Substituted indazole derivatives active as kinase inhibitors

Abstract

Substituted indazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification; the compounds of the invention may be useful in therapy in the treatment of diseases associated with a deregulated protein kinase activity, like cancer.

1 .- 20 . (canceled) 
     
     
         21 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Ar is group of formula: 
       
       
         
           
           
               
               
           
         
         R is aryl substituted with one or more halogen; 
         R1, R2, and R3 are hydrogen; 
         Ra is hydrogen, halogen, nitro, NHCOR4or NR5R6; 
         Rb is hydrogen, nitro, NR5R6, OR7, or R8R9N—C 1 -C 6  alkyl; 
         R4 is hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, NR5R6, OR7, SR7, R8R9N—C 1 -C 6  alkyl, R8O—C 1 -C 6  alkyl, an optionally further substituted straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl or heteroaryl; 
         R5 and R6 are independently hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, R8R9N—C 2 -C 6  alkyl, R8O—C 2 -C 6  alkyl, an optionally further substituted straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl or heteroaryl; or R5 and R6, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group; 
         R7 is hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, SOR10, SO 2 R10, R8R9N—C 2 -C 6  alkyl, R8O—C 2 -C 6  alkyl, an optionally further substituted straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl or heteroaryl; 
         R8 and R9 are independently hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, an optionally further substituted straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl or heteroaryl; or R8 and R9, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted heterocyclyl group; and 
         R10 is hydrogen, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, an optionally further substituted straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl, or heteroaryl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . A compound according to  claim 21 , wherein R is phenyl substituted with one or more fluoro, or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A compound according to  claim 21 , wherein:
 Ar is group of formula   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A compound according to  claim 23 , wherein R is phenyl substituted with one or more fluoro, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A compound according to  claim 21 , wherein Ra and Rb are NR5R6, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . A compound according to  claim 22 , wherein Ra and Rb are NR5R6, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A compound according to  claim 23 , wherein Ra and Rb are NR5R6, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A compound according to  claim 25 , wherein Ra is NR5R6, wherein R5 is hydrogen and R6 is heterocyclyl, or a pharmaceutically acceptable salt thereof. 
     
     
         29 . A compound according to  claim 25 , wherein Rb is NR5R6, wherein R5 and R6, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A compound according to  claim 21 , wherein:
 R is phenyl substituted with one or more fluoro;   Ar is group of formula   
       
         
           
           
               
               
           
         
       
       and
 Ra and Rb are NR5R6, or a pharmaceutically acceptable salt thereof. 
 
     
     
         31 . A compound according to  claim 30 , wherein:
 Ra is NR5R6, wherein R5 is hydrogen and R6 is heterocyclyl; and   Rb is NR5R6, wherein R5 and R6, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group, or a pharmaceutically acceptable salt thereof.   
     
     
         32 . A compound according to  claim 30 , wherein R is difluorophenyl, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A compound according to  claim 31 , wherein R is difluorophenyl, or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A compound according to  claim 21 , wherein:
 R is phenyl substituted with one or more fluoro;
 Ar is group of formula 
   
       
         
           
           
               
               
           
         
       
       and
   Ra and Rb are NR5R6, or a pharmaceutically acceptable salt thereof.   
 
     
     
         35 . A compound according to  claim 34 , wherein:
 Ra is NR5R6, wherein R5 is hydrogen and R6 is heterocyclyl; and   Rb is NR5R6, wherein R5 and R6, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocyclyl group, or a pharmaceutically acceptable salt thereof.   
     
     
         36 . A compound according to  claim 34 , wherein R is difluorophenyl, or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A compound according to  claim 35 , wherein R is difluorophenyl, or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 21 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient carrier or diluent. 
     
     
         39 . A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective of a compound according to  claim 21 , or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective of a pharmaceutical composition according to  claim 38 .