Substituted nucleosides, nucleotides and analogs thereof
Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.
1. A method of treating a metapneumovirus infection comprising administering to a subject infected with the metapneumovirus an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the following structure:
wherein:
B 1A is an optionally substituted purine-base or an optionally substituted pyrimidine-base;
R 1A is selected from the group consisting of hydrogen, an optionally substituted acyl and
the dashed line (------) is absent;
R 2A is selected from the group consisting of an unsubstituted C 1-6 alkyl, a halogen substituted C 1-6 alkyl, a hydroxy substituted C 1-6 alkyl, an alkoxy substituted C 1-6 alkyl and a sulfenyl substituted C 1-6 alkyl;
R 3A is selected from the group consisting of OH and —OC(═O)R″ A ;
R 4A is fluoro;
R 5A is hydrogen;
R 6A and R 7A are independently absent or hydrogen; or
R 6A is
and R 7A is absent or hydrogen;
R 12A , R 13A and R 14A are independently absent or hydrogen;
R″ A is an unsubstituted C 1-6 alkyl;
m is 0 or 1; and
Z 1A is O.
2. The method of claim 1 , wherein the metaphenumovirus is human metapneumovirus.
3. The method of claim 1 , wherein R 1A is
4. The method of claim 3 , wherein R 6A and R 7A are both hydrogen or both absent.
5. The method of claim 1 , wherein R 6A is
and R 7A is absent or hydrogen.
6. The method of claim 5 , wherein m is 0; and R 12A and R 13A are independently absent or hydrogen.
7. The method of claim 5 , wherein m is 1; and R 12A , R 13A and R 14A are independently absent or hydrogen.
8. The method of claim 1 , wherein R 1A is H.
9. The method of claim 1 , wherein R 1A is an unsubstituted acyl.
10. The method of claim 9 , wherein the unsubstituted acyl is —C(═O)R 39A , wherein R 39A is an unsubstituted C 1-6 alkyl.
11. The method of claim 1 , wherein B 1A is an optionally substituted purine-base.
12. The method of claim 1 , wherein B 1A is
13. The method of claim 1 , wherein B 1A is
14. The method of claim 1 , wherein B 1A is
15. The method of claim 1 , wherein B 1A is an optionally substituted pyrimidine-base.
16. The method of claim 1 , wherein R 2A is a halogen substituted C 1-6 alkyl.
17. The method of claim 16 , wherein R 3A is OH.
18. The method of claim 16 , wherein R 3A is —OC(═O)R ″A , wherein R ″A is an unsubstituted C 1-6 alkyl.
19. The method of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
21. The method of claim 19 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient.
25. The method of claim 24 , wherein the compound of Formula (I) is
or a pharmaceutically acceptable salt thereof.