Benzothiophene compound

Abstract

The present invention addresses the problem of providing a medicinal drug that can treat and / or prevent diseases linked to oxidative stress, by inhibiting the protein-protein interaction between Keap1 and Nrf2 to activate Nrf2. The present invention pertains to a compound represented by general formula (1) [in the formula, the respective symbols are as described in the description] or a pharmaceutically acceptable salt thereof. In addition, the present invention also pertains to a medicinal drug that contains the compound and that is for treating and / or preventing a disease that is linked to oxidative stress and that is selected from the group consisting of chronic kidney disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation dermatitis, radiation mucous membrane disorder, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

Description

Benzothiophene compounds

[0001] The present invention relates to a benzothiophene compound or a pharmaceutically acceptable salt thereof, which inhibits Kelch-like ECH-associated protein 1 (Keap1) and activates NF-E2-related factor 2 (Nrf2), and is thereby useful for the treatment and / or prevention of diseases associated with oxidative stress, particularly 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, or age-related macular degeneration.

[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. Increased or activated levels of these enzymes confer resistance 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 these compounds are structurally different from the compound of the present invention.

[0006] International Publication No. 2015 / 092713 International Publication No. 2016 / 202253 International Publication No. 2016 / 203400 International Publication No. 2016 / 203401 International Publication No. 2018 / 109643 International Publication No. 2018 / 109647 International Publication No. 2018 / 109648 International Publication No. 2019 / 224667 International Publication No. 2020 / 165776 International Publication No. 2018 / 181345 International Publication No. 2020 / 241853

[0007] Int. J. Biochem. Cell. Biol., 2012, 44, 1315?1320Nat. Rev. Drug. Discov., 2019, 18, 295-317Eur. J. Med. Chem., 2020, 202, 112532

[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 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, or age-related macular degeneration, by inhibiting the protein-protein interaction between Keap1 and Nrf2 and activating Nrf2.

[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]

[0011] [In the formula, R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, and R 2a and R 2b are each independently a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 3-6 represents a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b C, which may be substituted together with the carbon atom to which it is bonded with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, Z 1 -CH-, -CR 3 - or a nitrogen atom, R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, Z 2 -CH-, -CR 4 - or a nitrogen atom, R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, and n R 11are each independently a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, n represents an integer of 0 to 2, R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group, R 9a and R 9b are each independently a hydrogen atom or C 1-6 represents an alkyl group, W is -CH2-, -CHR 10 - or an oxygen atom, R 10 is C 1-6 represents an alkyl group, and X is represented by the following formula (A1) or (A2):

[0012]

[0013] (wherein * indicates the bonding position of X to the carbon atom to which it is bonded, R 5 is a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, and R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 C may be substituted with 1 to 3 substituents selected from a hydroxy group, a halogen atom, a cyano group, and substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl group and substituent group a 1-6 Alkoxy group or C 3-6 represents a cycloalkyl group.) where Z represents a group represented by the formula: 1 is -CH- or -CR 3 -, Z2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - is not possible. Substituent group a: hydroxy group, halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or a substituent group b 1-6 C substituted with alkyl group, substituent group b 1-6 Alkoxy group, 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, C 1-6 Alkylsulfonyl group Substituent group b: halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 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, has an excellent Nrf2 activation effect by inhibiting Keap1, and have thus completed the present invention.

[0014] That is, the present invention is as follows: [1] A compound represented by the following general formula (1):

[0015]

[0016] [In the formula, R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group, and R 2a and R 2b are each independently a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 3-6 represents a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2bC, which may be substituted together with the carbon atom to which it is bonded with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle, Z 1 -CH-, -CR 3 - or a nitrogen atom, R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, Z 2 -CH-, -CR 4 - or a nitrogen atom, R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, and n R 11 are each independently a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the substituent group a 1-6 represents an alkoxy group, n represents an integer of 0 to 2, R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group, R 9a and R 9b are each independently a hydrogen atom or C 1-6 represents an alkyl group, W is -CH2-, -CHR 10 - or an oxygen atom, R 10 is C1-6 represents an alkyl group, and X is represented by the following formula (A1) or (A2):

[0017]

[0018] (wherein * indicates the bonding position of X to the carbon atom to which it is bonded, R 5 is a hydrogen atom, a halogen atom, or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, and R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the substituent group a 1-6 represents an alkyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 C may be substituted with 1 to 3 substituents selected from a hydroxy group, a halogen atom, a cyano group, and substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from alkyl group and substituent group a 1-6 Alkoxy group or C 3-6 represents a cycloalkyl group.) where Z represents a group represented by the formula: 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - is not possible. Substituent group a: hydroxy group, halogen atom, cyano group, C 1-6 Alkyl group, C 1-6 C substituted with an alkoxy group or a substituent group b 1-6 C substituted with alkyl group, substituent group b 1-6 Alkoxy group, 1 or 2 C 1-6 an amino group optionally substituted with an alkyl group, C 1-6 Alkylsulfonyl group Substituent group b: halogen atom, cyano group, C 1-6 Alkyl group, C1-6 [2] A compound represented by the formula: R 1a and R 1b [3] The compound according to the above-mentioned [1], or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6 a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b C, along with the carbon atom to which it is attached 3-6 The compound according to the above [1] or [2], or a pharmaceutically acceptable salt thereof, which forms a cycloalkane. [4] R 2a and R 2b are each independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b [5] The compound according to the above [1] or [2], wherein Z forms a cyclopropane together with the carbon atom to which Z is bonded, or a pharmaceutically acceptable salt thereof. 1 is -CH- or -CR 3 - and Z 2 [6] The compound according to any one of the above-mentioned [1] to [4], wherein Z is a nitrogen atom, or a pharmaceutically acceptable salt thereof. 1 But, -CR 3 - and Z 2 [7] The compound according to any one of the above-mentioned [1] to [4], wherein R is a nitrogen atom, or a pharmaceutically acceptable salt thereof. 3 However, halogen atoms, hydroxy groups, amino groups, C 1-6 Alkylamino group or C 1-6 [8] The compound according to the above-mentioned [5] or [6], or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group. 3[9] The compound according to the above [5] or [6], wherein n is 1, and R is a hydroxy group, or a pharmaceutically acceptable salt thereof. 11

[10] The compound according to any one of the above [1] to [8], wherein n is 0, or a pharmaceutically acceptable salt thereof.

[11] The compound according to any one of the above [1] to [8], wherein R is a hydroxy group, or a pharmaceutically acceptable salt thereof. 8a and R 8b

[12] The compound according to any one of the above [1] to

[10] , wherein R 9a and R 9b

[13] The compound or pharmaceutically acceptable salt thereof according to any one of the above [1] to

[12] , wherein W is an oxygen atom.

[14] X is a group represented by the following formula (A2):

[0019]

[0020] (wherein each symbol has the same meaning as defined above) is a group represented by the formula [1] to

[13] above, or a pharmaceutically acceptable salt thereof.

[15] R 5 is a halogen atom or C 1-6 The compound according to the above-mentioned

[14] , or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group. 5

[17] The compound according to the above-mentioned

[14] , or a pharmaceutically acceptable salt thereof, wherein R is a methyl group. 6

[18] The compound according to any one of the above-mentioned

[14] to

[16] , wherein R is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, or a pharmaceutically acceptable salt thereof. 6

[19] The compound according to any one of the above-mentioned

[14] to

[16] , wherein R is a methyl group, or a pharmaceutically acceptable salt thereof. 7is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group, or a pharmaceutically acceptable salt thereof.

[20] 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)-2-ethyl-7-hydroxy-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)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid,(3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid, and(3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

[21] Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, and (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

[22] (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

[23] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid or a pharmaceutically acceptable salt thereof.

[24] (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid or a pharmaceutically acceptable salt thereof.

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

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

[26] The medicament according to

[25] above for activating Nrf2.

[27] The medicament according to

[25] above for inhibiting protein-protein interaction between Keap1 and Nrf2.

[28] The medicament according to

[25] above for preventing and / or treating an oxidative stress-related disease.

[29] The pharmaceutical according to the above-mentioned

[28] , 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.

[30] A kidney disease 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; a liver disease selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic fibrosis, and cirrhosis; a respiratory disease selected from the group consisting of bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; a skin disease selected from the group consisting of ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; a cardiovascular disease selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension; Alzheimer's disease, Parkinson's disease, Parkinson's disease, The medicament according to the above-mentioned

[25] for the prevention and / or treatment of a disease selected from the group consisting of: a central nervous system disease selected from the group consisting of Son's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease, and autism; a mitochondrial disease selected from the group consisting of Friedreich's ataxia and mitochondrial 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 ophthalmological 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.

[31] The medicament according to the above-mentioned

[25] 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, and age-related macular degeneration.

[32] The compound according to any of the above-mentioned [1] to

[24] or a pharmaceutically acceptable salt thereof 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, and age-related macular degeneration.

[33] The medicament according to the above-mentioned

[25] 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, and age-related macular degeneration.

[34] Use of the compound according to any of the above-mentioned [1] to

[24] 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, and age-related macular degeneration.

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

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

[36] A method for activating Nrf2 in a mammal, comprising administering a pharmaceutically effective amount of the compound of any of the above-mentioned [1] to

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

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

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

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

[24] above or a pharmaceutically acceptable salt thereof.

[39] An inhibitor of protein-protein interaction between Keap1 and Nrf2 comprising, as an active ingredient, the compound according to any one of [1] to

[24] above or a pharmaceutically acceptable salt thereof.

[40] The compound or salt thereof according to any one of the above-mentioned [1] to

[24] 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 damage, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[41] The medicament according to the above-mentioned

[25] 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 damage, heart failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma.

[42] The medicament according to any one of the above-mentioned

[25] to

[31] ,

[33] , and

[41] , which is administered in combination with another drug.

[43] The pharmaceutical composition according to the above

[42] , 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.

[44] The pharmaceutical composition according to the above

[42] or

[43] , wherein the pharmaceutical composition according to any of the above

[25] to

[31] ,

[33] , and

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

[45] The pharmaceutical composition according to the above

[42] or

[43] , wherein the compound according to any of the above [1] to

[24] or a pharmaceutically acceptable salt thereof and the other drug are contained in a single formulation.

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

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

[47] A method for producing the compound according to any one of the above [1] to

[24] or a pharmaceutically acceptable salt thereof.

[48] A prodrug of the compound according to any one of the above [1] to

[24] or a pharmaceutically acceptable salt thereof.

[0021] 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; 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 Ilzheimer'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 diseases include those 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.

[0022] 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.

[0023] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0024] In this specification, "C １－６ The term "alkyl group" means 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.

[0025] In this specification, "C １－６ The term "haloalkyl group" refers to the group defined above as "C １－６ It means a group in which one or more hydrogen atoms in an "alkyl group" are substituted with halogen. １－６Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, difluoroethyl (e.g., 1,1-difluoroethyl, 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.

[0026] In this specification, "C １－６ The "alkoxy group" is the same as the "C １－６ "alkyl" means a group 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.

[0027] In this specification, "C １－６ The "haloalkoxy group" is defined as the same as the "C １－６ It means a group in which one or more hydrogen atoms in an "alkoxy group" are 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.

[0028] 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.

[0029] In this specification, "C １－６ The term "alkylsulfonyl group" refers to the same group as defined above in "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.

[0030] 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 independently substituted with the above-mentioned "C 1-6 A group substituted with an "alkyl group", i.e., C 1-6 Alkylamino group or diC 1-6 It means an alkylamino 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] Substituent group a: C optionally substituted with 1 to 3 substituents selected from a hydroxy group, a halogen atom, a cyano group, and Substituent group b 1-6 C optionally substituted with 1 to 3 substituents selected from the alkyl group, substituent group b 1-6 an alkoxy group, C optionally substituted with 1 to 3 substituents selected from the substituent group b; 1-6 alkylsulfonyl group, 1 or 2 C 1-6 An amino group optionally substituted with an alkyl group

[0035] Substituent group b: halogen atoms, cyano groups, C 1-6 Alkyl group, C 1-6 Alkoxy group However, "optionally substituted C 1-6 "Alkyl group" or "Optionally substituted C 1-6 When 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.

[0036] 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.

[0037] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) that is involved in transporting the compound (1) of the present invention or a composition containing the same from one organ or organ to another.

[0038] 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.

[0039] 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.

[0040] 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.). Furthermore, "oxidative stress-related disease" refers to a disease in which such oxidative stress is involved in the onset or worsening of symptoms. Examples of the "oxidative stress-related disease" include: a kidney disease 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; a liver disease selected from the group consisting of alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic fibrosis, and cirrhosis; a respiratory disease selected from the group consisting of bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolitis, interstitial pneumonia, and asthma; a skin disease selected from the group consisting of ultraviolet and radiation-induced skin damage, radiation-induced mucosal damage, epidermolysis bullosa, psoriasis, atopic dermatitis, and scleroderma; a cardiovascular disease selected from the group consisting of heart failure, myocardial infarction, arteriosclerosis, and pulmonary arterial hypertension; Alzheimer's disease, Parkinson's disease central nervous system diseases selected from the group consisting of rheumatoid arthritis, 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, inter alia, 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.

[0041] 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.

[0042] 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.

[0043] As used herein, the term "pharmaceutically effective amount" means the amount of compound (1) of the present invention or a pharmaceutically acceptable salt thereof administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to a mammal.

[0044] 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.).

[0045] (Compound of the Present Invention (Compound (1))) Hereinafter, each group in the above formula (1) of compound (1) will be explained.

[0046] R 1a and R 1b are each independently a hydrogen atom or C 1-6 represents an alkyl group.

[0047] R 1a and R 1b are preferably each independently a hydrogen atom or a methyl group.

[0048] R 2a and R 2b are each independently a hydrogen atom, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkyl group or C 3-6represents a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 It forms a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle.

[0049] R 2a and R 2b are preferably each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6 a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b C, along with the carbon atom to which it is attached 3-6 Forming a cycloalkane, more preferably R 2a and R 2b are each independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b together with the carbon atom to which it is attached to form a cyclopropane.

[0050] Z 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group.) or a nitrogen atom.

[0051] Z 1 is preferably -CH- or -CR 3 -(R 3is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkylamino group or C 1-6 It is more preferably -CR 3 -(R 3 represents a hydroxy group.

[0052] Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group.) or a nitrogen atom.

[0053] Z 2 is preferably a nitrogen atom.

[0054] However, Z 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 -It will never be the case.

[0055] n R 11 are each independently a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group.

[0056] R 11 is preferably a hydroxy group.

[0057] n represents an integer of 0 to 2.

[0058] n is preferably 0 or 1, and more preferably 0.

[0059] R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 represents an alkoxy group.

[0060] R 8a and R 8b are preferably both hydrogen atoms.

[0061] R 9a and R 9b are each independently a hydrogen atom or C 1-6 represents an alkyl group.

[0062] R 9a and R 9b are preferably both hydrogen atoms.

[0063] W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group.) or an oxygen atom.

[0064] W is preferably an oxygen atom.

[0065] X is represented by the following formula (A1) or (A2):

[0066]

[0067] (wherein * indicates the bonding position of X to the carbon atom to which it is bonded, R 5 is a hydrogen atom, a halogen atom, or C which may be substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkyl group, and R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7C may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a. 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 It represents a cycloalkyl group.

[0068] X is preferably a group represented by the formula (A1) or (A2), in which * represents the bonding position of X to the carbon atom to which it is bonded, and R 5 is a halogen atom or C 1-6 is an alkyl group, and R 6 is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0069] X is more preferably a group represented by the formula (A1) or (A2), in which * represents the bonding position of X to the carbon atom to which it is bonded, and R 5 is a methyl group, and R 6 is a methyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0070] X is more preferably a group represented by the formula (A2), in which * represents the bonding position of X to the carbon atom to which it is bonded, and R 5 is a halogen atom or C 1-6 is an alkyl group, and R 6is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0071] X is particularly preferably a group represented by the formula (A2), in which * represents the bonding position of X to the carbon atom to which it is bonded, and R 5 is a methyl group, and R 6 is a methyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

[0072] The following compound is suitable as compound (1): [Compound (1A)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0073]

[0074] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0075] [Compound (1B)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2bare each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6 a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b C, along with the carbon atom to which it is attached 3-6 Form a cycloalkane (preferably R 2a and R 2b are each independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b together with the carbon atom to which Z is attached to form a cyclopropane; 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0076]

[0077] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0078] [Compound (1C)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 is -CH- or -CR 3 -(R 3 is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkylamino group or C 1-6 represents an alkyl group.) (Preferably, Z 1 But, -CR 3 -(R 3 represents a hydroxy group; Z 2 -CH-, -CR 4 -(R4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0079]

[0080] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0081] [Compound (1D)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2bC, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 is -CH- or -CR 3 -(R 3 is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkylamino group or C 1-6 represents an alkyl group.) (Preferably, Z 1 But, -CR 3 -(R 3 represents a hydroxy group; Z 2 is a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0082]

[0083] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group)), or a pharmaceutically acceptable salt thereof.

[0084] [Compound (1E)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 -CH-, -CR3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 is a hydroxy group; n is an integer of 0 to 2 (preferably 1, more preferably 0); R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0085]

[0086] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0087] [Compound (1F)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 R2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are both hydrogen atoms; R 9a and R 9b are each independently a hydrogen atom or C 1-6 alkyl groups (preferably both hydrogen atoms); W is -CH2-, -CHR10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A1) or (A2):

[0088]

[0089] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3-or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0090] [Compound (1G)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2 -CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is an oxygen atom; and X is a group represented by the following formula (A1) or (A2):

[0091]

[0092] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6 is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0093] [Compound (1H)] R 1a and R 1b are each independently a hydrogen atom or C 1-6 is an alkyl group; R 2a and R 2b 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 2a and R 2b are combined with each other to form R 2a and R 2b C, which together with the carbon atom to which is bonded, may be substituted with 1 to 3 substituents selected from the substituent group b 3-8 forming a cycloalkane or a 3- to 8-membered saturated oxygen-containing heterocycle; Z 1 -CH-, -CR 3 -(R 3 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; Z 2-CH-, -CR 4 -(R 4 is a halogen atom, a hydroxy group, one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 represents an alkoxy group; or a nitrogen atom; n R 11 each independently represents a halogen atom, a hydroxy group, or one or two C 1-6 an amino group optionally substituted with an alkyl group, C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with an alkyl group or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 n is an integer from 0 to 2; R 8a and R 8b are each independently a hydrogen atom, a halogen atom, a cyano group, or C 1-6 Alkyl group or C 1-6 is an alkoxy group; R 9a and R 9b are each independently a hydrogen atom or C 1-6 is an alkyl group; W is -CH2-, -CHR 10 -(R 10 is C 1-6 represents an alkyl group) or an oxygen atom; and X represents a group represented by the following formula (A2):

[0094]

[0095] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 C which may be substituted with a hydrogen atom, a halogen atom, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a halogen atom or C 1-6 an alkyl group, more preferably a methyl group), R 6is a hydrogen atom or C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 an alkyl group (preferably a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group, more preferably a methyl group); 7 - or a nitrogen atom, and R 7 C which may be substituted with a hydroxy group, a halogen atom, a cyano group, or 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 C optionally substituted with 1 to 3 substituents selected from the above-mentioned substituent group a 1-6 Alkoxy group or C 3-6 a cycloalkyl group (preferably a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), 1 is -CH- or -CR 3 -, Z 2 is a nitrogen atom, and Z 2 is -CH- or -CR 4 -, Z 1 is a nitrogen atom, and Z 1 and Z 2 Both of these are simultaneously -CH- and -CR 3 -or-CR 4 - Compound (1) or a pharmaceutically acceptable salt thereof.

[0096] [Compound (1J)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2a and R 2b are each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6 a cycloalkyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2bC, along with the carbon atom to which it is attached 3-6 Forming a cycloalkane; Z 1 is -CH- or -CR 3 -(R 3 is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkylamino group or C 1-6 represents an alkyl group; Z 2 is a nitrogen atom; n R 11 is a hydroxy group; n is 0 or 1; R 8a and R 8b are both hydrogen atoms; R 9a and R 9b are both hydrogen atoms; W is an oxygen atom; and X is a group represented by the following formula (A1) or (A2):

[0097]

[0098] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 is a halogen atom or C 1-6 R is an alkyl group (preferably a methyl group); 6 is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group (preferably a methyl group); Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), or a pharmaceutically acceptable salt thereof.

[0099] [Compound (1K)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2a and R 2b are each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6 a cycloalkyl group, or R 2aand R 2b are each independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b together with the carbon atom to which Z is attached to form a cyclopropane; 1 But, -CR 3 -(R 3 represents a hydroxy group; 2 is a nitrogen atom; n is 0; R 8a and R 8b are both hydrogen atoms; R 9a and R 9b are both hydrogen atoms; W is an oxygen atom; and X is the following (A2):

[0100]

[0101] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 is a halogen atom or C 1-6 R is an alkyl group (preferably a methyl group); 6 is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group (preferably a methyl group); Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), or a pharmaceutically acceptable salt thereof.

[0102] [Compound (1L)] R 1a and R 1b are each independently a hydrogen atom or a methyl group; R 2a and R 2b are each independently a hydrogen atom, C 1-6 Alkyl group, C 1-6 haloalkyl group or C 3-6a cycloalkyl group, or R 2a and R 2b are each independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b are combined with each other to form R 2a and R 2b together with the carbon atom to which Z is attached to form a cyclopropane; 1 But, -CR 3 -(R 3 represents a hydroxy group; 2 is a nitrogen atom; n is 0; R 8a and R 8b are both hydrogen atoms; R 9a and R 9b are both hydrogen atoms; W is an oxygen atom; and X is the following (A2):

[0103]

[0104] (wherein * is the bonding position to the carbon atom to which X is bonded, and R 5 is a methyl group and R 6 is a methyl group, and Y is -CH-, -CR 7 - or a nitrogen atom, and R 7 is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group), or a pharmaceutically acceptable salt thereof.

[0105] Specific examples of suitable compound (1) are the compounds of Examples 1 to 93 described below or pharmaceutically acceptable salts thereof, and more preferably 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)-2-ethyl-7-hydroxy-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)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid, and (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

[0106] Among them, particularly preferred are any of the compounds (1) selected from the following group or pharmaceutically acceptable salts thereof: (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, and (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

[0107] Compound (1) of the present invention has a basic group such as a nitrogen-containing heterocyclic group in the molecule, and therefore can form generally 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.

[0108] 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.

[0109] Since 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.

[0110] When the compound (1) of the present invention has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (i.e., diastereoisomers, optical isomers) based on the asymmetric carbon atom, and the present invention encompasses any one of these stereoisomers and a mixture containing these plurality of stereoisomers in any ratio. In addition, isomers due to conformation or tautomerism may be generated, and such isomers or mixtures thereof are also encompassed by the compound (1) of the present invention. In addition, in the name of the compound of the present invention, when the structure of the compound has a carbon atom that serves as an asymmetric center, its absolute configuration is indicated by R and S (indicated together with the position number). Furthermore, even when the optical isomers are separated, if the configuration of the carbon atom that serves as an asymmetric center in the structure of the compound is undetermined, R ＊ or S ＊Also, R ＊ and S ＊ The simultaneous use of may indicate relative configuration even when the absolute configuration has not been determined.

[0111] The 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 preventive 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 encompassed within the scope of the present invention.

[0112] The compound (1) of the present invention or a pharmaceutically acceptable salt thereof may be in the form of a crystal, and may be in a single crystalline form or a mixture of multiple crystalline forms.

[0113] The 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, a hydrate, an ethanol solvate, etc. are preferred.

[0114] The compound (1) of the present invention may be a prodrug.

[0115] 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.

[0116] 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);

[0117] The prodrug of compound (1) of the present invention can be produced from compound (1) by known methods. Prodrugs of compound (1) also include 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.

[0118] (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 will be described below. Compound (1) of the present invention can be produced by various production methods, and the production methods shown below and the Reference Examples and Examples described later are only examples, and the present invention should not be construed as being limited thereto.

[0119] Each starting compound may form a salt as long as it does not inhibit the reaction, and examples of such salts include the same as the pharmaceutically acceptable salts of compound (1) described above. Unless a specific production method is described, starting compounds may be readily available commercially and used, or may be produced by a method known per se or a method equivalent thereto. In addition, 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 may be used directly in the next reaction without isolation and purification.

[0120] The contents of all patent, non-patent, or literature references explicitly cited in this specification are hereby incorporated by reference in their entirety.

[0121] Compound (1), its pharmaceutically acceptable salts, and their intermediates can be produced by various known methods utilizing characteristics based on the types of their basic skeletons or 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] Compound (1) of the present invention can be produced, for example, by the following Method A or Method B. The production intermediates used in Method A or Method B can be produced, for example, by the following Methods C to J.

[0128] 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.

[0129] 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 3-6The 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.

[0130] (Method A) This production method is a method for producing compound (1) by condensing compound (2A) with compound (3) to obtain compound (4), and then removing the protecting group of compound (4).

[0131]

[0132] (In the formula, L １ represents a leaving group (preferably a halogen atom), and Pro １ is a protecting group (preferably a C group such as a methyl group, an ethyl group, or a tert-butyl group). 1-6 is an alkyl group, and the other symbols are as defined above.

[0133] (Step A-1) This step is a step of producing compound (4) by condensing compound (2A) and compound (3) in a solvent in the presence or absence of a base.

[0134] 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.

[0135] 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, etc.

[0136] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 0°C to 100°C.

[0137] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 72 hours, preferably 10 minutes to 48 hours.

[0138] (Step A-2) This step is to remove the protecting group (Pro) of compound (4). １ ) to produce compound (1).

[0139] This process is Pro １Depending on the type of Pro, a known method described in, for example, "Protective Groups in Organic Synthesis" by PG Wuts, 5th Edition, Wiley, 2014, etc. is appropriately selected and carried out according to the method. １ (Step A-2-1), or a method of removing Pro using an acid in a solvent. １ However, this step is not limited to this.

[0140] (Step A-2-1) The solvent 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, 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.

[0141] 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 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.

[0142] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 10°C to 90°C.

[0143] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 1 minute to 48 hours, preferably from 10 minutes to 24 hours.

[0144] (Step A-2-2) The solvent 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, 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, 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 organic solvents in any ratio; and mixed solvents containing the above organic solvent and water in any ratio.

[0145] The acid to be used is not particularly limited as long as it is an acid that is used in ordinary 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.

[0146] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from -78°C to 100°C.

[0147] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0148] (Method B) In this production method, compound (1) is produced by subjecting compound (2B) and compound (3) to a reductive amination reaction to give compound (4), and then deprotecting the protecting group of compound (4).

[0149]

[0150] (The symbols in the formula have the same meanings as defined above.)

[0151] (Step B-1) This step is a step of producing compound (4) by carrying out reductive amination reaction of compound (2B) with compound (3) using a reducing agent in a solvent in the presence or absence of an acid and in the presence or absence of an additive.

[0152] 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, 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.

[0153] The reducing agent to be used is not particularly limited, but examples thereof include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, picoline borane, pyridine borane, and the like.

[0154] The acid that can be used is not particularly limited as long as it is an acid that is used in ordinary reactions, 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.

[0155] Additives that can be used are not particularly limited, but examples include inorganic salts such as sodium sulfate and magnesium sulfate.

[0156] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0157] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 120 hours, preferably from 10 minutes to 96 hours.

[0158] (Step B-2) This step is to remove the protecting group (Pro １) to produce compound (1).

[0159] This step can be carried out under the same conditions as in the step A-2.

[0160] (Method C) This production method is a method for producing a compound (2A-1) and a compound (2B-1) (R in the formulas (2A) and (2B)) which are intermediate compounds used in the above-mentioned Method A or Method B. １ａ and R １ｂ This is a method for producing a compound in which both of the carbon atoms are hydrogen atoms.

[0161]

[0162] (In the formula, L ２ represents a leaving group (preferably a halogen atom), and the other symbols are as defined above.

[0163] (Step C-1) In this step, a compound (5) is reacted with an acrylic ester compound using a metal catalyst in a solvent in the presence or absence of a base and in the presence or absence of an additive to form a leaving group (L ２ ) to an acrylate group (-CH=CH-CO ２ Pro １ ) to produce compound (6).

[0164] 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.

[0165] 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;

[0166] The additive that can be used is not particularly limited as long as it is one that is used in a known method, but suitable examples include 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.

[0167] The metal catalyst used is not particularly limited as long as it is one that is used in known methods, 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.

[0168] The acrylic ester compound to be used is not particularly limited, but examples thereof include methyl acrylate, ethyl acrylate, and tert-butyl acrylate.

[0169] 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.

[0170] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0171] (Step C-2) This step is a step of producing compound (2C-1) by reacting compound (6) with compound (7) obtained by Method G 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.

[0172] 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.

[0173] 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, etc.; alkali metal hydrogencarbonates such as potassium hydrogencarbonate; alkaline earth metal hydrogencarbonates such as calcium hydrogencarbonate; 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;

[0174] 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.

[0175] The metal catalyst used is not particularly limited as long as it is one that is used in a known method. Suitable examples include rhodium catalysts such as bis(norbornadiene)rhodium(I) tetrafluoroborate and chloro(1,5-cyclooctadiene)rhodium(I) dimer.

[0176] 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.

[0177] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0178] (Step C-3) In this step, the hydroxy group of the compound (2C-1) is converted into a leaving group (L １ ) to produce compound (2A-1).

[0179] 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, 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.

[0180] 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.

[0181] 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, etc.

[0182] 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.

[0183] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0184] (Step C-4) This step is a step of converting the hydroxy group of compound (2C-1) to a formyl group using an appropriate oxidizing agent in a solvent to produce compound (2B-1).

[0185] 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, 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.

[0186] The oxidizing agent used is not particularly limited, and can be appropriately selected from known methods described in, for example, "Experimental Chemistry Lectures, 4th Edition (21. Organic Synthesis III: Aldehydes, Ketones, and Quinones)," Maruyama Kazuhiro et al., Chemical Society of Japan, Maruzen Co., Ltd., 1990, etc., and this 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 a combination of dicyclohexylcarbodiimide (DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, or oxalyl chloride and dimethyl sulfoxide (DMSO); and oxidation reactions using a hyperatomic iodine compound (Dess-Martin reagent).

[0187] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0188] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0189] (Method D) This production method is a method for producing compound (2A) and compound (2B), which are intermediate compounds used in the above-mentioned Method A or Method B.

[0190]

[0191] (In the formula, L ３ represents a leaving group (preferably a halogen atom), and Pro ２ represents a protecting group (preferably a p-methoxybenzyl group), and the other symbols are as defined above.

[0192] (Step D-1) In this step, compound (5) is reacted with an organometallic compound and a formylating agent in a solvent to form a leaving group (L ２ ) is converted into a formyl group to produce compound (8). ２ is a bromine atom, but the present invention is not limited to this.

[0193] 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; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio.

[0194] The organometallic compound to be used is not particularly limited, but examples thereof include organolithium compounds such as n-butyllithium and tert-butyllithium; mixtures of organolithium compounds with organomagnesium compounds such as methylmagnesium bromide and ethylmagnesium bromide in any ratio; and the like.

[0195] The formylating agent to be used is not particularly limited, but examples thereof include N,N-disubstituted formamides such as N,N-dimethylformamide; orthoformates such as trimethyl orthoformate; and N-ethoxymethyleneaniline.

[0196] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 100°C, preferably -80°C to 50°C.

[0197] 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.

[0198] (Step D-2) In this step, the leaving group (L ３ After converting L into a metal, the metal is reacted with the compound (8) obtained in step D-1 to produce the compound (10). ３ is a bromine atom, but the present invention is not limited to this.

[0199] 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; sulfoxides such as dimethyl sulfoxide; and mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio.

[0200] The base to be used is not particularly limited as long as it is one that is used as a base in ordinary reactions, and examples thereof include n-butyllithium, sec-butyllithium, and tert-butyllithium.

[0201] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually -100°C to 100°C, preferably -80°C to 50°C.

[0202] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0203] (Step D-3) In this step, the hydroxy group of compound (10) is converted into a leaving group (Step D-3-1), followed by the addition of an acetate group (—C(R １ａ ) (R １ｂ )-CO ２ Pro １ ) (Step D-3-2) to produce compound (11).

[0204] (Step D-3-1) The leaving group is not particularly limited, but examples thereof include a (2,2,2-trichloroacetimidoyl)oxy group, a chlorine atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a tosyloxy group, etc. Below, a method for converting the hydroxy group of compound (10) to a (2,2,2-trichloroacetimidoyl)oxy group by using trichloroacetonitrile in a solvent in the presence of a base will be described, but the method is not limited thereto.

[0205] 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.

[0206] 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, 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;

[0207] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -20°C to 150°C, preferably from 0°C to 100°C.

[0208] 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.

[0209] (Step D-3-2) In this step, the compound obtained in the above step D-3-1 is reacted with a ketene acetal in a solvent in the presence of a catalyst to form an acetate group (—C(R １ａ ) (R １ｂ )-CO ２Pro １ ) to produce compound (11).

[0210] 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 solvents in any ratio; and mixed solvents containing any of the organic solvents and water in any ratio.

[0211] The catalyst used may be, for example, a sulfonic acid anhydride such as trifluoromethanesulfonic acid anhydride.

[0212] Examples of the ketene acetals that can be used include dimethylketene methyltrimethylsilyl acetal, 1-(tert-butyldimethylsilyloxy)-1-methoxyethene, and the like.

[0213] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -20°C to 150°C, preferably from 0°C to 100°C.

[0214] 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.

[0215] (Step D-4) In this step, the protecting group (Pro) of compound (11) is reacted in a solvent. ２ ) to convert it into compound (2C). ２ When is a p-methoxybenzyl group, a deprotection method using an oxidizing agent (Step D-4-1) and a deprotection method using an acid (Step D-4-2) will be described, but the method is not limited thereto.

[0216] (Step D-4-1) (Deprotection Method Using an Oxidizing Agent) This step is a step of removing the p-methoxybenzyl group of compound (11) by using an appropriate oxidizing agent in a solvent.

[0217] 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.

[0218] The oxidizing agent used is not particularly limited as long as it is an oxidizing agent used in ordinary reactions, and examples thereof include 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0219] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -20°C to 150°C, preferably from 0°C to 100°C.

[0220] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0221] (Step D-4-2) (Deprotection Method Using an Acid) This step is a step of removing the p-methoxybenzyl group of compound (11) using an appropriate acid in a solvent or without a solvent, in the presence or absence of anisole.

[0222] 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.

[0223] The acid to be used is not particularly limited as long as it is an acid that is used in ordinary 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.

[0224] 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.

[0225] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0226] (Step D-5) In this step, the hydroxy group of compound (2C) is converted into a leaving group (L １ ) to produce compound (2A), and the reaction can be carried out under the same conditions as in the above-mentioned Step C-3.

[0227] (Step D-6) This step is a step of producing compound (2B) by converting the hydroxy group of compound (2C) to a formyl group using an appropriate oxidizing agent in a solvent, and the reaction can be carried out under the same conditions as in the above-mentioned Step C-4.

[0228] (Method E) This production method is a method for producing compound (3) (compound (3A) in which W is an oxygen atom), which is an intermediate compound used in the above-mentioned Methods A and B.

[0229]

[0230] (In the formula, Pro ３ represents a protecting group (preferably a tert-butoxycarbonyl group or a p-methoxybenzyl group), and the other symbols are as defined above.

[0231] (Step E-1) This step is a step of producing compound (14) by subjecting compound (12) to reductive amination with compound (13), and is carried out in accordance with the above-mentioned Step B-1, but is not limited thereto.

[0232] (Step E-2) This step is a step of converting compound (14) to compound (18), in which the amino group is protected by a protecting group (Pro ３ and a step of constructing a seven-membered ring by intramolecular ring closure (Step E-2b). Either Step E-2a or Step E-2b may be carried out first, and a person skilled in the art can easily select the appropriate order.

[0233] (Step E-2a) In this step, the amino group of compound (14) is protected with a protecting group (Pro ３ ) is a process for protecting the ３ Depending on the purpose, a known method described in, for example, "Protective Groups in Organic Synthesis" by PG Wuts, 5th Edition, Wiley, 2014, etc., is appropriately selected and carried out according to the method. ３ is a tert-butoxycarbonyl group (Step E-2a-1), and ３ A protection method (Step E-2a-2) in the case where is a method of protecting with a p-methoxybenzyl group will be described below, but the present invention is not limited thereto.

[0234] (Step E-2a-1) This step is a step of introducing a tert-butoxycarbonyl protecting group using a protecting reagent in a solvent in the presence of an appropriate base.

[0235] 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.

[0236] 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.

[0237] The protecting reagent used may be, for example, di-tert-butyl dicarbonate.

[0238] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0239] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0240] (Step E-2a-2) This step is a step of introducing a p-methoxybenzyl group, which is a protecting group. Below, a method for introducing a p-methoxybenzyl group by reductive amination (Step E-2a-2-1) and a method for introducing a p-methoxybenzyl group by alkylation (Step E-2a-2-2) will be described, but the present invention is not limited thereto.

[0241] (Step E-2a-2-1) This step is a step of introducing a p-methoxybenzyl group by reductive amination using p-methoxybenzaldehyde and an appropriate reducing agent in a solvent in the presence or absence of an acid.

[0242] 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, 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.

[0243] The reducing agent to be used is not particularly limited, but examples thereof include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, picoline borane, pyridine borane, and the like.

[0244] The acid that can be used is not particularly limited as long as it is an acid that is used in ordinary reactions, and examples thereof include Lewis acids such as boron trifluoride, boron trichloride, boron tribromide, and trimethylsilane iodide; organic acids such as acetic acid and trifluoroacetic acid; and inorganic acids such as hydrochloric acid.

[0245] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0246] The reaction time varies depending on the starting compounds, reagents, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 18 hours.

[0247] (Step E-2a-2-2) This step is a step of introducing a p-methoxybenzyl group by using an alkylating agent such as p-methoxybenzyl chloride or p-methoxybenzyl bromide in a solvent in the presence of a suitable base.

[0248] 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, 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.

[0249] 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.

[0250] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 200°C, preferably from 0°C to 150°C.

[0251] 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.

[0252] (Step E-2b) This step is a step of constructing a seven-membered ring by intramolecular ring closure in a solvent using an appropriate base.

[0253] 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, 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.

[0254] 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.

[0255] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0256] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0257] (Step E-3) This step is a step of alkylating the nitrogen atom of compound (16) with compound (15) in a solvent in the presence of a suitable base.

[0258] 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, 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.

[0259] 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.

[0260] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 100°C.

[0261] 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.

[0262] (Step E-4) This step is a step of converting compound (17) into compound (18) by intramolecular cyclization, and is carried out in accordance with the aforementioned Step E-2b, but is not limited thereto.

[0263] (Step E-5) This step is to remove the protecting group (Pro ３Depending on the protecting group used, a known method is appropriately selected and carried out according to the method described in, for example, P.G. Wuts, "Protective Groups in Organic Synthesis," 5th Edition, Wiley, 2014. Here, a method of removing the protecting group using an acid in a solvent (Step E-5-1) or a method of removing the protecting group using a catalyst in a solvent under a hydrogen atmosphere (Step E-5-2) will be described, but the method is not limited thereto.

[0264] (Step E-5-1) This step is a step of removing the protecting group by using an appropriate acid in a solvent in the presence or absence of anisole.

[0265] 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, 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.

[0266] The acid to be used is not particularly limited as long as it is an acid that is used in ordinary 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.

[0267] 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.

[0268] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0269] (Step E-5-2) This step is a step of removing the protecting group under a hydrogen atmosphere in a solvent in the presence or absence of an additive using a catalyst.

[0270] 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, 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.

[0271] The additives that can be used are not particularly limited, as long as they are used in known methods, such as hydrochloric acid.

[0272] The catalyst to be used is not particularly limited as long as it is one that is used in known methods. Suitable examples include metal catalysts such as palladium-activated carbon, tris(triphenylphosphine)rhodium chloride, and palladium hydroxide.

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

[0274] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 1 minute to 24 hours, preferably from 5 minutes to 10 hours.

[0275] (Method F) This production method is a method for producing compound (3B)), which is compound (3), an intermediate compound used in the above-mentioned Methods A and B.

[0276]

[0277] (Wherein W is —CH ２ -or-CHR１０ - (where R １０ has the same meaning as above, and Z ３ and Z ４ are Z １ and Z ２ represents a precursor group (a group with no substituent or a leaving group attached) of Pro ４ represents an amino-protecting group selected by a known method (for example, P.G. Wuts, "Protective Groups in Organic Synthesis", 5th edition, Wiley, 2014), and is not particularly limited as long as it is stable during the reaction and does not inhibit the reaction, but preferably represents a tert-butoxycarbonyl group. Other symbols have the same meanings as above.

[0278] (Step F-1) In this step, the amino group of compound (19) is protected with a protecting group (Pro ４ ) and is carried out in accordance with the above-mentioned Step E-2a, but is not limited thereto.

[0279] (Step F-2) This step is a step of producing compound (21) according to a known functional group transformation method, for example, the method described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd Edition, ACADEMIC PRESS, INC., 1989, "Comprehensive Organic Transformations", 2nd Edition, VCH Publishers Inc., 1999, etc. Those skilled in the art can appropriately perform the transformation by combining known methods.

[0280] (Step F-3) This step is to remove the protecting group (Pro ４ This is a step of removing the hydroxyl group 1, which is carried out in accordance with the above step E-2c, but is not limited thereto.

[0281] (Method G) This production method is a method for producing compound (7), which is an intermediate compound used in the above-mentioned Method C, from compound (22).

[0282]

[0283] (In the formula, Pro５ represents a protecting group for a hydroxy group selected by a known method (for example, P.G. Wuts, "Protective Groups in Organic Synthesis," 5th edition, Wiley, 2014), and is not particularly limited as long as it is stable during the reaction and does not inhibit the reaction, but preferably represents an acetyl group. Other symbols have the same meanings as above.

[0284] (Step G-1) This step is a step of preparing compound (23) by brominating compound (22) using a brominating agent in a solvent in the presence of a catalyst.

[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; 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.

[0286] Examples of the catalyst that can be used include radical initiators such as azobisisobutyronitrile and benzoyl peroxide.

[0287] Examples of the brominating agent that can be used include N-bromosuccinimide and N-bromoacetamide.

[0288] 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.

[0289] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0290] (Step G-2) In this step, the bromine atom of the compound (23) is protected by a protecting group (Pro ５) to produce compound (24). 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.

[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 examples include 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.

[0292] Examples of the metal carboxylates that can be used include potassium acetate, sodium acetate, potassium benzoate, and sodium benzoate.

[0293] 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.

[0294] 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.

[0295] (Step G-3) This step is to remove the protecting group (Pro ５ ) and can be carried out in accordance with the above-mentioned Step A-2.

[0296] (Step G-4) This step is carried out by reacting the leaving group (L) of compound (25) 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. ３ ) to a boronic acid ester to produce compound (7).

[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, 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.

[0298] The boron compound to be 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.

[0299] 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 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;

[0300] The additive that can be used is not particularly limited as long as it is one that is used in a known method, but suitable examples include 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.

[0301] 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, [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.

[0302] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 200°C, preferably from 0°C to 150°C.

[0303] 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.

[0304] (Method H) This production method is a method for producing a compound (5), which is an intermediate compound used in Methods C and D, in which X is a group represented by formula (A1) and L ２ is a bromine atom.

[0305]

[0306] (In the formula, L ４ represents a leaving group (preferably a halogen atom), and the other symbols are as defined above.

[0307] (Step H-1) In this step, the leaving group (L) of compound (26) is substituted with hydrazine monohydrate in a solvent or without a solvent. ４ ) to a hydrazino group to produce compound (27).

[0308] The solvent that can 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; organic bases such as pyridine; 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.

[0309] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -20°C to 200°C, preferably from 0°C to 150°C.

[0310] 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.

[0311] (Step H-2) This step is carried out by reacting R ６This is a process for producing compound (5A1) from compound (27) using appropriate carboxylic acid anhydrides, carboxylic acids, aliphatic nitro compounds or orthoesters corresponding to the above formula:

[0312] 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, 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.

[0313] 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, but 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.

[0314] The reaction temperature varies depending on the raw material compounds, reagents, etc., but is usually 0°C to 250°C, preferably 20°C to 200°C.

[0315] 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.

[0316] (Method J) This production method is a method for producing a compound (5), which is an intermediate compound used in Methods C and D, in which X is a group represented by formula (A2) and L ２ is a bromine atom.

[0317]

[0318] (In the formula, R １２ represents a hydrogen atom or an alkyl group, and the other symbols are as defined above.

[0319] (Step J-1) This step is a step of preparing compound (29) by brominating compound (28) using an appropriate brominating agent in a solvent.

[0320] 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, 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; organic acids such as acetic acid; and mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio.

[0321] The brominating agent to be used is not particularly limited, but suitable examples include N-bromosuccinimide, bromine, and the like.

[0322] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from -20°C to 50°C.

[0323] 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.

[0324] (Step J-2) This step is a step of converting compound (29) to compound (30), and includes a step of amidating the amino group (Step J-2a) and a step of nitrating (Step J-2b). Either Step J-2a or Step J-2b may be carried out first, and a person skilled in the art can easily select the appropriate order.

[0325] (Step J-2a) (Amidation Step) In this step, compound (29) (or a nitrated compound of compound (29)) is amidated with formic acid (R １２ represents a hydrogen atom) (Step J-2a-1), and a method of reacting compound (29) (or a nitrated compound of compound (29)) with an alkylcarboxylic acid (R１２ is an alkyl group １２ CO ２ H) using an appropriate condensing agent (Step J-2a-2) will be described, but the present invention is not limited thereto.

[0326] (Step J-2a-1) (Method Using Formic 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 examples include 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; and mixed solvents containing a plurality of the above-mentioned organic solvents in any ratio.

[0327] 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.

[0328] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 50°C.

[0329] 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.

[0330] (Step J-2a-2) (Method Using Carboxylic Acid and Condensing Agent) 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.; 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.

[0331] 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;

[0332] 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 of the condensing agent 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 Examples of suitable methyl methyl silimino(methylene)amino}ethyl-4-methylmorpholinium p-toluenesulfonate (CMC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis(1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (DMT), and the like may also be used. If necessary, additives such as 1-hydroxybenzotriazole (HOBT) and N,N-dimethylaminopyridine may also be added.

[0333] 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.

[0334] 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.

[0335] (Step J-2b) (Nitration Step) This step is a step of nitrating compound (29) (or an amidated form of compound (29)) using a suitable nitrating agent in a solvent in the presence or absence of a suitable acid.

[0336] 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.

[0337] 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.

[0338] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from -20°C to 50°C.

[0339] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0340] (Step J-3) This step is a step of converting compound (30) to compound (32) by reducing it with an appropriate reducing agent in a solvent.

[0341] 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.

[0342] 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 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.

[0343] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -100°C to 150°C, preferably from 0°C to 80°C.

[0344] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0345] (Step J-4) In this step, the fluorine atom of the compound (31) is converted to NMR. ６ After converting to a group (Step J-4-1), a bromine atom is introduced (Step J-4-2) (or after introducing a bromine atom, a fluorine atom is introduced into the NHR ６ In Step J-4, either Step J-4-1 or Step J-4-2 may be carried out first, and the order can be appropriately selected by a person skilled in the art.

[0346] (Step J-4-1) In this step, a primary amine (R ６ NH ２ (R in the formula ６ has the same meaning as above. ６ This is a process for converting the

[0347] 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-mentioned organic solvents in any ratio; and mixed solvents containing the above-mentioned organic solvent and water in any ratio.

[0348] 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;

[0349] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 0°C to 100°C.

[0350] 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.

[0351] (Step J-4-2) This step is a step of introducing a bromine atom in a solvent. This step can be carried out under the same conditions as in the above-mentioned Step J-1.

[0352] (Step J-5) This step is a step of producing compound (33) by converting the nitro group of compound (32) to an amino group in a solvent.

[0353] As methods for converting the nitro group of compound (32) to an amino group, a method using an appropriate metal and an appropriate acid (Step J-5-1), a method using hydrogen in the presence of an appropriate metal catalyst (Step J-5-2), and a method using a metal hydride (Step J-5-3) will be described below, but the method is not limited thereto.

[0354] (Step J-5-1) This step is a step of converting the nitro group of compound (32) to an amino group using a metal in a solvent in the presence of an acid.

[0355] 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 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.

[0357] The metal to be used is not particularly limited, but examples thereof include iron, zinc, tin, and the like.

[0358] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 0°C to 100°C.

[0359] 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.

[0360] (Step J-5-2) This step is a step of converting the nitro group of compound (32) to an amino group using hydrogen in a solvent in the presence of a suitable metal catalyst.

[0361] 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.

[0362] 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.

[0363] Examples of the hydrogen source that can be used include hydrogen gas, ammonium formate, and hydrazine.

[0364] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 0°C to 100°C.

[0365] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0366] (Step J-5-3) This step is a step of converting the nitro group of compound (32) to an amino group using an appropriate metal hydride in a solvent.

[0367] 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.

[0368] The metal hydride to be used is not particularly limited, but a suitable example is lithium aluminum hydride.

[0369] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -10°C to 150°C, preferably from 0°C to 100°C.

[0370] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 12 hours.

[0371] (Step J-6) This step is a step of producing compound (5A2) by constructing a triazole ring from compound (33). 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.

[0372] That is, this step is a step of constructing a triazole ring by reacting compound (33) with a nitrite or a nitrite ester in a solvent in the presence of an acid.

[0373] 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.

[0374] 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.

[0375] The nitrites to be used are not particularly limited, but examples thereof include alkali metal salts such as sodium nitrite.

[0376] The nitrite esters to be used are not particularly limited, but examples thereof include isobutyl nitrite and tert-butyl nitrite.

[0377] The reaction temperature varies depending on the starting compounds, reagents, etc., but is usually from -20°C to 100°C, preferably from -10°C to 60°C.

[0378] The reaction time varies depending on the starting compounds, reagents, etc., but is usually from 5 minutes to 24 hours, preferably from 10 minutes to 6 hours.

[0379] 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.

[0380] 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.

[0381] (Medicine (or Pharmaceutical Composition) of the Present Invention) The medicine of the present invention is a medicine for preventing and / or treating oxidative stress-related diseases, which contains compound (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0382] The pharmaceutical of the present invention may be either a pharmaceutical consisting of compound (1) or a pharmaceutically acceptable salt thereof alone, 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).

[0383] 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 (for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic 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, citrates, etc.), 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, salts, etc.), coloring agents (for example, water-soluble food tar dyes (e.g., 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 (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), etc.), sweeteners (e.g., saccharin sodium, dipotassium glycyrrhizinate, stevia, etc.), flavoring agents (e.g., fennel oil, cinnamon oil, ethyl vanillin, orange oil, etc.), fragrances, etc.;

[0384] 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 a sugar coating, 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.

[0385] The content of the compound (1) of the present invention or a pharmaceutically acceptable salt thereof in the medicament (pharmaceutical composition) of the present invention varies depending on the form of the preparation, but is 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.

[0386] 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.

[0387] Compound (1) of the present invention or a pharmaceutically acceptable salt thereof is useful for treating oxidative stress-related diseases, specifically, for example, 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 liver cirrhosis; bronchitis, pneumonia, pleurisy, chronic obstructive pulmonary disease, acute lung injury, diffuse panbronchiolar nephritis, and pulmonary fibrosis. respiratory diseases selected from the group consisting of pulmonary inflammation, 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 Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, cerebral infarction, polyglutamine disease, and autism; Friedreich's ataxia and mitochondrial diseases selected from the group consisting of mitochondrial myopathies; 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 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. The present invention is effective for the prevention and / or treatment of diseases, etc. selected from the group consisting of eye 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.

[0388] 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.

[0389] 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., veraprolactone, etc.), and the like. lost, etc.), endothelin receptor antagonists (e.g., bosentan, etc.), phosphodiesterase-5 inhibitors (e.g., sildenafil, etc.), soluble guanylate cyclase (sGC) stimulators (e.g., vericiguat, etc.), L-dopa, dopamine agonists (e.g., pramipexole, etc.), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone, etc.), monoamine oxidase B (MAO-B) inhibitors (e.g., selegiline, etc.), interferon-β, copaxone, etc.

[0390] When a concomitant drug is used, the timing of administration is not limited, and they may be administered to the subject at the same time, or at a different time from the administration of the medicament of the present invention (i.e., with a time lag). The 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 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.

[0391] The dosage of the concomitant drug can be appropriately selected based on the dose normally used in clinical practice. The compounding 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 (the subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0392] The mass ratio of compound (1) or a pharmaceutically acceptable salt thereof to the concomitant drug is not particularly limited.

[0393] 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).

[0394] The medicament or pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration and the like. 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. The instructions for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0395] Test Example 1: FP Assay (in vitro) The inhibitory activity of test compounds against the binding between Nrf2 and Keap1 was measured by 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 containing buffer without Keap1 served as negative controls. Wells without compound served 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 was defined as 0% inhibition. The percent inhibition upon addition of the test compound was calculated using the following formula:

[0396]

[0397] 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: concentration at which 50% inhibition rate is achieved (IC 50 ) ≦ 0.01, B: 0.01 < 50% inhibition concentration (IC 50 ) ≦ 0.03, C: 0.03 < 50% inhibition concentration (IC 50 ) ≦ 0.3, D: 0.3 < 50% inhibition concentration (IC 50 ) ≦ 3).

[0398]

[0399] Test Example 2: NAD(P)H:quinone oxidoreductase-1 (NQO1) enzyme induction test (in vitro) NQO1 assay was performed based on a previously reported method (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 x 10 cells were plated in a 96-well plate (Corning, REF. 353072). 4 Cells were seeded at 1000 cells / well. For background measurement, wells containing only medium without cells were prepared. The next day, test compounds dissolved in DMSO at a final concentration of 400 nM (final DMSO concentration: 0.004%) were added and the cells were cultured for approximately 48 hours. For basal activity measurement, wells to which no compound was added were prepared.

[0400] 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.

[0401]

[0402] 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, C: 1.5<NQO1 activity fold≦3).

[0403]

[0404] The above results suggest 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.

[0405] Test Example 3: Measurement of NQO1 activity in rat kidney (single administration) Test compound solutions for administration were prepared by dissolving or suspending the test compound in a 0.5 w / v% aqueous methylcellulose solution. The test compound was orally administered (3 mg / kg, 2 mL / kg) to SD rats (male, Japan SLC). A vehicle-administered group served as a control. The rats were anesthetized with isoflurane at 24 and 48 hours after administration for the test compound group and at 24 hours after administration for the control group, and then euthanized by exsanguination via abdominal aortic incision. The right kidney was immediately removed, and the renal cortex and medulla were excised and NQO1 activity was measured.

[0406] Homogenization buffer (10 mM Tris-HCl, 250 mM sucrose, pH 7.4) and assay buffer (25 mM Tris-HCl, 0.7 mg / mL BSA, pH 7.4) were prepared. One mL of homogenization buffer was added to the collected kidney sample, and the organ was homogenized uniformly on ice using a Polytron homogenizer (PHYSCOTRON, Microtec Co. Ltd.) or a TissueLyser II (QIAGEN). The homogenized sample was centrifuged (MX-305, TOMY) at 9,000 x g for 20 minutes at 4°C. The supernatant was diluted to approximately 2 mL with homogenization buffer and ultracentrifuged at 100,000 x g for 60 minutes at 4°C (centrifuge: OptimaL-100XP, rotor: 50.4Ti, Beckman Coulter). The protein concentration of the supernatant was measured using a Protein Assay BCA Kit (#06385-00, Nacalai Tesque), and the sample was diluted to 5 μg protein / 30 μL with homogenization buffer. Just before measurement, DMSO or dicoumarol-containing 2,6-dichlorophenolindophenol (DCPIP) reaction buffer (200 μM NADPH, 160 μM DCPIP added to assay buffer, 1 / 1000 volume of DMSO or 20 μM dicoumarol DMSO solution) was prepared. A DCPIP dilution series for the calibration curve was prepared as shown in Table 3 below.

[0407]

[0408] 230 μL of each standard curve solution was added to a 96-well plate (CORNING, 9017). 200 μL of DMSO-containing DCPIP reaction buffer or dicoumarol-containing DCPIP reaction buffer was added to 30 μL of the sample solution. The absorbance at 600 nm was immediately measured at 1-minute intervals for 10 minutes using a SpectraMax PLUS384 (Molecular Devices). The linear range (0 to N minutes) of absorbance decrease from the start to the end of the measurement was confirmed, and the amount of DCPIP (nmol) at the start of the measurement and after N minutes was calculated using the standard curve, and the amount of DCPIP decreased over N minutes (nmol / N minutes) was calculated. A regression line was used to create the standard curve.

[0409] The difference in the amount of DCPIP lost in the wells containing DMSO-containing DCPIP reaction buffer was divided by the protein amount (mg) and time (min) to determine the NQO1 activity (nmol / mg / min). Table 4 below shows the NQO1 activity of the compound-treated groups as a factor relative to the control group.

[0410]

[0411] These results demonstrate that oral administration of these compounds induces potent Nrf2 activation in renal tissue.

[0412] The present invention will be explained in detail by the following examples, but these examples are merely illustrative and do not limit the present invention, and may be changed 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 other. Nuclear magnetic resonance spectroscopy (hereinafter 1For H-NMR (resonance frequency 400 MHz or 500 MHz), chemical shift values ​​are reported as δ values ​​(ppm) using tetramethylsilane as the 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 dt: doublet of triplets td: triplet of doublets ddd: doublet of 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 tBu: tert-butyl 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

[0413] Unless otherwise specified, the reagents, solvents, equipment, etc. used in the following examples are commercially available. Furthermore, unless otherwise specified, the raw material compounds are known compounds and are either commercially available or synthesized and identified according to known methods or methods equivalent thereto.

[0414] Example 1 (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0415] Example 2 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0416] (1a) 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid

[0417] 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 cooled 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%).

[0418] (1b) 5-bromo-7-methyl-1-benzothiophene

[0419] 5-Bromo-7-methyl-1-benzothiophene-2-carboxylic acid (105 g) from Example 1a 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 - 95 / 5 (V / V)] to afford the title compound (49.8 g, yield: 57%) as an oil.

[0420] (1c) (5-Bromo-1-benzothiophen-7-yl)methyl acetate

[0421] 5-Bromo-7-methyl-1-benzothiophene (114.2 g) from Example 1b 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 cooled 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 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 column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 - 90 / 10 (V / V)] to obtain 94.4 g (yield: 66%) of the title compound as a solid.

[0422] (1d) (5-Bromo-1-benzothiophen-7-yl)methanol

[0423] (5-Bromo-1-benzothiophen-7-yl)methyl acetate (50.2 g) from Example 1c 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.

[0424] (1e) [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol

[0425] (5-Bromo-1-benzothiophen-7-yl)methanol (2.00 g) from Example 1d 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 - 70 / 30 (V / V)] to afford the title compound (2.75 g, quantitative yield) as an oil.

[0426] (1f) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[0427] [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (500 mg) from Example 1e was dissolved in a mixed solvent of 1,4-dioxane (11.2 mL) and water (5.6 mL), and 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 stirred at 90°C for 5 minutes. Next, chloro(1,5-cyclooctadiene)rhodium(I) dimer (42 mg) was added and stirred at 90°C for 15 minutes. 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, 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.

[0428] (1g) Ethyl 3-[7-(chloromethyl)-1-benzothiophen-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0429] To a solution of ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (380 mg) in dichloromethane (5 mL), thionyl chloride (0.135 mL) was added and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene to give the title compound (397 mg, quantitative yield) as a highly viscous oil.

[0430] (1h) (2R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride

[0431] tert-Butyl (2R)-2-ethyl-7-hydroxy-3,5-dihydro-2H-pyrido[2,3-f][1,4]oxazepine-4-carboxylate (WO 2020 / 16577) (1.57 g) was dissolved in dichloromethane (15 mL), and 4 M hydrogen chloride-1,4-dioxane solution (10 mL) was added and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the resulting residue was added with n-hexane and subjected to ultrasonic treatment. The resulting solid was collected by filtration. After drying in vacuo at 60 ° C for 3 hours, 1.23 g (yield: quantitative) of the title compound was obtained as a solid.

[0432] (1i) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate

[0433] To a solution of ethyl 3-[7-(chloromethyl)-1-benzothiophen-5-yl]-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (2.20 g) from Example 1g in acetonitrile (200 mL), N,N-diisopropylethylamine (0.740 mL) and (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (1.00 g) were added, stirred at 85°C for 48 hours, and cooled to room temperature. The reaction solution 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 solvent was distilled off under reduced pressure, and 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)] to give 1.40 g (yield: 55%) of the title compound as an oil.

[0434] (1j) = (1) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0435] (2a) = (2) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0436] To a mixture of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate (1.40 g) from Example 1i, ethanol (20 mL), and tetrahydrofuran (20 mL), 1 M aqueous sodium hydroxide solution (4.8 mL) was added and stirred at room temperature for 12 hours. 1 M hydrochloric acid (4.8 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 solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0-98 / 2 (V / V)] to give Compound 2. The first eluted product, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, was obtained as a solid in an amount of 0.300 g (yield: 23%).

[0437] Furthermore, 0.250 g (yield: 19%) of (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid was obtained as a solid after elution.

[0438] Example 3 (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid

[0439] (3a) 6-Bromo-2-(bromomethyl)-3-fluoropyridine

[0440] To a suspension of 6-bromo-3-fluoro-2-methylpyridine (71.3 g) in carbon tetrachloride (1.5 L), N-bromosuccinimide (201 g) and 2,2'-azodiisobutyronitrile (18.6 g) were added and the mixture was heated to reflux for 4 days. The reaction mixture was cooled to room temperature, and insoluble matter was filtered off. The resulting filtrate was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution of the resulting residue in tetrahydrofuran (1.5 L), N,N-diisopropylethylamine (65.3 mL) and diethyl phosphite (48.4 mL) were added at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / chloroform = 95 / 5 / 20 - 75 / 25 / 20 (V / V / V)]. n-Hexane was added to the resulting residue, and the mixture was sonicated. The solid was collected by filtration to obtain 80.8 g (yield: 80%) of the title compound as a solid.

[0441] (3b) 1-{[bis(4-methoxybenzyl)amino]methyl}cyclopropanol

[0442] Ethyl glycinate hydrochloride (64.1 g) was dissolved in acetonitrile (920 mL), and potassium carbonate (191 g), 4-methoxybenzyl chloride (125 mL), and sodium iodide (6.88 g) were added. The mixture was stirred at 50°C for 4 hours. The insoluble matter in the reaction mixture was filtered off and washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure to give 158.8 g of crude product as an oil. The resulting crude product (91.7 g) was dissolved in tetrahydrofuran (370 mL), and tetraisopropyl orthotitanate (19.0 mL) was added under a nitrogen atmosphere. Ethyl magnesium bromide (1.0 M tetrahydrofuran solution) (800 mL) was added over 50 minutes at 0°C, and the mixture was stirred at room temperature for 35 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was filtered through Celite to remove the insoluble matter. The mixture was then washed sequentially with a saturated aqueous ammonium chloride solution, water, and ethyl acetate. A saturated aqueous sodium bicarbonate solution was added to the resulting filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 - 80 / 20 (V / V)] to give 70.2 g (yield: 80%) of the title compound as an oil.

[0443] (3c) 1-{[(4-methoxybenzyl)amino]methyl}cyclopropanol

[0444] To a suspension of 20% palladium hydroxide on activated carbon (382 mg) in a small amount of ethyl acetate, a solution of 1-{[bis(4-methoxybenzyl)amino]methyl}cyclopropanol (7.64 g) from Example 3b in methanol (200 mL) and acetic acid (40 mL) were added, and catalytic hydrogenation was carried out at 50°C and 0.4 MPa for 35 minutes. Celite was added to the reaction mixture, and the insoluble material was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and azeotroped with toluene. The residue was purified by NH silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0-70 / 30 (V / V), chloroform / methanol = 100 / 0-97 / 3 (V / V)] to give 2.47 g (yield: 51%) of the title compound as an oil.

[0445] (3d) 1-({[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}methyl)cyclopropanol

[0446] 6-Bromo-2-(bromomethyl)-3-fluoropyridine (2.64 g) from Example 3a and 1-{[(4-methoxybenzyl)amino]methyl}cyclopropanol (2.07 g) from Example 3c were dissolved in acetonitrile (50 mL), potassium carbonate (1.80 g) was added, and the mixture was stirred at 50°C for 1 hour. After filtering off the insoluble matter from the reaction mixture, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 - 70 / 30 (V / V)] to afford 2.59 g (yield: 66%) of the title compound as an oil.

[0447] (3e) 7'-Bromo-4'-(4-methoxybenzyl)-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]

[0448] 1-({[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}methyl)cyclopropanol (2.31 g) of Example 3d was dissolved in a mixed solution of tetrahydrofuran (42 mL) and N,N-dimethylformamide (42 mL). After stirring at 60°C, 60% sodium hydride (257 mg) was added 20 minutes, 50 minutes, and 60 minutes later, and the mixture was stirred for a total of 80 minutes. The reaction mixture was cooled 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 purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0-65 / 35 (V / V)] to give 1.88 g (yield: 80%) of the title compound as an oil.

[0449] (3f) 4'-(4-Methoxybenzyl)-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-7'-ol

[0450] 7'-Bromo-4'-(4-methoxybenzyl)-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine] (750 mg) from Example 3e was dissolved in 1,4-dioxane (10 mL), and bis(dibenzylideneacetone)palladium(0) (57 mg), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (101 mg), and cesium hydroxide monohydrate (1.01 g) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 3.5 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid and saturated aqueous sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layer 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: chloroform / methanol = 100 / 0 to 92 / 8 (V / V)] to give 475 mg (yield: 75%) of the title compound as a solid.

[0451] (3g) 4',5'-Dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-7'-ol hydrochloride

[0452] 4'-(4-Methoxybenzyl)-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-7'-ol (443 mg) from Example 3f was dissolved in trifluoroacetic acid (14 mL) and subjected to microwave irradiation at 180 °C for 10 minutes. The reaction mixture was cooled to room temperature, and toluene was added for azeotropy. The resulting residue was dissolved in ethyl acetate (10 mL), and 1 M hydrogen chloride-ethyl acetate (4.0 mL) was added, followed by stirring at room temperature for 5 minutes. tert-Butyl methyl ether was added to the reaction mixture, and the solid was collected by filtration to give 354 mg (yield: quantitative) of the title compound as a solid.

[0453] (3h) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate

[0454] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (807 mg) from Example 1f was dissolved in dichloromethane (7.6 mL), and dimethyl sulfoxide (0.70 mL), N,N-diisopropylethylamine (1.0 mL), and sulfur trioxide-pyridine complex (1.05 g) were added. The mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (7.6 mL). 4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-7'-ol hydrochloride (586 mg) from Example 3g, N,N-diisopropylethylamine (0.41 mL), and acetic acid (0.023 mL) were added, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (835 mg) was added, followed by stirring at room temperature for 14.5 hours. Sodium triacetoxyborohydride (209 mg) was then added, followed by stirring at room temperature for 50 minutes. Further sodium triacetoxyborohydride (209 mg) was added, followed by stirring at room temperature for 15 minutes. Anhydrous magnesium sulfate (284 mg) was added to the reaction mixture, and the mixture was stirred at 40°C for 20 minutes. Saturated aqueous sodium bicarbonate was then added, and the mixture was stirred at 40°C 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 removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 40 / 60-0 / 100 (V / V), chloroform / methanol = 100 / 0-95 / 5 (V / V)] to give 706 mg (yield: 57%) of the title compound as a solid.

[0455] (3i) Ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate

[0456] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate (700 mg) of Example 3h was subjected to chiral HPLC [column: CHIRALPAK IG (20 mm ID x 250 mm), mobile phase: n-hexane:ethanol = 50:50] to obtain 340 mg of ethyl (3S)-3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate was obtained as the first peak (49%). Retention time: 9.773 min [Column: CHIRALPAK IG (4.6 mm ID × 250 mm), Mobile phase: n-hexane:ethanol = 50:50, Flow rate: 1.0 mL / min, Temperature: 40 °C, Wavelength: 254 nm]

[0457] (3j) = (3) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid

[0458] To a mixture of ethyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate (340 mg) from Example 3i, methanol (4 mL), and tetrahydrofuran (4 mL), 1 M aqueous sodium hydroxide (1.7 mL) was added and stirred at 60°C for 30 minutes. The reaction mixture was cooled to room temperature, and Dowex 50w-X8 was added to adjust the pH of the reaction mixture to 6-7. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 50 / 1-9 / 1 (V / V)]. Ethyl acetate and hexane were added to solidify the mixture to give 242 mg (yield: 75%) of the title compound as a solid.

[0459] Example 4 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid

[0460] (4a) Ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate

[0461] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate (700 mg) of Example 3h was subjected to chiral HPLC [column: CHIRALPAK IG (20 mm ID x 250 mm), mobile phase: n-hexane:ethanol = 50:50] to give 341 mg of ethyl (3R)-3-(1,4-Dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate was obtained as the second peak (49%). Retention time: 12.270 min [Column: CHIRALPAK IG (4.6 mm ID × 250 mm), Mobile phase: n-hexane:ethanol = 50:50, Flow rate: 1.0 mL / min, Temperature: 40 °C, Wavelength: 254 nm]

[0462] (4b) = (4) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid

[0463] To a mixture of ethyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoate (340 mg), methanol (4 mL), and tetrahydrofuran (4 mL), 1 M aqueous sodium hydroxide (1.7 mL) was added and stirred at 60 °C for 30 minutes. The reaction mixture was cooled to room temperature, and Dowex 50w-X8 was added to adjust the pH of the reaction mixture to 6-7. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 50 / 1-9 / 1 (V / V)]. Ethyl acetate and hexane were added to solidify the mixture to give 289 mg (yield: 89%) of the title compound as a solid.

[0464] Example 5 (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0465] Example 6 (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0466] (5a) 2-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}-1-cyclopropylethanol

[0467] To a solution of 2-amino-1-cyclopropylethanol (WO 2018 / 196662) (2.43 g) in dichloromethane (48 mL), 4-methoxybenzaldehyde (1.46 mL), anhydrous magnesium sulfate (2.89 g), and one drop of acetic acid were added. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (5.09 g) was added and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. Potassium carbonate (3.32 g) was added to a solution of the residue obtained by distilling off the solvent under reduced pressure and 6-bromo-2-(bromomethyl)-3-fluoropyridine (5.09 g) from Example 3a in dimethylformamide (60 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to give 4.65 g (yield: 95%) of the title compound as an oil.

[0468] (5b) 7-Bromo-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

[0469] 2-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}-1-cyclopropylethanol (5.50 g) from Example 5a was divided equally into two lots. To each N,N-dimethylformamide (96 mL) solution, 60% sodium hydride (808 mg) was added at room temperature and stirred at room temperature for 50 minutes. Saturated aqueous ammonium chloride and water were added to each reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residues were combined and purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0-85 / 15 (V / V)] to afford the title compound (3.57 g, yield: 68%) as an oil.

[0470] (5c) 2-Cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0471] To a solution of 7-bromo-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (3.57 g) from Example 5b in 1,4-dioxane (46 mL), bis(dibenzylideneacetone)palladium(0) (264 mg), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (465 mg), and cesium hydroxide monohydrate (4.62 g) were added and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and water and 2 M hydrochloric acid were added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 97 / 3 (V / V)] to give 2.36 g (yield: 70%) of the title compound as a solid.

[0472] (5d) (2R)-2-Cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0473] 2-Cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (930 mg) of Example 5c was subjected to chiral HPLC [Column: CHIRALART Cellulose-SZ (20 mm ID × 250 mm), mobile phase: n-hexane:ethanol:chloroform = 60:20:20] to obtain 388 mg of (2R)-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol as a second peak (yield: 42%). Retention time: 8.6367 min [Column: CHIRALART Cellulose-SZ (4.6 mm ID × 250 mm), Mobile phase: n-hexane:ethanol = 50:50, Flow rate: 1.0 mL / min, Temperature: 40°C, Wavelength: 280 nm]

[0474] (5e) (2R)-2-Cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride

[0475] To a solution of (2R)-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (480 mg) from Example 5d in trifluoroacetic acid (8 mL) was added anisole (1.6 mL) and stirred at 85°C for 4 hours. The reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure, and toluene (20 mL) was added for azeotropy. Ethyl acetate (10 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL) were added and stirred for 10 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was added with ethyl acetate and sonicated. The solid was collected by filtration and dried in vacuo to afford the title compound (440 mg, quantitative yield, 85% purity) as a solid.

[0476] (5f) Ethyl 3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0477] To a solution of ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (530 mg) from Example 1f in dichloromethane (6 mL) was added thionyl chloride (0.190 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and toluene was added for azeotropy. The resulting residue was dissolved in acetonitrile (5 mL) and added dropwise to a separate solution of (2R)-2-cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (300 mg) from Example 5e and N,N-diisopropylethylamine (1.5 mL) in acetonitrile (15 mL). The mixture was stirred at 90°C for 10 hours and cooled to room temperature. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 90 / 1 - 50 / 1 (V / V)] to give 417 mg (yield: 65%) of the title compound as a solid.

[0478] (5g) = (5) (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0479] (6a) = (6) (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0480] To a mixture of ethyl 3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (400 mg) from Example 5f, methanol (4 mL), and tetrahydrofuran (4 mL), 1 M aqueous sodium hydroxide solution (1.7 mL) was added and stirred at 60°C for 30 minutes. The reaction mixture was cooled to room temperature, and Dowex 50w-X8 was added to adjust the pH of the reaction mixture to 5-6. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 50 / 1-9 / 1 (V / V)]. Ethyl acetate and n-hexane were added to the compound eluted earlier, followed by sonication. The solid was collected by filtration and dried in vacuo to obtain 128 mg (yield: 34%) of (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid.

[0481] The compound eluted later was treated in the same manner to obtain 128 mg (yield: 34%) of (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid.

[0482] Example 7 (3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0483] Example 8 (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0484] (7a) (2S)-2-Cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0485] 2-Cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (930 mg) of Example 5c was subjected to chiral HPLC [Column: CHIRALART Cellulose-SZ (20 mm ID × 250 mm), mobile phase: n-hexane:ethanol:chloroform = 60:20:20] to obtain 380 mg of (2S)-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol as the first peak (yield: 41%). Retention time: 7.1100 min [Column: CHIRALART Cellulose-SZ (4.6 mm ID × 250 mm), Mobile phase: n-hexane:ethanol = 50:50, Flow rate: 1.0 mL / min, Temperature: 40 °C, Wavelength: 280 nm]

[0486] (7b) (2S)-2-Cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride

[0487] To a solution of (2S)-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (480 mg) from Example 7a in trifluoroacetic acid (8 mL), anisole (1.6 mL) was added, and the mixture was stirred at 85°C for 4 hours and cooled to room temperature. The solvent was evaporated under reduced pressure, and toluene (20 mL) was added for azeotropy. Ethyl acetate (10 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (4 mL) were added, and the mixture was stirred for 10 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the resulting residue, which was then sonicated. The solid was collected by filtration and dried under vacuum to give the title compound (393 mg, yield: 94%, purity: 85%) as a solid.

[0488] (7c) Ethyl 3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0489] To a solution of ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (411 mg) from Example 1f in dichloromethane (6 mL) was added thionyl chloride (0.150 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and toluene was added to the resulting residue for azeotropy. The resulting residue was dissolved in acetonitrile (5 mL) and added dropwise to a solution of (2S)-2-cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (300 mg) from Example 7b and N,N-diisopropylethylamine (1.3 mL) in acetonitrile (15 mL). The mixture was stirred at 90°C for 10 hours and cooled to room temperature. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel column chromatography [eluent: chloroform / methanol = 90 / 1 - 50 / 1 (V / V)] to give 383 mg (yield: 70%) of the title compound as an amorphous solid.

[0490] (7d) = (7) (3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0491] (8a) = (8) (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0492] To a mixture of ethyl 3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (370 mg) from Example 7c, methanol (4 mL), and tetrahydrofuran (4 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added and stirred at 60°C for 30 minutes. The reaction mixture was then cooled to room temperature. Dowex 50w-X8 was added to adjust the pH of the reaction mixture to 5-6, and the residue obtained after concentration under reduced pressure was purified by silica gel column chromatography [eluent: chloroform / methanol = 50 / 1-9 / 1 (V / V)]. Ethyl acetate and n-hexane were added to the compound eluted earlier, followed by sonication. The solid was collected by filtration and dried in vacuo to obtain 122 mg (yield: 39%) of (3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid.

[0493] Similarly, the compound eluted later was treated to obtain 136 mg (yield: 39%) of (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid.

[0494] Example 9 (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid

[0495] (9a) Ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate

[0496] Ethyl (2E)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)prop-2-enoate (International Publication No. 2015 / 092713) (2.5 g), and Example 1e [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (4.4 g) was used in the same manner as in Example 1f to obtain 2.4 g (yield: 58%) of the title compound as a solid.

[0497] (9b) Ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-formyl-1-benzothiophen-5-yl)propanoate

[0498] To a solution of ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (700 mg) from Example 9a in chloroform (40 mL), manganese(IV) oxide (2.2 g) was added and the mixture was stirred at 60°C for 5 hours. Subsequently, manganese(IV) oxide (740 mg) was added, the mixture was stirred at 90°C for 2 hours, and then cooled to room temperature. After filtering off insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 50 / 50 (V / V)] to give 642 mg (yield: 92%) of the title compound as a solid.

[0499] (9c) Ethyl (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate

[0500] To a solution of (2R)-2-cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (130 mg) from Example 5e in dichloromethane (3 mL) was added N,N-diisopropylethylamine (0.293 mL) and the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure. A solution of ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-formyl-1-benzothiophen-5-yl)propanoate (173 mg) from Example 9b in dichloromethane (10 mL) and sodium triacetoxyborohydride (339 mg) were added and the mixture was stirred at room temperature for 2.5 hours. Sodium triacetoxyborohydride (338 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. Acetic acid (0.040 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Acetic acid (0.040 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-95 / 5 (V / V)] and then subjected to chiral HPLC [column: CHIRALPAK OD-H (20 mm ID × 250 mm), mobile phase: n-hexane:ethanol = 50:50] to obtain 56.0 mg of ethyl (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate as the first peak (yield: 22%). Retention time: 6.183 min [Column: CHIRALPAK OD-H (4.6 mm ID × 250 mm), Mobile phase: n-hexane:ethanol = 50:50, Flow rate: 1.0 mL / min, Temperature: 40 °C, Wavelength: 210 nm]

[0501] (9d) = (9) (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid

[0502] To a mixture of ethyl (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate (56.0 mg) from Example 9c, ethanol (5 mL), and water (1 mL) was added lithium hydroxide monohydrate (12.6 mg), and the mixture was stirred at room temperature for 18 hours. 1 M hydrochloric acid (0.3 mL) was added to the reaction solution, and the mixture was stirred. The mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0 to 90 / 10 (V / V)] and further purified by slurry purification from hexane / ethyl acetate to give the title compound (33.6 mg) as a solid.

[0503] Example 10 (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid

[0504] (10a) Ethyl (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate

[0505] Example 9c, ethyl (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate (69.0 mg) was obtained as the second peak by chiral HPLC (yield: 27%). Retention time: 8.277 min [Column: CHIRALPAK OD-H (4.6 mm ID × 250 mm), mobile phase: n-hexane:ethanol = 50:50, flow rate: 1.0 mL / min, temperature: 40 °C, wavelength: 210 nm].

[0506] (10b) = (10) (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoic acid

[0507] Using ethyl (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)propanoate (69.0 mg) of Example 10a, in a similar manner to Example 9d, the title compound (36.3 mg) was obtained as a solid.

[0508] Example 11 (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid

[0509] (11a) 5-Bromo-7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophene

[0510] To a solution of (5-bromo-1-benzothiophen-7-yl)methanol (5.00 g) from Example 1d in N,N-dimethylformamide (42 mL) was added sodium hydride (55%, 987 mg) at 0°C and stirred at room temperature for 30 minutes. 4-Methoxybenzyl chloride (3.36 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride 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 removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 - 90 / 10 (V / V)] to afford the title compound (7.11 g, yield: 95%) as an oil.

[0511] (11b) (1,4-dimethyl-1H-benzotriazol-5-yl)(7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophen-5-yl)methanol

[0512] To a solution of 5-bromo-7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophene (3.24 g) from Example 11a in tetrahydrofuran (40 mL), a 1.6 M n-hexane solution of n-butyllithium (5.72 mL) was added at -78°C and stirred for 10 minutes. Next, a solution of 1,4-dimethyl-1H-benzotriazole-5-carbaldehyde (WO 2016 / 202253) (1.42 g) in tetrahydrofuran (40 mL) was added, and the mixture was stirred at -78°C for 15 minutes and then at 0°C for 2 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. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 80 / 0 - 60 / 40 - 55 / 45 (V / V)] to give 1.56 g (yield: 42%) of the title compound as an oil.

[0513] (11c) Methyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate

[0514] To a solution of (1,4-dimethyl-1H-benzotriazol-5-yl)(7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophen-5-yl)methanol (3.20 g) from Example 11b and trichloroacetonitrile (0.844 mL) in acetonitrile (100 mL), 1,8-diazabicyclo[5.4.0]-7-undecene (0.052 mL) was added and stirred at room temperature for 2 hours. Next, dimethylketene methyltrimethylsilyl acetal (3.53 mL) and bis(trifluoromethanesulfonyl)imide (196 mg) were added, and the mixture was stirred at room temperature for 5 hours and at 50°C for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 80 / 20 - 50 / 50 (V / V)] to obtain 2.97 g (yield: 79%) of the title compound as an oil.

[0515] (11d) Methyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate

[0516] To a solution of methyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(4-methoxybenzyl)oxy]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate (2.97 g) from Example 11c in dichloromethane (55 mL) and water (5.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.73 g) at 0°C, and the mixture was stirred at 0°C for 2 hours. 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 evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 50 / 50 - 30 / 70 (V / V)] to give 1.60 g (yield: 69%) of the title compound as an oil.

[0517] (11e) Methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate

[0518] Methyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (550 mg) of Example 11d was subjected to chiral HPLC [column: CHIRALPAK IH (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 85 / 15 (V / V)] to obtain 237 mg of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate as the first peak (yield: 43%). Retention time: 13.210 min [Column: CHIRALPAK IH (4.6 mm ID × 250 mm), Mobile phase: n-hexane / ethanol = 85 / 15 (V / V), Flow rate: 1.0 mL / min, Temperature: 40°C, Wavelength: 210 nm]

[0519] (11f) Methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate

[0520] To a solution of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (39.0 mg) from Example 11e in dichloromethane (2.0 mL) was added thionyl chloride (0.0141 mL) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and toluene was added for azeotropy. The resulting mixture was dissolved in acetonitrile (1.0 mL) and added to a solution of N,N-diisopropylethylamine (0.160 mL) and (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (25.5 mg) from Example 1h in acetonitrile (1.0 mL). The mixture was stirred at 80°C for 12 hours and then cooled to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V), ethyl acetate / methanol = 100 / 0 - 95 / 5 (V / V)] to afford 55.0 mg (yield: 100%) of the title compound as an oil.

[0521] (11g) = (11) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid

[0522] To a solution of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate (55.0 mg) from Example 11f in dimethyl sulfoxide (1.0 mL) was added 1 M aqueous potassium hydroxide solution (0.459 mL) and stirred at 70°C for 12 hours. The reaction mixture was neutralized with 1 M hydrochloric acid, saturated aqueous ammonium chloride solution 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 removed under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 30 / 70 - 0 / 100 (V / V), ethyl acetate / methanol = 100 / 0 - 95 / 5 (V / V)]. Ethyl acetate and n-hexane were added to the solid, and the mixture was sonicated. The solid was collected by filtration and dried in vacuo to give 53.0 mg (yield: 98.7%) of the title compound as a solid.

[0523] Example 12 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid

[0524] (12a) Methyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate

[0525] Methyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (148 mg) of Example 11d was subjected to chiral HPLC [column: CHIRALPAK IH (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 85 / 15 (V / V)] to obtain 75 mg of methyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate as a second peak (yield: 51%). Retention time: 15.753 min [Column: CHIRALPAK IH (4.6 mm ID × 250 mm), Mobile phase: n-hexane / ethanol = 85 / 15 (V / V), Flow rate: 1.0 mL / min, Temperature: 40°C, Wavelength: 254 nm]

[0526] (12b) Methyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate

[0527] To a solution of methyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (39.0 mg) from Example 12a in dichloromethane (2.0 mL) was added thionyl chloride (0.0141 mL) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and toluene was added for azeotropy. The residue was dissolved in acetonitrile (1.0 mL) and added to a solution of N,N-diisopropylethylamine (0.160 mL) and (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (25.5 mg) from Example 1h in acetonitrile (1.0 mL). The mixture was stirred at 80°C for 12 hours and then cooled to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V), ethyl acetate / methanol = 100 / 0 - 95 / 5 (V / V)] to afford 55.0 mg (yield: 100%) of the title compound as an oil.

[0528] (12c) = (12) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid

[0529] To a solution of methyl (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-2,2-dimethylpropanoate (55.0 mg) from Example 12b in dimethyl sulfoxide (1.0 mL) was added 1 M aqueous potassium hydroxide solution (0.459 mL) and stirred at 70°C for 12 hours. The reaction mixture was neutralized with 1 M hydrochloric acid, saturated aqueous ammonium chloride solution 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 removed under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 30 / 70 - 0 / 100 (V / V), ethyl acetate / methanol = 100 / 0 - 95 / 5 (V / V)]. Ethyl acetate and n-hexane were added to the solid, and the mixture was sonicated. The solid was collected by filtration and dried in vacuo to give 51.0 mg (yield: 94.9%) of the title compound as a solid.

[0530] Example 13 (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid

[0531] (13a) Methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoate

[0532] To a solution of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (366 mg) from Example 11e in dichloromethane (10 mL) was added thionyl chloride (0.126 mL) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and toluene was added for azeotropy. The resulting residue was dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (0.740 mL) and 4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepin]-7'-ol hydrochloride (217 mg) from Example 3g were added. The mixture was stirred at 85°C for 15 hours and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0 - 90 / 10 (V / V)] to give 489 mg (yield: 95%) of the title compound as an oil.

[0533] (13b) = (13) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid

[0534] To a solution of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoate (489 mg) from Example 13a in dimethyl sulfoxide (8 mL) was added 1 M aqueous potassium hydroxide (4.09 mL) and stirred at 70 °C for 24 hours. The reaction mixture was neutralized with 1 M hydrochloric acid, saturated aqueous ammonium chloride was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 40 / 60-30 / 70 (V / V)]. Diisopropyl ether was added to the solid and the mixture was sonicated. The solid was collected by filtration, washed with diisopropyl ether, and dried in vacuo at 60°C for 3 hours to give the title compound (379 mg, yield: 79%) as a solid.

[0535] Example 14 (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid

[0536] (14a) (2R)-2-Cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0537] To a solution of (2R)-2-cyclopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (1.1 g) from Example 5d in trifluoroacetic acid (10 mL), anisole (5.5 mL) was added and stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and toluene (20 mL) was added for azeotropy. The resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 90 / 1-20 / 1-9:1 (V / V)] to afford the title compound (537 mg, purity 70%, 54%) as an amorphous solid.

[0538] (14b) Methyl (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoate

[0539] To a solution of methyl (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-2,2-dimethylpropanoate (35 mg) from Example 11e in dichloromethane (2 mL) was added thionyl chloride (0.012 mL) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and toluene was added for azeotropy. The mixture was dissolved in acetonitrile (2 mL), and N,N-diisopropylethylamine (0.142 mL) and (2R)-2-cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (34 mg) from Example 14a were added, followed by stirring at 85°C for 12 hours. Further, (2R)-2-cyclopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (34 mg) was added, and the mixture was stirred at 85°C for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0 - 90 / 10 (V / V)] to afford 35 mg (yield: 69%) of the title compound as a yellow oil.

[0540] (14c) = (14) (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid

[0541] To a solution of methyl (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoate (35 mg) from Example 14b in dimethyl sulfoxide (1 mL), 1M aqueous potassium hydroxide solution (0.286 mL) was added and stirred at 70°C for 12 hours. The reaction mixture was neutralized with 1M hydrochloric acid, saturated aqueous ammonium chloride solution 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 90 / 10 (V / V)] to obtain 11 mg (yield: 32%) of the title compound as a pale yellow solid.

[0542] Example 15 (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0543] Example 16 (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0544] (15a) (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl]amino}propan-2-ol

[0545] To a solution of 6-bromo-3-fluoro-2-methylpyridine (1.90 g) in carbon tetrachloride (50 mL), N-bromosuccinimide (1.96 g) and 75% benzoyl peroxide (242 mg) were added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10 - 70 / 30 (V / V)]. The resulting residue was dissolved in dichloromethane (30 mL), and (2R)-1-aminopropan-2-ol (0.79 mL) and triethylamine (2.77 mL) were added. The mixture was stirred at room temperature for 15 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 99 / 1 to 95 / 5 (V / V)] to give 670 mg (yield: 25%) of the title compound as an oil.

[0546] (15b) (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}propan-2-ol

[0547] To a solution of (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl]amino}propan-2-ol (660 mg) from Example 15a in dichloromethane (10 mL) was added anisaldehyde (0.61 mL) and the mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (1.06 g) was then added and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10-70 / 30 (V / V)] to afford the title compound (940 mg, yield: 98%) as an oil.

[0548] (15c) (2R)-7-Bromo-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

[0549] To a solution of (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}propan-2-ol (820 mg) from Example 15b in N,N-dimethylformamide (30 mL), 60% sodium hydride (94 mg) was added at 0°C and stirred at room temperature for 16.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 90 / 10-0 / 100 (V / V)] to afford 210 mg (yield: 27%) of the title compound as an oil.

[0550] (15d) (2R)-4-(4-Methoxybenzyl)-2-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0551] To a solution of (2R)-7-bromo-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (330 mg) from Example 15c in 1,4-dioxane (5 mL), bis(dibenzylideneacetone)palladium(0) (26 mg), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (46 mg), and cesium hydroxide monohydrate (457 mg) were added and stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid and saturated aqueous sodium bicarbonate were added, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 95 / 5 (V / V)] to give 210 mg (yield: 77%) of the title compound as an oil.

[0552] (15e) (2R)-2-Methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride

[0553] A solution of (2R)-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (210 mg) from Example 15d in trifluoroacetic acid (5 mL) was heated under reflux for 60.5 hours. The reaction mixture was cooled to room temperature, and toluene was added for azeotropy. The resulting residue was dissolved in ethyl acetate (5 mL), and a 1 M hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 10 minutes. tert-Butyl methyl ether (5 mL) was added to the reaction mixture, and the solid was collected by filtration to give 180 mg (yield: quantitative) of the title compound as a solid.

[0554] (15f) Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate

[0555] Ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]propanoate (200 mg) from Example 1f was dissolved in dichloromethane (5 mL), and dimethyl sulfoxide (0.17 mL), N,N-diisopropylethylamine (0.21 mL), and sulfur trioxide-pyridine complex (194 mg) were added. After stirring at room temperature for 30 minutes, dimethyl sulfoxide (0.085 mL), N,N-diisopropylethylamine (0.10 mL), and sulfur trioxide-pyridine complex (97 mg) were added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (5 mL). (2R)-2-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (180 mg) from Example 15e, N,N-diisopropylethylamine (0.17 mL), and acetic acid (0.17 mL) were added, followed by stirring at room temperature for 20 minutes. Sodium triacetoxyborohydride (207 mg) was then added, and the mixture was stirred at room temperature for 1.5 hours. Further sodium triacetoxyborohydride (207 mg) was then added, followed by stirring at room temperature for 30 minutes and then at 40°C for 30 minutes. Anhydrous sodium sulfate (300 mg) was added to the reaction mixture, followed by stirring at 40°C for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by DIOL silica gel column chromatography [eluent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100 (V / V)] to obtain 230 mg (yield: 82%) of the title compound as a solid.

[0556] (15g) = (15) (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0557] (16a) = (16) (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0558] To a mixture of ethyl 3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate (230 mg) from Example 15f, tetrahydrofuran (3.6 mL), and methanol (1.2 mL), 1 M aqueous lithium hydroxide solution (0.12 mL) was added, and the mixture was stirred at 40° C. for 30 minutes and at 60° C. for 30 minutes. After stirring, 1 M aqueous lithium hydroxide solution (0.12 mL) was added, and the mixture was stirred at 60° C. for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The resulting aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 99 / 1-95 / 5 (V / V)]. Ethyl acetate and n-hexane were added to the compound eluted first, followed by ultrasonic treatment. The solid was collected by filtration to obtain 68.8 mg (yield: 31%) of (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid as a solid. Similarly, the compound eluted later was treated to obtain 61.3 mg (yield: 28%) of (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-7-hydroxy-2-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid as a solid.

[0559] Example 17 (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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

[0560] Example 18 (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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

[0561] (17a) (2R)-1-aminobutan-2-ol

[0562] 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.

[0563] (17b) (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}butan-2-ol

[0564] To a solution of (2R)-1-aminobutan-2-ol (1.16 g) from Example 17a and 4-methoxybenzaldehyde (0.79 mL) in dichloromethane (26 mL), anhydrous magnesium sulfate (1.56 g) and one drop of acetic acid were added and stirred at room temperature for 45 minutes. Sodium triacetoxyborohydride (2.76 g) was then added and stirred at room temperature for 80 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. Potassium carbonate (1.17 g) was added to a solution of the residue obtained by distilling off the solvent under reduced pressure and 6-bromo-2-(bromomethyl)-3-fluoropyridine (2.53 g) from Example 3a in acetonitrile (33 mL), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and the insoluble matter was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0 - 60 / 40 (V / V)] to give 2.22 g (yield: 86%) of the title compound as an oil.

[0565] (17c) (2R)-7-Bromo-2-ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine

[0566] A solution of (2R)-1-{[(6-bromo-3-fluoropyridin-2-yl)methyl](4-methoxybenzyl)amino}butan-2-ol (2.12 g) from Example 17b in tetrahydrofuran (38 mL) was added to a suspension of 60% sodium hydride (640 mg) in N,N-dimethylformamide (38 mL) at 60°C, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled 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 and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 100 / 0-60 / 40 (V / V)] to afford 1.84 g (yield: 87%) of the title compound as an oil.

[0567] (17d) (2R)-2-Ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0568] To a solution of (2R)-7-bromo-2-ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine (1.84 g) from Example 17c in 1,4-dioxane (24 mL), bis(dibenzylideneacetone)palladium(0) (140 mg), 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (247 mg), and cesium hydroxide monohydrate (2.45 g) were added and stirred at 100°C for 4 hours. The reaction mixture was cooled 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 dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 95 / 5 (V / V)] to give 1.07 g (yield: 70%) of the title compound as a solid.

[0569] (17e) (2R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol

[0570] To a solution of (2R)-2-ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (512 mg) from Example 17d in trifluoroacetic acid (8.2 mL), anisole (1.77 mL) was added, and the mixture was stirred and irradiated with microwaves for 95 minutes at 100° C. The reaction mixture was cooled to room temperature, and the residue obtained by azeotropy with toluene was purified by NH silica gel column chromatography [eluent: chloroform / methanol = 100 / 0 to 90 / 10 (V / V)] to give 274 mg (yield: 86%) of the title compound as a solid.

[0571] (17f) 4-Bromo-N,3,6-trimethyl-2-nitroaniline

[0572] 2,5-Dimethylaniline (25.1 g) was dissolved in N,N-dimethylformamide (207 mL), and N-bromosuccinimide (38.6 g) was added in portions over 17 minutes at 0°C. The mixture was stirred at 0°C for 15 minutes. 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 dissolved in dichloromethane (690 mL), and triethylamine (43.3 mL) was added. Trifluoroacetic anhydride (35.0 mL) was added dropwise over 11 minutes at 0°C. The mixture was stirred at room temperature for 25 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in concentrated sulfuric acid (150 mL). While cooling in an ice-salt bath, 69% concentrated nitric acid (13.6 mL) was added dropwise over 5 minutes, followed by stirring at room temperature for 45 minutes. The reaction mixture was poured into ice water, and the precipitate was collected by filtration and washed with water. The resulting solid was dissolved in chloroform, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. tert-Butyl methyl ether and n-hexane were added to the resulting residue, and the mixture was sonicated. The solid was then collected by filtration. 60% sodium hydride (7.40 g) was suspended in N,N-dimethylformamide (310 mL). The solid obtained in the previous reaction was added in portions over 10 minutes at 0°C, followed by stirring at room temperature for 18 minutes. Methyl iodide (11.5 mL) was added dropwise to the reaction mixture over 4 minutes at 0°C, followed by stirring at room temperature for 50 minutes, 5 minutes at 50°C, and 80 minutes at room temperature. The reaction mixture was added to a saturated aqueous solution of ammonium chloride at 0°C and 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 dissolved in ethanol (510 mL), and 5 M aqueous sodium hydroxide solution (154 mL) was added. The mixture was heated to reflux for 20 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with a mixed solvent of chloroform and methanol. The organic layer was 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 give 24.1 g of the title compound as a solid (yield: 45%).

[0573] (17g) 4-Bromo-N 1 ,3,6-trimethylbenzene-1,2-diamine

[0574] 4-Bromo-N,3,6-trimethyl-2-nitroaniline (24.1 g) from Example 17f was dissolved in acetic acid (280 mL), and zinc powder (30.4 g) was added in portions over 9 minutes. The mixture was stirred at room temperature for 14 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite to remove insoluble material. Saturated brine and water were added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / chloroform = 90 / 10 / 5 - 50 / 50 / 5 (V / V / V)] to afford the title compound (16.5 g, yield: 77%) as an oil.

[0575] (17h) 5-Bromo-1,4,7-trimethyl-1H-benzotriazole

[0576] Example 17g of 4-bromo-N 1 ,3,6-Trimethylbenzene-1,2-diamine (16.5 g) was dissolved in dichloromethane (144 mL) and cooled in an ice-salt bath. tert-Butyl nitrite (10.4 mL) was added dropwise over 5 minutes, followed by 42% tetrafluoroboric acid (23.0 mL) over 7 minutes, and the mixture was stirred at room temperature for 28 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate and n-hexane were added to the resulting residue, which was then sonicated. The solid was collected by filtration to give the title compound (13.5 g, yield: 78%) as a solid.

[0577] (17i) Ethyl (2E)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)prop-2-enoate

[0578] 5-Bromo-1,4,7-trimethyl-1H-benzotriazole (13.5 g) from Example 17h was dissolved in N,N-dimethylformamide (187 mL), followed by the addition of ethyl acrylate (61.2 mL), N,N-diisopropylethylamine (48.9 mL), tris(dibenzylideneacetone)dipalladium(0) (5.15 g), and tri(o-tolyl)phosphine (6.85 g). The mixture was stirred at 100°C for 11 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with a mixed solvent of ethyl acetate, methanol, and tetrahydrofuran. The organic layer was washed successively with water and saturated brine, 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 / chloroform = 90 / 10 / 10-40 / 60 / 20 (V / V / V)] to obtain 6.10 g (yield: 84%) of the title compound as a solid.

[0579] (17j) Ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoate

[0580] Using ethyl (2E)-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)prop-2-enoate (6.10 g) from Example 17i and [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (11.6 g) from Example 1e, 6.89 g (yield: 69%) of the title compound was obtained as a solid in the same manner as in Example 1f.

[0581] (17k) Ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-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)propanoate

[0582] To a solution of ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-(1,4,7-trimethyl-1H-benzotriazol-5-yl)propanoate (275 mg) from Example 17j in dichloromethane (2.6 mL) was added dimethyl sulfoxide (0.23 mL), N,N-diisopropylethylamine (0.35 mL), and sulfur trioxide-pyridine complex (345 mg) at 0°C and stirred at room temperature for 25 minutes. 2 M hydrochloric acid and water were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (4.2 mL). (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol (137 mg) from Example 17e and dimethyl sulfoxide (1 mL) were added. After stirring at 40°C for 5 minutes, anhydrous magnesium sulfate (156 mg) and one drop of acetic acid were added, and the mixture was stirred at 40°C for 30 minutes. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (276 mg) was added. The mixture was stirred at 35°C for 13 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 20 / 80-0 / 100 (V / V), chloroform / methanol = 100 / 0-96 / 4 (V / V)] to give 251 mg (yield: 65%) of the title compound as a solid.

[0583] (17l) = (17) (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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

[0584] (18a) = (18) (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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

[0585] To a mixture of ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-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)propanoate (251 mg) from Example 17k, tetrahydrofuran (3.9 mL), and methanol (1.3 mL), 1 M aqueous lithium hydroxide solution (1.3 mL) was added and stirred at 40°C for 2 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. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: chloroform / methanol = 100 / 0-95 / 5 (V / V)]. Ethyl acetate and n-hexane were added to the compound eluted earlier, and the mixture was sonicated. The solid was collected by filtration to give 98 mg (41%) of (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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 as a solid. Similarly, the compound eluted later was treated to give 60 mg (25%) of (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-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 as a solid.

[0586] Example 19 (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid

[0587] Example 20 (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid

[0588] (19a) 2-methyl-1-(3-methyl-2-nitroanilino)propan-2-ol

[0589] To a solution of 1-fluoro-3-methyl-2-nitrobenzene (1.00 g) and potassium carbonate (1.35 g) in ethanol (13 mL), 1-amino-2-methyl-2-propanol (1.83 mL) was added and stirred at 70°C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography [eluent: n-hexane / ethyl acetate = 95 / 5-80 / 20 (V / V)] to give 750 mg (yield: 52%) of the title compound as a solid.

[0590] (19b) 1-(4-bromo-3-methyl-2-nitroanilino)-2-methylpropan-2-ol

[0591] To a solution of 2-methyl-1-(3-methyl-2-nitroanilino)propan-2-ol (750 mg) from Example 19a in N,N-dimethylformamide (3.3 mL), N-bromosuccinimide (607 mg) was added at 0°C and stirred at room temperature for 24 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% 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 = 95 / 5-80 / 20 (V / V)] to afford the title compound (1.01 g, yield: 100%) as a solid.

[0592] (19c) 1-(2-amino-4-bromo-3-methylanilino)-2-methylpropan-2-ol

[0593] Using 1-(4-bromo-3-methyl-2-nitroanilino)-2-methylpropan-2-ol (1.01 g) from Example 19b, 810 mg (yield: 89%) of the title compound was obtained as a solid in the same manner as in Example 41e described below.

[0594] (19d) 1-(5-bromo-4-methyl-1H-benzotriazol-1-yl)-2-methylpropan-2-ol

[0595] Using 1-(2-amino-4-bromo-3-methylanilino)-2-methylpropan-2-ol (810 mg) of Example 19c, 589 mg (yield: 70%) of the title compound was obtained as a solid in the same manner as in Example 41f described below.

[0596] (19e) Ethyl (2E)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate

[0597] Using 1-(5-bromo-4-methyl-1H-benzotriazol-1-yl)-2-methylpropan-2-ol (284 mg) from Example 19d, 297 mg (yield: 98%) of the title compound was obtained as a solid in the same manner as in Example 41g described below.

[0598] (19f) Ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate

[0599] Using ethyl (2E)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate (297 mg) from Example 19e and [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (426 mg) from Example 1e, 148 mg (yield: 32%) of the title compound was obtained as an oily product in the same manner as in Example 1f.

[0600] (19g) Ethyl 3-(7-formyl-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate

[0601] Manganese(IV) oxide (136 mg) was added to a solution of ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (62.0 mg) from Example 19f in dichloromethane (2.0 mL), and the mixture was stirred at 40°C for 6 hours. The reaction mixture was cooled to room temperature, and the mixture was filtered through Celite to remove insoluble material. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 60 / 40 - 40 / 60 (V / V)] to afford the title compound (56.0 mg, yield: 91%) as an oil.

[0602] (19h) Ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate

[0603] To a solution of ethyl 3-(7-formyl-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (56.0 mg) from Example 19g, (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (41.6 mg) from Example 1h, N,N-diisopropylethylamine (0.0314 mL), and acetic acid (0.0620 mL) in dichloromethane (2.0 mL), sodium triacetoxyborohydride (95.6 mg) was added at 0°C and stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 90 / 10 (V / V / V)] to give 67.0 mg (yield: 87%) of the title compound as a solid.

[0604] (19i) = (19) (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid

[0605] (20a) = (20) (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid

[0606] To a mixture of ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (67.0 mg) from Example 19h, methanol (1.0 mL), and tetrahydrofuran (1.0 mL), 1 M aqueous sodium hydroxide solution (0.520 mL) was added and stirred at room temperature for 24 hours. 1 M hydrochloric acid (0.520 mL) was added to the reaction mixture, followed by stirring. The mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution and saturated brine were added, and the mixture was extracted with chloroform / 2-propanol = 3 / 1 (V / V). The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 80 / 20 (V / V / V)]. Ethyl acetate and n-hexane were added to the previously eluted compound, followed by sonication. The solid was collected by filtration and dried under vacuum to yield 25.0 mg (39% yield) of (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid as a solid. Similarly, the compound eluted later was treated to obtain 24.0 mg (yield: 38%) of (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-[1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-benzotriazol-5-yl]propanoic acid as a solid.

[0607] Example 21 (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0608] Example 22 (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0609] (21a) Ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0610] Ethyl (2E)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)prop-2-enoate (WO 2015 / 092713) (220 mg) was dissolved in a mixed solvent of 1,4-dioxane (4.0 mL) and water (1.3 mL) and heated to 90°C. Then, [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzothiophen-7-yl]methanol (348 mg) from Example 1e, triethylamine (0.499 mL), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (121 mg) were added in three portions every hour, and the mixture was heated and stirred for an additional 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate 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 = 70 / 30-40 / 60 (V / V)] to give 164 mg (yield: 47%) of the title compound as an oil.

[0611] (21b) Ethyl 3-(7-formyl-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0612] Manganese(IV) oxide (140 mg) was added to a solution of ethyl 3-[7-(hydroxymethyl)-1-benzothiophen-5-yl]-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (60.0 mg) from Example 21a in dichloromethane (2.0 mL), and the mixture was stirred at 40°C for 6 hours. The reaction mixture was cooled to room temperature, and the mixture was filtered through Celite to remove insoluble material. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate = 80 / 20 - 60 / 40 (V / V)] to afford the title compound (52.0 mg, yield: 87%) as an oil.

[0613] (21c) Ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate

[0614] To a solution of ethyl 3-(7-formyl-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (52.0 mg) from Example 21b, (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (41.1 mg) from Example 1h, N,N-diisopropylethylamine (0.0311 mL), and acetic acid (0.0612 mL) in dichloromethane (2.0 mL), sodium triacetoxyborohydride (94.5 mg) was added at 0°C and stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 90 / 10 (V / V / V)] to give 61.0 mg (yield: 83%) of the title compound as a solid.

[0615] (21d) = (21) (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0616] (22a) = (22) (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid

[0617] To a mixture of ethyl 3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoate (61.0 mg) from Example 21c, methanol (1.0 mL), and tetrahydrofuran (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.495 mL), and the mixture was stirred at room temperature for 24 hours. 1 M hydrochloric acid (0.495 mL) was added to the reaction mixture, followed by stirring. The mixture was concentrated under reduced pressure, and saturated aqueous ammonium chloride and saturated brine were added. The mixture was extracted with chloroform / 2-propanol = 3 / 1 (V / V). The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 80 / 20 (V / V / V)]. Ethyl acetate and n-hexane were added to the previously eluted compound, followed by sonication. The solid was collected by filtration and dried under vacuum to yield 26.0 mg (45% yield) of (3R)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid. Similarly, the compound eluted later was treated to obtain 24.0 mg (yield: 41%) of (3S)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid as a solid.

[0618] Example 23 (3R)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0619] (23a) Ethyl (3R)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate

[0620] To a solution of ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-formyl-1-benzothiophen-5-yl)propanoate (81.0 mg) from Example 9b, (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydrochloride (68.6 mg) from Example 1h, N,N-diisopropylethylamine (0.0518 mL), and acetic acid (0.102 mL) in dichloromethane (2.0 mL), sodium triacetoxyborohydride (158 mg) was added at 0°C and stirred at room temperature for 22 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 95 / 5 (V / V / V)]. The compound eluted first was ethyl (3R)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate (47.0 mg, yield: 40%) as an oil.

[0621] (23b) = (23) (3R)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0622] To a mixture of ethyl (3R)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate (Example 23a) (47.0 mg), methanol (1.0 mL), and tetrahydrofuran (1.0 mL), 1 M aqueous sodium hydroxide solution (0.401 mL) was added and stirred at room temperature for 18 hours. 1 M hydrochloric acid (0.401 mL) was added to the reaction mixture, followed by stirring. The mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution and saturated brine were added, and the mixture was extracted with chloroform / 2-propanol = 3 / 1 (V / V). The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane / ethyl acetate / dichloromethane / methanol = 30 / 70 / 0 / 0-0 / 100 / 0 / 0-0 / 0 / 100 / 0-0 / 0 / 90 / 10 (V / V / V / V)], and ethyl acetate and n-hexane were added. The mixture was sonicated. The solid was collected by filtration and dried in vacuo to give the title compound (38.0 mg, 85% yield) as a solid.

[0623] Example 24 (3S)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid

[0624] (24a) Ethyl (3S)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoate

[0625] To a solution of ethyl 3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-3-(7-formyl-1-benzothiophen-5-yl)propanoate (81.0 mg) from Example 9b, (2R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepin-7-ol hydroch...

Claims

1. The following general formula (1): 【Chemistry 1】 [In the formula, R 1a and R 1b Each of these is independently a hydrogen atom or C 1-6 It shows an alkyl group, R 2a and R 2b each independently represents a hydrogen atom, a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from substituent group a, or a C 3-6 cycloalkyl group optionally substituted with 1 to 3 substituents selected from substituent group a, or R 2a and R 2b are bonded to each other to form, together with the carbon atom to which R 2a and R 2b are attached, a C 3-8 cycloalkane optionally substituted with 1 to 3 substituents selected from substituent group b, or a 3- to 8-membered saturated oxygen-containing heterocyclic ring, Z 1 -CH-, -CR 3 -or indicates a nitrogen atom, R 3 This includes a halogen atom, a hydroxyl group, and one or two carbon atoms. 1-6 An amino group which may be substituted with an alkyl group, and a C which may be substituted with 1 to 3 substituents selected from substituent group a. 1-6 C may be substituted with an alkyl group or one to three substituents selected from substituent group a. 1-6 It shows an alkoxy group, Z 2 -CH-, -CR 4 -or indicates a nitrogen atom, R 4 This includes a halogen atom, a hydroxyl group, and one or two carbon atoms. 1-6 An amino group which may be substituted with an alkyl group, and a C which may be substituted with 1 to 3 substituents selected from substituent group a. 1-6 C may be substituted with an alkyl group or one to three substituents selected from substituent group a. 1-6 It shows an alkoxy group, n R 11 Each of these independently comprises a halogen atom, a hydroxyl group, and one or two carbon atoms. 1-6 An amino group which may be substituted with an alkyl group, and a C which may be substituted with 1 to 3 substituents selected from substituent group a. 1-6 C may be substituted with an alkyl group or one to three substituents selected from substituent group a. 1-6 It shows an alkoxy group, n represents an integer between 0 and 2. R 8a and R 8b These are, independently, a hydrogen atom, a halogen atom, a cyano group, and C 1-6 Alkyl alkyl group or C 1-6 It shows an alkoxy group, R 9a and R 9b Each of these is independently a hydrogen atom or C 1-6 It shows an alkyl group, W is -CH 2 -, -CHR 10 -or indicates an oxygen atom, R 10 C 1-6 The alkyl group is shown, and the row X is given by the following formula (A1) or (A2): 【Chemistry 2】 (In the formula, * indicates the bonding position of X with the carbon atom to which it is bonded. R 5 C may be substituted with a hydrogen atom, a halogen atom, or one to three substituents selected from substituent group a. 1-6 It shows an alkyl group, R 6 C may be substituted with a hydrogen atom or one to three substituents selected from substituent group a. 1-6 It shows an alkyl group, Y is -CH-, -CR 7 - or indicates a nitrogen atom, R 7 C may be substituted with 1 to 3 substituents selected from a hydroxyl group, a halogen atom, a cyano group, or substituent group a. 1-6 C may be substituted with alkyl groups or one to three substituents selected from substituent group a. 1-6 Alkoxy group, or C 3-6 (This indicates a cycloalkyl group.) This indicates the group represented by [the symbol]. However, Z 1 However, -CH- or -CR 3 - In the case of Z 2 is a nitrogen atom, Z 2 However, -CH- or -CR 4 - In the case of Z 1 is a nitrogen atom, Z 1 and Z 2 Both of them simultaneously have -CH- and -CR 3 - or -CR 4 - This will not happen. Substituent group a: Hydroxyl group, halogen atom, Cyano group, C 1-6 alkyl group, C 1-6 Alkoxy group, C substituted with substituent group b 1-6 alkyl group, C substituted with substituent group b 1-6 Alkoxy group, 1 or 2 C 1-6 amino groups which may be substituted with alkyl groups, C 1-6 Alkyl sulfonyl group Substituent group b: halogen atom, Cyano group, C 1-6 alkyl group, C 1-6 [Alkoxy group] A compound represented by or a pharmaceutically acceptable salt thereof.

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

3. R 2a and R 2b However, each is independent of the hydrogen atom and C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 3-6 It is a cycloalkyl group, or R 2a and R 2b However, when they combine with each other, R 2a and R 2b Along with the carbon atom to which it is bonded, C 3-6 A compound according to claim 1 or a pharmaceutically acceptable salt thereof that forms a cycloalkane.

4. R 2a and R 2b However, each is independently a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a difluoroethyl group, or R 2a and R 2b However, when they combine with each other, R 2a and R 2b The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which forms cyclopropane together with the bonded carbon atom.

5. Z 1 However, -CH- or -CR 3 - and Z 2 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a nitrogen atom.

6. Z 1 However, -CR 3 - and Z 2 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is a nitrogen atom.

7. R 3 However, halogen atoms, hydroxyl groups, amino groups, C 1-6 Alkylamino group or C 1-6 A compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is an alkyl group.

8. R 3 The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxyl group.

9. n is 1 and R 11 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxyl group.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0.

11. R 8a and R 8b The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both are hydrogen atoms.

12. R 9a and R 9b The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both are hydrogen atoms.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is an oxygen atom.

14. X is given by the following equation (A2): 【Transformation 3】 (Each symbol in the formula has the same meaning as described above.) A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a group represented by .

15. R 5 However, halogen atoms or C 1-6 A compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is an alkyl group.

16. R 5 The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a methyl group.

17. R 6 The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the group is a methyl group, an ethyl group, a dimethylaminoethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxy-2-methylpropyl group, or a 3-methanesulfonylpropyl group.

18. R 6 The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is a methyl group.

19. R 7 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a chlorine atom, a cyano group, a methyl group, a cyclopropyl group, a trifluoromethyl group, a methoxy group, a difluoromethoxy group, or a trifluoromethoxy group.

20. 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)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid, (3S)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid, (3R)-3-(7-{[(2S)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)propanoic acid, (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine-6-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3R)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, (3S)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)-2,2-dimethylpropanoic acid, and (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

21. Any compound selected from the following group or a pharmaceutically acceptable salt thereof: (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid, (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}1-benzothiophen-5-yl)-2,2-dimethylpropanoic acid, and (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid.

22. (3R)-3-(7-{[(2R)-2-cyclopropyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}-1-benzothiophene-5-yl)-3-(1,4-dimethyl-1H-benzotriazole-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

23. (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-(7-{[(2R)-2-ethyl-7-hydroxy-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-yl]methyl}1-benzothiophene-5-yl)-2,2-dimethylpropanoic acid or a pharmaceutically acceptable salt thereof.

24. (3S)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-3-{7-[(7'-hydroxy-3'H-spiro[cyclopropane-1,2'-pyrido[2,3-f][1,4]oxazepine]-4'(5'H)-yl)methyl]-1-benzothiophen-5-yl}-2,2-dimethylpropanoic acid or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical product containing a compound described in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof as an active ingredient.

26. The pharmaceutical agent according to claim 25 for activating Nrf2.

27. The pharmaceutical agent according to claim 25 for inhibiting the protein-protein interaction between Keap1 and Nrf2.

28. The pharmaceutical agent according to claim 25 for the prevention and / or treatment of oxidative stress-related diseases.

29. The pharmaceutical product according to claim 28, 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.

30. 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 nephropathy, nephrosclerosis, hydronephrosis, and tubulointerstitial nephritis; liver diseases selected from the group consisting of alcoholic fatty liver, non-alcoholic fatty liver disease, 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 Central nervous system disorders selected from the group consisting of 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, Sjögren's syndrome, type 1 diabetes mellitus, ulcerative colitis, and Crohn's disease; and eye diseases selected from the group consisting of allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, dry eye, corneal disorder, uveitis, Behçet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular diseases, retinitis pigmentosa, glaucoma, and cataracts. A pharmaceutical product according to claim 25 for the prevention and / or treatment of a disease selected from the group consisting of the following.

31. The pharmaceutical product according to claim 25 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, and age-related macular degeneration.

32. Use of a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof for the manufacture of a preventive and / or therapeutic agent for 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, and age-related macular degeneration.

33. An Nrf2 activator containing the compound described in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof as an active ingredient.

34. A Keap1-Nrf2 protein-protein interaction inhibitor comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof as an active ingredient.

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