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