Substituted heterocyclyl benzyl pyrazoles, and use thereof

Abstract

The present application relates to novel substituted 1-[3-(heterocyclyl)benzyl]-1H-pyrazole derivatives, to processes for preparation thereof, to use thereof for treatment and/or prevention of diseases and to use thereof for production of medicaments for treatment and/or prevention of diseases, more particularly for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be effected in the form of monotherapy or else in combination with other medicaments or further therapeutic measures.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         m is 1 or 2, 
         n is 1, 2 or 3, 
         R 1  is hydroxyl or cyano, 
         and 
         R 2  is trifluoromethoxy, trifluoromethylsulphanyl, trifluoromethylsulphonyl, pentafluorosulphanyl or a group of the formula 
       
       
         
           
           
               
               
           
         
       
       in which
   denotes the bonding site to the phenyl ring,   R 3A  and R 3B  are each independently fluorine or methyl
 or 
 are joined to one another and, together with the carbon atom to which they are bonded, form a cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring 
   and   R 4  is hydrogen, fluorine, methyl, trifluoromethyl or methoxy,   
 and the salts, solvates and solvates of the salts thereof. 
 
     
     
         2 . A compound of the formula (I) according to  claim 1 , in which
 m and n are each independently 1 or 2,   R 1  is hydroxyl or cyano,   and   R 2  is trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl or a group of the formula   
       
         
           
           
               
               
           
         
       
       in which
   * denotes the bonding site to the phenyl ring,   R 3A  and R 3B  are both methyl or are joined to one another and, together with the carbon atom to which they are bonded, form a cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring   and   R 4  is hydrogen, fluorine, methyl or trifluoromethyl,   
 and the salts, solvates and solvates of the salts thereof. 
 
     
     
         3 . A compound according to  claim 1 , in which
 m and n are both 1 or 2,   R 1  is hydroxyl or cyano,   and   is trifluoromethoxy or a group of the formula   
       
         
           
           
               
               
           
         
       
       in which
   * denotes the bonding site to the phenyl ring,   
 and the salts, solvates and solvates of the salts thereof. 
 
     
     
         4 . A compound according to  claim 1 , in which
 R 1  is hydroxyl,   and   m, n and R 2  are each as defined in  claim 1 ,   and the salts, solvates and solvates of the salts thereof.   
     
     
         5 . A compound of the formula (I-PD) 
       
         
           
           
               
               
           
         
         in which m, n and R 2  are each as defined in  claim 1   
         and 
         R PD  is a prodrug group of the formula 
       
       
         
           
           
               
               
           
         
       
       in which
   # denotes the bonding site to the oxygen atom,   R 5  is hydrogen or (C 1 -C 4 )-alkyl,   and   R 6A  and R 6B  are each independently hydrogen or methyl,   
 and the salts, solvates and solvates of the salts thereof. 
 
     
     
         6 . A compound according to  claim 5 , in which
 R PD  is a prodrug group of the formula   
       
         
           
           
               
               
           
         
         
           in which 
           # denotes the bonding site to the oxygen atom, 
         
         and the salts, solvates and solvates of the salts thereof. 
       
     
     
         7 . A process for preparing a compound of the formula (I) as defined in  claim 1 , wherein a compound of the formula (II) 
       
         
           
           
               
               
           
         
         in which R 2  is as defined in  claim 1   
         and 
         X is bromine or iodine, 
         in the presence of a suitable palladium catalyst and of a base, is coupled with a compound of the formula (III) 
       
       
         
           
           
               
               
           
         
         in which m, n and R 1  are each as defined in  claim 1 , 
         and the resulting compound of the formula (I) is optionally separated into the enantiomers and/or diastereomers thereof and/or converted using the appropriate (i) solvents and/or (ii) acids to the solvates, salts and/or solvates of the salts thereof. 
       
     
     
         8 . A process for preparing a compound of the formula (I-PD) as defined in  claim 5 , wherein a compound of the formula (I-A) 
       
         
           
           
               
               
           
         
         in which m, n and R 2  are each as defined in  claim 1   
         is esterified by customary methods with a compound of the formula (VIII)
   R PD —OH  (VIII)
 
 
         or an activated form of this compound in which R PD  is as defined in  claim 5 , 
         and the resulting compound of the formula (I-PD) is optionally separated into the enantiomers and/or diastereomers thereof and/or converted using the appropriate (i) solvents and/or (ii) acids to the solvates, salts and/or solvates of the salts thereof. 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . A pharmaceutical composition comprising a compound as defined  claim 1  in combination with one or more inert, nontoxic, pharmaceutically suitable excipients. 
     
     
         15 . A pharmaceutical composition comprising a compound as defined in  claim 1  in combination with one or more further active ingredients. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method for the treatment and/or prevention of a cancer or tumour in a human or animal in need thereof comprising administering to the human or animal an effective amount of at least one compound as defined in  claim 1 . 
     
     
         19 . A method for the treatment and/or prevention of ischaemic cardiovascular diseases, heart failure, myocardial infarction, arrhythmia, stroke, pulmonary hypertension, fibrotic diseases of the kidney and lung, psoriasis, diabetic retinopathy, macular degeneration, rheumatic arthritis or Chuvash polycythaemia in a human or animal in need thereof, comprising administering to the human or animal an effective amount of at least one compound as defined in  claim 1 .