Substituted nucleosides, nucleotides and analogs thereof
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 and/or Flaviviridae infection with one or more nucleosides, nucleotides and nucleotide analogs.
1. A method for ameliorating or treating a Picornaviridae viral infection comprising contacting a cell infected with the Picornaviridae virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
wherein:
B 1A is
wherein R G2 is an unsubstituted C 1-6 alkyl;
R 3A is selected from the group consisting of OH, OC(═O)R″ A and an unsubstituted O-linked α-amino acid;
R 4A is selected from the group consisting of OH and halo;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen or deuterium;
R 1A is selected from the group consisting of hydrogen,
R 2A is halo;
R 5A is selected from the group consisting of an unsubstituted C 1-6 alkyl and an unsubstituted C 2-6 alkenyl;
R 6A and R 7A are independently selected from the group consisting of absent, hydrogen and
or
R 6A is
and R 7A is absent or hydrogen; or
R 8A is absent, hydrogen, an optionally substituted phenyl or an optionally substituted naphthyl;
R 9A is an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C 1-6 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted C 6 aryl ester, an optionally substituted C 10 aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R 10A and R 11A are independently an optionally substituted N-linked amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the optionally substituted N-linked α-amino acid ester derivative is an unsubstituted C 1-6 alkyl ester, an optionally substituted C 3-6 cycloalkyl ester, an optionally substituted C 6 aryl ester, an optionally substituted Cm aryl ester or an optionally substituted benzyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked asparagine, N-linked aspartate, N-linked cysteine, N-linked glutamate, N-linked glutamine, N-linked glycine, N-linked proline, N-linked serine, N-linked tyrosine, N-linked arginine, N-linked histidine, N-linked isoleucine, N-linked leucine, N-linked lysine, N-linked methionine, N-linked phenylalanine, N-linked threonine, N-linked tryptophan and N-linked valine;
R 12A and R 13A are independently absent or hydrogen;
R 14A is O − , OH or methyl;
R 22A and R 23A are each hydrogen;
R 24A is selected from the group consisting of hydrogen, an unsubstituted C 1-24 alkyl, and an unsubstituted —O—C 1-24 alkyl;
R″ A is an unsubstituted C 1-24 alkyl;
m is 0 or 1;
s is 0, 1, 2 or 3; and
Z 1A , Z 2A , Z 3A and Z 4A are each O.
2. The method of claim 1 , wherein the virus is an Enterovirus.
3. The method of claim 1 , wherein the virus is a Rhinovirus.
4. The method of claim 1 , wherein B 1A is
5. The method of claim 1 , wherein B 1A is
wherein R G2 is ethyl.
6. The method of claim 1 , wherein R 2A is fluoro.
7. The method of claim 1 , wherein R 3A is OH.
8. The method of claim 1 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is an unsubstituted C 1-4 alkyl.
9. The method of claim 1 , wherein R 4A is OH.
10. The method of claim 1 , wherein R 4A is -halo.
11. The method of claim 10 , wherein R 4A is fluoro.
12. The method of claim 1 , wherein R 5A is an unsubstituted C 1-6 alkyl.
13. The method of claim 12 , wherein R 5A is methyl.
14. The method of claim 1 , wherein R 1A is hydrogen.
15. The method of claim 1 , wherein R 1A is
16. The method of claim 15 , wherein R 6A is
R 7A , R 12A and R 13A are independently absent or hydrogen; R 14A is O − and OH; and m is 0 or 1.
17. The method of claim 16 , wherein m is 1.
18. The method of claim 1 , wherein R a1 and R a2 are each hydrogen.
19. The method of claim 1 , wherein R A is hydrogen.
20. The method of claim 15 , wherein R 6A and R 7A are independently absent or hydrogen.
21. The method of claim 15 , wherein R 6A and R 7A are each
wherein s is 0.
22. The method of claim 15 , wherein R 6A and R 7A are each isopropyloxycarbonyloxymethyl.
23. The method of claim 1 , wherein R 1A is
24. The method of claim 23 , wherein R 8A is an optionally substituted phenyl.
25. The method of claim 24 , wherein R 8A is an unsubstituted phenyl.
26. The method of claim 25 , wherein R 9A is an unsubstituted C 1-6 alkyl ester or an unsubstituted C 3-6 cycloalkyl ester of an N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked isoleucine, N-linked leucine and N-linked valine.
27. The method of claim 25 , wherein R 9A is selected from the group consisting of
28. The method of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 , wherein B 1A is
wherein R G2 is —CH 2 CH 3 .
30. The method of claim 28 , wherein R 1A is H.
31. The method of claim 28 , wherein R 1A is
R 6A is
R 7A , R 12A and R 13A are independently absent or hydrogen; m is 1;
and R 14A is O − or OH.
32. The method of claim 28 , wherein R 1A is
R 6A and R 7A are each
s is 0; R 22A and R 23A are each hydrogen; and R 24A is an unsubstituted tert-butyl.
33. The method of claim 28 , wherein R 1A is
R 6A and R 7A are each
s is 0; R 22A and R 23A are each hydrogen; and R 24A is an unsubstituted O-isopropyl.
34. The method of claim 28 , wherein R 1A is
R 8A is an unsubstituted phenyl; and R 9A is
35. The method of claim 28 , wherein R 1A is
R 8A is an unsubstituted phenyl; and R 9A is
36. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein B 1A is
R G2 is —CH 2 CH 3 ; and R 1A is hydrogen.
37. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
38. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
39. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
40. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
41. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.