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 selected from the group consisting of:
R 3A is selected from the group consisting of OH, —OC(═O)R″ A and an optionally substituted O-linked α-amino acid;
R 4A is halogen;
R a1 and R a2 are independently hydrogen or deuterium;
R A is hydrogen;
R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl, an optionally substituted O-linked α-amino acid,
R 2A is —(CH 2 ) 1-6 Cl or —(CH 2 ) 1-6 N 3 ;
R 5A is hydrogen or halogen;
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 8A is an optionally substituted 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, an optionally substituted C 1-24 alkyl and an optionally substituted —O—C 1-24 alkyl;
R 25A is an optionally substituted C 1-24 alkyl;
R″ A is an optionally substituted C 1-24 alkyl;
m is 0 or 1;
w is 0;
s is 0; and
Z 1A , Z 2A , Z 3A and Z 4A are each O.
2. The method of claim 1 , wherein the Filoviridae virus is Ebola virus.
3. The method of claim 1 , wherein the Filoviridae virus is Marburg virus.
4. The method of claim 1 , wherein the R 2A is (CH 2 ) 1-6 N 3 .
5. The method of claim 4 , wherein R 1A is hydrogen.
6. The method of claim 4 , wherein R 1A is an optionally substituted acyl.
7. The method of claim 6 , wherein the optionally substituted acyl has the formula of C(═O)R 39A , wherein R 39A is an optionally substituted C 1-12 alkyl.
8. The method of claim 4 , wherein R 1A is C(═O)-unsubstituted C 1-4 alkyl.
9. The method of claim 4 , wherein R 1A is
R 6A is
R 7A is absent or hydrogen; R 12A and R 13A are independently absent or hydrogen; and R 14A is O − or OH.
10. The method of claim 4 , wherein R 3A is OH.
11. The method of claim 4 , wherein R 3A is —OC(═O)R″ A .
12. The method of claim 11 , wherein R″ A is an unsubstituted C 1-4 alkyl.
13. The method of claim 4 , wherein R 4A is F.
14. The method of claim 4 , wherein R 5A is hydrogen.
15. The method of claim 7 , wherein R 3A is —OC(═O)R″ A .
16. The method of claim 15 , wherein R″ A is an unsubstituted C 1-4 alkyl.
17. 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.
18. 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.
19. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
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.