Inhibitors of KEAP1-Nrf2 protein-protein interaction
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.
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.