Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

摘要

599778 Disclosed are 2-(1H-indazol-4-yloxy) / 2-(1H-benzimidazol-4-yloxy) and 2-(1H-benzotriazol-4-yloxy) N-({ pyridin-3-yl/phenyl} sulfonyl)benzamide derivatives, wherein the claimed compounds are selected from N-({ 5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 6-[(trans-4-carbamoylcyclohexyl)methoxy]-5-chloropyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-[(4-{ [(trans-4-cyanocyclohexyl)methyl]amino} -3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[2-(1H-imidazol-1-yl)ethoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(1-methyl-1H-imidazol-5-yl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [5-fluoro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl} -2-(1H-indazol-4-yloxy)benzamide; N-{ [5-chloro-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl} -4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(4,4-difluoro-1-hydroxycyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(2,2-difluorocyclopropyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(trans-4-cyanocyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl} sulfonyl)-4-(4-{ [4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl} piperazin-1-yl)-2-(1Hindazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-(trifluoromethyl)phenyl} sulfonyl)-2-(1Hindazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl} -2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzimidazol-4-yloxy)-N-({ 3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)benzamide; 2-(1H-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl} benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 3-cyano-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl} sulfonyl)-2-(1H-indazol-4-yloxy)benzamide; N-{ [3-chloro-4-(1,4-dioxan-2-ylmethoxy)phenyl]sulfonyl} -4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{ [(2S)-4-cyclopropylmorpholin-2-yl]methoxy} pyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)benzamide; N-[(5-chloro-6-{ [(2S)-4-cyclopropylmorpholin-2-yl]methoxy} pyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; methyl 2-{ [(4-{ [4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl} -2-nitrophenyl)amino]methyl} morpholine-4-carboxylate; 2-{ [(4-{ [4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzoyl]sulfamoyl} -2-nitrophenyl)amino]methyl} -N-ethyl-Nmethylmorpholine-4-carboxamide; 2-{ [(4-{ [2-(1H-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)benzoyl]sulfamoyl} -2-nitrophenyl)amino]methyl} -N-ethyl-N-methylmorpholine-4-carboxamide; N-({ 5-chloro-6-[(trans-4-ethyl-4-hydroxycyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(cis-4-ethyl-4-hydroxycyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 5-chloro-N-({ 5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1Hindazol-4-yloxy)benzamide; 5-chloro-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-[(4-{ [(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino} -3-nitrophenyl)sulfonyl]-2-(1Hindazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(cis-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1Hindazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(trans-1-fluoro-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzotriazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-[(4-{ [(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino} -3-nitrophenyl)sulfonyl]benzamide; 2-(1H-benzotriazol-4-yloxy)-N-({ 5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)benzamide; 2-(1H-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [3-chloro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl} benzamide; N-[(3-chloro-4-{ [4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy} phenyl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(cis-1-fluoro-4-hydroxycyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzotriazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl} sulfonyl)benzamide; N-[(5-chloro-6-{ [(1R,2R,4R,5R)-5-hydroxy-5-methylbicyclo[2.2.1]hept-2-yl]methoxy} pyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-({ 5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; N-[(5-chloro-6-{ [4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy} pyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzotriazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)benzamide; 4-(4-{ [2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1Hindazol-4-yloxy)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl} sulfonyl)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-[(4-{ [(trans-4-hydroxy-4-methylcyclohexyl)methyl]amino} -3-nitrophenyl)sulfonyl]-2-(1Hindazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-[(4-{ [(cis-4-hydroxy-4-methylcyclohexyl)methyl]amino} -3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide; 2-(1H-benzotriazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [4-({ [(2S)-4-cyclopropylmorpholin-2-yl]methyl} amino)-3-nitrophenyl]sulfonyl} benzamide; N-[(5-chloro-6-{ [4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy} pyridin-3-yl)sulfonyl]-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [4-({ [(2S)-4-cyclopropylmorpholin-2-yl]methyl} amino)-3-nitrophenyl]sulfonyl} -2-(1Hindazol-4-yloxy)benzamide; 2-(1H-benzimidazol-4-yloxy)-4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-{ [4-({ [(2S)-4-cyclopropylmorpholin-2-yl]methyl} amino)-3-nitrophenyl]sulfonyl} benzamide; N-({ 5-chloro-6-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]pyridin-3-yl} sulfonyl)-4-(4-{ [2-(4-chlorophenyl)-5,5-difluorocyclohex-1-en-1-yl]methyl} piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 4-[(cis-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl} sulfonyl)-2-(1H-indazol-4-yloxy)benzamide; 4-(4-{ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl} piperazin-1-yl)-N-({ 4-[(trans-4-hydroxy-4-methylcyclohexyl)methoxy]-3-nitrophenyl} s