Pyrazoloquinolones are potent parp inhibitors

Abstract

Compounds of Formula (I) inhibit the PARP enzyme and are useful for treating a disease or a disorder associated with PARP. Also disclosed are pharmaceutical compositions comprising compounds of Formula (I), methods of treatment comprising compounds of Formula (I), and methods of inhibiting the PARP enzyme comprising compounds of Formula (I).

1 .- 19 . (canceled) 
     
     
         20 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 R 1  and R 2  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, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl; 
 R 3  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, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl; 
 X is NR 4 ; 
 R 4  is selected from the group consisting of C1-C6 alkyl, alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, hydrogen, (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, -alkyl-O—C(O)—(NR A R B ), formylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, alkoxyalkyl, and haloalkyl; and 
 R A  and R B  are independently selected from the group consisting of hydrogen, C1-C6 alkyl, aryl, arylalkyl, arylalkylcarbonyl, arylalkoxy, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle; 
 if R 3  is Cl-alkyl and R 4  is Cl-alkyl and the ring formed by R 1  and R 2  is heterocycle then the heterocycle may not be substituted with methyl; 
 wherein the aryl, cycloalkyl, heterocycle and heterocyclealkyl represented by R 3  and R 4  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, —NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, (NR A R B )sulfonyl, alkylsulfonyl, heterocycle, heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the substituent moieties are themselves further unsubstituted. 
 
     
     
         21 . The compound of Formula (I) of claim  1   
       
         
           
           
               
               
           
         
       
       or a therapeutically acceptable salt thereof, wherein
 R 1  and R 2  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 NR A R B ; 
 R 3  is selected from the group consisting of C1-C6 alkyl, aryl, cycloalkyl, heterocycle, heteroaryl, hydrogen, and (NR A R B )alkyl; 
 X is NR 4 ; 
 R 4  is selected from the group consisting of C1-C6 alkyl, -alkyl-O—C(O)—(NR A R B ), alkoxycarbonylalkyl, arylalkyl, carboxyalkyl, cyanoalkyl, hydrogen, haloalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, formylalkyl, and (NR A R B )alkyl; 
 R A  and R B  are independently selected from the group consisting of hydrogen, C1-C6 alkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, and heterocycle; 
 if R 3  is Cl-alkyl and R 4  is Cl-alkyl and the ring formed by R 1  and R 2  is heterocycle then the heterocycle may not be substituted with methyl; and 
 wherein the aryl, cycloalkyl, heterocycle and heterocyclealkyl represented by R 3  and R 4  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, —NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, (NR A R B )sulfonyl, alkylsulfonyl, heterocycle, heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein the substituent moieties are themselves further unsubstituted. 
 
     
     
         22 . A compound according to claim  1 , wherein R 1  and R 2  together with the atoms to which they are attached form a 5, 6, or 7 membered heterocycle, and the heterocycle is unsubstituted. 
     
     
         23 . A compound according to claim  1 , wherein
 R 4  is C1-C6 alkyl; and   R 3  is selected from the group consisting of C1-C6 alkyl, aryl, cycloalkyl, heterocycle, and heteroaryl.   
     
     
         24 . 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. 
 
     
     
         25 . A pharmaceutical composition comprising a compound of Formula (I) of claim  1  or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.