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 - 15 . (canceled) 
     
     
         16 : The compound of  claim 1 , 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 - 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 - 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 - 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 - 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 - 100 . (canceled) 
     
     
         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 - 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 . (canceled) 
     
     
         120 : A method for the treatment of cancer comprising administering to the individual an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         121 - 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)