Piperazines, pharmaceutical compositions and methods of use thereof

1. A compound of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, C(═O)R 5 , C(═O)OR 5 and C(═O)NR 5 R 5 ;

V is selected from the group consisting of a bond, C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 R 6 , C(R 4 ) 2 C(R 4 ) 2 C(R 4 ) 2 R 6 , C(═O), C(═O)R 6 , C(═S), C(═S)R 6 , CH 2 C(═O), CH 2 C(═O)R 6 , CH 2 C(═S), CH 2 C(═S)R 6 , SO 2 , and SO 2 R 6 ;

A is a linking —C(R a ) 2 —X a —;

X a is selected from the group consisting of O, C(R 4 ) 2 O, OC(R 4 ) 2 , NR 5 , C(═O), C(R 4 ) 2 C(═O), C(═O)NR 5 , C(R 4 ) 2 NR 5 , NR 5 C(R 4 ) 2 , NR 5 C(═O), NR 5 C(═O)C(R 4 ) 2 , S, C(R 4 ) 2 S, and SC(R 4 ) 2 ;

when X a is C(R 4 ) 2 O, C(R 4 ) 2 NR 5 , C(═O), C(R 4 ) 2 C(═O), C(═O)NR 5 or C(R 4 ) 2 S, then each R a is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , halo, haloalkyl, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 S(═O) n R 5 , N(R 5 )C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 and OC(═O)R 5 , or both R a are taken together to form a 3 to 6 membered ring containing 0 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein said ring is substituted with one or more R 8 ;

and,

when X a is O, OC(R 4 ) 2 , NR 5 , NR 5 C(R 4 ) 2 NR 5 C(═O), NC(═O)R 5 C(R 4 ) 2 , S, or SC(R 4 ) 2 , then each R a is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , haloalkyl, C(═O)OR 5 , CN, C(═O)R 5 , C(═O)C(═O)R 5 and C(═O)NR 5 R 5 , or both R a are taken together to form a 3 to 6 membered ring containing 0 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein said ring is substituted with one or more R 8 ;

each R 4 is independently selected from the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , halo, haloalkyl, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 S(═O) n R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 and OC(═O)R 5 , or two R 4 are taken together to form a 3-6 membered ring comprising 0-3 heteroatoms, wherein said heteroatom is independently selected from the group consisting of N, O and S, and wherein said ring is substituted with one or more R 8 ;

each R 5 is independently selected from the group consisting of H, C1-C10 alkyl and C2-C10 alkenyl;

each R 6 is independently selected from the group consisting of C(R 4 ) 2 , C(R 4 ) 2 C(R 4 ) 2 , NR 5 , O, C(═O), C(═O)C(R4) 2 , C(═O)O, OC(R 4 ) 2 , C(R 4 ) 2 O, C(R 4 ) 2 S, C(R 4 ) 2 NR 5 , NR 5 CH 2 , S and SC(R 4 ) 2 ;

each R 7 is independently selected from the group consisting of halo, haloalkyl, OR 5 , SR 5 , C(═O)R 5 , OC(═O)R 5 , C(═O)OR 5 , NR 5 R 5 , NO 2 , CN, OC(═O)NR 5 R 5 , C(═O)NR 5 R 5 , N(R 5 )C(═O)R 5 , NR 5 C(═O)OR 5 , S(═O) n NR 5 R 5 , C3-C8 cycloalkyl, C4-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl, 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl, aryl, and heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more R 9 ;

each R 8 is independently selected from the group consisting of R 7 , C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, and C2-C10 alkynyl substituted with one or more R 7 ;

each R 9 is independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , halo, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)NR 5 R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 , OC(═O)R 5 , optionally substituted aryl, and optionally substituted heteroaryl;

R 12 is selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , aryl, heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more R 9 ;

each R 13 independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R 7 , C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or more R 8 , C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , 4-10 membered heterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted with one or more R 8 , C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , halo, OR 5 , SR 5 , NR 5 R 5 , C(═O)OR 5 , NO 2 , CN, C(═O)R 5 , C(═O)C(═O)R 5 , C(═O)NR 5 R 5 , NR 5 C(═O)R 5 , NR 5 S(═O) n R 5 , NR 5 C(═O)OR 5 , NR 5 C(═O)C(═O)R 5 , NR 5 C(═O)NR 5 R 5 , NR 5 S(═O) n NR 5 R 5 , NR 5 S(═O) n R 5 , S(═O) n R 5 , S(═O) n NR 5 R 5 , OC(═O)R 5 , optionally substituted aryl and optionally substituted heteroaryl;

n is 1 or 2; and

q is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein X a is selected from the group consisting of O and NR 5 and each R a is independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR 5 , halo and haloalkyl.

3. The compound of claim 2 , wherein R 12 is selected from the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or more R 7 , C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R 7 , C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R 8 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R 8 , aryl, heteroaryl, C5-C11 bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R 8 , C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R 8 , 5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted with one or more R 8 , 5-11 membered heterobicycloalkenyl, and 5-11 membered heterobicycloalkenyl substituted with one or more R 8 , wherein said aryl and heteroaryl are each optionally substituted with one or more R 9 .

4. The compound of claim 3 , wherein X a is O and V is a bond.

5. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and the compound of claim 1 .