Apoptosis promoters

1. A process for producing a compound having the formula (I)

comprising

reacting a compound having the formula (2)

and a compound having the formula Z 1 —CO 2 H in the presence of a coupling agent, and, optionally, a base,

wherein

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 from 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 , NHC(O)OR 1 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NHSO 2 NHR 1 and N(CH 3 )SO 2 N(CH 3 )R 1 , and the remainder of A 2 , B 1 , D 1 and E 1 are independently selected from H, F, Cl, Br, I, CN, CF 3 , C(O)OH, C(O)NH 2 and 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 17 , NH 2 , NHR 17 , 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 ;

or

B 1 and Y 1 , together with the atoms to which they are attached, are imidazole or triazole; and

one or two or each of A 2 , D 1 and E 1 are independently selected from 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 , NHC(O)OR 1 , NHC(O)NHR 1 , N(CH 3 )C(O)N(CH 3 )R 1 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NHSO 2 NHR 1 and N(CH 3 )SO 2 N(CH 3 )R 1 , and the remainder of A 2 , D 1 and E 1 are independently selected from H, F, Cl, Br, I, CF 3 , C(O)OH, C(O)NH 2 and C(O)OR 1A ;

R 1 is 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 , where R 2A is cycloalkane or heterocycloalkane;

R 3 is heteroaryl which is unfused or fused with benzene, heteroarene or R 3A , where 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 , where 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 substituents independently selected from 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 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, (O), N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and I;

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 , where 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 , where R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 9 is heteroaryl which is unfused or fused with benzene, heteroarene or R 9A , where R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 10 is C 3 -C 10 -cycloalkyl, C 4 -C 10 -cycloalkenyl, C 3 -C 10 -heterocycloalkyl or C 4 -C 10 -heterocycloalkenyl, each of which is unfused or fused with 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 substituents independently selected from R 12 , OR 12 , NHR 12 , N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and 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 , where 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 , where 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 , where 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 , where R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 19 is heteroaryl which is unfused or fused with benzene, heteroarene or R 19A , where 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 a substituent independently selected from O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2 and 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 , where 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 substituents independently selected from 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 and I;

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 , where R 23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 24 is heteroarene which is unfused or fused with benzene, heteroarene or R 24A , where 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 a substituent independently selected O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2 and 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 , where R 25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and

Z 1 —CO 2 H has the formula

2. The method of claim 1 , wherein the reacting step is performed in the presence of a base selected from the group consisting of triethylamine (“TEA”), 4-(dimethylamino)pyridine (“DMAP”), diisopropylethylamine (“DIEA”) and mixtures thereof.

3. The method of claim 1 , wherein the coupling agent is selected from the group consisting of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (“EDCI”), 1,1′-carbonyldiimidazole (“CDI”) and benzotriazol-1-yloxytris(pyrrolidino) phosphonium hexafluorophosphonate (“PyBOP”).

4. The method of claim 1 , wherein Z 1 —CO 2 H has the formula

5. The method of claim 4 further comprising preparing Z 1 —CO 2 H by

reacting 2-bromo-5,5-dimethylcyclohex-1-enecarbaldehyde and ethyl 4-(1-piperazinyl)benzoate to produce ethyl 4-(4-((2-bromo-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate;

reacting ethyl 4-(4-((2-bromo-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate with 4-chlorophenylboronic acid to produce ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate; and

removing the ethyl group from ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate, optionally, in a mixture comprising lithium hydroxide hydrate in dioxane and water.