Thieno[3,2-d]pyrimidine, furo[3,2-d]pyrimidine, and pyrrolo[3,2-D]pyrimidines useful for treating respiratory syncitial virus infections

Patent metadata

Field	Value
Publication number	US-9828388-B2
Application number	US-201514806227-A
Country	US
Kind code	B2
Filing date	Jul 22, 2015
Priority date	Jul 28, 2014
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

Provided herein are formulations, methods and substituted thieno[3,2-d]pyrimidine, furo[3,2-d]pyrimidine, and pyrrolo[3,2-d]pyrimidine compounds of Formula (I) for treating Pneumovirinae virus infections, including respiratory syncytial virus infections, as well as methods and intermediates for synthesis of substituted thieno[3,2-d]pyrimidine, furo[3,2-d]pyrimidine, and pyrrolo[3,2-d]pyrimidine compounds.

First claim

What is claimed is:

1. A compound of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein:
R 2 is F, Cl, OH, NH 2 , CN, and N 3 ;
R 3 is selected from the group of CN, N 3 , methyl, ethyl, propyl, vinyl, propenyl, ethynyl, CH 2 F, CHF 2 , CH 2 Cl, CH 2 SMe, and CH 2 OMe; and
R 4 is H or group of the formula:

wherein W 1 and W 2 are each, independently, OH or a group of the Formula Ia:

wherein:
each Y is independently a bond or O;
m is 0, 1, 2, or 3;
each R x is H, halogen or OH;
or
R 4 is selected from H and:

wherein:
n′ is selected from 1, 2, 3, and 4;
R 7 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 8 is selected from phenyl, 1-naphthyl, 2-naphthyl,

R 9 is selected from H and CH 3 ;
R 10 is selected from H or C 1 -C 6 alkyl;
R 11 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 of Formula (IX):

wherein:
R 1 is selected from the group of H, CH 3 , F, Cl, and NH 2 ;
R 2 is selected from the group of F, Cl, OH, NH 2 , CN, and N 3 ; and
R 3 is selected from the group of CN, N 3 , methyl, ethyl, propyl, vinyl, propenyl, ethynyl, CH 2 F, CHF 2 , CH 2 Cl, CH 2 SMe, and CH 2 OMe;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is F.

5. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is F.

6. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl.

7. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is N 3 .

8. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group of CN and N 3 .

9. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group of methyl, ethyl, and propyl.

10. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group of CH 2 F, CHF 2 , and CH 2 Cl.

11. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group of:

12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein R 8 , R 9 , R 10 , and R 11 are as defined in claim 1 .

13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein R 8 , R 9 , R 10 , and R 11 are as defined in claim 1 .

14. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein n′ is selected from 1, 2, 3, and 4; and R 7 is selected from the group of 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 .

15. A compound, or a pharmaceutically acceptable salt thereof, selected from the group of:

16. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 wherein the Pneumovirinae virus infection is a respiratory syncytial virus infection.

18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

19. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

20. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

21. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition comprising a compound of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human in need thereof a therapeutically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.

24. The method of claim 23 wherein the Pneumovirinae virus infection is a respiratory syncytial virus infection.

25. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human in need thereof a therapeutically effective amount of a compound of claim 8 , or a pharmaceutically acceptable salt thereof.

26. The method of claim 25 wherein the Pneumovirinae virus infection is a respiratory syncytial virus infection.

27. A method of treating Pneumovirinae virus infection in a human in need thereof, the method comprising administering to the human in need thereof a therapeutically effective amount of a compound of claim 15 , or a pharmaceutically acceptable salt thereof.

28. The method of claim 27 wherein the Pneumovirinae virus infection is a respiratory syncytial virus infection.

Assignees

• Gilead Sciences Inc

Inventors

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

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title