Novel phosphoramidate compounds and methods of use

Abstract

This invention provides compounds, compositions and methods for treating cancer, infectious disease, an autoimmune disorder or an inflammatory condition. Therapeutic compounds useful in the methods of this invention are 5′-phosphoramidatyl, 1,5-substituted pyrimidine compounds, derivatives, analogs and pharmaceutically acceptable salts thereof

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, vinyl, propargyl and substituted derivatives thereof; 
         wherein R 2  and R 3  are independently the same or different and are selected from the group consisting of Br, Cl, F, I, H, OH, OC(═O)CH 3 , —O— and —O—Rg, wherein Rg is a hydroxyl protecting group other than acetyl; 
         wherein R 8  is a side chain of any naturally occurring amino acid, its analogue or its isomer; 
         and wherein R 9  is selected from the group consisting of hydrogen, an aliphatic group, an alicyclic group, an aromatic group, a heterocyclic group and an adamantly group and derivatives and analogs thereof; 
         and any enantiomeric, diasteriomeric, or stereoisomeric form, including D-form, L-form, α-anomeric form, and β-anomeric form, and its pharmaceutically acceptable salts. 
       
     
     
         2 . The compound of  claim 1 , wherein R 8  is the side chain of a naturally occurring amino acid, its analogue or isomer, selected from the group consisting of alanine, glycine, tryptophan, leucine and aspartic acid. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is a halogen-substituted vinyl derivative. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is bromovinyl. 
     
     
         5 . The compound of  claim 4 , wherein R 8  is alanine, with the proviso that R 9  is not methyl. 
     
     
         6 . The compound of  claim 5 , wherein R 9  is selected from the group consisting of —CH 2 -phenyl, —CH 3 , —CH 2 -cyclopropyl, cyclohexyl, iso-propyl, —CH 2 -tert-butyl, cycloheptyl, cyclooctyl and —CH 2 -adamantyl. 
     
     
         7 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         27 . A composition comprising the compound of  claim 1  and a carrier. 
     
     
         28 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         29 . A method of inhibiting the proliferation of a cell selected from the group consisting of a cancer cell or a cell infected with an infectious agent, comprising contacting the cell with an effective amount of the compound of  claim 1 . 
     
     
         30 . A method for treating a cell or tissue related to an autoimmune disorder or inflammatory condition, comprising contacting the cell or tissue with an effective amount of the compound of  claim 1 .