2-amino-benzoxazinones for the treatment of viral infections

Abstract

A class of compounds for the treatment of viral infections. Compounds of particular interest are defined by Formula I wherein R-R 4 are as defined herein, or a pharmaceutically-acceptable salt thereof.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
         wherein R, R 2 , and R 3  are hydrido;  
         wherein R 1  is selected from the group consisting of alkyl and alkoxy;  
         wherein R 4  is selected from the group consisting of  
         hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl,  
         
           
             
             
                 
                 
             
           
         
         wherein n is 0-6, inclusive;  
         wherein R 15  is selected from the group consisting of hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, alkoxyalkyl, alkylaminoalkyl, and N-aryl-N-alkylaminoalkyl;  
         wherein R 17  is selected from the group consisting of alkyl, cycloalkyl, aralkyl;  
         wherein R 16  is selected from the group consisting of hydrido, alkyl, cycloalkyl,  
         cycloalkylalkyl, haloalkyl, guanidinylalkyl, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,  
         aralkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aryl, heterocyclyl,  
         aralkyl, heterocyclylalkyl, and  
         
           
             
             
                 
                 
             
           
         
         wherein R 20  is alkyl;  
         wherein R 23  is hydrido, alkyl, and aralkyl; and  
         wherein R 24  is selected from the group consisting of alkyl, cycloalkyl,  
         cycloalkylalkylaminoalkyl, aralkoxyalkyl, alkoxyalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl; or  
         a pharmaceutically-acceptable salt or tautomer thereof.  
       
     
     
         2 . The compound of  claim 1  selected from the compounds and their pharmaceutically-acceptable salts, of the group consisting of 
 5-methyl-2[[(1R)-1 phenylethyl]amino]-4H-3,1-benzoxazin-4-one;    N α -(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-N′-[(phenylmethoxy)carconyl]-L-lysine, 1,1-dimethylethyl ester;    N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-phenylalanine, methyl ester;    N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-tryptohphan, methyl ester;    N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-tryptophan, 1,1-dimethyl ester;    2-[[2-methoxy-(1S)-(1-phenyl]methyl)ethyl]amino]-5-methyl-4H-3,1-benzoxazin-4-one;    3,5-diiodo-N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-tyrosine, methyl ester;    N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-O-methyl-L-tyrosine, methyl ester;    N-(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)-L-phenylglycine, 1,1-dimethylethyl ester;    αS-[(5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl)amino]-4-methoxy-N-methyl-N-(phenylmethyl)benzenepropanamide;    5-methoxy-2-[[(1R)-1-phenylethyl]amino]-4H-3,1-benzoxazin-4-one; and    N-[5-methoxy-4-oxo-4H-3,1-benzoxazin-2-yl]-O-methyl-L-tyrosine, N-methyl-N-phenylmethylamide.    
     
     
         3 . A pharmaceutical composition comprising a therapeutically-effective amount of a compound selected from a compound of claims  1  or  2  and a pharmaceutically-acceptable carrier or diluent.  
     
     
         4 . A method of therapeutic treatment of a viral infection in a subject, said method comprising treating said subject with an effective amount of a compound according to claims  1  or  2 .  
     
     
         5 . The method of  claim 4  wherein the viral infection is caused by a herpesvirus.  
     
     
         6 . The method of  claim 6  wherein the viral infection is caused by CMV, HSV-1 or HSV-2.  
     
     
         7 . A method of inhibiting a viral protease in a subject infected with a virus having said protease, said method comprising treating said subject with an effective amount of a compound according to claims  1  or  2 .  
     
     
         8 . The method of  claim 7  wherein the viral infection is caused by a herpesvirus.  
     
     
         9 . The method of  claim 8  wherein the viral infection is caused by CMV, HSV-1 or HSV-2.