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 Coronaviridae virus, a Togaviridae virus, a Hepeviridae virus and/or a Bunyaviridae virus infection with one or more nucleosides, nucleotides and nucleotide analogs.
1. A method for ameliorating or treating a viral infection comprising contacting a cell infected with a 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 selected from the group consisting of:
wherein R G2 is an unsubstituted C 1-6 alkyl;
R 3A is halo or OH;
R 4A is OH or halo;
R a1 and R 2a are independently hydrogen or deuterium;
R A is hydrogen or deuterium;
R 1A is selected from the group consisting of hydrogen
R 2A is hydrogen, halo, —(CH 2 ) 1-6 halogen, or —(CH 2 ) 1-6 N 3 ;
R 5A is selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl and an unsubstituted C 2-6 alkynyl;
R 6A and R 7A are independently selected from the group consisting of absent, hydrogen and
R 6A is
and R 7A is absent or hydrogen;
R 8A is an optionally substituted phenyl or an optionally substituted naphtyl;
R 9A is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
R 10A and R 11A are independently an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative;
R 12A and R 13A are independently absent or hydrogen;
R 14A is O − or OH;
R 22A and R 23A are each hydrogen;
R 24A selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and substituted —O—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 O;
wherein the virus is selected from the group consisting of MERS-CoV, SARS-CoV, Venezuelan equine encephalitis virus, Chikungunya virus and coronavirus; and
when a group is substituted, the group is substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocycyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group; and
wherein an —N-linked α-amino acid ester derivate refers to an α-amino acid in which a main-chain carboxylic acid group has been converted to an ester group.
2. The method of claim 1 , wherein the virus is a coronavirus.
3. The method of claim 1 , wherein the virus is MERS-CoV or SARS-CoV.
4. The method of claim 1 , wherein the virus is a Venezuelan equine encephalitis virus or Chikungunya virus.
5. The method of claim 1 , wherein R 2A is hydrogen.
6. The method of claim 1 , wherein R 2A is halo.
7. The method of claim 6 , wherein the halo is fluoro.
8. The method of claim 1 , wherein R 2A is —(CH 2 ) 1-6 halogen or —(CH 2 ) 1-6 N 3 .
9. The method of claim 8 , wherein R 2A is —(CH 2 ) 1-6 F.
10. The method of claim 1 , wherein R 4A is OH.
11. The method of claim 1 , wherein R 4A is halo.
12. The method of claim 11 , wherein the halo is F or Cl.
13. The method of claim 1 , wherein R 5A is hydrogen.
14. The method of claim 1 , wherein R 5A is an unsubstituted C 1-6 alkyl.
15. The method of claim 1 , wherein R 1A is hydrogen.
16. The method of claim 1 , wherein R 1A is
17. The method of claim 16 , wherein R 6A is absent or hydrogen; and R 7A is absent or hydrogen.
18. The method of claim 16 , wherein R 6A and R 7A are independently
wherein s is 0; and R 24A is an unsubstituted C 1-4 alkyl.
19. The method of claim 1 , wherein R 1A is
20. The method of claim 19 , wherein R 8A is an optionally substituted; and R 9A is an optionally substituted N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine, and N-lined leucine, or an optionally substituted N-linked α-amino acid ester derivative, wherein the N-linked α-amino acid is selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, and the ester is selected from the group consisting of alkyl ester, cycloalkyl ester, and optionally substituted phenyl ester and an optionally substituted benzyl ester.
21. The method of claim 1 , wherein R 1A is
22. The method of claim 21 , wherein R 10A and R 11A are independently an optionally substituted N-linked α-amino acid selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, or an optionally substituted N-linked amino α-acid ester derivative, wherein the N-linked α-amino acid is selected from the group consisting of N-linked alanine, N-linked glycine, N-linked valine and N-linked leucine, and the ester is selected from the group consisting of alkyl ester, cycloalkyl ester, and optionally substituted phenyl ester and an optionally substituted benzyl ester.
23. The method of claim 1 , wherein R 3A is halo.
24. The method of claim 23 , wherein the halo is fluoro.
25. The method of claim 1 , wherein R 3A is OH.
26. The method of claim 1 , wherein R A is hydrogen.
27. The method of claim 1 , wherein R a1 and R a2 are both hydrogen.
28. The method of claim 1 , wherein B 1A is
29. The method of claim 1 , wherein B 1A is
30. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
31. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
32. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
33. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
34. The method of claim 1 , wherein R 5A is an unsubstituted C 2-6 alkynyl.
35. The method of claim 34 , wherein R 5A is an ethynyl.
36. The method of claim 14 , wherein R 5A is methyl.
37. The method of claim 16 , wherein R 6A and R 7A are independently
wherein s is 0; and R 24A is an unsubstituted —O—C 1-4 alkyl.
38. The method of claim 16 , wherein R 6A is
m is 0; and R 7A , R 12A and R 13A are independently absent or hydrogen.
39. The method of claim 16 , wherein R 6A is
m is 1; R 7A , R 12A and R 13A are independently absent or hydrogen; and R 14A is O − or OH.
40. The method of claim 1 , wherein R 2A is fluoromethyl.
41. The method of claim 1 , wherein R 2A is azidomethyl.
42. The method of claim 20 , wherein R 8A is an optionally substituted phenyl; and R 9A is selected from the group consisting of N-linked alanine, N-linked alanine isopropyl ester, N-linked alanine cyclohexyl ester and N-linked alanine neopentyl ester.
43. The method of claim 30 , wherein B 1A is
44. The method of claim 30 , wherein B 1A is
45. The method of claim 30 , wherein B 1A is
46. A method for ameliorating or treating a viral infection comprising contacting a cell infected with a 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 selected from the group consisting of:
wherein R G2 is an unsubstituted C 1-6 alkyl;
R 3A is O;
R 4A is halo;
R 1B is an —O-unsubstituted C 1-6 alkyl;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen or deuterium;
R 2A is halo;
R 5A is an unsubstituted C 1-6 alkyl;
Z 1B is O or S;
wherein the virus selected from the group consisting of MERS-CoV, SARS-CoV, Venezuelan equine encephalitis virus, Chikungunya virus and a coronavirus.
47. The method of claim 46 , wherein the compound is
is or a pharmaceutically acceptable salt thereof.
48. The method of claim 46 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.