Benzotriazole compounds

Abstract

The present invention addresses the problem of providing a drug capable of treating and / or preventing diseases associated with oxidative stress by inhibiting the protein-to-protein interaction between Keap1 and Nrf2 and activating Nrf2. The present invention pertains to a compound represented by general formula (1) (wherein each symbol is as described in the description) or a pharmaceutically acceptable salt thereof. ]. In addition, the invention also relates to a compound for preventing and / or treating chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation skin injury, radiation mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedel's ataxia, multiple sclerosis, and the like, which contains the compound and is used for preventing and / or treating the chronic obstructive pulmonary disease, radiation skin injury, radiation mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedel's ataxia, multiple sclerosis and the like. The invention relates to a medicament for treating oxidative stress-related diseases in age-related macular degeneration, retinitis pigmentosa and glaucoma. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a benzotriazole compound or a pharmaceutically acceptable salt thereof, which inhibits Kelch-like ECH-associated protein 1 (Keap1) to activate NF-E2-related factor 2 (Nrf2), thereby being useful for treating and / or preventing diseases associated with oxidative stress, particularly diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. Background Art

[0002] When reactive oxygen species generated during energy metabolism are detected, the body's defense systems, including antioxidant enzymes and detoxification enzymes, are activated. Nrf2 controls the activation of these defense systems.

[0003] It is known that when Nrf2 is activated, its target genes such as NAD(P)H quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), and γ-glutamate cysteine ​​ligase catalytic subunit (GCLC) are induced (Non-patent document 1). NQO1 is an enzyme in the second stage of the xenobiotic metabolism system and is important for detoxification. HO-1 and GCLC are known as typical antioxidant enzymes. When the amount of these enzymes increases or is activated, cells develop resistance to toxins, oxidative stress, inflammation, etc. Therefore, compounds that activate Nrf2 are considered to be therapeutic drugs for various diseases (Non-patent document 2).

[0004] In a stable state, Nrf2 is ubiquitinated by Keap1 and degraded by the protease system, so Keap1 inhibitory compounds will activate Nrf2. To date, compounds that activate Nrf2 by modifying the cysteine ​​residues of Keap1 are known, but due to their activation mechanism, there are concerns about low specificity. On the other hand, compounds that inhibit the protein-protein interaction (PPI) between Keap1 and Nrf2 are expected to be a more specific mechanism for activating Nrf2, and have been increasingly attracting attention in recent years as preventive and / or therapeutic drugs for various diseases based on oxidative stress (Non-Patent Document 3).

[0005] Conventionally, compounds that inhibit Keap1 and activate Nrf2 have been reported, for example, as described in Patent Documents 1 to 11. However, these compounds are structurally different from the compound of the present invention.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication No. 2015 / 092713

[0009] Patent Document 2: International Publication No. 2016 / 202253

[0010] Patent Document 3: International Publication No. 2016 / 203400

[0011] Patent Document 4: International Publication No. 2016 / 203401

[0012] Patent Document 5: International Publication No. 2018 / 109643

[0013] Patent Document 6: International Publication No. 2018 / 109647

[0014] Patent Document 7: International Publication No. 2018 / 109648

[0015] Patent Document 8: International Publication No. 2019 / 224667

[0016] Patent Document 9: International Publication No. 2020 / 165776

[0017] Patent Document 10: International Publication No. 2018 / 181345

[0018] Patent Document 11: International Publication No. 2020 / 241853

[0019] Non-patent literature

[0020] Non-patent literature 1: Int. J. Biochem. Cell. Biol., 2012, 44, 1315-1320

[0021] Non-patent literature 2: Nat. Rev. Drug Discov., 2019, 18, 295-317

[0022] Non-patent literature 3: Eur. J. Med. Chem., 2020, 202, 112532 Summary of the Invention

[0023] Problems to be solved by the invention

[0024] The present invention aims to provide a drug that inhibits the protein-protein interaction between Keap1 and Nrf2, thereby activating Nrf2 and thereby treating and / or preventing diseases associated with oxidative stress, particularly diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0025] Means used to solve problems

[0026] The present inventors conducted intensive studies to solve the above-mentioned problems and found that the compound represented by the following general formula (1) (hereinafter sometimes referred to as "compound (1)") or a pharmaceutically acceptable salt thereof has an excellent Nrf2 activation effect by inhibiting Keap1, thereby completing the present invention.

[0027] [Chemistry 1]

[0028]

[0029] [Where,

[0030] R 1a and R 1b Each independently represents a hydrogen atom or C 1-6 alkyl,

[0031] R 2 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0032] R 3 represents a hydrogen atom, a halogen atom, or C 1-6 alkyl,

[0033] Y represents -CH- or -CR 4 - or nitrogen atoms,

[0034] R 4 Represents hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0035] -V- represents a group represented by any of the following formulae:

[0036] [Chemistry 2]

[0037]

[0038] (Wherein, * and ** represent the bonding positions to the benzene ring.)

[0039] n R 7 Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0040] n represents an integer from 0 to 2, and

[0041] Z is a group represented by the following formula (A1), (A2) or (A3):

[0042] [Chemistry 3]

[0043]

[0044] (Where,

[0045] *** represents the bonding position of the carbon atom to which Z is bonded,

[0046] R 8 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0047] R 5a and R 5b Each independently represents a hydrogen atom, a C optionally substituted by 1 to 3 substituents selected from Substituent Group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0048] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form a C optionally substituted with 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0049] m R 6 Each independently represents a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0050] m represents an integer from 0 to 3,

[0051] W represents -CH2-, -CHR 9 - or oxygen atoms,

[0052] R 9 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0053] X represents -CH-, -CR 10 - or nitrogen atoms,

[0054] R 10 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0055] U represents -CH-, -CR 11 - or nitrogen atoms, and

[0056] R 11 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0057] Substituent group a:

[0058] Hydroxyl,

[0059] Halogen atoms,

[0060] cyano,

[0061] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 alkyl,

[0062] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkoxy,

[0063] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkylsulfonyl,

[0064] 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group

[0065] Substituent group b:

[0066] Halogen atoms,

[0067] cyano,

[0068] C 1-6 alkyl,

[0069] C 1-6 alkoxy].

[0070] That is, the present invention is as follows.

[0071] [1] A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[0072] [Chemistry 4]

[0073]

[0074] [Where,

[0075] R 1a and R 1b Each independently represents a hydrogen atom or C 1-6 alkyl,

[0076] R 2 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0077] R 3 represents a hydrogen atom, a halogen atom, or C 1-6 alkyl,

[0078] Y represents -CH- or -CR 4 - or nitrogen atoms,

[0079] R 4 Represents hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0080] -V- represents a group represented by any of the following formulae:

[0081] [Chemistry 5]

[0082]

[0083] (Wherein, * and ** represent the bonding positions to the benzene ring.)

[0084] n R 7 Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0085] n represents an integer from 0 to 2, and

[0086] Z represents a group represented by the following formula (A1), (A2) or (A3):

[0087] [Chemistry 6]

[0088]

[0089] (Where,

[0090] *** represents the bonding position of the carbon atom to which Z is bonded,

[0091] R 8 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0092] R 5a and R 5b Each independently represents a hydrogen atom, a C optionally substituted by 1 to 3 substituents selected from Substituent Group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0093] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form a C optionally substituted with 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0094] m R 6 Each independently represents a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0095] m represents an integer from 0 to 3,

[0096] W represents -CH2-, -CHR 9 - or oxygen atoms,

[0097] R 9 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0098] X represents -CH-, -CR 10 - or nitrogen atoms,

[0099] R 10 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0100] U represents -CH-, -CR 11 - or nitrogen atoms, and

[0101] R 11 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0102] Substituent group a:

[0103] Hydroxyl,

[0104] Halogen atoms,

[0105] cyano,

[0106] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 alkyl,

[0107] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkoxy,

[0108] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkylsulfonyl,

[0109] 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group

[0110] Substituent group b:

[0111] Halogen atoms,

[0112] cyano,

[0113] C 1-6 alkyl,

[0114] C 1-6 alkoxy].

[0115] [2] The compound described in [1] above or a pharmaceutically acceptable salt thereof, wherein R 1a and R1b are each independently a hydrogen atom or a methyl group.

[0116] [3] The compound described in [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl.

[0117] [4] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein R 3 A halogen atom or C 1-6 alkyl.

[0118] [5] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R 4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group.

[0119] [6] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein -V- is a group represented by any one of the following formulae:

[0120] [Chemistry 7]

[0121]

[0122] (Wherein, * and ** have the same meanings as above.)

[0123] [7] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [6] above, wherein n is 1, and R 7 C 1-6 alkyl.

[0124] [8] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [6], wherein n is 0.

[0125] [9] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [8] above, wherein Z is a group represented by the following formula (A1) or (A2):

[0126] [Chemistry 8]

[0127]

[0128] (The symbols in the formula have the same meanings as above.)

[0129]

[10] The compound described in [9] above or a pharmaceutically acceptable salt thereof, wherein R 8 It is methyl or ethyl.

[0130]

[11] The compound described in [9] or

[10] above, or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group;

[0131] Or, R 5a With R 5b They bond with each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran.

[0132]

[12] The compound or pharmaceutically acceptable salt thereof according to any one of [9] to

[11] , wherein m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group, and

[0133] m is an integer from 0 to 2.

[0134]

[13] The compound or pharmaceutically acceptable salt thereof according to any one of [9] to

[12] , wherein W is -CH2- or an oxygen atom.

[0135]

[14] A compound represented by the following general formula (1′) (hereinafter sometimes referred to as “compound (1′)”) or a pharmaceutically acceptable salt thereof:

[0136] [Chemistry 9]

[0137]

[0138] [Where,

[0139] R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group,

[0140] R 2’ represents a methyl group,

[0141] R 3’ represents a chlorine atom or a methyl group,

[0142] Y' represents -CH-, -CR 4’ - or nitrogen atoms,

[0143] R 4’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group,

[0144] -V'- represents a group represented by any of the following formulae:

[0145] [Chemistry 10]

[0146]

[0147] (Wherein, *' and **' indicate the bonding positions to the benzene ring.)

[0148] R 5a’ and R 5b’ Each independently represents a hydrogen atom or an ethyl group, or, R 5a’ With R 5b’ Bonded to each other to form cyclopropane,

[0149] m'R 6’ each independently represents a fluorine atom or a chlorine atom,

[0150] m' represents an integer from 0 to 2, and

[0151] W' represents an oxygen atom. ].

[0152]

[15] Any compound selected from the following group or a pharmaceutically acceptable salt thereof:

[0153] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0154] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0155] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0156] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0157] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0158] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0159] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid,

[0160] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0161] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0162] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0163] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0164] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0165] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid,

[0166] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid,

[0167] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, and

[0168] (3S)-3-(7-{[(4R)-8-Chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid.

[0169]

[16] Any compound selected from the following group or a pharmaceutically acceptable salt thereof:

[0170] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0171] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0172] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, and

[0173] (3R)-3-(7-{[(4R)-8-Chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid.

[0174]

[17] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0175]

[18] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0176]

[19] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0177]

[20] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[0178]

[21] A compound represented by the following general formula (1") (hereinafter sometimes referred to as "compound (1")) or a pharmaceutically acceptable salt thereof:

[0179] [Chemistry 11]

[0180]

[0181] [Where,

[0182] R 1a” and R 1b” each independently represents a hydrogen atom or a methyl group,

[0183] R 2” represents a methyl group,

[0184] R 3” represents a chlorine atom or a methyl group,

[0185] Y" represents -CH-, -CR 4” - or nitrogen atoms,

[0186] R 4” represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group,

[0187] -V"- represents a group represented by any of the following formulae:

[0188] [Chemistry 12]

[0189]

[0190] (Wherein, *" and **" indicate the bonding position to the benzene ring.)

[0192] R 5a” and R 5b” Each independently represents a hydrogen atom or an ethyl group, or,

[0193] R 5a” and R 5b” Bonded to each other to form cyclopropane,

[0194] R 8” represents a methyl or ethyl group,

[0195] m” R 6” each independently represents a chlorine atom or a hydroxyl group,

[0196] m" means 0 or 1,

[0197] U" represents a nitrogen atom, and

[0198] W" represents an oxygen atom.].

[0199]

[22] Any compound selected from the following group or a pharmaceutically acceptable salt thereof:

[0200] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0201] (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0202] (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0203] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0204] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0205] (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0206] (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0207] (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0208] (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0209] (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0210] (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0211] (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, and

[0212] (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid.

[0213]

[23] A drug containing the compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter sometimes referred to as "the drug of the present invention").

[0214]

[24] The drug described in

[23] above, which is used to activate Nrf2.

[0215]

[25] The drug described in

[23] above, which is used to inhibit the protein-protein interaction between Keap1 and Nrf2.

[0216]

[26] The drug described in

[23] above, which is used for preventing and / or treating diseases related to oxidative stress.

[0217]

[27] The drug described in

[26] above, wherein the oxidative stress-related disease is selected from kidney disease, liver disease, respiratory disease, skin disease, cardiovascular disease, central nervous system disease, autoimmune disease and eye disease.

[0218]

[28] The drug described in

[23] above, which is used for the prevention and / or treatment of the following diseases, wherein the diseases are selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal insufficiency, chronic renal insufficiency, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver hepatitis, liver fibrosis and cirrhosis; respiratory diseases selected from the group consisting of bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia and asthma; skin diseases selected from the group consisting of ultraviolet and radiation skin damage, radiation mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis and scleroderma; heart failure, myocardial infarction, arteriosclerosis and pulmonary hypertension a cardiovascular disease selected from among Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease and autism; a mitochondrial disease selected from among Friedreich's ataxia and mitochondrial encephalomyopathy; an autoimmune disease selected from among multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, type 1 diabetes, ulcerative colitis and Crohn's disease; and an eye disease selected from among allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal injury, uveitis, Behcet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma and cataract.

[0219]

[29] The medicament described in

[23] above, which is used for preventing and / or treating a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0220]

[30] The medicament described in the above-mentioned

[23] , which is used for preventing and / or treating a disease selected from the group consisting of glaucoma, age-related macular degeneration and retinitis pigmentosa.

[0221]

[31] The drug described in

[23] above, which is used for preventing and / or treating radiation-induced skin damage or radiation-induced mucosal damage.

[0222]

[32] The drug described in

[23] above, which is used for the prevention and / or treatment of chronic obstructive pulmonary disease.

[0223]

[33] Use of the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[22] above for preparing a preventive and / or therapeutic agent for a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0224]

[34] A method for preventing and / or treating a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma in a mammal, comprising administering a pharmaceutically effective amount of a compound described in any one of [1] to

[22] above, or a pharmaceutically acceptable salt thereof, to the mammal.

[0225]

[35] A method for activating Nrf2 in a mammal, comprising administering a pharmaceutically effective amount of a compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof to the mammal.

[0226]

[36] A method for inhibiting the protein-protein interaction between Keap1 and Nrf2 in a mammal, comprising administering a pharmaceutically effective amount of a compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof to the mammal.

[0227]

[37] An Nrf2 activator comprising the compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof as an active ingredient.

[0228]

[38] An inhibitor of protein-protein interaction between Keap1 and Nrf2, comprising the compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof as an active ingredient.

[0229]

[39] The compound or salt thereof according to any one of [1] to

[22] , for use in the prevention and / or treatment of a disease selected from the group consisting of chronic kidney disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0230]

[40] The drug described in

[23] above, which is used for preventing and / or treating a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0231]

[41] The drug described in any one of

[23] to

[32] and

[40] above, characterized in that it is administered in combination with other drugs.

[0232]

[42] The drug of the above-mentioned

[41] , wherein the other agent is a preventive and / or therapeutic agent for a disease selected from chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[0233]

[43] The drug described in

[41] or

[42] above, characterized in that the drug described in any one of

[23] to

[32] and

[40] above and other drugs can be contained as active ingredients in different preparations respectively and administered simultaneously or at different times.

[0234]

[44] The drug described in

[41] or

[42] above, characterized in that the compound described in any one of [1] to

[22] above or its pharmaceutically acceptable salt and other drugs are contained in a single preparation.

[0235]

[45] A pharmaceutical composition comprising the compound described in any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (hereinafter sometimes referred to as "the pharmaceutical composition of the present invention").

[0236]

[46] A method for producing the compound or a salt thereof according to any one of [1] to

[22] .

[0237]

[47] A prodrug of the compound or a salt thereof according to any one of the above-mentioned [1] to

[22] .

[0238] Effects of the Invention

[0239] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof exhibits an effect of effectively activating Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2. Specifically, by administering a drug containing the compound (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient to a mammal, the drug can be used to prevent and / or treat diseases in which symptoms are ameliorated by activating Nrf2. Diseases whose symptoms are improved by Nrf2 activation include diseases related to oxidative stress, and specifically, for example, diseases selected from the following: kidney diseases selected from chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis and tubulointerstitial nephritis; liver diseases selected from alcoholic fatty liver, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis; respiratory diseases selected from bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia and asthma; skin diseases selected from ultraviolet and radiation skin damage, radiation mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis and scleroderma; heart failure, myocardial infarction, arteriosclerosis and Cardiovascular diseases in pulmonary hypertension; central nervous system diseases selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease and autism; mitochondrial diseases selected from Friedreich's ataxia and mitochondrial encephalomyopathy; autoimmune diseases selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, type 1 diabetes, ulcerative colitis and Crohn's disease; and eye diseases selected from allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal injury, uveitis, Behcet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma and cataract, etc. Among them, suitable examples include those selected from chronic kidney disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. DETAILED DESCRIPTION

[0240] The definitions of the terms and symbols used in this specification are explained below. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as those generally understood by those skilled in the art in the art to which this invention belongs.

[0241] In this specification, a "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0242] In this manual, “C 1-6 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

[0243] In this manual, “C 1-6 "Haloalkyl" refers to the aforementioned "C 1-6 A group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen. 1-6 Examples of the haloalkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0244] In this manual, "C 1-6 "Alkoxy" refers to the aforementioned "C 1-6 A group obtained by bonding an alkyl group to an oxygen atom. 1-6 Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, and n-hexyloxy.

[0245] In this manual, “C 1-6 "Haloalkoxy" refers to the aforementioned "C 1-6 A group in which one or more hydrogen atoms in an alkoxy group are replaced by a halogen. 1-6 Examples of the haloalkoxy group include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy.

[0246] In this manual, "C 3-6The term "cycloalkyl" refers to a 3- to 6-membered monocyclic saturated hydrocarbon ring group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0247] In this manual, "C 1-6 "Alkylsulfonyl" refers to the aforementioned "C 1-6 A group obtained by bonding an alkyl group to the sulfur atom of a sulfonyl group. 1-6 Examples of the alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and n-pentylsulfonyl.

[0248] In this specification, "1 or 2 C 1-6 "Amino group optionally substituted by alkyl" refers to an unsubstituted amino group, or an amino group in which one or two hydrogen atoms are independently replaced by the aforementioned "C 1-6 As a group substituted with 1 or 2 C 1-6 Examples of the amino group optionally substituted with an alkyl group include amino, methylamino, dimethylamino, ethylamino, diethylamino, ethyl(methyl)amino, n-propylamino, di(n-propyl)amino, isopropylamino, n-butylamino, di(n-butyl)amino, sec-butylamino, tert-butylamino, n-pentylamino, and n-hexylamino.

[0249] In this manual, "C 3-8 "Cycloalkane" refers to a 3- to 8-membered monocyclic saturated hydrocarbon ring, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. "C 3-8 "Cycloalkane" is suitably cyclopropane or cyclobutane.

[0250] In this specification, "3- to 8-membered saturated oxygen-containing heterocycle" refers to a 3- to 8-membered monocyclic saturated oxygen-containing heterocycle, and examples thereof include ethylene oxide, oxetane, tetrahydrofuran, tetrahydropyran, hexylene oxide, and heptane oxide. "3- to 8-membered saturated oxygen-containing heterocycle" is preferably oxetane or tetrahydropyran.

[0251] In this specification, "optionally substituted" means unsubstituted or substituted with a specific number of specific substituents at any substitutable position (where any hydrogen atom is replaced by a substituent). Examples of such "substituents" include substituents selected from the following "Substituent Group a" and "Substituent Group b". When multiple substituents are present, each substituent may be the same or different.

[0252] Substituent group a:

[0253] Hydroxyl,

[0254] Halogen atoms,

[0255] cyano,

[0256] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 alkyl,

[0257] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkoxy,

[0258] C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkylsulfonyl,

[0259] 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group

[0260] Substituent group b:

[0261] Halogen atoms,

[0262] cyano,

[0263] C 1-6 alkyl,

[0264] C 1-6 Alkoxy

[0265] Wherein, "optionally substituted C 1-6 "alkyl" or "optionally substituted C 1-6 When any substituent of "alkoxy" is selected from the aforementioned substituent group a or substituent group b, the list of the aforementioned substituent group a or substituent group b does not include "C 1-6 alkyl".

[0266] In the present specification, "pharmaceutically acceptable salt" refers to a salt that can be used as a drug, including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0267] In this specification, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) involved in transporting the compound (1) (or compound (1') or compound (1")) of the present invention or a composition containing the same from a certain organ or viscera to another organ or viscera.

[0268] In this specification, "treatment" and its derivatives refer to the alleviation, alleviation or delay of the worsening of clinical symptoms of a disease, illness, injury, etc. (hereinafter referred to as "disease, etc.") in a patient suffering from the disease, illness, injury, etc.

[0269] As used herein, "prevent" and its derivatives refer to inhibiting, halting, controlling, slowing down or stopping the onset of clinical symptoms of a disease in a mammal that is likely to have a disease but has not yet developed the disease, or that is concerned about recurrence of the disease after treatment.

[0270] As used herein, "oxidative stress" refers to a state in which the balance of antioxidant defense mechanisms is disrupted by excessive production of reactive oxygen species due to external factors (e.g., ultraviolet rays, radiation, air pollution, tobacco, pharmaceuticals, and ingestion of oxidized substances). Furthermore, "oxidative stress-related diseases" refer to diseases in which such oxidative stress contributes to the onset or exacerbation of symptoms. Examples of the "oxidative stress-related diseases" include diseases selected from the following diseases: kidney diseases selected from chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from alcoholic fatty liver, non-alcoholic fatty liver hepatitis, liver fibrosis, and cirrhosis; respiratory diseases selected from bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; skin diseases selected from ultraviolet and radiation skin damage, radiation mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis, and scleroderma; heart failure, myocardial infarction, arteriosclerosis, and pulmonary hypertension. a cardiovascular system disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease and autism; a mitochondrial disease selected from the group consisting of Friedreich's ataxia and mitochondrial encephalomyopathy; an autoimmune disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, type 1 diabetes, ulcerative colitis and Crohn's disease; and an eye disease selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal injury, uveitis, Behcet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma and cataract. The "oxidative stress-related diseases" in the present invention are particularly selected from chronic kidney disease, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, radiation skin damage, radiation mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[0271] In this specification, "Keap1 and Nrf2 protein-protein interaction inhibitor" refers to a substance that normally forms a complex with Nrf2 and inhibits the action of Nrf2 by ubiquitination by E3 ubiquitin ligase, thereby inhibiting the formation of the complex and releasing Nrf2.

[0272] In this specification, "activating Nrf2" or "Nrf2 activator" refers to a substance that inhibits the protein-protein interaction between Keap1 and Nrf2, thereby preventing the formation of a Keap1-Nrf2 complex and allowing free Nrf2 to migrate to the nucleus, thereby promoting the expression of the antioxidant gene group or increasing the expression of the antioxidant gene group.

[0273] In this specification, "pharmaceutically effective amount" refers to the amount of compound (1) of the present invention (or compound (1') or compound (1")) or a pharmaceutically acceptable salt thereof administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to a mammal.

[0274] In this specification, the term "mammal" is not particularly limited, and includes humans and mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.).

[0275] (Compound of the present invention (Compound (1)))

[0276] Hereinafter, each group in the aforementioned formula (1) of the compound (1) will be described.

[0277] R 1a and R 1b Each independently represents a hydrogen atom or C 1-6 alkyl.

[0278] R 1a and R 1b Preferably, each independently represents a hydrogen atom or a methyl group.

[0279] R 2 represents the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl.

[0280] R 2 Preferably C 1-6 Alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl, more preferably methyl.

[0281] R 3 represents a hydrogen atom, a halogen atom, or C 1-6 alkyl.

[0282] R 3 Preferably a halogen atom or C 1-6 The alkyl group is more preferably a chlorine atom or a methyl group.

[0283] Y represents -CH- or -CR 4 -(where R 4 Represents hydroxyl, halogen atom, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy. ) or a nitrogen atom.

[0284] Y is preferably -CH- or -CR- 4 -(where R 4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group. ) or a nitrogen atom, more preferably -CH-, -CR 4 -(where R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group. ) or a nitrogen atom.

[0285] -V- represents a group represented by any of the following formulae:

[0286] [Chemistry 13]

[0287]

[0288] (Wherein, * and ** represent the bonding positions to the benzene ring.)

[0289] -V- is preferably a group represented by any of the following formulae:

[0290] [Chemistry 14]

[0291]

[0292] (Wherein, * and ** have the same meanings as above.)

[0293] More preferably, it is a group represented by any of the following formulae:

[0294] [Chemistry 15]

[0295]

[0296] (In the formula, * and ** have the same meanings as above.)

[0297] n R 7 Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy.

[0298] n R 7 Preferably C 1-6 alkyl.

[0299] n represents an integer from 0 to 2.

[0300] n is preferably 0 or 1, more preferably 0.

[0301] Z is a group represented by the following formula (A1), (A2) or (A3):

[0302] [Chemistry 16]

[0303]

[0304] (Where,

[0305] *** represents the bonding position of the carbon atom to which Z is bonded,

[0306] R 8 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0307] R 5a and R 5b Each independently represents a hydrogen atom, a C optionally substituted by 1 to 3 substituents selected from Substituent Group a 1-6 Alkyl, or C 3-6 Cycloalkyl, or

[0308] R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form a C optionally substituted with 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0309] m R 6 Each independently represents a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0310] m represents an integer from 0 to 3,

[0311] W represents -CH2-, -CHR 9 - or oxygen atoms,

[0312] R 9 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0313] X represents -CH-, -CR 10 - or nitrogen atoms,

[0314] R 10 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0315] U represents -CH-, -CR 11 - or nitrogen atoms, and

[0316] R 11 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0317] Z is preferably a group represented by the following formula (A1) or (A2):

[0318] [Chemistry 17]

[0319]

[0320] (The symbols in the formula have the same meanings as above.)

[0321] More preferably, it is a group represented by the following formula:

[0322] [Chemistry 18]

[0323]

[0324] (Where R 8 is methyl or ethyl,

[0325] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or,

[0326] R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0327] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0328] m is an integer from 0 to 2, and

[0329] W is -CH2- or an oxygen atom.)

[0330] or a group represented by the following formula:

[0331] [Chemistry 19]

[0332]

[0333] (Where R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or,

[0334] R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0335] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0336] m is an integer from 0 to 2, and

[0337] W is -CH2- or an oxygen atom.)

[0338] More preferably, it is a group represented by the following formula:

[0339] [Chemistry 20]

[0340]

[0341] (Where R 8 is methyl or ethyl,

[0342] R 5a and R 5b are each independently a hydrogen atom or an ethyl group;

[0343] Or, R 5a With R 5b Bonded to each other to form cyclopropane,

[0344] m R 6 are each independently a chlorine atom or a hydroxyl group,

[0345] m is 0 or 1, and

[0346] W is an oxygen atom.)

[0347] or a group represented by the following formula:

[0348] [Chemistry 21]

[0349]

[0350] (Where R 5a and R 5bare each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or,

[0351] R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0352] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0353] m is an integer from 0 to 2, and

[0354] W is an oxygen atom. ).

[0355] As compound (1), the following compounds are suitable.

[0356] [Compound (1A)]

[0357] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0358] R 1a and R 1b are each independently a hydrogen atom or a methyl group;

[0359] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl;

[0360] R 3 A hydrogen atom, a halogen atom or a C 1-6 alkyl;

[0361] Y is -CH-, -CR 4 - or nitrogen atom;

[0362] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0363] -V- is a group represented by any of the following formulas:

[0364] [Chemistry 22]

[0365]

[0366] (The symbols in the formula have the same meanings as above.)

[0367] n R 7are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 alkoxy;

[0368] n is an integer from 0 to 2; and

[0369] Z is a group represented by the following formula (A1), (A2) or (A3):

[0370] [Chemistry 23]

[0371]

[0372] (Where,

[0373] *** is the bonding position of the carbon atom to which Z is bonded,

[0374] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0375] R 5a and R 5b are each independently a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from Substituent Group a 1-6 Alkyl, or C 3-6 Cycloalkyl, or

[0376] R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0377] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0378] m is an integer from 0 to 3,

[0379] W is -CH2-, -CHR 9 - or oxygen atoms,

[0380] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0381] X is -CH-, -CR 10 - or nitrogen atoms,

[0382] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0383] U is -CH-, -CR 11 - or nitrogen atoms, and

[0384] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0385] [Compound (1B)]

[0386] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0387] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0388] R 2 C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl;

[0389] R 3 A hydrogen atom, a halogen atom or a C 1-6 alkyl;

[0390] Y is -CH-, -CR 4 - or nitrogen atom;

[0391] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6haloalkoxy;

[0392] -V- is a group represented by any of the following formulas:

[0393] [Chemistry 24]

[0394]

[0395] (The symbols in the formula have the same meanings as above.)

[0396] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 alkoxy;

[0397] n is an integer from 0 to 2; and

[0398] Z is a group represented by the following formula (A1), (A2) or (A3):

[0399] [Chemistry 25]

[0400]

[0401] (Where,

[0402] *** is the bonding position of the carbon atom to which Z is bonded,

[0403] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0404] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0405] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0406] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0407] m is an integer from 0 to 3,

[0408] W is -CH2-, -CHR 9 - or oxygen atoms,

[0409] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0410] X is -CH-, -CR 10 - or nitrogen atoms,

[0411] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0412] U is -CH-, -CR 11 - or nitrogen atoms, and

[0413] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0414] [Compound (1C)]

[0415] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0416] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0417] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0418] R 3 A halogen atom or C 1-6 alkyl;

[0419] Y is -CH-, -CR 4 - or nitrogen atom;

[0420] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0421] -V- is a group represented by any of the following formulas:

[0422] [Chemistry 26]

[0423]

[0424] (The symbols in the formula have the same meanings as above.)

[0425] n R 7 are each independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 alkoxy;

[0426] n is an integer from 0 to 2; and

[0427] Z is a group represented by the following formula (A1), (A2) or (A3):

[0428] [Chemistry 27]

[0429]

[0430] (Where,

[0431] *** is the bonding position of the carbon atom to which Z is bonded,

[0432] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0433] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from the substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0434] Or, R 5a With R 5bBonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0435] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0436] m is an integer from 0 to 3,

[0437] W is -CH2-, -CHR 9 - or oxygen atoms,

[0438] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0439] X is -CH-, -CR 10 - or nitrogen atoms,

[0440] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0441] U is -CH-, -CR 11 - or nitrogen atoms, and

[0442] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0443] [Compound (1D)]

[0444] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0445] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0446] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0447] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0448] Y is -CH-, -CR 4 - or nitrogen atom;

[0449] R 4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group;

[0450] -V- is a group represented by any of the following formulas:

[0451] [Chemistry 28]

[0452]

[0453] (The symbols in the formula have the same meanings as above.)

[0454] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 alkoxy;

[0455] n is an integer from 0 to 2; and

[0456] Z is a group represented by the following formula (A1), (A2) or (A3):

[0457] [Chemistry 29]

[0458]

[0459] (Where,

[0460] *** is the bonding position of the carbon atom to which Z is bonded,

[0461] R 8is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0462] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0463] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0464] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0465] m is an integer from 0 to 3,

[0466] W is -CH2-, -CHR 9 - or oxygen atoms,

[0467] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0468] X is -CH-, -CR 10 - or nitrogen atoms,

[0469] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0470] U is -CH-, -CR 11 - or nitrogen atoms, and

[0471] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0472] [Compound (1E)]

[0473] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0474] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0475] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0476] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0477] Y is -CH-, -CR 4 - or nitrogen atom;

[0478] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0479] -V- is a group represented by any of the following formulas:

[0480] [Chemistry 30]

[0481]

[0482] (Wherein, * and ** have the same meanings as above.)

[0483] n R 7are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0484] n is an integer from 0 to 2 (preferably 0 or 1); and

[0485] Z is a group represented by the following formula (A1), (A2) or (A3):

[0486] [Chemistry 31]

[0487]

[0488] (Where,

[0489] *** is the bonding position of the carbon atom to which Z is bonded,

[0490] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0491] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl, or R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0492] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0493] m is an integer from 0 to 3,

[0494] W is -CH2-, -CHR 9 - or oxygen atoms,

[0495] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0496] X is -CH-, -CR 10 - or nitrogen atoms,

[0497] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0498] U is -CH-, -CR 11 - or nitrogen atoms, and

[0499] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0500] [Compound (1F)]

[0501] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0502] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0503] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0504] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0505] Y is -CH-, -CR 4 - or nitrogen atom;

[0506] R 4 For hydroxyl, halogen atom, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0507] -V- is a group represented by any of the following formulas:

[0508] [Chemistry 32]

[0509]

[0510] (Wherein, * and ** have the same meanings as above.)

[0511] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0512] n is an integer from 0 to 2 (preferably 0 or 1); and

[0513] Z is a group represented by the following formula (A1) or (A2):

[0514] [Chemistry 33]

[0515]

[0516] (Where,

[0517] *** is the bonding position of the carbon atom to which Z is bonded,

[0518] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0519] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0520] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0521] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0522] m is an integer from 0 to 3,

[0523] W is -CH2-, -CHR 9 - or oxygen atoms,

[0524] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0525] X is -CH-, -CR 10 - or nitrogen atoms,

[0526] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0527] U is -CH-, -CR 11 - or nitrogen atoms, and

[0528] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0529] [Compound (1G)]

[0530] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0531] R 1a and R 1b are each independently a hydrogen atom or a C 1-6an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0532] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0533] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0534] Y is -CH-, -CR 4 - or nitrogen atom;

[0535] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0536] -V- is a group represented by any of the following formulas:

[0537] [Chemistry 34]

[0538]

[0539] (In the formula, * and ** have the same meanings as above.)

[0540] n R 7 are each independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0541] n is an integer from 0 to 2 (preferably 0 or 1); and

[0542] Z is a group represented by the following formula (A1) or (A2):

[0543] [Chemistry 35]

[0544]

[0545] (Where,

[0546] *** is the bonding position of the carbon atom to which Z is bonded,

[0547] R 8 is methyl or ethyl,

[0548] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from the substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0549] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0550] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0551] m is an integer from 0 to 3,

[0552] W is -CH2-, -CHR 9 - or oxygen atoms,

[0553] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0554] X is -CH-, -CR 10 - or nitrogen atoms,

[0555] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0556] U is -CH-, -CR11 - or nitrogen atoms, and

[0557] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0558] [Compound (1H)]

[0559] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0560] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0561] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0562] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0563] Y is -CH-, -CR 4 - or nitrogen atom;

[0564] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0565] -V- is a group represented by any of the following formulas:

[0566] [Chemistry 36]

[0567]

[0568] (Wherein, * and ** have the same meanings as above.)

[0569] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0570] n is an integer from 0 to 2 (preferably 0 or 1); and

[0571] Z is a group represented by the following formula (A1) or (A2):

[0572] [Chemistry 37]

[0573]

[0574] (Where,

[0575] *** is the bonding position of the carbon atom to which Z is bonded,

[0576] R 8 is methyl or ethyl,

[0577] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0578] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0579] m is an integer from 0 to 3,

[0580] W is -CH2-, -CHR 9 - or oxygen atoms,

[0581] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0582] X is -CH-, -CR 10 - or nitrogen atoms,

[0583] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0584] U is -CH-, -CR 11 - or nitrogen atoms, and

[0585] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0586] [Compound (1J)]

[0587] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0588] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0589] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0590] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0591] Y is -CH-, -CR 4 - or nitrogen atom;

[0592] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0593] -V- is a group represented by any of the following formulas:

[0594] [Chemistry 38]

[0595]

[0596] (Wherein, * and ** have the same meanings as above.)

[0597] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0598] n is an integer from 0 to 2 (preferably 0 or 1); and

[0599] Z is a group represented by the following formula (A1) or (A2):

[0600] [Chemistry 39]

[0601]

[0602] (Where,

[0603] *** is the bonding position of the carbon atom to which Z is bonded,

[0604] R 8 is methyl or ethyl,

[0605] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0606] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group, and

[0607] m is an integer from 0 to 2,

[0608] W is -CH2-, -CHR 9 - or oxygen atoms,

[0609] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0610] X is -CH-, -CR 10 - or nitrogen atoms,

[0611] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0612] U is -CH-, -CR 11 - or nitrogen atoms, and

[0613] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0614] [Compound (1K)]

[0615] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0616] R 1a and R 1b are each independently a hydrogen atom or a C 1-6 an alkyl group (preferably each independently a hydrogen atom or a methyl group);

[0617] R 2 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 Alkyl (preferably C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl);

[0618] R 3 A hydrogen atom, a halogen atom or a C 1-6 Alkyl (preferably a halogen atom or C 1-6 alkyl);

[0619] Y is -CH-, -CR 4 - or nitrogen atom;

[0620] R 4 For hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6a haloalkoxy group (preferably a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group, or a trifluoromethoxy group);

[0621] -V- is a group represented by any of the following formulas:

[0622] [Chemistry 40]

[0623]

[0624] (Wherein, * and ** have the same meanings as above.)

[0625] n R 7 are independently a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy (preferably each independently C 1-6 alkyl);

[0626] n is an integer from 0 to 2 (preferably 0 or 1); and

[0627] Z is a group represented by the following formula (A1) or (A2):

[0628] [Chemistry 41]

[0629]

[0630] (Where,

[0631] *** is the bonding position of the carbon atom to which Z is bonded,

[0632] R 8 is methyl or ethyl,

[0633] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0634] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group, and

[0635] m is an integer from 0 to 2,

[0636] W is -CH2- or an oxygen atom,

[0637] X is -CH-, -CR 10 - or nitrogen atoms,

[0638] R 10 Halogen atoms, cyano groups, C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0639] U is -CH-, -CR 11 - or nitrogen atoms, and

[0640] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0641] [Compound (1L)]

[0642] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0643] R 1a and R 1b are each independently a hydrogen atom or a methyl group;

[0644] R 2 C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl;

[0645] R 3 A halogen atom or C 1-6 alkyl;

[0646] Y is -CH-, -CR 4 - or nitrogen atom;

[0647] R 4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group;

[0648] -V- is a group represented by any of the following formulas:

[0649] [Chemistry 42]

[0650]

[0651] (Wherein, * and ** have the same meanings as above.)

[0652] n R 7 Each independently is C 1-6 alkyl;

[0653] n is 0 or 1; and

[0654] Z is a group represented by the following formula (A1) or (A2):

[0655] [Chemistry 43]

[0656]

[0657] (Where,

[0658] *** is the bonding position of the carbon atom to which Z is bonded,

[0659] R 8 is the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl,

[0660] R 5a and R 5b is a hydrogen atom, the aforementioned C optionally substituted by 1 to 3 substituents selected from the substituent group a 1-6 Alkyl, or C 3-6 Cycloalkyl;

[0661] Or, R 5a With R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form the aforementioned C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle,

[0662] m R 6 are independently a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group,

[0663] m is an integer from 0 to 3,

[0664] W is -CH2-, -CHR 9 - or oxygen atoms,

[0665] R 9 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0666] X is -CH-, -CR 10- or nitrogen atoms,

[0667] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0668] U is -CH-, -CR 11 - or nitrogen atoms, and

[0669] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0670] [Compound (1M)]

[0671] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0672] R 1a and R 1b are each independently a hydrogen atom or a methyl group;

[0673] R 2 C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl;

[0674] R 3 A halogen atom or C 1-6 alkyl;

[0675] Y is -CH-, -CR 4 - or nitrogen atom;

[0676] R 4 is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group;

[0677] -V- is a group represented by any of the following formulas:

[0678] [Chemistry 44]

[0679]

[0680] (Wherein, * and ** have the same meanings as above.)

[0681] n R 7Each independently is C 1-6 alkyl;

[0682] n is 0 or 1; and

[0683] Z is a group represented by the following formula (A1) or (A2):

[0684] [Chemistry 45]

[0685]

[0686] (Where,

[0687] *** is the bonding position of the carbon atom to which Z is bonded,

[0688] R 8 is methyl or ethyl,

[0689] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0690] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group, and

[0691] m is an integer from 0 to 2,

[0692] W is -CH2- or an oxygen atom,

[0693] X is -CH-, -CR 10 - or nitrogen atoms,

[0694] R 10 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy,

[0695] U is -CH-, -CR 11 - or nitrogen atoms, and

[0696] R 11 Halogen atoms, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy. ).

[0697] [Compound (1N)]

[0698] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0699] R 1a and R 1b are each independently a hydrogen atom or a methyl group;

[0700] R 2 is methyl;

[0701] R 3 is a chlorine atom or a methyl group;

[0702] Y is -CH-, -CR 4 - or nitrogen atom;

[0703] R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group;

[0704] -V- is a group represented by any of the following formulas:

[0705] [Chemistry 46]

[0706]

[0707] (Wherein, * and ** have the same meanings as above.)

[0708] n is 0; and

[0709] Z is a group represented by the following formula:

[0710] [Chemistry 47]

[0711]

[0712] (where *** is the bonding position of the carbon atom to which Z is bonded,

[0713] R 8 is methyl or ethyl,

[0714] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group;

[0715] Or, R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0716] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0717] m is an integer from 0 to 2, and

[0718] W is -CH2- or an oxygen atom. );

[0719] or a group represented by the following formula:

[0720] [Chemistry 48]

[0721]

[0722] (where *** is the bonding position of the carbon atom to which Z is bonded,

[0723] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group;

[0724] Or, R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0725] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0726] m is an integer from 0 to 2, and

[0727] W is -CH2- or an oxygen atom. ).

[0728] [Compound (1P)]

[0729] Compound (1) or a pharmaceutically acceptable salt thereof, wherein

[0730] R 1a and R 1b are each independently a hydrogen atom or a methyl group;

[0731] R 2 is methyl;

[0732] R 3 is a chlorine atom or a methyl group;

[0733] Y is -CH-, -CR 4 - or nitrogen atom;

[0734] R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group;

[0735] -V- is a group represented by any of the following formulas:

[0736] [Chemistry 49]

[0737]

[0738] (Wherein, * and ** have the same meanings as above.)

[0739] n is 0; and

[0740] Z is a group represented by the following formula:

[0741] [Chemistry 50]

[0742]

[0743] (where *** is the bonding position of the carbon atom to which Z is bonded,

[0744] R 8 is methyl or ethyl,

[0745] R 5a and R 5b are each independently a hydrogen atom or an ethyl group;

[0746] Or, R 5a With R 5b Bonded to each other to form cyclopropane,

[0747] m R 6 are each independently a chlorine atom or a hydroxyl group,

[0748] m is 0 or 1, and

[0749] W is an oxygen atom. );

[0750] or a group represented by the following formula:

[0751] [Chemistry 51]

[0752]

[0753] (where *** is the bonding position of the carbon atom to which Z is bonded,

[0754] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group;

[0755] Or, R 5a With R 5b Bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran,

[0756] m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group,

[0757] m is an integer from 0 to 2, and

[0758] W is an oxygen atom. ).

[0759] Another preferred embodiment of the compound (1) or a pharmaceutically acceptable salt thereof of the present invention is the compound (1) or a pharmaceutically acceptable salt thereof represented by the following formula (1'):

[0760] [Chemistry 52]

[0761]

[0762] [Where,

[0763] R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group,

[0764] R 2’ represents a methyl group,

[0765] R 3’ represents a chlorine atom or a methyl group,

[0766] Y' represents -CH-, -CR 4’ - or nitrogen atoms,

[0767] R 4’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group,

[0768] -V'- represents any group selected from the following formulae:

[0769] [Chemistry 53]

[0770]

[0771] (Wherein, *' and **' represent the bonding positions to the benzene ring.)

[0772] R 5a’ and R 5b’ Each independently represents a hydrogen atom or an ethyl group, or R 5a’ With R 5b’ Bonded to each other to form cyclopropane,

[0773] m' R 6’ each independently represents a fluorine atom or a chlorine atom,

[0774] m' represents an integer from 0 to 2, and

[0775] W' represents an oxygen atom. ];

[0776] Alternatively, a compound (1) represented by the following formula (1") or a pharmaceutically acceptable salt thereof:

[0777] [Chemistry 54]

[0778]

[0779] [Where,

[0780] R 1a” and R 1b” each independently represents a hydrogen atom or a methyl group,

[0781] R 2” represents a methyl group,

[0782] R 3” represents a chlorine atom or a methyl group,

[0783] Y" represents -CH-, -CR 4” - or nitrogen atoms,

[0784] R 4” represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group,

[0785] -V"- represents a group represented by any of the following formulae:

[0786] [Chemistry 55]

[0787]

[0788] (Wherein, *" and **" indicate the bonding position to the benzene ring.)

[0789] R 5a” and R 5b” Each independently represents a hydrogen atom or an ethyl group, or,

[0790] R 5a” and R 5b” Bonded to each other to form cyclopropane,

[0791] R 8” represents a methyl or ethyl group,

[0792] m” R 6” represents a chlorine atom or a hydroxyl group,

[0793] m" means 0 or 1,

[0794] U" represents a nitrogen atom, and

[0795] W" represents an oxygen atom.].

[0796] Specific examples of suitable compound (1) include the compounds of Examples 1 to 112 described below or their pharmaceutically acceptable salts, and more preferably any compound (1) or its pharmaceutically acceptable salt selected from the following group:

[0797] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0798] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0799] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0800] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0801] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0802] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0803] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid,

[0804] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0805] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0806] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0807] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0808] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid,

[0809] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid,

[0810] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid,

[0811] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, and

[0812] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid;

[0813] or any compound (1) or a pharmaceutically acceptable salt thereof selected from the following groups:

[0814] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0815] (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0816] (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0817] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0818] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0819] (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0820] (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0821] (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0822] (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0823] (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid,

[0824] (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid,

[0825] (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, and

[0826] (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid.

[0827] Particularly preferred

[0828] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0829] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,

[0830] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, and

[0831] (3R)-3-(7-{[(4R)-8-Chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid.

[0832] Since the compound (1) of the present invention has a basic group such as a nitrogen-containing heterocyclic group in the molecule, it can form a generally pharmaceutically acceptable acid addition salt. Examples of such acid addition salts include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; aryl sulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleic acid, mucic acid, and adipate; and amino acid salts such as ornithine, glutamate, and aspartate. Among these, hydrohalide salts, aryl sulfonates, and organic acid salts are preferred.

[0833] The acid addition salts of the compound (1) of the present invention include acid addition salts that can be formed by combining the acid added to the compound of the present invention with the compound (1) of the present invention in any ratio. For example, hydrochloride includes salts that can be formed such as 1-hydrochloride, 2-hydrochloride, and 3-hydrochloride; fumarate includes salts that can be formed such as 1-fumarate and 1 / 2-fumarate; and succinate includes salts that can be formed such as 1-succinate, 2 / 3-succinate, and 1 / 3-succinate.

[0834] Since the compound (1) of the present invention has a carboxyl group in the molecule, it can form a general pharmaceutically acceptable base addition salt. Examples of such base addition salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as benzhydrylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-benzhydrylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts.

[0835] When the compound (1) of the present invention has an asymmetric carbon atom in the molecule, it may exist as multiple stereoisomers (i.e., diastereomers, optical isomers) based on the asymmetric carbon atom. The present invention also includes any one of these stereoisomers and any mixture containing multiple stereoisomers in any ratio. In addition, isomers may be generated due to conformation or tautomerism. Such isomers or mixtures thereof are also included in the compound (1) of the present invention.

[0836] In the names of the compounds of the present invention, when the compound has a carbon atom as an asymmetric center in its structure, its absolute configuration is represented by R and S (described together with a position number).

[0837] In addition, even when optical isomers are separated, when the stereo configuration of the carbon atom serving as an asymmetric center in the structure of the compound is not determined, R * or S * express.

[0838] In addition, due to the simultaneous use of R * and S * , even when the absolute configuration is not determined, it sometimes indicates the relative configuration.

[0839] The compound (1) of the present invention may be an isotope element (e.g. 2 H. 3 H. 13 C. 14 C. 15 N. 18 F. 32 P. 35 S. 125 Compounds labeled or substituted with isotopes (e.g., 1, etc.) are useful as therapeutic or preventive agents, research reagents (e.g., test reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds of the present invention containing radioactive or non-radioactive isotopes in all proportions are within the scope of the present invention.

[0840] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof may be a crystal, and may be a single crystal form or a mixture of multiple crystal forms.

[0841] The compound (1) of the present invention may exist in the form of a non-solvate or a solvate. The solvate is not particularly limited as long as it is pharmaceutically acceptable, but specifically, hydrates, ethanolates, and the like are preferred.

[0842] The compound (1) of the present invention may be a prodrug.

[0843] The prodrug of compound (1) of the present invention is a compound that is converted to compound (1) in vivo by a reaction involving enzymes, gastric acid, etc. Prodrugs of compound (1) are considered to have a structure that is easily hydrolyzed or metabolized after administration to a patient.

[0844] Examples of prodrugs of compound (1) include, for example, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (1) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); and compounds in which the hydroxy group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxy group of compound (1) is acetylated). , palmitoylation, propionylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); compounds in which the carboxyl group of compound (1) is esterified or amidated (for example, the carboxyl group of compound (1) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthaloyl esterified, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, methylamidation, etc.) and the like.

[0845] The prodrug of compound (1) of the present invention can be prepared from compound (1) by known methods. Furthermore, prodrugs of compound (1) also include substances that convert to compound (1) under physiological conditions, as described in "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, pp. 163-198. Furthermore, the prodrug of compound (1) may be either a hydrate or a non-hydrate.

[0846] (Method for producing compound (1) of the present invention)

[0847] Representative methods for preparing compound (1) of the present invention or a pharmaceutically acceptable salt thereof are described below. Compound (1') and compound (1") of the present invention are also included in compound (1). Therefore, methods for preparing compound (1') and compound (1") are also included below and are referred to as methods for preparing compound (1).

[0848] The compound (1) of the present invention can be produced by various production methods. The production methods shown below, and the reference examples and examples described later are merely illustrative, and the present invention should not be construed as being limited thereto.

[0849] Each starting compound can form a salt as long as it does not inhibit the reaction. Examples of such salts include the same salts as the pharmaceutically acceptable salts of the aforementioned compound (1).

[0850] When a specific preparation method is not described, the raw material compound can be easily obtained using a commercially available product, or can be prepared using a method known to itself or a method based thereon. In addition, the preparation intermediate generated in the following preparation method can be isolated and purified using methods such as column chromatography (including normal phase and reverse phase) using silica gel or alumina, recrystallization, reprecipitation, and distillation, or can be directly used in the next reaction without isolation and purification.

[0851] The contents of all patent documents, non-patent documents, or reference documents explicitly cited in this specification are hereby incorporated by reference as a part of this specification.

[0852] Compound (1), its pharmaceutically acceptable salt, and its preparation intermediates can be prepared by various known preparation methods, utilizing the characteristics of their basic skeletons or substituent types. Examples of known methods include those described in "Organic Functional Group Preparations", 2nd edition, Academic Press, Inc., 1989, and "Comprehensive Organic Transformations", 2nd edition, VCH Publishers Inc., 1999.

[0853] In this case, depending on the type of functional group present in the compound, it may be effective in terms of production technology to protect the functional group in advance with an appropriate protecting group at the stage of a raw material or intermediate, or to replace it with a group that can be easily converted into the functional group.

[0854] Examples of such functional groups include amino, hydroxyl, formyl, carbonyl, and carboxyl groups, and examples of their protecting groups include those described in "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, by PGWuts.

[0855] The protecting group or the group that can be easily converted into the functional group may be appropriately selected and used according to the reaction conditions of each production method used for producing the compound.

[0856] According to such a method, the desired compound can be obtained by introducing the group and carrying out the reaction, and then removing the protecting group as needed or converting the group into the desired group.

[0857] In addition, prodrugs of compounds, similar to the above-mentioned protecting groups, can be prepared by introducing specific groups into raw materials or intermediates or by reacting the resulting compounds. Reactions for preparing prodrugs can be carried out using conventional methods known to those skilled in the art, such as esterification, amidation, dehydration, and hydrogenation.

[0858] The compound (1) of the present invention can be produced, for example, by the following methods A to C. The production intermediates used in methods A to C can be produced, for example, by the following methods D to J.

[0859] In the reactions of each step of the following methods A to J, the reaction temperature varies depending on the solvent, starting materials, reagents, etc., and the reaction time varies depending on the solvent, starting materials, reagents, reaction temperature, etc. In addition, the amounts of solvents, starting materials, reagents, etc. used can be appropriately determined depending on the progress of the reaction.

[0860] Furthermore, the functional group conversion of the heterocyclic ring in the production intermediate used in each step of the following method A to method J can be carried out by a method known per se (specifically, converting a halogen atom into a C 1-6 Alkyl or C 3-6 The reaction conditions for cycloalkylation are, for example, the methods described in Zou, G.; Reddy, YK; Falck, JR Tetrahedron Lett. 2001, 42, 7213, Molander, GA; Yun, C.-S. Tetrahedron 2002, 58, 1465, Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons, Inc.: England, 2004, Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.; Diederich, F.; Wiley-VCH: Weinheim, 2004, etc.) or methods based thereon, or methods described in the Examples described later or methods based thereon.

[0861] (Method A)

[0862] This production method is a method for producing compound (1) by condensing compound (IIA) and compound (III) to obtain compound (IV), and then removing the protecting group of compound (IV).

[0863] [Chemistry 56]

[0864]

[0865] (Where, L 1 Represents a leaving group, Pro 1 Represents a protecting group (suitably a C 1-6 alkyl, or 2-(trimethylsilyl)ethyl. ) Other symbols have the same meanings as above.

[0866] (Process A-1)

[0867] This step is a step of producing compound (IV) by condensing compound (IIA) and compound (III) in a solvent in the presence or absence of a base.

[0868] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0869] The base used is not particularly limited as long as it is a substance used as a base in a conventional reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, and the like.

[0870] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0871] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0872] (Step A-2)

[0873] This step is to remove the protective group (Pro 1 ) to prepare compound (1).

[0874] This process is based on Pro 1 The type of the method is appropriately selected from the known methods described in, for example, PGWuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, etc., and is carried out in accordance with the method. 1 Method for converting to hydrogen atoms (step A-2-1), using an acid in a solvent to convert Pro 1A method of converting Pro into a hydrogen atom (step A-2-2), or using a fluoride salt in a solvent to convert Pro 1 The method for converting hydrogen atoms (step A-2-3) is described above, but this step is not limited thereto.

[0875] (Step A-2-1)

[0876] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0877] The base used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction. For example, there can be mentioned organic bases such as triethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, etc.

[0878] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 10°C to 90°C.

[0879] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 1 minute to 24 hours, preferably 10 minutes to 6 hours.

[0880] (Process A-2-2)

[0881] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0882] The acid used is not particularly limited as long as it can be used as an acid in a general reaction. Examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; and organic acids such as trifluoroacetic acid.

[0883] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -78°C to 100°C.

[0884] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0885] (Process A-2-3)

[0886] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0887] The fluoride salt used is not particularly limited, and examples thereof include tetrabutylammonium fluoride and pyridine hydrogen fluoride.

[0888] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 100°C, preferably -20°C to 60°C.

[0889] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0890] (Method B)

[0891] This preparation method is a method for preparing compound (1) by performing a reductive amination reaction of compound (IIB) and compound (III) to obtain compound (IV) and then removing the protecting group of compound (IV).

[0892] [Chemistry 57]

[0893]

[0894] (Where, Pro 1 Represents a protecting group (suitably a C 1-6alkyl, or 2-(trimethylsilyl)ethyl. ) Other symbols have the same meanings as above.

[0895] (Process B-1)

[0896] This step is a step of producing compound (IV) by carrying out a reductive amination reaction of compound (IIB) with compound (III) using a reducing agent in a solvent in the presence or absence of an acid and in the presence or absence of an additive.

[0897] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[0898] The reducing agent used is not particularly limited, and examples thereof include reducing agents such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, picoline borane, and pyridine borane.

[0899] The acid that can be used is not particularly limited as long as it can be used as an acid in a general reaction. Examples thereof include Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0900] The additives that can be used are not particularly limited, and examples thereof include inorganic salts such as sodium sulfate and magnesium sulfate.

[0901] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably 0°C to 50°C.

[0902] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 168 hours, preferably 10 minutes to 120 hours.

[0903] (Process B-2)

[0904] This step is to remove the protective group (Pro 1 ) to prepare compound (1).

[0905] This step can be carried out under the same conditions as those of the aforementioned step A-2.

[0906] (C Method)

[0907] This production method is a method for producing compound (1) by performing a Mitsunobu reaction between compound (IIC) and compound (III) to obtain compound (IV), and then removing the protecting group of compound (IV).

[0908] [Chemistry 58]

[0909]

[0910] (Where, Pro 1 Represents a protecting group (suitably methyl, ethyl, tert-butyl, etc. C 1-6 alkyl, or 2-(trimethylsilyl)ethyl. ) Other symbols have the same meanings as above.

[0911] (Process C-1)

[0912] This step is a step of producing compound (IV) by subjecting compound (IIC) to a Mitsunobu reaction with compound (III) in a solvent.

[0913] Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; and ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Among these, halogenated hydrocarbons or ethers are suitable, and dichloromethane or tetrahydrofuran is more suitable.

[0914] The reagent used in the Mitsunobu reaction is not particularly limited as long as it is a known reagent that can be generally used in the Mitsunobu reaction. Suitable examples include di-lower alkyl azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate; combinations of azo compounds such as azodiamides such as 1,1'-azobis(N,N-dimethylformamide) and 1,1'-(azodicarbonyl)dipiperidine with triarylphosphines such as triphenylphosphine; and combinations of phosphines such as lower alkyl phosphines such as tri-n-butylphosphine. More suitable is a combination of di-tert-butyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine with tri-n-butylphosphine.

[0915] The reaction temperature varies depending on the starting compounds or reagents, but is usually -50°C to 100°C, preferably -10°C to 60°C.

[0916] The reaction time varies depending on the reaction temperature, starting compounds, reaction reagents or solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0917] (Process C-2)

[0918] This step is to remove the protective group (Pro1 ) to prepare compound (1).

[0919] This step can be carried out under the same conditions as those of the aforementioned step A-2.

[0920] (D method)

[0921] This preparation method is to prepare the intermediate compounds used in the above-mentioned methods A to C, namely, compound (IIA-1), compound (IIB-1) and compound (IIC-1) (R in the above-mentioned formulas (IIA), (IIB) and (IIC) 1a and R 1b are all hydrogen atoms) method.

[0922] [Chemistry 59]

[0923]

[0924] (Where R 12 represents a hydrogen atom, an alkyl group or a halogenated alkyl group, L 1 Represents a leaving group, Pro 1 Represents a protecting group (suitably a C 1-6 alkyl, or 2-(trimethylsilyl)ethyl. ) Other symbols have the same meanings as above.

[0925] (Process D-1)

[0926] This step is a step of converting compound (V) to compound (VI) in a solvent. Here, the bromination method is described, but the method is not limited thereto.

[0927] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; carboxylic acids such as acetic acid and trifluoroacetic acid; sulfonic acids such as methanesulfonic acid; mineral acids such as sulfuric acid; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[0928] The brominating agent used is not particularly limited, and examples thereof include N-bromosuccinimide and bromine.

[0929] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -20°C to 50°C.

[0930] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0931] (Process D-2)

[0932] This step is a step of converting Compound (VI) into an amide compound in a solvent (Step D-2-1) and then introducing a nitro group (Step D-2-2) (or converting the nitro group into an amide compound after the amide compound is introduced) to thereby convert Compound (VII).

[0933] (Step D-2-1) (Conversion into an amide compound)

[0934] Here, the compound (VI) is subjected to the reaction with formic acid (R 12 is a hydrogen atom. ) (Step D-2-1a), and a method of reacting compound (VI) and an alkyl carboxylic acid (R) in the presence or absence of a base. 12 R is an alkyl group or a haloalkyl group 12 CO2H.) A method for amidation using an appropriate condensing agent (step D-2-1b) is described below, but is not limited thereto.

[0935] (Process D-2-1a)

[0936] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[0937] The acid anhydride that can be used is not particularly limited as long as it can be used as an acid anhydride in a general reaction, and examples thereof include carboxylic acid anhydrides such as acetic anhydride.

[0938] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably 0°C to 50°C.

[0939] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0940] (Process D-2-1b)

[0941] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0942] The base used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, and the like.

[0943] The condensing agent to be used is not particularly limited as long as it is a substance that can be used as a condensing agent for forming an amide bond (for example, methods described in Masakazu Kusumoto et al., Experimental Science Lecture IV; Chemical Society of Japan; Maruzen, 1990; Nobuo Izumiya et al., Fundamentals and Experiments of Peptide Synthesis; Maruzen, 1985, etc.), and suitable examples include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDTA), and the like.

[0014] Examples of the present invention include 4-[(cyclohexylimino)methylene]amino}ethyl-4-methylmorpholinium p-toluenesulfonate (CMC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis(1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), and 2-chloro-4,6-dimethoxy-1,3,5-triazine (DMT). Furthermore, as needed, additives such as 1-hydroxybenzotriazole (HOBT) and N,N-dimethylaminopyridine may be added.

[0944] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0945] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0946] (Step D-2-2) (Nitro group introduction step)

[0947] This step is a step of introducing a nitro group using a nitrating agent. Here, a method of using a suitable nitrating agent on Compound (VI) in a solvent in the presence or absence of a suitable acid is described, but the present invention is not limited thereto.

[0948] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. An acid is preferably used as a solvent. Examples thereof include mineral acids such as sulfuric acid and mixed solvents containing a plurality of solvents at arbitrary ratios.

[0949] The nitrating agent used is not particularly limited as long as it can be used as a nitrating agent in a general reaction, and examples thereof include mineral acids such as nitric acid.

[0950] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -20°C to 50°C.

[0951] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0952] (Process D-3)

[0953] This step is a step of converting Compound (VII) into Compound (VIII) by reducing Compound (VII) with an appropriate reducing agent in a solvent.

[0954] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[0955] The reducing agent used is not particularly limited as long as it can be used as a reducing agent in a conventional reaction, and examples thereof include metal hydrides such as lithium aluminum hydride, diisobutylaluminum hydride, and sodium bis(2-methoxyethoxy)aluminum hydride; boron hydrides such as borane; and silicon hydrides such as triethylsilane.

[0956] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably 0°C to 80°C.

[0957] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0958] (Process D-4)

[0959] This step is to convert the fluorine atom of compound (IX) into NHR 2 After the bromine atom is introduced (step D-4-2) (or after the bromine atom is introduced, the fluorine atom is converted to NHR 2 In step D-4, either step D-4-1 or step D-4-2 may be performed first, and a person skilled in the art can select an appropriate order.

[0960] (Process D-4-1)

[0961] This step is to react a primary amine (R 2 NH2(R 2 The fluorine atom is converted to NHR by reacting 2 Basic process.

[0962] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0963] The base that can be used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide, and the like.

[0964] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0965] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 12 hours.

[0966] (Process D-4-2)

[0967] This step is a step of introducing bromine atoms into a solvent. This step can be carried out under the same conditions as in the aforementioned step D-1.

[0968] (Process D-5)

[0969] This step is a step of producing compound (X) by converting the nitro group of compound (VIII) to an amino group in a solvent.

[0970] As methods for converting the nitro group of compound (VIII) into an amino group, the following describes a method using an appropriate metal and an appropriate acid (step D-5-1), a method using hydrogen in the presence of an appropriate metal catalyst (step D-5-2), and a method using a metal hydride (step D-5-3), but is not limited thereto.

[0971] (Process D-5-1)

[0972] This step is a step of converting the nitro group of compound (VIII) to an amino group using a metal in a solvent in the presence of an acid.

[0973] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0974] The acid used is not particularly limited as long as it can be used as an acid in a conventional reaction. Suitable examples include inorganic acids such as hydrochloric acid, sulfuric acid, and ammonium chloride; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0975] The metal used is not particularly limited, and examples thereof include iron, zinc, and tin.

[0976] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0977] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0978] (Process D-5-2)

[0979] This step is a step of converting the nitro group of compound (VIII) into an amino group using hydrogen in a solvent in the presence of an appropriate metal catalyst.

[0980] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0981] The metal catalyst used is not particularly limited, and suitable examples include metal catalysts such as palladium-activated carbon, platinum-activated carbon, nickel, and osmium-activated carbon.

[0982] Examples of the hydrogen source to be used include hydrogen gas, ammonium formate, and hydrazine.

[0983] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0984] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0985] (Process D-5-3)

[0986] This step is a step of converting the nitro group of compound (VIII) into an amino group using an appropriate metal hydride in a solvent.

[0987] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; and mixed solvents containing a plurality of the aforementioned organic solvents in any ratio.

[0988] The metal hydride used is not particularly limited, and suitable examples include lithium aluminum hydride.

[0989] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0990] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0991] (Process D-6)

[0992] This step is a step of preparing Compound (XI) by constructing a triazole ring from Compound (X). The following describes a method using nitrites or nitrite esters in a solvent in the presence of an acid, but the method is not limited thereto.

[0993] That is, this step is a step of reacting compound (X) with nitrites or nitrite esters in a solvent in the presence of an acid to construct a triazole ring.

[0994] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[0995] The acid used is not particularly limited as long as it can be used as an acid in a conventional reaction. Suitable examples include inorganic acids such as hydrochloric acid, sulfuric acid, and tetrafluoroboric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0996] The nitrites used are not particularly limited, and examples thereof include alkali metal salts such as sodium nitrite.

[0997] The nitrites used are not particularly limited, and examples thereof include isobutyl nitrite and tert-butyl nitrite.

[0998] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -20°C to 100°C, preferably -10°C to 60°C.

[0999] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1000] (Process D-7)

[1001] This step is to react an acrylate compound in a solvent in the presence or absence of a base, in the presence or absence of an additive, and in the presence of a metal catalyst to convert the bromine group of compound (XI) into an acrylate group (-CH=CH-CO2Pro 1 ) to prepare compound (XII).

[1002] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1003] The base that can be used is not particularly limited as long as it is a substance used as a base in a common reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide, and the like.

[1004] The additives that can be used are not particularly limited as long as they are substances that can be used as known methods. Suitable examples include metal oxides such as silver oxide and aluminum oxide; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP); phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; and ammonium salts such as tetrabutylammonium bromide. These can be used in combination in any ratio.

[1005] The metal catalyst used is not particularly limited as long as it is a substance used in a known method, and suitable examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, di-palladium acetate, dichloropalladium diphenylphosphinoferrocene complex, dichloropalladium benzonitrile complex, dichloropalladium acetonitrile complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium, and palladium-activated carbon.

[1006] The acrylate compound used is not particularly limited, and examples thereof include methyl acrylate, ethyl acrylate, and t-butyl acrylate.

[1007] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 120°C.

[1008] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[1009] (Process D-8)

[1010] This step is a step of preparing compound (IIC-1) by reacting compound (XII) with compound (XIII) obtained by method E described below using a metal catalyst in a solvent in the presence or absence of a base and in the presence or absence of an additive.

[1011] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1012] The base that can be used is not particularly limited as long as it is a substance used as a base in a common reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide, and the like.

[1013] Usable additives are not particularly limited as long as they are used in a known manner. Suitable examples include phosphines such as 2,3-bis(diphenylphosphino)butane. Different types of phosphines may be used in combination at any ratio.

[1014] The metal catalyst used is not particularly limited as long as it is used in a known method. Suitable examples include rhodium catalysts such as bis(norbornadiene)rhodium(I) tetrafluoroborate and chloro(1,5-cyclooctadiene)rhodium(I) dimer.

[1015] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 100°C.

[1016] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[1017] (Process D-9)

[1018] In this step, the hydroxyl group of compound (IIC-1) is converted into a leaving group (L) by reacting an acid chloride or an acid anhydride in a solvent in the presence or absence of a base. 1 ), thereby preparing compound (IIA-1).

[1019] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[1020] The acid chloride or acid anhydride used is not particularly limited, and suitable examples include acid chlorides of sulfurous acid such as thionyl chloride, substituted or unsubstituted alkylsulfonic anhydrides or arylsulfonic anhydrides such as trifluoromethanesulfonic anhydride; substituted or unsubstituted alkylsulfonyl chlorides or arylsulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride; substituted or unsubstituted alkylphosphonic acid chlorides or arylphosphonic acid chlorides, and the like.

[1021] The base that can be used is not particularly limited as long as it is a substance used as a base in a common reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, and the like.

[1022] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -80°C to 40°C.

[1023] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1024] (Process D-10)

[1025] This step is a step of converting the hydroxyl group of compound (IIC-1) into a formyl group using a suitable oxidizing agent in a solvent to produce compound (IIB-1).

[1026] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1027] The oxidizing agent used is not particularly limited. For example, a known method described in the fourth edition of Experimental Chemistry Lectures (21. Organic Synthesis III: Aldehydes, Ketones, and Quinones), Maruyama Kazuhiro et al., The Chemical Society of Japan, Maruzen Co., Ltd., 1990, etc., can be appropriately selected and this step can be carried out according to the method. Representative oxidation reactions include oxidation reactions using chromic acid such as chromic anhydride, chromium (VI) oxide-pyridine complex (Collins reagent), pyridinium chlorochromate (PCC), and pyridinium dichromate (PDC); oxidation reactions using activated manganese dioxide; oxidation reactions using a combination of dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or oxalyl chloride and dimethyl sulfoxide (DMSO); and oxidation reactions using a superatomic iodine compound (Dess-Martin reagent).

[1028] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably 0°C to 50°C.

[1029] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1030] (E Method)

[1031] This preparation method is to prepare the intermediate compounds used in the above-mentioned methods A to C, namely compound (IIA-2), compound (IIB-2) and compound (IIC-2) (R in the above-mentioned formulas (IIA), (IIB) and (IIC) 1a and R 1b Each independently is C 1-6 alkyl compounds).

[1032] [Chemistry 60]

[1033]

[1034] (Where, Pro 1 Represents a protecting group (suitably a C 1-6 alkyl, or 2-(trimethylsilyl)ethyl. ), Pro 2 represents a protecting group (suitably p-methoxybenzyl). Other symbols have the same meanings as above.

[1035] (Process E-1)

[1036] This step is to protect the hydroxyl group of compound (IIC-1) with a protective group (Pro 2 Here, the method in which the protecting group is p-methoxybenzyl and an appropriate protecting agent is used in the presence of an acid is described, but the present invention is not limited thereto.

[1037] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1038] The acid used is not particularly limited as long as it can be used as an acid in a conventional reaction. Examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and tetrafluoroboric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; organic acids such as acetic acid and trifluoroacetic acid; and sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and (S)-(+)-camphor-10-sulfonic acid.

[1039] Examples of the protecting agent used include 4-methoxybenzyl-2,2,2-trichloroacetimidate and 2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine.

[1040] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -50°C to 150°C, preferably -20°C to 100°C.

[1041] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[1042] (Process E-2)

[1043] This step is carried out by using a suitable base in a solvent or without a solvent, and C 1-6 Alkyl halide or C 1-6 Alkyl pseudohalides are then introduced into the α position of the ester group of compound (XIV) in sequence. 1-6 Alkyl R 1a and R 1b The process for preparing compound (XV).

[1044] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[1045] The base used is not particularly limited, and suitable examples include organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide; metal amides such as lithium diisopropylamide and sodium hexamethyldisilazide; organometallic compounds such as tert-butyllithium; metal hydrides such as potassium hydride and sodium hydride, and the like.

[1046] A pseudohalide is a substituent known to undergo a substitution reaction similar to a halide in an alkylation reaction. The substituent is not particularly limited as long as it is known to induce such a substitution reaction. Examples include sulfonyloxy groups such as trifluoromethanesulfonyloxy, methanesulfonyloxy, and p-toluenesulfonyloxy; and acyloxy groups such as acetoxy. The alkyl halide or alkyl pseudohalide used is not particularly limited and can be a known compound or one synthesized according to known methods.

[1047] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -80°C to 150°C, preferably -20°C to 60°C.

[1048] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[1049] (Process E-3)

[1050] This step is to remove the protecting group (Pro 2 ) process. Here, for Pro 2 In the case of p-methoxybenzyl group, a method of removing it using a suitable oxidizing agent in a solvent (step E-3a) and a method of removing it using a suitable acid in the presence or absence of anisole (step E-3b) are described, but the present invention is not limited to these.

[1051] (Step E-3a) (Deprotection Step Using an Oxidizing Agent)

[1052] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1053] Examples of the oxidizing agent to be used include 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[1054] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -20°C to 150°C, preferably 0°C to 100°C.

[1055] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[1056] (Step E-3b) (Deprotection step using an acid)

[1057] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1058] The acid used is not particularly limited as long as it can be used as an acid in a general reaction. Examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilyl iodide; and organic acids such as trifluoroacetic acid.

[1059] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -78°C to 100°C.

[1060] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1061] (Process E-4)

[1062] This step is a step for converting compound (IIC-2) into compound (IIA-2), and can be carried out according to the above-mentioned step D-9.

[1063] (Process E-5)

[1064] This step is a step for converting compound (IIC-2) into compound (IIB-2), and can be carried out according to the above-mentioned step D-10.

[1065] (F method)

[1066] This production method is a method for producing compound (XIII), an intermediate compound used in the above-mentioned method D, from compound (XVI).

[1067] [Chemistry 61]

[1068]

[1069] (Where, L 2 Represents a leaving group, Pro 3 represents a protecting group (suitably an acetyl group), and other symbols have the same meanings as above.

[1070] (Process F-1)

[1071] This step is a step of producing Compound (XVII) by introducing a bromine group into Compound (XVI). Here, a method using a brominating agent in a solvent in the presence of a suitable catalyst is described, but the method is not limited thereto.

[1072] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[1073] Examples of the catalyst to be used include radical initiators such as azobisisobutyronitrile and benzoyl peroxide.

[1074] Examples of the brominating agent used include N-bromosuccinimide and N-bromoacetamide.

[1075] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 200°C, preferably 20°C to 150°C.

[1076] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[1077] (Process F-2)

[1078] This step is to convert the bromo group of compound (XVII) into a protected group (Pro 3 Here, the method using a metal salt of a carboxylic acid in a solvent is described, but the invention is not limited thereto.

[1079] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1080] Examples of the carboxylic acid metal salts used include potassium acetate, sodium acetate, potassium benzoate, and sodium benzoate.

[1081] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 100°C.

[1082] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[1083] (Process F-3)

[1084] This step is to remove the protective group (Pro 3 ) can be carried out according to the above-mentioned step A-2-1.

[1085] (Process F-4)

[1086] This step is carried out by removing the leaving group (L) of compound (XIX) from the solvent in an inert gas (nitrogen or argon) atmosphere in the presence or absence of a base and in the presence or absence of an additive using an appropriate metal catalyst and a boron compound. 2 ) is converted into a borate ester to prepare compound (XIII).

[1087] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1088] The boron compound used is not particularly limited as long as it is a compound generally used in borate ester synthesis, and suitable examples include bis(pinacolato)diboron and pinacol borane.

[1089] The base that can be used is not particularly limited as long as it is a substance used as a base in a general reaction. Suitable examples include organic bases such as triethylamine and N,N-diisopropylethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and cesium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal acetates such as sodium acetate and potassium acetate; alkali metal phosphates such as tripotassium phosphate; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide, etc.

[1090] The additives that can be used are not particularly limited as long as they can be used as a known method. Suitable examples include metal oxides such as silver oxide and aluminum oxide; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP); phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; and ammonium salts such as tetrabutylammonium bromide. These can be used in combination in any proportion.

[1091] The metal catalyst used is not particularly limited as long as it is a substance used in a known method. Suitable examples include tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, di-palladium acetate, dichloropalladium diphenylphosphinoferrocene complex, dichloropalladium benzonitrile complex, dichloropalladium acetonitrile complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium, and palladium catalysts such as palladium-activated carbon.

[1092] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -10°C to 200°C, preferably 0°C to 150°C.

[1093] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 12 hours.

[1094] (G method)

[1095] This production method is a method for producing compound (XIII), an intermediate compound used in the above-mentioned method D, from compound (XX).

[1096] [Chemistry 62]

[1097]

[1098] (Where, L 3 Represents a leaving group, Pro 4 Represents a protecting group (suitably a C 1-6 Alkyl. ), other symbols have the same meanings as above. )

[1099] (Process G-1)

[1100] This step is a step of converting Compound (XX) to Compound (XXI) by inserting carbon monoxide using a metal catalyst in a solvent in the presence or absence of a base, in the presence or absence of an additive, and in the presence of an alcohol.

[1101] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1102] The base that can be used is not particularly limited as long as it is a substance used as a base in a common reaction. Suitable examples include organic bases such as triethylamine and N,N-diisopropylethylamine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate; metal alkanols such as sodium tert-butoxide and potassium tert-butoxide, etc.

[1103] The additives that can be used are not particularly limited as long as they are substances used as known methods. Suitable examples include metal oxides such as silver oxide and aluminum oxide; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (X-PHOS), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); phosphine oxides such as triphenylphosphine oxide; metal salts such as lithium chloride, potassium fluoride, and cesium fluoride; ammonium salts such as tetrabutylammonium bromide; acid anhydrides such as acetic anhydride, etc., which can be used in combination in any proportion.

[1104] The metal catalyst used is not particularly limited as long as it is a substance used in a known method, and suitable examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, di-palladium acetate, dichloropalladium diphenylphosphinoferrocene complex, dichloropalladium benzonitrile complex, dichloropalladium acetonitrile complex, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, 3-chloropyridine[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium, and palladium-activated carbon.

[1105] As the alcohol used (Pro 4 OH) is not particularly limited, and examples thereof include methanol and ethanol.

[1106] The carbon monoxide source used is not particularly limited, and examples thereof include carbon monoxide gas, lithium formate, and 2,4,6-trichlorophenyl formate.

[1107] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 120°C.

[1108] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[1109] (Process G-2)

[1110] This step is to introduce a leaving group L into compound (XXI) 2 (suitably a halogen atom or a pseudohalogen atom group) to prepare compound (XXII), for example, L 2 In the case of a bromo group, the above-mentioned step D-1 can be followed, but the process is not limited thereto.

[1111] (Process G-3)

[1112] This step is a step of producing compound (XIX) by reducing compound (XXII) using an appropriate reducing agent in a solvent.

[1113] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[1114] The reducing agent used is not particularly limited as long as it is a substance used as a reducing agent in a general reaction, and examples thereof include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium borohydride.

[1115] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably -78°C to 80°C.

[1116] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1117] (Process G-4)

[1118] This step is to convert the carboxyl group of compound (XXIII) into C 1-6 The step of preparing compound (XXI) by forming an alkyl ester group is described here as a method of condensing with a corresponding alcohol in the presence of an acid, but the present invention is not limited to this method.

[1119] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. For example, alcohols such as methanol, ethanol, and n-butanol, or mixed solvents containing these alcohols and organic solvents in any ratio can be suitably used as both solvent and reactant.

[1120] The acid used is not particularly limited, and examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid; and organic acids such as p-toluenesulfonic acid.

[1121] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually 0°C to 200°C, preferably 20°C to 130°C.

[1122] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1123] (Process G-5)

[1124] This step is to introduce a leaving group L into compound (XXIII) in a solvent. 2 (suitably a halogen atom or a pseudohalogen atom group) to prepare compound (XXIV), for example, L 2 In the case of a bromo group, the above-mentioned step D-1 can be followed, but the process is not limited thereto.

[1125] (Process G-6)

[1126] This step is a step of producing compound (XIX) by reducing compound (XXIV) using an appropriate reducing agent in a solvent.

[1127] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include ethers such as diethyl ether and tetrahydrofuran.

[1128] The reducing agent used is not particularly limited as long as it can be used as a reducing agent in a general reaction, and examples thereof include lithium aluminum hydride and a borane-tetrahydrofuran complex.

[1129] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 100°C, preferably -78°C to 50°C.

[1130] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1131] (Process G-7)

[1132] This step is to make the leaving group (L 2 The step of converting ) into a borate ester to prepare compound (XIII) can be carried out according to the above-mentioned step F-4.

[1133] (H method)

[1134] This preparation method is a method for preparing Compound (III) wherein Z is a group represented by Formula A1, which is an intermediate compound used in Methods A and B. The following describes a method for preparing Compound (IIIA1-1) wherein the group W in Formula A1 is an oxygen atom, but is not limited thereto.

[1135] [Chemistry 63]

[1136]

[1137] (Where, L 4 represents a leaving group (suitably a halogen atom or a pseudohalogen atom), Pro 5 represents a protecting group (suitably p-methoxybenzyl, allyl or benzyl). Other symbols have the same meanings as above.

[1138] (Process H-1)

[1139] This step is to introduce a substituent R by subjecting the formyl group of compound (XXV) to a nucleophilic addition reaction using an appropriate organometallic compound in a solvent. 8 , a process for preparing compound (XXVI).

[1140] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the aforementioned organic solvents in arbitrary ratios.

[1141] Examples of the organometallic reagent include organolithium compounds such as methyllithium and n-butyllithium; Grignard reagents such as methylmagnesium bromide and ethylmagnesium bromide; and organozinc compounds such as diethylzinc.

[1142] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 100°C, preferably -80°C to 50°C.

[1143] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 12 hours, preferably 10 minutes to 6 hours.

[1144] (Process H-2)

[1145] This step is a step of oxidizing the hydroxyl group of compound (XXVI) to a carbonyl group, and can be carried out according to the above-mentioned step D-10.

[1146] (Process H-3)

[1147] This step is a step for preparing compound (XXX) from compound (XXVI) and compound (XXVIII). The following describes a method in which the hydroxyl group of compound (XXVI) is converted to a leaving group (step H-3-1) and then condensed with compound (XXVIII) (step H-3-2), but the present invention is not limited thereto.

[1148] (Process H-3-1)

[1149] This step can be carried out according to the above-mentioned step D-9.

[1150] (Process H-3-2)

[1151] This step can be carried out according to the above-mentioned step A-1.

[1152] (Process H-4)

[1153] This step is a step for preparing compound (XXX) by a reductive amination reaction of compound (XXVII) and compound (XXVIII). The following describes a method using a hydrogenation reducing agent in a solvent (step H-4a) and a method using formic acid in the presence of an iridium catalyst (step H-4b), but the method is not limited thereto.

[1154] (Process H-4a)

[1155] This step can be carried out according to the above-mentioned step B-1.

[1156] (Process H-4b)

[1157] This step can be carried out using formic acid in a solvent in the presence of an iridium catalyst.

[1158] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1159] The iridium catalyst used is not particularly limited as long as it is a substance used in a known method, and suitable examples include chloro(pentamethylcyclopentadiene)(8-hydroxyquinoline)iridium(III) and chloro(pentamethylcyclopentadiene)(4-dimethylamino-8-hydroxyquinoline)iridium(III).

[1160] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -20°C to 150°C, preferably 0°C to 100°C.

[1161] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1162] (Process H-5)

[1163] This step is a step for preparing compound (XXXI) from compound (XXVI) and compound (XXIX), and can be carried out according to the above-mentioned step H-3.

[1164] (Process H-6)

[1165] This step is a step for producing Compound (XXXI) by a reductive amination reaction of Compound (XXVII) and Compound (XXIX), and can be carried out according to the above-mentioned Step H-4.

[1166] (Process H-7)

[1167] This step is a step of producing compound (IIIA1-1) from compound (XXX) using an appropriate base in a solvent.

[1168] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1169] The base used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction, and examples thereof include organic bases such as triethylamine; alkali metal alkanols such as potassium tert-butoxide and sodium tert-butoxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, etc.

[1170] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 150°C, preferably 0°C to 80°C.

[1171] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1172] (Process H-8)

[1173] This step is to remove the secondary amino group of compound (XXX) by protecting it with a protective group (Pro 5 ) protection to prepare compound (XXXI), according to Pro 5 The type of the method is appropriately selected, for example, from the well-known method described in PGWuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014, and the like, and is performed in accordance therewith. 5 In the case of p-methoxybenzyl group, a method of reductive amination (step H-8a) and a method using p-methoxybenzyl halide (step H-8b) are described, but the present invention is not limited thereto.

[1174] (Process H-8a)

[1175] This step is a step of reductive amination using compound (XXX) and p-anisaldehyde, and can be carried out according to the above-mentioned step B-1.

[1176] (Process H-8b)

[1177] This step is a step of protecting the secondary amino group of compound (XXX) using p-methoxybenzyl chloride, p-methoxybenzyl bromide or the like in a solvent in the presence of an appropriate base.

[1178] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the foregoing organic solvents in arbitrary ratios.

[1179] The base used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction, and examples thereof include organic bases such as triethylamine; alkali metal alkanols such as potassium tert-butoxide and sodium tert-butoxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; metal hydrides such as sodium hydride; alkali metal phosphates such as tripotassium phosphate, etc.

[1180] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 200°C, preferably 0°C to 150°C.

[1181] The reaction time varies depending on the starting compounds, reagents, etc., but is generally 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[1182] (Process H-9)

[1183] This step is a step for preparing compound (IIIA1-1) from compound (XXXI). It is a step of forming a 7-membered ring from compound (XXXI) using an appropriate base in a solvent (step H-9-1) and then removing the protective group (Pro 5 ) (Step H-9-2), thereby converting to Compound (IIIA1-1).

[1184] (Process H-9-1)

[1185] This step can be carried out according to the above-mentioned step H-7.

[1186] (Process H-9-2)

[1187] This step is to remove the protecting group (Pro 5 ) process can be carried out according to process E-3.

[1188] (I method)

[1189] This preparation method is a method for preparing the intermediate compound used in the above-mentioned methods A and C, the compound (III) wherein Z is a group represented by the above-mentioned formula A2. The method is described below for the compound (IIIA2-1) wherein the group W in the above-mentioned formula A2 is an oxygen atom, but is not limited thereto.

[1190] [Chemistry 64]

[1191]

[1192] (Where, L 5 and L 6 Each independently represents a leaving group (suitably a halogen atom or a pseudo-halogen atom group). Other symbols have the same meanings as above.

[1193] (Step I-1)

[1194] This step is a step of producing compound (XXXIII) by condensing compound (XXXII) with compound (XXVIII) in a solvent in the presence or absence of a base.

[1195] The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Suitable examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, and tert-butanol; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; a mixed solvent containing a plurality of the aforementioned organic solvents in any ratio; a mixed solvent containing the aforementioned organic solvents and water in any ratio, etc.

[1196] The base used is not particularly limited as long as it is a substance that can be used as a base in a conventional reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, and the like.

[1197] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -80°C to 100°C, preferably -20°C to 50°C.

[1198] The reaction time varies depending on the starting compounds, reagents, etc., and is generally 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[1199] (Step I-2)

[1200] This step is a step for preparing compound (IIIA2-1) from compound (XXXIII), and can be carried out according to the above-mentioned step H-7.

[1201] (J Method)

[1202] This preparation method is a method for preparing the intermediate compound used in Methods A and C, Compound (III) wherein Z is a group represented by Formula A3. The following describes a method for preparing Compound (IIIA3-1) wherein the group W in Formula A3 is an oxygen atom, but is not limited thereto.

[1203] [Chemistry 65]

[1204]

[1205] (Where, L 7 and L 8 Each independently represents a leaving group (suitably a halogen atom or a pseudo-halogen atom group). Other symbols have the same meanings as above.

[1206] (Process J-1)

[1207] This step is a step of producing compound (XXXV) by condensing compound (XXXIV) and compound (XXVIII), and can be carried out according to the above-mentioned step I-1.

[1208] (Process J-2)

[1209] This step is a step for preparing compound (IIIA3-1) from compound (XXXV), and can be carried out according to the above-mentioned step H-7.

[1210] Compound (1) or a pharmaceutically acceptable salt thereof obtained by the above-mentioned production method can be isolated and purified by conventional separation means such as recrystallization, distillation, chromatography, etc.

[1211] When the compound (1) of the present invention or a pharmaceutically acceptable salt thereof exists as optical isomers based on asymmetric carbon atoms, it can be separated into individual optical isomers by conventional optical resolution means (e.g., fractional crystallization, resolution using a chiral column). Furthermore, optical isomers can be synthesized using optically pure starting materials. Furthermore, optical isomers can be synthesized by stereoselectively carrying out each reaction using an asymmetric auxiliary group or an asymmetric catalyst.

[1212] (Drug (or pharmaceutical composition) of the present invention)

[1213] The medicament of the present invention is a medicament containing compound (1) or a pharmaceutically acceptable salt thereof as an active ingredient and is used for preventing and / or treating oxidative stress-related diseases.

[1214] The drug of the present invention may be a drug comprising compound (1) or a pharmaceutically acceptable salt thereof alone, or a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The drug of the present invention may be administered in a pharmaceutically effective amount to a subject (e.g., mammals such as humans, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys).

[1215] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, granulated sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethyl cellulose, talc, etc.), solubilizers (e.g., water for injection, physiological saline, Ringer's solution, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), and solubilizers. Suspension agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.), suspending agents (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and other surfactants; polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, etc.), hydrophilic polymers such as propyl cellulose; polysorbates, polyoxyethylene hardened castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose, etc.), buffers (e.g., phosphate, acetate, carbonate, citrate buffers, etc.), analgesics (e.g., benzyl alcohol, etc.), preservatives (e.g., parabens, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbate, etc.), dyes Coloring agents (for example, water-soluble edible tar pigments (for example, edible red No. 2 and No. 3, edible yellow No. 4 and No. 5, edible blue No. 1 and No. 2, etc.), water-insoluble lake pigments (for example, aluminum salts of the aforementioned water-soluble edible tar pigments), natural pigments (for example, β-carotene, chlorophyll, ferric oxide (bengala)), etc.), sweeteners (for example, sodium saccharin, dipotassium glycyrrhizate, stevia, etc.), flavoring agents (for example, anise oil, cinnamon oil, ethyl vanillin, orange oil, etc.), fragrances, etc.

[1216] The drug (pharmaceutical composition) of the present invention can be prepared into oral dosage forms such as tablets, pills, granules, granules, capsules, dry syrups and elixirs after mixing the above-mentioned ingredients according to known means; or injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drops, etc.), external preparations (e.g., transdermal absorption preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, liposome preparations, etc.) for non-oral administration. Tablets or pills can be coated with sugar coatings, or gastric or enteric coatings as needed. Preparations for non-oral administration can be sterilized by, for example, filtration based on a filter that retains bacteria, the combination of a bactericide, or irradiation with radiation. Furthermore, a composition obtained by dissolving or suspending a sterile solid composition in sterile water or a solvent for injection before use can also be used as a preparation for parenteral administration.

[1217] The content of the compound (1) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but is generally in the range of about 0.001 to 100% by weight, preferably in the range of about 0.01 to 50% by weight, and more preferably in the range of about 0.01 to 20% by weight, relative to the entire preparation.

[1218] The dosage and frequency of administration of the compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be appropriately determined according to various circumstances, such as the symptoms and the age or sex of the subject. The dosage is generally 0.001 mg / kg to 100 mg / kg per dose for adults when administered orally, and 0.0001 mg / kg to 10 mg / kg per dose for adults when administered intravenously. The frequency of administration is generally once to six times a day or once to seven days.

[1219] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof is effective for the prevention and / or treatment of oxidative stress-related diseases, specifically, for example, diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal insufficiency, chronic renal insufficiency, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis and renal tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis and cirrhosis; and bronchial Respiratory diseases selected from the group consisting of inflammation, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia and asthma; skin diseases selected from the group consisting of ultraviolet and radiation skin damage, radiation mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis and scleroderma; cardiovascular diseases selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis and pulmonary hypertension; diseases selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease and autism central nervous system diseases selected from Friedreich's ataxia and mitochondrial encephalomyopathy; mitochondrial diseases selected from multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, type 1 diabetes, ulcerative colitis and Crohn's disease; and allergic conjunctival diseases, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal injury, uveitis, Behcet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous choroidergic optic neuropathy, retinal vein occlusion, central serous choroidergic optic neuropathy, retinal detachment ... venous occlusion, central serous choroidergic optic neuropathy, retinal venous occlusion, central serous choroidergic optic neuropathy, retinal venous occlusion, central serous choroidergic optic neuropathy, retinal ven The invention is particularly effective in the prevention and / or treatment of eye diseases selected from the group consisting of retinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma and cataracts, and in particular, diseases associated with oxidative stress selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

[1220] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof may be used in combination with other drugs (concomitant drugs) as long as the efficacy thereof is not impaired. The concomitant drug is not particularly limited. For example, one or more known drugs previously used in the treatment of oxidative stress-related diseases selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma may be suitably used.

[1221] Other drugs (concomitant drugs) suitable for use in combination with the compound (1) of the present invention or a pharmaceutically acceptable salt thereof are not limited thereto, but examples thereof include ACE inhibitors (e.g., enalapril, etc.), angiotensin II receptor antagonists (e.g., olmesartan, etc.), beta-blockers (e.g., carvedilol, etc.), aldosterone antagonists (e.g., spironolactone, etc.), bronchodilators (e.g., anticholinergics, theophylline, etc.), steroids (e.g., prednisolone, etc.), prostacyclin preparations (e.g., beraprost, etc.), endothelin receptor antagonists (e.g., bosentan, etc.), phosphodiesterase 5 inhibitors (e.g., sildenafil, etc.), soluble guanylate cyclase (sGC) stimulators (e.g., vericipexole, etc.), levodopa, dopamine agonists (e.g., pramipexole, etc.), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone, etc.), monoamine oxidase B (MAO-B) inhibitors (e.g., selegiline, etc.), interferon β, copaxone, etc.

[1222] When using a combination of drugs, the time of administration is not limited. They can be administered to the subjects simultaneously or with a time difference. In the case of administration with a time difference, the drug of the present invention can be administered first and then the combination of drugs, or the combination of drugs can be administered first and then the drug of the present invention. The respective administration methods can be the same or different. In addition, the drug can be administered in the form of a single preparation (compound) containing the compound of the present invention (1) or a pharmaceutically acceptable salt thereof and the combination of drugs. As a pharmaceutically acceptable carrier that can be used for the preparation of the combination of drugs, the same carrier as that used in the aforementioned pharmaceutical composition of the present invention can be cited.

[1223] The dosage of the combined drug can be appropriately selected based on the dosage usually used clinically. In addition, the compound of the present invention or its pharmaceutically acceptable salt etc. and the combination ratio of the combined drug can be appropriately selected based on the subject (age, weight, general health status, sex, degree of symptom etc. of the subject), route of administration, kind of disease, kind of combined drug etc.

[1224] The mass ratio of compound (1) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[1225] Furthermore, the combination drugs that supplement and / or enhance the therapeutic effect of compound (1) or a pharmaceutically acceptable salt thereof include not only those discovered so far but also those discovered in the future based on the above-mentioned mechanism (i.e., the Nrf2 activation mechanism based on the inhibition of the protein-protein interaction between Keap1 and Nrf2).

[1226] The drug or pharmaceutical composition of the present invention can be provided in the form of a kit together with instructions for administration, etc. The drug contained in the kit is supplied in a container made of a material that effectively maintains the activity of the components of the drug or pharmaceutical composition for a long time, does not adsorb to the interior of the container, and does not deteriorate the components. For example, a sealed glass ampoule can contain a buffer sealed in the presence of a neutral and non-reactive gas such as nitrogen.

[1227] In addition, the kit may include instructions for use. The instructions for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM for the user.

[1228] Test Example 1: FP detection (in vitro)

[1229] The inhibitory activity of the test compound on the binding between Nrf2 and Keap1 was determined by fluorescence polarization. A solution containing 50mM Tris-HCl pH.8.0 (NACALAI, REF: 06938-15) and 5mM DTT (SIGMA-ALDRICH, REF: 646563-10X.5mL) was used as a buffer. 8μL of a buffer containing 40nM GST-fused human Keap1 (amino acid residues: 325-642) protein (Protein tech, REF: Ag0779) was taken to a black 384-well plate (final concentration 20nM), and 4μL of a test compound solution prepared with the buffer at each concentration was added. A portion of the wells containing the Keap1-free buffer was set up as a negative control. The wells without compound addition were used as positive controls. 40 nM FITC-labeled Nrf2 peptide (FITC-X-LQLDEETGEFLPIQ (X = ε-Acp), Peptide Research Institute Co., Ltd.) was added (final concentration 10 nM). The cells were incubated at room temperature for 2 hours, and the fluorescence polarization at an excitation wavelength of 485 nm and a fluorescence wavelength of 535 nm was measured using a plate reader SPECTRAMAX Paradigm (Molecular Devices). The fluorescence polarization of the negative control was taken as 100% inhibition, and the fluorescence polarization of the positive control was taken as 0% inhibition. The inhibition rate when the test compound was added was calculated using the following formula.

[1230] [Expression 1] Inhibition rate (%) = ((fluorescence polarization of negative control - fluorescence polarization when test compound is added) / (fluorescence polarization of positive control - fluorescence polarization of negative control)) × 100

[1231] The results of each test compound in this test are shown in the following Table 1 within the range of two concentrations (μM) at which the inhibition rate was 50% (A: Inhibition rate 50% concentration (IC 50)≤0.01, B: 0.01<50% inhibition concentration (IC 50 )≤0.03, C:0.03<50% inhibition concentration (IC 50 )≤0.1).

[1232] [Table 1]

[1233]

[1234] Test Example 2: NAD(P)H:quinone oxidoreductase-1 (NQO1) enzyme induction test (in vitro)

[1235] NQO1 detection was performed according to a previous report (Methods in Enzymology 2004; 382: 243-258). Hepa1c1c7 cells (mouse hepatocyte line, ATCC, cat. No. CRL-2026) were cultured in D-MEM medium containing 10% FBS and 1% penicillin / streptomycin (5% CO2, 37°C) and plated in 96-well plates (Corning, REF. 353072) at a density of 1 × 10 4 Cells / well were seeded. For partial background assays, wells containing only culture medium were prepared without cells. The next day, the test compound was added to a final concentration of 400 nM in DMSO (final DMSO concentration 0.004%) and incubated for approximately 48 hours. For partial basal activity assays, wells were prepared without compound addition.

[1236] Prepare cell lysis buffer (containing 0.8% digitonin and 2 mM EDTA), reaction solution (containing 25 mM tris-HCl, 0.07% albumin, 0.01% Tween-20, 2 U / mL glucose-6-phosphate dehydrogenase, 5 μM flavin adenine dinucleotide, 1 μM glucose-6-phosphate, 30 μM nicotinamide adenine dinucleotide phosphate, 0.03% 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT), and 50 μM menadione), and stop solution (containing 0.3 mM dicoumarol and 5 mM potassium dihydrogen phosphate, pH 7.4). After removing the culture medium, add 50 μL of the cell lysis buffer, incubate at 37°C for 10 minutes, and then shake at room temperature for 10 minutes. Add 200 μL of the reaction solution and let it stand at room temperature for 5 minutes. 50 μL of stop solution was added, and the absorbance at 610 nm was measured using SpectraMax PLUS384 (Molecular Devices) or POWERSCAN HT (DS Phytomedical). The results were analyzed using Excel, and the NQO1 activity when 400 nM of the test compound was added was calculated as a multiple of the basal activity when no compound was added.

[1237] [Number 2]

[1238] NQO1 activity fold when the test compound is added = (absorbance when the test compound is added - absorbance of the medium alone) / (absorbance when no compound is added - absorbance of the medium alone)

[1239] The results of each test compound in this test are shown in the following Table 2 (A: 5<NQO1 activity fold, B: 3<NQO1 activity fold≤5).

[1240] [Table 2]

[1241]

[1242] Based on the above results, it was confirmed that the compound (1) of the present invention or a pharmaceutically acceptable salt thereof has the effect of activating Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2.

[1243] Test Example 3: Plasma drug concentration measurement test after oral administration in rats

[1244] Male SD rats (7 weeks old, Japan Essershi) were forcibly administered with 10 mg / 2 mL / kg of the test compound suspended in a 0.5% methylcellulose solution. Blood was collected from the jugular vein using a heparinized syringe 0.5, 1, 2, 4, 6, and 24 hours after administration. After blood collection, an equal amount of acetonitrile was added to 20 μL of plasma obtained by centrifugation, and 200 μL of internal standard (IS) solution was added. After stirring, the supernatant was centrifuged and filtered through a full filter, and the recovered filtrate was used as a test sample. In addition, an equal amount of a test compound solution prepared with acetonitrile was added to blank plasma, and the sample treated in the same manner as above was used as a test line sample. The prepared sample was measured using LC / MS / MS, and the area under the concentration-time curve (AUC) in the blood was calculated based on the plasma compound concentration.

[1245] The test results are shown in Table 3 below.

[1246] [Table 3]

[1247] Example Maximum plasma concentration (μM) AUC0-24 (μM*time) Example 4 0.029 0.050 Example 5 0.006 0.035 Example 7 0.009 0.030 Example 8 0.005 0.023

[1248] Among the example compounds, it was confirmed that the four compounds described in Table 3 above have particularly excellent kinetics without systemic exposure and exhibit excellent pharmacokinetics as a drug for local administration.

[1249] Example

[1250] The present invention is described in detail with reference to the following examples. These examples are merely exemplary and do not limit the present invention. The present invention may be varied without departing from the scope of the present invention.

[1251] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. % refers to mol / mol when it is the yield, and refers to volume % when it is the solvent used for chromatography, and refers to weight % otherwise.

[1252] Nuclear magnetic resonance spectroscopy (hereinafter 1 In H-NMR, resonance frequency 400 MHz or 500 MHz, tetramethylsilane was used as a standard substance, or the chemical shift value of the deuterated solvent used was used as a reference value, and the chemical shift value was recorded as δ value (ppm).

[1253] Other abbreviations used herein have the following meanings.

[1254] s: singlet

[1255] d: doublet

[1256] dd: doublet of doublets

[1257] t:triplet

[1258] q: quartet

[1259] m: multiplet (multiplet)

[1260] br: broad

[1261] J: coupling constant

[1262] Hz:Hertz

[1263] CDCl3: deuterated chloroform

[1264] DMSO-d6: deuterated dimethyl sulfoxide

[1265] CD3OD: deuterated methanol

[1266] XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl

[1267] 1 H-NMR: Proton Nuclear Magnetic Resonance

[1268] HPLC: High-speed liquid chromatography

[1269] APCI: Atmospheric Pressure Chemical Ionization

[1270] ESI: electrospray ionization

[1271] Unless otherwise specified, the reagents, solvents, and apparatus used in the following examples and test examples are commercially available. Furthermore, raw material compounds, unless otherwise specified, can be obtained by using known compounds or commercially available sources, or synthesized and identified using methods known to the public or in accordance with such methods.

[1272] (Example 1)

[1273] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1274] (1a)

[1275] (2R)-1-Aminobutan-2-ol

[1276] To a solution of (2R)-2-ethyloxirane (25 mL) in ethanol (100 mL) was added 28% aqueous ammonia solution (100 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and toluene was added for azeotropic distillation. 21.6 g of a mixture containing the title compound was obtained as an oil.

[1277] (1b)

[1278] 2,5-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[1279] To a mixture of (2R)-1-aminobutane-2-ol (5.10 g), sodium bicarbonate (2.00 g), and tetrahydrofuran (71 mL) of Example 1 (1a) was added water (13 mL), and the mixture was stirred at room temperature for 5 minutes. Subsequently, 2,5-dichloropyridine-3-sulfonyl chloride (3.5 g) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] to obtain 4.38 g of the title compound as an oily substance (yield: 100%).

[1280] (1c)

[1281] (4R)-8-Chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[1282] 2,5-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide (4.38 g) and potassium tert-butoxide (4.93 g) from Example 1(1b) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, poured into water (100 mL), and 1M hydrochloric acid (1.35 mL) was added and stirred, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to obtain 3.18 g of the title compound as a solid (yield: 83%).

[1283] (1d)

[1284] 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid

[1285] Diisopropylamine (86.7 g) was dissolved in tetrahydrofuran (800 mL), and n-butyllithium (1.6 M n-hexane solution) (500 mL) was added dropwise at -78°C over 25 minutes, followed by stirring for 30 minutes. A solution of 4-bromo-1-fluoro-2-methylbenzene (108 g) in tetrahydrofuran (300 mL) was then added dropwise over 35 minutes, followed by stirring at -78°C for 30 minutes. N,N-dimethylformamide (53.3 mL) was added to the reaction mixture at -78°C, stirred for 10 minutes, and then stirred for 1 hour while warming to room temperature. 2M hydrochloric acid (800 mL) 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 that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (830 mL), potassium carbonate (86.5 g) and ethyl mercaptoacetate (54.7 mL) were added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (820 mL), 5M aqueous sodium hydroxide solution (209 mL) was added, and the mixture was stirred at room temperature for 1 hour. 6M hydrochloric acid (228 mL) was added to the reaction mixture at 0°C, and the mixture was stirred at 0°C for 30 minutes. The solid was filtered and washed with water. The obtained solid was dissolved in a mixed solvent of ethyl acetate (1 L) and tetrahydrofuran (1 L), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. In addition, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residues obtained above were combined, n-hexane was added, and the solid was filtered to obtain 120.0 g of the title compound as a solid (yield: 78%).

[1286] (1e)

[1287] 5-Bromo-7-methyl-1-benzothiophene

[1288] 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid (105 g) from Example 1 (1d) was dissolved in 1-methyl-2-pyrrolidone (390 mL), and 1,8-diazabicyclo[5.4.0]-7-undecene (289 mL) was added, followed by stirring at 190°C for 20.5 hours. 3M hydrochloric acid (720 mL) was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5 (v / v)] to obtain 49.8 g of the title compound as an oil (yield: 57%).

[1289] (1f)

[1290] (5-Bromo-1-benzothiophen-7-yl)methyl acetate

[1291] 5-Bromo-7-methyl-1-benzothiophene (114.2 g) of Example 1 (1e) was dissolved in carbon tetrachloride (1.0 L), N-bromosuccinimide (98.5 g) and 2,2'-azobisisobutyronitrile (8.26 g) were added, and the mixture was heated under reflux for 12 hours. The reaction mixture was returned to room temperature and the insoluble matter was separated by filtration. The filtrate was washed with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (535 mL), potassium acetate (247 g) was added, and the mixture was stirred at room temperature for 1 hour. 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, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 - 90 / 10 (V / V)] to obtain 94.4 g (yield: 66%) of the title compound as a solid.

[1292] (1g)

[1293] (5-Bromo-1-benzothiophen-7-yl)methanol

[1294] (5-Bromo-1-benzothiophen-7-yl)methyl acetate (50.2 g) of Example 1 (1f) was dissolved in a mixed solvent of methanol (290 mL) and tetrahydrofuran (290 mL), and a 2M aqueous sodium hydroxide solution (264 mL) was added, followed by stirring at room temperature for 1 hour. 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 sodium sulfate, and the solvent was distilled off under reduced pressure. n-hexane was added to the resulting residue, and the mixture was sonicated. The solid was filtered off to obtain 39.6 g of the title compound as a solid (yield: 92%).

[1295] (1h)

[1296] [5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol

[1297] (5-Bromo-1-benzothiophen-7-yl)methanol (2.00 g) from Example 1 (1 g) was dissolved in 1,4-dioxane (25 mL), and bis(pinacolato)diboron (2.51 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (672 mg), and potassium acetate (2.42 g) were added. The mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30 (V / V)] to obtain 2.75 g of the title compound as an oil (yield: quantitative).

[1298] (1i)

[1299] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionic acid ethyl ester

[1300] [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (500 mg) from Example 1 (1h) was dissolved in a mixed solvent of 1,4-dioxane (11.2 mL) and water (5.6 mL). Triethylamine (0.48 mL) and ethyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (International Publication No. 2015 / 092713) (423 mg) were added, and the mixture was stirred at 90°C for 5 minutes. Chloro(1,5-cyclooctadiene)rhodium(I) dimer (42 mg) was then added, and the mixture was stirred at 90°C for 15 minutes. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20-30 / 70 (V / V)] to obtain 276 mg of the title compound as a solid (yield: 39%).

[1301] (1j)

[1302] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid ethyl ester

[1303] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (127 mg) from Example 1(1i) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (98 mg) from Example 1(1c) were dissolved in tetrahydrofuran (1 mL). Tri-n-butylphosphine (0.12 mL) and 1,1'-(azodicarbonyl)dipiperidine (117 mg) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60 (V / V)]. The obtained residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 - 50 / 50 (V / V)] to obtain 155 mg of the title compound as a solid (yield: 76%).

[1304] (1k)

[1305] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1306] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (155 mg) of Example 1(1j) was dissolved in a mixed solvent of tetrahydrofuran (2.1 mL) and methanol (0.71 mL), 1 M aqueous lithium hydroxide solution (0.71 mL) was added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride solution 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 sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: chloroform / methanol = 100 / 0-90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the obtained residue, followed by sonication, and the solid was collected by filtration to obtain 75.3 mg of the title compound as a solid (yield: 51%).

[1307] (Example 2)

[1308] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoic acid

[1309] (2a)

[1310] 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionic acid ethyl ester

[1311] Using [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (300 mg) and (2E)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (International Publication No. 2015 / 092713) (275 mg) from Example 1 (1h), the title compound (167 mg, yield: 39%) was obtained as a solid using the same method as in Example 1 (1i).

[1312] (2b)

[1313] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1314] Using ethyl 3-(4-chloro-1-methyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propanoate (100 mg) from Example 2 (2a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (76 mg) from Example 1 (1c), the same method as in Example 1 (1j) was used to obtain 141 mg of the title compound in the form of a solid (yield: 87%).

[1315] (2c)

[1316] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoic acid

[1317] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoate (141 mg) from Example 2(2b) was dissolved in a mixed solvent of tetrahydrofuran (1.8 mL) and methanol (0.63 mL). 1M aqueous lithium hydroxide solution (0.63 mL) was added, and the mixture was stirred at 40°C for 1 hour. Saturated aqueous ammonium chloride solution 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 sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: chloroform / methanol = 100 / 0-90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the resulting residue, followed by sonication. The solid was collected by filtration to obtain 91.3 mg of the title compound as a solid (yield: 68%).

[1318] (Example 3)

[1319] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1320] (3a)

[1321] 1-Oxo-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester

[1322] 4-Bromo-2,3-dihydro-1H-inden-1-one (31.7 g) was dissolved in N,N-dimethylformamide (750 mL), and lithium formate monohydrate (52.5 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.34 g), tris(dibenzylideneacetone)dipalladium(0) (6.87 g), lithium chloride (38.2 g), N,N-diisopropylethylamine (103 mL), and acetic anhydride (56.7 mL) were added. The mixture was stirred at 80°C for 17 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature, 1M hydrochloric acid and ethyl acetate were added, and the mixture was filtered through Celite to remove insoluble matter. The filtrate was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (40.4 g) was dissolved in N,N-dimethylformamide (450 mL), potassium carbonate (31.1 g) and iodomethane (11.2 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. 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 that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10-65 / 35 (V / V), chloroform] to obtain 24.9 g of the title compound as a solid (yield: 87%).

[1323] (3b)

[1324] 2,3-Dihydro-1H-indene-4-carboxylic acid methyl ester

[1325] After dissolving 1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (21.4 g) of Example 3 (3a) in methanol (330 mL), sodium borohydride (8.51 g) was added portionwise at 0°C and stirred at room temperature for 20 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in trifluoroacetic acid (200 mL), triethylsilane (30 mL) was added, and stirred at room temperature for 10 minutes. Triethylsilane (30 mL) was then added and stirred at room temperature for 70 minutes. A suspension of sodium bicarbonate (200 g) in water (1 L) was added to the reaction mixture, and saturated sodium bicarbonate water was further added to make it alkaline, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 - 90 / 10 (V / V)] to obtain 10.0 g (yield: 53%) of the title compound as an oily substance.

[1326] (3c)

[1327] (6-Bromo-2,3-dihydro-1H-inden-4-yl)methanol

[1328] 2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (10.0 g) of Example 3 (3b) was dissolved in methanesulfonic acid (100 mL), N-bromosuccinimide (10.6 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a suspension of sodium bicarbonate (200 g) in water (1 L) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (210 mL), and lithium aluminum hydride (2.15 g) was added portionwise at 0°C over 7 minutes, and stirred at 0°C for 30 minutes. Water (2.2 mL), 5M sodium hydroxide aqueous solution (2.2 mL), and water (6.6 mL) were added to the reaction mixture, stirred at room temperature for 25 minutes, and the precipitate was separated by filtration. The filtrate was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 - 60 / 40 (V / V)] to obtain 8.13 g (yield: 63%) of the title compound as an oily substance.

[1329] (3d)

[1330] [6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl]methanol

[1331] Using (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol (8.13 g) from Example 3 (3c), the title compound (7.85 g, yield: 80%) was obtained as a solid in the same manner as in Example 1 (1h).

[1332] (3e)

[1333] 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionic acid ethyl ester

[1334] Ethyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (International Publication No. 2015 / 092713) (3.979 g), [6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl]methanol (17.7 g) from Example 3(3d), triethylamine (11.4 mL), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (1.58 g) were suspended in a mixed solvent of 1,4-dioxane (52 mL) and water (13.6 mL). The mixture was purged with nitrogen and heated with stirring at 80°C for 3 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate solution were added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100 (v / v)] to obtain 4.651 g of the title compound as a solid (yield: 73%).

[1335] (3f)

[1336] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid ethyl ester

[1337] 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionic acid ethyl ester (2.50 g) from Example 3 (3e) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (1.70 g) from Example 1 (1c) were dissolved in toluene (32 mL). Di-tert-butyl azodicarboxylate (4.40 g) was added under a nitrogen atmosphere, followed by triphenylphosphine (5.00 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 - 50 / 50 (V / V)] to obtain 4.16 g of the title compound as an oily substance (yield: quantitative).

[1338] (3g)

[1339] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1340] To a mixture of ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (4.16 g) of Example 3(3f), ethanol (30 mL), and tetrahydrofuran (30 mL) was added 1 M aqueous sodium hydroxide solution (32.6 mL), and stirred at room temperature for 12 hours. 1 M hydrochloric acid (32.6 mL) was added to the reaction solution, stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 95 / 5 (v / v / v)]. Ethyl acetate and n-hexane were added to the eluted compound, and sonication was performed. The solid was collected by filtration and dried in vacuo to obtain 2.00 g of the title compound (yield: 50%).

[1341] (Example 4)

[1342] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1343] (4a)

[1344] Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1345] (4b)

[1346] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1347] The ethyl 3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (59 g) of Example 3 (3e) was subjected to chiral HPLC [column: CHIRALPAKIG (50 mm I.D. × 250 mm), mobile phase: acetonitrile, temperature: 40°C], thereby obtaining 27.5 g of ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate as the first peak (yield: 47%).

[1348] Similarly, 27.3 g of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate was obtained as the second peak (yield: 46%).

[1349] Analytical HPLC conditions [column: CHIRALPAK IG (4.6 mm ID × 250 mm), mobile phase: acetonitrile, flow rate: 1.0 mL / min, temperature: 40°C, wavelength: 260 nm]; retention time: 4.187 min (1st peak), 5.087 min (2nd peak)

[1350] (4c)

[1351] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1352] To a mixture of ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (61.7 mg) of Example 4(4a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (49.4 mg) of Example 1(1c) were added di-tert-butyl azodicarboxylate (50.5 mg), tetrahydrofuran (2.24 mL), and tri-n-butylphosphine (0.0664 mL) in this order under a nitrogen atmosphere, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 - 50 / 50 (V / V)] to obtain 96.5 mg (yield: 96%) of the title compound as an oily substance.

[1353] (4d)

[1354] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1355] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (720 mg) of Example 4(4c) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), 1 M aqueous sodium hydroxide solution (2.2 mL) was added, and the mixture was stirred at room temperature for 24 hours. 1 M hydrochloric acid was added to the reaction solution to adjust the pH to 5-6, and the reaction solvent was distilled off under reduced pressure. After adding ethanol and performing azeotropic distillation, the resulting residue was suspended in chloroform, anhydrous magnesium sulfate was added, and the mixture was stirred for 10 minutes. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: chloroform / methanol = 90 / 1-20 / 1 (V / V)]. Ethyl acetate and n-hexane were added to solidify, thereby obtaining 446 mg of the title compound as a solid (yield: 64%).

[1356] (Example 5)

[1357] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1358] (5a)

[1359] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1360] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (3.15 g) from Example 4(4b) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (2.31 g) from Example 1(1c) were dissolved in toluene (50 mL). 1,1'-(Azodicarbonyl)dipiperidine (3.03 g) was added under a nitrogen atmosphere, followed by tri-n-butylphosphine (2.99 mL), and the mixture was stirred at room temperature for 3 hours. Tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 2 / 1 to 4 / 6 (v / v)]. The fraction containing impurities was further purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 6 / 4 to 4 / 6 (v / v)]. Further purification was repeated twice using NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 2 / 1 to 1 / 1 (v / v)] to obtain 3.78 g of the title compound as a solid (yield: 74%).

[1361] (5b)

[1362] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1363] To a mixture of ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (3.75 g) of Example 5(5a), ethanol (30 mL), and tetrahydrofuran (60 mL) was added 1 M aqueous sodium hydroxide solution (30 mL), and stirred at 40°C for 3 hours. The reaction solution was cooled to room temperature, 1 M hydrochloric acid (33 mL) was added and stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was dissolved in ethanol (100 mL) and recrystallized. The precipitated solid was collected by filtration, washed with a small amount of ethanol, and then dried at 50°C under reduced pressure to obtain 2.20 g (yield: 61%) of the title compound as a solid.

[1364] (Example 6)

[1365] 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1366] (6a)

[1367] 4-Bromo-3-fluoro-N 1 -Methylbenzene-1,2-diamine

[1368] 3-Fluoro-N-methyl-2-nitroaniline (International Publication No. 2011 / 021676) (5.27g) was dissolved in N,N-dimethylformamide (60mL), and a solution of N-bromosuccinimide (4.88g) in N,N-dimethylformamide (30mL) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. 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, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. N-hexane was added to the resulting residue, and the solid was filtered off. The resulting solid was suspended in ethanol (50mL), tin (II) chloride dihydrate (10.6g) was added, and the mixture was heated to reflux for 1 hour. After returning to room temperature, the reaction mixture was added to a suspension obtained by adding sodium bicarbonate (15g) to water (100mL) and ethyl acetate (100mL), and stirred at room temperature for 0.5 hours. The mixture was filtered through celite to remove insoluble matter, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 80 / 20 (v / v)] to obtain 2.95 g of the title compound as a solid (yield: 89%).

[1369] (6b)

[1370] 5-Bromo-4-fluoro-1-methyl-1H-benzotriazole

[1371] The 4-bromo-3-fluoro-N 1-Methylbenzene-1,2-diamine (2.95 g) was dissolved in acetonitrile (27 mL), and tert-butyl nitrite (2.4 mL) and 42% tetrafluoroboric acid (4.3 mL) were added dropwise at 0°C, and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate 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 sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to obtain 620 mg of the title compound as a solid (yield: 17%).

[1372] (6c)

[1373] (2E)-3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester

[1374] 5-Bromo-4-fluoro-1-methyl-1H-benzotriazole (620 mg) from Example 6 (6b) was dissolved in N,N-dimethylformamide (8.0 mL), and ethyl acrylate (2.46 mL), N,N-diisopropylethylamine (2.0 mL), tris(dibenzylideneacetone)dipalladium(0) (207 mg), and tri(o-tolyl)phosphine (275 mg) were added. The mixture was stirred at 100°C for 13.5 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15 to 60 / 40 (V / V)] to obtain 370 mg of the title compound as a solid (yield: 43%).

[1375] (6d)

[1376] 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoic acid ethyl ester

[1377] Using [6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-4-yl]methanol (481 mg) from Example 3 (3d) and (2E)-3-(4-fluoro-1-methyl-1H-benzotriazole-5-yl)prop-2-enoic acid ethyl ester (370 mg) from Example 6 (6c), the same method as in Example 95 (95a) was used to obtain 390 mg of the title compound in the form of a solid (yield: 84%).

[1378] (6e)

[1379] 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1380] Using ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (190 mg) of Example 6 (6d) and (4R)-4-methyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (International Publication No. 2015 / 092713) (122 mg), the same method as in Example 2 (2b) was used to obtain 260 mg of the title compound as a solid (yield: 92%).

[1381] (6f)

[1382] 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1383] Using ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (260 mg) of Example 6 (6e), the same method as in Example 2 (2c) was used to obtain 186 mg of the title compound in the form of a solid (yield: 68%).

[1384] (Example 7)

[1385] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1386] (7a)

[1387] Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[1388] (7b)

[1389] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoic acid ethyl ester

[1390] The ethyl 3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propanoate (120 g) of Example 1(1i) was subjected to chiral SFC [column: CHIRALPAK AD (50 mm ID×250 mm), mobile phase: carbon dioxide / ethanol = 60 / 40 (V / V)] to obtain 51.0 g of ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propanoate as the first peak (yield: 43%).

[1391] Similarly, 52.5 g of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate was obtained as the second peak (yield: 44%).

[1392] Analytical SFC conditions [column: CHIRALPAK AD-3 (4.6 mm ID × 50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3.0 mL / min, temperature: 35°C, wavelength: 220 nm]; retention time: 2.078 min (first peak), 2.455 min (second peak)

[1393] (7c)

[1394] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1395] Using (3S)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propionic acid ethyl ester (0.20 g) of Example 7 (7a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (0.141 g) of Example 1 (1c), 0.34 g (yield: quantitative) of the title compound was obtained as an oily substance using the same method as in Example 3 (3f).

[1396] (7d)

[1397] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1398] Using (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (0.35 g) of Example 7 (7c), the same method as Example 3 (3 g) was used to obtain 0.24 g of the title compound (yield: 72%).

[1399] (Example 8)

[1400] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1401] (8a)

[1402] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1403] Using (3R)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propionic acid ethyl ester (0.20 g) of Example 7 (7b) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (0.141 g) of Example 1 (1c), 0.32 g (yield: quantitative) of the title compound was obtained as an oily substance using the same method as in Example 3 (3f).

[1404] (8b)

[1405] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1406] Using (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (0.34 g) of Example 8 (8a), the same method as in Example 3 (3 g) was used to obtain 0.15 g of the title compound (yield: 46%).

[1407] (Example 9)

[1408] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1409] (9a)

[1410] 2,6-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[1411] Using (2R)-1-aminobutan-2-ol (2.0 g) and 2,6-dichloropyridine-3-sulfonyl chloride (1.4 g) from Example 1(1a), 1.4 g (yield: 82%) of the title compound was obtained as an oil by the same method as in Example 1(1b).

[1412] (9b)

[1413] (4R)-7-Chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[1414] Using 2,6-dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide (1.25 g) of Example 9(9a), the title compound (1.04 g, yield: 95%) was obtained as a solid in the same manner as in Example 1(1c).

[1415] (9c)

[1416] 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1417] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (200 mg) from Example 3(3e) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (133 mg) from Example 9(9b), the same method as in Example 3(3f) was used to obtain 172 mg of the title compound in the form of a solid (yield: 53%).

[1418] (9d)

[1419] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1420] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (80 mg) of Example 9(9c), the same method as in Example 3(3 g) was used to obtain 14 mg (yield: 18%) of the title compound.

[1421] (Example 10)

[1422] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1423] (10a)

[1424] 2-Chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide

[1425] Using (2R)-1-aminobutan-2-ol (1.41 g) and 2-chloro-5-methylpyridine-3-sulfonyl chloride (0.90 g) from Example 1(1a), 1.1 g (yield: quantitative) of the title compound was obtained as an oil by the same method as in Example 1(1b).

[1426] (10b)

[1427] (4R)-4-Ethyl-8-methyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[1428] Using 2-chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide (1.2 g) of Example 10(10a), the title compound (0.68 g, yield: 65%) was obtained as a solid in the same manner as in Example 1(1c).

[1429] (10c)

[1430] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1431] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (100 mg) from Example 3(3e) and (4R)-4-ethyl-8-methyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (120 mg) from Example 10(10b), the same method as in Example 3(3f) was used to obtain 165 mg of the title compound in the form of a solid (yield: 53%).

[1432] (10d)

[1433] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1434] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (165 mg) of Example 10 (10c), the same method as in Example 3 (3 g) was used to obtain 90 mg of the title compound in the form of a solid (yield: 57%).

[1435] (Example 11)

[1436] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1437] (11a)

[1438] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1439] Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (79 mg) from Example 9(9c), a 50% tetrahydrofuran solution of trimethylboroxine (0.087 mL), palladium acetate (2.8 mg), cesium carbonate (120 mg), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.1 mg) were dissolved in toluene (3.0 mL) and heated with stirring at 100°C for 4 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100 (v / v)] to obtain 60 mg of the title compound as an oil (yield: 78%).

[1440] (11b)

[1441] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1442] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (60 mg) of Example 11 (11a), the same method as in Example 3 (3 g) was used to obtain 35 mg of the title compound in the form of a solid (yield: 62%).

[1443] (Example 12)

[1444] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1445] (12a)

[1446] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1447] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (140 mg) and (4R)-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (International Publication No. 2015 / 092713) (80 mg) of Example 3(3e), the title compound (140 mg, yield: 65%) was obtained as a solid using the same method as Example 3(3f).

[1448] (12b)

[1449] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1450] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (140 mg) of Example 12 (12a), the same method as in Example 3 (3 g) was used to obtain 120 mg of the title compound as a solid (yield: 90%).

[1451] (Example 13)

[1452] 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1453] (13a)

[1454] 5-Chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[1455] Using (2R)-1-aminobutan-2-ol (0.72 g) of Example 1(1a) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.50 g), the title compound (0.70 g, quantitative yield) was obtained as an oil by the same method as Example 1(1b).

[1456] (13b)

[1457] (4R)-8-Chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[1458] Using 5-chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (0.35 g) from Example 13(13a), the title compound (0.22 g, yield: 67%) was obtained as a solid in the same manner as in Example 1(1c).

[1459] (13c)

[1460] 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1461] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (100 mg) from Example 3(3e) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (80 mg) from Example 13(13b), the same method as in Example 3(3f) was used to obtain 140 mg of the title compound in the form of a solid (yield: 84%).

[1462] (13d)

[1463] 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1464] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (140 mg) of Example 13 (13c), the same method as in Example 3 (3 g) was used to obtain 90 mg of the title compound in the form of a solid (yield: 67%).

[1465] (Example 14)

[1466] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1467] (14a)

[1468] 5-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[1469] Using (2R)-1-aminobutan-2-ol (1.0 g) of Example 1(1a) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.56 g), the title compound (1.3 g, yield: quantitative) was obtained as an oil by the same method as Example 1(1b).

[1470] (14b)

[1471] (4R)-8-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[1472] Using 5-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.3 g) of Example 14(14a), 1.0 g (yield: 83%) of the title compound was obtained as a solid in the same manner as in Example 1(1c).

[1473] (14c)

[1474] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1475] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (140 mg) from Example 3 (3e) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (95 mg) from Example 14 (14b), the same method as in Example 3 (3f) was used to obtain 160 mg of the title compound in the form of a solid (yield: 71%).

[1476] (14d)

[1477] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1478] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (160 mg) of Example 14 (14c), the same method as in Example 3 (3 g) was used to obtain 140 mg of the title compound in the form of a solid (yield: 92%).

[1479] (Example 15)

[1480] 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1481] (15a)

[1482] 4-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[1483] Using (2R)-1-aminobutan-2-ol (1.55 g) and 4-chloro-2-fluorobenzenesulfonyl chloride (1.0 g) from Example 1(1a), 1.2 g (yield: 98%) of the title compound was obtained as an oil by the same method as in Example 1(1b).

[1484] (15b)

[1485] (4R)-7-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[1486] Using 4-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.2 g) of Example 15(15a), the title compound (0.92 g, yield: 83%) was obtained as a solid in the same manner as in Example 1(1c).

[1487] (15c)

[1488] 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1489] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (100 mg) from Example 3 (3e) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (75 mg) from Example 15 (15b), the same method as in Example 3 (3f) was used to obtain 160 mg of the title compound in the form of a solid (yield: 99%).

[1490] (15d)

[1491] 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1492] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (160 mg) of Example 15 (15c), the same method as in Example 3 (3 g) was used to obtain 110 mg of the title compound in the form of a solid (yield: 72%).

[1493] (Example 16)

[1494] 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1495] (16a)

[1496] 3-Chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[1497] Using (2R)-1-aminobutan-2-ol (1.55 g) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.0 g) from Example 1(1a), 1.2 g (yield: 98%) of the title compound was obtained as an oil by the same method as in Example 1(1b).

[1498] (16b)

[1499] (4R)-6-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[1500] Using 3-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.2 g) of Example 16(16a), the title compound (0.90 g, yield: 81%) was obtained as a solid in the same manner as in Example 1(1c).

[1501] (16c)

[1502] 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1503] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (160 mg) from Example 3 (3e) and (4R)-6-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (117 mg) from Example 16 (16b), the same method as in Example 3 (3f) was used to obtain 250 mg of the title compound in the form of a solid (yield: 96%).

[1504] (16d)

[1505] 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1506] Using ethyl 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (250 mg) of Example 16 (16c), the same method as in Example 3 (3 g) was used to obtain 160 mg of the title compound in the form of a solid (yield: 67%).

[1507] (Example 17)

[1508] 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1509] (17a)

[1510] 2-Chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[1511] Using (2R)-1-aminobutan-2-ol (1.1 g) of Example 1(1a) and 2-chloro-6-fluorobenzenesulfonyl chloride (0.70 g), the title compound (0.90 g, yield: quantitative) was obtained as an oil by the same method as Example 1(1b).

[1512] (17b)

[1513] (4R)-9-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[1514] Using 2-chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (0.90 g) from Example 17(17a), the title compound (598 mg, yield: 72%) was obtained as a solid in the same manner as in Example 1(1c).

[1515] (17c)

[1516] 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1517] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (150 mg) from Example 3 (3e) and (4R)-9-chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (110 mg) from Example 17 (17b), the same method as in Example 3 (3f) was used to obtain 100 mg of the title compound in the form of a solid (yield: 41%).

[1518] (17d)

[1519] 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1520] Using ethyl 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (100 mg) of Example 17 (17c), the same method as in Example 3 (3 g) was used to obtain 65 mg of the title compound as a solid (yield: 68%).

[1521] (Example 18)

[1522] 3-(7-{[(4R)-8-chloro-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1523] 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid (400 mg) from Example 13 (13d) was dissolved in ethanol (25 mL), and a 1 M aqueous sodium hydroxide solution (3.2 mL) was added, followed by stirring at room temperature for 48 hours. 1 M hydrochloric acid (3.2 mL) was added to the reaction solution, which was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60 (V / V)] to obtain 250 mg of the title compound as a solid (yield: 60%).

[1524] (Example 19)

[1525] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[1526] (19a)

[1527] 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propionic acid ethyl ester

[1528] Using ethyl 3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophene-5-yl]propanoate (130 mg) of Example 1(1i) and (4R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (65 mg) of Example 9(9b), the same method as in Example 3(3f) was used to obtain 150 mg of the title compound in the form of a solid (yield: 93%).

[1529] (19b)

[1530] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[1531] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (150 mg) of Example 19 (19a), the same method as in Example 3 (3 g) was used to obtain 85 mg of the title compound in the form of a solid (yield: 58%).

[1532] (Example 20)

[1533] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1534] (20a)

[1535] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tri(propan-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propanoic acid ethyl ester

[1536] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propionic acid ethyl ester (520 mg) of Example 4(4b) was dissolved in N,N-dimethylformamide (5 mL), and imidazole (110 mg) and triisopropylsilyl chloride (380 mg) were added, followed by stirring at room temperature for 3 hours. Water (2.5 mL) was added to the reaction solution, stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to obtain 720 mg of the title compound as an oily substance (yield: 99%).

[1537] (20b)

[1538] tert-Butyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tri(propan-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1539] (3R)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-({[tri(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propionic acid ethyl ester (720 mg) of Example 20 (20a) was dissolved in tetrahydrofuran (3 mL), and ethanol (3 mL) and 1M sodium hydroxide aqueous solution (0.30 mL) were added, and the mixture was stirred at room temperature for 12 hours. 1M hydrochloric acid (0.30 mL) was added to the reaction mixture and stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in tert-butyl alcohol (5 mL), and di-tert-butyl dicarbonate (600 mg) and 4-dimethylaminopyridine (48 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40 (v / v)] to obtain 540 mg of the title compound as an oil (yield: 71%).

[1540] (20c)

[1541] Tert-butyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1542] Tert-butyl (3R)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-({[tri(propane-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propanoate (540 mg) of Example 20 (20b) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (2.8 mL) was added and stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30-20 / 80 (V / V)] to obtain 283 mg of the title compound as a solid (yield: 72%).

[1543] (20d)

[1544] tert-Butyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[1545] Using tert-butyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (283 mg) from Example 20 (20c) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (73 mg) from Example 13 (13b), the same method as in Example 3 (3f) was used to obtain 140 mg of the title compound in the form of a solid (yield: 79%).

[1546] (20e)

[1547] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1548] Example 20 (20d) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid tert-butyl ester (140 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. Sodium bicarbonate water was added to the reaction mixture, stirred, and then extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 - 20 / 80 (V / V)] to obtain 73 mg of the title compound as a solid (yield: 57%).

[1549] (Example 21)

[1550] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1551] (21a)

[1552] tert-Butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tri(propan-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1553] Using (3S)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoic acid ethyl ester (520 mg) of Example 4(4a), the same method as in Examples 20(20a) and 20(20b) was used to obtain 754 mg of the title compound as an oil (yield: 98%).

[1554] (21b)

[1555] Tert-butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1556] Using tert-butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-({[tri(propan-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]propanoate (754 mg) from Example 21 (21a), the same method as in Example 20 (20c) was used to obtain 484 mg of the title compound in the form of a solid (yield: 88%).

[1557] (21c)

[1558] tert-Butyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[1559] Using tert-butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (110 mg) from Example 21 (21b) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (73 mg) from Example 13 (13b), the same method as in Example 3 (3f) was used to obtain 145 mg of the title compound in the form of a solid (yield: 81%).

[1560] (21d)

[1561] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1562] Using tert-butyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (145 mg) from Example 21 (21c), the same method as in Example 20 (20e) was used to obtain 77 mg of the title compound as a solid (yield: 58%).

[1563] (Example 22)

[1564] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1565] (22a)

[1566] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1567] Using (3R)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionic acid ethyl ester (200 mg) of Example 7 (7b) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (136 mg) of Example 13 (13b), the same method as in Example 3 (3f) was used to obtain 350 mg of the title compound in the form of a solid (yield: quantitative).

[1568] (22b)

[1569] (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1570] To a mixture of ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (350 mg) of Example 22 (22a), tert-butanol (3.0 mL), and tetrahydrofuran (2.0 mL) was added 1 M aqueous sodium hydroxide solution (1.5 mL), and stirred at room temperature for 12 hours. 1 M hydrochloric acid (1.5 mL) was added to the reaction solution, stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 95 / 5 (v / v / v)]. Ethyl acetate and n-hexane were added to the eluted compound, and sonication was performed. The solid was collected by filtration and dried in vacuo to obtain 148 mg of the title compound (yield: 44%).

[1571] (Example 23)

[1572] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1573] (23a)

[1574] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[1575] Using (3S)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propionic acid ethyl ester (200 mg) of Example 7 (7a) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (136 mg) of Example 13 (13b), 330 mg of the title compound (yield: quantitative) was obtained in the form of a solid using the same method as in Example 3 (3f).

[1576] (23b)

[1577] (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[1578] Using (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (350 mg) of Example 23 (23a), the same method as in Example 22 (22b) was used to obtain 70 mg of the title compound in the form of a solid (yield: 21%).

[1579] (Example 24)

[1580] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1581] (24a)

[1582] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1583] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (90 mg) and (4R)-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (International Publication No. 2015 / 092713) (60 mg) of Example 3(3e), the title compound (130 mg, yield: 94%) was obtained as a solid using the same method as Example 3(3f).

[1584] (24b)

[1585] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1586] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (130 mg) of Example 24 (24a), the same method as in Example 3 (3 g) was used to obtain 70 mg of the title compound in the form of a solid (yield: 56%).

[1587] (Example 25)

[1588] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1589] (25a)

[1590] 2-Chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide

[1591] Using (2R)-1-aminobutan-2-ol (1.27 g) and 2-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (1.0 g) from Example 1(1a), 417 mg (yield: 35%) of the title compound was obtained as an oil by the same method as in Example 1(1b).

[1592] (25b)

[1593] (4R)-4-Ethyl-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[1594] Using 2-chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide (417 mg) of Example 25(25a), the title compound (370 mg, yield: quantitative) was obtained as a solid in the same manner as in Example 1(1c).

[1595] (25c)

[1596] [(6-Bromo-2,3-dihydro-1H-inden-4-yl)methoxy](tert-butyl)dimethylsilane

[1597] To a mixture of (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol (70 g), imidazole (42 g), and dichloromethane (800 mL) from Example 3(3c) was added tert-butyldimethylsilyl chloride (70 g), and the mixture was stirred at 15°C for 1 hour. The reaction mixture was diluted with dichloromethane, and the organic layer was washed twice with water and once with saturated brine, then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether] to obtain 98 g of the title compound as a solid (yield: 93%).

[1598] (25d)

[1599] tert-Butyl(dimethyl){[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl]methoxy}silane

[1600] Using [(6-bromo-2,3-dihydro-1H-inden-4-yl)methoxy](tert-butyl)dimethylsilane (49 g) from Example 25 (25c), the title compound (51 g, yield: 91%) was obtained as a solid in the same manner as in Example 1 (1h).

[1601] (25e)

[1602] tert-Butyl 3-[7-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-inden-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[1603] Bis(norbornadiene)rhodium(I) tetrafluoroborate (152 mg), (2S,3S)-bisdiphenylphosphinobutane (87 mg), and (2R,3R)-bisdiphenylphosphinobutane (87 mg) were dissolved in a mixed solvent of 1,4-dioxane (27 mL) and water (7.2 mL), and the mixture was stirred at room temperature for 15 minutes. Next, (2E)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)prop-2-enoic acid tert-butyl ester (International Publication No. 2018 / 109646) (2.22 g) and tert-butyl (dimethyl) {[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl] methoxy} silane (4.73 g) of Example 25 (25d) were added, and 1M potassium hydroxide aqueous solution (8.12 mL) was added, followed by heating and stirring at 50 ° C for 4 hours. The reaction mixture was returned to room temperature, saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 - 60 / 40 (V / V)] to obtain 4.0 g (yield: 92%) of the title compound as an oily substance.

[1604] (25f)

[1605] tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[1606] Using tert-butyl 3-[7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H-indene-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (4.0 g) from Example 25 (25e), the same method as in Example 20 (20c) was used to obtain 3.0 g (yield: 95%) of the title compound in the form of a solid.

[1607] (25g)

[1608] tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[1609] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (100 mg) from Example 25 (25f) and (4R)-4-ethyl-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (70 mg) from Example 25 (25b), the same method as in Example 3 (3f) was used to obtain 116 mg of the title compound in the form of a solid (yield: 70%).

[1610] (25h)

[1611] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1612] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxo-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (116 mg) from Example 25 (25 g), the same method as in Example 20 (20e) was used to obtain 75 mg of the title compound as a solid (yield: 70%).

[1613] (Example 26)

[1614] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1615] (26a)

[1616] 1-Fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide

[1617] Using (2R)-1-aminobutan-2-ol (1.10 g) of Example 1(1a) and 1-fluoronaphthalene-2-sulfonyl chloride (0.75 g), the title compound (0.90 mg, yield: 99%) was obtained as a solid by the same method as Example 1(1b).

[1618] (26b)

[1619] (2R)-2-Ethyl-3,4-dihydro-2H-naphtho[1,2-b][1,4,5]oxathiazepine 5,5-dioxide

[1620] Using 1-fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide (900 mg) of Example 26(26a), the title compound (700 mg, yield: 83%) was obtained as a solid in the same manner as in Example 1(1c).

[1621] (26c)

[1622] tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[1623] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-indene-5-yl]propanoate (110 mg) from Example 25 (25f) and (2R)-2-ethyl-3,4-dihydro-2H-naphtho[1,2-b][1,4,5]oxathiazepine 5,5-dioxide (72 mg) from Example 26 (26b), the same method as in Example 3 (3f) was used to obtain 170 mg of the title compound in the form of a solid (yield: 96%).

[1624] (26d)

[1625] 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1626] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxo-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (180 mg) from Example 26 (26c), the same method as in Example 20 (20e) was used to obtain 100 mg of the title compound as a solid (yield: 61%).

[1627] (Example 27)

[1628] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1629] (27a)

[1630] (4S * )-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide

[1631] To a toluene (500 mL) solution of 2-chloro-N-(2-methylenebutyl)pyridine-3-sulfonamide (International Publication No. 2018 / 109643) (30 g) was added 2,2'-azobis(isobutyronitrile) (10 g) at room temperature, and the reaction mixture was heated to 65°C. Tributyltin hydride (70 g) was added, and the reaction mixture was stirred at 85°C for 16 hours. A solution of potassium fluoride (50 g) in water (500 mL) was added to the reaction mixture, and after stirring at 15°C for 10 hours, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 20 / 1-5 / 1 (V / V)], followed by purification by fractional HPLC [column: Phenomenex Luna C18 (100 mm ID × 250 mm), mobile phase: 0.225% formic acid aqueous solution / acetonitrile = 75 / 25-55 / 45 (V / V)] to obtain a racemic form of the title compound. This was subjected to chiral SFC [column: CHIRALPAK IC (30 mm ID × 250 mm), mobile phase: carbon dioxide / 2-propanol (0.1% ammonia water) = 60 / 40 (V / V)] to obtain 7.09 g of (4S * )-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide was obtained as the first peak (yield: 26%).

[1632] Analytical SFC conditions [column: CHIRALPAKAS-3 (4.6 mm ID × 50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3 mL / min, temperature: 35°C, wavelength: 220 nm]; retention time: 1.081 min (first peak)

[1633] (27b)

[1634] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1635] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (158 mg) of Example 4(4b) and (4S) of Example 27(27a), the * )-4-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide (90 mg) was added and the title compound (230 mg, yield: 95%) was obtained as a solid by the same method as in Example 3(3f).

[1636] (27c)

[1637] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1638] Using the (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester (120 mg) was added and the title compound 50 mg (yield: 44%) was obtained as a solid by the same method as in Example 3 (3 g).

[1639] (Example 28)

[1640] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1641] (28a)

[1642] (4S *)-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide

[1643] 4-Ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide (International Publication No. 2017 / 060854) (16 g) was subjected to chiral SFC [column: CHIRALPAKAD (30 mm ID×250 mm), mobile phase: carbon dioxide / methanol (0.1% ammonia water) = 70 / 30 (V / V)] to obtain 4.8 g of (4S * )-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide is the first peak.

[1644] Analytical SFC conditions [column: CHIRALPAKAY-3 (4.6 mm ID × 50 mm), mobile phase: carbon dioxide / ethanol (0.05% diethylamine) = 95 / 5-60 / 40 (V / V), flow rate: 3 mL / min, temperature: 35°C, wavelength: 220 nm]; retention time: 1.513 min (first peak)

[1645] (28b)

[1646] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid ethyl ester

[1647] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (158 mg) of Example 4(4b) and (4S * )-4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide (90 mg) was added and the title compound (100 mg, yield: 41%) was obtained as a solid by the same method as in Example 3(3f).

[1648] (28c)

[1649] (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[1650] Using the (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * To the mixture was added ethyl]-4-ethyl-1,1-dioxo-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (100 mg), and the title compound was obtained as a solid in the same manner as in Example 3 (3 g) to give 85 mg (yield: 89%).

[1651] (Example 29)

[1652] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoic acid

[1653] (29a)

[1654] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester

[1655] Ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (181 mg) of Example 95 (95a) and (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (115 mg) of Example 1 (1c) were dissolved in toluene (5 mL). Under a nitrogen atmosphere, 1,1'-(azodicarbonyl)dipiperidine (221 mg) was added, followed by the addition of tri-n-butylphosphine (0.218 mL) and stirred at room temperature for 25 hours. The reaction mixture was diluted with dichloromethane and purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 2 / 1-1 / 2 (V / V)] to obtain 270 mg of the title compound as a solid (yield: 94%).

[1656] (29b)

[1657] 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoic acid

[1658] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-indene-5-yl)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)propanoate (270 mg) of Example 29 (29a), the same method as in Example 3 (3 g) was used to obtain 218 mg of the title compound as a solid (yield: 84%).

[1659] (Example 30)

[1660] (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[1661] (30a)

[1662] 4-Bromo-6-chloro-N,3-dimethyl-2-nitroaniline

[1663] 4-Bromo-N,3-dimethyl-2-nitroaniline (International Publication No. 2020 / 165776) (5.04 g) was dissolved in N,N-dimethylformamide, and N-chlorosuccinimide (2.88 g) was added. The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere and cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5.72 g of the unpurified title compound as a solid (yield: quantitative).

[1664] (30b)

[1665] 4-Bromo-6-chloro-N 1 ,3-Dimethylbenzene-1,2-diamine

[1666] Using 4-bromo-6-chloro-N,3-dimethyl-2-nitroaniline (5.84 g) from Example 30 (30a), the title compound (2.69 g, yield: 52%) was obtained as an oil in the same manner as in Example 54 (54d).

[1667] (30c)

[1668] 5-Bromo-7-chloro-1,4-dimethyl-1H-benzotriazole

[1669] The 4-bromo-6-chloro-N 1 ,3-Dimethylbenzene-1,2-diamine (2.69 g) was suspended in 5M hydrochloric acid (50 mL), and a solution of sodium nitrite (1.49 g) in water (6 mL) was added dropwise at 0°C for 20 minutes under a nitrogen atmosphere. After stirring at room temperature for 1 and a half hours, the reaction mixture was cooled to 0°C and neutralized by adding 5M aqueous sodium hydroxide solution (50 mL). The reaction mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.76 g of the unpurified title compound as a solid (yield: 98%).

[1670] (30d)

[1671] (2E)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester

[1672] A mixture of 5-bromo-7-chloro-1,4-dimethyl-1H-benzotriazole (2.76 g) from Example 30 (30c), palladium (II) acetate (238 mg), tri(o-tolyl)phosphine (645 mg), and N,N-dimethylformamide (20 mL) was purged with nitrogen, and N,N-diisopropylethylamine (9.1 mL) was added, followed by ethyl acrylate (2.3 mL), and the mixture was heated and stirred at 90°C for 2 hours. Tris(dibenzylideneacetone)dipalladium(0) (485 mg), tri(o-tolyl)phosphine (645 mg), and ethyl acrylate (2.3 mL) were added to the reaction mixture, and the m...

Claims

1. A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, [Chemistry 1] In the formula, R 1a and R 1b Each independently represents a hydrogen atom or a C 1-6 alkyl, R 2 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl, R 3 represents a hydrogen atom, a halogen atom or a C 1-6 alkyl, Y represents -CH-, -CR 4 - or nitrogen atoms, R 4 Represents hydroxyl, halogen atom, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy, -V- represents a group represented by any of the following formulae: [Chemistry 2] In the formula, * and ** represent the bonding position with the benzene ring, n R 7 Each independently represents a halogen atom, a cyano group, a C 1-6 Alkyl or C 1-6 Alkoxy, n represents an integer from 0 to 2, and Z represents a group represented by the following formula (A1), (A2) or (A3): [Chemistry 3] In the formula, *** represents the bonding position of the carbon atom to which Z is bonded, R 8 represents C optionally substituted by 1 to 3 substituents selected from substituent group a 1-6 alkyl, R 5a and R 5b Each independently represents a hydrogen atom, a C optionally substituted by 1 to 3 substituents selected from Substituent Group a 1-6 Alkyl, or C 3-6 Cycloalkyl; Or, R 5aWith R 5b Bonded to each other and R 5a and R 5b The carbon atoms to which they are bonded together form a C optionally substituted by 1 to 3 substituents selected from substituent group b. 3-8 Cycloalkane, or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 Each independently represents a hydroxyl group, a halogen atom, a cyano group, a C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group, m represents an integer from 0 to 3, W represents -CH2-, -CHR 9 - or oxygen atoms, R 9 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy, X represents -CH-, -CR 10 - or nitrogen atoms, R 10 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy, U represents -CH-, -CR 11 - or nitrogen atoms, and R 11 Represents a halogen atom, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy, Substituent group a: Hydroxyl, Halogen atoms, Cyano, C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 alkyl, C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkoxy, C optionally substituted by 1 to 3 substituents selected from substituent group b 1-6 Alkylsulfonyl, 1 or 2 C 1-6 an amino group optionally substituted by an alkyl group, Substituent group b: Halogen atoms, Cyano, C 1-6 alkyl, C 1-6 Alkoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently a hydrogen atom or a methyl group.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 2 C 1-6 alkyl, 2-dimethylaminoethyl, 2,2,2-trifluoroethyl, 2-hydroxy-2-methylpropyl or 3-(methylsulfonyl)propyl.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3 is a halogen atom or C 1-6 alkyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a hydroxyl group, a chlorine atom, a cyano group, a methyl group, a methoxy group, a cyclopropyl group, a trifluoromethyl group, a difluoromethoxy group or a trifluoromethoxy group.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: -V- is a group represented by any of the following formulas: [Chemistry 4] In the formula, * and ** have the same meanings as above.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein n is 1, and R 7 C 1-6 alkyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein n is 0.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Z is a group represented by the following formula (A1) or (A2): [Chemistry 5] The symbols in the formula have the same meanings as above.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 8 It is methyl or ethyl.

11. The compound according to claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group or a cyclopropyl group, or, R 5a With R 5b They bond with each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran.

12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein: m R 6 are each independently a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group or a trifluoromethyl group, and m is an integer from 0 to 2.

13. The compound according to claims 9 to 12 or a pharmaceutically acceptable salt thereof, wherein: W is -CH2- or an oxygen atom.

14. A compound represented by the following general formula (1') or a pharmaceutically acceptable salt thereof: [Chemistry 6] In the formula, R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group, R 2’ represents methyl, R 3’ represents a chlorine atom or a methyl group, Y' represents -CH-, -CR 4’ - or nitrogen atoms, R 4’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group, -V'- represents a group represented by any of the following formulae: [Chemistry 7] In the formula, *' and **' represent the bonding position with the benzene ring, R 5a’ and R 5b’ Each independently represents a hydrogen atom or an ethyl group, or, R 5a’ With R 5b’ Bonded to each other to form cyclopropane, m'R 6’ each independently represents a fluorine atom or a chlorine atom, m' represents an integer from 0 to 2, and W' represents an oxygen atom.

15. Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, and (3S)-3-(7-{[(4R)-8-Chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid.

16. Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, and (3R)-3-(7-{[(4R)-8-Chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid.

17. (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

18. (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

19. (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

20. (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxo-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

21. A compound represented by the following general formula (1") or a pharmaceutically acceptable salt thereof: [Chemistry 8] In the formula, R 1a” and R 1b” each independently represents a hydrogen atom or a methyl group, R 2” represents methyl, R 3” represents a chlorine atom or a methyl group, "Y" represents -CH-, -CR 4” - or nitrogen atoms, R 4” represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group, -V"- represents a group represented by any of the following formulae: [Chemistry 9] In the formula, "*" and "**" represent the bonding position with the benzene ring, R 5a” and R 5b” Each independently represents a hydrogen atom or an ethyl group, or, R 5a” and R 5b” Bonded to each other to form cyclopropane, R 8” represents a methyl or ethyl group, m” R 6” each independently represents a chlorine atom or a hydroxyl group, m" means 0 or 1, U" represents a nitrogen atom, and W" represents an oxygen atom.

22. Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid, (3R)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid, (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid, (3S)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3R)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, and (3S)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R,5S)-2-ethyl-5-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid.

23. A medicament comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 as an active ingredient.

24. The medicament according to claim 23, for activating Nrf2. The medicament according to claim 23, which is used for inhibiting the protein-protein interaction between Keap1 and Nrf2.

26. The medicament according to claim 23, which is used for preventing and / or treating diseases associated with oxidative stress.

27. The drug according to claim 26, wherein The oxidative stress-related disease is selected from kidney disease, liver disease, respiratory system disease, skin disease, cardiovascular system disease, central nervous system disease, autoimmune disease and eye disease.

28. The medicament according to claim 23, for use in the prevention and / or treatment of a disease selected from: Kidney diseases selected from chronic kidney disease, acute nephritis, chronic nephritis, acute renal insufficiency, chronic renal insufficiency, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty nephropathy, nephrosclerosis, hydronephrosis and tubulointerstitial nephritis; liver diseases selected from alcoholic fatty liver, non-alcoholic fatty liver, liver fibrosis and cirrhosis; respiratory diseases selected from bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia and asthma; skin diseases selected from ultraviolet and radiation skin damage, radiation mucosal damage, bullous epidermolysis, psoriasis, atopic dermatitis and scleroderma; cardiovascular diseases selected from heart failure, myocardial infarction, arteriosclerosis and pulmonary hypertension; Alzheimer's disease Central nervous system diseases selected from among: leukemia, atrophy, leukopenia ...

29. The medicament according to claim 23, which is used for the prevention and / or treatment of a disease selected from the group consisting of chronic kidney disease, nonalcoholic fatty liver disease, chronic obstructive pulmonary disease, radiation skin damage, radiation mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

30. The medicament according to claim 23, which is used for the prevention and / or treatment of a disease selected from the group consisting of glaucoma, age-related macular degeneration and retinitis pigmentosa.

31. The medicament according to claim 23, which is used for the prevention and / or treatment of radiation-induced skin damage or radiation-induced mucosal damage.

32. The medicament according to claim 23, which is used for the prevention and / or treatment of chronic obstructive pulmonary disease.

33. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22 for preparing a preventive and / or therapeutic agent for a disease selected from chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation skin damage, radiation mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

34. A method for preventing and / or treating a disease, comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to a mammal, wherein the disease is selected from the group consisting of chronic kidney disease, non-alcoholic fatty hepatitis, chronic obstructive pulmonary disease, radiation skin damage, radiation mucosal damage, heart failure, pulmonary hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma in the mammal.

35. A method of activating Nrf2 in a mammal, comprising administering to the mammal a pharmaceutically effective amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

36. A method for inhibiting the protein-protein interaction between Keap1 and Nrf2 in a mammal, comprising administering a pharmaceutically effective amount of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof to the mammal.

37. An Nrf2 activator comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.

38. An inhibitor of protein-protein interaction between Keap1 and Nrf2, comprising the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.

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