Pyrroloquinoxalinone inhibitors of poly(ADP-ribose)polymerase

1. A compound having formula I

or a pharmarceutically acceptable salt thereof, wherein

X is a bond;

A 1 and A 2 , together with the atoms to which they are attached, are pyrrole;

A 3 and A 4 , together with the atoms to which they are attached, are benzene which is substituted with S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)NH 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NR 11 C(O)R 11 , NHSO 2 R 11 , NR 11 SO 2 R 11 , NHC(O)OR 1 , NR 1 C(O)OR 1 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , C(O)OH, or alkyl, wherein the alkyl is substituted with one or two independently selected R 6 , C(O)OH, NH 2 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , NHC(O)R 6 , or NR 6 C(O)R 6 ;

R 1 is R 2 , R 3 , R 4 or R 5 ;

R 2 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 3 is heteroarene which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 6 , C(O)OH, NH 2 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , NHC(O)R 6 , or NR 6 C(O)R 6 ;

R 6 is R 7 , R 8 , R 9 or R 10 ;

R 7 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 8 is heteroarene which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 10 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 11 , C(O)OH, NH 2 , 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 , F, Cl, Br or I;

R 11 is R 12 , R 13 , or R 14 ;

R 12 is phenyl which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 13 is heteroarene which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

R 14 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene, cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;

wherein the moieties represented by A 1 and A 2 and A 2 and A 3 and the moieties represented by R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 12 , R 13 and R 14 are independently unsubstituted or substituted with R 15 , OR 15 , SR 15 , S(O)R 15 , SO 2 R 15 , NH 2 , NHR 15 , N(R 15 ) 2 , C(O)R 15 , C(O)NH 2 , C(O)NHR 15 , C(O)N(R 15 ) 2 , NHC(O)R 15 , NR 15 C(O)R 15 , NHSO 2 R 15 , NR 15 SO 2 R 15 , NHC(O)OR 15 , NR 15 C(O)OR 15 , SO 2 NH 2 , SO 2 NHR 15 , SO 2 N(R 15 ) 2 , NHC(O)NH 2 , NHC(O)NHR 15 , NHC(O)N(R 15 ) 2 , NR 15 C(O)N(R 15 ) 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;

wherein R 15 is R 16 , R 17 , R 18 or R 19 ;

R 16 is phenyl which is unfused or fused with benzene;

R 17 is heteroaryl which is unfused or fused with benzene;

R 18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene;

R 19 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 20 , C(O)OH, NH 2 , NHR 20 , N(R 20 ) 2 , C(O)R 20 , C(O)NH 2 , C(O)NHR 20 , C(O)N(R 20 ) 2 , NHC(O)R 20 , NR 20 C(O)R 20 , F, Cl, Br or I;

R 20 is R 21 or R 21A ;

R 21 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

R 21A is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two of independently selected R 22 , C(O)OH, NH 2 , NHR 22 , N(R 22 ) 2 , C(O)R 22 , C(O)NH 2 , C(O)NHR 22 , C(O)N(R 22 ) 2 , NHC(O)R 22 , NR 22 C(O)R 22 , F, Cl, Br or I; and

R 22 is phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl.

2. The compound of claim 1 wherein

A 3 and A 4 , together with the atoms to which they are attached, are benzene which is substituted with C(O)R 1 , C(O)NHR 1 , C(O)N(R 1 ) 2 , or alkyl which is substituted with one or two of independently selected R 6 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , or NR 6 C(O)R 6 ;

R 1 is R 2 , R 3 , R 4 or R 5 ;

R 2 is phenyl;

R 3 is heteroarene;

R 4 is cycloalkyl or heterocycloalkyl;

R 5 is alkyl which is unsubstituted or substituted with one or two of independently selected R 6 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , or NR 6 C(O)R 6 ;

R 6 is R 7 , R 8 , R 9 or R 10 ;

R 7 is phenyl;

R 8 is heteroarene;

R 9 is cycloalkyl or heterocycloalkyl;

R 10 is alkyl which is unsubstituted or substituted with one or two of independently selected R 11 , C(O)OH, N(R 11 ) 2 , or C(O)R 11 ;

R 11 is R 12 or R 14 ;

R 12 is phenyl;

R 14 is cycloalkyl or heterocycloalkyl;

wherein the moieties represented by R 2 , R 4 , and R 9 are independently unsubstituted or substituted with R 15 , SO 2 R 15 , NH 2 , N(R 15 ) 2 , or (O);

R 15 is R 18 or R 19 ;

R 18 is heterocycloalkyl; and

R 19 is alkyl.

3. The compound of claim 1 wherein

A 3 and A 4 , together with the atoms to which they are attached, are benzene which is substituted with R 1A and R 1B as described in Formula IV

one of R 1A and R 1B is H, and the other is selected from with S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)NH 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NR 11 C(O)R 11 , NHSO 2 R 11 NR 11 SO 2 R 11 , NHC(O)OR 1 , NR 1 C(O)OR 1 , SO 2 NH 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHC(O)NH 2 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , C(O)OH, or alkyl, wherein the alkyl is substituted with one or two independently selected R 6 , C(O)OH, NH 2 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , NHC(O)R 6 , or NR 6 C(O)R 6 .

4. The compound of claim 3 wherein one of R 1A and R 1B is H, and the other is C(O)R 1 , NHC(O)R 1 , or NR 11 C(O)R 11 .

5. The compound of claim 3 wherein one of R 1A and R 1B is H, and the other is alkyl which is substituted with one or two of independently selected R 6 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , or NR 6 C(O)R 6 .

6. The compound of claim 5 wherein

one of R 1A and R 1B is H, and the other is alkyl which is substituted with NHR 6 or N(R 6 ) 2 ;

R 6 is R 9 or R 10 ;

R 9 is cycloalkyl or heterocycloalkyl;

R 10 is alkyl which is unsubstituted or substituted with one or two of independently selected R 11 , C(O)OH, N(R 11 ) 2 , or C(O)R 11 ;

R 11 is R 12 R 14 ;

R 12 is phenyl;

R 14 is cycloalkyl or heterocycloalkyl;

wherein the moiety represented by R 9 is independently unsubstituted or substituted with R 15 , SO 2 R 15 , NH 2 , N(R 15 ) 2 , or (O);

R 15 is R 18 or R 19 ;

R 18 is heterocycloalkyl; and

R 19 is alkyl.

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. The compound of claim 1 , selected from the group consisting of:

7-[(cyclohexylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-{[(cyclohexylmethyl)amino]methyl}pyrrolo [1,2-a]quinoxalin-4(5H)-one;

7-[(cyclobutylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-[(cyclopentylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-[(cyclopropylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-(piperidin-1-ylmethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-(pyrrolidin-1-ylmethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-[(cyclohexylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-[(cyclohexylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-[(isopropylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

7-[(benzylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-[(isopropylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-{[(2-phenylethyl)amino]methyl}pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-(pyrrolidin-1-ylmethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-[(cyclobutylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-(morpholin-4-ylmethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-[(cyclopentylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one;

8-(piperidin-1-ylmethyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one; and

8-[(benzylamino)methyl]pyrrolo[1,2-a]quinoxalin-4(5H)-one.