Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors

Abstract

The present invention provides protein kinase having one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer 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, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.

1 - 48 . (canceled) 
     
     
         49 . A process for preparing Compound A: 
       
         
           
           
               
               
           
         
         comprising reacting 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (int-1) with 2-(trans-4-aminocyclohexyl)propan-2-ol (int-2) to form Compound A: 
       
       
         
           
           
               
               
           
         
       
     
     
         50 . The process of  claim 49 , wherein the reaction is conducted in the presence of a base. 
     
     
         51 . The process of  claim 50 , wherein the base comprises an amine. 
     
     
         52 . The process of  claim 50 , wherein the base comprises N,N-Diisopropylethylamine (DIEA). 
     
     
         53 . The process of  claim 49 , wherein the reaction is conducted in the presence of a solvent. 
     
     
         54 . The process of  claim 53 , wherein the solvent comprises a polar aprotic solvent. 
     
     
         55 . The process of  claim 53 , wherein the solvent comprises dimethyl sulfoxide (DMSO). 
     
     
         56 . The process of  claim 49 , wherein the reaction is conducted at an elevated temperature. 
     
     
         57 . The process of  claim 56 , wherein the elevated temperature is above 50° C. 
     
     
         58 . The process of  claim 56 , wherein the elevated temperature is above 150° C. 
     
     
         59 . The process of  claim 49 , wherein the reaction is conducted in the presence of a catalyst. 
     
     
         60 . The process of  claim 59 , wherein the catalyst is cesium fluoride (CsF). 
     
     
         61 . The process of  claim 49 , wherein the 2-(trans-4-aminocyclohexyl)propan-2-ol (int-2) is prepared according to the following steps:
 i) stirring a mixture of hydrochloride salt of trans-4-aminocyclohexanecarboxylic acid and benzyl bromide (BnBr) in the presence of a base to form trans-benzyl 4-(dibenzylamino)-cyclohexanecarboxylate:   
       
         
           
           
               
               
           
         
         ii) stirring the product of step i) in the presence of a Grignard reagent to form 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol (methylmagnesium chloride): 
       
       
         
           
           
               
               
           
         
       
       and
 iii) stirring the product of step ii) with a palladium catalyst to form 2-(trans-4-aminocyclohexyl)propan-2-ol (int-2) 
 
       
         
           
           
               
               
           
         
       
     
     
         62 . The process of  claim 61 , wherein the base in step i) comprises a carbonate salt. 
     
     
         63 . The process of  claim 61 , wherein the base in step i) comprises potassium carbonate (K 2 CO 3 ). 
     
     
         64 . The process of  claim 61 , wherein the Grignard reagent in step ii) comprises methylmagnesium bromide (MeMgBr). 
     
     
         65 . The process of  claim 61 , wherein the palladium catalyst in step iii) comprises palladium hydroxide (Pd(OH) 2 ). 
     
     
         66 . The process of  claim 61 , wherein steps i), ii), and iii) are conducted in the presence of one or more polar aproic solvents. 
     
     
         67 . The process of  claim 66 , wherein the polar aprotic solvents are DMF, THF, or EtOAc. 
     
     
         68 . The process of  claim 61 , wherein step i) is conducted at an elevated temperature. 
     
     
         69 . The process of  claim 49 , wherein the 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (int-1) is prepared according to the following steps:
 i) mixing 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-(trifluoromethyl)-phenylboronic in the presence of a solvent and a base:   
       
         
           
           
               
               
           
         
       
       and
 ii) stirring the mixture at an elevated temperature to form int-1. 
 
     
     
         70 . The process of  claim 69 , wherein the base in step i) comprises a carbonate salt. 
     
     
         71 . The process of  claim 70 , wherein the base in step i) comprises potassium carbonate (K 2 CO 3 ). 
     
     
         72 . The process of  claim 69 , wherein the solvent comprises an aprotic solvent. 
     
     
         73 . The process of  claim 69 , wherein the solvent comprises dioxane. 
     
     
         74 . The process of  claim 69 , wherein the solvent comprises dioxane and water. 
     
     
         75 . The process of  claim 69 , wherein the reaction is conducted in the presence of a palladium catalyst. 
     
     
         76 . The process of  claim 75 , wherein the palladium catalyst comprises Pd(PPh 3 ) 4 . 
     
     
         77 . The process of  claim 69 , wherein the elevated temperature is about 80° C. 
     
     
         78 . The process of  claim 49 , further comprising mixing Compound A in ethyl acetate and adding HCl/ethyl acetate to the mixture to form an HCl salt of Compound A. 
     
     
         79 . 6-Chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (int-1). 
     
     
         80 . A compound selected from 2-(trans-4-aminocyclohexyl)propan-2-ol (int-2) and trans-benzyl 4-(dibenzylamino)-cyclohexanecarboxylate.