Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors

Abstract

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

1 . A pyrazolo-quinazoline derivative of formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R is substituted or unsubstituted phenyl; 
 X is —NH—; 
 R 1  is an optionally substituted straight or branched C 1 -C 6  alkyl; 
 R 2  is —NR″R″′, wherein
 R″ is hydrogen or an optionally substituted straight or branched C 1 -C 6  alkyl; 
 R″′ is hydrogen or an optionally substituted group selected from phenyl and straight or branched C 1 -C 6  alkyl; and 
 
 A is —(CH 2 ) 2 —, —CH 2 —C(CH 3 ) 2 —, or —C(CH 3 ) 2 —CH 2 —. 
 
     
     
         2 . The compound of  claim 1 , wherein R is phenyl substituted with heterocyclyl or heterocyclylalkyl. 
     
     
         3 . The compound of  claim 2 , wherein the heterocyclyl is selected from piperazinyl, morpholinyl, and imidazolyl. 
     
     
         4 . The compound of  claim 1 , wherein R is phenyl substituted with one or more groups independently selected from halogen, hydroxy, polyfluorinated alkyl, and aminocarbonyl. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is straight or branched C 1 -C 6  alkyl substituted with one or more groups independently selected from halogen and hydroxy. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is unsubstituted straight or branched C 1 -C 6  alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 1  is methyl. 
     
     
         8 . The compound of  claim 1 , wherein R″′ is unsubstituted straight or branched C 1 -C 6  alkyl or straight or branched C 1 -C 6  alkyl substituted with one or more groups independently selected from halogen, hydroxy, aryl, heterocyclyl, and di-(C 1 -C 6  alkyl)amino. 
     
     
         9 . The compound of  claim 8 , wherein the aryl is phenyl. 
     
     
         10 . The compound of  claim 8 , wherein the heterocyclyl is pyridyl. 
     
     
         11 . The compound of  claim 1 , wherein A is —CH 2 —C(CH 3 ) 2 —. 
     
     
         12 . A method for treating a disease selected from the group consisting of ovarian cancer, acute myeloid leukemia, prostate cancer, breast cancer, liver cancer, melanoma, colon cancer, non-small lung cancer, pancreatic cancer, and pancreatic adenocarcinoma, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for inhibiting Aurora 2 activity, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method for inhibiting cell cycle dependent kinase activity, comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.