Substituted nucleosides, nucleotides and analogs thereof

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.

What is claimed is: 
     
         1 . A compound selected from Formula (I), Formula (II), and Formula (III), or a pharmaceutically acceptable salt of the foregoing: 
       
         
           
           
               
               
           
         
         wherein: 
         B 1A  B 1B  and B 1C  are independently an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; 
         R 1A  is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, 
       
       
         
           
           
               
               
           
         
         when the dashed line ( ) of Formula (I) is a single bond, R 2A  is CH 2 , and R 3A  is O (oxygen); 
         when the dashed line ( ) of Formula (I) is absent, R 2A  is selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted —O—C 1-6  alkyl, an optionally substituted —O—C 3-6  alkynyl, an optionally substituted —O—C 3-6  alkynyl and cyano, and R 3A  is selected from the group consisting of OH, —OC(═O)R″ A  and an optionally substituted O-linked amino acid; 
         R 1B  is selected from the group consisting of O − , OH, 
       
       
         
           
           
               
               
           
         
       
       an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative;
 R 1C  and R 2C  are independently selected from the group consisting of O − , OH, an optionally substituted C 1-6  alkoxy, 
 
       
         
           
           
               
               
           
         
       
       an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; or
 R 1C  is 
 
       
         
           
           
               
               
           
         
       
       and R 2C  is O −  or OH;
 R 2B  and R 3C  are independently selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted —O—C 1-6  alkyl, an optionally substituted —O—C 3-6  alkenyl, an optionally substituted —O—C 3-6  alkynyl and cyano; 
 R 4C  is selected from the group consisting of OH, —OC(═O)R″ C  and an optionally substituted O-linked amino acid; 
 R 4A , R 3B  and R 5C  are independently a halogen; 
 R 5A , R 4B  and R 6C  are independently hydrogen or halogen; 
 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 2-24  alkenyl, an optionally substituted C 2-24  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 1A ) 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 30A R 31A , 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 , R 13A  and R 14A  are independently absent or hydrogen; 
 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 , R 23A , R 5B , R 6B , R 8B , R 9B , R 9C , R 10C , R 12C  and R 13C  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl and an optionally substituted aryl; 
 R 21A , R 24A , R 7B , R 10B , R 11C  and R 14C  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 and an optionally substituted —O-aryl; 
 R 25A , R 29A , R 11B  and R 15C  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-24  alkyl and an optionally substituted aryl; 
 R 16C , R 17C  and R 18C  are independently absent or hydrogen; 
 R 26A  and R 27A  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 28A  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 30A  and R 31A  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 and an optionally substituted C 3-6  cycloalkenyl; 
 for Formula (III),   is a single bond or a double bond;
 when   is a single bond, each R 7C  and each R 8C  is independently hydrogen or halogen; and 
 when   is a double bond, each R 7C  is absent and each R 8C  is independently hydrogen or halogen; 
 
 R″ A  and R ″C  are independently an optionally substituted C 1-24 -alkyl; 
 m and n are independently 0 or 1; 
 p and q are independently selected from the group consisting of 1, 2 and 3; 
 r is 1 or 2; 
 Z 1A , Z 2A , Z 3A , Z 4A , Z 1B , Z 2B  and Z 1C  are independently O or S; and 
 provided that when the dashed line ( ) of Formula (I) is absent; R 1A  is 
 
       
         
           
           
               
               
           
         
       
       wherein R 8A  is an unsubstituted C 1-4  alkyl or phenyl optionally para-substituted with a halogen or methyl and R 9A  is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tryptophan, methionine and proline; R 3A  is OH; R 4A  is fluoro; R 5A  is fluoro or hydrogen; and B 1A  is an unsubstituted uracil; then R 2A  cannot be —OCH 3 ;
 provided that when the dashed line ( ) of Formula (I) is absent; R 1A  is H; R 3A  is OH; R 4A  is fluoro; R 5A  is fluoro; and B 1A  is an unsubstituted cytosine; then R 2A  cannot be allenyl; 
 provided that when the dashed line ( ) of Formula (I) is absent; R 1A  is H; R 3A  is OH; R 4A  is fluoro; R 5A  is hydrogen; and B 1A  is an unsubstituted thymine; then R 2A  cannot be C 1  alkyl substituted with an N-amido; and 
 provided that when the dashed line ( ) of Formula (I) is absent; R 1A  is H; R 3A  is OH; R 4A  is fluoro; R 5A  is fluoro; and B 1A  is an unsubstituted cytosine; then R 2A  cannot be ethynyl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1A  is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein R 1A  is an optionally substituted acyl. 
     
     
         4 . The compound of  claim 1 , wherein R 1A  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 1A  is an optionally substituted O-linked amino acid. 
     
     
         6 . The compound of  claim 1 , wherein R 1A  is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 6 , wherein both R 6A  and R 7A  are 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, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C 1-6  alkyl). 
     
     
         8 . The compound of  claim 6 , wherein both R 6A  and R 7A  are independently selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 6 , wherein R 6A  and R 7A  are both 
       
         
           
           
               
               
           
         
       
       *—(CR 15A R 16A ) p —O—C 1-24  alkyl or *—(CR 17A R 18A ) q —O—C 2-24  alkenyl; or wherein R 6A  and R 7A  can be 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. 
     
     
         10 . The compound of  claim 6 , wherein R 8A  is selected from the group consisting of absent, 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; and 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 and NR 30A R 31A . 
     
     
         11 . The compound of  claim 6 , wherein R 8A  is an optionally substituted aryl; and R 9A  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. 
     
     
         12 . The compound of  claim 6 , wherein R 10A  and R 11A  are both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative. 
     
     
         13 . The compound of  claim 1 , wherein B 1A  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R A2  is selected from the group consisting of hydrogen, halogen and NHR J2 , wherein R J2  is selected from the group consisting of hydrogen, —C(═O)R K2  and —C(═O)OR L2 ; 
         R B2  is halogen or NHR W2 , wherein R W2  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R M2  and —C(═O)OR N2 ; 
         R C2  is hydrogen or NHR O2 , wherein R O2  is selected from the group consisting of hydrogen, —C(═O)R P2  and —C(═O)OR Q2 ; 
         R D2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         R E2  is selected from the group consisting of hydrogen, hydroxy, an optionally substituted C 1-6  alkyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R R2  and —C(═O)OR S2 ; 
         R F2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         Y 2  and Y 3  are independently N or CR I2 , wherein R I2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 2-6 -alkenyl and an optionally substituted C 2-6 -alkynyl; 
         R G2  is an optionally substituted C 1-6  alkyl; 
         R H2  is hydrogen or NHR T2 , wherein R T2  is independently selected from the group consisting of hydrogen, —C(═O)R U2  and —C(═O)OR V2 ; and 
         R K2 , R L2 , R M2 , R N2 , R P2 , R Q2  R R2 , R S2 , R U2  and R V2  are independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 3-6  cycloalkenyl, C 6-10  aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6  alkyl), heteroaryl(C 1-6  alkyl) and heteroalicyclyl(C 1-6  alkyl). 
       
     
     
         14 . The compound of  claim 1 , wherein the dashed line (------) is absent, R 2A  is selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 2-6  alkynyl, an optionally substituted —O—C 1-6  alkyl, an optionally substituted —O—C 3-6  alkenyl, an optionally substituted —O—C 3-6  alkynyl and cyano, and R 3A  is selected from the group consisting of OH, —OC(═O)R ″A  and an optionally substituted O-linked amino acid. 
     
     
         15 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of the foregoing. 
       
     
     
         17 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of the foregoing. 
     
     
         18 . The compound of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of the foregoing. 
     
     
         19 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. 
     
     
         20 . A method for ameliorating or treating a viral infection comprising contacting a cell infected with the virus in a subject identified as suffering from the viral infection with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and wherein the viral infection is selected from a paramyxovirus viral infection and an orthomyxovirus viral infection. 
     
     
         21 . A method for ameliorating or treating a viral infection in combination with one or more agents comprising administering to or contacting a cell in a subject identified as suffering from the viral infection with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and wherein the viral infection is selected from a paramyxovirus viral infection and an orthomyxovirus viral infection.