Jak2 and alk2 inhibitors and methods for their use

Abstract

Compounds having activity as inhibitors of ALK2 kinase and/or JAK2 kinase are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, z and A are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

1 . (canceled) 
     
     
         2 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 X is —NH—; 
 Y is N; 
 R 1  is H or C 1 -C 6  alkoxy; 
 R 2  is halo or C 1 -C 6  alkoxy; 
 R 3  is C 1 -C 6  alkoxy or 
 
       
         
           
           
               
               
           
         
       
       wherein R x  is H, C 1 -C 6  alkyl, C 1 -C 6  carboxyalkylcarbonyl, or C 1 -C 6  hydroxylalkyl;
 R 4  is H; 
 R 5  is, at each occurrence, independently H, halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CN or C 1 -C 6  nitrilylalkyl; 
 R 6  is H, C 1 -C 6  alkyl, C 1 -C 6  nitrilylalkyl, or C 3 -C 6  nitrilylcycloalky; 
 R 7  is H, halo, C 1 -C 6  alkyl, C 1 -C 6  nitrilylalkyl, or C 3 -C 6  nitrilylcycloalky; 
 R 8  is heteroaryl; and 
 z is 0, 1 or 2. 
 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The compound of  claim 2 , wherein R 1  is H. 
     
     
         7 . The compound of  claim 2 , wherein R 1  is C 1 -C 6  alkoxy. 
     
     
         8 . The compound of  claim 7 , wherein R 1  is methoxy. 
     
     
         9 . The compound of  claim 2 , wherein R 2  is halo. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is F or Cl. 
     
     
         11 . The compound of  claim 2 , wherein R 2  is C 1 -C 6  alkoxy. 
     
     
         12 . The compound of  claim 11 , wherein R 2  is methoxy. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 2 , wherein R x  is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  carboxyalkylcarbonyl and C 1 -C 6  hydroxylalkyl. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 2 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 18 , wherein R 5  is H. 
     
     
         20 - 22 . (canceled) 
     
     
         23 . The compound of  claim 18 , wherein R 5  is methoxy. 
     
     
         24 . The compound of  claim 18 , wherein at least one of R 6  and R 7  is H. 
     
     
         25 - 34 . (canceled) 
     
     
         35 . The compound of  claim 2 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising a compound of  claim 2 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         38 - 49 . (canceled) 
     
     
         50 . The compound of  claim 2 , wherein the pharmaceutically acceptable salt is an acid addition salt of an inorganic acid. 
     
     
         51 . The compound of  claim 50 , wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid.