Methods for treating
Provided are methods for treating Arenaviridae and Coronaviridae virus infections by administering nucleosides and prodrugs thereof, of Formula I: wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Lassa virus and Junin virus infections.
1. A method for treating Coronaviridae infection in a human in need thereof, comprising administering a therapeutically effective amount of a compound of Formula III:
or a pharmaceutically acceptable salt thereof;
wherein
R 2 and R 3 are each OR a ;
R 6 is CN;
R 7 is —(C═O)R 11 or
R 8 is NH 2 ;
R 9 is H;
each occurrence of R a is independently H or —(C═O)R;
R 11 is H or (C 1 -C 8 )alkyl which is optionally substituted by NH 2 ;
each occurrence of R is independently H or (C 1 -C 8 )alkyl which is optionally substituted by NH 2 ;
R f is H or (C 1 -C 8 )alkyl; and
one or more hydrogens attached to a carbon of the compound are optionally replaced by deuterium.
2. The method of claim 1 , wherein R 7 is
3. The method of claim 2 , wherein R f is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.
4. The method of claim 1 , wherein R 2 and R 3 are each OH.
5. The method of claim 4 , wherein R 7 is —(C═O)R 11 and R 11 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
6. The method of claim 5 , wherein R 11 is —CH(CH 3 ) 2 .
7. The method of claim 5 , wherein R 11 is —CH(NH 2 )CH(CH 3 ) 2 .
8. The method of claim 5 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
9. The method of claim 6 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
10. The method of claim 7 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
11. The method of claim 1 , wherein R 2 and R 3 are each —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl groups of R 2 and R 3 are each optionally substituted with NH 2 .
12. The method of claim 11 , wherein the (C 1 -C 8 )alkyl groups of R 2 and R 3 are each selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted with NH 2 .
13. The method of claim 12 , wherein each of R 2 and R 3 is selected from the group consisting of —O(C═O)—CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
14. The method of claim 13 , wherein R 2 and R 3 are —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 and —O(C═O)—CH(CH 3 ) 2 , respectively; —O(C═O)—CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 , respectively; or —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 and —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 , respectively.
15. The method of claim 13 , wherein R 2 and R 3 are each —O(C═O)—CH(CH 3 ) 2 .
16. The method of claim 11 , wherein R 7 is —(C═O)R 11 and R 11 is —(C 1 -C 8 )alkyl optionally substituted by NH 2 .
17. The method of claim 16 , wherein R 11 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
18. The method of claim 17 , wherein R 11 is —CH(CH 3 ) 2 .
19. The method of claim 17 , wherein R 11 is —CH(NH 2 )CH(CH 3 ) 2 .
20. The method of claim 11 , wherein R 2 is —O(C═O)—CH(CH 3 ) 2 , R 3 is —O(C═O)—CH(CH 3 ) 2 , R 7 is —(C═O)R 11 , and R 11 is —CH(CH 3 ) 2 .
21. The method of claim 18 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
22. The method of claim 19 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
23. The method of claim 20 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
24. The method of claim 20 , wherein one hydrogen attached to a carbon of the compound is replaced by deuterium.
25. The method of claim 1 , wherein R 2 is OH and R 3 is —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl of R 3 is optionally substituted by NH 2 .
26. The method of claim 25 , wherein the (C 1 -C 8 )alkyl of R 3 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
27. The method of claim 26 , wherein R 3 is —O(C═O)—CH(CH 3 ) 2 .
28. The method of claim 26 , wherein R 3 is —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
29. The method of claim 25 , wherein R 7 is —(C═O)R 11 and R 11 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
30. The method of claim 29 , wherein R 11 is —CH(CH 3 ) 2 .
31. The method of claim 29 , wherein R 11 is —CH(NH 2 )CH(CH 3 ) 2 .
32. The method of claim 30 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
33. The method of claim 31 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
34. The method of claim 1 , wherein R 3 is OH and R 2 is —O(C═O)(C 1 -C 8 )alkyl, wherein the (C 1 -C 8 )alkyl of R 2 is optionally substituted by NH 2 .
35. The method of claim 34 , wherein the (C 1 -C 8 )alkyl of R 2 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, or 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
36. The method of claim 35 , wherein R 2 is —O(C═O)—CH(CH 3 ) 2 .
37. The method of claim 35 , wherein R 2 is —O(C═O)—CH(NH 2 )CH(CH 3 ) 2 .
38. The method of claim 34 , wherein R 7 is —(C═O)R 11 and R 11 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl, each of which is optionally substituted by NH 2 .
39. The method of claim 38 , wherein R 11 is —CH(CH 3 ) 2 .
40. The method of claim 38 , wherein R 11 is —CH(NH 2 )CH(CH 3 ) 2 .
41. The method of claim 39 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
42. The method of claim 40 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.
43. The method of claim 1 , wherein the Coronaviridae infection is caused by a SARS virus.
44. The method of claim 1 , wherein the Coronaviridae infection is caused by a Coronaviridae virus selected from the group consisting of SARS, MERS, 229E, NL63, OC43, and HKU1.
45. The method of claim 1 , wherein one or more hydrogens attached to a carbon of the compound are replaced by deuterium.