Pyrazoloquinolones are potent parp inhibitors

A compound of Formula (I)

• or a therapeutically acceptable salt thereof, wherein
• R1 and R2 together with the atoms to which they are attached form a 5, 6, 7, or 8 membered heterocycle, the heterocycle may be unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6 alkyl, alkynyl, aryl, arylalkoxycarbonyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, and (NRARB)sulfonyl;
• R3 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-C6 alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, heterocyclesulfonyl, heteroaryl, heteroarylalkyl, hydrogen, hydroxy, hydroxyalkyl, nitro, NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, and (NRARB)sulfonyl;
• X is NR4;
• R4 is selected from the group consisting of C1-C6 alkyl, alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, hydrogen, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, -alkyl-O—C(O)—(NRARB), formylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, alkoxyalkyl, and haloalkyl;
• and
• RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl, aryl, arylalkyl, arylalkylcarbonyl, arylalkoxy, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle;
• if R3 is Cl-alkyl and R4 is Cl-alkyl and the ring formed by R1 and R2 is heterocycle then the heterocycle may not be substituted with methyl;
• wherein the aryl, cycloalkyl, heterocycle and heterocyclealkyl represented by R3 and R4 either themselves or as part of another moiety, are independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, —NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, (NRARB)sulfonyl, alkylsulfonyl, heterocycle, heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the substituent moieties are themselves further unsubstituted.

The compound of Formula (I) of claim 1

• or a therapeutically acceptable salt thereof, wherein
• R1 and R2 together with the atoms to which they are attached form a 5, 6, or 7 membered heterocycle, the heterocycle may be unsubstituted or substituted with a substituent independently selected from the group consisting of heterocycle and NRARB;
• R3 is selected from the group consisting of C1-C6 alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, hydrogen, and (NRARB)alkyl;
• X is NR4;
• R4 is selected from the group consisting of C1-C6 alkyl, -alkyl-O—C(O)—(NRARB), alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl, hydrogen, haloalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, formylalkyl, and (NRARB)alkyl;
• RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle;
• if R3 is Cl-alkyl and R4 is Cl-alkyl and the ring formed by R1 and R2 is heterocycle then the heterocycle may not be substituted with methyl;
• and
• wherein the aryl, cycloalkyl, heterocycle and heterocyclealkyl represented by R3 and R4 either themselves or as part of another moiety, are independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, C1-C6-alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, —NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)carbonylalkyl, (NRARB)sulfonyl, alkylsulfonyl, heterocycle, heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the substituent moieties are themselves further unsubstituted.

A compound according to claim 1 selected from the group consisting of

• 1-cyclopropyl-3-methyl-4,6,8,9-tetrahydro-3H-7-oxa-2,3,4-triaza-cyclopenta[a]naphthalen-5-one;
• 1-cyclopropyl-3-methyl-3,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-c]-2,7-naphthyridin-5-one;
• and
• 7,9-dimethyl-1,2,3,4,6,7-hexahydro-5H-pyrazolo[3,4-h]-1,6-naphthyridin-5-one;
• or a pharmaceutically acceptable salt thereof.