Phthalazine derivatives as parp inhibitors

Abstract

The present invention provides compounds of formula (I), their use as PARP inhibitors as well as pharmaceutical compositions comprising said compounds of formula (I) wherein R 1 , R 2 , L 1 , L 2 , X, Y, Q and Z have defined meanings.

1 .- 12 . (canceled) 
     
     
         13 . A method of treating an animal having a PARP mediated disorder, comprising administering to such animal a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         the dotted line represents an optional bond; 
         n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; 
         Q is —C(═O)— or —CR 3 — wherein R 3  is halo or C 1-6 alkyl; and
 when Q is —CR 3 — the dotted line represents a bond; 
 
         each X is independently —N< or —CH<; and when X is —CH< then Y is —N<, or —NH—; 
         each Y is independently —N<, —NH—, —CH< or —CH 2 —; 
         except when X is —CH< then Y is —N<, or —NH—; 
         L 1  is a direct bond or a bivalent radical selected from -C 1-6 alkanediyl-NH—, —NH— or —NH-C 1-6 alkanediyl-NH—; 
         L 2  is a direct bond or a bivalent radical selected from -C 1-6 alkanediyl-, -C 2-6 alkenediyl-, carbonyl or -C 1-6 alkanediyl-substituted with one substituent selected from hydroxy or aryl; 
         R 1  is hydrogen, nitro, halo or amino; 
         R 2  is hydrogen, C 1-6 alkyl or arylC 1-6 alkyl; 
         the central 
       
       
         
           
           
               
               
           
         
       
       moiety may also be bridged (i.e. forming a bicyclic moiety) with an ethylene bridge;
 Z is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, aryloxy, amino, cyano, arylC 1-6  alkylamino or benzthiazolyl(C 1-6  alkyl)amino or 
 a ring system selected from 
 
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are each independently selected from hydrogen, halo, C 1-6 alkyl, C 1-6 alkyloxy or trihalomethyl; and 
         aryl is phenyl, or phenyl substituted with one or two substituents each independently selected from halo, C 1-6 alkyl or C 1-6 alkyloxy. 
       
     
     
         14 . The method of  claim 13 , wherein the treatment involves chemosensitization. 
     
     
         15 . The method of  claim 13 , wherein the treatment involves radiosensitization.