Cyanoisoquinoline compounds and methods of use thereof

Abstract

The present invention relates to cyanoisoquinoline compounds suitable for use in treating hypoxia inducible factor-mediated and/or erythropoictin-associated conditions. The cyanoisoquinoline compounds of the invention have the following structure:

What is claimed is: 
     
         1 . A compound of formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R 3 , R 32 , R 33  and R 34  are independently selected from the group consisting of hydrogen, substituted alkyl, aryl, aryloxy, and aryloxy optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkoxy, and alkyl; and 
         R 35  is hydrogen or methyl; 
         or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; or an ester or amide of the carboxylic acid moiety on the glycine- or alanine-based substituent of the cyanoisoquinoline ring. 
       
     
     
         2 . The compound of  claim 1 , wherein R 31 , R 32 , R 33  and R 34  are independently selected from the group consisting of hydrogen, phenoxy and phenoxy substituted with halogen; and R 35  is hydrogen or methyl. 
     
     
         3 . The compound of  claim 2 , wherein one of R 31 , R 32 , R 33  and R 34  is phenoxy substituted with halogen, the other three of R 31 , R 32 , R 33  and R 34  are hydrogen, and R 35  is hydrogen. 
     
     
         4 . The compound of  claim 3 , wherein R 31  is phenoxy substituted with halogen, R 32 , R 33  and R 34  are hydrogen, and R 35  is hydrogen. 
     
     
         5 . The compound of  claim 3 , wherein R 32  is phenoxy substituted with halogen, R 31 , R 33  and R 34  are hydrogen, and R 35  is hydrogen. 
     
     
         6 . The compound of  claim 3 , wherein R 33  is phenoxy substituted with halogen, R 31 , R 32  and R 34  are hydrogen, and R 35  is hydrogen. 
     
     
         7 . The compound of  claim 3 , wherein R 34  is phenoxy substituted with halogen, R 31 , R 32  and R 33  are hydrogen, and R 35  is hydrogen. 
     
     
         8 . A pharmaceutical composition comprising one or more compounds of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         9 . The composition of  claim 8 , further comprising at least one additional therapeutic agent. 
     
     
         10 . The composition of  claim 9 , wherein the agent is selected from the group consisting of vitamin B12, folic acid, ferrous sulfate, human erythropoietin and an erythropoiesis stimulating protein (ESP).