Substituted piperazines as cb1 antagonists

A compound of Formula (I):

• or a pharmaceutically acceptable salt, thereof,
• wherein:
• Ar1 is unsubstituted aryl or unsubstituted heteroaryl;
• Ar2 is aryl or heteroaryl, wherein said aryl or heteroaryl of Ar2 is substituted with two or more groups independently selected from Y1;
• n and m are independently 0 or 1;
• with the proviso that when Ar2 is pyridine or pyrimidine, a nitrogen of said pyridine or pyrimidine is not in the para position relative to the point of attachment to the piperazine ring;
• A is selected from the group consisting of —C(O)—, —S(O)2—, —C(═N—OR2)—, and —(C(R2)2)q— wherein q is 1, 2, or 3;
• B is selected from the group consisting of —N(R2)—, —C(O)—, and —(C(R3)2)r— wherein r is 1 or 2,
• with the proviso that when B is —C(O)—, then A is —C(O)— or —(C(R2)2)q—;
• X is selected from the group consisting of H, alkyl, —C(O)N(R6)2, —S-alkyl, —S(O)2-alkyl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —S(O)2-aryl, —S(O)2-heteroaryl, cycloalkyl, benzo-fused cycloalkyl-, benzo-fused heterocycloalkyl-, benzo-fused heterocycloalkenyl-, heterocycloalkyl, —S-aryl, —N(R4)2, —NR4R6, —N(R6)2, —(C(R2)2)s-heteroaryl, —C(O)—O-alkyl, —O-aryl, —O-heteroaryl, —C(O)-aryl, —C(O)-heteroaryl, —N═O, —C(S-alkyl)=N—S(O)2-aryl, —C(N(R2)2)═N—S(O)2-aryl, and —(C(R2)2)s-aryl wherein s is 0, 1, or 2,
• wherein each of the heteroaryl portions of said —(C(R2)2)s-heteroaryl, the aryl portion of said —C(R2)═C(R2)-aryl, the heteroaryl portion of said —C(R2)═C(R2)-heteroaryl, the aryl portion of said —S-aryl, the aryl portion of said —S(O)2-aryl, the heteroaryl portion of said —S(O)2-heteroaryl, the aryl portion of said —O-aryl, the heteroaryl portion of said —O-heteroaryl, the aryl portion of said —C(O)-aryl, the heteroaryl portion of said —C(O)-heteroaryl, the aryl portion of said —(C(R2)2)s-aryl, the aryl portion of said —C(S-alkyl)=N—S(O)2-aryl, the aryl portion of said —C(N(R2)2)═N—S(O)2-aryl, the benzo portion of said benzo-fused cycloalkyl, the benzo portion of said benzo-fused heterocycloalkyl, and the benzo portion of said benzo-fused heterocycloalkenyl of X is unsubstituted or substituted with one or more groups independently selected from Y1, and
• wherein said cycloalkyl, the cycloalkyl portion of said —S(O)2-cycloalkyl, said heterocycloalkyl, the cycloalkyl portion of said benzo-fused cycloalkyl, the heterocycloalkyl portion of said benzo-fused heterocycloalkyl, and the heterocycloalkenyl portion of said benzo-fused heterocycloalkenyl of X are unsubstituted or substituted with one or more groups independently selected from Y2;
• each R1 is independently selected from the group consisting of alkyl, haloalkyl, -alkylene-N(R5)2, -alkylene-NR5R2, -alkylene-OR2, alkylene-N3, -alkylene-CN, and alkylene-O—S(O)2-alkyl;
• or
• two R1 groups attached to the same ring carbon atom form a carbonyl group;
• p is 0, 1, 2, 3, or 4;
• each R2 is independently H, alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl,
• wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R2 is unsubstituted or optionally substituted with one or more groups independently selected from Y1;
• each R3 is independently selected from the group consisting of H, alkyl, unsubstituted aryl, aryl substituted with one or more Y1 groups, —OR2, -alkylene-O-alkyl, and -alkylene-OH;
• each R4 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —S(O)2alkyl, —S(O)2aryl, —S(O)2heteroaryl, —S(O)2cycloalkyl, and —S(O)2heterocycloalkyl,
• wherein each of said aryl, the aryl portion of said —C(O)O-aryl, the aryl portion of said —C(O)-aryl, the aryl portion of said —S(O)2aryl of R4, and each heteroaryl, the heteroaryl portion of said —C(O)O-heteroaryl, the heteroaryl portion of said —C(O)-heteroaryl, the heteroaryl portion of said —S(O)2heteroaryl of R4, is unsubstituted or substituted with one or more groups independently selected from Y1, and
• wherein each of said cycloalkyl, the cycloalkyl portion of said —C(O)O-cycloalkyl, the cycloalkyl portion of said —C(O)-cycloalkyl, the cycloalkyl portion of said —S(O)2 cycloalkyl of R4, is unsubstituted or substituted with one or more groups independently selected from Y2, or
• two R4 groups, together with the nitrogen to which they are attached, form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group;
• each R5 is independently selected from the group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —S(O)2-alkyl, —S(O)2-aryl, —S(O)2-heteroaryl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —C(O)—N(R2)2, —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, and -alkylene-OH,
• wherein said aryl, the aryl portion of said —S(O)2-aryl, the aryl portion of said —C(O)-aryl, and the aryl portion of said —C(O)O-aryl of R5, and each said heteroaryl, the heteroaryl portion of said —S(O)2-heteroaryl, the heteroaryl portion of said —C(O)-heteroaryl, and the heteroaryl portion of said —C(O)O-heteroaryl of R5 are unsubstituted or substituted with one or more groups independently selected from Z, or
• two R5 groups, together with the nitrogen to which they are attached, form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group;
• each Y1 is independently selected from the group consisting of halo, —CN, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, -alkylene-aryl, heteroaryl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, —S-aryl, —S-alkyl, —S-haloalkyl, —S-heteroaryl, —S-cycloalkyl, —S-heterocycloalkyl, —S(O)2-alkyl, —S(O)2-cycloalkyl, —S(O)2-heterocycloalkyl, —S(O)2-aryl, —S(O)2-heteroaryl, —alkylene-CN, —C(O)-alkyl, —C(O)-aryl, —C(O)-haloalkyl, —C(O)-heteroaryl, —C(O)-cycloalkyl, —C(O)-heterocycloalkyl, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O-haloalkyl, —C(O)O-heteroaryl, —C(O)O-cycloalkyl, —C(O)O-heterocycloalkyl, —N(R2)C(O)-alkyl, —N(R2)C(O)—N(R2)2, —OH, -alkylene-OH, -alkylene-C(O)—O-alkyl, —O-alkylene-aryl, —N(R5)2, —C(O)N(R6)2, —S(O)2N(R6)2, —O-Q-L1-R7, —O-Q-CN, —O-Q-C(O)N(R6)2, —O-Q-S(O)2N(R6)2, —O-Q-OC(O)N(R6)2, and —O-Q-N(R6)C(O)N(R6)2;
• wherein each said aryl, each -alkylene-aryl, each heteroaryl, each aryl portion of said —O-aryl, each heteroaryl portion of said —O-heteroaryl, each aryl portion of said —S-aryl, each heteroaryl portion of said —S-heteroaryl, each aryl portion of said —S(O)2-aryl, each heteroaryl portion of said —S(O)2-heteroaryl, each aryl portion of said —C(O)-aryl, each heteroaryl portion of said —C(O)-heteroaryl, each aryl portion of said —C(O)O-aryl, and each heteroaryl portion of said —C(O)O-heteroaryl of Y1 is unsubstituted or substituted with one or more groups independently selected from Z;
• or
• two groups Y1 form a —O—CH2—O— group;
• each Y2 is independently selected from the group consisting of alkyl, halo, haloalkyl, aryl, -alkylene-aryl, -alkylene-OH, —CN, —OH, —O-alkyl, —C(O)-alkyl, —S(O)2-cycloalkyl, -alkylene-N(R4)2, —C(O)-alkylene-N(R4)2, —C(O)—O-alkyl, —C(O)-aryl, —C(O)-haloalkyl, and —C(O)N(R6)2,
• wherein each said aryl, the aryl portion of said —C(O)-aryl, and the alkylene portion of said -alkylene-aryl, -alkylene-OH of Y2 is unsubstituted or substituted with one or more groups independently selected from Z;
• or
• two groups Y2 form a —O—CH2CH2—O— group;
• or
• two of said Y2 substituents attached to the same ring carbon atom of a cycloalkyl, benzo-fused cycloalkyl, benzo-fused heterocycloalkyl, benzo-fused heterocycloalkenyl, or heterocycloalkyl ring, together with the ring carbon atom to which they are both attached, form a carbonyl group;
• each -Q- is a divalent radical independently selected from -alkylene-, -alkenylene-, -alkynylene-, -cycloalkylene-, -heterocycloalkylene-, -alkylene-cycloalkylene-, -cycloalkylene-alkylene-, -cycloalkylene-alkylene-cycloalkylene-
• wherein the alkylene, alkenylene, alkynylene, cycloalkylene, and heterocycloalkylene portion of said Q is optionally substituted with one to three groups independently selected from
• and Z, wherein t is 0, 1, 2, or 3;
• each L1 is independently selected from the group consisting of —O—, —S—, —S(O)—, —(O)2—, —OS(O)2—, —C(O)—, —C(O)O—, and —OC(O)—;
• each R6 is independently selected from the group consisting of H, alkyl, halo alkyl, alkoxy, cycloalkyl, heterocycloalkyl, unsubstituted aryl, aryl substituted with one or more groups independently selected from Z, unsubstituted heteroaryl, heteroaryl substituted with one or more groups independently selected from Z, cycloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-O-aryl, -alkylene-OC(O)-alkyl, -alkylene-OC(O)-aryl, -alkylene-OC(O)-heteroaryl, and alkylene-N(R4)2, or
• two R6 groups, together with the nitrogen to which they are attached, form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group;
• each R7 is independently selected from the group consisting of H, alkyl, —N(R6)2, cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituents are independently selected from Z and —C(O)N(R6)2;
• and
• each Z is independently selected from the group consisting of alkyl, halo, haloalkyl, —OH, —O-alkyl, and —CN,
• with the proviso that when n=0, m=0, p=0, Ar2 is phenyl substituted with alkoxy and -alkylene-OH, then X is not alkyl,
• with the proviso that when X is alkyl and m=n=0, or X is alkyl or unsubstituted phenyl and A is —(C(R2)2)q— and B is —(C(R3)2)r— and r+q≧1 and R2 and R3 are each independently selected from H and alkyl, and Ar2 is phenyl or heteroaryl substituted with two or more groups independently selected from halogen, alkyl, and alkoxy, then p=2 and two R1 groups attached to the same ring carbon atom form a carbonyl group.