IP Library › Patent Application 13294318

Patent Application

App. No. 13/294,318

NAMPT INHIBITORS

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App. No.: 13/294,318

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Abstract

Disclosed are compounds which inhibit the activity of NAMPT, compositions containing the compounds and methods of treating diseases during which NAMPT is expressed.

Claims (264)

1 . A compound of Formula (I), or pharmaceutically acceptable salts thereof

wherein

X 1 and X 2 and X 3 are CH; or

X 1 and X 3 are CH; and X 2 is N; or

X 2 and X 3 are H; and X 1 is N; or

X 1 is CR 1 ; and X 2 and X 3 are CH; or

X 2 is CR 1 ; and X 1 and X 3 are CH; or

X 3 is CR 1 ; and X 1 and X 2 are CH;

R 1 is R 3 , OR 3 , SR 3 , S(O)R 3 , SO 2 R 3 , C(O)R 3 , C(O)OR 3 , OC(O)R 3 , NHR 3 , N(R 3 ) 2 , C(O)NH 2 , C(O)NHR 3 , C(O)N(R 3 ) 2 , NHC(O)R 3 , NR 3 C(O)R 3 , NHC(O)OR 3 , NR 3 C(O)OR 3 , SO 2 NH 2 , SO 2 NHR 3 , SO 2 N(R 3 ) 2 , NHSO 2 R 3 , NR 3 SO 2 R 3 , NHSO 2 NHR 3 , NHSO 2 N(R 3 ) 2 , NR 3 SO 2 NHR 3 , NR 3 SO 2 N(R 3 ) 2 , C(O)NHSO 2 R 3 , NHSO 2 NHR 3 , F, Cl, Br, I, CN, NH 2 , NO 2 , N 3 , OH, C(O)H, CF 3 , C(O)OH, or C(O)NH 2 ;

R 2 is alkyl, alkenyl, alkynyl, phenyl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 4 , OR 4 , SR 4 , S(O)R 4 , SO 2 R 4 , C(O)R 4 , CO(O)R 4 , OC(O)R 4 , OC(O)OR 4 , NH 2 , NHR 4 , N(R 4 ) 2 , NHC(O)R 4 , NR 4 C(O)R 4 , NHS(O) 2 R 4 , NR 4 S(O) 2 R 4 , NHC(O)OR 4 , NR 4 C(O)OR 4 , NHC(O)NH 2 , NHC(O)NHR 4 , NHC(O)N(R 4 ) 2 , NR 4 C(O)NHR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)NH 2 , C(O)NHR 4 , C(O)N(R 4 ) 2 , C(O)NHOH, C(O)NHOR 4 , C(O)NHSO 2 R 4 , C(O)NR 4 SO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 N(R 4 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; wherein each phenyl is optionally additionally substituted at the para position with one independently selected R 5 , OCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , SR 5 , S(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR 5 , NHC(O)N(R 5 ) 2 , NR 5 C(O)NHR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)NHOH, C(O)NHOR 5 , C(O)NHSO 2 R 5 , C(O)NR 5 SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 N(R 5 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , Br or I; wherein each phenyl is optionally additionally substituted with one F; wherein each heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more independently selected R 5 , OR 5 , SR 5 , S(O)R 5 , SO 2 R 5 , C(O)R 5 , CO(O)R 5 , OC(O)R 5 , OC(O)OR 5 , NH 2 , NHR 5 , N(R 5 ) 2 , NHC(O)R 5 , NR 5 C(O)R 5 , NHS(O) 2 R 5 , NR 5 S(O) 2 R 5 , NHC(O)OR 5 , NR 5 C(O)OR 5 , NHC(O)NH 2 , NHC(O)NHR 5 , NHC(O)N(R 5 ) 2 , NR 5 C(O)NHR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)NH 2 , C(O)NHR 5 , C(O)N(R 5 ) 2 , C(O)NHOH, C(O)NHOR 5 , C(O)NHSO 2 R 5 , C(O)NR 5 SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , SO 2 N(R 5 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; wherein R 2 is not 4-methylphenyl;

R 3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 6 , OR 6 , SR 6 , S(O)R 6 , SO 2 R 6 , C(O)R 6 , CO(O)R 6 , OC(O)R 6 , OC(O)OR 6 , NH 2 , NHR 6 , N(R 6 ) 2 , NHC(O)R 6 , NR 6 C(O)R 6 , NHS(O) 2 R 6 , NR 6 S(O) 2 R 6 , NHC(O)OR 6 , NR 6 C(O)OR 6 , NHC(O)NH 2 , NHC(O)NHR 6 , NHC(O)N(R 6 ) 2 , NR 6 C(O)NHR 6 , NR 6 C(O)N(R 6 ) 2 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , C(O)NHOH, C(O)NHOR 6 , C(O)NHSO 2 R 6 , C(O)NR 6 SO 2 R 6 , SO 2 NH 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 4 is alkyl, alkenyl, alkynyl, aryl or heterocyclyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , C(O)R 7 , CO(O)R 7 , OC(O)R 7 , OC(O)OR 7 , NH 2 , NHR 7 , N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHS(O) 2 R 7 , NR 7 S(O) 2 R 7 , NHC(O)OR 7 , NR 7 C(O)OR 7 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)N(R 7 ) 2 , NR 7 C(O)NHR 7 , NR 7 C(O)N(R 7 ) 2 , C(O)NH 2 , C(O)NHR 7 , C(O)N(R 7 ) 2 , C(O)NHOH, C(O)NHOR 7 , C(O)NHSO 2 R 7 , C(O)NR 7 SO 2 R 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; wherein each aryl and heterocycyl is optionally substituted with one or more independently selected R 8 , OR 8 , SR 8 , S(O)R 8 , SO 2 R 8 , C(O)R 8 , CO(O)R 8 , OC(O)R 8 , OC(O)OR 8 , NH 2 , NHR 8 , N(R 8 ) 2 , NHC(O)R 8 , NR 8 C(O)R 8 , NHS(O) 2 R 8 , NR 8 S(O) 2 R 8 , NHC(O)OR 8 , NR 8 C(O)OR 8 , NHC(O)NH 2 , NHC(O)NHR 8 , NHC(O)N(R 8 ) 2 , NR 8 C(O)NHR 8 , NR 8 C(O)N(R 8 ) 2 , C(O)NH 2 , C(O)NHR 8 , C(O)N(R 8 ) 2 , C(O)NHOH, C(O)NHOR 8 , C(O)NHSO 2 R 8 , C(O)NR 8 SO 2 R 8 , SO 2 NH 2 , SO 2 NHR 8 , SO 2 N(R 8 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 9 , OR 9 , SR 9 , S(O)R 9 , SO 2 R 9 , C(O)R 9 , CO(O)R 9 , OC(O)R 9 , OC(O)OR 9 , NH 2 , NHR 9 , N(R 9 ) 2 , NHC(O)R 9 , NR 9 C(O)R 9 , NHS(O) 2 R 9 , NR 9 S(O) 2 R 9 , NHC(O)OR 9 , NR 9 C(O)OR 9 , NHC(O)NH 2 , NHC(O)NHR 9 , NHC(O)N(R 9 ) 2 , NR 9 C(O)NHR 9 , NR 9 C(O)N(R 9 ) 2 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , C(O)NHOH, C(O)NHOR 9 , C(O)NHSO 2 R 9 , C(O)NR 9 SO 2 R 9 , SO 2 NH 2 , SO 2 NHR 9 , SO 2 N(R 9 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 10 , OR 10 , SR 10 , S(O)R 10 , SO 2 R 10 , NHR 10 , N(R 10 ) 2 , C(O)R 10 , C(O)NH 2 , C(O)NHR 10 , C(O)N(R 10 ) 2 , NHC(O)R 10 , NR 10 C(O)R 10 , NHSO 2 R 10 , NHC(O)OR 10 , SO 2 NH 2 , SO 2 NHR 10 , SO 2 N(R 10 ) 2 , NHC(O)NH 2 , NHC(O)NHR 10 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;

R 7 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 11 , OR 11 , SR 11 , S(O)R 11 , SO 2 R 11 , NHR 11 , N(R 11 ) 2 , C(O)R 11 , C(O)NH 2 , C(O)NHR 11 , C(O)N(R 11 ) 2 , NHC(O)R 11 , NR 11 C(O)R 11 , NHSO 2 R 11 , NHC(O)OR 11 , SO 2 NH 2 , SO 2 NHR 11 , SO 2 N(R 11 ) 2 , NHC(O)NH 2 , NHC(O)NHR 11 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;

R 8 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 12 , OR 12 , SR 12 , S(O)R 12 , SO 2 R 12 , NHR 12 , N(R 12 ) 2 , C(O)R 12 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , NHC(O)R 12 , NR 12 C(O)R 12 , NHSO 2 R 12 , NHC(O)OR 12 , SO 2 NH 2 , SO 2 NHR 12 , SO 2 N(R 12 ) 2 , NHC(O)NH 2 , NHC(O)NHR 12 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;

R 9 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected OCH 3 , aryl, or heterocyclyl;

R 10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R 11 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R 12 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

wherein the cyclic moieties represented by R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are optionally substituted with one or more independently selected R 13 , OR 13 , SR 13 , S(O)R 13 , SO 2 R 13 , C(O)R 13 , CO(O)R 13 , OC(O)R 13 , OC(O)OR 13 , NH 2 , NHR 13 , N(R 13 ) 2 , NHC(O)R 13 , NR 13 C(O)R 13 , NHS(O) 2 R 13 , NR 13 S(O) 2 R 13 , NHC(O)OR 13 , NR 13 C(O)OR 13 , NHC(O)NH 2 , NHC(O)NHR 13 , NHC(O)N(R 13 ) 2 , NR 13 C(O)NHR 13 , NR 13 C(O)N(R 13 ) 2 , C(O)NH 2 , C(O)NHR 13 , C(O)N(R 13 ) 2 , C(O)NHOH, C(O)NHOR 13 , C(O)NHSO 2 R 13 , C(O)NR 13 SO 2 R 13 , SO 2 NH 2 , SO 2 NHR 13 , SO 2 N(R 13 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 14 , OR 14 , SR 14 , S(O)R 14 , SO 2 R 14 , C(O)R 14 , CO(O)R 14 , OC(O)R 14 , OC(O)OR 14 , NH 2 , NHR 14 , N(R 14 ) 2 , NHC(O)R 14 , NR 14 C(O)R 14 , NHS(O) 2 R 14 , NR 14 S(O) 2 R 14 , NHC(O)OR 14 , NR 14 C(O)OR 14 , NHC(O)NH 2 , NHC(O)NHR 14 , NHC(O)N(R 14 ) 2 , NR 14 C(O)NHR 14 , NR 14 C(O)N(R 14 ) 2 , C(O)NH 2 , C(O)NHR 14 , C(O)N(R 14 ) 2 , C(O)NHOH, C(O)NHOR 14 , C(O)NHSO 2 R 14 , C(O)NR 14 SO 2 R 14 , SO 2 NH 2 , SO 2 NHR 14 , SO 2 N(R 14 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more independently selected R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , C(O)R 15 , CO(O)R 15 , OC(O)R 15 , OC(O)OR 15 , NH 2 , NHR 15 , N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHS(O) 2 R 15 , NR 15 S(O) 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , NHC(O)NH 2 , NHC(O)NHR 15 , NHC(O)N(R 15 ) 2 , NR 15 C(O)NHR 15 , NR 15 C(O)N(R 15 ) 2 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , C(O)NHOH, C(O)NHOR 15 , C(O)NHSO 2 R 15 , C(O)NR 15 SO 2 R 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected NH 2 , SO 2 NH 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; and

R 15 is alkyl.

2 . A compound having Formula (V), or pharmaceutically acceptable salts thereof

wherein

X 1 and X 2 and X 3 are CH; or

X 1 and X 3 are CH; and X 2 is N; or

X 2 and X 3 are H; and X 1 is N; or

X 1 is CR 1 ; and X 2 and X 3 are CH; or

X 2 is CR 1 ; and X 1 and X 3 are CH; or

X 3 is CR 1 ; and X 1 and X 2 are CH;

R 10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

wherein the cyclic moieties represented by R 3 , R 5 , R 6 , R 9 , and R 10 , are optionally substituted with one or more independently selected R 13 , OR 13 , SR 13 , S(O)R 13 , SO 2 R 13 , C(O)R 13 , CO(O)R 13 , OC(O)R 13 , OC(O)OR 13 , NH 2 , NHR 3 , N(R 13 ) 2 , NHC(O)R 13 , NR 13 C(O)R 13 , NHS(O) 2 R 13 , NR 13 S(O) 2 R 13 , NHC(O)OR 13 , NR 13 C(O)OR 13 , NHC(O)NH 2 , NHC(O)NHR 13 , NHC(O)N(R 13 ) 2 , NR 13 C(O)NHR 13 , NR 13 C(O)N(R 13 ) 2 , C(O)NH 2 , C(O)NHR 13 , C(O)N(R 13 ) 2 , C(O)NHOH, C(O)NHOR 13 , C(O)NHSO 2 R 13 , C(O)NR 13 SO 2 R 13 , SO 2 NH 2 , SO 2 NHR 13 , SO 2 N(R 13 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is optionally substituted with one or more independently selected R 14 , OR 14 , SR 14 , S(O)R 14 , SO 2 R 14 C(O)R 14 , CO(O)R 14 , OC(O)R 14 , OC(O)OR 14 , NH 2 , NHR 14 , N(R 14 ) 2 , NHC(O)R 14 , NR 14 C(O)R 14 , NHS(O) 2 R 14 , NR 14 S(O) 2 R 14 , NHC(O)OR 14 , NR 14 C(O)OR 14 , NHC(O)NH 2 , NHC(O)NHR 14 , NHC(O)N(R 14 ) 2 , NR 14 C(O)NHR 14 , NR 14 C(O)N(R 14 ) 2 , C(O)NH 2 , C(O)NHR 14 , C(O)N(R 14 ) 2 , C(O)NHOH, C(O)NHOR 14 , C(O)NHSO 2 R 14 , C(O)NR 14 SO 2 R 14 , SO 2 NH 2 , SO 2 NHR 14 , SO 2 N(R 14 ) 2 , C(O)H, C(O)OH, OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I; wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more independently selected R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , C(O)R 15 , CO(O)R 15 , OC(O)R 15 , OC(O)OR 15 , NH 2 , NHR 15 , N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHS(O) 2 R 15 , NR 15 S(O) 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , NHC(O)NH 2 , NHC(O)NHR 15 , NHC(O)N(R 15 ) 2 , NR 15 C(O)NHR 15 , NR 15 C(O)N(R 15 ) 2 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , C(O)NHOH, C(O)NHOR 15 , C(O)NHSO 2 R 15 , C(O)NR 15 SO 2 R 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 15 is alkyl.

3 . A compound having Formula (IV), or pharmaceutically acceptable salts thereof

wherein

X 1 and X 2 and X 3 are CH; or

X 1 and X 3 are CH; and X 2 is N; or

X 2 and X 3 are H; and X 1 is N; or

X 1 is CR 1 ; and X 2 and X 3 are CH; or

X 2 is CR 1 ; and X 1 and X 3 are CH; or

X 3 is CR 1 ; and X 1 and X 2 are CH;

R 10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

wherein the cyclic moieties represented by R 3 , R 5 , R 6 , R 9 , and R 10 , are optionally substituted with one or more independently selected R 13 , OR 13 , SR 13 , S(O)R 13 , SO 2 R 13 , C(O)R 13 , CO(O)R 13 , OC(O)R 13 , OC(O)OR 13 , NH 2 , NHR 13 , N(R 13 ) 2 , NHC(O)R 13 , NR 13 C(O)R 13 , NHS(O) 2 R 13 , NR 13 S(O) 2 R 13 , NHC(O)OR 13 , NR 13 C(O)OR 13 , NHC(O)NH 2 , NHC(O)NHR 13 , NHC(O)N(R 13 ) 2 , NR 13 C(O)NHR 13 , NR 13 C(O)N(R 13 ) 2 , C(O)NH 2 , C(O)NHR 13 , C(O)N(R 13 ) 2 , C(O)NHOH, C(O)NHOR 13 , C(O)NHSO 2 R 13 , C(O)NR 13 SO 2 R 13 , SO 2 NH 2 , SO 2 NHR 13 , SO 2 N(R 13 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 15 is alkyl.

4 . A compound having Formula (VI), or pharmaceutically acceptable salts thereof

wherein

indicates a single or a double bond;

X 1 and X 2 and X 3 are CH; or

X 1 and X 3 are CH; and X 2 is N; or

X 2 and X 3 are H; and X 1 is N; or

X 1 is CR 1 ; and X 2 and X 3 are CH; or

X 2 is CR 1 ; and X 1 and X 3 are CH; or

X 3 is CR 1 ; and X 1 and X 2 are CH;

R 10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R y is R 13 , OR 13 , SR 13 , S(O)R 13 , SO 2 R 13 , C(O)R 13 , CO(O)R 13 , OC(O)R 13 , OC(O)OR 13 , NH 2 , NHR 13 , N(R 13 ) 2 , NHC(O)R 13 , NR 13 C(O)R 13 , NHS(O) 2 R 13 , NR 13 S(O) 2 R 13 , NHC(O)OR 13 , NR 13 C(O)OR 13 , NHC(O)NH 2 , NHC(O)NHR 13 , NHC(O)N(R 13 ) 2 , NR 13 C(O)NHR 13 , NR 13 C(O)N(R 13 ) 2 , C(O)NH 2 , C(O)NHR 13 , C(O)N(R 13 ) 2 , C(O)NHOH, C(O)NHOR 13 , C(O)NHSO 2 R 13 , C(O)NR 13 SO 2 R 13 , SO 2 NH 2 , SO 2 NHR 13 , SO 2 N(R 13 ) 2 , C(O)H, C(O)OH, OH, CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;

R 15 is alkyl.

5 . The compound of any one of claims 1 - 4 , or pharmaceutically acceptable salts thereof; wherein

X 1 , X 2 , and X 3 are CH; or

X 1 is CR 1 and X 2 and X 3 are CH; or

X 2 is CR 1 and X 1 and X 3 are CH.

6 . The compound of any one of claims 1 - 4 , or pharmaceutically acceptable salts thereof; wherein

X 1 and X 3 are CH; and X 2 is N; or

X 2 and X 3 are CH; and X 1 is N.

7 . The compound of claim 4 , or pharmaceutically acceptable salts thereof; wherein

is a double bond.

8 . A compound selected from the group consisting of

N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide;

N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide;

6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide;

6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide;

N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide;

N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide;

N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

tert-butyl 4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate;

N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-hexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide;

ethyl 6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate;

N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide and N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide and N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide and N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxamide;

and pharmaceutically acceptable salts thereof.

9 . The compound of claim 2 selected from the group consisting of