Benzotriazole compound

Patent metadata

Field	Value
Publication number	US-12378260-B2
Application number	US-202418927756-A
Country	US
Kind code	B2
Filing date	Oct 25, 2024
Priority date	Apr 28, 2022
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

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

The invention claimed is:

1. 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.

2. The compound according to claim 1 , 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.

3. The compound according to claim 1 , 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.

4. The compound according to claim 1 , 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.

5. The compound according to claim 1 , 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.

6. The compound according to claim 1 , 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.

7. The compound according to claim 1 , 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.

8. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

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