Tricyclic inhibitors of poly(ADP-ribose) polymerases

A compound of the formula:

• wherein:
• Y is N or CR3, where R3 is:
• H;
• halogen;
• cyano;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or
• —C(W)—R20, where W is O or S, and R20 is:
• H;
• OH;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group;
• or NR27R28, where R27 and R28 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• —CR═N—R30, where R29 is H or an optionally substituted amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl O-alkyl, o-aryl, s-alkyl, or s-aryl group, and R30 is H, OH, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group, or NR31R32, where R31 and R32 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• R11 is an aryl or heteroaryl group unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, alkyl, aryl, heteroaryl, alkoxy, aryloxy, and heteroaryloxy groups, wherein said alkyl, aryl, heteroaryl, alkoxy, aryloxy, and heteroaryloxy groups are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, lower alkoxy, cyano, nitro, and amino;
• R14 is H or halogen;
• and
• R15 is H, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• wherein said substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, O-aryl, amino, S-alkyl, and S-aryl groups are substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo, acyl, sulfonyl, mercapto, nitro, cyano, amino, alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylthio, cycloalkyl, heterocycloalkyl, carboxy, carbamoyl, arylthio, and heteroarylthio groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, ethers, trifluoromethyl, alkylcarboyl, alkyl, aryl, and amino;
• and
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising:

• (a) an effective amount of a PARP-inhibiting agent selected from a compound of the formula:
• wherein:
• X is O or S;
• Y is N or CR3, where R3 is:
• H;
• halogen;
• cyano;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or
• —C(W)—R20, where W is O or S, and R20 is:
• H;
• OH;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group;
• or NR27R28, where R27 and R28 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• —CR29═N—R30, where R29 is H or an optionally substituted amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl O-alkyl, o-aryl, s-alkyl, or s-aryl group, and R30 is H, OH, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group, or NR31R32, where R31 and R32 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• R1 is cyano;
• a substituted alkyl or an optionally substituted alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• C(O)R12, where R12 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or OR19 or NR21R22, where R19, R21 and R22 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• OR13, where R13 is H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• S(O)nR16, where n is 0, 1 or 2, and R16 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or NR23R24, where R23 and R24 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or
• NR17R18, where R17 and R18 are each independently:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• C(O)R201, where R201 is H, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group, or NR27R28, where R27 and R28 are each independently H, OH, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group or S(O)2NR25N26, where R25 and R26 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• R2 is H or alkyl;
• R4 is H or alkyl;
• R5, R6, R7, and R8 are each independently selected from:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• and
• —C(O)—R50, where R50 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or OR51 or NR52R53, where R51, R52 and R53 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• wherein said substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, O-aryl, amino, S-alkyl, and S-aryl groups are substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo, acyl, sulfonyl, mercapto, nitro, cyano, amino, alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylthio, cycloalkyl, heterocycloalkyl, carboxy, carbamoyl, arylthio, and heteroarylthio groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, ethers, trifluoromethyl, alkylcarboyl, alkyl, aryl, and amino;
• and
• where when Y is CR3, R1, R2, R3, R4, R5, R6, R7, and R8 are not all H;
• or a pharmaceutically acceptable salt thereof;
• and
• (b) a pharmaceutically acceptable carrier for said PARP-inhibiting agent.

A compound of the formula:

• wherein:
• X is O or S;
• Y is N or CR3, where R3 is:
• H;
• halogen;
• cyano;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or
• —C(W)—R20, where W is O or S, and R20 is:
• H;
• OH;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group;
• or NR27R28, where R27 and R28 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• —CR29═N—R30, where R29 is H or an optionally substituted amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl O-alkyl, o-aryl, s-alkyl, or s-aryl group, and R30 is H, OH, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group, or NR31R32, where R31 and R32 are each independently H, OH, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• R1 is cyano;
• a substituted alkyl or an optionally substituted alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• C(O)R12, where R12 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or OR19 or NR21R22, where R19, R21 and R22 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• OR13, where R13 is H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• S(O)nR16, where n is 0, 1 or 2, and R16 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or NR23R24, where R23 and R24 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or
• NR17R18, where R17 and R18 are each independently:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• C(O)R201, where R201 is H, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, or O-aryl group, or NR27R28, where R27 and R28 are each independently H, OH, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl;
• or heteroaryl group or S(O)2NR25N26, where R25 and R26 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• R2 is H or alkyl;
• R4 is H or alkyl;
• R5, R6, R7, and R8 are each independently selected from:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• and
• —C(O)—R50, where R50 is:
• H;
• an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• or OR51 or NR52R53, where R51, R52 and R53 are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
• wherein said substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-alkyl, O-aryl, amino, S-alkyl, and S-aryl groups are substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo, acyl, sulfonyl, mercapto, nitro, cyano, amino, alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylthio, cycloalkyl, heterocycloalkyl, carboxy, carbamoyl, arylthio, and heteroarylthio groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, ethers, trifluoromethyl, alkylcarboyl, alkyl, aryl, and amino;
• and
• where when Y is CR3, R1, R2, R3, R4, R5, R6, R7, and R8 are not all H;
• or a pharmaceutically acceptable salt thereof.