Substituted nucleosides, nucleotides and analogs thereof

Abstract

Disclosed herein are nucleosides, nucleotides and nucleotide analogs, methods of synthesizing the same and methods of treating diseases and/or conditions such as a Picornavirus infection with one or more nucleosides, nucleotides and nucleotide analogs.

What is claimed is: 
     
         1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         B 1A  is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; 
         R A  is hydrogen or deuterium; 
         R 1A  is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, 
       
       
         
           
           
               
               
           
         
         R a1  and R a2  are independently hydrogen or deuterium; 
         R 2A  is an unsubstituted C 1-4  alkyl, an unsubstituted C 2-4  alkenyl, an unsubstituted C 2-4  alkynyl, a C 1-6  haloalkyl, a C 1-6  azidoalkyl or a C 1-6  aminoalkyl; 
         R 3A  is selected from the group consisting of hydrogen, deuterium, halo, OH, —OC(═O)R′ A  and an optionally substituted O-linked amino acid; 
         R 4A  is hydrogen or deuterium; 
         R 5A  is hydrogen, deuterium, halogen, N 3 , OH, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         R 6A , R 7A  and R 8A  are independently selected from the group consisting of absent, hydrogen, an optionally substituted C 1-24  alkyl, an optionally substituted C 3-24  alkenyl, an optionally substituted C 3-24  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 3-6  cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C 1-6  alkyl), an optionally substituted *—(CR 15A R 16A ) p —O—C 1-24  alkyl, an optionally substituted *—(CR 17A R 18A ) q —O—C 1-24  alkenyl, 
       
       
         
           
           
               
               
           
         
         R 6A  is 
       
       
         
           
           
               
               
           
         
       
       and R 7A  is absent or hydrogen; or
 R 6A  and R 7A  are taken together to form a moiety selected from the group consisting of an optionally substituted 
 
       
         
           
           
               
               
           
         
       
       and an optionally substituted 
       
         
           
           
               
               
           
         
       
       wherein the oxygens connected to R 6A  and R 7A , the phosphorus and the moiety form a six-membered to ten-membered ring system;
 R 9A  is independently selected from the group consisting of an optionally substituted C 1-24  alkyl, an optionally substituted C 2-24  alkenyl, an optionally substituted C 2-24  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 3-6  cycloalkenyl, NR 31A R 32A  an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; 
 R 10A  and R 11A  are independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; 
 R 12A  and R 13A  are independently absent or hydrogen; 
 R 14A  is O—, OH or methyl; 
 each R 15A , each R 16A , each R 17A  and each R 18A  are independently hydrogen, an optionally substituted C 1-24  alkyl or alkoxy; 
 R 19A , R 20A , R 22A  and R 23A  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl and an optionally substituted aryl; 
 R 21A  and R 24A  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24  alkyl, an optionally substituted —O-aryl an optionally substituted —O-heteroaryl, an optionally substituted —O-monocyclic heterocyclyl and 
 
       
         
           
           
               
               
           
         
         R 25A , R 26A  and R 30A  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl and an optionally substituted aryl; 
         R 27A  and R 28A  are independently —C≡N or an optionally substituted substituent selected from the group consisting of C 2-8  organylcarbonyl, C 2-8  alkoxycarbonyl and C 2-8  organylaminocarbonyl; 
         R 29A  is selected from the group consisting of hydrogen, an optionally substituted C 1 -24 alkyl, an optionally substituted C 2-24  alkenyl, an optionally substituted C 2-24  alkynyl, an optionally substituted C 3-6  cycloalkyl and an optionally substituted C 3-6  cycloalkenyl; 
         R 31A  and R 32A  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl, an optionally substituted C 2-24  alkenyl, an optionally substituted C 2-24  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 3-6  cycloalkenyl and an optionally substituted aryl(C 1-4  alkyl); 
         R″ A  is an optionally substituted C 1-24  alkyl; 
         m and t are independently 0 or 1; 
         p and q are independently selected from the group consisting of 1, 2 and 3; 
         s is 0, 1, 2 or 3; 
         r and u are independently 1 or 2; 
         y is 3, 4 or 5; and 
         Z 1A , Z 2A , Z 3A  and Z 4A  are independently O or S. 
       
     
     
         2 . A method for ameliorating or treating a picornavirus viral infection comprising administering to a subject identified as suffering from the picornavirus viral infection an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.