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 erythropoietin-associated conditions. The cyanoisoquinoline compounds of the invention have the following structure:

1 - 36 . (canceled) 
     
     
         37 . A method of inhibiting the activity of a HIF hydroxylase enzyme, the method comprising bringing into contact the HIF hydroxylase enzyme and an inhibitory-effective amount of a compound of represented by formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 
         R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halo, cyano, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, —OR 7 , —SR 7 , —SOR 7 , and —SOR 7  wherein R 7  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen or C 1-3  alkyl; 
         or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, and/or prodrugs thereof. 
       
     
     
         38 . The method of  claim 37 , wherein the HIF hydroxylase enzyme is an asparaginyl hydroxylase. 
     
     
         39 . The method of  claim 38 , wherein the asparaginyl hydroxylase is a factor inhibiting HIF. 
     
     
         40 . The method of  claim 37 , wherein the HIF hydroxylase enzyme is a prolyl hydroxylase. 
     
     
         41 . The method of  claim 40 , wherein the prolyl hydroxylase is selected from the group consisting of human EGLN1, EGLN2, and EGLN3. 
     
     
         42 . A method of treating, pretreating, or delaying onset of a condition associated with hypoxia inducible factor (HIF), the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds represented by formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 
         R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halo, cyano, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, —OR 7 , —SR 7 , —SOR 7 , and —SO 2 R 7  wherein R 7  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen or C 1-3  alkyl; 
         or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, and/or prodrugs thereof, and a pharmaceutically acceptable excipient. 
       
     
     
         43 . The method of  claim 42 , wherein the condition associated with HIF is tissue damage associated with ischemia or hypoxia. 
     
     
         44 . The method of  claim 43 , wherein the ischemia is an acute ischemic event selected from the group consisting of myocardial infarction, pulmonary embolism, intestinal infarction, ischemic stroke, and renal ischemic-reperfusion injury. 
     
     
         45 . The method of  claim 43 , wherein the ischemia is chronic ischemic event selected from the group consisting of cardiac cirrhosis, macular degeneration, chronic kidney failure, and congestive heart failure. 
     
     
         46 . A method of treating, pretreating, or delaying onset of a condition associated with erythropoietin (EPO), the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds represented by formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 
         R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halo, cyano, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, —OR 7 , —SR 7 , —SOR 7 , and —SO 2 R 7  wherein R 7  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen or C 1-3  alkyl; 
         or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, and/or prodrugs thereof, and a pharmaceutically acceptable excipient. 
       
     
     
         47 . A method of treating, pretreating, or delaying onset of anemia, the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds represented by formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 
         R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halo, cyano, hydroxyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, —OR 7 , —SR 7 , —SOR 7 , and —SO 2 R 7  wherein R 7  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         R 5  and R 6  are independently selected from the group consisting of hydrogen or C 1-3  alkyl; 
         or pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, and/or prodrugs thereof, and a pharmaceutically acceptable excipient.