Potent PARP Inhibitors

Abstract

The present invention relates to 1H-benzimidazole-4-carboxamides of formula (I), their preparation, and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase for the preparation of drugs.

1 . A compound of Formula (I)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein 
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;  
 X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ; wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;  
 G 1  is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and oxo;  
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C  or R D  are aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroalyl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R C  or R D  may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, and arylalkoxycarbonyl;  
 R A  and R B  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl; and  
 n is 1.  
 
   
   
       2 . A compound of Formula (I)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein 
 R 1 , R 2 , R 3  and R 4  are hydrogen;  
 X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, (NR C R D )carbonyl, or (NR C R D )alkyl; wherein if X is aryl, arylalkyl, heteroaryl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, or cycloalkyl, then X may be unsubstituted or substituted with 1 or 2 substituents, Z, independently selected from the group consisting of alkyl, nitro, —CN, halogen, alkoxy, alkoxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, carboxy, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;  
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C  or R D  are arylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R C  or R D  may be unsubstituted or substituted with one substituent selected from the group consisting of alkoxy, alkylcarbonyl and arylalkoxycarbonyl;  
 R A  and R B  are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; and  
 n is 1.  
 
   
   
       3 . A compound of Formula (II)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein 
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;  
 X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ;  
 wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;  
 G 1  is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and oxo;  
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl;  
 wherein if R C  or R D  are aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R C  or R D  may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, and arylalkoxycarbonyl; and  
 R A  and R B  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl.  
 
   
   
       4 . A compound of Formula (III)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein 
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR A R B , and (NR A R B )carbonyl;  
 X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR C R D , (NR C R D )carbonyl, (NR C R D )alkyl, (NR C R D )carbonylalkyl, or -alkyl-CO 2 G 1 ; wherein if X is aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;  
 G 1  is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle, and the heterocycle moiety of heterocyclealkyl are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and oxo;  
 R C  and R D  are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR A R B )alkyl, and (NR A R B )alkylcarbonyl; wherein if R C  or R D  are aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R C  or R D  may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, and arylalkoxycarbonyl; and  
 R A  and R B  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl.  
 
   
   
       5 . A compound according to  claim 3  wherein X is aryl or arylalkyl wherein the aryl or arylalkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, and (NR C R D )carbonylalkyl; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.  
   
   
       6 . A compound according to  claim 3  wherein X is heteroaryl which may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (R C R D )carbonyl, and (NR C R D )carbonylalkyl; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.  
   
   
       7 . A compound according to  claim 3  wherein X is heterocycle or heterocyclealkyl wherein the heterocycle or heterocyclealkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.  
   
   
       8 . A compound according to  claim 4  wherein X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, (NR C R D )carbonyl, (NR C R D )alkyl, or aryl wherein if X is heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or aryl, then X may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z, independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR C R D , (NR C R D )alkyl, (NR C R D )carbonyl, (NR C R D )carbonylalkyl, and oxo; wherein the aryl and the heteroaryl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Z are independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl.  
   
   
       9 . A compound according to  claim 1  wherein R 1 , R 2 , R 3  and R 4  are hydrogen.  
   
   
       10 . A compound selected from the group consisting of 3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one; 
 3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(3-aminophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;    N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethyl}-acetamide;    N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide;    benzyl 4-({acetyl [3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)piperidine-1-carboxylate;    2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    methyl 4-(5-oxo-4, 5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate;    2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-1-ylpropionamide;    2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    benzyl 3-(5-oxo-4, 5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxylate;    2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-ethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    (S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)pentanamide;    (R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2-phenylacetamide;    N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide;    N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1-yl-propionamide;    N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pyrrolidin-1-yl-propionamide;    2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)acetamide;    3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-propionamide;    2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;    2-(3-bromobenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile;    2-[3-(aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;    2-(3-pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    2-[3-(2-oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;    3′-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1′-biphenyl-2-carbaldehyde;    2-[3-(2-fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;    methyl 3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate;    3-[(4-methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;    3-(pyrrolidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    N,N-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    3-(piperidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    N-cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    N-ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    N-benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    5-oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    3-(azepan-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    3-(morpholin-4-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    3-(piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    N-cyclohexyl-5-oxo-4, 5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    3-(1H-imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-S (4H)-one;    5-oxo-N-(piperidin-4-ylmethyl)-4, 5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    3-{[3-(aminomethyl)piperidin-1-yl]carbonyl}pyrazolo[1,5-a]quinazolin-5(4H)-one;    5-oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}butanoic acid;    3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoic acid;    5-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;    3-(hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one;    3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzamide;    3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine;    4-chloro-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]butanamide;    4-oxo-4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}butanoic acid;    1-acetyl-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]piperidine-4-carboxamide;    2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}ethyl acetate;    3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;    1-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]pyrrolidine-2,5-dione; and    N-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide; or a pharmaceutically acceptable salt thereof.    
   
   
       11 . A method of treating inflammation in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       12 . A method of treating sepsis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       13 . A method of treating septic shock in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       14 . A method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       15 . A pharmaceutical composition comprising a compound of Formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.