Imidazo[4,5-c]quinolines as dna-pk inhibitors

Abstract

The invention relates to compounds of the formulae (I) and (II) in which R1, R2, R3, R4, R5, R8, X and m have the meaning indicated in the claims, and/or physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. The compounds of the formula (I) can be used for the inhibition of serine/threonine protein kinases and for the sensitisation of cancer cells to anticancer agents and/or ionising radiation. The invention also relates to the use of the compounds of the formula (I) in the prophylaxis, therapy or progress control of cancer, tumours, metastases or angiogenesis disorders, in combination with radiotherapy and/or an anticancer agent. The invention furthermore relates to a process for the preparation of the compounds of the formula (I).

1 . Compounds of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R1 denotes Y or —(CY 2 ) n —Ar, 
         R2 denotes Y, —(CY 2 ) p —(C[YR6]) s —R7 or -alk-R7, 
         R3 denotes Y or CN, 
         R4 denotes Y, Hal, —(CY 2 ) p —COOY or —(CY 2 ) p —CO—NYY, 
         R5 denotes A, Hal, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 )—COOY, —(CY 2 ) p —CO—NYY or —(CY 2 ) p —NY—COY, 
         R6 denotes Y, Hal, —(CY 2 ) n —NYY, —(CY 2 ) n —NY—COO—(CY 2 )—SiA 3 , —(CY 2 ) n —COOY, —CO—NYY, —CO—NY—(CY 2 )—OY, —CO—NY—(CY 2 ) n —NYY or SO 2 A, 
         R7 denotes —(CY 2 ) p —Ar or —(CY 2 ) p -Het 1 , 
         X denotes CH 2 , O, S or a single bond, 
         Y denotes H or A, 
         A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced, independently of one another, by Hal, 
         Alk denotes alkenyl having 1, 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3 or 4 H atoms may be replaced, independently of one another, by Hal and/or OY, 
         Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY or —(CY 2 ) p —NY—COY, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY, —(CY 2 ) p —NY—COY or —SO 2 —Het 2 , 
         Het 2  denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted by A, 
         Hal denotes F, Cl, Br or I, 
         m denotes 0, 1, 2, 3 or 4, and 
         n, p, s, independently of one another, denote 0, 1, 2, 3, 4, 5 or 6, 
         in the form of pharmaceutically usable derivatives, hydrates, solvates or precursors thereof, including mixtures thereof in all ratios. 
       
     
     
         2 . The derivatives, hydrates, solvates or precursors of the compounds according to  claim 1  having the sub-formula (IA) 
       
         
           
           
               
               
           
         
         in which 
         R2 denotes Y or —(CY 2 ) p —C(YR6)-R7, 
         R5 denotes Y or Hal, 
         R6 denotes Y, —(CY 2 ) n —NYY, —CO—NYY or —CO—NY—(CY 2 ) n —OY, 
         R7 denotes Ar or Het 1 , 
         Y denotes H or A, 
         A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, where 1, 2 or 3 H atoms may be replaced, independently of one another, by Hal, 
         Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be unsubstituted or mono- or disubstituted by Hal, A, OY or —SO 2 —Het 2 , 
         Het 2  denotes a monocyclic saturated heterocycle having 3, 4 or 5 C atoms and 1 or 2 N and/or O atoms, 
         Hal denotes F, Cl, Br or I, and 
         n, p, independently of one another, denote 0, 1, 2 or 3, 
         and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         3 . The derivatives, hydrates, solvates or precursors of the compounds according to  claim 1  having the sub-formula (IB) 
       
         
           
           
               
               
           
         
         in which 
         R2 denotes R7, -alk-Ar or -alk-Het 1 , 
         R5 denotes Y or Hal, 
         R7 denotes —(CY 2 ) p —Ar or —(CY 2 ) p -Het 1 , 
         Y denotes H or A, 
         A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, where 1, 2 or 3 H atoms may be replaced, independently of one another, by Hal, 
         Alk denotes alkenyl having 1, 2 or 3 C atoms, where 1 or 2 H atoms may be replaced by Hal and/or OH, 
         Ar denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be unsubstituted or mono- or disubstituted by Hal, A, OY or —SO 2 —Het 2 , 
         Het 2  denotes a monocyclic saturated heterocycle having 3, 4 or 5 C atoms and 1 or 2 N and/or O atoms, 
         Hal denotes F, Cl, Br or I, and 
         p denotes 0, 1, 2 or 3, 
         and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         4 . The derivatives, hydrates, solvates or precursors of the compounds according to  claim 3  having the sub-formula (IB-1) 
       
         
           
           
               
               
           
         
         in which 
         R2 denotes R7, -alk-Ar or -alk-Het 1 , 
         R5 denotes Hal, 
         R7 denotes Ar or Het 1 , 
         A denotes unbranched or branched alkyl having 1, 2, 3 or 4 C atoms, where 1, 2 or 3 H atoms may be replaced, independently of one another, by Hal, 
         Alk denotes alkenyl having 1 or 2 C atoms, 
         Ar denotes phenyl which is unsubstituted or monosubstituted by Hal, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2 or 3 N and/or S atoms, which may be unsubstituted or mono- or disubstituted by Hal or A or, and 
         Hal denotes F, Cl, Br or I, 
         and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         5 . The derivatives, hydrates, solvates or precursors of the compounds according to  claim 1 , of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or mixtures thereof in all ratios. 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A method for the inhibition of serine/threonine protein kinases in vitro comprising introducing a compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         R1 denotes Y or —(CY 2 ) n —Ar 
         R2 denotes Y, —(CY 2 ) p —(C[YR6]) s -R7 or -alk-R7, 
         R3 denotes Y or CN, 
         R4 denotes Y, Hal, —(CY 2 ) p —COOY or —(CY 2 ) p —CO—NYY, 
         R5 denotes A, Hal, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY or —(CY 2 ) p —NY—COY, 
         R6 denotes Y, Hal, —(CY 2 ) n —NYY, —(CY 2 ) n —NY—COO—(CY 2 ) n —SiA 3 , —(CY 2 ) n —COOY, —CO—NYY, —CO—NY—(CY 2 ) n —OY, —CO—NY—(CY 2 ) n —NYY or SO 2 A, 
         R7 denotes —(CY 2 ) p —Ar or —(CY 2 ) p -Het 1 , 
         X denotes CH 2 , O, S or a single bond, 
         Y denotes H or A, 
         A denotes unbranched or branched alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, where 1, 2, 3, 4, 5, 6 or 7 H atoms may be replaced, independently of one another, by Hal, 
         Alk denotes alkenyl having 1, 2, 3, 4, 5 or 6 C atoms, where 1, 2, 3 or 4 H atoms may be replaced, independently of one another, by Hal and/or OY, 
         Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY or —(CY 2 ) p —NY—COY, 
         Het 1  denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, CN, —(CY 2 ) p —OY, —(CY 2 ) p —NYY, —(CY 2 ) p —COOY, —(CY 2 ) p —CO—NYY, —(CY 2 ) p —NY—COY or —SO 2 —Het 2 , 
         Het 2  denotes a monocyclic saturated heterocycle having 2, 3, 4, 5, 6 or 7 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted by A, 
         Hal denotes F, Cl, Br or I, 
         m denotes 0, 1, 2, 3 or 4, and 
         n, p, s, independently of one another, denote 0, 1, 2, 3, 4, 5 or 6, 
         and/or physiologically acceptable salts, tautomers and/or stereoisomers thereof, including mixtures thereof in all ratios to a sample containing serine/threonine protein kinases. 
       
     
     
         11 . (canceled) 
     
     
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         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled)