Tricyclic inhibitors of poly(adp-ribose)polymerase

Abstract

The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-1(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP-ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein
 each R A  and R B  is independently halo, substituted or unsubstituted C 1 -C 6  alkyl or R A  and R B  are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted 5, 6 or 7-membered ring containing 0, 1 or 2 heteroatoms selected from S, O and N; 
 each R 1  and R 2  is independently hydrogen, halo, hydroxy, substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 Z is a 5 or 6-membered aryl or heteroaryl substituted with R C  and R P ; 
 R C  is hydrogen, halo, —CF 3 , substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 R P  is a moiety of the formula (Ia) or (Ib): 
 
       
       
         
           
           
               
               
           
         
         
           each X is independently O, S or absent; 
           R D  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —SO 2 R 3 , —C(O)R 4 , —C(═N—CN)NR 8 R 9  or —C(O)NR 5 R 6 ; 
           R 3  is a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
           R 4  is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocyclyl; 
           each R 5  and R 6  is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
           each R 8  and R 9  is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, or R 8  and R 9  are taken together with the nitrogen to which they are attached to form a heterocyclyl; 
           R E  is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or —OR 7 ; and 
           R 7  is a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein each R 1  and R 2  is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         3 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein R A  and R B  are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted 5, 6 or 7-membered ring containing 0, 1 or 2 heteroatoms selected from S, O and N; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         12 . The compound of  claim 11 , wherein R A  and R B  are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted 5, 6 or 7-membered carbocycle; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . The compound of  claim 11 , wherein the compound is of the formula (II): 
       
         
           
           
               
               
           
         
         wherein
 R F  is hydrogen, halo, —CF 3 , substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         17 . The compound of  claim 16 , wherein R F  is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The compound of  claim 17 , wherein each R 1  and R 2  is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         21 . The compound of  claim 20 , wherein one or both of R 1  and R 2  is deuterium; or a pharmaceutically acceptable salt or solvate thereof 
     
     
         22 . The compound of  claim 17 , wherein one of R 1  and R 2  is hydrogen and the other one of R 1  and R 2  is hydroxy; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         23 . The compound of  claim 1 , wherein Z is a 5 or 6-membered heteroaryl substituted with R C  and R P ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         24 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , wherein the compound is of the formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         31 . The compound of  claim 30 , wherein R F  is hydrogen or fluoro; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The compound of  claim 30 , wherein each R 1  and R 2  is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         35 - 37 . (canceled) 
     
     
         38 . The compound of  claim 1 , wherein R C  is fluoro; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         39 - 44 . (canceled) 
     
     
         45 . The compound of  claim 1 , wherein the compound is of the formula (IIIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         46 . (canceled) 
     
     
         47 . The compound of  claim 45 , wherein R D  is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         48 . The compound of  claim 47 , wherein R D  is substituted or unsubstituted C 1 -C 6  alkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         49 . (canceled) 
     
     
         50 . The compound of  claim 47 , wherein R D  is a substituted or unsubstituted C 3 -C 8  cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         51 . The compound of  claim 47 , wherein R D  is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, isopentyl, trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl and cyclopentyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         52 . The compound of  claim 45 , wherein R D  is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —C(O)NR 5 R 6 , —C(═N—CN)NR 8 R 9 , or —SO 2 R 3 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         53 . The compound of  claim 52 , wherein R D  is substituted or unsubstituted phenyl; a substituted or unsubstituted heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, quinazolinyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl, thiazolyl, and thiadiazolyl; —C(O)NR 5 R 6  wherein R 5  and R 6  is independently hydrogen or an unsubstituted alkyl; —C(═N—CN)NR 8 R 9  wherein R 8  and R 9  are taken together with the nitrogen to which they are attached to form a heterocyclyl; or —SO 2 R 3  wherein R 3  is cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         54 - 68 . (canceled) 
     
     
         69 . The compound of  claim 45 , wherein R D  is —C(O)R 4 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         70 . (canceled) 
     
     
         71 . The compound of  claim 69 , wherein R 4  is an unsubstituted C 1 -C 6  alkyl or unsubstituted C 3 -C 8  cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         72 . (canceled) 
     
     
         73 . The compound of  claim 69 , wherein R 4  is a substituted or unsubstituted heterocyclyl selected from pyrrolidinyl and tetrahydrofuranyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         74 - 76 . (canceled) 
     
     
         77 . The compound of  claim 1 , wherein the compound is of the formula (IIIb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         78 . (canceled) 
     
     
         79 . The compound of  claim 77 , wherein R E  is substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         80 . (canceled) 
     
     
         81 . The compound of  claim 77 , wherein R E  is substituted or unsubstituted aryl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         82 . The compound of  claim 77 , wherein R E  is —OR 7 ; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         83 . The compound of  claim 82 , wherein R 7  is a substituted or unsubstituted C 1 -C 6  alkyl or substituted or unsubstituted C 3 -C 8  cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         84 . (canceled) 
     
     
         85 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 4-(3-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(cyclopentanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(cyclopropanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(cyclobutanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(3,3-dimethylbutanoyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(tetrahydrofuran-2-carbonyl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N,N-dimethyl-1,4-azaphosphinane-1-carboxamide 4-oxide;   4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   N-(azetidin-1-yl(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)methylene)cyanamide;   4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-(6-chloropyridazin-3-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)nicotinonitrile;   4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)benzonitrile;   2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)nicotinonitrile;   4-(3-(1-(2-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-(4-chloropyrimidin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(quinazolin-4-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-(6-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-(3-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(5-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-(6-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(4-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(3-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-(3,5-difluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-(5-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(quinazolin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(6-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(thiazol-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(thiadiazol-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(3-(acetyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   (±)-4-(4-fluoro-3-(4-oxido-1-(3-(1-hydoxyethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(5-(fluoro)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(5-(chloro)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(5-(n-propyl)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(3-(1-cyclobutyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-methyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-isopropyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-(cyclopropylmethyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-isobutyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-45propyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(4-fluoro-3-(1-isopentyl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;   4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;   4-[[4-fluoro-3-(4-methyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;   4-[[4-fluoro-3-(4-ethyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;   4-[[4-fluoro-3-(4-isopropyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;   4-[[4-fluoro-3-(4-ethoxyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;   4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)-7-fluorophthalazin-1(2H)-one;   4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorophenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one;   4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)-7-fluorophthalazin-1(2H)-one;   4-[(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one;   (±)-4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1-phenyl)(hydroxymethl)]phthalazin-1(2H)-one; and   (±)-4-{[4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)](hydroxymethyl)]-7-fluorophthalazin-1(2H)-one;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         86 . A compound of the formula (IV): 
       
         
           
           
               
               
           
         
         wherein
 R C  is hydrogen, halo, —CF 3 , substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 R P  is a moiety of the formula (Ia) or (Ib): 
 
       
       
         
           
           
               
               
           
         
         
           X is O; 
           R D  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —SO 2 R 3 , —C(O)R 4 , —C(═N—CN)NR 8 R 9  or —C(O)NR 5 R 6 ; 
           R 3  is a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
           R 4  is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heterocyclyl; 
           each R 5  and R 6  is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
           each R 8  and R 9  is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl, or R 8  and R 9  are taken together with the nitrogen to which they are attached to form a heterocyclyl; 
           R E  is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or —OR 7 ; and 
           R 7  is a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; 
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         87 . The compound of  claim 86 , wherein the compound is of the formula (IVa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         88 . The compound of  claim 87 , wherein R C  is fluoro; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         89 - 99 . (canceled) 
     
     
         100 . The compound of  claim 87 , wherein R D  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         101 . The compound of  claim 86 , wherein the compound is of the formula (IVb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         102 - 105 . (canceled) 
     
     
         106 . A compound of the formula (V): 
       
         
           
           
               
               
           
         
         wherein
 each R 1  and R 2  is independently hydrogen, halo, hydroxy, substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 R D  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; and 
 R F  is hydrogen, halo, —CF 3 , substituted or unsubstituted C 1 -C 3  alkyl or substituted or unsubstituted C 1 -C 3  alkoxy; 
 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         107 - 108 . (canceled) 
     
     
         109 . The compound of  claim 106 , wherein R F  is fluoro, each R 1  and R 2  is hydrogen, and R D  is cyclopropyl or 2-pyrimidinyl; or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         110 - 115 . (canceled) 
     
     
         116 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         117 . (canceled) 
     
     
         118 . A method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         119 . The method of  claim 118 , wherein the condition which can be ameliorated by inhibition of PARP is a condition selected from the group consisting of cancer, inflammatory diseases, and ischemic conditions. 
     
     
         120 . (canceled) 
     
     
         121 . The method of  claim 118 , wherein the condition which can be ameliorated by inhibition of PARP is a breast cancer, an ovarian cancer or a brain cancer. 
     
     
         122 - 128 . (canceled) 
     
     
         129 . A kit for the treatment or prevention in an individual of a condition mediated by PARP enzymatic activity, comprising:
 (a) a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof; and   (b) packaging.   
     
     
         130 - 132 . (canceled)