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

Patent metadata

Field	Value
Publication number	US-10059716-B2
Application number	US-201715610104-A
Country	US
Kind code	B2
Filing date	May 31, 2017
Priority date	Nov 11, 2013
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

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;
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.

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07H7/06

  Heterocyclic radicals · CPC title

• C07D405/04

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