D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease

Abstract

Provided herein are compounds, compositions, and methods for the treatment of viral infections, for example, Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds are D-amino acid phosphoramidate halogeno pyrimidine nucleoside analog compounds which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the compounds are of Formula I: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein: PD, X, R 1 , R 2 , R A , and R B are as described herein.

1 . A compound according to Formula XII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof, wherein:
 X is phenyl or napthyl; 
 R 1  is alkyl; 
 R 2  is hydroxyl or amino; 
 R A  is fluoro, chloro, bromo, or iodo; and 
 R B  is hydroxyl, fluoro, or chloro. 
 
     
     
         2 . The compound of  claim 1  according to Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         3 . The compound of  claim 1  according to Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         4 . The compound of  claim 1  according to Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         5 . The compound of  claim 1  according to Formula V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         6 . The compound of  claim 1  according to Formula VI: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         7 . The compound of  claim 1  according to Formula XI: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         8 . The compound of  claim 1  according to Formula VII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         9 . The compound of  claim 1  according to Formula VIII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         10 . The compound of  claim 1  according to Formula IX: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         11 . The compound of  claim 1  according to Formula X: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form, or polymorphic form thereof. 
     
     
         12 . The compound of  claim 1  wherein R 1  is methyl, CF 3 , CCl 3 , CFCl 2 , CF 2 Cl, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl. 
     
     
         13 . The compound of  claim 1  wherein R 1  is isopropyl. 
     
     
         14 . The compound of  claim 1  according to Formula XIIa or XIIb: 
       
         
           
           
               
               
           
         
       
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient, carrier, or diluent; wherein the composition is an oral formulation. 
     
     
         17 . (canceled) 
     
     
         18 . A method for the treatment of a host infected with a virus, comprising the administration of an effective amount of a compound of  claim 1 ; wherein the host is a human; and wherein the virus is a hepatitis C virus. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18  comprising directing a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host. 
     
     
         22 . The method of  claim 18  comprising administering a second anti-viral agent in combination or alternation with the compound or the composition, wherein the second anti-viral agent is an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, or a combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof. 
     
     
         24 . The method of  claim 22 , wherein the second anti-viral agent is samatasvir, simeprevir, sofosbuvir, telaprevir, boceprevir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, or a combination thereof, and further wherein the administration is not in combination or alternation with ribavirin. 
     
     
         25 . The compound of  claim 1 , wherein:
 R 2  is —NR 1′ R 2′ ; and   R 1′  and R 2′  are each independently hydrogen, methyl, CF 3 , CCl 3 , CFCl 2 , CF 2 Cl, ethyl, CH 2 CF 3 , CF 2 CF 3 , propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, ethenyl, n-propenyl, isopropenyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, adamantyl, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, 1,3,5-trithianyl, phenyl, biphenyl, naphthyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl.