Classifications

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  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

• This invention pertains to compounds which selectively inhibit the activity of anti-apoptotic Bcl-2 family proteins, compositions containing the compounds, and methods of treating diseases during which anti-apoptotic Bcl-2 proteins are expressed.
• Anti-apoptotic Bcl-2 family proteins are associated with a number of diseases and are5 under investigation as potential therapeutic drug targets. These targets for interventional therapy include, for example, the Bcl-2 family proteins Bcl-2, BC1-XL and Bcl-w. Recently, inhibitors of Bcl-2 family proteins have been reported in commonly-owned
• a typical measure of binding affinity of an anti-apoptotic protein inhibitor is the balance between the binding and dissociation processes between the protein and the inhibitor (Kj).
• the inhibition constant (3 ⁇ 4) is the dissociation constant of an enzyme-inhibitor complex or a protein/small molecule complex, wherein the small molecule is inhibiting binding of one protein to another protein. So a large K; value indicates a low binding affinity, and a small K;0 value indicates a high binding affinity.
• a typical measure of cellular activity of an anti-apoptotic protein inhibitor is the concentration eliciting 50% cellular effect (EC5 0 ).
• This invention therefore comprises a series of compounds that demonstrate unexpected properties with respect to their selectivity for binding to, and inhibiting the activity of anti-apoptotic Bcl-2 protein over anti-apoptotic BC1-XL protein as significantly higher than those of the compounds taught in PCT/US/2004/36770 and
• a 1 is N or C(A 2 );
• a 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R 1 , SO2R 1 , C(0)R 1 , C(0)OR 1 , OC(0)R 1 , NHR 1 , NCR 1 )!, C(0)NHR 1 , C(0)N(R 1 ) 2 ,
• NHSO2R 1 NHS0 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, CI, Br, I, CN, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• Y 1 is H, CN, N0 2 , C(0)OH, F, CI, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(0)R 17 , C(0)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(0)R 17 , C(0)NH 2 , C(0)NHR 17 , C(0)N(R 17 ) 2 , NHS(0)R 17 or NHS0 2 R 17 ;
• B 1 and Y 1 together with the atoms to which they are attached, are imidazole or triazole;
• one or two or each of A 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , NHC(0)R 1 ,
• NHSO 2 R 1 NHSO 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, CI, Br, I, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• R 1 is R 2 , R 3 , R 4 or R 5 ;
• R 1A is Ci-Ce-alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R 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 arene, heteroarene or R 4A ;
• R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(0)R 7 , S0 2 R 7 , NHR 7 , N(R 7 ) 2 , C(0)R 7 , C(0)NH 2 , C(0)NHR 7 , NHC(0)R 7 , NHS0 2 R 7 , NHC(0)OR 7 , SO 2 NH 2 , SO 2 NHR 7 , S0 2 N(R 7 ) 2 , NHC(0)NH 2 , NHC(0)NHR 7 ,
• R 6 is C 2 -C5-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, CI, 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-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-l-yl, each having one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH;
• R 7 is R 8 , R 9 , R 10 or R n ;
• R 8 is phenyl which is unfused or fused with arene, heteroarene or R 8A ;
• R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 9 is heteroaryl which is unfused or fused with arene, heteroarene or R 9A ;
• R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 10 is C 3 -Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two C3 ⁇ 4 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 12 , C(0)N(R 12 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, 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 arene, heteroarene or R 13A ;
• R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 14 is heteroaryl, each of which is unfused or fused with arene, 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 arene, 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 arene, heteroarene or R 18A ;
• R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 19 is heteroaryl which is unfused or fused with arene, heteroarene or R 19A ;
• R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 20 is C3-Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 22 , C(0)N(R 22 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, Br or I substituents;
• R 22 is R 23 , R 24 or R 25 ;
• R 23 is phenyl which is unfused or fused with arene, heteroarene or R 23A ;
• R 23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 24 is heteroarene which is unfused or fused with arene, heteroarene or R 24A ;
• R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 25 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is
• R 25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• Z 1 is R 26 or R 27 , each of which is substituted with R 28 , R 29 or R 30 , each of which is substituted with F, CI, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(0)R 37 , OR 37 , SR 37 , S(0)R 37 , S0 2 R 37 , NHR 37 or N(R 32 )R 37 ;
• R 26 is phenyl which is unfused or fused with arene or heteroarene
• R 27 is heteroarene which is unfused or fused with arene or heteroarene
• R 28 is phenyl which is unfused or fused with arene, heteroarene or R 28A ;
• R 28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 29 is heteroaryl or R 29A ;
• R 29A 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 30A ;
• R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;
• R 31 and R 31A are independently F, CI, Br or alkyl or are taken together and are C 2 -C5-spiroalkyl;
• R 32 is R 33 , C(0)R 33 or C(0)OR 33 ;
• R 33 is R 34 or R 35 ;
• R 34 is phenyl which is unfused or fused with aryl, heteroaryl 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 arene, 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, CI, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(0)OR 41 , SR 41 , S(0)R 41 or S0 2 R 41 ;
• R 38 is phenyl which is unfused or fused with arene, heteroarene or R 38A ;
• R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 39 is heteroaryl which is unfused or fused with arene, heteroarene or R 39A ;
• R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 40 is C3-C8-cycloalkyl or C4-Cs-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is
• R 41 is R ⁇ R ⁇ or R 45 ;
• R 42 is phenyl which is unfused or fused with arene, heteroarene or R 42A ;
• R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 43 is heteroaryl which is unfused or fused with arene, heteroarene or R 43A ;
• R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 44 is C 3 -C9-cycloalkyl or C 4 -C7-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 44A ;
• R UA 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(0)NH 2 , C(0)NHR 46 ,
• R 46 is R 47 R 48 or R 49.
• R 47 is phenyl which is unfused or fused with arene, heteroarene or R 47A ;
• R 47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 48 is heteroaryl or R 48A ;
• R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 49A ;
• R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 26 and R 27 are further substituted by one or two or three of independently selected R 50A , OR 50A , SR 50A , S(O)R 50A , SO 2 R 50A or NHR 50A ;
• R 50A is R 51A R 52A R 53A or R 54A.
• R 51A is phenyl which is unfused or fused with benzene, heteroarene or R 51AA , wherein R 51AA is cycloalkane, cycloalkene or heterocycloalkane heterocycloalkene,
• R 52A is heteroaryl
• R 53A 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), S0 2
• 53AA is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 54A is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 55AA , OR 55AA , SR 55AA , S(0)R 55AA , S0 2 R 55AA , NHR 55AA , N(R 55AA ) 2 , C(0)R 55AA , C(0)NH 2 , C(0)NHR 55AA , NHC(0)R 55AA , NHS0 2 R 55AA , NHC(0)OR 55AA , S0 2 NH 2 , S0 2 NHR 55AA , S0 2 N(R 55AA ) 2 , NHC(0)NH 2 , NHC(0)NHR 55AA , OH, (O), C(0)OH, (O), N 3 , CN, NH 2 , CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , F, CI, Br or I substituents;
• R 56A is C 3 -C6-cycloalkyl or C4-C6-cycloalkyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N;
• R , R , R , and R are independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five independently selected R 50AA 5 R 50 5 OR 50 , SR 50 , S(0)R 50 , S0 2 R 50 , C(0)R 50 , CO(0)R 5 °, OC(0)R 5 °, OC(0)OR 5 °, NH 2 , NHR 50 , N(R 50 ) 2 , C(0)NH 2 , C(0)NHR 50 , C(O)N(R 50 ) 2 , C(0)NHOH, C(0)NHOR 5 °, C(0)NHS0 2 R 50 , C(O)NR 50 SO 2 R 50 , S0 2 NH 2 , S0 2 NHR 50 , SO 2 N(R 50 ) 2 , CF 3 , CF 2 CF 3 , C(0)H, C(0)OH,
• R 50AA is spirocyclyl
• R 50 is R 51 , R 52 , R 53 or R 54 ;
• R 51 is phenyl which is unfused or fused with arene, heteroarene or R 51B ;
• R 51B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 52 is heteroaryl
• R 53 is C 3 -C6-cycloalkyl or C 4 -C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 53B ;
• R 53B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 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(0)R 55 , S0 2 R 55 , NHR 55 , N(R 55 ) 2 , C(0)R 55 , C(0)NH 2 , C(0)NHR 55 , NHC(0)R 55 , NHS0 2 R 55 , NHC(0)OR 55 , S0 2 NH 2 ,
• R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ;
• alkyl, alkenyl, alkynyl are unsubstituted or substituted with OCH 3 ; and R 56 is C 3 -Cs-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N.
• Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as selective inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (II)
• R 100 is as described for substituents on R 26 ;
• n 0, 1, 2, or 3;
• a 1 is N or C(A 2 );
• one or two or three or each of A 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 ,
• Y 1 is H, CN, NOz, C(0)OH, F, CI, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(0)R 17 , C(0)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(0)R 17 , C(0)NH 2 , C(0)NHR 17 , C(0)N(R 17 ) 2 , NHS(0)R 17 or NHS0 2 R 17 ;
• B 1 and Y 1 together with the atoms to which they are attached, are imidazole or triazole;
• a 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ S0 2 R ⁇ C(0)R ⁇ C(0)OR ⁇ OC(0)R ⁇ NHR 1 , ⁇ ) 2 , C(0)NHR 1 , C ⁇ NCR 1 ) ⁇ NHC(0)R 1 ,
• R 1 is R 2 , R 3 , R 4 or R 5 ;
• R 1A is Ci-Ce-alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R 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 arene, heteroarene or R 4A ;
• R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(0)R 7 , S0 2 R 7 , NHR 7 , N(R 7 ) 2 , C(0)R 7 , C(0)NH 2 , C(0)NHR 7 , NHC(0)R 7 , NHS0 2 R 7 , NHC(0)OR 7 , S0 2 NH 2 , S0 2 NHR 7 , S0 2 N(R 7 ) 2 , NHC(0)NH 2 , NHC(0)NHR 7 ,
• R 6 is C 2 -C5-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, CI, 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-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-l-yl, each having one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH;
• R 7 is R 8 , R 9 , R 10 or R n ;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 9 is heteroaryl which is unfused or fused with arene, heteroarene or R 9A ;
• R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 10 is C 3 -Cio-cycloalkyl or C 4 -Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 12 , C(0)N(R 12 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, 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 arene, heteroarene or R 13A ;
• R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 14 is heteroaryl, each of which is unfused or fused with arene, 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 arene, 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 arene, heteroarene or R 18A ;
• R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 19 is heteroaryl which is unfused or fused with arene, heteroarene or R 19A ;
• R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 20 is C 3 -Cio-cycloalkyl or C 4 -Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 22 , C(0)N(R 22 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, Br or I substituents;
• R 22 is R 23 , R 24 or R 25 ;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 24 is heteroarene which is unfused or fused with arene, heteroarene or R 24A ;
• R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 25 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 30A ;
• R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is substituted with F, CI, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(0)R 37 , OR 37 , SR 37 , S(0)R 37 , S0 2 R 37 , NHR 37 or N(R 32 )R 37 ;
• R 31 and R 31A are independently F, CI, Br or alkyl or are taken together and are C 2 -C5-spiroalkyl;
• R 32 is R 33 , C(0)R 33 or C(0)OR 33 ;
• R 33 is R 34 or R 35 ;
• R 34 is phenyl which is unfused or fused with aryl, heteroaryl 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 arene, 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, CI, Br, I, R 41 , OR 41 , NHR 41 ,
• R 38 is phenyl which is unfused or fused with arene, heteroarene or R 38A ;
• R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 39 is heteroaryl which is unfused or fused with arene, heteroarene or R 39A ;
• R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 40 is C 3 -C8-cycloalkyl or C4-Cs-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is
• R 41 is R ⁇ R ⁇ or R 45 ;
• R 42 is phenyl which is unfused or fused with arene, heteroarene or R 42A ;
• R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 43 is heteroaryl which is unfused or fused with arene, heteroarene or R 43A ;
• R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 44 is C 3 -C9-cycloalkyl or C4-C7-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 44A ;
• R UA 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(0)NH 2 , C(0)NHR 46 ,
• R 46 is R 47 R 48 or R 49.
• R 47 is phenyl which is unfused or fused with arene, heteroarene or R 47A ;
• R 47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 48 is heteroaryl or R 48A ;
• R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 49 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 49A ;
• R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• 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
• R 50AA is spirocyclyl
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 52 is heteroaryl
• R 53 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 53B ;
• 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(0)R 55 , S0 2 R 55 , NHR 55 , N(R 55 ) 2 , C(0)R 55 , C(0)NH 2 , C(0)NHR 55 , NHC(0)R 55 , NHS0 2 R 55 , NHC(0)OR 55 , S0 2 NH 2 ,
• R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ;
• alkyl, alkenyl, alkynyl are unsubstituted or substituted with OCH 3 ; and R 56 is C 3 -C8-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N.
• Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as selective inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (III)
• R 100 is as described for substituents on R 26 ;
• n 0, 1, 2, or 3;
• a 1 is N or C(A 2 );
• a 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ SO 2 R 1 , C(0)R ⁇ C(0)0R 1 , OC(0)R ⁇ NHR 1 , NCR 1 )!, C(0)NHR 1 , CCO R 1 ⁇ ,
• NHSO 2 R 1 NHSO 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, CI, Br, I, CN, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• Y 1 is H, CN, NO 2 , C(0)OH, F, CI, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(0)R 17 , C(0)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(0)R 17 , C(0)NH 2 , C(0)NHR 17 , C(0)N(R 17 ) 2 , NHS(0)R 17 or NHS0 2 R 17 ;
• B 1 and Y 1 together with the atoms to which they are attached, are imidazole or triazole;
• a 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ SO 2 R 1 , C(0)R 1 , C(0)OR 1 , OC(0)R 1 , NHR 1 , ⁇ ) 2 , C(0)NHR 1 , C(0)N(R 1 ) 2 , NHC(0)R 1 , NHSO 2 R 1 , NHSO 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, CI, Br, I, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• R 1 is R 2 , R 3 , R 4 or R 5 ;
• R 1A is Ci-Ce-alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
• R 2 is phenyl which is unfused or fused with arene, 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 arene, heteroarene or R 4A ;
• R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(0)R 7 , S0 2 R 7 , NHR 7 , N(R 7 ) 2 , C(0)R 7 , C(0)NH 2 , C(0)NHR 7 , NHC(0)R 7 , NHS0 2 R 7 , NHC(0)OR 7 , S0 2 NH 2 , S0 2 NHR 7 , S0 2 N(R 7 ) 2 , NHC(0)NH 2 , NHC(0)NHR 7 ,
• R 6 is C 2 -C5-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N 3 ,
• 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-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-l-yl, each having one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH;
• R 7 is R 8 , R 9 , R 10 or R n ;
• R 8 is phenyl which is unfused or fused with arene, heteroarene or R 8A ;
• R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 9 is heteroaryl which is unfused or fused with arene, heteroarene or R 9A ;
• R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 10 is C 3 -Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 12 , C(0)N(R 12 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, 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 arene, heteroarene or R 13A ;
• R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 14 is heteroaryl, each of which is unfused or fused with arene, 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 arene, 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 arene, heteroarene or R 18A ;
• R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 19 is heteroaryl which is unfused or fused with arene, heteroarene or R 19A ;
• R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 20 is C3-Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 22 , C(0)N(R 22 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, Br or I substituents;
• R 22 is R 23 , R 24 or R 25 ;
• R 23 is phenyl which is unfused or fused with arene, heteroarene or R 23A ;
• R 23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 24 is heteroarene which is unfused or fused with arene, heteroarene or R 24A ;
• R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 25 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused
• R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is substituted with F, CI, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(0)R 37 , OR 37 , SR 37 , S(0)R 37 , S0 2 R 37 , NHR 37 or N(R 32 )R 37 ;
• R 31 and R 31A are independently F, CI, Br or alkyl or are taken together and are C 2 -C5-spiroalkyl;
• R 32 is R 33 , C(0)R 33 or C(0)OR 33 ;
• R 33 is R 34 or R 35 ;
• R 34 is phenyl which is unfused or fused with aryl, heteroaryl 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 arene, 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, CI, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(0)OR 41 , SR 41 , S(0)R 41 or S0 2 R 41 ;
• R 38 is phenyl which is unfused or fused with arene, heteroarene or R 38A ;
• R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 39 is heteroaryl which is unfused or fused with arene, heteroarene or R 39A ;
• R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 40 is C3-C8-cycloalkyl or C 4 -Cs-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 40A ; R 40A cycloalkane, cycloalkene,
• R 41 is R ⁇ R ⁇ or R 45 ;
• R 42 is phenyl which is unfused or fused with arene, heteroarene or R 42A ;
• R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 43 is heteroaryl which is unfused or fused with arene, heteroarene or R 43A ;
• R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 44 is C3-C9-cycloalkyl or C 4 -C7-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 44A ;
• R UA 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(0)NH 2 , C(0)NHR 46 ,
• R 46 isR 47 ,R 48 orR 49 ;
• R 47 is phenyl which is unfused or fused with arene, heteroarene or R 47A ; R 47A is
• cycloalkane cycloalkene, heterocycloalkane or heterocycloalkene
• R 48 is heteroaryl or R 48A ;
• R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;
• R 49 is C3-C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties0 unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 49A ;
• R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 50AA is spirocyclyl
• R 50 is R 51 ,R 52 , R 53 orR 54 ;
• R 51 is phenyl which is unfused or fused with arene, heteroarene or R 51B ;
• R 51B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 52 is heteroaryl
• R 53 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH, S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 53B ;
• R 53B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 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(0)R 55 , S0 2 R 55 , NHR 55 , N(R 55 ) 2 , C(0)R 55 , C(0)NH 2 , C(0)NHR 55 , NHC(0)R 55 , NHS0 2 R 55 , NHC(0)OR 55 , S0 2 NH 2 ,
• R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ;
• alkyl, alkenyl, alkynyl are unsubstituted or substituted with OCH 3 ; and R 56 is C 3 -Cs-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N.
• Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as selective inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (IV)
• R 100 is as described for substituents on R 26 ;
• n 0, 1, 2, or 3;
• a 1 is N or C(A 2 );
• one or two or three or each of A 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 ,
• Y 1 is H, CN, NOz, C(0)OH, F, CI, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(0)R 17 , C(0)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(0)R 17 , C(0)NH 2 , C(0)NHR 17 , C(0)N(R 17 ) 2 , NHS(0)R 17 or NHS0 2 R 17 ;
• B 1 and Y 1 together with the atoms to which they are attached, are imidazole or triazole;
• a 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ S0 2 R ⁇ C(0)R ⁇ C(0)OR ⁇ OC(0)R ⁇ NHR 1 , ⁇ ) 2 , C(0)NHR 1 , C ⁇ NCR 1 ) ⁇ NHC(0)R 1 ,
• R 1 is R 2 , R 3 , R 4 or R 5 ;
• R 1A is Ci-Ce-alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R 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 arene, heteroarene or R 4A ;
• R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(0)R 7 , S0 2 R 7 , NHR 7 , N(R 7 ) 2 , C(0)R 7 , C(0)NH 2 , C(0)NHR 7 , NHC(0)R 7 , NHS0 2 R 7 , NHC(0)OR 7 , S0 2 NH 2 , S0 2 NHR 7 , S0 2 N(R 7 ) 2 , NHC(0)NH 2 , NHC(0)NHR 7 ,
• R 6 is C 2 -C5-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, CI, 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-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-l-yl, each having one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH;
• R 7 is R 8 , R 9 , R 10 or R n ;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 9 is heteroaryl which is unfused or fused with arene, heteroarene or R 9A ;
• R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 10 is C 3 -Cio-cycloalkyl or C 4 -Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 12 , C(0)N(R 12 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, 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 arene, heteroarene or R 13A ;
• R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 14 is heteroaryl, each of which is unfused or fused with arene, 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 arene, 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 arene, heteroarene or R 18A ;
• R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 19 is heteroaryl which is unfused or fused with arene, heteroarene or R 19A ;
• R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 20 is C 3 -Cio-cycloalkyl or C 4 -Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 22 , C(0)N(R 22 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, Br or I substituents;
• R 22 is R 23 , R 24 or R 25 ;
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 24 is heteroarene which is unfused or fused with arene, heteroarene or R 24A ;
• R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 25 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 30A ;
• R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is substituted with F, CI, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(0)R 37 , OR 37 , SR 37 , S(0)R 37 , S0 2 R 37 , NHR 37 or N(R 32 )R 37 ;
• R 31 and R 31A are independently F, CI, Br or alkyl or are taken together and are C 2 -C5-spiroalkyl;
• R 32 is R 33 , C(0)R 33 or C(0)OR 33 ;
• R 33 is R 34 or R 35 ;
• R 34 is phenyl which is unfused or fused with aryl, heteroaryl 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 arene, 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, CI, Br, I, R 41 , OR 41 , NHR 41 ,
• R 38 is phenyl which is unfused or fused with arene, heteroarene or R 38A ;
• R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 39 is heteroaryl which is unfused or fused with arene, heteroarene or R 39A ;
• R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 40 is C 3 -C8-cycloalkyl or C4-Cs-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is
• R 41 is R ⁇ R ⁇ or R 45 ;
• R 42 is phenyl which is unfused or fused with arene, heteroarene or R 42A ;
• R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 43 is heteroaryl which is unfused or fused with arene, heteroarene or R 43A ;
• R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 44 is C 3 -C9-cycloalkyl or C4-C7-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 44A ;
• R UA 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(0)NH 2 , C(0)NHR 46 ,
• R 46 is R 47 R 48 or R 49.
• R 47 is phenyl which is unfused or fused with arene, heteroarene or R 47A ;
• R 47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 48 is heteroaryl or R 48A ;
• R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 49 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 49A ;
• R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• 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
• R 50AA is spirocyclyl
• R is phenyl which is unfused or fused with arene, heteroarene or R ;
• R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 52 is heteroaryl
• R 53 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 53B ;
• 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(0)R 55 , S0 2 R 55 , NHR 55 , N(R 55 ) 2 , C(0)R 55 , C(0)NH 2 , C(0)NHR 55 , NHC(0)R 55 , NHS0 2 R 55 , NHC(0)OR 55 , S0 2 NH 2 ,
• R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ;
• alkyl, alkenyl, alkynyl are unsubstituted or substituted with OCH 3 ; and R 56 is C 3 -C8-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N.
• Another embodiment of this invention pertains to compounds or therapeutically acceptable salts, prodrugs or salts of prodrugs thereof, which are useful as selective inhibitors of anti-apoptotic Bcl-2 proteins, the compounds having Formula (V)
• R 100 is as described for substituents on R 26 ;
• n 0, 1, 2, or 3;
• a 1 is N or C(A 2 );
• a 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ SO2R 1 , C(0)R ⁇ C(0)OR ⁇ OC(0)R ⁇ NHR 1 , NCR 1 )!, C(0)NHR 1 , CCO R 1 ⁇ ,
• NHSO 2 R 1 NHSO 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, CI, Br, I, CN, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• Y 1 is H, CN, NO 2 , C(0)OH, F, CI, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(0)R 17 , C(0)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(0)R 17 , C(0)NH 2 , C(0)NHR 17 , C(0)N(R 17 ) 2 , NHS(0)R 17 or NHS0 2 R 17 ;
• B 1 and Y 1 together with the atoms to which they are attached, are imidazole or triazole;
• a 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(0)R ⁇ SO 2 R 1 , NHR 1 , NCR 1 )!, C(0)NHR 1 , C(0)N(R 1 ) 2 , NHC(0)R 1 , NHC(0)OR 1 , NHC(0)NHR 1 , N(CH 3 )C(0)N(CH 3 )R 1 , SO 2 NHR 1 , SOzNCR 1 ⁇ , NHSO 2 R 1 , NHSO 2 NHR 1 or N(CH 3 )S0 2 N(CH 3 )R ⁇ and the remainder are independently selected H, F, CI, Br, I, CF 3 , C(0)OH, C(0)NH 2 or C(0)OR 1A ;
• R 1 is R 2 , R 3 , R 4 or R 5 ;
• R 1A is Ci-Ce-alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
• R 2 is phenyl which is unfused or fused with arene, 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 arene, heteroarene or R 4A ;
• R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(0)R 7 , S0 2 R 7 , NHR 7 , N(R 7 ) 2 , C(0)R 7 , C(0)NH 2 , C(0)NHR 7 , NHC(0)R 7 , NHS0 2 R 7 , NHC(0)OR 7 , S0 2 NH 2 , S0 2 NHR 7 , S0 2 N(R 7 ) 2 , NHC(0)NH 2 , NHC(0)NHR 7 ,
• R 6 is C 2 -C5-spiroalkyl, each of which is unsubstituted or substituted with OH, (O), N 3 ,
• 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-l-yl, azetidin-l-yl, pyrrolidin-l-yl or piperidin-l-yl, each having one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH;
• R 7 is R 8 , R 9 , R 10 or R n ;
• R 8 is phenyl which is unfused or fused with arene, heteroarene or R 8A ;
• R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 9 is heteroaryl which is unfused or fused with arene, heteroarene or R 9A ;
• R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 10 is C 3 -Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 12 , C(0)N(R 12 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, 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 arene, heteroarene or R 13A ;
• R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 14 is heteroaryl, each of which is unfused or fused with arene, 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 arene, 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 arene, heteroarene or R 18A ;
• R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 19 is heteroaryl which is unfused or fused with arene, heteroarene or R 19A ;
• R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 20 is C3-Cio-cycloalkyl or C4-Cio-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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(0)NH 2 , C(0)NHR 22 , C(0)N(R 22 ) 2 , OH, (O), C(0)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, CI, Br or I substituents;
• R 22 is R 23 , R 24 or R 25 ;
• R 23 is phenyl which is unfused or fused with arene, heteroarene or R 23A ;
• R 23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 24 is heteroarene which is unfused or fused with arene, heteroarene or R 24A ;
• R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 25 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, 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), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused
• R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; each of which is substituted with F, CI, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(0)R 37 , OR 37 , SR 37 , S(0)R 37 , S0 2 R 37 , NHR 37 or N(R 32 )R 37 ;
• R 31 and R 31A are independently F, CI, Br or alkyl or are taken together and are C 2 -C5-spiroalkyl;
• R 32 is R 33 , C(0)R 33 or C(0)OR 33 ;
• R 33 is R 34 or R 35 ;
• R 34 is phenyl which is unfused or fused with aryl, heteroaryl 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 arene, 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, CI, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(0)OR 41 , SR 41 , S(0)R 41 or S0 2 R 41 ;
• R 38 is phenyl which is unfused or fused with arene, heteroarene or R 38A ;
• R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 39 is heteroaryl which is unfused or fused with arene, heteroarene or R 39A ;
• R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 40 is C3-C8-cycloalkyl or C 4 -Cs-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 40A ; R 40A cycloalkane, cycloalkene,
• R 41 is R ⁇ R ⁇ or R 45 ;
• R 42 is phenyl which is unfused or fused with arene, heteroarene or R 42A ;
• R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 43 is heteroaryl which is unfused or fused with arene, heteroarene or R 43A ;
• R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 44 is C3-C9-cycloalkyl or C 4 -C7-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 44A ;
• R UA 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(0)NH 2 , C(0)NHR 46 ,
• R 46 isR 47 ,R 48 orR 49 ;
• R 47 is phenyl which is unfused or fused with arene, heteroarene or R 47A ; R 47A is
• cycloalkane cycloalkene, heterocycloalkane or heterocycloalkene
• R 48 is heteroaryl or R 48A ;
• R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene ;
• R 49 is C3-C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties0 unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 49A ;
• R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 50AA is spirocyclyl
• R 50 is R 51 ,R 52 , R 53 orR 54 ;
• R 51 is phenyl which is unfused or fused with arene, heteroarene or R 51B ;
• R 51B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
• R 52 is heteroaryl
• R 53 is C 3 -C6-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH, S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with arene, heteroarene or R 53B ;
• R 53B is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
• R 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(0)R 55 , S0 2 R 55 , NHR 55 , N(R 55 ) 2 , C(0)R 55 , C(0)NH 2 , C(0)NHR 55 , NHC(0)R 55 , NHS0 2 R 55 , NHC(0)OR 55 , S0 2 NH 2 ,
• R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R 56 ;
• alkyl, alkenyl, alkynyl are unsubstituted or substituted with OCH 3 ;
• R 56 is C 3 -Cs-cycloalkyl or C4-C6-cycloalkenyl, each having one or two CH 2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH , S, S(O), S0 2 or NH and one or two CH moieties unreplaced or replaced with N.
• Another embodiment pertains to compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) wherein A 1 is C(A 2 ); and A 2 is H.
• Another embodiment pertains to compounds of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) wherein A 1 is C(A 2 ) or N; A 2 is H; and B 1 is NHR 1 .
• Another embodiment pertains to compounds of Formula (I), Formula (II), Formula
• a 1 is C(A 2 ) or N; A 2 is H; B 1 is NHR 1 ; and D 1 is H.
• a 1 is C(A 2 ) or N; A 2 is H; B 1 is NHR ⁇ D 1 is H; and E 1 is H.
• a 1 is C(A 2 ) or N; A 2 is H; B 1 is NHR ⁇ D 1 is H; E 1 is H; and Y 1 is N0 2.
• Still another embodiment pertains to compounds having Formula I which are 4-(4-((4'-chloro-l,l'-biphenyl-2-yl)methyl)piperazin-l-yl)-N-((3-nitro-4-((tetrahydro-2H- pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
• 4_ ⁇ 4_ [ 1 -(4'-chloro- 1 , 1 '-biphenyl-2-yl)ethyl]piperazin- 1 -yl ⁇ -2-( 1 H-indol-4-yloxy)-N-( ⁇ 4- [(3- morpholin-4-ylpropyl)amino]-3-nitrophenyl ⁇ sulfonyl)benzamide;

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