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;
R 2 is H;
R 3 is OH;
R 4 is CN, or C 1 -C 2 haloalkyl;
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 and 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, of Formula (II):
wherein:
R 3 is OH;
R 4 is CN or C 1 -C 2 haloalkyl;
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 5 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 and 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.
3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CN, —CH 2 Cl, —CH 2 F, —CHF 2 , or —CF 3 .
4. A compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CN, —CH 2 Cl, or —CH 2 F.
5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CN.
6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 2 haloalkyl.
7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CN or halomethyl.
8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
9. A compound according to claim 1 , 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.
10. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is
11. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is
12. A compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 12 is C 1 -C 8 alkyl.
13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group of:
14. A compound, or a pharmaceutically acceptable salt thereof, selected from the group of:
15. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 wherein the Pneumovirinae virus infection in the human is a human respiratory syncytial virus infection.
17. 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.
18. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound of claim 7 , or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 wherein the Pneumovirinae virus infection in the human is a human respiratory syncytial virus infection.
20. A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.