Phosphoramidates for the treatment of hepatitis b virus

Abstract

Disclosed are compounds and compositions to the treatment of infectious diseases and methods of treating such diseases. The compounds and compositions include derivatives of clevudine. The compounds and compositions include derivatives of clevudine in combination with another antiviral agent. The compounds and compositions include derivatives of clevudine in combination with a phosphoramnidate of lamivudine, adefovir, tenofovir, telbivudine, entecavir, or combinations thereof.

1 - 56 . (canceled) 
     
     
         57 . A method of treating an infection caused by a DNA virus comprising providing to a host in need thereof a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is independently selected from hydrogen or a group having the formula: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each X is, independently, O or S; 
         Z is N or CR 7 ; 
         U is O or S; 
         W is CH 2 O, CD 2 O, CF 2 O, CH 2 CH 2 ; 
         Y is O or S; 
         Y 1  is OH, OAryl, OAlkyl, or BH 3   − M + ; 
         Y 2  is OH or BH 3   − M + ; 
         Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, or 4-bromophenyl; 
         R 2  is Cl, Br, I, methyl, triflouromethyl, cyano, alkyl, alkenyl, propargyl, substituted alkyl, substituted alkenyl, substituted alkynyl, alkoxy, substituted ethnyl, hydroxymethyl, fluoromethyl, difluoromethyl, formyl, acyl, amino, substituted amino, azido, thiol, hydroxyamino, or substituted thio; and 
         R 3  is hydrogen, deuterium, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl, amino, fluoro, chloro, bromo, iodo, hydroxyl, cyano, formyl, acyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted amino, or hydroxymethyl; 
         R 4  is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, cycloalkyl, or lipid; 
         R 5  is hydrogen, deuterium, hydroxyl, cyano, azido, amino, substituted amino, aryl, heteroaryl, substituted aryl, lipid, C 1-22  alkoxy, C 1-22  alkyl, C 2-22  alkenyl, C 2-22  alkynyl, or substituted heteroaryl; 
         R 6  is methyl, ethyl, tert-butyl, C 1-22  alkoxy, C 1-22  alkyl, branched alkyl, cycloalkyl, aryl, substituted aryl, or alkyoxy; and 
         R 7  is H, D, hydroxyl, thiol, amino, alkyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, alkenyl, alkynyl, ethynyl, azido, halo, fluoro, chloro, bromo, iodo, acyl, esteryl, formyl, alkoxy, substituted amino, or cyano; and 
         a second antiviral agent. 
       
     
     
         58 . The method of  claim 57 , wherein the DNA virus comprises a hepadnavirus. 
     
     
         59 . The method of  claim 57 , wherein the second antiviral agent is selected from the group consisting of abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbovir, stavudine, telaprevir, telbivudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, zidovudine, and combinations thereof. 
     
     
         60 . The method of  claim 57 , where the second antiviral agent comprises a phosphoramidate of lamivudine, adefovir, tenofovir, telbivudine, entecavir, or a combination thereof. 
     
     
         61 . The method of  claim 57 , wherein U is O. 
     
     
         62 . The method of  claim 57 , wherein W is CH 2 O. 
     
     
         63 . The method of  claim 57 , wherein X is in case O. 
     
     
         64 . The method of  claim 57 , wherein Z is CH. 
     
     
         65 . The method of  claim 57 , wherein R 3  is CH 3 . 
     
     
         66 . The method of  claim 57 , wherein R 2  is F. 
     
     
         67 . The method of  claim 57 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 57 , wherein R 1  is: 
       
         
           
           
               
               
           
         
         wherein Y is O, and Y 2  is OH. 
       
     
     
         69 . The method of  claim 57 , wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
         70 . The method of  claim 69 , wherein aryl is phenyl. 
     
     
         71 . The method of  claim 69 , wherein R 4  is hydrogen. 
     
     
         72 . The method of  claim 69 , wherein R 4  is methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, neopentyl, benzyl, alkyl, branched alkyl, or cycloalkyl. 
     
     
         73 . The method of  claim 57 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         74 . The method of  claim 57 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         75 . The method of  claim 74 , wherein the second antiviral agent comprises tenofovir, tenofovir alafenamide, or tenofovir disoproxil. 
     
     
         76 . The method of  claim 74 , wherein the second antiviral agent comprises tenofovir disoproxil.