Benzotriazole compound

Patent metadata

Field	Value
Publication number	US-2025092064-A1
Application number	US-202418927756-A
Country	US
Kind code	A1
Filing date	Oct 25, 2024
Priority date	Apr 28, 2022
Publication date	Mar 20, 2025
Grant date	—

Abstract

The present invention aims to provide a medicament capable of treating and/or preventing diseases associated with oxidative stress by inhibiting the protein-protein interaction between Keap1 and Nrf2 and activating Nrf2. The present invention relates to a compound represented by the following formula (1):wherein each symbol is as described in the DESCRIPTION, or a pharmaceutically acceptable salt thereof. In addition, the present invention also relates to a medicament containing the aforementioned compound, for the prophylaxis and/or treatment of diseases involving oxidative stress selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation skin disorder, radiation mucosal disorder, cardiac failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa and glaucoma.

First claim

1 - 38 . (canceled)

39 . A compound represented by the following formula (1′):

wherein
R 1a′ and R 1b′ are each independently a hydrogen atom or a methyl group,
R 2′ is a methyl group,
R 3′ is a chlorine atom or a methyl group,
Y′ is —CH—, —CR 4′ — or a nitrogen atom,
R 4′ is a chlorine atom, a methyl group, a cyclopropyl group, a difluoromethoxy group or a trifluoromethoxy group,
—V′— is a group represented by any of the following formulas:

wherein *′ and *′ are each a bonding position to a benzene ring,
R 5a′ and R 5b′ are each independently a hydrogen atom or an ethyl group, or R 5a′ and R 5b′ are bonded together to form cyclopropane,
R 6′ in the number of m′ are each independently a fluorine atom or a chlorine atom,
m′ is an integer of 0 to 2, and
W′ is an oxygen atom,
or a pharmaceutically acceptable salt thereof.

40 . The compound according to claim 39 , which is selected from the group consisting of:
(3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)-2,2-dimethylpropanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(7-cyclopropyl-1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[1,4-dimethyl-7-(trifluoromethoxy)-1H-benzotriazol-5-yl]propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, and (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-[7-(difluoromethoxy)-1,4-dimethyl-1H-benzotriazol-5-yl]propanoic acid, or a pharmaceutically acceptable salt thereof.

41 . The compound according to claim 39 , which is selected from the group consisting of:
(3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, and (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid, or a pharmaceutically acceptable salt thereof.

42 . The compound according to claim 39 , which is (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

43 . The compound according to claim 39 , which is (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-1-benzothiophen-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

44 . The compound according to claim 39 , which is (3S)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

45 . The compound according to claim 39 , which is (3R)-3-(7-{[(4R)-8-chloro-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[2,3-b][1,4,5]oxathiazepin-2-yl]methyl}-2,3-dihydro-1H-inden-5-yl)-3-(1,4-dimethyl-1H-benzotriazol-5-yl)propanoic acid or a pharmaceutically acceptable salt thereof.

46 . A pharmaceutical composition comprising the compound according to claim 39 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

47 . A method for the treatment of a disease selected from the group consisting of chronic kidney disease, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, radiation skin disorder, radiation mucosal disorder, cardiac failure, pulmonary arterial hypertension, Parkinson's disease, Friedreich's ataxia, multiple sclerosis, age-related macular degeneration, retinitis pigmentosa, and glaucoma in a mammal, comprising administering to a mammal a pharmaceutically effective amount of the compound according to claim 39 or a pharmaceutically acceptable salt thereof.

48 . The method according to claim 47 , for the treatment of a disease selected from the group consisting of glaucoma, age-related macular degeneration and retinitis pigmentosa.

49 . The method according to claim 47 , for the treatment of a radiation skin disorder or a radiation mucosal disorder.

50 . The method according to claim 47 , for the treatment of a chronic obstructive pulmonary disease.

Assignees

• Daiichi Sankyo Co Ltd
• Kyoto Pharma Ind

Inventors

• Ogura Yoshihiro
• Takano Rieko
• Kawai Junya
• Fujimoto Teppei
• Inui Masaharu
• Ofuku Masafumi
• Miyazaki Masaki
• Fujii Masaya
• Ishii Ken
• Yokozeki Wakana
• Otake Kazuya
• Takashima Shunsuke
• Ando Masafumi

Classifications

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D333/52

  Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes · CPC title

• C07D249/18

  Benzotriazoles · CPC title

• C07D211/90

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07C317/34

  having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring · CPC title