Benzotriazole Compounds

Abstract

The present invention addresses the problem of providing a medicine capable of treating and / or preventing a disease associated with oxidative stress through the inhibition of a protein-protein interaction between Keap1 and Nrf2 to activate Nrf2. The present invention relates to a compound represented by general formula (1): [wherein each symbol is as described in the description] or a pharmaceutically acceptable salt thereof. The present invention also relates to a medicine for preventing and / or treating a disease associated with oxidative stress, in which the disease is selected from the group consisting of chronic kidney disease, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, radiation-induced skin damages, radiation-induced mucosal damages, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma, and the medicine contains the compound.

Description

[Technical Field]

[0001] The present invention relates to a benzotriazole compound or a pharmaceutically acceptable salt thereof, which is useful for the treatment and / or prevention of 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 injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma, by inhibiting Kelch-like ECH-associated protein 1 (Keap1) and activating NF-E2-related factor 2 (Nrf2). [Background technology]

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

[0003] Activation of Nrf2 is known to induce its target genes, such as NAD(P)H quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), and gamma-glutamate cysteine ​​ligase catalytic subunit (GCLC) (Non-Patent Document 1). NQO1 is a phase 2 enzyme in xenobiotic metabolism and is important for detoxification. HO-1 and GCLC are known as typical antioxidant enzymes. When the levels of these enzymes are increased or activated, cells become resistant to toxins, oxidative stress, inflammation, and other conditions. Therefore, compounds that activate Nrf2 are thought to be therapeutic agents for various diseases (Non-Patent Document 2).

[0004] Because Nrf2 is ubiquitinated by Keap1 and degraded in the proteasome system under steady-state conditions, compounds that inhibit Keap1 activate Nrf2. Although compounds that activate Nrf2 by modifying cysteine ​​residues in Keap1 are known, their activation mechanism raises concerns about low specificity. Meanwhile, compounds that inhibit the protein-protein interaction (PPI) between Keap1 and Nrf2 are expected to more specifically activate Nrf2 and have recently attracted increasing attention as potential preventive and / or therapeutic agents for various diseases caused by oxidative stress (Non-Patent Document 3).

[0005] To date, compounds that inhibit Keap1 and activate Nrf2 have been reported, for example, as described in Patent Documents 1 to 11, but all of them are structurally different from the compound of the present invention. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2015 / 092713 [Patent Document 2] International Publication No. 2016 / 202253 [Patent Document 3] International Publication No. 2016 / 203400 [Patent Document 4] International Publication No. 2016 / 203401 [Patent Document 5] International Publication No. 2018 / 109643 [Patent Document 6] International Publication No. 2018 / 109647 [Patent Document 7] International Publication No. 2018 / 109648 [Patent Document 8] International Publication No. 2019 / 224667 [Patent Document 9] International Publication No. 2020 / 165776 [Patent Document 10] International Publication No. 2018 / 181345 [Patent Document 11] International Publication No. 2020 / 241853 [Non-patent literature]

[0007] [Non-Patent Document 1] Int. J. Biochem. Cell. Biol., 2012, 44, 1315-1320 [Non-patent document 2] Nat. Rev. Drug. Discov., 2019, 18, 295-317 [Non-patent document 3] Eur. J. Med. Chem., 2020, 202, 112532 Summary of the Invention [Problem to be solved by the invention]

[0008] An objective of the present invention is to provide a pharmaceutical agent that can treat and / or prevent 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 injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma, by inhibiting the protein-protein interaction between Keap1 and Nrf2 and activating Nrf2. [Means for solving the problem]

[0009] As a result of extensive investigations to solve the above problems, the present inventors have found that a compound represented by the following general formula (1):

[0010] [ka]

[0011] [In the formula, R 1a and R 1bare each independently a hydrogen atom or C 1-6 represents an alkyl group, R 2 C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, R 3 is a hydrogen atom, a halogen atom or C 1-6 represents an alkyl group, Y is -CH-, -CR 4 - or a nitrogen atom, R 4 is a hydroxy group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, -V- is represented by the following formula:

[0012] [ka]

[0013] (In the formula, * and ** indicate the bonding positions to the benzene ring.) represents a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group, n represents an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0014] [ka]

[0015] (In the formula, *** indicates the bonding position of Z to the carbon atom, R 8C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, R 5a and R 5b are each independently a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl group or C 3-6 represents a cycloalkyl group, or Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 represents an amino group optionally substituted with an alkyl group, m represents an integer of 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C1-6 represents a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group. represents a group represented by the formula: Substituent group a: hydroxy groups, halogen atoms, cyano group, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkyl groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkoxy groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkylsulfonyl groups, 1 or 2 Cs 1-6 An amino group optionally substituted with an alkyl group Substituent group b: halogen atoms, cyano group, C 1-6 alkyl groups, C 1-6 alkoxy group] The present inventors have found that a compound represented by the formula (I) (hereinafter sometimes abbreviated as "compound (1)") or a pharmaceutically acceptable salt thereof exhibits excellent Nrf2 activation activity by inhibiting Keap1, and have completed the present invention.

[0016] That is, the present invention is as follows. [1] The following general formula (1):

[0017] [ka]

[0018] [In the formula, R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, R 2 C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, R 3 is a hydrogen atom, a halogen atom or C 1-6 represents an alkyl group, Y is -CH-, -CR 4 - or a nitrogen atom, R 4 is a hydroxy group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, -V- is represented by the following formula:

[0019] [ka]

[0020] (In the formula, * and ** indicate the bonding positions to the benzene ring.) represents a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group, n represents an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0021] [ka]

[0022] (In the formula, *** indicates the bonding position of Z to the carbon atom, R 8 C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, R 5a and R 5b are each independently a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl group or C 3-6 represents a cycloalkyl group, or Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 represents an amino group optionally substituted with an alkyl group, m represents an integer of 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group. represents a group represented by the formula: Substituent group a: hydroxy groups, halogen atoms, cyano group, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkyl groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkoxy groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkylsulfonyl groups, 1 or 2 Cs 1-6 An amino group optionally substituted with an alkyl group Substituent group b: halogen atoms, cyano group, C 1-6 alkyl groups, C 1-6 alkoxy group] or a pharmaceutically acceptable salt thereof. [2]R 1a and R 1b are each independently a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. [3]R 2 But C 1-6The compound according to the above [1] or [2], wherein R is an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group, or a pharmaceutically acceptable salt thereof. [4]R 3 is a halogen atom or C 1-6 The compound according to any one of the above [1] to [3], wherein the group is an alkyl group, or a pharmaceutically acceptable salt thereof. [5]R 4 is a hydroxy 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 pharmaceutically acceptable salt thereof. [6]-V- is the following formula:

[0023] [ka]

[0024] (In the formula, * and ** are as defined above.) The compound according to any one of the above [1] to [5], or a pharmaceutically acceptable salt thereof, wherein the compound is a group represented by any one of the following: [7] n is 1 and R 7 But C 1-6 The compound according to any one of the above [1] to [6], wherein the group is an alkyl group, or a pharmaceutically acceptable salt thereof. [8] The compound according to any one of the above [1] to [6], wherein n is 0, or a pharmaceutically acceptable salt thereof. [9] Z is represented by the following formula (A1) or (A2):

[0025] [ka]

[0026] (The symbols in the formula are as defined above.) The compound according to any one of the above [1] to [8], wherein the group is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[10] R 8 is a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof.

[11] R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group; Or, R 5a and R 5b are bonded to each other to form cyclopropane, cyclobutane, oxetane or tetrahydropyran, or a pharmaceutically acceptable salt thereof according to the above [9] or

[10] .

[12] m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, and The compound according to any one of the above [9] to

[11] , wherein m is an integer of 0 to 2, or a pharmaceutically acceptable salt thereof.

[13] The compound according to any one of the above [9] to

[12] , wherein W is -CH2- or an oxygen atom, or a pharmaceutically acceptable salt thereof.

[14] The following general formula (1'):

[0027] [ka]

[0028] [In the formula, R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group, R 2’ indicates a methyl group, R 3’ represents a chlorine atom or a methyl group, Y' is -CH-, -CR 4’ - or a nitrogen atom, R 4’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V'- is represented by the following formula:

[0029] [ka]

[0030] (In the formula, *' and **' indicate the bonding positions to the benzene ring.) represents a group represented by any one of the following: R 5a’ and R 5b’ each independently represents a hydrogen atom or an ethyl group, or R 5a’ and R 5b’ are bonded together 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. (hereinafter, may be abbreviated as "compound (1')") or a pharmaceutically acceptable salt thereof.

[15] Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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] The following general formula (1 ''):

[0031] [ka]

[0032] [In the formula, R 1a’’ and R 1b’’ each independently represents a hydrogen atom or a methyl group, R 2’’ indicates a methyl group, R 3’’ represents a chlorine atom or a methyl group, Y'' is -CH-, -CR 4’’ - or a nitrogen atom, R 4’’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V''- is represented by the following formula:

[0033] [ka]

[0034] (In the formula, *'' and **'' indicate the bonding positions to the benzene ring.) represents a group represented by any one of the following: R 5a’’ and R 5b’’ each independently represents a hydrogen atom or an ethyl group, or R 5a’’ and R 5b’’ are bonded together to form cyclopropane, R 8’’ represents a methyl group or an ethyl group, m'' R 6’’ each independently represents a chlorine atom or a hydroxy group, m'' represents 0 or 1; U'' represents a nitrogen atom, and W'' represents an oxygen atom. (hereinafter, may be abbreviated as "compound (1")") or a pharmaceutically acceptable salt thereof.

[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 pharmaceutical comprising, as an active ingredient, the compound according to any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof (hereinafter, sometimes abbreviated as "the pharmaceutical of the present invention").

[24] The pharmaceutical agent according to

[23] above, for activating Nrf2.

[25] The pharmaceutical agent according to the above

[23] for inhibiting the protein-protein interaction between Keap1 and Nrf2.

[26] The pharmaceutical composition according to

[23] above for the prevention and / or treatment of oxidative stress-related diseases.

[27] The pharmaceutical according to

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

[28] Renal diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic 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-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; cardiovascular diseases selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension; Alzheimer's disease, Parkinson's disease a central nervous system disease selected from the group consisting of leukemia, leukemia, leukemia-associated ... The pharmaceutical composition according to the above

[23] for the prevention and / or treatment of a disease selected from the group consisting of:

[29] The pharmaceutical agent according to

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

[30] The pharmaceutical composition according to

[23] above 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 pharmaceutical agent according to the above

[23] for the prevention and / or treatment of radiation-induced skin damage or radiation-induced mucosal damage.

[32] The pharmaceutical agent according to the above

[23] for the prevention and / or treatment of chronic obstructive pulmonary disease.

[33] Use of the compound according to any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the prophylaxis and / or treatment of a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary arterial 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 in a mammal selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of the above [1] to

[22] or a pharmaceutically acceptable salt thereof.

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

[22] above or a pharmaceutically acceptable salt thereof.

[37] An Nrf2 activator comprising, as an active ingredient, the compound according to any one of [1] to

[22] above or a pharmaceutically acceptable salt thereof.

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

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

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

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

[40] The pharmaceutical composition according to

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

[41] The pharmaceutical agent according to any one of

[23] to

[32] and

[40] above, which is administered in combination with other drugs.

[42] The pharmaceutical composition according to

[41] above, wherein the other drug is 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 injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[43] The pharmaceutical agent according to any one of

[23] to

[32] and

[40] above and the other drug are contained separately as active ingredients in different formulations, and are administered simultaneously or at different times.

[44] The pharmaceutical composition according to

[41] or

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

[22] above or a pharmaceutically acceptable salt thereof and another drug are contained in a single formulation.

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

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

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

[22] above.

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

[22] above. [Effects of the Invention]

[0035] Compound (1) of the present invention or a pharmaceutically acceptable salt thereof exhibits the effect of effectively activating Nrf2 by inhibiting the protein-protein interaction between Keap1 and Nrf2. That is, by administering to a mammal a pharmaceutical comprising compound (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, it can be used for the prevention and / or treatment of diseases whose symptoms are improved by activation of Nrf2. Diseases whose symptoms are improved by activating Nrf2 include oxidative stress-related diseases, and specific examples thereof include kidney diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic 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-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; and heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension. selected cardiovascular diseases; central nervous system 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; mitochondrial diseases selected from the group consisting of Friedreich's ataxia and mitochondrial myopathy; autoimmune diseases selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and ophthalmological diseases selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, keratopathy, 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. Among these, preferred examples include 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 arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma. DETAILED DESCRIPTION OF THE INVENTION

[0036] 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 commonly understood by those skilled in the art to which this invention belongs.

[0037] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0038] In this specification, "C 1-6 The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, an n-hexyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, and a 2-ethylbutyl group.

[0039] In this specification, "C 1-6 The term "haloalkyl group" refers to the group defined above as "C 1-6 C means a group in which one or more hydrogen atoms in an "alkyl group" have been substituted with halogen. 1-6Examples of haloalkyl groups 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.

[0040] In this specification, "C 1-6 The "alkoxy group" refers to the "C 1-6 C means a group in which an "alkyl group" is bonded to an oxygen atom. 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, an isopentoxy group, a 2-methylbutoxy group, and an n-hexyloxy group.

[0041] In this specification, "C 1-6 The "haloalkoxy group" refers to the group defined above as "C 1-6 C means a group in which one or more hydrogen atoms in an alkoxy group have been substituted with halogen. 1-6 Examples of haloalkoxy groups 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.

[0042] In this specification, "C 3-6 The term "cycloalkyl group" means a 3- to 6-membered monocyclic saturated hydrocarbon ring group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0043] In this specification, "C 1-6 The "alkylsulfonyl group" is the same as the "C 1-6 It means a group in which an "alkyl group" and a sulfur atom of a sulfonyl group are bonded. 1-6 Examples of the alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, and an n-pentylsulfonyl group.

[0044] In the present specification, "one or two C 1-6 The term "amino group which may be substituted with an alkyl group" refers to an unsubstituted amino group, or an amino group in which one or two hydrogen atoms are each independently substituted with one of the above-mentioned "C 1-6 It means a group substituted with "alkyl group". 1-6 Examples of the amino group optionally substituted with an alkyl group include an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, an ethyl(methyl)amino group, an n-propylamino group, a di(n-propyl)amino group, an isopropylamino group, an n-butylamino group, a di(n-butyl)amino group, a sec-butylamino group, a tert-butylamino group, an n-pentylamino group, and an n-hexylamino group.

[0045] In this specification, "C 3-8 "Cycloalkane" means a 3- to 8-membered monocyclic saturated hydrocarbon ring, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. 3-8 The "cycloalkane" is preferably cyclopropane or cyclobutane.

[0046] In the present specification, the term "3- to 8-membered saturated oxygen-containing heterocycle" means a 3- to 8-membered monocyclic saturated oxygen-containing heterocycle, and examples thereof include oxirane, oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, etc. The "3- to 8-membered saturated oxygen-containing heterocycle" is preferably oxetane or tetrahydropyran.

[0047] In this specification, "optionally substituted" means unsubstituted or substituted with a specific number of specific substituents at any substitutable position (any hydrogen atom is replaced with a substituent). Examples of the "substituent" include substituents selected from the group consisting of "substituent group a" and "substituent group b" below. When multiple substituents are present, the respective substituents may be the same or different.

[0048] Substituent group a: hydroxy groups, halogen atoms, cyano group, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkyl groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkoxy groups, C optionally substituted with 1 to 3 substituents selected from the substituent group b 1-6 alkylsulfonyl groups, 1 or 2 Cs 1-6 An amino group optionally substituted with an alkyl group

[0049] Substituent group b: halogen atoms, cyano group, C 1-6 alkyl groups, C 1-6 alkoxy group However, "optionally substituted C 1-6 "Alkyl group" or "Optionally substituted C 1-6When the optional substituents of the "alkoxy group" are selected from the substituent group a or the substituent group b, the list of the substituent group a or the substituent group b includes "C 1-6 "Alkyl groups" are not included.

[0050] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can be used as a medicine, and includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0051] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) involved in transporting compound (1) of the present invention (or compound (1') or compound (1'')) or a composition containing the same from one organ or organ to another.

[0052] As used herein, the term "treatment" and its derivatives refer to the alleviation, mitigation, or delay of worsening of clinical symptoms of a disease, illness, disorder, etc. (hereinafter referred to as "disease, etc.") in a patient who has developed the disease, etc.

[0053] As used herein, the term "prevention" and its derivatives refer to inhibiting, suppressing, controlling, slowing down, or halting the onset of clinical symptoms of a disease or the like in a mammal that may develop the disease or the like but has not yet developed the disease or that is at risk of recurrence of the disease or the like after treatment of the disease or the like.

[0054] As used herein, "oxidative stress" refers to a state in which the balance of the antioxidant defense mechanism is disrupted due to excessive production of reactive oxygen species caused by external factors (e.g., ultraviolet rays, radiation, air pollution, tobacco, drugs, intake of oxidized substances, etc.). "Oxidative stress-related diseases" refer to diseases in which such oxidative stress is involved in the onset or worsening of symptoms. Examples of the "oxidative stress-related disease" include kidney diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic 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-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; cardiovascular diseases selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension; central nervous system diseases selected from the group consisting of Marsh's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease, and autism; mitochondrial diseases selected from the group consisting of Friedreich's ataxia and mitochondrial myopathy; autoimmune diseases selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and ophthalmological diseases selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, keratopathy, 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 disease" in the present invention is particularly 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 arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0055] As used herein, the term "inhibitor of the protein-protein interaction between Keap1 and Nrf2" refers to a substance that exhibits the effect of inhibiting the formation of a complex in which Keap1 and Nrf2 normally form a complex and inhibits the function of Nrf2 through ubiquitination by E3 ubiquitin ligase, thereby liberating Nrf2.

[0056] As used herein, "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 complex between Keap1 and Nrf2, and allowing the liberated Nrf2 to translocate into the nucleus and enhance the expression of antioxidant genes, or that increases the expression of antioxidant genes.

[0057] As used herein, the term "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 (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to a mammal.

[0058] As used herein, the term "mammal" includes, but is not limited to, humans and non-human mammals (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.).

[0059] (Compound of the present invention (compound (1))) Each group in the formula (1) of the compound (1) will be explained below.

[0060] R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group.

[0061] R 1a and R 1b are preferably each independently a hydrogen atom or a methyl group.

[0062] R 2 C may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a. 1-6 represents an alkyl group.

[0063] R 2 is preferably C 1-6 It is an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group, and more preferably a methyl group.

[0064] R 3 is a hydrogen atom, a halogen atom or C 1-6 represents an alkyl group.

[0065] R 3 is preferably a halogen atom or C 1-6 It is an alkyl group, and more preferably a chlorine atom or a methyl group.

[0066] Y is -CH-, -CR 4 -(In the formula, R 4 is a hydroxy group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group.) or a nitrogen atom.

[0067] Y is preferably -CH-, -CR 4 -(In the formula, R 4 is a hydroxy 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, and more preferably, -CH-, -CR 4 -(In the formula, R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group. ) or a nitrogen atom.

[0068] -V- is represented by the following formula:

[0069] [ka]

[0070] (In the formula, * and ** indicate the bonding positions to the benzene ring.) The group represented by any one of the following formulas:

[0071] -V- is preferably a group of the following formula:

[0072] [ka]

[0073] (In the formula, * and ** are as defined above.) and more preferably a group represented by the following formula:

[0074] [ka]

[0075] (In the formula, * and ** are as defined above.) It is a group represented by any one of the following:

[0076] n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group.

[0077] n R 7 is preferably C 1-6 It is an alkyl group.

[0078] n represents an integer of 0 to 2.

[0079] n is preferably 0 or 1, and more preferably 0.

[0080] Z is represented by the following formula (A1), (A2), or (A3):

[0081] [ka]

[0082] (In the formula, *** indicates the bonding position of Z to the carbon atom, R 8 C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, R 5a and R 5b are each independently a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl group or C 3-6 represents a cycloalkyl group, or R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 represents an amino group optionally substituted with an alkyl group, m represents an integer of 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 represents a haloalkoxy group. represents a group represented by the formula:

[0083] Z is preferably represented by the following formula (A1) or (A2):

[0084] [ka]

[0085] (The symbols in the formula are as defined above.) and more preferably a group represented by the following formula:

[0086] [ka]

[0087] (In the formula, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is —CH— or an oxygen atom. or a group represented by the following formula:

[0088] [ka]

[0089] (In the formula, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is —CH— or an oxygen atom. and more preferably a group represented by the following formula:

[0090] [ka]

[0091] (In the formula, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom or an ethyl group, Or, R 5a and R5b combine with each other to form cyclopropane, m R 6 are each independently a chlorine atom or a hydroxy group, m is 0 or 1, and W is an oxygen atom. or a group represented by the following formula:

[0092] [ka]

[0093] (In the formula, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is an oxygen atom. It is a group represented by the following formula:

[0094] As the compound (1), the following compounds are suitable. [Compound (1A)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group; R 3 is a hydrogen atom, a halogen atom or C 1-6 is an alkyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group; -V- is the following formula:

[0095] [ka]

[0096] (The symbols in the formula are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; n is an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0097] [ka]

[0098] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b each independently represents a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, or R 5a and R 5b are combined with each other to form R 5a and R 5bC, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0099] [Compound (1B)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 But C 1-6 an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group; R 3 is a hydrogen atom, a halogen atom or C 1-6 is an alkyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group; -V- is the following formula:

[0100] [ka]

[0101] (The symbols in the formula are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; n is an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0102] [ka]

[0103] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0104] [Compound (1C)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a halogen atom or C 1-6 is an alkyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C1-6 a haloalkoxy group; -V- is the following formula:

[0105] [ka]

[0106] (The symbols in the formula are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; n is an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0107] [ka]

[0108] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0109] [Compound (1D)] R 1a and R 1b are each independently a hydrogen atom or C 1-6alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 is a hydroxy 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; -V- is the following formula:

[0110] [ka]

[0111] (The symbols in the formula are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; n is an integer from 0 to 2; and Z is represented by the following formula (A1), (A2), or (A3):

[0112] [ka]

[0113] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0114] [Compound (1E)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0115] [ka]

[0116] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is a group of the following formula (A1), (A2) or (A3):

[0117] [ka]

[0118] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, or R 5a and R 5b are combined with each other to form R 5a and R 5bC, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0119] [Compound (1F)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0120] [ka]

[0121] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is represented by the following formula (A1) or (A2):

[0122] [ka]

[0123] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0124] [Compound (1G)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0125] [ka]

[0126] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is represented by the following formula (A1) or (A2):

[0127] [ka]

[0128] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0129] [Compound (1H)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0130] [ka]

[0131] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is represented by the following formula (A1) or (A2):

[0132] [ka]

[0133] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0134] [Compound (1J)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0135] [ka]

[0136] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is represented by the following formula (A1) or (A2):

[0137] [ka]

[0138] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy 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; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0139] [Compound (1K)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably, each independently a hydrogen atom or a methyl group); R 2 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl groups (preferably C 1-6 alkyl group, 2-dimethylaminoethyl group, 2,2,2-trifluoroethyl group, 2-hydroxy-2-methylpropyl group, or 3-(methylsulfonyl)propyl group); R 3 is a hydrogen atom, a halogen atom or C 1-6 Alkyl group (preferably a halogen atom or C 1-6 alkyl group); Y is -CH-, -CR 4 - or a nitrogen atom; R 4 However, hydroxyl groups, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 a haloalkoxy group (preferably a hydroxy 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); -V- is the following formula:

[0140] [ka]

[0141] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 Alkoxy groups (preferably, each independently, C 1-6 alkyl group); n is an integer from 0 to 2 (preferably 0 or 1); and Z is represented by the following formula (A1) or (A2):

[0142] [ka]

[0143] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy 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; W is —CH— or an oxygen atom; X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0144] [Compound (1L)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2 But C 1-6 an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group; R 3 is a halogen atom or C 1-6 is an alkyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 is a hydroxy 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; -V- is the following formula:

[0145] [ka]

[0146] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 However, independently, C 1-6 is an alkyl group; n is 0 or 1; and Z is represented by the following formula (A1) or (A2):

[0147] [ka]

[0148] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 C, which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 is an alkyl group, R 5a and R 5b C which may be substituted with a hydrogen atom or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6 a cycloalkyl group, Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C, which together with the carbon atom to which it is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 Forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group, or 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, m is an integer from 0 to 3; W is -CH2-, -CHR 9 - or an oxygen atom, R 9 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C1-6 haloalkyl group or C 1-6 is a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0149] [Compound (1M)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2 But C 1-6 an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group; R 3 is a halogen atom or C 1-6 is an alkyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 is a hydroxy 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; -V- is the following formula:

[0150] [ka]

[0151] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n R 7 However, independently, C 1-6 is an alkyl group; n is 0 or 1; and Z is represented by the following formula (A1) or (A2):

[0152] [ka]

[0153] (In the formula, *** is the bonding position of the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy 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; W is —CH— or an oxygen atom; X is -CH-, -CR 10 - or a nitrogen atom, R 10 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6is a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 However, halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 haloalkyl group or C 1-6 It is a haloalkoxy group. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0154] [Compound (1N)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2 is a methyl group; R 3 is a chlorine atom or a methyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group; -V- is the following formula:

[0155] [ka]

[0156] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n is 0; and Z is expressed by the following formula:

[0157] [ka]

[0158] (wherein *** represents the bonding position to the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group; Or, R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is —CH— or an oxygen atom. or a group represented by the following formula:

[0159] [ka]

[0160] (wherein *** represents the bonding position to the carbon atom to which Z is bonded, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group; Or, R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is —CH— or an oxygen atom. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0161] [Compound (1P)] R1a and R 1b are each independently a hydrogen atom or a methyl group; R 2 is a methyl group; R 3 is a chlorine atom or a methyl group; Y is -CH-, -CR 4 - or a nitrogen atom; R 4 is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group; -V- is the following formula:

[0162] [ka]

[0163] (In the formula, * and ** are as defined above.) is a group represented by any one of the following: n is 0; and Z is expressed by the following formula:

[0164] [ka]

[0165] (wherein *** represents the bonding position to the carbon atom to which Z is bonded, R 8 is a methyl group or an ethyl group, R 5a and R 5b are each independently a hydrogen atom or an ethyl group, Or, R 5a and R 5b combine with each other to form cyclopropane, m R 6 are each independently a chlorine atom or a hydroxy group, m is 0 or 1, and W is an oxygen atom. or a group represented by the following formula:

[0166] [ka]

[0167] (wherein *** represents the bonding position to the carbon atom to which Z is bonded, R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group; Or, R 5a and R 5b are bonded to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran; m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, m is an integer from 0 to 2, and W is an oxygen atom. is a group represented by Compound (1) or a pharmaceutically acceptable salt thereof.

[0168] Another preferred embodiment of the compound (1) of the present invention or a pharmaceutically acceptable salt thereof is represented by the following formula (1'):

[0169] [ka]

[0170] [In the formula, R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group, R 2’ indicates a methyl group, R 3’ represents a chlorine atom or a methyl group, Y' is -CH-, -CR 4’ - or a nitrogen atom, R 4’represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V'- is represented by the following formula:

[0171] [ka]

[0172] (wherein *' and **' indicate the bonding positions to the benzene ring), R 5a’ and R 5b’ each independently represents a hydrogen atom or an ethyl group, or R 5a’ and R 5b’ are bonded together 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. or a pharmaceutically acceptable salt thereof, or a compound represented by the following formula (1″):

[0173] [ka]

[0174] [In the formula, R 1a’’ and R 1b’’ each independently represents a hydrogen atom or a methyl group, R 2’’ indicates a methyl group, R 3’’ represents a chlorine atom or a methyl group, Y'' is -CH-, -CR 4’’ - or a nitrogen atom, R 4’’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V''- is represented by the following formula:

[0175] [ka]

[0176] (In the formula, *'' and **'' indicate the bonding positions to the benzene ring.) represents a group represented by any one of the following: R 5a’’ and R 5b’’ each independently represents a hydrogen atom or an ethyl group, or R 5a’’ and R 5b’’ are bonded together to form cyclopropane, R 8’’ represents a methyl group or an ethyl group, m'' R 6’’ represents a chlorine atom or a hydroxy group, m'' represents 0 or 1; U'' represents a nitrogen atom, and W'' represents an oxygen atom. or a pharmaceutically acceptable salt thereof.

[0177] Specific examples of suitable compound (1) include the compounds of Examples 1 to 112 described below or pharmaceutically acceptable salts thereof, and more preferably, Any compound (1) selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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 or Any compound (1) 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 is.

[0178] Particularly preferably, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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.

[0179] Since Compound (1) of the present invention has a basic group such as a nitrogen-containing heterocyclic group in the molecule, it can generally form pharmaceutically acceptable acid addition salts. Examples of such acid addition salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates 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, hydrohalides, arylsulfonates, and organic acid salts are preferred.

[0180] The acid addition salts of compound (1) of the present invention include acid addition salts that can be formed by combining an acid added to the compound of the present invention with compound (1) of the present invention in any ratio. For example, hydrochloride salts include salts that can be formed such as monohydrochloride, dihydrochloride, trihydrochloride, etc., fumarate salts include salts that can be formed such as monofumarate, 1 / 2fumarate, etc., and succinate salts include salts that can be formed such as monosuccinate, 2 / 3succinate, 1 / 3succinate, etc.

[0181] Since the compound (1) of the present invention has a carboxy group in the molecule, it can generally form pharmaceutically acceptable base addition salts. Examples of such base addition salts include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as dibenzylamine salt, morpholine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt.

[0182] When compound (1) of the present invention has an asymmetric carbon atom in the molecule, it can exist as multiple stereoisomers (i.e., diastereoisomers, optical isomers) based on the asymmetric carbon atom, and the present invention encompasses any single stereoisomer and a mixture containing multiple stereoisomers in any ratio. In addition, isomers may be produced due to conformation or tautomerism, and such isomers or mixtures thereof are also encompassed by compound (1) of the present invention. In the names of the compounds of the present invention, when the structure of the compound has a carbon atom that serves as an asymmetric center, the absolute configuration is indicated by R and S (along with the position number). Even when optical isomers are separated, if the configuration of the carbon atom that is the asymmetric center in the structure of the compound has not been determined, R * or S * It is shown by. Also, R * and S * The simultaneous use of may indicate relative configuration even when the absolute configuration has not been determined.

[0183] Compound (1) of the present invention may contain an isotope (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 F, 32 P, 35 S, 125 The compound (1) may be a compound labeled or substituted with an isotope (e.g., I), and the isotope-labeled or substituted compound (1) is useful as a therapeutic or preventative agent, a research reagent (e.g., an assay reagent), and a diagnostic agent (e.g., an in vivo imaging diagnostic agent). Compounds of the present invention containing radioactive or non-radioactive isotopes in all proportions are within the scope of the present invention.

[0184] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof may be crystalline, and may be in a single crystalline form or a mixture of multiple crystalline forms.

[0185] Compound (1) of the present invention may exist as a non-solvate or a solvate. The solvate is not particularly limited as long as it is pharmaceutically acceptable, but specifically, hydrates, ethanolates, etc. are preferred.

[0186] The compound (1) of the present invention may be a prodrug.

[0187] The prodrug of compound (1) of the present invention refers to a compound that is converted to compound (1) in vivo by a reaction with an enzyme, gastric acid, etc. The prodrug of compound (1) may have a structure that is easily hydrolyzed or metabolized after administration to a patient.

[0188] Examples of prodrugs of compound (1) include, when compound (1) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of compound (1) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when compound (1) has a hydroxy group, compounds in which the hydroxy group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxy group of compound (1) has been acetylated, palmitoylated, or propanoylated). compounds in which the carboxy group of compound (1) is esterified or amidated (for example, compounds in which the carboxy group of compound (1) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, 1-{(ethoxycarbonyl)oxy}ethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl-esterified, or methylamidized);

[0189] The prodrug of compound (1) of the present invention can be produced from compound (1) by known methods. The prodrug of compound (1) also includes those that are converted to compound (1) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163-198, Hirokawa Shoten, 1990. Furthermore, the prodrug of compound (1) may be either a hydrate or a non-hydrate.

[0190] (Method for producing compound (1) of the present invention) Representative methods for producing compound (1) of the present invention or a pharmaceutically acceptable salt thereof are described below. Since compound (1) also includes compound (1') and compound (1"). Therefore, hereinafter, the methods for producing compound (1') and compound (1") are also referred to as the method for producing compound (1). 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 examples, and the present invention should not be construed as being limited thereto.

[0191] Each raw material compound may form a salt as long as it does not inhibit the reaction. Examples of such salts include the same pharmaceutically acceptable salts of compound (1) as described above. Unless a specific production method is described, the starting material compounds can be easily obtained from commercial sources and used, or can be produced by known methods or methods similar thereto. Furthermore, the production intermediates produced in the following production methods may be isolated and purified by methods such as column chromatography (including normal phase and reverse phase) using silica gel or alumina, recrystallization, reprecipitation, distillation, etc., or can be used directly in the next reaction without isolation and purification.

[0192] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0193] Compound (1), its pharmaceutically acceptable salts, and their intermediates can be produced by various known methods utilizing the characteristics of their basic skeletons or the types of substituents, such as those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd ed., ACADEMIC PRESS, INC., 1989, and "Comprehensive Organic Transformations," 2nd ed., VCH Publishers Inc., 1999.

[0194] In this case, depending on the type of functional group present in the compound, it may be effective from the viewpoint of production technology to protect the functional group with an appropriate protecting group at the stage of a raw material or intermediate, or to replace the functional group with a group that can be easily converted into the functional group.

[0195] Examples of such functional groups include an amino group, a hydroxy group, a formyl group, a carbonyl group, and a carboxy group, and examples of protecting groups for these groups include those described in P.G. Wuts, "Protective Groups in Organic Synthesis," 5th Edition, Wiley, 2014.

[0196] The protecting group or the group that can be easily converted into the functional group may be appropriately selected depending on the reaction conditions of the production method for producing the compound.

[0197] According to such a method, after the reaction is carried out by introducing the group, the protecting group can be removed or converted into the desired group as necessary to obtain the desired compound.

[0198] Similarly to the above-mentioned protecting groups, prodrugs of compounds can be produced by introducing a specific group into a raw material or intermediate, or by carrying out a reaction using the resulting compound. The reaction for producing a prodrug can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation, etc.

[0199] 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.

[0200] In the reactions in 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. The amounts of solvent, starting materials, reagents, etc. used can be appropriately determined depending on the progress of the reaction.

[0201] In addition, functional group conversion on the heterocycle in the production intermediates used in each step of the following Methods A to J can be carried out by a method known per se (specifically, by converting a halogen atom to C 1-6 Alkyl group or C 3-6 The reaction conditions for conversion to a cycloalkyl group can be, for example, the methods described in Zou, G.; Reddy, YK; Falck, J.R. Tetrahedron Lett. 2001, 42, 7213; Molander, G.A.; 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) or methods equivalent thereto, or the methods described in the Examples below or methods equivalent thereto.

[0202] (Method A) In this production method, compound (IIA) and compound (III) are condensed to give compound (IV), and then the protecting group of compound (IV) is removed to produce compound (1).

[0203] [ka]

[0204] (In the formula, L 1 indicates a leaving group, and Pro 1 is a protecting group (preferably a C protecting group such as a methyl group, an ethyl group, or a tert-butyl group). 1-6 an alkyl group, or a 2-(trimethylsilyl)ethyl group; and the other symbols are as defined above.

[0205] (Process A-1) 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.

[0206] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0207] The base to be used is not particularly limited as long as it is one that is used as a base in a normal 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; and alkali metal phosphates such as tripotassium phosphate.

[0208] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0209] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0210] (Process A-2) This step is to remove the protecting group (Pro 1 ) to produce compound (1).

[0211] This process is Pro 1 Depending on the type of Pro, a known method described in, for example, "Protective Groups in Organic Synthesis" by P.G. Wuts, 5th Edition, Wiley, 2014, etc. is appropriately selected and carried out according to the method. 1 a method of converting Pro into a hydrogen atom (Step A-2-1), 1 or by converting Pro into a hydrogen atom (Step A-2-2), or by using a fluoride salt in a solvent. 1 to a hydrogen atom (Step A-2-3), but this step is not limited thereto.

[0212] (Process A-2-1) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; esters such as ethyl acetate, propyl acetate, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0213] The base used is not particularly limited as long as it is one that is used as a base in a usual reaction, and examples thereof include 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 hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0214] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 10°C and 90°C.

[0215] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 1 minute to 24 hours, preferably from 10 minutes to 6 hours.

[0216] (Process A-2-2) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; esters such as ethyl acetate, propyl acetate, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0217] The acid to be used is not particularly limited as long as it is an acid that is commonly used in reactions, and examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide and trimethylsilane iodide; and organic acids such as trifluoroacetic acid.

[0218] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between -78°C and 100°C.

[0219] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0220] (Process A-2-3) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; esters such as ethyl acetate, propyl acetate, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0221] The fluoride salt to be used is not particularly limited, but examples thereof include tetrabutylammonium fluoride, hydrogen fluoride pyridine, and the like.

[0222] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 100°C, preferably between -20°C and 60°C.

[0223] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0224] (Method B) In this production method, compound (IIB) is subjected to a reductive amination reaction with compound (III) to give compound (IV), and then the protecting group of compound (IV) is removed to produce compound (1).

[0225] [ka]

[0226] (In the formula, Pro 1 is a protecting group (preferably a C protecting group such as a methyl group, an ethyl group, or a tert-butyl group). 1-6 an alkyl group, or a 2-(trimethylsilyl)ethyl group; and the other symbols are as defined above.

[0227] (Process B-1) This step is a step of producing compound (IV) by carrying out a reductive amination reaction between compound (IIB) and 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.

[0228] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0229] The reducing agent to be used is not particularly limited, but examples thereof include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, picoline borane, pyridine borane, and the like.

[0230] The acid that can be used is not particularly limited as long as it is an acid that is used as an acid in a normal reaction, and examples thereof include Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0231] Additives that can be used are not particularly limited, but examples include inorganic salts such as sodium sulfate and magnesium sulfate.

[0232] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between 0°C and 50°C.

[0233] The reaction time varies depending on the raw material compounds, reagents, etc., but is usually 5 minutes to 168 hours, preferably 10 minutes to 120 hours.

[0234] (Process B-2) This step is to remove the protecting group (Pro 1 ) to produce compound (1).

[0235] The reaction in this step can be carried out under the same conditions as in the above step A-2.

[0236] (C method) In this production method, compound (IIC) and compound (III) are subjected to a Mitsunobu reaction to obtain compound (IV), and then the protecting group of compound (IV) is removed to produce compound (1).

[0237] [ka]

[0238] (In the formula, Pro 1 is a protecting group (preferably a C group such as a methyl group, an ethyl group, a tert-butyl group, etc.) 1-6 an alkyl group, or a 2-(trimethylsilyl)ethyl group; and the other symbols are as defined above.

[0239] (Process C-1) This step is a step of producing compound (IV) by carrying out the Mitsunobu reaction between compound (IIC) and compound (III) in a solvent.

[0240] Examples of the solvent to be used 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 preferred, and dichloromethane or tetrahydrofuran is more preferred.

[0241] The reagent used in the Mitsunobu reaction is not particularly limited as long as it is a known reagent that can normally be used in the Mitsunobu reaction. Preferred examples include combinations of azo compounds such as di-lower alkyl azodicarboxylates, such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate; azodicarboxamides, such as 1,1'-azobis(N,N-dimethylformamide) and 1,1'-(azodicarbonyl)dipiperidine, with phosphines such as triarylphosphines, such as triphenylphosphine; and tri-lower alkylphosphines, such as tri-n-butylphosphine; and more preferred is a combination of di-tert-butyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine with tri-n-butylphosphine.

[0242] The reaction temperature varies depending on the starting compounds or reagents, but is usually between -50°C and 100°C, preferably between -10°C and 60°C.

[0243] The reaction time varies depending on the reaction temperature, the starting compounds, the reaction reagents, and the types of solvent used, but is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0244] (Process C-2) This step is to remove the protecting group (Pro 1 ) to produce compound (1).

[0245] The reaction in this step can be carried out under the same conditions as in the above step A-2.

[0246] (D method) This production method involves producing compound (IIA-1), compound (IIB-1), and compound (IIC-1) (R in the formulas (IIA), (IIB), and (IIC)), which are intermediate compounds used in the above-mentioned methods A to C. 1a and R 1b This is a method for producing a compound in which both the aryl and aryl groups are hydrogen atoms.

[0247] [ka]

[0248] (In the formula, R 12 represents a hydrogen atom, an alkyl group, or a haloalkyl group; L 1 indicates a leaving group, and Pro 1 is a protecting group (preferably a C protecting group such as a methyl group, an ethyl group, or a tert-butyl group). 1-6 an alkyl group, or a 2-(trimethylsilyl)ethyl group; and the other symbols are as defined above.

[0249] (Process D-1) This step is a step of converting compound (V) to compound (VI) in a solvent. Here, a bromination method will be described, but the present invention is not limited to this.

[0250] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; carboxylic acids such as acetic acid, trifluoroacetic acid, etc.; sulfonic acids such as methanesulfonic acid; mineral acids such as sulfuric acid; and mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio.

[0251] The brominating agent to be used is not particularly limited, but examples thereof include N-bromosuccinimide, bromine, and the like.

[0252] 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.

[0253] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0254] (Process D-2) In this step, compound (VI) is converted into an amide compound in a solvent (step D-2-1), and then a nitro group is introduced (step D-2-2) (or a nitro group is introduced and then the compound is converted into an amide compound), thereby converting the compound into compound (VII).

[0255] (Step D-2-1) (Conversion step to amide compound) Here, compound (VI) is reacted with formic acid (R 12 represents a hydrogen atom (Step D-2-1a), and a method of reacting compound (VI) with an alkylcarboxylic acid (R 12 R is an alkyl group or a haloalkyl group12 A method for amidating a compound represented by formula (C1H) using an appropriate condensing agent (Step D-2-1b) will be described below, but the present invention is not limited to this.

[0256] (Process D-2-1a) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0257] The acid anhydride that can be used is not particularly limited as long as it is an acid anhydride that is used in ordinary reactions, and examples thereof include carboxylic acid anhydrides such as acetic anhydride.

[0258] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between 0°C and 50°C.

[0259] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0260] (Process D-2-1b) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0261] The base to be used is not particularly limited as long as it is one that is used as a base in a usual 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; and alkali metal phosphates such as tripotassium phosphate.

[0262] The condensing agent used is not particularly limited as long as it is a condensing agent used to form an amide bond (for example, the methods described in Kusumoto Shoichi et al., Experimental Science Lectures IV; Chemical Society of Japan; Maruzen, 1990; Izumiya Nobuo et al., Fundamentals and Experiments of Peptide Synthesis; Maruzen, 1985). Preferred 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 (EDCI), 4-(2-{[(cyclohexyl)methyl]pyridinium tetrafluoroborate)} Examples of suitable methyl ...

[0263] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0264] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0265] (Step D-2-2) (Nitro group introduction step) This step is a step of introducing a nitro group using a nitrating agent. Here, a method of using a suitable nitrating agent in a solvent in the presence or absence of a suitable acid will be described, but the present invention is not limited to this.

[0266] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting materials to some extent. However, it is preferable to use an acid that also serves as a solvent. Examples of the acid include mineral acids such as sulfuric acid and mixed solvents containing a plurality of solvents in any ratio.

[0267] The nitrating agent used is not particularly limited as long as it is one that is used as a nitrating agent in ordinary reactions, and examples thereof include mineral acids such as nitric acid.

[0268] 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.

[0269] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0270] (Process D-3) In this step, compound (VII) is reduced with a suitable reducing agent in a solvent to convert it into compound (VIII).

[0271] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide, etc.; and mixed solvents containing a plurality of the above organic solvents in any ratio.

[0272] The reducing agent used is not particularly limited as long as it is one that is used as a reducing agent in ordinary reactions, 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.

[0273] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between 0°C and 80°C.

[0274] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0275] (Process D-4) In this step, the fluorine atom of compound (IX) is converted to NHR 2 After converting to a group (Step D-4-1), a bromine atom is introduced (Step D-4-2) (or after introducing a bromine atom, a fluorine atom is introduced to NHR 2 In step D-4, either step D-4-1 or step D-4-2 may be carried out first, and the order can be appropriately selected by a person skilled in the art.

[0276] (Process D-4-1) This step is carried out by reacting a primary amine (R 2 NH2 (R in the formula 2 has the same meaning as above. 2 This is a process for converting the

[0277] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; alcohols such as methanol, ethanol, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above organic solvents in any ratio; and mixed solvents containing the above organic solvent and water in any ratio.

[0278] The base that can be used is not particularly limited as long as it is one that is used as a base in a usual reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; 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;

[0279] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0280] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.

[0281] (Process D-4-2) This step is a step of introducing a bromine atom in a solvent, and the reaction can be carried out under the same conditions as in the above-mentioned step D-1.

[0282] (Process D-5) This step is a step of producing compound (X) by converting the nitro group of compound (VIII) to an amino group in a solvent.

[0283] Methods for converting the nitro group of compound (VIII) to an amino group include, but are not limited to, 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).

[0284] (Process D-5-1) This step is a step of converting the nitro group of compound (VIII) into an amino group using a metal in a solvent in the presence of an acid.

[0285] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0286] The acid to be used is not particularly limited as long as it is an acid that is used in ordinary reactions. 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 trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0287] The metal to be used is not particularly limited, but examples thereof include iron, zinc, tin, and the like.

[0288] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0289] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0290] (Process D-5-2) 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 a suitable metal catalyst.

[0291] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0292] The metal catalyst to be used is not particularly limited, but suitable examples include metal catalysts such as palladium-activated carbon, platinum-activated carbon, nickel, and osmium-activated carbon.

[0293] Examples of the hydrogen source that can be used include hydrogen gas, ammonium formate, and hydrazine.

[0294] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0295] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0296] (Process D-5-3) This step involves converting the nitro group of compound (VIII) to an amino group using an appropriate metal hydride in a solvent.

[0297] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above organic solvents in any ratio.

[0298] The metal hydride to be used is not particularly limited, but a suitable example is lithium aluminum hydride.

[0299] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 150°C, preferably between 0°C and 100°C.

[0300] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0301] (Process D-6) This step is a step of producing compound (XI) by constructing a triazole ring from compound (X). Hereinafter, a method using a nitrite or a nitrite ester in a solvent in the presence of an acid will be described, but the present invention is not limited thereto.

[0302] That is, this step is a step of constructing a triazole ring by reacting compound (X) with a nitrite or a nitrite ester in a solvent in the presence of an acid.

[0303] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0304] The acid to be used is not particularly limited as long as it is an acid that is used in ordinary reactions. 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 trimethylsilane iodide; and organic acids such as acetic acid and trifluoroacetic acid.

[0305] The nitrites to be used are not particularly limited, but examples thereof include alkali metal salts such as sodium nitrite.

[0306] The nitrite esters to be used are not particularly limited, but examples thereof include isobutyl nitrite and tert-butyl nitrite.

[0307] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -20°C and 100°C, preferably between -10°C and 60°C.

[0308] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0309] (Process D-7) In this step, an acrylate compound is reacted 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 bromo group of compound (XI) into an acrylate group (-CH=CH-COPro 1 ) to produce compound (XII).

[0310] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0311] The base that can be used is not particularly limited as long as it is one that is used as a base in a usual reaction, but suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; 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;

[0312] The additives that can be used are not particularly limited as long as they are used in known methods. Suitable additives include, for example, metal oxides such as silver oxide and alumina; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-toluyl)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, and these may be used in combination in any ratio.

[0313] The metal catalyst used is not particularly limited as long as it is one that is used in a known method, but suitable examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride diphenylphosphinoferrocene complex, palladium dichloride benzonitrile complex, palladium dichloride 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.

[0314] The acrylic acid ester compound to be used is not particularly limited, but examples thereof include methyl acrylate, ethyl acrylate, and tert-butyl acrylate.

[0315] 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.

[0316] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0317] (Process D-8) This step is a step of producing 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.

[0318] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0319] The base that can be used is not particularly limited as long as it is one that is used as a base in a normal reaction. Suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkaline earth metal carbonates such as magnesium carbonate, etc.; alkali metal hydrogencarbonates such as potassium hydrogencarbonate, etc.; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate, etc.; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides such as magnesium hydroxide, etc.; alkali metal phosphates such as tripotassium phosphate, etc.;

[0320] The additives that can be used are not particularly limited as long as they are used in known methods. Preferred examples include phosphines such as 2,3-bis(diphenylphosphino)butane, and different types of phosphines may be used in combination at any ratio.

[0321] The metal catalyst used is not particularly limited as long as it is one 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.

[0322] 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.

[0323] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0324] (Process D-9) In this step, the hydroxy group of compound (IIC-1) is converted into a leaving group (L 1 ) to produce compound (IIA-1).

[0325] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide, etc.; and mixed solvents containing a plurality of the above organic solvents in any ratio.

[0326] The acid chloride or acid anhydride to be used is not particularly limited, but suitable examples include acid chlorides of sulfurous acid such as thionyl chloride; substituted or unsubstituted alkylsulfonic acid anhydrides or arylsulfonic acid anhydrides such as trifluoromethanesulfonic acid anhydride; substituted or unsubstituted alkylsulfonyl chlorides or arylsulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride; substituted or unsubstituted alkylphosphate chlorides or arylphosphate chlorides; and the like.

[0327] The base that can be used is not particularly limited as long as it is one that is used as a base in a normal reaction, but suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; 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; and alkali metal phosphates such as tripotassium phosphate.

[0328] 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.

[0329] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0330] (Process D-10) In this step, the hydroxy group of compound (IIC-1) is converted to a formyl group using an appropriate oxidizing agent in a solvent to produce compound (IIB-1).

[0331] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0332] The oxidizing agent used is not particularly limited, but can be appropriately selected from known methods described in, for example, "Experimental Chemistry Lectures, 4th Edition (21. Organic Synthesis III: Aldehydes, Ketones, and Quinones)" by Kazuhiro Maruyama et al., Chemical Society of Japan, Maruzen Co., Ltd., 1990, and the present step is carried out in accordance with such methods. Representative examples of 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 dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or a combination of oxalyl chloride and dimethyl sulfoxide (DMSO); and oxidation reactions using hyperatomic iodine compounds (Dess-Martin reagents).

[0333] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between 0°C and 50°C.

[0334] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0335] (Law E) This production method involves producing compound (IIA-2), compound (IIB-2) and compound (IIC-2) (R in the formulas (IIA), (IIB) and (IIC)), which are intermediate compounds used in the above methods A to C. 1a and R 1b However, each independently, C 1-6 This is a method for producing a compound in which the alkyl group is an alkyl group.

[0336] [ka]

[0337] (In the formula, Pro 1 is a protecting group (preferably a C group such as a methyl group or an ethyl group) 1-6 alkyl group or 2-(trimethylsilyl)ethyl group, and Pro 2 represents a protecting group (preferably a p-methoxybenzyl group), and the other symbols are as defined above.

[0338] (Process E-1) In this step, the hydroxy group of compound (IIC-1) is protected by a protecting group (Pro 2 Here, the protecting group is a p-methoxybenzyl group, and a method using an appropriate protecting reagent in the presence of an acid will be described, but the present invention is not limited thereto.

[0339] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the above organic solvents in any ratio.

[0340] The acid to be used is not particularly limited as long as it is an acid that is used as an acid in a normal reaction, and 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 trimethylsilane 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.

[0341] Examples of the protecting reagent to be used include 4-methoxybenzyl-2,2,2-trichloroacetimidate, 2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine, and the like.

[0342] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -50°C and 150°C, preferably between -20°C and 100°C.

[0343] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0344] (Process E-2) This step is carried out by reacting a compound C with a suitable base in a solvent or without a solvent. 1-6 Alkyl halide or C 1-6 By using an alkyl pseudohalide, C is added to the α-position of the ester group of compound (XIV). 1-6 Alkyl group R 1a and R 1b to produce compound (XV).

[0345] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0346] The base to be used is not particularly limited, but 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 alkoxides such as sodium tert-butoxide and potassium tert-butoxide; metal amides such as lithium diisopropylamide and sodium hexamethyldisilazide; organometallic compounds such as tert-butyllithium; and metal hydrides such as potassium hydride and sodium hydride.

[0347] A pseudohalide refers to a substituent known to undergo a substitution reaction in an alkylation reaction, similar to a halide. It is not particularly limited as long as it is a substituent known to undergo the substitution reaction, but 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 as long as it is a known compound or can be synthesized according to a known method.

[0348] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -80°C and 150°C, preferably between -20°C and 60°C.

[0349] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0350] (Process E-3) This step involves removing the protecting group (Pro 2 ) is removed. 2 When is a p-methoxybenzyl group, a method for removing it using an appropriate oxidizing agent in a solvent (Step E-3a) and a method for removing it using an appropriate acid in the presence or absence of anisole (Step E-3b) will be described, but the method is not limited thereto.

[0351] (Step E-3a) (Deprotection step using an oxidizing agent) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0352] The oxidizing agent used may be, for example, 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0353] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -20°C and 150°C, preferably between 0°C and 100°C.

[0354] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0355] (Step E-3b) (Deprotection step using acid) The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0356] The acid to be used is not particularly limited as long as it is an acid that is commonly used in reactions, and examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid; Lewis acids such as boron trifluoride, boron trichloride, boron tribromide and trimethylsilane iodide; and organic acids such as trifluoroacetic acid.

[0357] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between -78°C and 100°C.

[0358] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0359] (Process E-4) This step is a step of converting compound (IIC-2) to compound (IIA-2), and can be carried out in accordance with the above step D-9.

[0360] (Process E-5) This step is a step of converting compound (IIC-2) to compound (IIB-2), and can be carried out in accordance with the above step D-10.

[0361] (F method) This production method is a method for producing compound (XIII), which is an intermediate compound used in the above-mentioned Method D, from compound (XVI).

[0362] [ka]

[0363] (In the formula, L 2 indicates a leaving group, and Pro 3 represents a protecting group (preferably an acetyl group), and the other symbols are as defined above.

[0364] (Process F-1) This step is a step of producing compound (XVII) by introducing a bromo 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 present invention is not limited to this method.

[0365] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the above organic solvents in any ratio.

[0366] Examples of the catalyst that can be used include radical initiators such as azobisisobutyronitrile and benzoyl peroxide.

[0367] Examples of the brominating agent that can be used include N-bromosuccinimide and N-bromoacetamide.

[0368] 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.

[0369] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0370] (Process F-2) In this step, the bromo group of compound (XVII) is converted into a protecting group (Pro 3 ) to produce compound (XVIII). Here, a method using a carboxylic acid metal salt in a solvent will be described, but the present invention is not limited to this method.

[0371] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0372] Examples of the metal carboxylates that can be used include potassium acetate, sodium acetate, potassium benzoate, and sodium benzoate.

[0373] 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.

[0374] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0375] (Process F-3) This step is to remove the protecting group (Pro 3 ) to produce compound (XIX), which can be carried out in accordance with the above-mentioned step A-2-1.

[0376] (Process F-4) This step is carried out by reacting the leaving group (L) of compound (XIX) with a suitable metal catalyst and a boron compound in a solvent under an inert gas (nitrogen or argon) atmosphere, in the presence or absence of a base, and in the presence or absence of an additive. 2 ) to a boronic acid ester to produce compound (XIII).

[0377] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0378] The boron compound used is not particularly limited as long as it is one that is commonly used in the synthesis of boronate esters, but suitable examples include bis(pinacolato)diboron, pinacolborane, and the like.

[0379] The base that can be used is not particularly limited as long as it is one that is used as a base in a usual reaction, but 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 hydrogencarbonates such as sodium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; 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;

[0380] The additives that can be used are not particularly limited as long as they are used in known methods. Suitable additives include, for example, metal oxides such as silver oxide and alumina; phosphines such as triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-toluyl)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, and these may be used in combination in any ratio.

[0381] The metal catalyst used is not particularly limited as long as it is one used in a known method, but suitable examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride diphenylphosphinoferrocene complex, palladium dichloride benzonitrile complex, palladium dichloride 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-activated carbon.

[0382] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -10°C and 200°C, preferably between 0°C and 150°C.

[0383] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 12 hours.

[0384] (G method) This production method is a method for producing compound (XIII), which is an intermediate compound used in the above-mentioned Method D, from compound (XX).

[0385] [ka]

[0386] (In the formula, L 3 indicates a leaving group, and Pro 4 is a protecting group (preferably a C group such as a methyl group or an ethyl group) 1-6 is an alkyl group, and the other symbols are as defined above.

[0387] (Process G-1) 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.

[0388] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0389] The base that can be used is not particularly limited as long as it is one that is used as a base in a usual reaction, but 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 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 metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide.

[0390] The additives that can be used are not particularly limited as long as they are used in known methods, but preferred examples include metal oxides such as silver oxide and alumina; triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri(o-toluyl)phosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropyl ... Examples of suitable phosphines include phosphines such as 2,2'-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; and acid anhydrides such as acetic anhydride, and these may be used in any combination.

[0391] The metal catalyst used is not particularly limited as long as it is one that is used in a known method, but suitable examples include palladium catalysts such as tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, palladium diacetate, palladium dichloride diphenylphosphinoferrocene complex, palladium dichloride benzonitrile complex, palladium dichloride 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.

[0392] The alcohol used (Pro 4 OH) is not particularly limited, but examples thereof include methanol and ethanol.

[0393] The carbon monoxide source to be used is not particularly limited, but examples thereof include carbon monoxide gas, lithium formate, and 2,4,6-trichlorophenyl formate.

[0394] 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.

[0395] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0396] (Process G-2) In this step, compound (XXI) is added with a leaving group L 2 (preferably a halogen atom or a pseudohalogen atom group) to produce compound (XXII). For example, 2 When is a bromo group, the reaction can be carried out in accordance with the above step D-1, but is not limited thereto.

[0397] (Process G-3) In this step, compound (XXII) is reduced with an appropriate reducing agent in a solvent to produce compound (XIX).

[0398] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0399] The reducing agent used is not particularly limited as long as it is used as a reducing agent in a usual reaction, and examples thereof include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium borohydride.

[0400] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between -78°C and 80°C.

[0401] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0402] (Process G-4) In this step, the carboxy group of compound (XXIII) is converted to C 1-6 This is a step of producing compound (XXI) by converting the alkyl ester group to an alkyl ester group. Here, a method of condensing with a corresponding alcohol in the presence of an acid is described, but the present invention is not limited to this.

[0403] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, for example, alcohols such as methanol, ethanol, n-butanol, etc., or mixed solvents containing any ratio of such alcohols and organic solvents can be used as the solvent and reactant.

[0404] The acid to be used is not particularly limited, but examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid; and organic acids such as p-toluenesulfonic acid.

[0405] 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.

[0406] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0407] (Process G-5) In this step, compound (XXIII) is reacted with a leaving group L 2 (preferably a halogen atom or a pseudohalogen atom group) to produce compound (XXIV). For example, 2 When is a bromo group, the reaction can be carried out in accordance with the above step D-1, but is not limited thereto.

[0408] (Process G-6) In this step, compound (XXIV) is reduced with an appropriate reducing agent in a solvent to produce compound (XIX).

[0409] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but suitable examples include ethers such as diethyl ether and tetrahydrofuran.

[0410] The reducing agent used is not particularly limited as long as it is used as a reducing agent in ordinary reactions, and examples thereof include lithium aluminum hydride, borane-tetrahydrofuran complex, and the like.

[0411] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 100°C, preferably between -78°C and 50°C.

[0412] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0413] (Process G-7) This step is carried out by reacting the leaving group (L 2 ) to a boronic acid ester to produce compound (XIII), which can be carried out in accordance with the above step F-4.

[0414] (H method) This production method is a method for producing compound (III), which is an intermediate compound used in the above-mentioned Methods A and B, and in which Z is a group represented by the above-mentioned formula A1. Below, a method for producing compound (IIIA1-1), in which the group W in the above-mentioned formula A1 is an oxygen atom, will be described, but the present invention is not limited thereto.

[0415] [ka]

[0416] (In the formula, L 4 represents a leaving group (preferably a halogen atom or a pseudohalogen atom group), and Pro 5 represents a protecting group (preferably a p-methoxybenzyl group, an allyl group, or a benzyl group), and the other symbols are as defined above.

[0417] (Process H-1) In this step, a nucleophilic addition reaction is carried out on the formyl group of compound (XXV) using an appropriate organometallic compound in a solvent to form a substituent R 8 to produce compound (XXVI).

[0418] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above organic solvents in any ratio.

[0419] Examples of the organometallic reagent to be used include organolithium compounds such as methyllithium and n-butyllithium; Grignard reagents such as methylmagnesium bromide and ethylmagnesium bromide; and organozinc compounds such as diethylzinc.

[0420] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 100°C, preferably between -80°C and 50°C.

[0421] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 12 hours, preferably 10 minutes to 6 hours.

[0422] (Process H-2) This step is a step of oxidizing the hydroxy group of compound (XXVI) to a carbonyl group, and can be carried out in accordance with the above step D-10.

[0423] (Process H-3) This step is a step for producing compound (XXX) from compound (XXVI) and compound (XXVIII). Hereinafter, a method will be described in which the hydroxy group of compound (XXVI) is converted to a leaving group (step H-3-1), followed by condensation with compound (XXVIII) (step H-3-2), but the method is not limited thereto.

[0424] (Process H-3-1) This step can be carried out in accordance with the above step D-9.

[0425] (Process H-3-2) This step can be carried out in accordance with the above step A-1.

[0426] (Process H-4) This step is a step of producing compound (XXX) by reductive amination reaction of compound (XXVII) and compound (XXVIII). Below, a method using a hydride reducing agent in a solvent (step H-4a) and a method using formic acid in the presence of an iridium catalyst (step H-4b) will be described, but the present invention is not limited to these.

[0427] (Process H-4a) This step is carried out in accordance with the above step B-1.

[0428] (Process H-4b) This step can be carried out using formic acid in a solvent in the presence of an iridium catalyst.

[0429] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0430] The iridium catalyst used is not particularly limited as long as it is one used in a known method, but suitable examples include chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium(III), chloro(pentamethylcyclopentadienyl)(4-dimethylamino-8-quinolinolato)iridium(III), and the like.

[0431] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -20°C and 150°C, preferably between 0°C and 100°C.

[0432] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0433] (Process H-5) This step is a step for producing compound (XXXI) from compound (XXVI) and compound (XXIX), and can be carried out in accordance with the above step H-3.

[0434] (Process H-6) This step is a step of producing compound (XXXI) by reductive amination reaction of compound (XXVII) with compound (XXIX), and is carried out in accordance with the above step H-4.

[0435] (Process H-7) This step is a step of producing compound (IIIA1-1) from compound (XXX) by using an appropriate base in a solvent.

[0436] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0437] The base to be used is not particularly limited as long as it is one that is used as a base in a usual reaction, and examples thereof include organic bases such as triethylamine; alkali metal alkoxides 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 hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; and alkali metal phosphates such as tripotassium phosphate.

[0438] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 150°C, preferably between 0°C and 80°C.

[0439] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0440] (Process H-8) In this step, the secondary amino group of compound (XXX) is protected by a protecting group (Pro 5 ) to prepare compound (XXXI), 5 Depending on the type of the compound, a known method described in, for example, "Protective Groups in Organic Synthesis" by P.G. Wuts, 5th Edition, Wiley, 2014, is appropriately selected and carried out according to the method. 5 When is a p-methoxybenzyl group, a method using reductive amination (Step H-8a) and a method using p-methoxybenzyl halides (Step H-8b) will be described, but the present invention is not limited thereto.

[0441] (Process H-8a) This step is a reductive amination step using compound (XXX) and p-methoxybenzaldehyde, and can be carried out in accordance with the above step B-1.

[0442] (Process H-8b) 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 a suitable base.

[0443] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some 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 above-mentioned organic solvents in any ratio.

[0444] The base to be used is not particularly limited as long as it is one that is used as a base in a usual reaction, and examples thereof include organic bases such as triethylamine; alkali metal alkoxides 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 hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; metal hydrides such as sodium hydride; and alkali metal phosphates such as tripotassium phosphate.

[0445] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -100°C and 200°C, preferably between 0°C and 150°C.

[0446] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0447] (Process H-9) This step is a step for producing compound (IIIA1-1) from compound (XXXI), and involves forming a 7-membered ring from compound (XXXI) using an appropriate base in a solvent (step H-9-1), and then removing a protecting group (Pro 5 ) (Step H-9-2) to convert it into compound (IIIA1-1).

[0448] (Process H-9-1) This step can be carried out in accordance with the above step H-7.

[0449] (Process H-9-2) This step involves removing the protecting group (Pro 5 ) and can be carried out in accordance with step E-3.

[0450] (I Method) This production method is a method for producing compound (III), which is an intermediate compound used in the above-mentioned Methods A and C, and in which Z is a group represented by the above-mentioned formula A2. Below, a method for producing compound (IIIA2-1), in which the group W in the above-mentioned formula A2 is an oxygen atom, will be described, but the present invention is not limited thereto.

[0451] [ka]

[0452] (In the formula, L 5 and L 6 each independently represents a leaving group (preferably a halogen atom or a pseudohalogen atom group), and the other symbols have the same meanings as defined above.

[0453] (Process I-1) 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.

[0454] The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, etc.; esters such as ethyl acetate, propyl acetate, etc.; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.; alcohols such as methanol, ethanol, tert-butanol, etc.; nitriles such as acetonitrile; amides such as formamide, N,N-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide; mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0455] The base to be used is not particularly limited as long as it is one that is used as a base in a normal reaction, but suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkaline earth metal carbonates such as magnesium carbonate, etc.; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate, etc.; alkali metal hydroxides such as sodium hydroxide, etc.; alkaline earth metal hydroxides such as magnesium hydroxide, etc.; alkali metal phosphates such as tripotassium phosphate, etc.

[0456] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually between -80°C and 100°C, preferably between -20°C and 50°C.

[0457] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0458] (Process I-2) This step is a step for producing compound (IIIA2-1) from compound (XXXIII), and can be carried out in accordance with the above step H-7.

[0459] (J method) This production method is a method for producing compound (III), which is an intermediate compound used in the above-mentioned Methods A and C, and in which Z is a group represented by the above-mentioned formula A3. Below, a method for producing compound (IIIA3-1), in which group W in the above-mentioned formula A3 is an oxygen atom, will be described, but the present invention is not limited thereto.

[0460] [ka]

[0461] (In the formula, L 7 and L 8each independently represents a leaving group (preferably a halogen atom or a pseudohalogen atom group), and the other symbols have the same meanings as defined above.

[0462] (Process J-1) This step is a step of producing compound (XXXV) by condensing compound (XXXIV) with compound (XXVIII), and can be carried out in accordance with the above step I-1.

[0463] (Process J-2) This step is a step for producing compound (IIIA3-1) from compound (XXXV), and can be carried out in accordance with the above step H-7.

[0464] The compound (1) or a pharmaceutically acceptable salt thereof obtained by the above-mentioned production method can be isolated and purified by a conventional separation means such as recrystallization, distillation, chromatography, etc.

[0465] When compound (1) of the present invention or a pharmaceutically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon, it can be separated into individual optical isomers by conventional optical resolution methods (e.g., fractional crystallization, resolution using a chiral column). Alternatively, 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.

[0466] (Medicine (or pharmaceutical composition) of the present invention) The pharmaceutical of the present invention is a pharmaceutical for preventing and / or treating oxidative stress-related diseases, which contains compound (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0467] The pharmaceutical of the present invention may be either a pharmaceutical consisting solely of compound (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, etc. The pharmaceutical of the present invention can be administered in a pharmaceutically effective amount to a subject (e.g., a mammal such as a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, or monkey).

[0468] Examples of pharmaceutically acceptable carriers include excipients (e.g., starch, lactose, sugar, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (e.g., magnesium stearate, talc, etc.), disintegrants (e.g., carboxymethylcellulose, talc, etc.), solvents (e.g., water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.), solubilizers (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., surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.); hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.;Polysorbates, polyoxyethylene hydrogenated castor oil, etc.), isotonic agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), buffers (e.g., buffer solutions such as phosphates, acetates, carbonates, and citrates), soothing agents (e.g., benzyl alcohol, etc.), preservatives (e.g., parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, etc.), etc.), coloring agents (for example, water-soluble food tar dyes (for example, food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (for example, aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (for example, β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (for example, saccharin sodium, dipotassium glycyrrhizinate, stevia, etc.), flavoring agents (for example, fennel oil, cinnamon oil, ethyl vanillin, orange oil, etc.), fragrances, etc.;

[0469] The medicament (pharmaceutical composition) of the present invention can be prepared by mixing the above-mentioned components and then processing the mixture by known methods into oral preparations such as tablets, pills, fine granules, granules, capsules, dry syrups, and elixirs; or parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, implants, microcapsules, and liposome preparations. Tablets or pills may be coated with sugar or a gastric or enteric coating agent, if necessary. Preparations for parenteral administration can be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a disinfectant, or irradiation. Furthermore, a sterile solid composition can be dissolved or suspended in sterile water or a solvent for injection before use, and the resulting composition can be used as a preparation for parenteral administration.

[0470] The content of 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 usually in the range of about 0.001 to 100% by weight, preferably about 0.01 to 50% by weight, and more preferably about 0.01 to 20% by weight, based on the total weight of the preparation.

[0471] The dosage and frequency of administration of compound (1) or a pharmaceutically acceptable salt thereof of the present invention are determined appropriately for each individual case, taking into consideration the symptoms, age, sex, etc. of the patient. The dosage is usually 0.001 mg / kg to 100 mg / kg per dose for an adult when administered orally, and 0.0001 mg / kg to 10 mg / kg per dose for an adult when administered intravenously. The frequency of administration is usually 1 to 6 times per day, or 1 to 7 days.

[0472] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof is useful for treating oxidative stress-related diseases, specifically, for example, renal diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic 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-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; and heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension. cardiovascular diseases; central nervous system 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; mitochondrial diseases selected from the group consisting of Friedreich's ataxia and mitochondrial myopathy; autoimmune diseases selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and ophthalmological diseases selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, keratopathy, 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 cataracts. and in particular, it is particularly effective for the prevention and / or treatment of an oxidative stress-related disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation-induced skin injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0473] Compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with other drugs (concomitant drugs) as long as the efficacy of the compound (1) is not impaired. The concomitant drugs are not particularly limited, and suitable examples include one or more known drugs conventionally 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 injury, radiation-induced mucosal injury, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[0474] Other drugs (concomitant drugs) suitable for use in combination with compound (1) of the present invention or a pharmaceutically acceptable salt thereof include, but are not limited to, ACE inhibitors (e.g., enalapril, etc.), angiotensin II receptor antagonists (e.g., olmesartan, etc.), β-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., verapamil, etc.), and the like. These include endothelin receptor antagonists (e.g., bosentan), phosphodiesterase-5 inhibitors (e.g., sildenafil), soluble guanylate cyclase (sGC) stimulators (e.g., vericiguat), L-dopa, dopamine agonists (e.g., pramipexole), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone), monoamine oxidase B (MAO-B) inhibitors (e.g., selegiline), interferon beta, and copaxone.

[0475] When a concomitant drug is used, the timing of administration is not limited, and they may be administered to the subject simultaneously or at staggered times. Staggered administration may involve administering the medicament of the present invention first and the concomitant drug later, or the concomitant drug first and the medicament of the present invention later. The respective administration methods may be the same or different. Furthermore, compound (1) of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug may be administered in combination as a single preparation (combined preparation). Examples of pharmaceutically acceptable carriers that may be used in the preparation of such a combination preparation include those used in the pharmaceutical composition of the present invention described above.

[0476] The dosage of the concomitant drug can be appropriately selected based on the dosage normally used in clinical practice. The mixing ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof to the concomitant drug can be appropriately selected depending on the subject of administration (the subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0477] The mass ratio of compound (1) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0478] Furthermore, concomitant drugs that complement and / or enhance the therapeutic effect of compound (1) or a pharmaceutically acceptable salt thereof also include those that have not been discovered to date but will be discovered in the future, based on the above-mentioned mechanism (i.e., the mechanism of Nrf2 activation through inhibition of the protein-protein interaction between Keap1 and Nrf2).

[0479] The medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration, etc. The drugs contained in the kit are supplied in a container made of a material that maintains the activity of the components of the medicament or pharmaceutical composition effectively for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas. The kit may also include instructions for use, which may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0480] Test Example 1: FP assay (in vitro) The inhibitory activity of test compounds against the binding between Nrf2 and Keap1 was measured using fluorescence polarization. A solution consisting of 50 mM Tris-HCl pH 8.0 (NACALAI, REF: 06938-15) and 5 mM DTT (SIGMA-ALDRICH, REF: 646563-10X, 5 mL) was used as the buffer. 8 μL of buffer containing 40 nM GST-fused human Keap1 (amino acid residues 325-642) protein (Protein Tech, REF: Ag0779) was placed in a black 384-well plate (final concentration: 20 nM), and 4 μL of test compound solution prepared at various concentrations in buffer was added. Some wells were left with buffer containing no Keap1 as negative controls. Wells without compound were used as positive controls. To this solution, 40 nM FITC-labeled Nrf2 peptide (FITC-X-LQLDEETGEFLPIQ (X = ε-Acp), Peptide Institute, Inc.) was added (final concentration 10 nM). After incubation at room temperature for 2 hours, fluorescence polarization was measured using a SPECTRAMAX Paradigm plate reader (Molecular Devices) at an excitation wavelength of 485 nm and an emission wavelength of 535 nm. The fluorescence polarization of the negative control was defined as 100% inhibition, and the fluorescence polarization of the positive control as 0% inhibition. The inhibition rate upon addition of the test compound was calculated using the following formula:

[0481]

number

[0482] The results of this test for each test compound are shown in Table 1 below, in a range of two concentrations (μM) that encompass a 50% inhibition rate (A: 50% inhibition rate concentration (IC 50 ) ≦ 0.01, B: 0.01 < 50% inhibitory concentration (IC 50) ≦ 0.03, C: 0.03 < 50% inhibitory concentration (IC 50 ) ≦ 0.1).

[0483] [Table 1]

[0484] Test Example 2: NAD(P)H: Quinone Oxidoreductase-1 (NQO1) Enzyme Induction Test (in vitro) The NQO1 assay was performed as previously reported (Methods in Enzymology 2004; 382: 243-258). Hepa1c1c7 cells (mouse hepatocyte cell line, ATCC, cat. No. CRL-2026) were cultured in D-MEM medium containing 10% FBS and 1% penicillin / streptomycin (5% CO2, 37°C). 1 × 10 cells were plated in a 96-well plate (Corning, REF. 353072). 4 Cells were seeded at 1000 cells / well. For background measurement, some wells were prepared with medium only, without cells seeded. The next day, the test compound dissolved in DMSO was added at a final concentration of 400 nM (final DMSO concentration: 0.004%), and the cells were cultured for approximately 48 hours. For basal activity measurement, some wells were prepared without adding any compound.

[0485] The following components were prepared: cell lysis solution (0.8% digitonin, 2 mM EDTA), reaction solution (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 (0.3 mM dicoumarol and 5 mM potassium dihydrogen phosphate, pH 7.4). After removing the medium, 50 μL of cell lysis solution was added and incubated at 37°C for 10 minutes, followed by shaking at room temperature for 10 minutes. 200 μL of reaction solution was added, and the mixture was allowed to stand at room temperature for 5 minutes. 50 μL of stop solution was added, and the absorbance at 610 nm was measured using a SpectraMax PLUS384 (Molecular Devices) or a POWERSCAN HT (DS Pharma Biomedical). The test results were analyzed using Excel, and NQO1 activity in the presence of 400 nM test compound was calculated as a fold increase over the baseline activity in the absence of compound.

[0486]

number

[0487] The results of this test for each test compound are shown in Table 2 below (A: 5 < NQO1 activity fold, B: 3 < NQO1 activity fold ≦ 5).

[0488] [Table 2]

[0489] From the above results, it was confirmed that 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.

[0490] Test Example 3 Plasma drug concentration measurement test after oral administration in rats Male SD rats (7 weeks old, Japan SLC) were orally administered 10 mg / 2 mL / kg of the test compound suspended in 0.5% methylcellulose solution. Blood samples were collected from the jugular vein using a heparinized syringe 0.5, 1, 2, 4, 6, and 24 hours after administration. After collection, 20 μL of plasma was obtained by centrifugation, and an equal volume of acetonitrile was added, followed by 200 μL of internal standard (IS) solution. After stirring, the mixture was centrifuged and the entire supernatant was filtered. The collected filtrate was used as the measurement sample. Additionally, an equal volume of the test compound solution prepared in acetonitrile was added to blank plasma, and the resulting sample was treated in the same manner as above. This sample was used as a calibration curve sample. The prepared samples were measured using LC / MS / MS, and the area under the blood concentration-time curve (AUC) was calculated from the plasma compound concentration. The test results are shown in Table 3 below.

[0491] [Table 3]

[0492] Among the example compounds, the four compounds listed in Table 3 above were confirmed to have excellent pharmacokinetics, with no systemic exposure, and to exhibit excellent pharmacokinetics as drugs for local administration. [Example]

[0493] The present invention will be described in detail by the following examples, but these examples are merely illustrative and do not limit the present invention, and may be modified within the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. % indicates mol / mol% for yield, vol% for solvents used in chromatography, and wt% for others. Nuclear magnetic resonance spectrum (hereafter 1For H-NMR (resonance frequency 400 MHz or 500 MHz), chemical shift values ​​are reported as δ values ​​(ppm) using tetramethylsilane as a standard substance or the chemical shift value of the deuterated solvent used as the reference value. Other abbreviations used in the text have the following meanings: s: singlet d: doublet dd: doublet of doublets t: triplet q:quartet m: multiplet br: broad J: Coupling constant Hz: Hertz CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide CD3OD: deuterated methanol XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl 1 H-NMR: proton nuclear magnetic resonance HPLC: High-performance liquid chromatography APCI: atmospheric pressure chemical ionization ESI: Electrospray ionization

[0494] Unless otherwise specified, the reagents, solvents, equipment, etc. used in the following examples and test examples are commercially available. Furthermore, unless otherwise specified, the raw material compounds used are known compounds and are either commercially available or synthesized and identified according to known methods or methods equivalent thereto.

[0495] Example 1 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0496] (1a) (2R)-1-aminobutan-2-ol

[0497] To a solution of (2R)-2-ethyloxirane (25 mL) in ethanol (100 mL) was added 28% aqueous ammonia (100 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and toluene was added to the residue for azeotropy. 21.6 g of a mixture containing the title compound was obtained as an oil.

[0498] (1b) 2,5-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[0499] To a mixture of (2R)-1-aminobutan-2-ol (5.10 g) from Example 1(1a), sodium bicarbonate (2.00 g), and tetrahydrofuran (71 mL), water (13 mL) was added and stirred at room temperature for 5 minutes. Next, 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 then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] to give 4.38 g (yield: 100%) of the title compound as an oil.

[0500] (1c) (4R)-8-Chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0501] 2,5-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide (4.38 g) from Example 1(1b) and potassium tert-butoxide (4.93 g) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and poured into water (100 mL). 1 M 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. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to afford the title compound (3.18 g, yield: 83%) as a solid.

[0502] (1d) 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid

[0503] Diisopropylamine (86.7 g) was dissolved in tetrahydrofuran (800 mL), and n-butyllithium (1.6 M n-hexane solution) (500 mL) was added dropwise over 25 minutes at −78°C, followed by stirring for 30 minutes. Next, a solution of 4-bromo-1-fluoro-2-methylbenzene (108 g) in tetrahydrofuran (300 mL) was 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, and the mixture was stirred for 10 minutes. After stirring for 1 hour while warming to room temperature, 2 M hydrochloric acid (800 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (830 mL), and potassium carbonate (86.5 g) and ethyl thioglycolate (54.7 mL) were added. 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 successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethanol (820 mL), 5 M aqueous sodium hydroxide solution (209 mL) was added, and the mixture was stirred at room temperature for 1 hour. 6 M 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 collected by filtration and washed with water. The resulting 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 evaporated under reduced pressure to obtain a residue. 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 evaporated under reduced pressure. The residues obtained earlier were combined, n-hexane was added, and the solid was collected by filtration to give the title compound as a solid (120.0 g, yield: 78%).

[0504] (1e) 5-Bromo-7-methyl-1-benzothiophene

[0505] 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid (105 g) from Example 1 (1d) was dissolved in 1-methyl-2-pyrrolidinone (390 mL), and 1,8-diazabicyclo[5.4.0]-7-undecene (289 mL) was added. The mixture was stirred at 190°C for 20.5 hours. 3 M 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 successively with water and 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 [eluent: n-hexane / ethyl acetate = 100 / 0 to 95 / 5 (V / V)] to give 49.8 g (yield: 57%) of the title compound as an oil.

[0506] (1f) (5-Bromo-1-benzothiophen-7-yl)methyl acetate

[0507] 5-Bromo-7-methyl-1-benzothiophene (114.2 g) from Example 1 (1e) was dissolved in carbon tetrachloride (1.0 L), and N-bromosuccinimide (98.5 g) and 2,2'-azodiisobutyronitrile (8.26 g) were added. The mixture was heated to reflux for 12 hours. The reaction mixture was returned to room temperature, and insoluble matter was filtered off. The filtrate was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (535 mL), and potassium acetate (247 g) was added. 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 evaporated under reduced pressure. The resulting residue was purified by column chromatography [eluent: n-hexane / ethyl acetate=100 / 0 to 90 / 10 (V / V)] to give 94.4 g (yield: 66%) of the title compound as a solid.

[0508] (1g) (5-Bromo-1-benzothiophen-7-yl)methanol

[0509] (5-Bromo-1-benzothiophen-7-yl)methyl acetate (50.2 g) from Example 1 (1f) was dissolved in a mixed solvent of methanol (290 mL) and tetrahydrofuran (290 mL), and 2 M aqueous sodium hydroxide solution (264 mL) was added and 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 saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. n-Hexane was added to the resulting residue, and the mixture was sonicated. The solid was collected by filtration to obtain 39.6 g (yield: 92%) of the title compound as a solid.

[0510] (1h) [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol

[0511] (5-Bromo-1-benzothiophen-7-yl)methanol (2.00 g) from Example 1 (1g) 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 cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30 (V / V)] to afford the title compound (2.75 g, yield: quantitative) as an oil.

[0512] (1i) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[0513] [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. Next, chloro(1,5-cyclooctadiene)rhodium(I) dimer (42 mg) was added, and the mixture was stirred at 90°C for 15 minutes. 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 saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography [eluent: n-hexane / ethyl acetate=80 / 20-30 / 70 (V / V)] to give 276 mg (yield: 39%) of the title compound as a solid.

[0514] (1j) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate

[0515] 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), and tri-n-butylphosphine (0.12 mL) and 1,1'-(azodicarbonyl)dipiperidine (117 mg) were added and 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 [eluent: n-hexane / ethyl acetate = 90 / 10-40 / 60 (V / V)]. The resulting residue was purified by NH silica gel column chromatography [eluent: n-hexane / ethyl acetate=90 / 10-50 / 50 (V / V)] to give 155 mg (yield: 76%) of the title compound as a solid.

[0516] (1k) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0517] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate (155 mg) from Example 1 (1j) was dissolved in a mixed solvent of tetrahydrofuran (2.1 mL) and methanol (0.71 mL), and 1 M aqueous lithium hydroxide solution (0.71 mL) was added. The mixture was stirred at room temperature for 15 hours. A 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 then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the resulting residue, followed by ultrasonic treatment. The solid was collected by filtration to give the title compound (75.3 mg, yield: 51%) as a solid.

[0518] Example 2 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0519] (2a) Ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[0520] Using [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (300 mg) from Example 1 (1h) and ethyl (2E)-3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoate (International Publication No. 2015 / 092713) (275 mg), the title compound (167 mg, yield: 39%) was obtained as a solid in the same manner as in Example 1 (1i).

[0521] (2b) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0522] Using ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-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), in the same manner as in Example 1 (1j), 141 mg (yield: 87%) of the title compound was obtained as a solid.

[0523] (2c) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0524] Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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), and 1 M aqueous lithium hydroxide solution (0.63 mL) was added. The mixture was stirred at 40°C for 1 hour. A 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 then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 90 / 10 (V / V)]. Ethyl acetate and n-hexane were added to the resulting residue, followed by ultrasonic treatment. The solid was collected by filtration to give 91.3 mg (yield: 68%) of the title compound as a solid.

[0525] Example 3 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0526] (3a) Methyl 1-oxo-2,3-dihydro-1H-indene-4-carboxylate

[0527] 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, and 1 M hydrochloric acid and ethyl acetate were added. The mixture was filtered through Celite to remove insoluble material, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue (40.4 g) was dissolved in N,N-dimethylformamide (450 mL), potassium carbonate (31.1 g) and methyl iodide (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 successively with water and 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 [eluent: n-hexane / ethyl acetate = 90 / 10-65 / 35 (V / V), chloroform] to give 24.9 g (yield: 87%) of the title compound as a solid.

[0528] (3b) Methyl 2,3-dihydro-1H-indene-4-carboxylate

[0529] Methyl 1-oxo-2,3-dihydro-1H-indene-4-carboxylate (21.4 g) from Example 3(3a) was dissolved in methanol (330 mL), and sodium borohydride (8.51 g) was added in portions at 0°C. The mixture was stirred at room temperature for 20 minutes. 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 evaporated under reduced pressure. The resulting residue was dissolved in trifluoroacetic acid (200 mL), and triethylsilane (30 mL) was added. The mixture was stirred at room temperature for 10 minutes. Triethylsilane (30 mL) was added, and the mixture was stirred at room temperature for 70 minutes. The reaction mixture was added to a suspension of sodium bicarbonate (200 g) in water (1 L), and saturated sodium bicarbonate water was added to make the mixture basic. The mixture was then extracted 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 [eluent: n-hexane / ethyl acetate=100 / 0-90 / 10 (V / V)] to give 10.0 g (yield: 53%) of the title compound as an oil.

[0530] (3c) (6-Bromo-2,3-dihydro-1H-inden-4-yl)methanol

[0531] Methyl 2,3-dihydro-1H-indene-4-carboxylate (10.0 g) from 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 evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (210 mL), and lithium aluminum hydride (2.15 g) was added in portions over 7 minutes at 0°C. The mixture was stirred at 0°C for 30 minutes. Water (2.2 mL), 5 M aqueous sodium hydroxide solution (2.2 mL), and water (6.6 mL) were added to the reaction mixture. The mixture was stirred at room temperature for 25 minutes, and the precipitate was filtered off. The filtrate was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate=90 / 10-60 / 40 (V / V)] to give 8.13 g (yield: 63%) of the title compound as an oil.

[0532] (3d) [6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl]methanol

[0533] 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).

[0534] (3e) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0535] Ethyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (WO 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), purged with nitrogen, and heated and stirred at 80 °C for 3 hours. The reaction mixture was returned to room temperature, concentrated under reduced pressure, and the resulting residue was mixed with ethyl acetate and saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then 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 [eluent: n-hexane / ethyl acetate = 80 / 20 - 0 / 100 (V / V)] to obtain 4.651 g (yield: 73%) of the title compound as a solid.

[0536] (3f) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0537] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (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), and di-tert-butyl azodicarboxylate (4.40 g) and then triphenylphosphine (5.00 g) were added under a nitrogen atmosphere. 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 [eluent: n-hexane / ethyl acetate=70 / 30-50 / 50 (V / V)] to give 4.16 g (yield: quantitative) of the title compound as an oil.

[0538] (3g) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0539] To a mixture of ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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) from Example 3 (3f), ethanol (30 mL), and tetrahydrofuran (30 mL), 1 M aqueous sodium hydroxide solution (32.6 mL) was added and stirred at room temperature for 12 hours. 1 M hydrochloric acid (32.6 mL) was added to the reaction mixture, followed by stirring and extraction 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. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 95 / 5 (V / V / V)]. Ethyl acetate and n-hexane were added to the eluted compound, followed by ultrasonic treatment. The solid was collected by filtration and dried in vacuo to give 2.00 g (yield: 50%) of the title compound.

[0540] Example 4 (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0541] (4a) Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (4b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0542] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (59 g) from Example 3 (3e) was subjected to chiral HPLC [column: CHIRALPAK IG (50 mm ID × 250 mm), mobile phase: acetonitrile, temperature: 40 ° C.] to obtain 27.5 g of ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate as the first peak (yield: 47%). 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%). Analytical HPLC conditions: CHIRALPAK IG column (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 (first peak), 5.087 min (second peak).

[0543] (4c) Ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0544] 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) from 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) from Example 1 (1c), di-tert-butyl azodicarboxylate (50.5 mg), tetrahydrofuran (2.24 mL), and tri-n-butylphosphine (0.0664 mL) were added 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 [eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50 (V / V)] to give 96.5 mg (yield: 96%) of the title compound as an oil.

[0545] (4d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0546] Ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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 (720 mg) from Example 4(4c) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and 1 M aqueous sodium hydroxide solution (2.2 mL) was added and 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 evaporated under reduced pressure. Ethanol was added to perform azeotropy, and 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 [eluent: chloroform / methanol = 90 / 1 to 20 / 1 (V / V)]. Ethyl acetate and n-hexane were added to solidify the residue, affording 446 mg of the title compound (yield: 64%) as a solid.

[0547] Example 5 (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0548] (5a) Ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0549] 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), and 1,1'-(azodicarbonyl)dipiperidine (3.03 g) and then tri-n-butylphosphine (2.99 mL) were added under a nitrogen atmosphere and stirred at room temperature for 3 hours. Tetrahydrofuran (10 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 2 / 1-4 / 6 (V / V)]. The impurity-containing fraction was purified again by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 6 / 4-4 / 6 (V / V)]. Further purification by NH silica gel column chromatography [eluent: n-hexane / ethyl acetate = 2 / 1-1 / 1 (V / V)] was repeated twice to give 3.78 g (yield: 74%) of the title compound as a solid.

[0550] (5b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0551] To a mixture of ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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) from Example 5 (5a), ethanol (30 mL), and tetrahydrofuran (60 mL), 1 M aqueous sodium hydroxide solution (30 mL) was added 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 the mixture was stirred 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 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.

[0552] Example 6 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0553] (6a) 4-Bromo-3-fluoro-N 1 -Methylbenzene-1,2-diamine

[0554] 3-Fluoro-N-methyl-2-nitroaniline (WO 2011 / 021676) (5.27 g) was dissolved in N,N-dimethylformamide (60 mL), and a solution of N-bromosuccinimide (4.88 g) in N,N-dimethylformamide (30 mL) was added at 0°C. 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 evaporated under reduced pressure. n-Hexane was added to the resulting residue, and the solid was collected by filtration. The resulting solid was suspended in ethanol (50 mL), and tin(II) chloride dihydrate (10.6 g) was added. The mixture was heated to reflux for 1 hour. The reaction mixture was returned to room temperature and added to a separate suspension of sodium bicarbonate (15 g) in water (100 mL) and ethyl acetate (100 mL), and the mixture was 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 removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10-80 / 20 (V / V)] to give 2.95 g (yield: 89%) of the title compound as a solid.

[0555] (6b) 5-Bromo-4-fluoro-1-methyl-1H-benzotriazole

[0556] 4-Bromo-3-fluoro-N of Example 6(6a) 1 1,2-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. The mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate 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. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to give 620 mg (yield: 17%) of the title compound as a solid.

[0557] (6c) Ethyl (2E)-3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)prop-2-enoate

[0558] 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 evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to give the title compound (370 mg, yield: 43%) as a solid.

[0559] (6d) Ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0560] Example 3 (3d) [6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-inden-4-yl] methanol (481 mg) and Example 6 (6c) ethyl (2E) -3- (4-fluoro-1-methyl-1H-benzotriazol-5-yl) prop-2-enoate (370 mg) were used in the same manner as in Example 95 (95a), to obtain the title compound 390 mg (yield: 84%) as a solid.

[0561] (6e) Ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0562] Example 6 (6d) ethyl 3- (4-fluoro-1-methyl-1H-benzotriazol-5-yl) -3- [7- (hydroxymethyl) -2,3-dihydro-1H-inden-5-yl] propanoate (190 mg), and (4R) -4-methyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (International Publication No. 2015 / 092713) (122 mg) was used to prepare the title compound 260 mg (yield: 92%) as a solid in the same manner as in Example 2 (2b).

[0563] (6f) 3-(4-Fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0564] Using ethyl 3-(4-fluoro-1-methyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-methyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (260 mg) from Example 6 (6e), in the same manner as in Example 2 (2c), 186 mg of the title compound (yield: 68%) was obtained as a solid.

[0565] Example 7 (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0566] (7a) Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (7b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[0567] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (120 g) from 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-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate as a first peak (yield: 43%). 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%). Analytical SFC conditions: 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).

[0568] (7c) Ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate

[0569] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (0.20 g) from 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) from Example 1 (1c), in the same manner as in Example 3 (3f), 0.34 g of the title compound (yield: quantitative) was obtained as an oil.

[0570] (7d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0571] Using ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate (0.35 g) from Example 7 (7c), the title compound 0.24 g (yield: 72%) was obtained in the same manner as in Example 3 (3g).

[0572] Example 8 (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0573] (8a) Ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate

[0574] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (0.20 g) from 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) from Example 1 (1c), in the same manner as in Example 3 (3f), 0.32 g of the title compound (yield: quantitative) was obtained as an oil.

[0575] (8b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0576] Using ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate (0.34 g) from Example 8 (8a), the title compound 0.15 g (yield: 46%) was obtained in the same manner as in Example 3 (3g).

[0577] Example 9 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0578] (9a) 2,6-Dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide

[0579] 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 oily substance in the same manner as in Example 1(1b).

[0580] (9b) (4R)-7-Chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0581] Using 2,6-dichloro-N-[(2R)-2-hydroxybutyl]pyridine-3-sulfonamide (1.25 g) from Example 9 (9a), 1.04 g (yield: 95%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0582] (9c) Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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

[0583] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 172 mg of the title compound (yield: 53%) was obtained as a solid.

[0584] (9d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0585] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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) from Example 9 (9c), the title compound 14 mg (yield: 18%) was obtained in the same manner as in Example 3 (3g).

[0586] Example 10 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0587] (10a) 2-chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide

[0588] Using (2R)-1-aminobutan-2-ol (1.41 g) from Example 1(1a) and 2-chloro-5-methylpyridine-3-sulfonyl chloride (0.90 g), 1.1 g (yield: quantitative) of the title compound was obtained as an oily product in the same manner as in Example 1(1b).

[0589] (10b) (4R)-4-Ethyl-8-methyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0590] Using 2-chloro-N-[(2R)-2-hydroxybutyl]-5-methylpyridine-3-sulfonamide (1.2 g) from Example 10 (10a), 0.68 g (yield: 65%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0591] (10c) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0592] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 165 mg of the title compound (yield: 53%) was obtained as a solid.

[0593] (10d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0594] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-8-methyl-1,1-dioxide-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) from Example 10 (10c), in the same manner as in Example 3 (3g), 90 mg of the title compound (yield: 57%) was obtained as a solid.

[0595] Example 11 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0596] (11a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0597] Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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), trimethylboroxine 50% tetrahydrofuran solution (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 and stirred at 100°C for 4 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 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 [eluent: n-hexane / ethyl acetate = 80 / 20 - 0 / 100 (V / V)] to give 60 mg (yield: 78%) of the title compound as an oil.

[0598] (11b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0599] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-7-methyl-1,1-dioxide-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) from Example 11 (11a), in the same manner as in Example 3 (3g), the title compound 35 mg (yield: 62%) was obtained as a solid.

[0600] Example 12 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0601] (12a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0602] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (140 mg) from Example 3 (3e) and (4R)-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (WO 2015 / 092713) (80 mg), 140 mg of the title compound (yield: 65%) was obtained as a solid in the same manner as in Example 3 (3f).

[0603] (12b) 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0604] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (140 mg) from Example 12 (12a), in the same manner as in Example 3 (3g), 120 mg of the title compound (yield: 90%) was obtained as a solid.

[0605] Example 13 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0606] (13a) 5-chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0607] Using (2R)-1-aminobutan-2-ol (0.72 g) from Example 1(1a) and 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.50 g), 0.70 g (yield: quantitative) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0608] (13b) (4R)-8-Chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[0609] Using 5-chloro-2,4-difluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (0.35 g) from Example 13 (13a), 0.22 g (yield: 67%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0610] (13c) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0611] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 140 mg of the title compound (yield: 84%) was obtained as a solid.

[0612] (13d) 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0613] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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 (140 mg) from Example 13 (13c), in the same manner as in Example 3 (3g), the title compound 90 mg (yield: 67%) was obtained as a solid.

[0614] Example 14 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0615] (14a) 5-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0616] Using (2R)-1-aminobutan-2-ol (1.0 g) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.56 g) from Example 1(1a), 1.3 g (yield: quantitative) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0617] (14b) (4R)-8-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[0618] Using 5-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.3 g) from Example 14 (14a), the title compound (1.0 g, yield: 83%) was obtained as a solid in the same manner as in Example 1 (1c).

[0619] (14c) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0620] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 160 mg of the title compound (yield: 71%) was obtained as a solid.

[0621] (14d) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0622] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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 (160 mg) from Example 14 (14c), in the same manner as in Example 3 (3g), 140 mg of the title compound (yield: 92%) was obtained as a solid.

[0623] Example 15 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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

[0624] (15a) 4-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0625] Using (2R)-1-aminobutan-2-ol (1.55 g) from Example 1(1a) and 4-chloro-2-fluorobenzenesulfonyl chloride (1.0 g), 1.2 g (yield: 98%) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0626] (15b) (4R)-7-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[0627] Using 4-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.2 g) from Example 15 (15a), 0.92 g (yield: 83%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0628] (15c) Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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

[0629] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 160 mg of the title compound (yield: 99%) was obtained as a solid.

[0630] (15d) 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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

[0631] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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 (160 mg) from Example 15 (15c), in the same manner as in Example 3 (3g), the title compound (110 mg, yield: 72%) was obtained as a solid.

[0632] Example 16 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxide-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

[0633] (16a) 3-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0634] Using (2R)-1-aminobutan-2-ol (1.55 g) from Example 1(1a) and 5-chloro-2-fluorobenzenesulfonyl chloride (1.0 g), 1.2 g (yield: 98%) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0635] (16b) (4R)-6-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[0636] Using 3-chloro-2-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (1.2 g) from Example 16 (16a), 0.90 g (yield: 81%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0637] (16c) Ethyl 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxide-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

[0638] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 250 mg of the title compound was obtained as a solid (yield: 96%).

[0639] (16d) 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxide-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

[0640] Using ethyl 3-(7-{[(4R)-6-chloro-4-ethyl-1,1-dioxide-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 (250 mg) from Example 16 (16c), in the same manner as in Example 3 (3g), 160 mg of the title compound (yield: 67%) was obtained as a solid.

[0641] Example 17 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxide-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

[0642] (17a) 2-chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide

[0643] Using (2R)-1-aminobutan-2-ol (1.1 g) and 2-chloro-6-fluorobenzenesulfonyl chloride (0.70 g) from Example 1(1a), 0.90 g (yield: quantitative) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0644] (17b) (4R)-9-Chloro-4-ethyl-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide

[0645] Using 2-chloro-6-fluoro-N-[(2R)-2-hydroxybutyl]benzenesulfonamide (0.90 g) from Example 17 (17a), 598 mg (yield: 72%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0646] (17c) Ethyl 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxide-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

[0647] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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), in the same manner as in Example 3 (3f), 100 mg of the title compound was obtained as a solid (yield: 41%).

[0648] (17d) 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxide-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

[0649] Using ethyl 3-(7-{[(4R)-9-chloro-4-ethyl-1,1-dioxide-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 (100 mg) from Example 17 (17c), in the same manner as in Example 3 (3g), 65 mg of the title compound (yield: 68%) was obtained as a solid.

[0650] Example 18 3-(7-{[(4R)-8-chloro-7-ethoxy-4-ethyl-1,1-dioxide-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

[0651] 3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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) of Example 13 (13d) was dissolved in ethanol (25 mL), and 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, followed by stirring, and then extraction 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 [eluent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60 (V / V)] to give 250 mg (yield: 60%) of the title compound as a solid.

[0652] Example 19 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0653] (19a) Ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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)propanoate

[0654] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (130 mg) from 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) from Example 9 (9b), in the same manner as in Example 3 (3f), 150 mg of the title compound (yield: 93%) was obtained as a solid.

[0655] (19b) 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-7-ethoxy-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0656] Using ethyl 3-(7-{[(4R)-7-chloro-4-ethyl-1,1-dioxide-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)propanoate (150 mg) from Example 19 (19a), in the same manner as in Example 3 (3g), the title compound 85 mg (yield: 58%) was obtained as a solid.

[0657] Example 20 (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0658] (20a) Ethyl (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

[0659] Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (520 mg) from Example 4(4b) was dissolved in N,N-dimethylformamide (5 mL), and imidazole (110 mg) and triisopropylsilyl chloride (380 mg) were added. The mixture was stirred at room temperature for 3 hours. Water (2.5 mL) was added to the reaction mixture, and the mixture was stirred and 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. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to give 720 mg (yield: 99%) of the title compound as an oil.

[0660] (20b) 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

[0661] Ethyl (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 (720 mg) from Example 20 (20a) was dissolved in tetrahydrofuran (3 mL), and ethanol (3 mL) and 1 M aqueous sodium hydroxide solution (0.30 mL) were added. The mixture was stirred at room temperature for 12 hours. 1 M hydrochloric acid (0.30 mL) was added to the reaction mixture, and the mixture was stirred and 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. The resulting residue was dissolved in tert-butyl alcohol (5 mL). 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 mixture 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. The residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10 - 60 / 40 (V / V)] to give 540 mg (yield: 71%) of the title compound as an oil.

[0662] (20c) tert-Butyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0663] 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 (540 mg) of Example 20 (20b) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (2.8 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction mixture, and the mixture was stirred 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 [eluent: n-hexane / ethyl acetate = 70 / 30-20 / 80 (V / V)]. This gave 283 mg (yield: 72%) of the title compound as a solid.

[0664] (20d) tert-Butyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0665] Using tert-butyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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 title compound 140 mg (yield: 79%) was obtained as a solid in the same manner as in Example 3 (3f).

[0666] (20e) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0667] Tert-butyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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 (140 mg) of Example 20 (20d) 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, and the mixture was stirred, followed by extraction with dichloromethane. 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 [eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80 (V / V)] to obtain 73 mg (yield: 57%) of the title compound as a solid.

[0668] Example 21 (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0669] (21a) 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

[0670] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (520 mg) from Example 4 (4a), 754 mg (yield: 98%) of the title compound was obtained as an oily substance in the same manner as in Example 20 (20a) and 20 (20b).

[0671] (21b) tert-Butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0672] 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 title compound (484 mg, yield: 88%) was obtained as a solid in the same manner as in Example 20 (20c).

[0673] (21c) tert-Butyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0674] Using tert-butyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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 title compound 145 mg (yield: 81%) was obtained as a solid in the same manner as in Example 3 (3f).

[0675] (21d) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0676] Using tert-butyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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 (145 mg) from Example 21 (21c), the title compound 77 mg (yield: 58%) was obtained as a solid in the same manner as in Example 20 (20e).

[0677] Example 22 (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0678] (22a) Ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0679] Using ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (200 mg) from Example 7 (7b) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (136 mg) from Example 13 (13b), the title compound 350 mg (yield: quantitative) was obtained as a solid in the same manner as in Example 3 (3f).

[0680] (22b) (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0681] To a mixture of Example 22 (22a) ethyl (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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), tert-butanol (3.0 mL), and tetrahydrofuran (2.0 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added and stirred at room temperature for 12 hours. 1 M hydrochloric acid (1.5 mL) was added to the reaction mixture, followed by stirring and extraction 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. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 95 / 5 (V / V / V)]. Ethyl acetate and n-hexane were added to the eluted compound, followed by ultrasonic treatment. The solid was collected by filtration and dried under vacuum to give 148 mg (yield: 44%) of the title compound.

[0682] Example 23 (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0683] (23a) Ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-3,4-dihydro-2H-5,1,2-benzoxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0684] Using ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (200 mg) from Example 7 (7a) and (4R)-8-chloro-4-ethyl-7-fluoro-3,4-dihydro-2H-5,1,2-benzoxathiazepine 1,1-dioxide (136 mg) from Example 13 (13b), the title compound 330 mg (yield: quantitative) was obtained as a solid in the same manner as in Example 3 (3f).

[0685] (23b) (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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

[0686] Using ethyl (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-7-fluoro-1,1-dioxide-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 23 (23a), in the same manner as in Example 22 (22b), 70 mg of the title compound (yield: 21%) was obtained as a solid.

[0687] Example 24 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0688] (24a) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0689] Example 3 (3e) 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) was used to prepare the title compound 130 mg (yield: 94%) as a solid in the same manner as in Example 3 (3f).

[0690] (24b) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0691] Using ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-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) from Example 24 (24a), in the same manner as in Example 3 (3g), 70 mg of the title compound (yield: 56%) was obtained as a solid.

[0692] Example 25 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-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

[0693] (25a) 2-chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide

[0694] Using (2R)-1-aminobutan-2-ol (1.27 g) from Example 1(1a) and 2-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (1.0 g), 417 mg (yield: 35%) of the title compound was obtained as an oily substance in the same manner as in Example 1(1b).

[0695] (25b) (4R)-4-Ethyl-8-(trifluoromethyl)-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide

[0696] Using 2-chloro-N-[(2R)-2-hydroxybutyl]-5-(trifluoromethyl)pyridine-3-sulfonamide (417 mg) from Example 25 (25a), 370 mg (yield: quantitative) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0697] (25c) [(6-bromo-2,3-dihydro-1H-inden-4-yl)methoxy](tert-butyl)dimethylsilane

[0698] To a mixture of (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol (70 g) from Example 3(3c), imidazole (42 g), and dichloromethane (800 mL), tert-butyldimethylchlorosilane (70 g) was added and 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, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: petroleum ether] to give 98 g (yield: 93%) of the title compound as a solid.

[0699] (25d) tert-Butyl(dimethyl){[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl]methoxy}silane

[0700] Using [(6-bromo-2,3-dihydro-1H-inden-4-yl)methoxy](tert-butyl)dimethylsilane (49 g) from Example 25 (25c), 51 g (yield: 91%) of the title compound was obtained as a solid in the same manner as in Example 1 (1h).

[0701] (25e) 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

[0702] 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 solution was stirred at room temperature for 15 minutes. Next, tert-butyl (2E)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (WO 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) from Example 25 (25d), and 1 M aqueous potassium hydroxide solution (8.12 mL) were 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 the mixture was 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 [eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40 (V / V)] to obtain 4.0 g (yield: 92%) of the title compound as an oil.

[0703] (25f) tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate

[0704] Using 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 (4.0 g) from Example 25 (25e), the title compound 3.0 g (yield: 95%) was obtained as a solid in the same manner as in Example 20 (20c).

[0705] (25g) tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-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

[0706] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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 title compound (116 mg, yield: 70%) was obtained as a solid in the same manner as in Example 3 (3f).

[0707] (25h) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-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

[0708] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-4-ethyl-1,1-dioxide-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 title compound 75 mg (yield: 70%) was obtained as a solid in the same manner as in Example 20 (20 e).

[0709] Example 26 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxide-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0710] (26a) 1-Fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide

[0711] Using (2R)-1-aminobutan-2-ol (1.10 g) and 1-fluoronaphthalene-2-sulfonyl chloride (0.75 g) from Example 1(1a), 0.90 mg (yield: 99%) of the title compound was obtained as a solid by a method similar to that of Example 1(1b).

[0712] (26b) (2R)-2-Ethyl-3,4-dihydro-2H-naphtho[1,2-b][1,4,5]oxathiazepine 5,5-dioxide

[0713] Using 1-fluoro-N-[(2R)-2-hydroxybutyl]naphthalene-2-sulfonamide (900 mg) from Example 26 (26a), 700 mg (yield: 83%) of the title compound was obtained as a solid in the same manner as in Example 1 (1c).

[0714] (26c) tert-Butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxide-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0715] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-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 title compound (170 mg, yield: 96%) was obtained as a solid in the same manner as in Example 3 (3f).

[0716] (26d) 3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxide-2,3-dihydro-4H-naphtho[1,2-b][1,4,5]oxathiazepin-4-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0717] Using tert-butyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-5,5-dioxide-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 title compound (100 mg, yield: 61%) was obtained as a solid in the same manner as in Example 20 (20e).

[0718] Example 27 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-Ethyl-1,1-dioxide-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0719] (27a) (4S *)-4-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide

[0720] To a solution of 2-chloro-N-(2-methylidenebutyl)pyridine-3-sulfonamide (WO 2018 / 109643) (30 g) in toluene (500 mL) 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, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: petroleum ether / ethyl acetate = 20 / 1-5 / 1 (V / V)] and then purified by preparative HPLC [column: Phenomenex Luna C18 (100 This was purified by chiral SFC [column: CHIRALPAK IC (30 mm ID × 250 mm), mobile phase: 0.225% formic acid aqueous solution / acetonitrile = 75 / 25 - 55 / 45 (V / V)] to give the racemic title compound. This was subjected to chiral SFC [column: CHIRALPAK IC (30 mm ID × 250 mm), mobile phase: carbon dioxide / 2-propanol (0.1% aqueous ammonia) = 60 / 40 (V / V)] to give 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%). Analytical SFC conditions: Column: CHIRALPAK AS-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).

[0721] (27b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S *)-4-Ethyl-1,1-dioxide-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0722] 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 * Using 2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide (90 mg), the title compound (230 mg, yield: 95%) was obtained as a solid in the same manner as in Example 3 (3f).

[0723] (27c) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-Ethyl-1,1-dioxide-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0724] Example 27 (27b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * Using )-4-ethyl-1,1-dioxide-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (120 mg), the title compound 50 mg (yield: 44%) was obtained as a solid in the same manner as in Example 3 (3g).

[0725] Example 28 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S *)-4-Ethyl-1,1-dioxide-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0726] (28a) (4S * )-4-Ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide

[0727] 4.8 g of (4S) was obtained by subjecting 4-ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide (WO 2017 / 060854) (16 g) to chiral SFC [column: CHIRALPAK AD (30 mm ID × 250 mm), mobile phase: carbon dioxide / methanol (0.1% aqueous ammonia) = 70 / 30 (V / V)]. * )-4-Ethyl-2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide was obtained as the first peak. Analytical SFC conditions: CHIRALPAK AY-3 column (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).

[0728] (28b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-Ethyl-1,1-dioxide-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate

[0729] 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* Using 2,3,4,5-tetrahydro-1,2-benzothiazepine 1,1-dioxide (90 mg), 100 mg (yield: 41%) of the title compound was obtained as a solid in the same manner as in Example 3 (3f).

[0730] (28c) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * )-4-Ethyl-1,1-dioxide-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoic acid

[0731] Example 28 (28b) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4S * Using )-4-ethyl-1,1-dioxide-4,5-dihydro-1,2-benzothiazepin-2(3H)-yl]methyl}-2,3-dihydro-1H-inden-5-yl)propanoate (100 mg), the title compound 85 mg (yield: 89%) was obtained as a solid in the same manner as in Example 3 (3g).

[0732] Example 29 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0733] (29a) Ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate

[0734] Example 95 (95a) ethyl 3-(4-chloro-1-methyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-2,3-dihydro-1H-inden-5-yl]propanoate (181 mg) and Example 1 (1c) (4R)-8-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepine 1,1-dioxide (115 mg) were dissolved in toluene (5 mL), and under a nitrogen atmosphere, 1,1'-(azodicarbonyl)dipiperidine (221 mg) and then tri-n-butylphosphine (0.218 mL) were added and the mixture was stirred at room temperature for 25 hours. The reaction mixture was diluted with dichloromethane and purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate=2 / 1-1 / 2 (V / V)] to give 270 mg (yield: 94%) of the title compound as a solid.

[0735] (29b) 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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

[0736] Using ethyl 3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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)propanoate (270 mg) from Example 29 (29a), in the same manner as in Example 3 (3g), the title compound 218 mg (yield: 84%) was obtained as a solid.

[0737] Example 30 (3S)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0738] (30a) 4-Bromo-6-chloro-N,3-dimethyl-2-nitroaniline

[0739] 4-Bromo-N,3-dimethyl-2-nitroaniline (WO 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 under a nitrogen atmosphere for 2 hours and then 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 crude title compound (yield: quantitative) as a solid.

[0740] (30b) 4-Bromo-6-chloro-N 1 ,3-Dimethylbenzene-1,2-diamine

[0741] 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).

[0742] (30c) 5-Bromo-7-chloro-1,4-dimethyl-1H-benzotriazole

[0743] Example 30 (30b) 4-bromo-6-chloro-N 1,3-Dimethylbenzene-1,2-diamine (2.69 g) was suspended in 5 M hydrochloric acid (50 mL) and a solution of sodium nitrite (1.49 g) in water (6 mL) was added dropwise over 20 minutes at 0°C under a nitrogen atmosphere. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled to 0°C and neutralized by the dropwise addition of 5 M 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 give 2.76 g (yield: 98%) of the crude title compound as a solid.

[0744] (30d) Ethyl (2E)-3-(7-chloro-1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate

[0745] A mixture of 5-bromo-7-chloro-1,4-dimethyl-1H-benzotriazole (2.76 g), palladium(II) acetate (238 mg), tri(o-tolyl)phosphine (645 mg), and N,N-dimethylformamide (20 mL) from Example 30 (30c) was purged with nitrogen, and N,N-diisopropylethylamine (9.1 mL) and then ethyl acrylate (2.3 mL) were added. 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 mixture was heated and stirred at 90°C for 3 hours. The reaction mixture was returned to room temperature, and ethyl acetate and saturated aqueous sodium bicarbonate were added and stirred. The insoluble matter was then filtered through a cotton plug. The organic layer of the filtrate was separated by a separation operation, washed twice with water and once 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 [eluent: n-hexane / dichloromethane / ethyl acetate = 90 / 0 / 10-75 / 0 / 25-0 / 100 / 0-0 / 90 / 10 (V / V / V)]. The resulting solid was slurry-washed with n-hexane / ethyl acetate to give 2.23 g (yield: 75%) of the title compound as a solid.

[0746] (30e) Ethyl 3-(7...

Claims

1. The following general formula (1): 【Chemistry 1】 [In the formula, R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, R 2 C may be substituted with 1 to 3 substituents selected from the substituent group a. 1-6 represents an alkyl group, R 3 is a hydrogen atom, a halogen atom or C 1-6 represents an alkyl group, Y is -CH-, -CR 4 - or a nitrogen atom, R 4 is a hydroxyl group, halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group or C 1-6 represents a haloalkoxy group, -V- is represented by the following formula: 【Chemistry 2】 (In the formula, * and ** indicate the bonding positions to the benzene ring.) [0043] n R 7 are each independently a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group, n represents an integer from 0 to 2; and Z is represented by the following formula (A1), (A2) or (A3): 【Chemistry 3】 (In the formula, *** indicates the bonding position of the carbon atom to which Z is bonded, R 8 C may be substituted with 1 to 3 substituents selected from the substituent group a. 1-6 represents an alkyl group, R 5a and R 5b each independently represents a hydrogen atom or C which may be substituted with 1 to 3 substituents selected from the substituent group a 1-6 Alkyl group or C 3-6 represents a cycloalkyl group; Or, R 5a and R 5b are combined with each other to form R 5a and R 5b C may be substituted with 1 to 3 substituents selected from the substituent group b together with the carbon atom to which it is bonded. 3-8 Forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, m R 6 are each independently a hydroxy group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 haloalkoxy group or 1 or 2 C 1-6 represents an amino group which may be substituted with an alkyl group, m represents an integer from 0 to 3; W is -CH 2 -, -CHR 9 - or an oxygen atom, R 9 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group or C 1-6 represents a haloalkoxy group, X is -CH-, -CR 10 - or a nitrogen atom, R 10 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group or C 1-6 represents a haloalkoxy group, U is -CH-, -CR 11 - or a nitrogen atom, and R 11 is a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group or C 1-6 represents a haloalkoxy group. The group represented by the formula: Substituent group a: Hydroxy groups, Halogen atoms, Cyano group, C which may be substituted with 1 to 3 substituents selected from the substituent group b 1-6 Alkyl groups, C which may be substituted with 1 to 3 substituents selected from the substituent group b 1-6 C may be substituted with 1 to 3 substituents selected from an alkoxy group and a substituent group b. 1-6 Alkylsulfonyl groups, 1 or 2 C's 1-6 An amino group which may be substituted with an alkyl group Substituent group b: Halogen atoms, Cyano group, C 1-6 Alkyl groups, C 1-6 Alkoxy group] or a pharma- ceutically acceptable salt thereof.

2. R 1a and R 1b The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein each of the is independently a hydrogen atom or a methyl group.

3. R 2 But, C 1-6 2. The compound according to claim 1, wherein the alkyl group is an alkyl group, a 2-dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-(methylsulfonyl)propyl group, or a pharma- ceutically acceptable salt thereof.

4. R 3 is a halogen atom or C 1-6 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the group is an alkyl group.

5. R 4 The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is a hydroxy 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. -V- is represented by the following formula: 【Chemistry 4】 (In the formula, * and ** are as defined above.) 2. The compound according to claim 1, wherein the compound is a group represented by any one of the following formulas:

7. n is 1 and R 7 But, C 1-6 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the group is an alkyl group.

8. 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

9. Z is represented by the following formula (A1) or (A2): 【Chemistry 5】 (The symbols in the formula are as defined above.) The compound according to claim 1, wherein the compound is a group represented by the following formula:

10. R 8 The compound according to claim 9, or a pharma- ceutically acceptable salt thereof, wherein is a methyl group or an ethyl group.

11. R 5a and R 5b are each independently a hydrogen atom, a methyl group, an ethyl group, or a cyclopropyl group, or R 5a and R 5b The compound according to claim 9, or a pharma- ceutically acceptable salt thereof, wherein: are linked to each other to form a cyclopropane, cyclobutane, oxetane, or tetrahydropyran.

12. m R 6 are each independently a hydroxy group, a fluorine atom, a chlorine atom, a methyl group, an ethoxy group, or a trifluoromethyl group, and 10. The compound according to claim 9, wherein m is an integer of 0 to 2, or a pharma- ceutically acceptable salt thereof.

13. W is -CH 2 10. The compound according to claim 9, or a pharma- ceutically acceptable salt thereof, wherein R is - or an oxygen atom.

14. The following general formula (1'): 【Chemistry 6】 [In the formula, R 1a’ and R 1b’ each independently represents a hydrogen atom or a methyl group, R 2’ indicates a methyl group, R 3’ represents a chlorine atom or a methyl group, Y' is -CH-, -CR 4’ - or a nitrogen atom, R 4’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V'- is represented by the following formula: 【Chemistry 7】 (In the formula, *' and **' indicate the bonding positions to the benzene ring.) [0043] R 5a’ and R 5b’ each independently represents a hydrogen atom or an ethyl group, or R 5a’ and R 5b’ combine with each other to form cyclopropane, m' R's 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. or a pharma- ceutically acceptable salt thereof.

15. A compound selected from the following group, or a pharma- ceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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. A compound selected from the following group, or a pharma- ceutically acceptable salt thereof: (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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 pharmacy acceptable salt thereof.

18. (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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 pharmacy acceptable salt thereof.

19. (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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 pharmacy acceptable salt thereof.

20. (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxide-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 pharmacy acceptable salt thereof.

21. A compound represented by the following general formula (1″) or a pharma- ceutical 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’’ indicates a methyl group, R 3’’ represents a chlorine atom or a methyl group, Y'' is -CH-, -CR 4’’ - or a nitrogen atom, R 4’’ represents a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group, or a trifluoromethoxy group, -V''- is represented by the following formula: 【Chemistry 9】 (In the formula, *'' and **'' indicate the bonding positions to the benzene ring.) [0043] R 5a’’ and R 5b’’ each independently represents a hydrogen atom or an ethyl group, or R 5a’’ and R 5b’’ combine with each other to form cyclopropane, R 8’’ represents a methyl group or an ethyl group, m'' R 6’’ each independently represents a chlorine atom or a hydroxyl group, m″ represents 0 or 1; U″ represents a nitrogen atom, and W'' represents an oxygen atom.

22. A compound selected from the following group, or a pharma- ceutically 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. 23. A medicine comprising the compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof as an active ingredient.

24. The pharmaceutical composition according to claim 23, for activating Nrf2.

25. The pharmaceutical composition according to claim 23, for inhibiting the protein-protein interaction between Keap1 and Nrf2.

26. The pharmaceutical composition according to claim 23, for the prevention and / or treatment of oxidative stress-related diseases.

27. The pharmaceutical composition according to claim 26, wherein the oxidative stress-related disease is selected from the group consisting of renal diseases, liver diseases, respiratory diseases, skin diseases, cardiovascular diseases, central nervous system diseases, autoimmune diseases and eye diseases.

28. renal diseases selected from the group consisting of chronic kidney disease, acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, nonalcoholic steatohepatitis, hepatic 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-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis and scleroderma; cardiovascular diseases selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis and pulmonary arterial hypertension; Alzheimer's disease, Parkinson's disease a central nervous system disease selected from the group consisting of cerebral infarction, 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 myopathy; an autoimmune disease selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, type 1 diabetes, ulcerative colitis, and Crohn's disease; and an ophthalmic disease selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, keratopathy, 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 pharmaceutical composition according to claim 23, for the prevention and / or treatment of a disease selected from the group consisting of:

29. The pharmaceutical composition according to claim 23, for the prevention and / or treatment of a disease selected from the group consisting of chronic kidney disease, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, radiation-induced skin damage, radiation-induced mucosal damage, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

30. The pharmaceutical composition according to claim 23, 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 pharmaceutical composition according to claim 23, for preventing and / or treating radiation-induced skin damage or radiation-induced mucosal damage.

32. The pharmaceutical composition according to claim 23 for the prevention and / or treatment of chronic obstructive pulmonary disease.

33. Use of the compound according to any one of claims 1 to 22 or a pharma- ceutical acceptable salt thereof for the manufacture of an agent for the prophylaxis 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 arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

34. 23. An Nrf2 activator comprising, as an active ingredient, the compound according to any one of claims 1 to 22 or a pharma- ceutical acceptable salt thereof.

35. 23. A protein-protein interaction inhibitor of Keap1 and Nrf2, comprising the compound according to any one of claims 1 to 22 or a pharma- ceutical acceptable salt thereof as an active ingredient.

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