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 halogen, OH, and —OC(═O)R″ A ;
R 4A is selected from the group consisting of OH and halogen;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen, deuterium, or cyano;
R 1A is selected from the group consisting of hydrogen,
R 2A is halogen or halogen(C 1-6 alkyl);
R 5A is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and cyano;
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;
R 8A is absent, hydrogen or aryl;
R 9A is N-alanine, N-valine, N-leucine, N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester or N-leucine isopropyl ester;
R 10A and R 11A are independently N-alanine, N-valine, N-leucine, N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester or N-leucine isopropyl ester;
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 C 1-24 alkyl and —O—C 1-24 alkyl;
and
Z 1A , Z 2A , Z 3A 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 2A is halogen.
5. The method of claim 1 , wherein R 2A is fluoro.
6. The method of claim 1 , wherein R 2A is halogen(C 1-6 alkyl).
7. The method of claim 1 , wherein R 2A is —CH 2 F.
8. The method of claim 1 , wherein R 1A is hydrogen.
9. The method of claim 1 , wherein R 1A is
10. The method of claim 9 , wherein R 6A and R 7A are independently
11. The method of claim 9 , wherein R 6A and R 7A are each isopropyloxycarbonyloxymethyl.
12. The method of claim 9 , wherein R 6A is
R 7A is absent or hydrogen and m is 0.
13. The method of claim 9 , wherein R 6A is
R 7A is absent or hydrogen and m is 1.
14. The method of claim 1 , wherein R 1A is
15. The method of claim 14 , wherein R 8A is aryl.
16. The method of claim 14 , wherein R 8A is phenyl.
17. The method of claim 14 , wherein R 9A is N-alanine isopropyl ester, N-alanine cyclohexyl ester or N-alanine neopentyl ester.
18. The method of claim 1 , wherein R 3A is halogen.
19. The method of claim 1 , wherein R 3A is fluoro.
20. The method of claim 1 , wherein R 3A is OH.
21. The method of claim 1 , wherein R 3A is —OC(═O)R″ A , wherein R″ A is C 1-4 alkyl.
22. The method of claim 1 , wherein R 3A is —OC(═O)CH 3 .
23. The method of claim 1 , wherein R 4A is OH.
24. The method of claim 1 , wherein R 4A is halogen.
25. The method of claim 1 , wherein R 4A is fluoro.
26. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
28. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
29. The method of claim 28 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
30. A method for inhibiting replication of 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 halogen, OH, and —OC(═O)R″ A ;
R 4A is selected from the group consisting of OH and halogen;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen, deuterium or cyano;
R 1A is selected from the group consisting of hydrogen,
R 2A is halogen or halogen(C 1-6 alkyl);
R 5A is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and cyano;
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;
R 8A is absent, hydrogen or aryl;
R 9A is N-alanine, N-valine, N-leucine, N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester or N-leucine isopropyl ester;
R 10A and R 11A are independently N-alanine, N-valine, N-leucine, N-alanine isopropyl ester, N-alanine cyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl ester or N-leucine isopropyl ester;
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, C 1-24 alkyl, and —O—C 1-24 alkyl;
R″ A is 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.