Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

1 - 12 . (canceled) 
     
     
         13 . A compound having Formula (IV) 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, 
       wherein
 n is 0, whereby R 100  is absent; 
 A 1  is C(A 2 ); 
 A 2  is H; 
 B 1  is NHR 1 ; 
 D 1  and E 1  are each H; 
 R 1  is R 5 , wherein R 5  is alkyl which is unsubstituted or substituted with one or two or three substituents independently selected from R 6 , R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2  R 7 , NHR 7 , N(R 7 ) 2 , C(O)R 7 , C(O)NH 2 , C(O)NHR 7 , C(O)N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHSO 2  R 7 , NHC(O)OR 7 , SO 2 NH 2 , SO 2  NHR 7 , SO 2 N(R 7 ) 2 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)CH(CH 3 )NHC(O)CH(CH 3 )NH 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and I; 
 Y 1  is NO 2 ; 
 Z 2  is R 30 , wherein R 30  is unfused piperazinyl; 
 L 1  is R 37 , wherein R 37  is methylene; 
 Z 3  is R 40 , wherein R 40  is unfused cyclohexenyl; 
 R 6  is C 2 -C 5 -spiroalkyl, which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, Cl, Br, I, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ; 
 R 7  is R 8 , R 9 , R 10  or R 11 ; 
 R 8  is phenyl, which is unfused or fused with benzene, heteroarene or R 8A ; R 8A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 9  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 9A ; R 9A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 10  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyleach of which is unfused or fused with benzene, heteroarene or R 10A ; R 10A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 11  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 12 , OR 12 , SR 12 , S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO(O)R 12 , OC(O)R 12 , OC(O)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(O)R 12 , NR 12 C(O)R 12 , NHS(O) 2 R 12 , NR 12 S(O) 2 R 12 , NHC(O)OR 12 , NR 12 C(O)OR 12 , NHC(O)NH 2 , NHC(O)NHR 12 , NHC(O)N(R 12 ) 2 , NR 12 C(O)NHR 12 , NR 12 C(O)N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , C(O)NHOH, C(O)NHOR 12 , C(O)NHSO 2 R 12 , C(O)NR 12 SO 2 R 12 , SO 2 NH 2 , SO 2 NHR 12 , SO 2 N(R 12 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 12 , C(N)N(R 12 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; 
 R 12  is R 13 , R 14 , R 15  or R 16 ; 
 R 13  is phenyl, which is unfused or fused with benzene, heteroarene or R 13A ; R 13A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 14  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 14A ; R 14A  is cycloalkane, cycloakene, heterocycloalkane or heterocycloalkene; 
 R 15  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R 15A ; R 15A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 16  is alkyl, alkenyl or alkynyl; 
 at least one of R 102  is selected from the group consisting of R 50 , OR 50 , SR 50 , S(O)R 50 , SO 2 R 50 , C(O)R 50 , CO(O)R 50 , OC(O)R 50 , OC(O)OR 50 , NH 2 , NHR 50 , N(R 50 ) 2 , NHC(O)R 50 , NR 50 C(O)R 50 , NHS(O) 2 R 50 , NR 50 S(O) 2 R 50 , NHC(O)OR 50 , NR 50 C(O)OR 50 , NHC(O)NH 2 , NHC(O)NHR 50 , NHC(O)N(R 50 ) 2 , NR 50 C(O)NHR 50 , NR 50 C(O)N(R 50 ) 2 , C(O)NH 2 , C(O)NHR 50 , C(O)N(R 50 ) 2 , C(O)NHOH, C(O)NHOR 50 , C(O)NHSO 2 R 50 , C(O)NR 50 SO 2 R 50 , SO 2 NH 2 ,SO 2 NHR 50 , SO 2 N(R 50 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 50 , C(N)N(R 50 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I, and the remainder of R 102  are H; 
 R 50  is R 51 , R 52 , R 53  or R 54 ; 
 R 51  is phenyl, which is unfused or fused with benzene, heteroarene or R 51 A; R 51 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 52  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 52 A; R 52 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 53  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 53 A; R 53 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 54  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 55 , OR 55 , SR 55 , S(O)R 55 , SO 2 R 55 , C(O)R 55 , CO(O)R 55 , OC(O)R 55 , OC(O)OR 55 , NH 2 , NHR 55 , N(R 55 ) 2 , NHC(O)R 55 , NR 55 C(O)R 55 , NHS(O) 2 R 55 , NR 55 S(O) 2 R 55 , NHC(O)OR 55 , NR 55 C(O)OR 55 , NHC(O)NH 2 , NHC(O)NHR 55 , NHC(O)N(R 55 ) 2 , NR 55 C(O)NHR 55 , NR 55 C(O)N(R 55 ) 2 , C(O)NH 2 , C(O)NHR 55 , C(O)N(R 55 ) 2 , C(O)NHOH, C(O)NHOR 55 , C(O)NHSO 2 R 55 , C(O)NR 55 SO 2 R 55 , SO 2 NH 2 , SO 2 NHR 55 , SO 2 N(R 55 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 55 , C(N)N(R 55 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; 
 R 55  is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; 
 wherein each cyclic moiety represented by R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 40 , R 51 , R 52 , R 53  and R 55  is independently unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R 57A , R 57 , OR 57 , SR 57 , S(O)R 57 , SO 2 R 57 , C(O)R 57 , CO(O)R 57 , OC(O)R 57 , OC(O)OR 57 , NH 2 , NHR 57 , N(R 57 ) 2 , NHC(O)R 57 , NR 57 C(O)R 57 , NHS(O) 2 R 57 , NR 57 S(O) 2 R 57 , NHC(O)OR 57 , NR 57 C(O)OR 57 , NHC(O)NH 2 , NHC(O)NHR 57 , NHC(O)N(R 57 ) 2 , NR 57 C(O)NHR 57 , NR 57 C(O)N(R 57 ) 2 , C(O)NH 2 , C(O)NHR 57 , C(O)N(R 57 ) 2 , C(O)NHOH, C(O)NHOR 57 , C(O)NHSO 2 R 57 , C(O)NR 57 SO 2 R 57 , SO 2 NH 2 , SO 2 NHR 57 , SO 2 N(R 57 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 57 , C(N)N(R 57 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; 
 
       R 57A  is spirocyclyl; 
       R 57  is R 58 , R 59 , R 60  or R 61 ; 
       R 58  is phenyl, which is unfused or fused with benzene, heteroarene or R 58 ; R 58 A is cycloalkane, cycloalkane, heterocycloalkane or heterocycloalkene; 
       R 59  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 59 A; R 59A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
       R 60  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 60A ; R 60A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
 R 61  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 62 , OR 62 , SR 62 , S(O)R 62 , SO 2 R 62 , C(O)R 62 , CO(O)R 62 , OC(O)R 62 , OC(O)OR 62 , NH 2 , NHR 62 , N(R 62 ) 2 , NHC(O)R 62 , NR 62 C(O)R 62 , NHS(O) 2 R 62 , NR 62 S(O) 2 R 62 , NHC(O)OR 62 , NR 62 C(O)OR 62 , NHC(O)NH 2 , NHC(O)NHR 62 , NHC(O)N(R 62 ) 2 , NR 62 C(O)NHR 62 , NR 62 C(O)N(R 62 ) 2 , C(O)NH 2 , C(O)NHR 62 , C(O)N(R 62 ) 2 , C(O)NHOH, C(O)NHOR 62 , C(O)NHSO 2 R 62 , C(O)NR 62 SO 2 R 62 , SO 2 NH 2 , SO 2 NHR 62 , SO 2 N(R 62 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 62 , C(N)N(R 62 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; 
 R 62  is R 63 , R 64 , R 65  or R 66 ; 
 R 63  is phenyl, which is unfused or fused with benzene, heteroarene or R 63 A; R 63 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 64  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 64 A; R 64 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 65  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fursed with benzene, heteroarene or R 65 A; R 65 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 66  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 67 , OR 67 , SR 67 , S(O)R 67 , SO 2 R 67 , C(O)R 67 , CO(O)R 67 , OC(O)R 67 , OC(O)OR 67 , NH 2 , NHR 67 , N(R 67 ) 2 , NHC(O)R 67 , NR 67 C(O)R 67 , NHS(O) 2 R 67 , NR 67 S(O) 2 R 67 , NHC(O)OR 67 , NR 67 C(O)OR 67 , NHC(O)NH 2 , NHC(O)NHR 67 , NHC(O)N(R 67 ) 2 , NR 67 C(O)NHR 67 , NR 67 C(O)N(R 67 ) 2 , C(O)NH 2 , C(O)NHR 67 , C(O)N(R 67 ) 2 , C(O)NHOH, C(O)NHOR 67 , C(O)NHSO 2 R 67 , C(O)NR 67 SO 2 R 67 , SO 2 NH 2 , SO 2 NHR 67 , SO 2 N(R 67 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 67 , C(N)N(R 67 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I substituents; 
 R 67  is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; 
 wherein the moieties represented by R 57A , R 58 , R 59 , R 60 , R 63 , R 64 , R 65 , andR 67  are unsubstituted or substituted with one or two or three or four substituents independently selected from R 68 , OR 68 , SR 68 , S(O)R 68 , SO 2 R 68 , C(O)R 68 , CO(O)R 68 , OC(O)R 68 , OC(O)OR 68 , NH 2 , NHR 68 , N(R 68 ) 2 , NHC(O)R 68 , NR 68 C(O)R 68 , NHS(O) 2 R 68 , NR 68 S(O) 2 R 68 , NHC(O)OR 68 , NR 68 C(O)OR 68 , NHC(O)NH 2 , NHC(O)NHR 68 , NHC(O)N(R 68 ) 2 , NR 68 C(O)NHR 68 , NR 68 C(O)N(R 68 ) 2 , C(O)NH 2 , C(O)NHR 68 , C(O)N(R 68 ) 2 , C(O)NHOH, C(O)NHOR 68 , C(O)NHSO 2 R 68 , C(O)NR 68 SO 2 R 68 , SO 2 NH 2 , SO 2 NHR 68 , SO 2 N(R 68 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 68 , C(N)N(R 68 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; 
 R 68  is R 69 , R 70 , R 71  or R 72 ; 
 
       R 69  is phenyl which is unfused or fused with benzene, heteroarene or R 69A ; R 69A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
       R 70  is heteroaryl, which is unfused or fused with benzene, heteroarene or R 70A ; R 70A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
 R 71  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 71 A; R 71 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
 R 72  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 73 , OR 73 , SR 73 , S(O)R 73 , SO 2 R 73 , C(O)R 73 , CO(O)R 73 , OC(O)R 73 , OC(O)OR 73 , NH 2 , NHR 73 , N(R 73 ) 2 , NHC(O)R 73 , NR 73 C(O)R 73 , NHS(O) 2 R 73 , NR 73 S(O) 2 R 73 , NHC(O)OR 73 , NR 73 C(O)OR 73 , NHC(O)NH 2 , NHC(O)NHR 73 , NHC(O)N(R 73 ) 2 , NR 73 C(O)NHR 73 , NR 73 C(O)N(R 73 ) 2 , C(O)NH 2 , C(O)NHR 73 , C(O)N(R 73 ) 2 , C(O)NHOH, C(O)NHOR 73 , C(O)NHSO 2 R 73 , C(O)NR 73 SO 2 R 73 , SO 2 NH 2 , SO 2 NHR 73 , SO 2 N(R 73 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 73 , C(N)N(R 73 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I; 
 R 73  is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; and 
 the moieties represented by R 69 , R 70 , and R 71  are unsubstituted or substituted with one or two or three or four substituents independently selected from NH 2 , C(O)NH 2 , C(O)NNOH, SO 2 NH 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, C(N)NH 2 , OH, (O), CN, N 3 , NO 2 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I. 
 
     
     
         14 . A compound or a therapuetically acceptable salt thereof, wherein the compound is selected from the group consisting of:
 4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-yl)oxy)benzamide;   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;   tert-butyl 4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylate;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;   2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;   2-[(3-chloro-1H-indol-4-yl)oxy]-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)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;   2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; and   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide.   
     
     
         15 . A pharmaceutical composition comprising the compound or therapeutically acceptable salt of  claim 13  and an excipient. 
     
     
         16 . A pharmaceutical composition comprising the compound or therapeutically acceptable salt of  claim 14  and an excipient.