Substituted nucleosides, nucleotides and analogs thereof
Disclosed herein are nucleosides, nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Filoviridae virus infection with one or more nucleosides and/or nucleotide analogs.
1. A method for ameliorating or treating a Filoviridae viral infection comprising contacting a cell infected with a Filoviridae 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
R 3A is selected from the group consisting of OH and —OC(═O)R″ A ;
R 4A is halogen;
R a1 and R a2 are each hydrogen;
R A is hydrogen;
R 1A is selected from the group consisting of hydrogen, an unsubstituted acyl and
R 2A is azidomethyl;
R 5A is hydrogen;
R 6A and R 7A are independently selected from the group consisting of absent, hydrogen,
or
R 6A is
and R 7A is absent or hydrogen;
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 is selected from the group consisting of hydrogen, an unsubstituted C 1-24 alkyl and an optionally unsubstituted O—C 1-24 alkyl;
R 25A is selected from the group consisting of hydrogen and an unsubstituted C 1-24 alkyl;
R″ A is an unsubstituted C 1-24 alkyl;
m is 0 or 1;
w is 0;
s is 0, 1, 2 or 3; and
Z 1A and Z 4A are each O.
2. The method of claim 1 , wherein the Filoviridae virus is Ebolavirus.
3. The method of claim 1 , wherein the Filoviridae virus is Marburgvirus.
4. The method of claim 1 , wherein R 1A is an unsubstituted acyl having the formula —C(═O)R 39A , wherein R 39A is an unsubstituted C 1-12 alkyl.
5. The method of claim 1 , wherein R 1A is hydrogen.
6. The method of claim 1 , wherein R 1A is
7. The method of claim 6 , wherein R 6A is
R 7A is absent or hydrogen; and m is 0.
8. The method of claim 6 , wherein R 6A is
R 7A is absent or hydrogen; and m is 1.
9. The method of claim 6 , wherein R 6A and R 7A are independently absent or hydrogen.
10. The method of claim 6 , wherein R 6A and R 7A are each
11. The method of claim 6 , wherein R 6A and R 7A are each isopropyloxycarbonyloxymethyl.
12. The method of claim 6 , wherein R 6A and R 7A are each pivaloyloxymethyl.
13. The of claim 6 , wherein R 6A and R 7A are each
14. The method of claim 6 , wherein R 6A and R 7A are each
15. The method of claim 1 , wherein R 3A is OH.
16. The method of claim 1 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is an unsubstituted C 1-24 alkyl.
17. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein R 1A is hydrogen.
19. The method of claim 17 , wherein R 1A is —C(═O)—unsubstituted C 1-4 alkyl.
20. The method of claim 17 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is an unsubstituted C1-4 alkyl.
21. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. 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.
24. A method for inhibiting replication of a Filoviridae virus comprising contacting a cell infected with a Filoviridae 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
R 3A is selected from the group consisting of OH and —OC(═O)R″ A ;
R 4A is halogen;
R a1 and R a2 are each hydrogen;
R A is hydrogen;
R 1A is selected from the group consisting of hydrogen, an unsubstituted acyl and
R 2A is azidomethyl;
R SA is hydrogen;
R 6A and R 7A are independently selected from the group consisting of absent, hydrogen,
or
R 6A is
and R 7A is absent or hydrogen;
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 is selected from the group consisting of hydrogen, an unsubstituted C 1-24 alkyl and an optionally unsubstituted —O—C 1-24 alkyl;
R 25A is selected from the group consisting of hydrogen and an unsubstituted C 1-24 alkyl;
R″ A is an unsubstituted C 1-24 alkyl;
m is 0 or 1;
w is 0;
s is 0, 1, 2 or 3; and
Z 1A and Z 4A are each O.
25. The method of claim 24 , wherein R 1A is hydrogen.
26. The method of claim 24 , wherein R 1A is an unsubstituted acyl having the formula —C(═O)R 39A , wherein R 39A is an unsubstituted C 1-12 alkyl.
27. The method of claim 24 , wherein R 1A is
28. The method of claim 27 , wherein R 6A is
R 7A is absent or hydrogen; and m is 0.
29. The method of claim 27 , wherein R 6A is
R 7A is absent or hydrogen; and m is 1.
30. The method of claim 27 , wherein R 6A and R 7A are independently absent or hydrogen.
31. The method of claim 24 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
32. The method of claim 31 , wherein R 1A is hydrogen.
33. The method of claim 31 , wherein R 1A is —C(═O)—unsubstituted C 1-4 alkyl.
34. The method of claim 31 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is an unsubstituted C 1-4 alkyl.
35. The method of claim 24 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
36. The method of claim 24 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
37. The method of claim 24 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.