Inhibitors of KEAP1-Nrf2 protein-protein interaction

Patent metadata

Field	Value
Publication number	US-10947252-B2
Application number	US-201916544462-A
Country	US
Kind code	B2
Filing date	Aug 19, 2019
Priority date	Aug 20, 2018
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

Sultam compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with the KEAP1-Nrf2 interaction, such as inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

First claim

What is claimed is:

1. A compound selected from the group consisting of
(*R)-3-(7-(Difluoromethoxy)-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((*R)-5,5-dioxido-7,7a,8,9,10,11-hexahydro-6H-dipyrido[2,1-d:2′,3′-f][1,2,5]thiadiazepin-6-yl)methyl)-4-methylphenyl)propanoic acid;
(*R)-3-(7-Cyclopropoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-5,5-dioxido-7a,8,9,10-tetrahydropyrido[2,3-f]pyrrolo[2,1-d][1,2,5]thiadiazepin-6(7H)-yl)methyl)-4-methylphenyl)propanoic acid;
(*R)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid;
(*S)-3-(3-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid;
(*R)-3-(3-((7′-(((1R,3R)-3-Hydroxycyclobutyl)amino)-8‘-methyl-1’,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid;
(*R)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-7′-(((1-morpholinopropan-2-yl)amino)-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid;
(*S)-2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-di oxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid;
(*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8‘-methyl-1’,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid;
(*S)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid;
(*R)-3-(3-(((*S)-1′,1′-Dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid;
(*R)-2,2-Dimethyl-3-(4-methyl-3-(((*S)-8′-methyl-1′,1′-dioxido-4,5-dihydro-2H-spiro[furan-3,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)propanoic acid;
(*S)-3-(3-Cyclopropyl-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8‘-methyl-1’,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid;
(*R)-3-(1-Cyclopropyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(6-methyl-5-((8‘-methyl-1’,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-3-yl)propanoic acid;
(*R)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid;
(*S)-3-(6-((1′,1′-Dioxido-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)-5-methylpyridin-2-yl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;
(*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(4-methyl-3-((8‘-methyl-’,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)phenyl)propanoic acid;
(*S)-3-(1-Ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid;
(*S)-2,2-dimethyl-3-(4-methyl-3-((8′-methyl-7′-(2-morpholinoethoxy)-1′,1′-dioxidospiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid;
(*S) 2,2-Dimethyl-3-(4-methyl-3-((8′-methyl-1′,1′-dioxido-7′-(((*R)-1-(piperidin-1-yl)propan-2-yl)oxy)-2,3,5,6-tetrahydrospiro[pyran-4,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′,(3′H)-yl)methyl)phenyl)-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl)propanoic acid;
(*S)-2,2-Dimethyl-3-(8-methyl-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(5-methyl-6-((8′-methyl-1′,1′-dioxido-7′-(2-(pyrrolidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid;
(*S)-3-(3-(Difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-2,2-dimethyl-3-(5-methyl-4-((8′-methyl-1′,1′-dioxido-7′-(2-(piperidin-1-yl)ethoxy)spiro[cyclopropane-1,4′-pyrido[2,3-b][1,4,5]oxathiazepin]-2′(3′H)-yl)methyl)pyridin-2-yl)propanoic acid; and
pharmaceutically acceptable salts, and combinations thereof.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Barbay J Kent
• Chai Wenying
• Hirst Gavin C
• Kreutter Kevin D
• Kummer David A
• Mcclure Kelly J
• Nishimura Rachel T
• Shih Amy Y
• Venable Jennifer D
• Venkatesan Hariharan
• Wei Jianmei

Classifications

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D513/14 Primary

  Ortho-condensed systems · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title