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.

What is claimed is: 
     
         1 . A compound having Formula (I), Formula (II), or Formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         A 1  is N or C(A 2 ); 
         A 2  is H, R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)OR, NR 1 C(O)OR 1 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , NHSO 2 NHR 1 , NHSO 2 N(R 1 ) 2 , NR 1 SO 2 NHR 1 , NR 1 SO 2 N(R 1 ) 2 , C(O)NHNOH, C(O)NHNOR 1 , C(O)NHSO 2 R 1 , C(NH)NH 2 , C(NH)NHR 1 , C(NH)N(R 1 ) 2  NHSO 2 NHR 1 , NHSO 2 N(CH 3 )R 1 , N(CH 3 )SO 2 N(CH 3 )R 1 , F, Cl, Br, I, CN, NO 2 , N 3 , OH, C(O)H, CHNOH, CH(NOCH 3 ), CF 3 , C(O)OH, C(O)NH 2  or C(O)OR 1A ; 
         B 1  is H, R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)OR, NR 1 C(O)OR 1 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , NHSO 2 NHR 1 , NHSO 2 N(R 1 ) 2 , NR 1 SO 2 NHR 1 , NR 1 SO 2 N(R 1 ) 2 , C(O)NHNOH, C(O)NHNOR 1 , C(O)NHSO 2 R 1 , C(NH)NH 2 , C(NH)NHR 1 , C(NH)N(R 1 ) 2  NHSO 2 NHR 1 , NHSO 2 N(CH 3 )R 1 , N(CH 3 )SO 2 N(CH 3 )R 1 , F, Cl, Br, I, CN, NO 2 , N 3 , OH, C(O)H, CHNOH, CH(NOCH 3 ), CF 3 , C(O)OH, C(O)NH 2  or C(O)OR 1A ; 
         D 1  is H, R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)OR, NR 1 C(O)OR 1 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , NHSO 2 NHR 1 , NHSO 2 N(R 1 ) 2 , NR 1 SO 2 NHR 1 , NR 1 SO 2 N(R 1 ) 2 , C(O)NHNOH, C(O)NHNOR 1 , C(O)NHSO 2 R 1 , C(NH)NH 2 , C(NH)NHR 1 , C(NH)N(R 1 ) 2  NHSO 2 NHR 1 , NHSO 2 N(CH 3 )R 1 , N(CH 3 )SO 2 N(CH 3 )R 1 , F, Cl, Br, I, CN, NO 2 , N 3 , OH, C(O)H, CHNOH, CH(NOCH 3 ), CF 3 , C(O)OH, C(O)NH 2  or C(O)OR 1A ; 
         E 1  is H, R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R, NR 1 C(O)R 1 , NHC(O)OR, NR 1 C(O)OR 1 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , NHSO 2 NHR 1 , NHSO 2 N(R 1 ) 2 , NR 1 SO 2 NHR 1 , NR 1 SO 2 N(R 1 ) 2 , C(O)NHNOH, C(O)NHNOR 1 , C(O)NHSO 2 R 1 , C(NH)NH 2 , C(NH)NHR 1 , C(NH)N(R 1 ) 2  NHSO 2 NHR 1 , NHSO 2 N(CH 3 )R 1 ,_N(CH 3 )SO 2 N(CH 3 )R 1 , F, Cl, Br, I, CN, NO 2 , N 3 , OH, C(O)H, CHNOH, CH(NOCH 3 ), CF 3 , C(O)OH, C(O)NH 2  or C(O)OR 1A ; and 
         Y 1  is H, CN, NO 2 , C(O)OH, F, Cl, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(O)R 17 , C(O)OR 17 , SR 7 , NH 2 , NHR 1 , N(R 17 ) 2 , NHC(O)R 17 , C(O)NH 2 , C(O)NHR 17 , C(O)N(R 17 ) 2 , NHS(O)R 17  or NHSO 2 R 17 ; 
         G 1  is R 1B , ORB, or NHR 1B ; 
         wherein the R 1B , or a substituent on R 1B , is substituted or further substituted with S(O) 2 (OH), C(O)OR 50 OP(O)(OH)(OH), C(O)R 50 OP(O)(OH)(OH), C(O)NH(R 50 )NH 2 , C(O)R 50 C(O)NR 50 ; OR 50 P(O)(OH)(OH), OP(O)(OH)(OH), or OC(O)CH 2 OP(O)(OH)(OH); 
         R 1  and R 1B  are each independently R 2 , R 3 , R 4  or R 5 ; 
         R 1A  is C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl; 
         R 2  is phenyl which is unfused or fused with benzene, heteroarene or R 2A ; R 2A  is cycloalkane or heterocycloalkane; 
         R 3  is heteroaryl which is unfused or fused with benzene, heteroarene or R 3A ; R 3A  is cycloalkane or heterocycloalkane; 
         R 4  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 4A ; R 4A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 5  is alkyl, alkenyl or alkynyl, each of which is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), 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 , NHC(O)R 7 , NHSO 2 R 7 , NHC(O)OR 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 1 ) 2 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)CH(CH 3 )NHC(O)CH(CH 3 )NH 2 , NHC(O)CH(CH 3 )NHC(O)CH(CH 3 )NHR 1 , OH, (O), C(O)OH, (O), N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I substituents; 
         R 6  is C 2 -C 5 -spiroalkyl, each of 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 6A  and R 6B  are independently selected alkyl or, together with the N to which they are attached, R 6C ; 
         R 6C  is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH 2  moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH; 
         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 C 3 -C 10 -cycloalkyl or C 4 -C 10 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each 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 independently selected R 12 , OR 12 , NHR 12 , N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 2 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I substituents; 
         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, each of which is unfused or fused with benzene, heteroarene or R 14A ; R 14A  is cycloalkane, cycloalkene, 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; 
         R 17  is R 18 , R 19 , R 20  or R 21 ; 
         R 18  is phenyl which is unfused or fused with benzene, heteroarene or R 18A ; R 18A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 19  is heteroaryl which is unfused or fused with benzene, heteroarene or R 19A ; R 19A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 20  is C 3 -C 10 -cycloalkyl or C 4 -C 10 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 20A ; R 20A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 21  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 22 , OR 22 , NHR 22 , N(R 22 ) 2 , C(O)NH 2 , C(O)NHR 22 , C(O)N(R 22 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I substituents; 
         R 22  is R 23 , R 24  or R 25 ; 
         R 23  is phenyl which is unfused or fused with benzene, heteroarene or R 23A ; R 23A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 24  is heteroarene which is unfused or fused with benzene, heteroarene or R 24A ; R 24A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 25  is C 3 -C 6 -cycloalkyl or C 4 -C 6 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 25A ; R 25A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 30  is cycloalkyl or cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 30A ; R 30A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         wherein R 30  is substituted with F, Cl, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(O)R 37 , OR 37 , SR 37 , S(O)R 37 , SO 2 R 37 , NHR 37  or N(R 32 )R 37 ; 
         R 31  and R 31A  are independently F, Cl, Br or alkyl or are taken together and are C 2 -C 5 -spiroalkyl; 
         R 32  is R 33 , C(O)R 33 , or C(O)OR 33 ; 
         R 33  is R 34  or R 35 ; 
         R 34  is phenyl which is unfused or fused with benzene, heteroarene, or R 34A ; R 34A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 35  is alkyl which is unsubstituted or substituted with R 36 ; 
         R 36  is phenyl which is unfused or fused with benzene, heteroarene or R 36A ; R 36A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 37  is R 38 , R 39  or R 40 , each of which is substituted with F, Cl, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(O)OR 41 , SR 41 , S(O)R 41  or SO 2 R 41 ; 
         R 38  is phenyl which is unfused or fused with benzene, heteroarene or R 38A ; R 38A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 39  is heteroaryl which is unfused or fused with benzene, heteroarene or R 39A ; R 39A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 40  is C 3 -C 8 -cycloalkyl or C 4 -C 8 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 40A ; R 40A  cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 41  is R 42 , R 43 , R 44  or R 45 ; 
         R 42  is phenyl which is unfused or fused with benzene, heteroarene or R 42A ; R 42A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 43  is heteroaryl which is unfused or fused with benzene, heteroarene or R 43A ; R 43A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 44  is C 3 -C 9 -cycloalkyl or C 4 -C 7 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 44A ; R 44A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 45  is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R 46 , OR 46 , NHR 46 , N(R 46 ) 2 , C(O)NH 2 , C(O)NHR 46 , C(O)N(R 46 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I substituents; 
         R 46  is R 47 , R 48  or R 49 ; 
         R 47  is phenyl which is unfused or fused with benzene, heteroarene or R 47A ; R 47A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 48  is heteroaryl or R 48A ; R 48A  is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; 
         R 49  is C 3 -C 6 -cycloalkyl or C 4 -C 6 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 49A ; R 49A  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         wherein the moieties represented by R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , R 6 , R 6C , R 8 , R 8A , R 9 , R 9A , R 10 , R 10A , R 13 , R 13A , R 14 , R 14A , R 15 , R 15A , R 18 , R 18A , R 19 , R 19A , R 20 , R 20A , R 23 , R 23A , R 24 , R 24A , R 25 , R 25A , R 30 , R 30A , R 31  and R 31A  taken together, R 34 , R 34A , R 36 , R 36A , R 38 , R 38A , R 39 , R 39A , R 40 , R 40A , R 42 , R 42A , R 43 , R 43A , R 44 , R 44A , R 47 , R 47A , R 48 , R 48A , R 49 , and R 49A  are independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five independently selected 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 , 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 55 SO 2 R 50 , SO 2 NH 2 , SO 2 NHR 50 , SO 2 N(R 50 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 0 , C(N)N(R 50 ) 2 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I substituents; 
         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 51B ; R 51B  is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; 
         R 52  is heteroaryl; 
         R 53  is C 3 -C 6 -cycloalkyl or C 4 -C 6 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with benzene, heteroarene or R 53B ; 
         wherein R 53B  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 independently selected R 55 , OR 55 , SR 55 , S(O)R 55 , SO 2 R 55 , NHR 55 , N(R 55 ) 2 , C(O)R 55 , C(O)NH 2 , C(O)NHR 55 , NHC(O)R 55 , NHSO 2 R 55 , NHC(O)OR, SO 2 NH 2 , SO 2 NHR 55 , SO 2 N(R 55 ) 2 , NHC(O)NH 2 , NHC(O)NHR 55 , OH, (O), C(O)OH, (O), N 3 , CN, NH 2 , CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , F, Cl, Br or I substituents; 
         R 55  is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ; 
         wherein the alkyl, alkenyl, and alkynyl are unsubstituted or substituted with OCH 3 ; and 
         R 56  is C 3 -C 8 -cycloalkyl or C 4 -C 6 -cycloalkenyl, each having one or two CH 2  moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2  or NH and one or two CH moieties unreplaced or replaced with N. 
       
     
     
         2 . The compound of  claim 1 , wherein
 A 1  is C(A 2 ); and   A 2  is H.   
     
     
         3 . The compound of  claim 1 , wherein
 A 1  is C(A 2 );   A 2  is H; and   B 1  is OR 1  or NHR 1 .   
     
     
         4 . The compound of  claim 1 , wherein
 A 1  is C(A 2 );   A 2  is H;   B 1  is OR 1  or NHR 1 ; and   D 1  is H.   
     
     
         5 . The compound of  claim 1 , wherein
 A 1  is C(A 2 );   A 2  is H;   B 1  is OR 1  or NHR 1 ;   D 1  is H; and   E 1  is H.   
     
     
         6 . The compound of  claim 1 , wherein
 A 1  is C(A 2 );   A 2  is H;   B 1  is OR 1  or NHR 1 ;   D 1  is H;   E 1  is H; and   Y 1  is NO 2 .   
     
     
         7 . The compound of  claim 1 , wherein
 A 1  is C(A 2 );   A 2  is H;   B 1  is OR 1  or NHR 1 ;   D 1  is H;   E 1  is H;   Y 1  is NO 2 ; and   G 1  is R 1B , OR 1B , or NHR 1 ;   wherein the R 1B , or a substituent on R 1B , is substituted or further substituted with OP(O)(OH)(OH).   
     
     
         8 . A compound of  claim 1 , wherein the compound is chosen from:
 (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl dihydrogen phosphate;   {5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-{[(4-{[(trans-4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}phenoxy]-7H-pyrrolo[2,3-b]pyridin-7-yl}methyl dihydrogen phosphate;   (5-{5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)carbamoyl]phenoxy}-7H-pyrrolo[2,3-b]pyridin-7-yl)methyl dihydrogen phosphate;   3-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenyl)amino]-2,2-dimethylpropyl dihydrogen phosphate;   trans-4-[(4-{[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoyl]sulfamoyl}-2-nitrophenoxy)methyl]cyclohexyl dihydrogen phosphate; and therapeutically acceptable salts, and metabolites thereof.   
     
     
         9 . A composition for treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer, said composition comprising an excipient and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         10 . A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 . 
     
     
         11 . A method of treating bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer or spleen cancer in a patient, said method comprising administering to the patient therapeutically effective amount of the compound of  claim 1  and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.