Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections
Provided herein are formulations, methods and substituted tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of tetrahydrofuranyl-pyrrolo[1,2-f][1,2,4]triazine-4-amine compounds.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is H or F;
R 2 is H or F;
R 3 is OH or F;
R 4 is CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 cycloalkyl, azido, halogen, or C 1 -C 2 haloalkyl, with the proviso that, when R 3 is F, R 4 is not methyl;
R 6 is OH;
R 5 is selected from the group of H and:
wherein:
n′ is selected from 1, 2, 3, and 4;
R 8 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 -C 3 -C 6 cycloalkyl, —O—CH 2 -C 3 -C 6 cycloalkyl, and CF 3 ;
R 9 is selected from phenyl, 1-naphthyl, 2-naphthyl,
R 10 is selected from H and CH 3 ;
R 11 is selected from H or C 1 -C 6 alkyl;
R 12 is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.
2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 1 and R 2 are H, and R 3 is OH.
3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 1 and R 2 are H, R 3 is F.
4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (II):
wherein:
R 3 is OH or F;
R 4 is CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 cycloalkyl, azido, halogen, or C 1 -C 2 haloalkyl, with the proviso that, when R 3 is F, R 4 is not methyl;
R 5 is selected from the group of H and:
wherein:
n′ is selected from 1, 2, 3, and 4;
R 8 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 -C 3 -C 6 cycloalkyl, —O—CH 2 -C 3 -C 6 cycloalkyl, and CF 3 ;
R 9 is phenyl;
R 10 is selected from H and CH 3 ;
R 11 is selected from H or C 1 -C 6 alkyl;
R 12 is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.
5. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CN, methyl, ethyl, ethenyl, ethynyl, azido, F, Cl, —CH 2 Cl, —CH 2 F, —CHF 2 , or —CF 3 .
6. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F.
7. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof,wherein R 3 is OH.
8. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F and R 4 is CN.
9. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is OH and R 4 is CN.
10. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F, and R 4 is methyl, ethyl, vinyl, or ethynyl.
11. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is OH, and R 4 is methyl, ethyl, vinyl, or ethynyl.
12. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F and R 4 is halomethyl.
13. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is OH and R 4 is halomethyl.
14. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
15. A compound according to claim 5 , or a pharmaceutically acceptable salt thereof,
wherein R 5 is selected from the group of:
R 8 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, and —CH 2 —C 3 -C 6 cycloalkyl; and
R 12 is selected from C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.
16. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each C 1 -C 8 alkyl.
17. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each selected from C 1 -C 6 alkyl.
18. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each selected from C 1 -C 4 alkyl.
19. A compound according to claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group of H and:
20. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
21. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
22. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
23. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
24. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
25. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
26. A method of treating Pneumovirinae virus infection in a human, the method comprising administering to the human a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 wherein the Pneumovirinae virus infection in a human is a human respiratory syncytial virus infection.
28. A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
29. A compound selected from Formula (A), Formula (B), Formula (C), Formula (D), and Formula (E):
wherein X 1 is an oxygen protecting group and X 2 is an amine protecting group.
30. A compound of claim 29 selected from: