R B11 and R B12 Similarly for hydrogen atoms,

[1881] L 1 is a C5 alkane diyl,

[1882] As the distance R between one of the carbon atoms in the C5 alkane diyl group 2 Two or more nitrogen atoms bonded thereto may be replaced by atoms of the formula -O-;

[1883] R 4 represents a group represented by the following formula [VI]

[1884] [Chemistry 290]

[1885] ,

[1886] in,

[1887] Ring C is phenyl,

[1888] The phenyl group may be substituted by three identical or different groups selected from C2 alkoxy and C1 alkylcarbonyl groups, and further,

[1889] It may be substituted by one halogen atom.

[1890] In this embodiment (J), further preferred embodiments are as follows.

[1891] In the aforementioned formula [I-8],

[1892] R X is methyl, ethyl, or tert-butyl;

[1893] W is a structure represented by the following formula [III-5], [III-10], or [III-13]

[1894] [Chemistry 291]

[1895] ;

[1896] Ring B 1 is phenyl,

[1897] R B11 and R B12 Similarly for hydrogen atoms,

[1898] L 1 The structure shown in the following formula [V-14]

[1899] [Chemistry 292]

[1900] ;

[1901] R 4 It is a group represented by the following formula [VI-10] or [VI-11]

[1902] [Chemistry 293]

[1903] .

[1904] Furthermore, in this embodiment (J), a particularly preferred embodiment is as follows.

[1905] The compound represented by the aforementioned formula [I-8] is any of the following:

[1906] [Chemistry 294]

[1907]

[1908] [Chemistry 295]

[1909]

[1910] [Chemistry 296]

[1911] .

[1912] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1913] The compound represented by the aforementioned formula [I-8] is as follows:

[1914] [Chemistry 297]

[1915] .

[1916] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1917] The compound represented by the aforementioned formula [I-8] is as follows:

[1918] [Chemistry 298]

[1919] .

[1920] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1921] The compound represented by the aforementioned formula [I-8] is as follows:

[1922] [Chemistry 299]

[1923] .

[1924] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1925] The compound represented by the aforementioned formula [I-8] is as follows:

[1926] [Chemistry 300]

[1927] .

[1928] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1929] The compound represented by the aforementioned formula [I-8] is as follows:

[1930] [Chemistry 301]

[1931] .

[1932] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1933] The compound represented by the aforementioned formula [I-8] is as follows:

[1934] [Chemistry 302]

[1935] .

[1936] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1937] The compound represented by the aforementioned formula [I-8] is as follows:

[1938] [Chemistry 303]

[1939] .

[1940] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1941] The compound represented by the aforementioned formula [I-8] is as follows:

[1942] [Chemistry 304]

[1943] .

[1944] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1945] The compound represented by the aforementioned formula [I-8] is as follows:

[1946] [Chemistry 305]

[1947] .

[1948] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1949] The compound represented by the aforementioned formula [I-8] is as follows:

[1950] [Chemistry 306]

[1951] .

[1952] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1953] The compound represented by the aforementioned formula [I-8] is as follows:

[1954] [Chemistry 307]

[1955] .

[1956] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1957] The compound represented by the aforementioned formula [I-8] is as follows:

[1958] [Chemistry 308]

[1959] .

[1960] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1961] The compound represented by the aforementioned formula [I-8] is as follows:

[1962] [Chemistry 309]

[1963] .

[1964] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1965] The compound represented by the aforementioned formula [I-8] is as follows:

[1966] [Chemistry 310]

[1967] .

[1968] In addition, in this embodiment (J), other particularly preferred embodiments are as follows.

[1969] The compound represented by the aforementioned formula [I-8] is as follows:

[1970] [Chemistry 311]

[1971] .

[1972] The compound of the present invention is a compound having a urea structure as a basic skeleton, and may be a pharmaceutically acceptable salt thereof or a hydrate thereof.

[1973] 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 such as 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 with organic bases such as ammonium, triethylamine, diisopropylamine, cyclohexylamine, and N-methyl-D-glucamine. Salts include aqueous salts.

[1974] The compounds of the present invention may have asymmetric centers, in which case various optical isomers exist. Therefore, the compounds of the present invention may exist as individual optically active forms (R) and (S), as well as as racemates or (RS) mixtures. Furthermore, in the case of compounds having two or more asymmetric centers, diastereomers may exist due to the respective optical isomers. The compounds of the present invention also include mixtures containing all of 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 optically active forms can be obtained by well-known organic chemical methods for this purpose. Furthermore, geometric isomers such as cis-isomers and trans-isomers may exist in the compounds of the present invention. Furthermore, the compounds of the present invention exhibit tautomerism, and various tautomers exist. The compounds of the present invention also include these isomers and mixtures containing these isomers in any proportion.

[1975] Furthermore, when the compound of the present invention or a salt thereof forms a hydrate or a solvate, these are also included in the scope of the present invention.

[1976] As described above, LPA1 receptors, LPA3 receptors, and the like play various roles in the body.

[1977] Examples of diseases caused by LPA receptors include diseases associated with fibrosis (idiopathic pulmonary fibrosis, systemic scleroderma, chronic kidney disease, chronic hepatitis, chronic rejection after organ transplantation, etc.), inflammatory diseases (rheumatoid arthritis, osteoarthritis, 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 (neuropathic pain, diabetic neuropathy, etc.).

[1978] Drugs that inhibit the physiological activity of LPA receptors, particularly antagonists of the EDG family such as LPA1 and LPA3 receptors, are considered to be useful as preventive or therapeutic agents for diseases associated with organ fibrosis, such as idiopathic pulmonary fibrosis, systemic scleroderma, chronic kidney disease, and chronic hepatitis; circulatory system diseases such as arteriosclerosis; proliferative diseases including various cancers; urinary system diseases such as benign prostatic hyperplasia; and central and peripheral nervous system diseases.

[1979] The LPA receptor antagonistic effect of the compound of the present invention can be evaluated according to known methods such as the methods described in the Test Examples later in this specification.

[1980] The medicament of the present invention, comprising the compound of the present invention, ie, the compound antagonizing the LPA1 receptor, or a pharmaceutically acceptable salt or hydrate thereof, can be administered alone or together with a pharmaceutically or pharmaceutically acceptable additive.

[1981] As additives, commonly used excipients or diluents, as well as commonly used binders, disintegrants, lubricants, coating agents, sugar coating agents, pH regulators, solubilizers, or aqueous or non-aqueous solvents can be used. Specifically, water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzoate, 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), etc., or other commonly used additives can be mentioned.

[1982] The medicine of the present invention may be in any form of a solid composition, a liquid composition or other compositions, and the best form may be selected according to needs.

[1983] The drugs of the present invention can be prepared by adding the aforementioned additives to the compounds of the present invention and using common formulation techniques to form tablets, pills, capsules, granules, powders, dispersants, solutions, emulsions, suspensions, injections, and the like.

[1984] Furthermore, the drug of the present invention can be formulated by forming an inclusion compound of the compound of the present invention with α-, β-, or γ-cyclodextrin or methylated cyclodextrin.

[1985] The drug of the present invention and the compound that can be used in combination with the compound of the present invention may be prepared as a single preparation (combination preparation) or as two or more preparations prepared separately (combination preparation).

[1986] When these compounds are formulated into two or more preparations, each preparation can be administered simultaneously or at a certain time interval. In this case, any one of them can be administered first. The two or more preparations can each be administered at different times per day. In addition, the two or more preparations can be administered in different routes.

[1987] When these compounds are formulated separately to form two preparations, they may be administered simultaneously or at very short intervals. For example, it is preferable to describe the combined use of these drugs in the accompanying instructions, sales brochures, and other instructions of the commercially available drugs.

[1988] Furthermore, it is also preferable to prepare these active ingredients separately as a kit containing two preparations.

[1989] When the compound of the present invention is used as an LPA1 receptor antagonist, the compound of the present invention can be directly orally administered. Alternatively, the compound of the present invention can be formulated into a pharmaceutical preparation containing the compound of the present invention as an active ingredient and administered orally.

[1990] When the compound of the present invention is used as a preventive or therapeutic agent for systemic scleroderma, the compound of the present invention can be directly orally administered. Alternatively, the compound of the present invention can be formulated into a pharmaceutical preparation containing the compound of the present invention as an active ingredient and administered orally.

[1991] The dosage of the compound of the present invention varies depending on the subject of administration, route of administration, target disease, symptoms, etc. For example, when administered orally to adult patients, the dosage is generally 0.1 mg to 1000 mg, preferably 1 mg to 200 mg per dose. Ideally, this dosage is administered once to three times a day, or once every two to three days.

[1992] Hereinafter, the method for producing the compound [I] of the present invention will be described in detail, but the production method is not particularly limited to the exemplified ones.

[1993] In the production of the compound [I] of the present invention, the order of each step in each production method can be changed as appropriate.

[1994] The solvent used in the reaction is not particularly limited to the following description as long as it does not inhibit each reaction.

[1995] In each of the following production methods, the starting compound may be used in the form of a salt. In addition, the target compound may be prepared as a salt.

[1996] Among these, examples of usable salts include the aforementioned "pharmaceutically acceptable salts."

[1997] In addition, the compound [Ia] of the present invention can be produced by the method for producing the compound [I] or a method based thereon.

[1998] The compound [I] of the present invention can be produced by a method known per se, for example, the following production methods 1 to 6 or methods based thereon.

[1999] Specifically, in the compound [I] of the present invention, X is a carboxyl group or a C 1-4 The method for producing an alkoxycarbonyl compound is shown in Production Method 1, and the methods for producing its production intermediates are shown in Production Methods 2 to 8.

[2000] In addition, methods for producing a compound in which X is a tetrazolyl group, a compound in which X is a group represented by the following formula [II-1] (hereinafter, sometimes referred to as compound [II-1]), a compound in which X is a carbamoyl group, a compound in which X is a group represented by the following formula [II-2], [II-3], or [II-4] (hereinafter, sometimes referred to as compound [II-2], compound [II-3], or compound [II-4], respectively), and a compound in which X is a group represented by the following formula [II-5] (hereinafter, sometimes referred to as compound [II-5]) are shown in Production Method 9.

[2001] [Chemistry 312]

[2002]

[2003] In this general production method, "reductive amination reaction" refers to a reaction in which an aldehyde compound or a ketone compound is reacted with an amine compound to form a corresponding imine compound in an inert solvent or in the absence of a solvent at a temperature from ice-cold to reflux temperature in the presence or absence of an acid such as formic acid or acetic acid, and then a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-methylpyridine borane, or an iridium catalyst such as chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium(III) (described in Advanced Synthesis and Catalysis, Vol. 360, p. 322, 2018) is allowed to act to produce an amine compound.

[2004] In this general production method, "condensation reaction" means, for example, a reaction in which a carboxylic acid compound and an amine compound react with a condensing agent in an inert solvent at room temperature to reflux temperature in the presence or absence of a base and additives to produce an amide compound.

[2005] Examples of the condensing agent used in the “condensation reaction” include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,1'-carbonyldiimidazole (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM).

[2006] Examples of the additive used in the “condensation reaction” include N-hydroxybenzotriazole monohydrate (HOBt) and N-hydroxysuccinimide.

[2007] Examples of the base used in the "condensation reaction" include aliphatic tertiary amines such as N,N-diisopropylethylamine and triethylamine, and pyridine.

[2008] Furthermore, in this general production method, "hydrolysis reaction" means, for example, a reaction in an inert solvent at ice-cold to reflux temperature using a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide to produce a carboxylic acid compound and an alcohol compound from an ester compound.

[2009] In the compound [I] of the present invention, X is a carboxyl group and R 1 Compounds containing hydrogen atoms [1-d] and R 1 The compound [1-f] having a methyl group can be produced, for example, by the following production method 1 or a method based thereon.

[2010] Manufacturing method 1:

[2011] Scheme 1 (Method for producing compounds [1-d] and [1-f] from compound [1-a]):

[2012] [Chemistry 313]

[2013]

[2014] In the plan,

[2015] R 2 、R 3 、R4 and W are the same as above,

[2016] Alk 1 Indicates C 1-4 alkyl.

[2017] Step 1-1:

[2018] Preparation method of compound [1-c]: Compound [1-a] is used as a starting material, and compound [1-b] is reacted in an inert solvent at ice-cold to reflux temperature in the presence of a base such as triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and a ureidating agent such as 4-nitrophenyl chloroformate, CDI, or triphosgene to produce compound [1-c].

[2019] Step 1-2:

[2020] Method for producing compound [1-d]: Compound [1-c] is used as a starting material and subjected to a hydrolysis reaction to produce compound [1-d].

[2021] Steps 1-3:

[2022] Preparation method of compound [1-e]: Compound [1-c] is used as a starting material, and reacted with a methylating agent such as iodomethane in an inert solvent at a temperature from ice-cold to reflux temperature in the presence of a base such as sodium hydride to produce compound [1-e].

[2023] Steps 1-4:

[2024] Method for producing compound [1-f]: Compound [1-e] is used as a starting material, and a "hydrolysis reaction" is carried out by the method described in step 1-2 above or a method based thereon, thereby producing compound [1-f].

[2025] The compounds [1-d] and [1-f] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2026] It should be noted that in the compound [I] of the present invention, X is C 1-4 Alkoxycarbonyl compounds can be produced as compounds [1-c] or [1-e] by, for example, this production method 1 or a method based thereon.

[2027] Among the production intermediates of the compound [I] of the present invention, compounds [1-a] and [1-b] described in Scheme 1 can be produced by known methods or purchased as commercially available products.

[2028] Furthermore, compound [1-a] can also be produced by, for example, the production method 2 described later or a method based thereon.

[2029] Similarly, compound [1-b] can also be produced by, for example, the production method 8 described later or a method based thereon.

[2030] An example of the production of compound [1-a], which is a production intermediate of compound [I] of the present invention, is shown in Scheme 2-1 of the following Production Method 2.

[2031] Manufacturing method 2:

[2032] Scheme 2-1 (Method for producing compound [1-a] from compound [2-a]):

[2033] [Chemistry 314]

[2034]

[2035] In the plan,

[2036] 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 above definition;

[2037] Ring B 1 C is expressed in the same way as above 3-8 Cycloalkyl, 4- to 8-membered saturated heterocyclic group containing nitrogen atoms, phenyl, or 5- to 6-membered heteroaryl containing nitrogen atoms,

[2038] Ring B 2 Similarly to the above, it represents a partially saturated 9- to 10-membered fused ring aryl group or a 9- to 10-membered fused ring heteroaryl group containing a nitrogen atom,

[2039] LG 1 represents a leaving group,

[2040] in,

[2041] LG 1 The "leaving group" shown in the figure represents a halogen atom such as a chlorine atom, a bromine atom, a C 1-4 Alkylsulfonyloxy; or arylsulfonyloxy such as p-toluenesulfonyloxy;

[2042] R 2 ' indicates C 5-9 Alkyl, C 5-9 Alkenyl, C5-9 an alkynyl group, or a group represented by the following formula [IV-1'] or [IV-2'],

[2043] [Chemistry 315]

[2044]

[2045] in,

[2046] Ring B 1 , Ring B 2 、R B11 、R B12 、R B21 , and R B22 Same as the above definition,

[2047] L 1 ' indicates C 2-7 Alkanediyl (the C 2-7 The alkanediyl group may be substituted with 1 to 5 fluorine atoms) or the structure represented by the following formula [V-1'],

[2048] [Chemistry 316]

[2049]

[2050] in,

[2051] n12 and n13 are the same as above.

[2052] n11' represents an integer from 1 to 2,

[2053] also,

[2054] L 1 ' for C 2-7 Alkanediyl (the C 2-7 When the alkanediyl group may be substituted by 1 to 5 fluorine atoms, 2-7 The distance R between one of the carbon atoms in the alkane diradical 2’ The carbon atom of the bonded carboxyl or formyl group with more than one atom can be represented by the formula -O-, -S-, or -N(R L11 )-replaced,

[2055] in,

[2056] R L11 Same as the above definition,

[2057] also,

[2058] L 1 ' for C 2-7 Alkanediyl (the C 2-7 When the alkanediyl group may be substituted by 1 to 5 fluorine atoms, the C 2-7Two consecutive carbon atoms in an alkanediyl group can be represented by the formula -C(=O)N(R L12 )-replaced,

[2059] in,

[2060] R L12 Same as the above definition,

[2061] L 2 ' indicates C 2-7 Alkanediyl (the C 2-7 The alkanediyl group may be substituted with 1 to 5 fluorine atoms) or the structure represented by the following formula [V-2'],

[2062] [Chemistry 317]

[2063]

[2064] in,

[2065] n22 and n23 are the same as above.

[2066] n21' represents an integer from 1 to 2,

[2067] also,

[2068] L 2 ' for C 2-7 Alkanediyl (the C 2-7 When the alkanediyl group may be substituted by 1 to 5 fluorine atoms, 2-7 The distance R between one of the carbon atoms in the alkane diradical 2’ The carbon atom of the bonded carboxyl or formyl group with more than one atom can be represented by the formula -O-, -S-, or -N(R L21 )-replaced,

[2069] in,

[2070] R L21 Same as above, it represents a hydrogen atom or C 1-3 alkyl,

[2071] also,

[2072] The C 2-7 Two consecutive carbon atoms in an alkanediyl group can be represented by the formula -C(=O)N(R L22 )-replaced,

[2073] in,

[2074] R L22 Same as above, it represents a hydrogen atom or C 1-3 alkyl.

[2075] Step 2-1:

[2076] Method for producing compound [1-a]: Compound [2-a] is reacted with compound [2-b] in an inert solvent at room temperature to reflux temperature in the presence of a base to produce compound [1-a].

[2077] Examples of the base used in this reaction include amine compounds such as triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[4,3,0]undec-7-ene; 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 alkali metal alkoxides such as potassium tert-butoxide.

[2078] Step 2-2:

[2079] Another method for producing compound [1-a]: Compound [1-a] can also be produced by performing a "reductive amination reaction" of compound [2-a] with compound [2-c], [2-c'], or [2-c"].

[2080] Steps 2-3:

[2081] Method for producing compound [2-e]: Compound [2-e] can also be produced by performing a "condensation reaction" of compound [2-a] and compound [2-d].

[2082] Steps 2-4:

[2083] Another method for producing compound [1-a]: Compound [2-e] is used as a starting material, and a reducing agent such as a borane-tetrahydrofuran complex or a borane-dimethyl sulfide complex is allowed to act in an inert solvent at a temperature from ice-cold to reflux to produce compound [1-a].

[2084] Furthermore, compound [1-a] can also be produced by, for example, the production method shown in the following Scheme 2-2 or a method based thereon.

[2085] Scheme 2-2 (Method for producing compound [1-a] from compound [2-f]):

[2086] [Chemistry 318]

[2087]

[2088] In the plan,

[2089] R 2 、R 3 and R 4 Same as the above definition.

[2090] Steps 2-5:

[2091] Another method for producing compound [1-a]: Compound [1-a] can be produced by performing a "reductive amination reaction" of compound [2-f] and compound [2-g].

[2092] Furthermore, in compound [1-a], R 3 C 1-3 The alkyl compound [1-a'] can also be produced by, for example, the production method shown in the following Scheme 2-3 or a method based thereon.

[2093] Scheme 2-3 (Method for producing compound [1-a'] from compound [2-h]):

[2094] [Chemistry 319]

[2095]

[2096] In the plan,

[2097] R 2 and R 4 Same as the above definition,

[2098] R 3 ' indicates C 1-3 alkyl.

[2099] Steps 2-6:

[2100] Preparation method of compound [2-j]: Compound [2-h] is used as a starting material, and compound [2-g] is reacted in the presence or absence of an acid such as formic acid or acetic acid in an inert solvent or without a solvent at ice-cold temperature to reflux temperature to prepare compound [2-j].

[2101] Steps 2-7:

[2102] Method for producing compound [1-a']: Compound [2-j] is used as a starting material, and compound [2-k] is allowed to react in an inert solvent at ice-cold temperature to room temperature to produce compound [1-a'].

[2103] Alternatively, Step 2-6 and Step 2-7 may be performed continuously without removing the imine compound [2-j] produced in Step 2-6 (without performing post-treatment on the reaction of Step 2-6).

[2104] The compounds [1-a] and [1-a'] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2105] It should be noted that the compound [2-j] obtained in step 2-6 can also be prepared by reacting the compound [2-j] obtained in step 2-6 with the reducing agent used in the "reductive amination reaction" to produce the compound [1-a] wherein R 3 A compound containing hydrogen atoms.

[2106] Among the production intermediates of compound [I] of the present invention, compounds [2-a], [2-b], [2-c], [2-c'], [2-c"], and [2-d] described in Scheme 2-1, compounds [2-f] and [2-g] described in Scheme 2-2, and compounds [2-g], [2-h], and [2-k] described in Scheme 2-3 can be produced by known methods or purchased as commercially available products.

[2107] Among these compounds, the compound [2-a] whose structure is represented by [2-a'] described later (hereinafter, sometimes referred to as compound [2-a']) can be produced, for example, by the production method 3 described later or a method based thereon, and the compound [2-f] whose structure is represented by [2-f'] described later (hereinafter, sometimes referred to as compound [2-f']) and [2-h] can be produced, for example, by the production method 6 described later or a method based thereon.

[2108] [Chemistry 320]

[2109]

[2110] Similarly, compounds [2-b], [2-c], compounds [2-d] whose structure is represented by [5-e] described later (hereinafter, sometimes referred to as compound [5-e]), compounds [2-d] whose structure is represented by [5-e'] described later (hereinafter, sometimes referred to as compound [5-e']), and [2-g] can be produced by, for example, the production methods 4, 5, or 7 described later, or methods based thereon.

[2111] [Chemistry 321]

[2112]

[2113] An example of the production of compound [2-a'], which is a production intermediate of compound [I] of the present invention, is shown in Scheme 3-1 of the following Production Method 3.

[2114] Manufacturing method 3:

[2115] Scheme 3-1 (Method for producing compound [2-a'] from compound [2-h]):

[2116] [Chemistry 322]

[2117]

[2118] In the plan,

[2119] R 3 ' and R 4 Same as the above definition,

[2120] M represents a lithium atom or a formula -MgX M ,

[2121] X M represents a chlorine atom, a bromine atom or an iodine atom,

[2122] Compound [2-k'] (R 3 '-M) represents an alkyl metal reagent,

[2123] Alk 2 represents tert-butyl, etc.

[2124] Step 3-1:

[2125] Preparation method of compound [3-b]: Compound [2-h] is used as a starting material, and compound [3-a] is reacted in an inert solvent at room temperature to 160°C in the presence of a Lewis acid such as tetraethyl orthotitanate to produce compound [3-b].

[2126] Step 3-2:

[2127] Method for producing compound [3-c]: Compound [3-b] is used as a starting material, and compound [2-k'] is reacted in an inert solvent at -20°C to room temperature to produce compound [3-c].

[2128] Step 3-3:

[2129] Method for producing compound [2-a']: Compound [3-c] is used as a starting material, and an acid such as hydrochloric acid is allowed to act in an inert solvent at ice-cold temperature to room temperature to produce compound [2-a'].

[2130] In addition, steps 3-1, 3-2, and 3-3 can be carried out with reference to the methods described in, for example, Journal of Combinatorial Chemistry, Vol. 5, p. 590, 2003; and Organic Letters, Vol. 3, p. 3707, 2001.

[2131] In the present scheme 3-1, by reacting the optically active compound [3-a] in step 3-1, the compound [2-a'] can be stereoselectively produced.

[2132] In addition, in compound [2-a], R 4 is a substituted phenyl group and the para position of the phenyl group is replaced by C1-6 Alkylcarbonyl-substituted compounds [3-e], and C 1-6 Alkyl-substituted compounds [3-f] can also be produced by, for example, the method described in the following Scheme 3-2 or a method based thereon.

[2133] Scheme 3-2 (Method for producing compounds [3-e] and [3-f] from compound [3-c']):

[2134] [Chemistry 323]

[2135]

[2136] In the plan,

[2137] R 3 and Alk 2 Same as the above definition,

[2138] Alk 3 and Alk 4 Each independently represents C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl,

[2139] R α1 Indicates C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one hydroxyl group), halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkylcarbonyl, and halogenated C 1-6 Alkylcarbonyl,

[2140] Alk 5 Indicates C 1-6 Alkyl or hydroxy-substituted C 1-6 alkyl,

[2141] LG 2 represents a leaving group.

[2142] Among them, LG 2 The "leaving group" shown here represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom.

[2143] Step 3-4:

[2144] Preparation method of compound [3-d]: Compound [3-c'] is used as a starting material, and a vinyl ether such as ethylene glycol monovinyl ether or butyl vinyl ether is reacted in an inert solvent at ice-cold to reflux temperature in the presence of a palladium catalyst such as palladium (II) acetate, a phosphine ligand such as 1,3-bis(diphenylphosphino)propane or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, potassium carbonate, or a base such as triethylamine to produce compound [3-d].

[2145] This step can be carried out with reference to the methods described in, for example, The Journal of Organic Chemistry, Vol. 66, p. 4340, 2001; The Journal of Organic Chemistry, Vol. 72, p. 6390, 2007.

[2146] Steps 3-5:

[2147] Preparation method of compound [3-e]: Compound [3-d] is used as a starting material, and an acid such as hydrochloric acid is allowed to act in an inert solvent at ice-cold temperature to room temperature to prepare compound [3-e].

[2148] It should be noted that steps 3-4 and 3-5 can also be carried out continuously as a one-pot reaction. In addition, this step can also be carried out in a subsequent step.

[2149] Steps 3-6:

[2150] Preparation method of compound [3-f]: Compound [3-e] is used as a starting material, and a reducing agent such as lithium aluminum hydride (LiAlH4) or lithium borohydride (LiBH4) is allowed to act in an inert solvent at -78°C to room temperature to produce compound [3-f].

[2151] The compounds [2-a'], [3-e] and [3-f] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2152] Among the production 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 produced by known methods or purchased from commercially available products.

[2153] Among these compounds, compound [3-c′] can also be produced by, for example, the method described in step 3-2 above or a method based thereon.

[2154] Among the production intermediates of the compound [I] of the present invention, the following compound [2-b] described in Production Method 2 can also be produced, for example, by the following Production Method 4 or a method based thereon.

[2155] [Chemistry 324]

[2156]

[2157] An example of the production of compound [2-b], which is a production intermediate of compound [I] of the present invention, is shown in the following Scheme 4-1.

[2158] Manufacturing method 4:

[2159] Scheme 4-1: Method for producing compound [2-b] from compound [4-a]

[2160] [Chemistry 325]

[2161]

[2162] In the plan,

[2163] R 2 and LG 1 Same as the above definition.

[2164] Step 4-1:

[2165] The preparation method of compound [2-b] is as follows: using compound [4-a] as a starting material, (i) in an inert solvent, at ice-cold temperature to room temperature, in the presence of a base such as triethylamine, in the presence or absence of an additive such as trimethylamine hydrochloride, an arylsulfonyl chloride such as p-toluenesulfonyl chloride, a C 1-4 Compound [2-b] can be produced by reacting with an alkylsulfonyl chloride, or (ii) reacting with a brominating agent such as lithium bromide in an inert solvent at room temperature to reflux temperature.

[2166] This step can be carried out with reference to the method described in, for example, Tetrahedron, Vol. 55, p. 2183, 1999.

[2167] In addition, the compound [4-a] used as a raw material compound in the above-mentioned step 4-1 can be produced by a known method or can be obtained by purchasing a commercial product.

[2168] Among the compounds [4-a], the compound having a structure represented by the formula [5-b] described later (hereinafter sometimes referred to as compound [5-b]) can be produced by, for example, the method described in Scheme 5-1 of the production method 5 described later or a method based thereon.

[2169] [Chemistry 326]

[2170]

[2171] In addition, in compound [2-b], R 2 is a group represented by the aforementioned formula [IV-1], and L 1 A compound of C4 alkanediyl substituted by one fluorine atom [4-m], and L 1 The compound [4-h] which is a C4 alkanediyl group substituted with two fluorine atoms can also be produced by, for example, the production method described in the following Scheme 4-5 or a method based thereon.

[2172] [Chemistry 327]

[2173]

[2174] The production examples of the aforementioned compounds [4-m] and [4-h] are shown in Scheme 4-2.

[2175] Among them, the compound [4-m] substituted with one fluorine atom can be prepared by fluorinating the corresponding hydroxy compound [4-d] using the compound [4-b] as a starting material to produce the compound [4-j]. The compound [4-h] substituted with two fluorine atoms can be prepared by fluorinating the corresponding ketone compound [4-e] to produce the compound [4-f].

[2176] In the functional group conversion, protection and deprotection of a hydroxyl group or the like can be appropriately performed.

[2177] Scheme 4-2 (Method for producing compound [4-h] or compound [4-m] from compound [4-b]):

[2178] [Chemistry 328]

[2179]

[2180] In the plan,

[2181] Ring B 1 LG 1 、R B11 and R B12 Same as the above definition,

[2182] PG 1 represents a protective group for a hydroxyl group such as an acetyl group,

[2183] LG 3 represents a leaving group.

[2184] Among them, LG 3 The "leaving group" shown represents, for example, C 1-6 Alkoxy.

[2185] Step 4-2:

[2186] Preparation method of compound [4-c]: Compound [4-b] is used as a starting material, and a reducing agent is allowed to act in an inert solvent at ice-cold temperature to room temperature to prepare compound [4-c].

[2187] As a reducing agent, LG 3 C 1-6 In the case of an alkoxy group, for example, lithium aluminum hydride and lithium borohydride can be used.

[2188] Step 4-3:

[2189] Preparation method of compound [4-d]: Compound [4-c] is used as a starting material, and reacted with acetic anhydride or the like in an inert solvent at ice-cold to room temperature in the presence of a base such as N,N-diisopropylethylamine to selectively protect the primary hydroxyl group, thereby preparing compound [4-d].

[2190] Step 4-4:

[2191] Preparation method of compound [4-e]: Compound [4-d] is used as a starting material, and an oxidizing agent such as manganese dioxide or Dess-Martin periodinane is allowed to act in an inert solvent at ice-cold temperature to room temperature to prepare compound [4-e].

[2192] Steps 4-5:

[2193] Preparation method of compound [4-f]: Compound [4-e] is used as a starting material, and a fluorinating agent such as bis(2-methoxyethyl)aminosulfur trifluoride or (diethylamino)sulfur trifluoride is allowed to react in an inert solvent or in the absence of a solvent at ice-cold temperature to 50°C to prepare compound [4-f].

[2194] Steps 4-6:

[2195] Preparation method of compound [4-g]: Compound [4-f] is used as a starting material, and an alkaline aqueous solution such as an aqueous sodium hydroxide solution is allowed to act in an inert solvent at ice-cold temperature to room temperature to deprotect the hydroxyl group, thereby preparing compound [4-g].

[2196] Steps 4-7:

[2197] Method for producing compound [4-h]: Compound [4-h] can be produced by the method described in step 4-1 above or a method based thereon using compound [4-g] as a starting material.

[2198] Steps 4-8:

[2199] Method for producing compound [4-j]: Compound [4-j] can be produced by the method described in step 4-5 above or a method based thereon using compound [4-d] as a starting material.

[2200] Steps 4-9:

[2201] Method for producing compound [4-k]: Compound [4-k] can be produced by the method described in step 4-6 above or a method based thereon using compound [4-j] as a starting material.

[2202] Steps 4-10:

[2203] Method for producing compound [4-m]: Compound [4-k] can be produced by the method described in step 4-7 above or a method based thereon using compound [4-k] as a starting material.

[2204] In Scheme 4-2, by using compound [4-b'] instead of compound [4-b] as the starting material, R can be produced by the same method as the above-mentioned production method involving compounds [4-h] and [4-m]. 2 is a group represented by the aforementioned formula [IV-2], and L 2 A compound of C4 alkanediyl substituted by one fluorine atom [4-m'], and L 2 Compound [4-h'] is a C4 alkanediyl group substituted with two fluorine atoms. Compound [4-b'] can be produced by a known method or purchased from a commercial product.

[2205] [Chemistry 329]

[2206]

[2207] Where,

[2208] Ring B 2 、R B21 、R B22 LG 1 and LG 3 Same as the above definition.

[2209] In addition, in compound [2-b], R 2 is a group represented by the aforementioned formula [IV-1], and L 1 A compound [4-x] wherein the C4 alkanediyl group is substituted with one fluorine atom, and L 1 The compound [4-u] which is a C4 alkanediyl group substituted with two fluorine atoms can also be produced by, for example, the production method described in the following Scheme 4-3 or a method based thereon.

[2210] [Chemistry 330]

[2211]

[2212] The production examples of the aforementioned compounds [4-x] and [4-u] are shown in Scheme 4-3.

[2213] Among them, the compound [4-x] substituted with one fluorine atom can be produced by fluorinating the corresponding hydroxy compound [4-q] using the compound [4-n] as a starting material to produce the compound [4-v]. The compound [4-u] substituted with two fluorine atoms can be produced by fluorinating the corresponding ketone compound [4-r] to produce the compound [4-s].

[2214] In the functional group conversion, protection and deprotection of a hydroxyl group or the like can be appropriately performed.

[2215] Scheme 4-3 (Method for producing compound [4-u] or compound [4-x] from compound [4-n]):

[2216] [Chemistry 331]

[2217]

[2218] In the plan,

[2219] Ring B 1 、R B11 、R B12 PG 1 LG 1 and LG 3 Same as the above definition.

[2220] Steps 4-11:

[2221] Method for producing compound [4-p]: Compound [4-p] can be produced by the method described in step 4-2 above or a method based thereon, using compound [4-n] as a starting material.

[2222] Steps 4-12:

[2223] Method for producing compound [4-q]: Compound [4-q] can be produced using compound [4-p] as a starting material by the method described in step 4-3 above or a method based thereon.

[2224] Steps 4-13:

[2225] Method for producing compound [4-r]: Compound [4-r] can be produced by the method described in step 4-4 above or a method based thereon using compound [4-q] as a starting material.

[2226] Steps 4-14:

[2227] Method for producing compound [4-s]: Compound [4-s] can be produced using compound [4-r] as a starting material by the method described in step 4-5 above or a method based thereon.

[2228] Steps 4-15:

[2229] Method for producing compound [4-t]: Compound [4-t] can be produced using compound [4-s] as a starting material by the method described in step 4-6 above or a method based thereon.

[2230] Steps 4-16:

[2231] Method for producing compound [4-u]: Compound [4-u] can be produced using compound [4-t] as a starting material by the method described in step 4-7 above or a method based thereon.

[2232] Steps 4-17:

[2233] Method for producing compound [4-v]: Compound [4-v] can be produced by the method described in step 4-8 above or a method based thereon using compound [4-q] as a starting material.

[2234] Steps 4-18:

[2235] Method for producing compound [4-w]: Compound [4-w] can be produced by the method described in step 4-9 above or a method based thereon using compound [4-v] as a starting material.

[2236] Steps 4-19:

[2237] Method for producing compound [4-x]: Compound [4-x] can be produced using compound [4-w] as a starting material by the method described in step 4-10 above or a method based thereon.

[2238] In Scheme 4-3, by using compound [4-n'] instead of compound [4-n] as the starting material, R can be produced by the same method as the above-mentioned production method involving compounds [4-x] and [4-u]. 2 is a group represented by the aforementioned formula [IV-2], and L 2 A compound [4-x'] of a C4 alkanediyl group substituted with one fluorine atom, and L 2 Compound [4-u'] is a C4 alkanediyl group substituted with two fluorine atoms. Compound [4-n'] can be produced by a known method or purchased from a commercial product.

[2239] [Chemistry 332]

[2240]

[2241] Where,

[2242] Ring B 2 、R B21 、R B22 LG 1 and LG 3 Same as the above definition.

[2243] The compounds [2-b], [4-h], [4-h'], [4-m], [4-m'], [4-u], [4-u'], [4-x] and [4-x'] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

[2244] Among the production intermediates of compound [I] of the present invention, compound [4-a] described in Scheme 4-1, compound [4-b] described in Scheme 4-2, and compound [4-n] described in Scheme 4-3 can be produced by a known method or obtained by purchasing a commercially available product.

[2245] Among the production intermediates of the compound [I] of the present invention, the following compounds [2-c] and [5-e] described in Production Method 2 can also be produced, for example, by the following Production Method 5 or a method based thereon.

[2246] [Chemistry 333]

[2247]

[2248] Manufacturing method 5:

[2249] An example of the production of compound [2-c], which is a production intermediate of compound [I] of the present invention, is shown in the following Scheme 5-1.

[2250] Scheme 5-1 (Method for producing compound [2-c] from compound [2-d]):

[2251] [Chemistry 334]

[2252]

[2253] In the plan,

[2254] R 2 'Same as the above definition,

[2255] LG 4 represents a leaving group.

[2256] Among them, LG4 The "leaving group" shown represents, for example, C 1-6 Alkoxy.

[2257] Step 5-1:

[2258] Preparation method of compound [5-a]: Compound [2-d] is used as a starting material, and an acid such as sulfuric acid is allowed to act in an alcohol solvent such as methanol or ethanol at a temperature from ice-cold to reflux temperature to prepare compound [5-a].

[2259] Step 5-2:

[2260] Method for producing compound [5-b]: Compound [5-b] can be produced by using compound [5-a] as a starting material and the method described in step 4-2 above or a method based thereon.

[2261] Step 5-3:

[2262] Another method for producing compound [5-b]: Compound [2-d] is used as a starting material, and a reducing agent such as a borane-tetrahydrofuran complex is allowed to act in an inert solvent at ice-cold temperature to room temperature to produce compound [5-b].

[2263] Step 5-4:

[2264] Method for producing compound [2-c]: Compound [2-c] can be produced by the method described in step 4-4 above or a method based thereon, using compound [5-b] as a starting material.

[2265] In addition, the compound [2-d] used as a raw material compound in the above-mentioned steps 5-1 and 5-3 can be produced by a known method or obtained by purchasing a commercial product.

[2266] An example of the production of compound [5-e] is shown in the following Scheme 5-2.

[2267] Scheme 5-2 (Method for producing compound [5-e] from compound [5-c]):

[2268] [Chemistry 335]

[2269]

[2270] In the plan,

[2271] Ring B 1 、R B11 , and R B12 Same as the above definition,

[2272] LG 5 represents a leaving group,

[2273] Among them, LG 5 The "leaving group" shown in the figure represents a halogen atom such as a chlorine atom, a bromine atom, a C 1-4 Alkylsulfonyloxy; or arylsulfonyloxy such as p-toluenesulfonyloxy,

[2274] Y 1 Indicates the formula -O-, -S- or -N (R L11 )-,

[2275] Among them, R L11 Same as the above definition,

[2276] L X11 Indicates C 1-5 Alkanediyl,

[2277] L X12 represents a single bond or a C that may be substituted by 1 to 5 fluorine atoms 1-5 Alkanediyl.

[2278] Step 5-5:

[2279] Preparation method of compound [5-e]: Compound [5-c] is used as a starting material, and compound [5-d] is reacted in an inert solvent such as tetrahydrofuran or N-methylpyrrolidone at a temperature from ice-cold to reflux temperature in the presence of a base such as sodium hydride to produce compound [5-e].

[2280] In Scheme 5-2, compound [5-c'] is used as the starting material instead of compound [5-c], and compound [5-d'] is used as the starting material instead of compound [5-d]. Compound [5-e'] can be produced by the same method as the above-mentioned production method for compound [5-e]. In addition, compounds [5-c'] and [5-d'] can be produced by a known method or purchased as a commercial product.

[2281] [Chemistry 336]

[2282]

[2283] Where,

[2284] Ring B 2 、R B21 、R B22 , and LG 5 Same as the above definition,

[2285] Y 2 Indicates the formula -O-, -S- or -N (R L21 )-,

[2286] Among them, R L21Same as the above definition,

[2287] L X21 Indicates C 1-5 Alkanediyl,

[2288] L X22 represents a single bond or a C that may be substituted by 1 to 5 fluorine atoms 1-5 Alkanediyl.

[2289] The compounds [2-c], [5-e], and [5-e'] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2290] Among the production 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 produced by known methods or obtained by purchasing commercially available products.

[2291] Among the production intermediates of the compound [I] of the present invention, the following compound [2-f'] described in Production Method 2 can also be produced, for example, by the following Production Method 6 or a method based thereon.

[2292] [Chemistry 337]

[2293]

[2294] Manufacturing method 6:

[2295] An example of the production of compound [2-f'], which is a production intermediate of compound [I] of the present invention, is shown in the following Scheme 6-1.

[2296] Scheme 6-1 (Method for producing compound [2-f'] from compound [6-a]):

[2297] [Chemistry 338]

[2298]

[2299] In the plan,

[2300] R 3 '、R 4 and M are the same as above,

[2301] LG 6 represents a leaving group.

[2302] in,

[2303] LG 6 The "leaving group" shown here means, for example, a group represented by the formula -N(CH3)OCH3.

[2304] Step 6-1:

[2305] Method for producing compound [2-f']: Compound [6-a] is used as a starting material, and alkyl lithium [2-k] is reacted in an inert solvent at -78°C to room temperature to produce compound [2-f'].

[2306] This step can be performed with reference to the method described in, for example, Synlett, Vol. 26, p. 1395, 2015.

[2307] Step 6-2:

[2308] Method for producing compound [6-a']: Compound [6-a'] can be produced by conducting a "condensation reaction" of compound [6-a] with an amine compound such as N,O-dimethylhydroxylamine hydrochloride.

[2309] Step 6-3:

[2310] Another method for producing compound [2-f']: Compound [2-f'] can be produced by reacting compound [6-a'] with compound [2-k'] in an inert solvent at ice-cold to room temperature.

[2311] Scheme 6-2 (Method for producing compound [2-h] from compound [6-b]):

[2312] [Chemistry 339]

[2313]

[2314] In the plan,

[2315] R 4 Same as the above definition,

[2316] LG 7 represents a leaving group.

[2317] Among them, LG 7 The "leaving group" shown here represents, for example, a hydroxyl group, a C 1-6 Alkoxy.

[2318] Step 6-4:

[2319] Method for producing compound [6-c]: Compound [6-b] is used as a starting material, and a reducing agent is allowed to act in an inert solvent at ice-cold temperature to room temperature to produce compound [6-c].

[2320] As a reducing agent, (i)LG 7When LG is a hydroxyl group, for example, a borane-tetrahydrofuran complex can be used in the same manner as in step 5-3 above; (ii) LG 7 C 1-6 In the case of an alkoxy group, for example, lithium aluminum hydride or lithium borohydride can be used in the same manner as in the above-mentioned step 4-2.

[2321] Step 6-5:

[2322] Method for producing compound [2-h]: Compound [2-h] can be produced using compound [6-c] as a starting material by the method described in step 4-4 above or a method based thereon.

[2323] In addition, in compound [2-h], R 4 The compound [6-g] in which the ortho position of a substituted phenyl group is substituted with a chlorine atom can be produced, for example, by the method described in the following Scheme 6-3 or a method based thereon.

[2324] Scheme 6-3 (Method for producing compound [6-g] from compound [6-d]):

[2325] [Chemistry 340]

[2326]

[2327] In the plan,

[2328] Alk 3 and Alk 4 Same as the above definition,

[2329] Alk 6 Indicates C 1-6 alkyl,

[2330] R α2 Indicates C 1-6 Alkyl (the C 1-6 The alkyl group may be substituted with one hydroxyl group), halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkylcarbonyl, and halogenated C 1-6 Alkylcarbonyl.

[2331] Step 6-6:

[2332] Preparation method of compound [6-e]: Compound [6-d] is used as a starting material, and a chlorinating agent such as sulfonyl chloride or N-chlorosuccinimide (NCS) is allowed to react in an inert solvent at -60°C to 100°C to prepare compound [6-e].

[2333] It should be noted that this chlorination reaction can also be carried out in a single step.

[2334] In this step, by using 2 equivalents of a 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.

[2335] [Chemistry 341]

[2336]

[2337] Steps 6-7:

[2338] Method for producing compound [6-f]: Compound [6-f] can be produced using compound [6-e] as a starting material by the method described in step 4-2 above or a method based thereon.

[2339] Steps 6-8:

[2340] Method for producing compound [6-g]: Compound [6-g] can be produced by the method described in step 4-4 above or a method based thereon using compound [6-f] as a starting material.

[2341] In addition, in compound [2-h], R 4 The compound [6-m] in which the ortho-position of a substituted phenyl group is substituted with a methyl group can be produced, for example, by the method described in the following Scheme 6-4 or a method based thereon.

[2342] Scheme 6-4 (Method for producing compound [6-m] from compound [6-d]):

[2343] [Chemistry 342]

[2344]

[2345] In the plan,

[2346] Alk 3 、Alk 4 、Alk 6 and R α2 Same as the above definition.

[2347] Steps 6-9:

[2348] Preparation method of compound [6-h]: Compound [6-d] is used as a starting material, and an iodizing agent such as iodine is allowed to act in an inert solvent at ice-cold temperature to room temperature in the presence of a silver compound such as silver trifluoroacetate to produce compound [6-h].

[2349] It should be noted that this iodination reaction can also be carried out in a single step.

[2350] Steps 6-10:

[2351] Method for producing compound [6-j]: Compound [6-h] is reacted with a methylating agent such as methylboronic acid in an inert solvent at room temperature to 160°C in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) and a base such as tripotassium phosphate, thereby producing compound [6-j]. This methylation reaction can also be carried out in a single step.

[2352] Steps 6-11:

[2353] Method for producing compound [6-k]: Compound [6-k] can be produced by the method described in step 6-7 above or a method based thereon using compound [6-j] as a starting material.

[2354] Steps 6-12:

[2355] Method for producing compound [6-m]: Compound [6-m] can be produced by the method described in step 6-8 above or a method based thereon using compound [6-k] as a starting material.

[2356] Scheme 6-5 (Another method for producing compound [6-j] from compound [6-d]):

[2357] [Chemistry 343]

[2358]

[2359] In the plan,

[2360] Alk 3 、Alk 4 、Alk 6 and R α2 Same as the above definition.

[2361] Steps 6-13:

[2362] Preparation method of compound [6-n]: Compound [6-d] is used as a starting material, and dichloromethyl methyl ether is reacted in an inert solvent at ice-cold temperature to room temperature in the presence of a Lewis acid such as titanium (IV) chloride to produce compound [6-n].

[2363] It should be noted that the formylation reaction can also be carried out in a single step.

[2364] Steps 6-14:

[2365] Another method for producing compound [6-j]: Compound [6-n] is prepared by reacting the starting material with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid at a temperature between ice-cold and room temperature. This methylation reaction can also be carried out in a single step.

[2366] Among the production intermediates of compound [I] of the present invention, the following compound [2-g] described in Production Method 2 can be produced by a known method or obtained by purchasing a commercially available product. It can also be produced by, for example, the following Production Method 7 or a method based thereon.

[2367] [Chemistry 344]

[2368]

[2369] Manufacturing method 7:

[2370] The production example of compound [2-g], which is a production intermediate of compound [I] of the present invention, is shown in the following Scheme 7.

[2371] Scheme 7 (Method for producing compound [2-g] from compound [2-b]):

[2372] [Chemistry 345]

[2373]

[2374] In the plan,

[2375] R 2 and LG 1 Same as the above definition,

[2376] PG 2 represents a protecting group for an amino group such as tert-butoxycarbonyl,

[2377] PG 3 represents a protective group for a hydrogen atom or an amino group such as a tert-butoxycarbonyl group,

[2378] also,

[2379] PG 2 and PG 3 The amino group can also be protected by forming phthalimide together with the adjacent nitrogen atom.

[2380] Step 7-1:

[2381] Preparation method of compound [7-a]: Compound [2-b] is used as a starting material, and potassium phthalimide, di-tert-butyl iminodicarboxylate, etc. are reacted in an inert solvent at room temperature to 120°C in the presence or absence of a base such as potassium carbonate to produce compound [7-a].

[2382] Step 7-2:

[2383] Method for producing compound [2-g]: Compound [2-g] can be produced by using compound [7-a] as a starting material and following any one of the reaction conditions (i) to (ii).

[2384] (i) In an inert solvent, at ice-cold temperature to 100°C, react with an acid such as hydrochloric acid, or

[2385] (ii) Conditions for reacting hydrazine monohydrate or the like in an inert solvent at room temperature to reflux temperature

[2386] The compound [2-b] used as a starting compound in the above-mentioned Step 7-1 can be produced by a known method per se, produced by the method shown in the above-mentioned Scheme 4-1, or obtained by purchasing a commercially available product.

[2387] The compound [2-g] thus obtained can be isolated and purified by known isolation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2388] Among the production intermediates of the compound [I] of the present invention, the compound [2-b] described in Scheme 7 can be produced by a known method or obtained by purchasing a commercially available product.

[2389] Among the production intermediates of compound [I] of the present invention, the compound having a structure represented by formula [1-b] (hereinafter sometimes referred to as compound [1-b]) can also be produced by, for example, the following production method 8 or a method based thereon.

[2390] [Chemistry 346]

[2391]

[2392] Manufacturing method 8:

[2393] Compound [1-b], which is a production intermediate of compound [I] of the present invention, can be produced by a known method or purchased as a commercial product. It can also be produced by, for example, the method described in the following Scheme 8-1 or a method based thereon.

[2394] Scheme 8-1 (Method for producing compound [1-b] from compound [8-a]):

[2395] [Chemistry 347]

[2396]

[2397] In the plan,

[2398] W and Alk 1 Same as the above definition,

[2399] PG 4 It represents a protecting group for an amino group such as benzyloxycarbonyl, tert-butoxycarbonyl, and allyloxycarbonyl.

[2400] Step 8-1:

[2401] Method for producing compound [8-b]: Compound [8-a] can be produced by using compound [8-a] as a starting material and any one of the following reaction conditions (i) to (iii).

[2402] (i) in an inert solvent at room temperature to reflux temperature, in the presence or absence of a base such as potassium carbonate, with an alkylating agent such as iodomethane,

[2403] (Ii) 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., an alcohol such as methanol or ethanol is reacted; or

[2404] (iii) In an inert solvent, at room temperature to reflux temperature, in the presence of a silver compound such as silver oxide, an alkylating agent such as iodomethane is reacted

[2405] Step 8-2:

[2406] Preparation method of compound [1-b]: Compound [8-b] can be prepared by using compound [8-b] as a starting material and carrying out the following deprotection reactions (i) to (iii) in an inert solvent.

[2407] (i) Deprotection reaction using an acid such as hydrochloric acid, hydrobromic acid, or trifluoroacetic acid at ice-cold temperature to 80°C,

[2408] (ii) a deprotection reaction using palladium carbon or the like at ice-cold temperature to room temperature, under a hydrogen atmosphere and under pressure or without pressure, in the presence or absence of an acid, or

[2409] (iii) Deprotection reaction 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 between ice-cold and 80°C

[2410] Among the compounds [1-b], the compound [8-f] in which W is a structure represented by the above-mentioned formula [III-1] can be produced by a known method or obtained by purchasing a commercially available product.

[2411] Furthermore, the compound can also be produced by, for example, the method described in the following Scheme 8-2 or a method based thereon.

[2412] [Chemistry 348]

[2413]

[2414] Scheme 8-2 (Method for producing compound [8-f] from compound [8-c]):

[2415] [Chemistry 349]

[2416]

[2417] In the plan,

[2418] Ring A 1 、R A11 、R A12 、Alk 1 and PG 4 Same as the above definition.

[2419] Step 8-3:

[2420] Method for producing compound [8-d]: Compound [8-c] is used as a starting material, and tetramethylammonium hydroxide, tetraethylammonium hydroxide, or the like is allowed to act in an inert solvent at ice-cold to room temperature, thereby selectively hydrolyzing only one of the two esters of compound [8-c] to produce compound [8-d].

[2421] This step can be carried out with reference to the method described in, for example, The Journal of Organic Chemistry, Vol. 82, p. 12863, 2017.

[2422] Step 8-4:

[2423] Preparation method of compound [8-e]: Compound [8-d] is used as a starting material, and an azidating agent such as diphenylphosphoryl azide is allowed to react in an inert solvent at ice-cold temperature to 100°C in the presence of a base such as triethylamine to form the corresponding isocyanate, and then an alcohol such as benzyl alcohol, tert-butyl alcohol, or allyl alcohol is allowed to react to produce compound [8-e].

[2424] Step 8-5:

[2425] Method for producing compound [8-f]: Compound [8-f] can be produced using compound [8-e] as a starting material by the method described in step 8-2 above or a method based thereon.

[2426] In addition, compounds [8-f'] and [8-f"] in which W in compound [1-b] is a structure represented by formula [III-2] or [III-3] can be produced by a known method or obtained by purchasing a commercially available product.

[2427] Furthermore, these compounds can also be produced by, for example, the method described in the above-mentioned Scheme 8-2 or a method based thereon.

[2428] [Chemistry 350]

[2429]

[2430] Where,

[2431] Ring A 2 Ring A 3 、R A21 、R A22 、R A31 、R A32 and Alk 1 Same as the above definition.

[2432] In compound [1-b], W is the structure shown in the above formula [III-1], and in the structure, ring A 1 is selected from "hydroxyl, C 1-6 C substituted with one of the following: alkoxy, and 4-6 membered saturated heterocyclic group containing nitrogen atom 3-8 The cycloalkane compound [8-p] can be produced by a known method or obtained by purchasing a commercially available product.

[2433] In addition, the compound may also be substituted with an oxo-substituted C 3-8 The cycloalkane compound [8-g] is used as a starting material and is produced by the method described in the following Scheme 8-3 or a method based thereon.

[2434] [Chemistry 351]

[2435]

[2436] Scheme 8-3 (Method for producing compound [8-p] from compound [8-g]):

[2437] [Chemistry 352]

[2438]

[2439] In the plan,

[2440] Alk 1 and PG 4 Same as the above definition,

[2441] Ring A 1 ' for C 3-8 Cycloalkanes,

[2442] PG 5 Indicates C 1-3 alkyl,

[2443] in,

[2444] 2 PGs 5 It can form a 5- to 6-membered ring together with the bonded oxygen atom and carbon atom (the 5- to 6-membered ring may be substituted with 1 to 2 groups selected from methyl and phenyl groups) to protect the carbonyl group.

[2445] R A11 ' represents hydroxyl group, C 1-6 Alkoxy, or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom (the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 alkyl substitution).

[2446] Step 8-6:

[2447] Preparation method of compound [8-h]: Compound [8-g] is used as a starting material, and an alcohol such as methanol, ethylene glycol, or diphenyl glycol, or an orthoester such as triethyl orthoformate is reacted in an inert solvent at room temperature to reflux temperature in the presence of an acid such as p-toluenesulfonic acid to produce compound [8-h].

[2448] Step 8-7:

[2449] Method for producing compound [8-j]: Compound [8-j] can be produced by using compound [8-h] as a starting material and the method described in step 8-3 above or a method based thereon.

[2450] Step 8-8:

[2451] Method for producing compound [8-k]: Compound [8-k] can be produced by the method described in step 8-4 above or a method based thereon, using compound [8-j] as a starting material.

[2452] Steps 8-9:

[2453] Preparation method of compound [8-m]: Compound [8-k] can be prepared by a deprotection reaction using an acid such as hydrochloric acid or trifluoroacetic acid in an inert solvent at room temperature to reflux temperature using compound [8-k] as a starting material.

[2454] Steps 8-10:

[2455] Method for producing compound [8-n]: Compound [8-n] can be produced by carrying out any one of the following reactions (i) to (iv) using compound [8-m] as a starting material.

[2456] (i) Reduction reaction using a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, borane-tetrahydrofuran, etc. in an inert solvent at a temperature between -80°C and reflux in the presence or absence of an additive such as zinc chloride;

[2457] (ii) After the operation of steps 8-10 (i), in an inert solvent, at ice-cold temperature to reflux temperature, in the presence of a phosphorus compound such as triphenylphosphine and an azodicarboxylic acid diester such as bis(2-methoxyethyl)azodicarboxylate, a "hydrolysis reaction" of 4-nitrobenzoic acid,

[2458] (iii) After carrying out the operation of step 8-10(i) or 8-10(ii), in an inert solvent, at room temperature to reflux temperature, in the presence of a silver compound such as silver oxide, a reaction using an alkyl halide such as iodomethane or iodoethane, or

[2459] (iv) with the value corresponding to R A11 'Reductive amination of amines

[2460] The above steps 8-10(i) can be carried out with reference to the method described in, for example, Bioorganic & Medicinal Chemistry, Vol. 17, p. 1982, 2009.

[2461] Furthermore, in this step 8-10(i), by selecting an appropriate reducing agent, compound [8-n] can be produced stereoselectively.

[2462] Steps 8-11:

[2463] Method for producing compound [8-p]: Compound [8-p] can be produced by the method described in step 8-2 above or a method based thereon, using compound [8-n] as a starting material.

[2464] In addition, the present compound [8-p] can also be prepared by, for example, using the oxo-substituted C 3-8 The cycloalkane compound, namely compound [8-m], is used as a starting material and is produced by the method described in the following Scheme 8-4 or a method based thereon.

[2465] Scheme 8-4 (Method for producing compound [8-p] from compound [8-m]):

[2466] [Chemistry 353]

[2467]

[2468] In the plan,

[2469] Alk 1 PG4 Ring A 1 ' and R A11 'Same as the above definition.

[2470] Steps 8-12:

[2471] Method for producing compound [1-b']: Compound [1-b'] can be produced by the method described in step 8-2 above or a method based thereon, using compound [8-m] as a starting material.

[2472] Steps 8-13:

[2473] Preparation method of compound [8-q]: Compound [1-b'] is used as a starting material, and phthalic anhydride or the like is reacted in an inert solvent at room temperature to reflux temperature in the presence of a base such as triethylamine to produce compound [8-q].

[2474] Steps 8-14:

[2475] Method for producing compound [8-r]: Compound [8-r] can be produced by the method described in step 8-10 above or a method based thereon using compound [8-q] as a starting material.

[2476] Steps 8-15:

[2477] Preparation method of compound [8-p]: Compound [8-r] can be prepared by reacting an acid such as hydrochloric acid, hydrazine, etc. with compound [8-r] as a starting material in an inert solvent at ice-cold to reflux temperature.

[2478] In compound [1-b], W is a structure represented by the above formula [III-2] or [III-3], and in the structure, ring A 2 Ring A 3 They are selected from "hydroxyl, C 1-6 C substituted with one of the following: alkoxy, and 4-6 membered saturated heterocyclic group containing nitrogen atom 3-8 The cycloalkane compounds [8-p'] and [8-p"] can be produced by a known method or purchased from commercially available products.

[2479] Furthermore, these compounds can also be produced by, for example, the methods described in the above-mentioned Schemes 8-3 and 8-4, or methods based thereon.

[2480] [Chemistry 354]

[2481]

[2482] Where,

[2483] Alk1 Same as the above definition,

[2484] Ring A 2 ' and Ring A 3 'with ring A 1 ' is defined identically to C 3-8 Cycloalkanes,

[2485] R A21 ' and R A31 'with R A11 ' is defined similarly as hydroxyl, C 1-6 Alkoxy, or a 4- to 6-membered saturated heterocyclic group containing a nitrogen atom (the 4- to 6-membered saturated heterocyclic group containing a nitrogen atom may be replaced by 1 C 1-3 alkyl substitution).

[2486] In compound [1-b], W is the structure represented by the aforementioned formula [III-1] and in which ring A 1 C substituted by one hydroxyl group 3-8 Cycloalkane compound [8-w], and ring A 1 For 1 C 1-6 Alkoxy-substituted C 3-8 The cycloalkane compound [8-z] can be produced by a known method or can be obtained by purchasing a commercially available product.

[2487] In addition, these compounds can also be substituted by oxo- 3-8 The cycloalkane compound [8-g] is used as a starting material and is produced by the method described in the following Scheme 8-5 or a method based thereon.

[2488] In addition, when compounds [8-w] and [8-z] each exist as corresponding enantiomers or diastereomers, the enantiomers or diastereomers can also be produced by a known method, produced by the method shown in Scheme 8-5, or obtained by purchasing a commercially available product.

[2489] [Chemistry 355]

[2490]

[2491] Scheme 8-5 (Method for producing compounds [8-w] and [8-z] from compound [8-g]):

[2492] [Chemistry 356]

[2493]

[2494] In the plan,

[2495] Alk 1 Ring A1 ' and PG 4 Same as the above definition,

[2496] R A11a Indicates C 1-6 Alkoxy.

[2497] Steps 8-16:

[2498] Method for producing compound [8-s]: Compound [8-s] can be produced using compound [8-g] as a starting material by the method described in step 8-10 (i) above or a method based thereon.

[2499] Steps 8-17:

[2500] Method for producing compound [8-t]: Compound [8-t] can be produced by the method described in step 8-3 above or a method based thereon using compound [8-s] as a starting material.

[2501] Steps 8-18:

[2502] Preparation method of compound [8-u]: Compound [8-t] is used as a starting material, and an azide such as diphenylphosphoryl azide is allowed to react in an inert solvent at a temperature from ice-cold to reflux temperature in the presence of a base such as triethylamine to produce compound [8-u].

[2503] Steps 8-18 can be carried out with reference to the method described in, for example, Journal of the Organic Chemistry, Vol. 82, p. 12863, 2017.

[2504] Steps 8-19:

[2505] Preparation method of compound [8-v]: Compound [8-u] is used as a starting material, and a base such as potassium hydroxide and water are reacted in an inert solvent at ice-cold temperature to reflux temperature to prepare compound [8-v].

[2506] Steps 8-20:

[2507] Method for producing compound [8-w]: Compound [8-w] can also be produced by the method described in step 8-1 (ii) above or a method based thereon using compound [8-v] as a starting material.

[2508] Steps 8-21:

[2509] Preparation method of compound [8-x]: Compound [8-w] is used as a starting material, and di-tert-butyl dicarbonate, allyl chloroformate, benzyl chloroformate, etc. are reacted in an inert solvent at ice-cold temperature to reflux temperature in the presence of a base such as triethylamine, sodium hydroxide, sodium carbonate, etc., thereby preparing compound [8-x].

[2510] Steps 8-22:

[2511] Preparation method of compound [8-y]: Compound [8-x] is used as a starting material, and an alkyl halide such as iodomethane or iodoethane is reacted in an inert solvent at room temperature to reflux temperature in the presence of a silver compound such as silver oxide to produce compound [8-y].

[2512] Steps 8-23:

[2513] Method for producing compound [8-z]: Compound [8-z] can also be produced by the method described in step 8-2 above or a method based thereon, using compound [8-y] as a starting material.

[2514] In compound [1-b], W is the structure represented by the aforementioned formula [III-1] and in which ring A 1 To be selected as "C 1-4 Alkylcarbonyl and C 1-4 The nitrogen-containing 4- to 8-membered saturated heterocyclic compound [8-ac] substituted with one group in the "alkoxycarbonyl" group can be produced by a known method or obtained by purchasing a commercially available product.

[2515] Alternatively, the compound can be produced by the method described in the following Scheme 8-6 or a method based thereon, using, for example, compound [8-aa], a 4- to 8-membered saturated heterocyclic compound containing a nitrogen atom, as a starting material.

[2516] [Chemistry 357]

[2517]

[2518] Scheme 8-6 (Method for producing compound [8-ac] from compound [8-aa]):

[2519] [Chemistry 358]

[2520]

[2521] In the plan,

[2522] Alk 1 and PG 4 Same as the above definition,

[2523] Ring A 1" is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom,

[2524] R A11 " means C 1-4 Alkylcarbonyl or C 1-4 Alkoxycarbonyl.

[2525] Steps 8-24:

[2526] Method for producing compound [8-ac]: Compound [8-ab] can be produced by carrying out the following reaction (i) or (ii) using compound [8-aa] as a starting material.

[2527] (i) In an inert solvent, at ice-cold temperature to 50°C, in the presence of a base, use acetyl chloride or the like to react with the corresponding A11″ The acyl chloride or acetic anhydride corresponds to R A11″ The reaction of anhydride, or

[2528] (ii) In an inert solvent, at ice-cold temperature to 50°C, in the presence or absence of a base, use ethyl chloroformate or the like to react with the corresponding A11″ Reaction of chloroformates

[2529] Steps 8-25:

[2530] Method for producing compound [8-ac]: Compound [8-ac] can be produced by the method described in step 8-2 above or a method based thereon using compound [8-ab] as a starting material.

[2531] In compound [1-b], W is a structure represented by the above formula [III-2] or [III-3], and the ring A in the structure 2 Ring A 3 They were selected from “C 1-4 Alkylcarbonyl and C 1-4 The nitrogen-containing 4- to 8-membered saturated heterocyclic compounds [8-ac'] and [8-ac"] substituted with one group in the "alkoxycarbonyl" group can be produced by a known method or obtained by purchasing a commercially available product.

[2532] Furthermore, these compounds can also be produced by, for example, the method described in the above-mentioned Scheme 8-6 or a method based thereon.

[2533] [Chemistry 359]

[2534]

[2535] Where,

[2536] Alk 1 Same as the above definition,

[2537] Ring A 2” and Ring A 3” With Ring A 1” The same definition is a 4- to 8-membered saturated heterocyclic ring containing a nitrogen atom,

[2538] R A21 ” and R A31 ” and R A11 " is defined similarly to C 1-4 Alkylcarbonyl or C 1-4 Alkoxycarbonyl.

[2539] 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"] thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, and chromatography.

[2540] Among the production 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 produced by a known method or obtained by purchasing a commercially available product.

[2541] Among the compounds [I] of the present invention, compounds wherein X is a carbamoyl group, compounds wherein X is a group represented by the following formula [II-2], [II-3], [II-4], [II-5], or [II-1], and compounds wherein X is a tetrazolyl group can be produced, for example, by the following production method 9 or a method based thereon.

[2542] [Hua360]

[2543]

[2544] In the compound [I] of the present invention, a production example 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 shown in the following Scheme 9-1.

[2545] Manufacturing method 9:

[2546] Scheme 9-1 (Method for producing compound [9-a] from compound [1-d]):

[2547] [Chemistry 361]

[2548]

[2549] In the plan,

[2550] R 1 、R 2 、R 3 、R 4 , and W are the same as defined above,

[2551] EQ 1 represents a hydrogen atom or a group selected from the following formula group [II']

[2552] [Chemistry 362]

[2553] .

[2554] Step 9-1:

[2555] Preparation method of [9-a]: Compound [1-d] is used as a starting material, and an amine compound such as methanesulfonamide, sulfonamide, N,N-dimethylsulfonamide, or ammonium chloride is reacted in an inert solvent at a temperature from ice-cold to reflux temperature in the presence or absence of a base such as N,N-diisopropylethylamine, in the presence or absence of an additive such as 4-dimethylaminopyridine or HOBt, and in the presence of a condensing agent such as EDC or CDI to produce compound [9-a].

[2556] Among the compounds [I] of the present invention, a production example of a compound [9-h] in which X is a group represented by the formula [II-5] is shown in the following Scheme 9-2.

[2557] Scheme 9-2 (Method for producing compound [9-h] from compound [9-b]):

[2558] [Chemistry 363]

[2559]

[2560] In the plan,

[2561] R 2 、R 3 、R 4 、R A11 and R A12 Same as the above definition,

[2562] Ring D represents C 3-8 Cycloalkanes, partially saturated 9- to 10-membered fused hydrocarbon aromatic rings, 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,

[2563] in,

[2564] The sulfur atom in the 4- to 8-membered saturated heterocyclic ring containing a sulfur atom may be substituted by 1 to 2 oxo groups.

[2565] The nitrogen atom in the 4-8 membered saturated heterocyclic ring containing nitrogen atom can be selected from C 1-4 Alkylcarbonyl and C 1-4 One group in the alkoxycarbonyl group is substituted,

[2566] PG 5 represents a protecting group for a phosphate group such as benzyl,

[2567] PG 6 It represents a protecting group for an amino group such as a diphenylmethyl group.

[2568] Step 9-2:

[2569] Preparation method of compound [9-e]: Compounds [9-b], [9-c] and [9-d] are used as starting materials, and a Lewis acid such as bismuth (III) chloride is allowed to react in an inert solvent at room temperature to 120°C to obtain compound [9-e].

[2570] This step can be carried out with reference to the method described in, for example, Organic Letters, Vol. 1, p. 1395, 1999.

[2571] In addition, this reaction can also be carried out under microwave irradiation.

[2572] Step 9-3:

[2573] Method for producing compound [9-f]: Compound [9-e] is used as a starting material. An oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is allowed to react in an inert solvent at room temperature to 100°C to form the corresponding imine. Thereafter, an acidic aqueous solution such as hydrochloric acid is allowed to react in an inert solvent at room temperature to 60°C to produce compound [9-f].

[2574] This step can be carried out with reference to the method described in, for example, Organic Letters, Vol. 1, p. 1395, 1999.

[2575] Step 9-4:

[2576] Preparation method of compound [9-g]: Compound [9-f] is used as a starting material, and compound [1-a] is reacted in an inert solvent at ice-cold to reflux temperature in the presence of a base such as triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and a ureidating agent such as 4-nitrophenyl chloroformate, CDI, or triphosgene to produce compound [9-g].

[2577] Step 9-5:

[2578] Preparation method of compound [9-h]: Compound [9-g] is used as a starting material, and compound [9-h] can be prepared by a deprotection reaction using palladium carbon or the like in an inert solvent at ice-cold to room temperature, under a hydrogen atmosphere and under pressure or without pressure, in the presence or absence of an acid.

[2579] Among the compounds [I] of the present invention, a production example of a compound [9-r] in which X is a group represented by the formula [II-1] is shown in the following Scheme 9-3.

[2580] Scheme 9-3 (Method for producing compound [9-q] from compound [8-a]):

[2581] [Chemistry 364]

[2582]

[2583] In the plan,

[2584] PG 4 、R 2 、R 3 、R 4 and W are the same as defined above.

[2585] Step 9-6:

[2586] Method for producing compound [9-j]: Compound [9-j] can be produced by conducting a "condensation reaction" of compound [8-a] with an amine compound such as ammonium chloride.

[2587] Step 9-7:

[2588] Preparation method of compound [9-k]: Compound [9-j] is used as a starting material, and an arylsulfonyl chloride such as p-toluenesulfonyl chloride or a C-terminal arylsulfonyl chloride such as methanesulfonyl chloride is reacted with the compound [9-j] in an inert solvent at a temperature between ice-cold and 50°C in the presence of a base such as pyridine. 1-4 Compound [9-k] can be prepared by reacting with alkylsulfonyl chloride.

[2589] Step 9-8:

[2590] Method for producing compound [9-m]: Compound [9-m] can be produced by the method described in step 8-2 above or a method based thereon using compound [9-k] as a starting material.

[2591] Step 9-9:

[2592] Method for producing compound [9-n]: Compound [9-n] can be produced by the method described in step 9-4 above or a method based thereon, using compound [9-m] as a starting material.

[2593] Steps 9-10:

[2594] Preparation method of compound [9-p]: Compound [9-n] is used as a starting material, and hydroxylamine hydrochloride is reacted in an inert solvent at ice-cold temperature to 90°C in the presence or absence of a base such as sodium carbonate or N,N-diisopropylethylamine to produce compound [9-p].

[2595] Steps 9-11:

[2596] Preparation method of compound [9-q]: Compound [9-p] is used as a starting material, and CDI or the like is reacted in an inert solvent at ice-cold temperature to room temperature in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene to produce compound [9-q].

[2597] Among the compounds [I] of the present invention, a production example of the compound [9-v] in which X is a tetrazolyl group is shown in the following Scheme 9-4.

[2598] Scheme 9-4 (Method for producing compound [9-v] from compound [9-k]):

[2599] [Chemistry 365]

[2600]

[2601] In the plan,

[2602] PG 4 、R 2 、R 3 、R 4 , and W are the same as defined above,

[2603] PG 7 It represents a protecting group for tetrazolyl such as triphenylmethyl and benzyl.

[2604] Steps 9-12:

[2605] Preparation method of compound [9-r]: Compound [9-k] is used as a starting material. In an inert solvent, at room temperature to 150°C, in the presence of an inorganic acid salt of an amine compound such as ammonium chloride or trimethylamine hydrochloride, and in the presence or absence of a copper catalyst, an azide such as sodium azide is reacted to produce compound [9-r]. This reaction can also be carried out under microwave irradiation.

[2606] Steps 9-13:

[2607] Preparation method of compound [9-s]: Compound [9-r] is used as a starting material, and trityl chloride, benzyl bromide, etc. are reacted in an inert solvent at ice-cold temperature to room temperature in the presence of a base such as triethylamine or potassium carbonate to produce compound [9-s].

[2608] Steps 9-14:

[2609] Method for producing compound [9-t]: Compound [9-t] can be produced using compound [9-s] as a starting material by the method described in step 8-2 above or a method based thereon.

[2610] Steps 9-15:

[2611] Method for producing compound [9-u]: Compound [9-u] can be produced by using compound [9-t] as a starting material and the method described in step 9-4 or a method based thereon.

[2612] Steps 9-16:

[2613] Preparation method of compound [9-v]: Compound [9-u] is used as a starting material, and compound [9-v] can be prepared by (i) reacting with an acid such as hydrochloric acid in an inert solvent at ice-cold temperature to room temperature; or (ii) performing a deprotection reaction using palladium carbon or the like in a hydrogen atmosphere under pressure or non-pressure in the presence or absence of an acid.

[2614] The compounds [9-a], [9-h], [9-q] and [9-v] thus obtained can be isolated and purified by isolation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

[2615] Among the production 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 produced by known methods or purchased from commercially available products.

[2616] The present invention is further described in detail by the following reference examples, examples, and test examples. However, these examples are not intended to limit the present invention, and modifications may be made without departing from the scope of the present invention.

[2617] In the following reference examples and examples, the yield may exceed the theoretical amount due to the influence of residual solvents and the like.

[2618] In the following Reference Examples and Examples, silica gel column chromatography used packed columns (Reveleris (registered trademark) Flash Cartridges Silica, manufactured by Gleise Corporation, or Biotage (registered trademark) SNAP Cartridge HP-Sphere, manufactured by Biotage). NH silica gel column chromatography used packed columns (Reveleris (registered trademark) Flash Cartridges Amino, manufactured by Gleise Corporation, or Biotage (registered trademark) SNAP Cartridge KP-NH, manufactured by Biotage). Preparative thin-layer chromatography used PLC plates (20 × 20 cm, Silica Gel 60 F254, 2 mm, manufactured by Merck). Unless otherwise specified, the ratio of elution solvents is expressed by volume. A phase separator used was an ISOLUTE (registered trademark) Phase Separator manufactured by Biotage.

[2619] The abbreviations used in this specification have the following meanings.

[2620] s: singlet

[2621] d: doublet

[2622] t: triplet

[2623] q: quartet

[2624] quin: Five Peaks (quintet)

[2625] sxt: six peaks (sextet)

[2626] spt: Septet

[2627] dd : double doublet

[2628] dt : double triplet

[2629] td : triple doublet

[2630] tt : triple triplet

[2631] qd :quarter doublet

[2632] m: multiplet

[2633] br : broad

[2634] J: coupling constant

[2635] Hz : Hertz

[2636] CHLOROFORM-d : Deuterated chloroform

[2637] DMSO-d6: deuterated dimethyl sulfoxide

[2638] METHANOL-d4: Deuterated methanol

[2639] ACETONE-d6: deuterated acetone

[2640] D2O : Heavy Water

[2641] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[2642] EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[2643] CDI: 1,1'-Carbonyldiimidazole

[2644] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[2645] HOBt: N-hydroxybenzotriazole monohydrate

[2646] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[2647] Rf: retardation factor

[2648] posi : positive (mode)

[2649] nega : negative (mode)

[2650] 1 H-NMR (proton nuclear magnetic resonance spectroscopy) was measured by the following Fourier transform NMR method using tetramethylsilane as an internal standard, and the total δ value is expressed in ppm.

[2651] 200MHz: Gemini2000 (Agilent Technologies)

[2652] 300MHz: Inova300 (Agilent Technologies)

[2653] 400MHz: AVANCE III HD400 (Bruker)

[2654] 500MHz: JNM-ECA500 (JEOL)

[2655] 600MHz: JNM-ECA600 (JEOL)

[2656] The analysis was performed using ACD / Spectrus Processor 2015 ACD / Labs 2015 Release (File Version S30S41, Build 76327, 28 Feb 2015) (trade name), etc. Very gentle peaks of protons such as hydroxyl, amino, amide, pyrazole, urea, and carboxyl groups are sometimes not recorded.

[2657] In the analysis of a compound, there may be protons that overlap with peaks of water or a solvent and cannot be identified.

[2658] MS (mass spectrometry) was measured using the following apparatus.

[2659] PlatformLC (Waters)

[2660] LCMS-2010EV (Shimadzu)

[2661] LCMS-IT-TOF (Shimadzu)

[2662] Agilent 6130 (Agilent)

[2663] Agilent6150 (Agilent).

[2664] Ionization methods used include ESI (electrospray ionization), EI (electron ionization), or dual ionization combining ESI and APCI (atmospheric pressure chemical ionization). Data are reported as found values. While molecular ion peaks are typically observed, compounds containing a tert-butoxycarbonyl (-Boc) group may also observe peaks resulting from the detachment of the tert-butoxycarbonyl or tert-butyl group as fragment ions. Furthermore, compounds containing a tetrahydropyranyl (THP) group may also observe peaks resulting from the detachment of the tetrahydropyranyl group as fragment ions. Furthermore, compounds containing a hydroxyl (-OH) group may also observe peaks resulting from the detachment of H2O or OH radicals as fragment peaks. In the case of salts, molecular ion peaks or fragment ion peaks of the free form are typically observed.

[2665] The following conditions are used for the measurement of analytical data and are described as Mode M.

[2666] Device: LCMS-IT-TOF (Shimadzu)

[2667] Ionization method: ESI / APCI multimode

[2668] The LC-MS in the Examples and Reference Examples was measured under the following conditions.

[2669] HPLC: Agilent 1290 Infinity

[2670] MS: Agilent 6130 or 6150

[2671] [HPLC conditions]

[2672] Column: Acquity UPLC CSH C18, 1.7μm, 2.1X50mm (WATERS)

[2673] Solvent: Solution A: water containing 0.1% formic acid, Solution B: acetonitrile containing 0.1% formic acid

[2674] (Method A, Normal mode)

[2675] Gradient: 0.00 min (Solution A / Solution B = 80 / 20), 1.20 min (Solution A / Solution B = 1 / 99), 1.40 min (Solution A / Solution B = 1 / 99), 1.41 min (Solution A / Solution B = 80 / 20), 1.50 min (Solution A / Solution B = 80 / 20)

[2676] (Method B, HP mode)

[2677] Gradient: 0.00 min (solution A / solution B = 95 / 5), 0.80 min (solution A / solution B = 60 / 40), 1.08 min (solution A / solution B = 1 / 99), 1.38 min (solution A / solution B = 1 / 99), 1.41 min (solution A / solution B = 95 / 5), 1.50 min (solution A / solution B = 80 / 20)

[2678] (Method C, LP mode)

[2679] Gradient: 0.00 min (Solution A / Solution B = 70 / 30), 0.80 min (Solution A / Solution B = 1 / 99), 1.40 min (Solution A / Solution B = 1 / 99), 1.42 min (Solution A / Solution B = 70 / 30), 1.50 min (Solution A / Solution B = 70 / 30)

[2680] Injection volume: 0.5 μL, flow rate: 0.8 mL / min

[2681] Detection method: UV210nm, 254nm

[2682] Agilent 385-ELSD with an evaporative light scattering detector (ELSD)

[2683] MS conditions

[2684] Ionization method: ESI or ESI / APCI multimode

[2685] The measurement conditions for the analytical data are as follows.

[2686] [Table 1-1]

[2687]

[2688] Purification by preparative HPLC in Examples and Reference Examples was carried out under the following conditions.

[2689] Instrument: Gilson high-throughput purification system

[2690] Column: Triart C18, 5μm, 30×50mm (YMC), or X-Bridge Prep C18 5um OBD, 30x50 (Waters)

[2691] Solvent: 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

[2692] (Method A)

[2693] Gradient: 0.00 min (solution A / solution B = 90 / 10), 2.00 min (solution A / solution B = 90 / 10), 11.0 min (solution A / solution B = 20 / 80), 12.0 min (solution A / solution B = 5 / 95), 13.52 min (solution A / solution B = 5 / 95), 15.0 min (solution A / solution B = 90 / 10)

[2694] (Method B)

[2695] Gradient: 0.00 min (liquid A / liquid B = 95 / 5), 3.00 min (liquid A / liquid B = 95 / 5), 8.53 min (liquid A / liquid B = 80 / 20), 10.0 min (liquid A / liquid B = 80 / 20), 11.0 min (liquid A / liquid B = 50 / 50), 12.02 min (liquid A / liquid B = 5 / 95), 13.5 min (liquid A / liquid B = 5 / 95), 13.65 min (liquid A / liquid B = 95 / 5), 15.0 min (liquid A / liquid B = 95 / 5)

[2696] (Method C)

[2697] Gradient: 0.00 min (solution A / solution B = 80 / 20), 2.00 min (solution A / solution B = 80 / 20), 10.0 min (solution A / solution B = 5 / 95), 11.0 min (solution A / solution B = 1 / 99), 13.5 min (solution A / solution B = 1 / 99), 13.55 min (solution A / solution B = 80 / 20), 15.0 min (solution A / solution B = 80 / 20)

[2698] Flow rate: 40 mL / min

[2699] Detection method: UV210nm, UV254nm

[2700] SofTA MODEL 300S ELSD with ELSD attached

[2701] In the following examples, diastereoisomer separation was performed by preparative HPLC.

[2702] [HPLC conditions]

[2703] [Table 2-1]

[2704]

[2705] Detection method: UV210nm, 254nm

[2706] The chiral HPLC preparations in the examples were carried out under the following conditions.

[2707] HPLC: Gilson high-throughput purification system or Waters preparative LC system

[2708] [HPLC conditions]

[2709] [Table 3-1]

[2710]

[2711]

[2712] [Table 3-2]

[2713]

[2714]

[2715] [Table 3-3]

[2716]

[2717] Detection method: UV210nm, 254nm

[2718] The chiral supercritical fluid chromatography (SFC) preparation in the examples was carried out under the following conditions.

[2719] SFC: SFC30 manufactured by WATERS

[2720] [SFC conditions]

[2721] [Table 4-1]

[2722]

[2723] Detection method: UV210nm, 254nm

[2724] An optical rotation measuring apparatus used was Autopol V manufactured by Rudolph Research Analytical Co., Ltd., and a sodium D line (589 nm) was used as a light source.

[2725] X-ray crystallographic structure analysis was performed using an R-AXIS RAPIDII (manufacturer: Rigaku).

[2726] As a microwave reaction apparatus, an Initiator produced by Biotage or a MONOWAVE 300 produced by Anton-Paar was used.

[2727] Differential thermal analysis / thermal mass analysis (TG / DTA) was performed using a Thermo Plus Evo TG8120 (Rigaku).

[2728] Compound names were generated using 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.

[2729] The stereostructures shown in this specification represent absolute configurations of asymmetric carbon atoms in the compounds of Reference Examples and Examples, but relative configurations are shown for meso-forms.

[2730] Regarding an asymmetric carbon, a compound having the absolute configuration thereof is an optically active form.

[2731] In compounds where an asterisk (*) is marked at an asymmetric carbon in a structural formula, the asterisk indicates that the stereoisomerism at the asymmetric carbon indicated by the asterisk is predominantly one absolute configuration. It should be noted that such compounds preferably have substantially a single absolute configuration. Furthermore, the absolute configuration of the asymmetric carbon may not be specified.

[2732] In this specification, "room temperature" means 20 to 30°C unless otherwise specified. "Cold temperature" means 0 to 5°C unless otherwise specified.

[2733] The present invention is further described in detail by the following reference examples, examples, and test examples. However, these examples are not intended to limit the present invention, and modifications may be made without departing from the scope of the present invention.

[2734] Reference Example 1-1-1

[2735] Methyl 3-methoxy-5-(methoxymethyl)benzoate

[2736] [Chemistry 366]

[2737]

[2738] To a solution of methyl 3-(bromomethyl)-5-methoxybenzoate (150 mg) in methanol-tetrahydrofuran (2.9 mL-2.9 mL) was added potassium carbonate (168 mg), and the mixture was stirred at 55°C for 3 hours and then at room temperature overnight. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated to obtain a mixture containing the title compound (327 mg) as a colorless solid.

[2739] MS ESI posi: 211[M+H] + .

[2740] Retention time: 0.912 min (Method B)

[2741] Reference Example 1-1-2

[2742] 6-Ethoxy-1-ethyl-2,3-dihydro-1H-indole-4-carboxylic acid ethyl ester

[2743] [Chemistry 367]

[2744]

[2745] (1) A solution of ethyl 6-ethoxy-1H-indole-4-carboxylate (0.488 g) in N,N-dimethylformamide (4.2 mL) was ice-cooled, sodium hydride (60% mineral oil dispersion, 92.0 mg) was added, and 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 returning to room temperature. The reaction mixture was ice-cooled, 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, the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (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.

[2746] (2) Sodium cyanoborohydride (0.144 g) was slowly added to a solution of the compound obtained in (1) (0.2 g) in acetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 80:20) to obtain the title compound (0.142 g) as a light yellow oil.

[2747] MS ESI posi: 264[M+H] + .

[2748] Retention time: 1.264 min (Method B)

[2749] Reference Example 1-2-1

[2750] 3,5-diethoxy-2,4-dimethylbenzoic acid methyl ester

[2751] [Chemistry 368]

[2752]

[2753] (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 n-hexane and ethyl acetate (2:1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered out, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-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), respectively, as colorless powders.

[2754] (2) Under a nitrogen atmosphere, a chloroform (0.8 mL) solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) obtained in (1) above was ice-cooled, and titanium (IV) chloride (0.506 mL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes, 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 returning to room temperature. A saturated aqueous ammonium chloride 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 with 0.1 mol / L hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine in that order, dried over anhydrous magnesium sulfate, and the desiccant was filtered out. The filtrate was then concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=85:15) to obtain methyl 3,5-diethoxy-2-formyl-4-methylbenzoate (0.527 g) as a yellow oily substance.

[2755] (3) To a solution of the compound obtained in (2) (0.1 g) in trifluoroacetic acid (0.3 mL) was added triethylsilane (0.72 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 80:20) to obtain the title compound (0.062 g) as a colorless oil.

[2756] MS ESI posi: 253[M+H] + .

[2757] Retention time: 1.057 min (Method A)

[2758] Reference Example 1-2-2

[2759] Methyl 3,5-diethoxy-2-fluoro-4-methylbenzoate

[2760] [Chemistry 369]

[2761]

[2762] Under a nitrogen atmosphere, a solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) in acetonitrile (1.0 mL) obtained in Reference Example 1-2-1 (1) was ice-cooled, and a solution of N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (1.12 g) in acetonitrile (21 mL) was added, followed by stirring at room temperature for 23 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only, n-hexane:ethyl acetate = 90:10) to obtain the title compound (0.32 g) as a yellow oily substance.

[2763] MS ESI posi: 257[M+H] + 、279[M+Na] + .

[2764] Retention time: 0.953 min (Method A)

[2765] Reference Example 1-2-3

[2766] Ethyl 2-chloro-3,5-diethoxy-4-methylbenzoate

[2767] [Chemistry 370]

[2768]

[2769] (1) To a solution of 3,5-dihydroxy-4-methylbenzoic acid (2 g) in methanol (30 mL) was added N-chlorosuccinimide (1.75 g), and the mixture was stirred at 60°C for 4 hours and at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering out the desiccant, the filtrate was concentrated to obtain 2-chloro-3,5-dihydroxy-4-methylbenzoic acid (2.55 g) as a light yellow powder.

[2770] (2) 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) was added iodoethane (4.81 mL) and stirred at room temperature for 18 hours. Water was added to the reaction solution and extracted with a mixed solvent of n-hexane and ethyl acetate (2:1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering out the desiccant, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only - n-hexane:ethyl acetate = 90:10) to obtain the title compound (2.99 g) as a colorless oily substance.

[2771] MS ESI posi: 287[M+H] + 、309[M+Na] + .

[2772] Retention time: 1.023 min (Method A)

[2773] Reference Example 1-3-1

[2774] 3-Ethoxy-5-(methoxymethyl)-4-methylbenzoic acid

[2775] [Chemistry 371]

[2776]

[2777] (1) 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) was added pyridine (0.23 mL) and trifluoromethanesulfonic anhydride (0.288 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting 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.

[2778] (2) This reaction was carried out according to the method described in the reference (Organic Letters, Vol. 14, p. 1278, 2012). Under a nitrogen atmosphere, sodium carbonate (0.186 g), potassium (acetoxymethyl) trifluoroborate (0.316 g), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] methanesulfonate palladium (II) (RuPhosPdG3, Sigma-Aldrich, 97.7 mg) were added to a mixed solution of the compound obtained in (1) (400 mg) in 1,4-dioxane-water (2 mL-0.2 mL), and the mixture was stirred at 100°C for 5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 20:80) to obtain methyl 3-ethoxy-5-(hydroxymethyl)-4-methylbenzoate (250 mg) as a colorless oil.

[2779] (3) Sodium hydride (60% mineral oil dispersion, 67 mg) was added to a solution of the compound obtained in (2) above (250 mg) in tetrahydrofuran (11 mL), and the mixture was stirred under ice-cooling for 1 hour. Iodomethane (0.1 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence, and anhydrous magnesium sulfate was added. The desiccant was filtered off and the mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to obtain methyl 3-ethoxy-5-(methoxymethyl)-4-methylbenzoate (84 mg) as a brown oily substance.

[2780] (4) To a solution of the compound obtained in (3) (84 mg) in tetrahydrofuran (3.5 mL) was added a 1 mol / L aqueous sodium hydroxide solution (3.5 mL) and methanol (1.8 mL), and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was concentrated, acidified by the addition of 1 mol / L hydrochloric acid, and extracted with chloroform. The organic layer was filtered through a phase separator and concentrated to obtain the title compound (85 mg) as a colorless powder.

[2781] MS ESI posi: 225[M+H] + .

[2782] MS ESI nega: 223[MH] - .

[2783] Retention time: 1.128 min (Method B)

[2784] Reference Example 1-4-1

[2785] 4-Bromo-3,5-dimethoxybenzaldehyde

[2786] [Chemistry 372]

[2787]

[2788] (1) A solution of 4-bromo-3,5-dimethoxybenzoic acid (3.0 g) in tetrahydrofuran (7.7 mL) was ice-cooled, 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 at room temperature for 2 hours. The reaction mixture was ice-cooled, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was filtered and concentrated using a phase separator to obtain (4-bromo-3,5-dimethoxyphenyl)methanol (2.8 g) as a colorless powder.

[2789] (2) To a toluene (62 mL) solution of the compound (2.3 g) obtained in (1) above was added manganese dioxide (8.1 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated to obtain the title compound (2.18 g) as a light yellow powder.

[2790] MS ESI posi: 254[M+H] + .

[2791] Retention time: 0.996 min (Method B)

[2792] Reference Example 1-4-2

[2793] 3,5-diethoxy-4-methylbenzaldehyde

[2794] [Chemistry 373]

[2795]

[2796] (1) A solution of methyl 3,5-diethoxy-4-methylbenzoate (1.1 g) obtained in Reference Example 1-2-1 (1) in tetrahydrofuran (18 mL) was ice-cooled, and lithium aluminum hydride (0.26 g) was added, followed by stirring at room temperature for 1 hour. Sodium sulfate decahydrate (3 g) was added, and the mixture was stirred for 2 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated to obtain (3,5-diethoxy-4-methylphenyl)methanol (0.98 g) as a light yellow solid.

[2797] (2) The compound obtained in (1) (0.98 g) was reacted and post-treated according to the method described in Reference Example 1-4-1 (2). The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 60:40) to obtain the title compound (205 mg) as a yellow solid.

[2798] MS ESI posi: 209[M+H] + .

[2799] Retention time: 1.196 min (Method B)

[2800] The following Reference Examples 1-4-3 to 1-4-6 were synthesized using commercially available compounds or compounds synthesized according to methods described in or based on literature, and were synthesized by the methods described in or based on Reference Examples 1-4-1 and 1-4-2. The structures and LCMS data of the compounds are shown in Table 5-1.

[2801] [Table 5-1]

[2802]

[2803] Reference Example 1-5-1

[2804] 1-(4-Bromo-3,5-diethoxyphenyl)ethan-1-one

[2805] [Chemistry 374]

[2806]

[2807] (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 mixed solution of n-hexane and ethyl acetate (4:3, 7 mL) was added to the obtained residue to dissolve it, and n-hexane (12 mL) was further added. The precipitated solid was filtered out, and the filtrate was concentrated. Ethyl acetate (3 mL) was added to the obtained residue to dissolve it, and n-hexane (16 mL) was further added to filter out the precipitated solid. The obtained solids were combined to obtain ethyl 4-bromo-3,5-diethoxybenzoate (5.11 g) as a colorless solid.

[2808] (2) The compound obtained in (1) (5.11 g) was reacted according to the method described in Reference Example 1-3-1 (4) to obtain 4-bromo-3,5-diethoxybenzoic acid (4.68 g) as a colorless solid.

[2809] (3) To a solution of the compound (4.68 g) obtained in (2) above in N,N-dimethylformamide (26 mL) were added N,O-dimethylhydroxylamine hydrochloride (1.65 g), HATU (9.19 g), and N,N-diisopropylethylamine (11.2 mL), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate 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 resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 60:40) to obtain 4-bromo-3,5-diethoxy-N-methoxy-N-methylbenzamide (6.2 g) as a light yellow oily substance.

[2810] (4) Under a nitrogen atmosphere, a solution of the compound obtained in (3) above (5.36 g) in tetrahydrofuran (54 mL) was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 16.1 mL) was added, followed by stirring at the same temperature for 30 minutes and at room temperature for 4.5 hours. The reaction solution was ice-cooled, and a saturated aqueous ammonium chloride solution was added, followed by extraction 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 resulting residue, and the precipitated solid was filtered to obtain the title compound (3.18 g) as a colorless solid.

[2811] MS ESI posi: 287, 289[M+H] + .

[2812] Retention time: 1.149 min (Method B)

[2813] Reference Example 1-5-2

[2814] 1-(3,5-diethoxy-4-methylphenyl)ethan-1-one

[2815] [Chemistry 375]

[2816]

[2817] (1) Using 3,5-dihydroxy-4-methylbenzoic acid (3 g), a 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.

[2818] (2) The compound obtained in (1) (4.2 g) was reacted according to the method described in Reference Example 1-3-1 (4) to obtain 3,5-diethoxy-4-methylbenzoic acid (3.74 g) as a colorless powder.

[2819] (3) This 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 ice-cooled, methyl lithium (1 mol / L diethyl ether solution, 50 mL) was added, and the mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature overnight. The reaction mixture was ice-cooled, water was slowly added, and the mixture was acidified with 2 mol / L hydrochloric acid, stirred for 30 minutes, and extracted three times with diethyl ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution (60 mL) and saturated brine (60 mL) in sequence, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 88:12 to ethyl acetate alone) to obtain the title compound (2.0 g) as a colorless powder.

[2820] MS ESI posi: 223[M+H] + .

[2821] Retention time: 0.931 min (Method A)

[2822] The following Reference Examples 1-5-3 to 1-5-30 were synthesized using the 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 methods described in or based on literature, and were synthesized by the methods described in or based on Reference Examples 1-5-1 or 1-5-2. The structures and LCMS data of the compounds are shown in Tables 6-1 to 6-6.

[2823] [Table 6-1]

[2824]

[2825] [Table 6-2]

[2826]

[2827] [Table 6-3]

[2828]

[2829] [Table 6-4]

[2830]

[2831] [Table 6-5]

[2832]

[2833] [Table 6-6]

[2834]

[2835] Reference Example 1-6-1

[2836] 1-(4-Bromo-3,5-dimethoxyphenyl)ethan-1-one

[2837] [Chemistry 376]

[2838]

[2839] (1) A solution of the compound obtained in Reference Example 1-4-1 (506 mg) in tetrahydrofuran (4.1 mL) was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 688 μL) was added, followed by stirring at room temperature for 2.5 hours. The reaction mixture was ice-cooled, and a saturated aqueous ammonium chloride 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 obtain 1-(4-bromo-3,5-dimethoxyphenyl)ethan-1-ol (443 mg) as a colorless solid.

[2840] (2) The compound obtained in (1) above (443 mg) was reacted according to the method described in Reference Example 1-4-1 (2) to obtain the title compound (394 mg) as a colorless powder.

[2841] MS ESI posi: 259[M+H] + .

[2842] Retention time: 1.012 min (Method B)

[2843] The following Reference Example 1-6-2 was synthesized by the method described in Reference Example 1-6-1 or a method based thereon, using the compound obtained in Reference Example 1-4-3, a commercially available compound, or a compound synthesized according to a method described in the literature or a method based thereon. The structure and LCMS data of the compound are shown in Table 7-1.

[2844] [Table 7-1]

[2845]

[2846] Reference Example 1-7-1

[2847] 1-(3-Ethoxy-5-propylphenyl)ethan-1-one

[2848] [Chemistry 377]

[2849]

[2850] This reaction was carried out according to the method described in the reference document (The Journal of Organic Chemistry, Vol. 74, p. 3626, 2009). To the compound obtained in Reference Example 1-5-8 (0.05 g), ethylboric acid (22.8 mg), potassium carbonate (85.3 mg), palladium(II) acetate (9.23 mg), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 38.4 mg) were added toluene (2.1 mL) and water (0.206 mL). The mixture was stirred at 120°C for 70 minutes under microwave irradiation. The insoluble matter in the reaction solution was filtered off, and the filtrate was concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 80:20) to obtain the title compound (32.3 mg) as a colorless oil.

[2851] MS ESI posi: 207[M+H] + .

[2852] Retention time: 1.265 min (Method B)

[2853] Reference Example 1-7-2

[2854] 3-Acetyl-5-ethoxybenzamide

[2855] [Chemistry 378]

[2856]

[2857] To a solution of the compound (53.6 mg) obtained in Reference Example 1-5-6 in dimethyl sulfoxide (1 mL) were added a 1 mol / L aqueous sodium hydroxide solution (2.83 mL), hydrogen peroxide (30% aqueous solution, 86.8 μL), and ethanol (1 mL), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium thiosulfate-water mixture (1:1) was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 70:30 to ethyl acetate alone) to obtain the title compound (66.1 mg) as a colorless solid.

[2858] MS ESI posi: 208[M+H] + .

[2859] Retention time: 0.741 min (Method B)

[2860] Reference Example 1-7-3

[2861] 3-Acetyl-5-ethoxy-N-methylbenzamide

[2862] [Chemistry 379]

[2863]

[2864] A solution of the compound obtained in Reference Example 1-5-9 (1.5 g) in tetrahydrofuran (23 mL) was cooled to ice, and methylamine (2 mol / L tetrahydrofuran solution, 25 mL), EDC (2.8 g), and HOBt (2.2 g) were added, followed by stirring at room temperature for 17 hours. The reaction mixture was cooled to ice, and saturated aqueous sodium bicarbonate solution and water were added, followed by extraction three times with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The resulting residue was purified by preparative HPLC to obtain the title compound (35 mg) as a light yellow oil.

[2865] MS ESI / APCI Multi posi: 222[M+H] + .

[2866] Retention time: 0.965 min (Method F)

[2867] Reference Example 1-7-4

[2868] 1,1'-(2-ethoxy-6-fluoro-1,4-phenylene)bis(ethane-1-one)

[2869] [Chemistry 380]

[2870]

[2871] (1) This reaction was carried out according to the method described in the reference document (WO2014 / 191535). Potassium carbonate (3.38 g) and water (1.2 mL) were added to a solution of 4-bromo-2,6-difluorobenzaldehyde (3 g) in N,N-dimethylformamide (14 mL), and the mixture was stirred at 90°C for 11 hours and then at room temperature overnight. Potassium carbonate (1.78 g) and iodoethane (3.91 mL) were added to the reaction solution, and the mixture was stirred at 65°C for 7 hours. The reaction solution was filtered through Celite (registered trademark), water was added to the filtrate, and the mixture 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, filtered using a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to obtain 4-bromo-2-ethoxy-6-fluorobenzaldehyde (0.752 g) as a colorless solid.

[2872] (2) The compound obtained in (1) above (0.2 g) was reacted according to the method described in Reference Example 1-6-1 (1) to obtain 1-(4-bromo-2-ethoxy-6-fluorophenyl)ethane-1-ol (218 mg) as a pale pink oily substance.

[2873] (3) To a solution of the compound obtained in (2) (218 mg) in n-hexane (10 mL) was added manganese dioxide (0.8 g), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 70:30) to obtain 1-(4-bromo-2-ethoxy-6-fluorophenyl)ethan-1-one (81.3 mg) as a colorless oily substance.

[2874] (4) To a mixed solution of the compound (81.3 mg) obtained in (3) above in N,N-dimethylformamide-water (1.56 mL-0.156 mL) were added butyl vinyl ether (200 μL), palladium (II) acetate (2.10 mg), 1,3-bis(diphenylphosphino)propane (7.70 mg), and potassium carbonate (0.129 g), and the mixture was stirred at 120°C for 1 hour under microwave irradiation. Additional butyl vinyl ether (200 μL), palladium (II) acetate (6.99 mg), and 1,3-bis(diphenylphosphino)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% aqueous potassium carbonate 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 to n-hexane:ethyl acetate = 70:30) to obtain the title compound (18.3 mg) as a pale yellow oily substance.

[2875] MS ESI posi: 225[M+H] + .

[2876] Retention time: 0.879 min (Method B)

[2877] Reference Example 1-7-5

[2878] 1-[3-Ethoxy-5-fluoro-4-(1-hydroxyethyl)phenyl]ethan-1-one

[2879] [Chemistry 381]

[2880]

[2881] The compound obtained in Reference Example 1-7-4 (2) (95.3 mg) was used to react according to the method described in Reference Example 1-7-4 (4) to obtain the title compound (22.4 mg) as a colorless solid.

[2882] MS ESI posi: 209[M-OH] + .

[2883] Retention time: 0.773 min (Method B)

[2884] Reference Example 1-7-6

[2885] 4-Ethoxy-1-ethyl-1H-indazole-6-carbaldehyde

[2886] [Chemistry 382]

[2887]

[2888] (1) To a solution of the compound (5.8 g) obtained in Reference Example 1-7-4 (1) in N-methylpyrrolidone (8.7 mL) was added ethylhydrazine oxalate (3.9 g) and stirred at room temperature for 24 hours. N-methylpyrrolidone (78 mL) was added to the reaction solution and stirred at 200°C for 2.5 hours. n-Hexane, ethyl acetate, water, and saturated brine were added to the reaction solution and partitioned into two layers. The aqueous layer was extracted with a mixed solvent of n-hexane and ethyl acetate. The organic layers were combined, washed with water and saturated brine in sequence, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 60:40). n-Hexane was added to the residue, insoluble matter was filtered off, and the residue was concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=98:2 to 60:40) to obtain 6-bromo-4-ethoxy-1-ethylindazole (2.48 g) as a light green oily substance.

[2889] (2) Under a nitrogen atmosphere, a solution of the compound obtained in (1) (2.48 g) and copper (I) cyanide (1.57 g) in N,N-dimethylacetamide (31 mL) was stirred at 150°C for 30 hours. After cooling to room temperature, 10% aqueous ammonia, saturated saline, and water were added to the reaction solution, extracted with ethyl acetate, and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to ethyl acetate alone). A mixed solvent of n-hexane-ethyl acetate was added to the resulting residue. The organic layer was washed with water and saturated saline in sequence, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to obtain 4-ethoxy-1-ethylindazole-6-carbonitrile (800 mg) as a pale yellow powder.

[2890] (3) Under a nitrogen atmosphere, a toluene (36 mL) solution of the compound obtained in (2) above (1.54 g) was cooled to -40°C, and diisobutylaluminum hydride (1.0 mol / L toluene solution, 8.6 mL) was added, followed by stirring at the same temperature for 1 hour. Diisobutylaluminum hydride (1.0 mol / L toluene solution, 3.0 mL) was further added, and the mixture was stirred at the same temperature for 10 minutes. Isopropyl alcohol (6 mL) was added dropwise to the reaction solution, and silica gel was added and stirred for 5 minutes. The reaction solution was returned to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated to obtain the title compound (1.37 g) as a light yellow oily substance.

[2891] MS ESI / APCI Multi posi: 219 [M+H] + .

[2892] Retention time: 0.980 min (Method E)

[2893] Reference Example 1-7-7

[2894] 1-[3,5-bis(cyclopropyloxy)-4-methylphenyl]ethan-1-one

[2895] [Chemistry 383]

[2896]

[2897] (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), and 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 with a mixed solvent of n-hexane and ethyl acetate and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 98:2 to 80:20) to obtain a mixture containing methyl 3,5-bis(cyclopropyloxy)-4-methylbenzoate (540 mg) as a colorless solid.

[2898] (2) To a solution of the mixture (540 mg) obtained in (1) above in tetrahydrofuran (21 mL) were added a 1 mol / L aqueous sodium hydroxide solution (21 mL) and methanol (10 mL), and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated, and the aqueous layer was washed with n-hexane. 3 mol / L hydrochloric acid was added dropwise to the aqueous layer to adjust the pH to 5-6, and the insoluble matter was filtered off. The resulting residue was purified by preparative HPLC to obtain 3,5-bis(cyclopropyloxy)-4-methylbenzoic acid (75 mg) as a colorless powder.

[2899] (3) A solution of the compound obtained in (2) above (72 mg) in tetrahydrofuran (1.5 mL) was ice-cooled, and methyllithium (1 mol / L diethyl ether solution, 0.87 mL) was added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was ice-cooled, and isopropyl alcohol was added dropwise. 1 mol / L hydrochloric acid was added to adjust the acidity, and the mixture was extracted with ethyl acetate. The organic layer was 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 only to n-hexane:ethyl acetate to 70:30) to obtain the title compound (92 mg) as a colorless oil.

[2900] MS ESI posi: 247 [M+H] + .

[2901] Retention time: 0.942 min (Method A)

[2902] Reference Example 1-7-8

[2903] 5-Acetyl-3-ethoxy-1-ethylpyridin-2(1H)-one

[2904] [Chemistry 384]

[2905]

[2906] (1) Under a nitrogen atmosphere, a solution of 5-bromopyridine-2,3-diol (2 g) in N,N-dimethylformamide (35 mL) was ice-cooled, sodium hydride (60% mineral oil dispersion, 1.0 g) was added, and the mixture was stirred at the same temperature for 45 minutes. Ethyl iodide (2.0 mL) was added dropwise, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 92:8 to 34:66) to obtain 5-bromo-3-ethoxy-1-ethylpyridin-2-one (2.31 g) as a light yellow oily substance.

[2907] (2) The compound obtained in (1) (0.512 g) was reacted according to the method described in Example 1-7-6 (2). However, N-methylpyrrolidone was used instead of N,N-dimethylacetamide, and the reaction temperature was 180°C. 5-Ethoxy-1-ethyl-6-oxopyridine-3-carbonitrile (0.3 g) was obtained as a colorless oily substance.

[2908] (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 ice-cooled, and methylmagnesium 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 stirred for 12 hours while slowly returning to room temperature. Toluene (10 mL) was added to the reaction solution, and the mixture was stirred at 65°C for 2 hours. The reaction solution was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 0.53 mL) was added, and the mixture was stirred at room temperature for 40 minutes and at 60°C for 50 minutes. The reaction solution was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 0.53 mL) was added, and the mixture was stirred at room temperature for 10 minutes and at 60°C for 80 minutes, and then returned to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. To the aqueous layer, add 2 mol / L hydrochloric acid and 1 mol / L sodium hydroxide aqueous solution to adjust the pH to 6-7, and extract with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtering out the desiccant, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 85:15 to ethyl acetate alone) to obtain the title compound (0.069 g) as a colorless powder.

[2909] MS ESI / APCI Multi posi: 210 [M+H] + .

[2910] Retention time: 1.156 min (Method F)

[2911] Reference Example 1-7-9

[2912] 1-(4-Ethoxy-1-ethyl-1H-benzimidazol-6-yl)ethan-1-one

[2913] [Chemistry 385]

[2914]

[2915] (1) Potassium hydroxide (0.38 g) was added to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1.5 g) in ethanol (20 mL). The mixture was stirred at room temperature for 2.5 days and then at 90°C for 45 minutes. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed with water and saturated brine in that order. The mixture was dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated to obtain 5-bromo-1-ethoxy-3-fluoro-2-nitrobenzene (1.63 g) as an orange oily substance.

[2916] (2) A solution of the compound obtained in (1) (1.63 g) in tetrahydrofuran (12 mL) was cooled on ice, and a 12 mol / L aqueous ethylamine solution (2.1 mL) was added, followed by stirring at room temperature for 23 hours. The reaction mixture was concentrated, and diethyl ether was added. The mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated to obtain 5-bromo-3-ethoxy-N-ethyl-2-nitroaniline (1.79 g) as an orange powder.

[2917] (3) The compound obtained in (2) (1.62 g) was reacted according to the method described in Reference Example 1-7-8 (2) to obtain 3-ethoxy-5-(ethylamino)-4-nitrobenzonitrile (1.0 g) as a red powder.

[2918] (4) A mixture of the compound obtained in (3) above (0.5 g), iron powder (0.593 g), saturated aqueous ammonium chloride solution (5 mL) and ethanol (16 mL) was stirred at room temperature for 11 hours and at 65°C for 80 minutes. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 9-10, and the mixture was filtered through Celite (registered trademark) and the filtrate was concentrated. Water and ethyl acetate were added to the residue to partition into two layers. A 1 mol / L aqueous sodium hydroxide 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 over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only - n-hexane:ethyl acetate = 50:50) to obtain 4-amino-3-ethoxy-5-(ethoxyamino)benzonitrile (222 mg) as a beige powder.

[2919] (5) To a solution of the compound obtained in (4) (0.1 g) and triethyl orthoformate (2.4 mL) was added p-toluenesulfonic acid monohydrate (9 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and concentrated. The resulting residue was purified by preparative HPLC to obtain 7-ethoxy-3-ethylbenzimidazole-5-carbonitrile (82 mg) as a colorless gum.

[2920] (6) A solution of the compound (82 mg) obtained in (5) above in diethyl ether (3.8 mL) was ice-cooled, and methylmagnesium 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 ice-cooled. Methylmagnesium 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 ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 1 mL) was added. The mixture was stirred at room temperature for 1 hour, and 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 obtain the title compound (35 mg) as a colorless solid.

[2921] MS ESI posi: 233 [M+H] + .

[2922] Retention time: 0.752 min (Method C)

[2923] Reference Example 1-8-1

[2924] 4-Acetyl-2,6-diethoxybenzonitrile

[2925] [Chemistry 386]

[2926]

[2927] To a solution of the compound obtained in Reference Example 1-5-1 (232 mg) in N,N-dimethylacetamide (3.2 mL) was added copper (I) cyanide (217 mg), and the mixture was stirred at 150°C for 1 hour under microwave irradiation. Ethyl acetate was added to the reaction solution, which was then added to a 10% aqueous ammonium solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 50:50) to obtain the title compound (31.7 mg) as a colorless solid.

[2928] MS ESI posi: 234[M+H] + .

[2929] Retention time: 1.004 min (Method B)

[2930] Reference Example 1-8-2

[2931] 1-(4-cyclopropyl-3,5-diethoxyphenyl)ethan-1-one

[2932] [Chemistry 387]

[2933]

[2934] The compound obtained in Reference Example 1-5-1 (50 mg) and cyclopropylboronic acid (22.4 mg) were reacted according to the method described in Reference Example 1-7-1 to obtain the title compound (34 mg) as a colorless solid.

[2935] MS ESI posi: 249[M+H] + .

[2936] Retention time: 1.199 min (Method B)

[2937] The following Reference Examples 1-8-3 and 1-8-4 were synthesized using the compound obtained in Reference Example 1-5-1, commercially available compounds, or compounds synthesized according to methods described in or based on literature, and were 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 8-1.

[2938] [Table 8-1]

[2939]

[2940] Reference Example 1-8-5

[2941] 1,1'-(2,6-diethoxy-1,4-phenylene)bis(ethane-1-one)

[2942] [Chemistry 388]

[2943]

[2944] This reaction was carried out according to the method described in the reference document (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(diphenylphosphino)propane (43.1 mg), potassium carbonate (722 mg), and water (0.87 mL) were added to a solution of the compound obtained in Reference Example 1-5-1 (0.5 g) 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 stirred at room temperature for 3 hours. A 10% aqueous potassium carbonate solution (50 mL) was then added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 60:40) to obtain the title compound (407 mg) as a colorless solid.

[2945] MS ESI posi: 251[M+H] + .

[2946] Retention time: 0.994 min (Method B)

[2947] Reference Example 1-8-6

[2948] 1-[3,5-diethoxy-4-(propan-2-yl)phenyl]ethan-1-one

[2949] [Chemistry 389]

[2950]

[2951] To a solution of the compound (37 mg) obtained in Reference Example 1-8-3 in methanol (3 mL) was added palladium on carbon (19 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble matter was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 75:25) to obtain the title compound (29 mg) as a colorless solid.

[2952] MS ESI posi: 251[M+H] + .

[2953] Retention time: 1.338 min (Method B)

[2954] The following Reference Example 1-8-7 was synthesized using the compound obtained in Reference Example 1-14-6 and cyclopropylboronic acid by the method described in Reference Example 1-8-2 or a method based thereon. The structure and LCMS data of the compound are shown in Table 8-2.

[2955] [Table 8-2]

[2956]

[2957] Reference Example 1-9-1

[2958] 1-[3,5-diethoxy-4-(1-hydroxycyclopropyl)phenyl]ethan-1-one

[2959] [Chemistry 390]

[2960]

[2961] (1) To a toluene (21 mL) solution of the compound obtained in Reference Example 1-5-1 (0.604 g), ethylene glycol (8.42 mL) and p-toluenesulfonic acid monohydrate (40.0 mg) were added, and the mixture was stirred under reflux for 3 hours. The reaction mixture was ice-cooled, added with a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 to 90:10) to obtain 2-(4-bromo-3,5-diethoxyphenyl)-2-methyl-1,3-dioxolane (0.633 g) as a colorless solid.

[2962] (2) This reaction was carried out according to the method described in the reference document (WO2015 / 159233). Under a nitrogen atmosphere, a diethyl ether (3.6 mL) suspension of magnesium (66 mg) and iodine (14 mg) was added with a diethyl ether-tetrahydrofuran mixed solution (1:1, 1.8 mL) of the compound (900 mg) obtained in the above (1) and tetrahydrofuran (3.6 mL), and the mixture was slowly heated and stirred under reflux for 5 hours. The reaction solution was ice-cooled, and a tetrahydrofuran (3.6 mL) solution of 1,3-dichloroacetone (345 mg) was added, and the mixture was stirred at room temperature for 80 minutes. The reaction solution was ice-cooled, and a tetrahydrofuran (1.8 mL) solution of iron (III) chloride (9 mg) and ethylmagnesium 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 mixture was ice-cooled, and saturated aqueous ammonium chloride (18 mL) was added. 1 mol / L hydrochloric acid was added to acidify the mixture, and ethyl acetate was added to partition the mixture into two layers. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 94:6 to 60:40) to obtain 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]cyclopropan-1-ol (220 mg) as a pale yellow solid.

[2963] (3) A solution of the compound obtained in (2) above (0.11 g) in tetrahydrofuran (2.5 mL) was cooled to ice, 1 mol / L hydrochloric acid (2.5 mL) was added, and 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 mixture was filtered and concentrated using a phase separator to obtain the ...

Claims

1. A compound represented by the following formula [I-7] or a pharmaceutically acceptable salt thereof, In the above formula [I-7], X represents a carboxyl group or a tetrazolyl group; W is a structure represented by the following formula [III-5], [III-8] to [III-11] or [III-13] R 2 represents a group represented by the following formula [IV-1] or [IV-2] in, Ring B 1 represents phenyl, R B11 and R B12 The same is true for hydrogen atoms, L 1 represents a structure represented by the following formula [V-3], [V-12] or [V-14], (CH2) n4 - [V-3], in, n4 represents the integer 4, also, Ring B 2 represents dihydroindanyl, R B21 and R B22 The same is true for hydrogen atoms, L 2 It represents the structure represented by the following formula [V-20] -(CH2) n5 - [V-20], in, n5 represents the integer 2; R 4 represents a group represented by the following formula [VI] Wherein, ring C represents a phenyl group; The phenyl group may be selected from halogen atoms, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 One of the alkylcarbonyl groups is substituted, and further, The phenyl group may be selected from hydroxyl, carboxyl, carbamoyl, cyano, halogen atoms, hydroxyl and C 1-6 One of the alkoxy groups substituted C 1-6 Alkyl, halogenated C which may be substituted with 1 hydroxyl group 1-6 Alkyl, C 2-6 Alkenyl, C may be substituted with 1 hydroxyl group 3-8 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, mono-C 1-6 Alkylamino, di-C 1-6 Alkylamino, C 1-6 Alkylcarbonyl, haloC 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl and single C 1-6 The alkylaminocarbonyl 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, wherein R 4 represents a group represented by the following formula [VI] in, 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, The phenyl group may be selected from a halogen atom, a C 1-3 Alkyl, C 1-2 The alkoxy group or C1 alkylcarbonyl group may be substituted by 1 to 3 groups which may be the same or different.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 4 A group represented by the following formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11] or [VI-12] 。 4. A compound represented by the following formula [Ia] or a pharmaceutically acceptable salt thereof, 5. A compound represented by the following formula [Ib] or a pharmaceutically acceptable salt thereof, 6. A compound represented by the following formula [Ic] or a pharmaceutically acceptable salt thereof, 7. A compound represented by the following formula [Id] or a pharmaceutically acceptable salt thereof, 8. A compound represented by the following formula [Ie] or a pharmaceutically acceptable salt thereof, 9. A medicine comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient.

10. An LPA1 receptor antagonist comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A preventive or therapeutic agent for systemic scleroderma, comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 as an active ingredient.

12. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of an LPA1 receptor antagonist.

13. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for preparing a preventive or therapeutic drug for systemic scleroderma.

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