IMIDAZO[1,2-beta]PYRIDAZINE AND PYRAZOLO[1,5-alpha]PYRIMIDINE DERIVATIVES AND THEIR USE AS PROTEIN KINASE INHIBITORS

Abstract

The present invention provides protein kinase inhibitors comprising imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine compounds of the following structure (I) and (II): or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein R, R 1 , R 2 and X are as defined herein. Compositions and methods for using the same in the treatment of cancer and other Pim kinase-associated conditions are also disclosed.

1 - 28 . (canceled) 
   
   
       29 . A method for treating a protein kinase-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to structure (I) below: 
     
       
         
         
             
             
         
       
       (I) 
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
 wherein:
 X is NH; 
 R is H, —OH, halo, alkyl, haloalkyl, alkoxy or haloalkoxy; 
 R 1  is phenyl or substituted phenyl; and 
 R 2  is —(CH 2 ) 1,2 -piperid-4-yl, substituted —(CH 2 ) 1,2 -piperid-4-yl, 
 
 
     —(CH 2 ) 1,2 -piperazin-1-yl, or substituted —(CH 2 ) 1,2 -piperazin-1-yl. 
   
   
       30 - 34 . (canceled) 
   
   
       35 . The method of  claim 29  wherein R is hydrogen. 
   
   
       36 . The method of  claim 29  wherein R is methyl. 
   
   
       37 . The method of  claim 29  wherein R 1  is substituted phenyl having at least one p, o or m substituent selected from —OCF 3 , —OCHF 2 , —CF 3 , —OCH 3 , and —OH. 
   
   
       38 . The method of  claim 29  wherein R 1  is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       39 . The method of  claim 29  wherein R 2  is substituted —(CH 2 ) 1,2 -piperid-4-yl or substituted —(CH 2 ) 1,2 -piperazin-1-yl having one or two substituents selected from alkyl. 
   
   
       40 . The method of  claim 39  wherein R 2  is selected from: 
     
       
         
         
             
             
         
       
     
   
   
       41 . The method of  claim 29 , wherein the compound is:
 N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-29);   N-(2-(4-methylpiperazin-1-yl)butyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-31);   7-methyl-N-((1-methylpiperidin-4-yl)methyl)-3-(3-trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-37); or   N-((1-ethylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)-phenyl)imidazo[1,2-b]pyridazin-6-amine (Compound 7-39).   
   
   
       42 . The method of  claim 29  wherein the compound is administered to the subject in the form of a composition comprising the compound in combination with a pharmaceutically acceptable excipient. 
   
   
       43 . The method of any one of  claims 29  and  41 , wherein the protein-kinase mediated disease is a cancer. 
   
   
       44 . The method of  claim 43  wherein the cancer is colon cancer. 
   
   
       45 . The method of  claim 43  wherein the cancer is breast cancer. 
   
   
       46 . The method of  claim 43  wherein the cancer is stomach cancer. 
   
   
       47 . The method of  claim 43  wherein the cancer is prostate cancer. 
   
   
       48 . The method of  claim 43  wherein the cancer is pancreatic cancer. 
   
   
       49 . The method of  claim 43  wherein the cancer is ovarian cancer.