Pyrrolo[1,2-f][1,2,4]triazines useful for treating respiratory syncitial virus infections

Patent metadata

Field	Value
Publication number	US-9388208-B2
Application number	US-201414534715-A
Country	US
Kind code	B2
Filing date	Nov 6, 2014
Priority date	Nov 11, 2013
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

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.

First claim

What is claimed:

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:

Assignees

• Gilead Sciences Inc

Inventors

• Clarke Michael O'Neil Hanrahan
• Doerffler Edward
• Mackman Richard L
• Siegel Dustin

Classifications

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• C07H7/06 Primary

  Heterocyclic radicals · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title