Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Patent metadata

Field	Value
Publication number	US-9522912-B2
Application number	US-201514977347-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Dec 23, 2014
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

Compounds for use in the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (Ia):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein A′, R 1 , R 2 and R 3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

First claim

We claim:

1. A compound of Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein:
A′ is selected from the group consisting of C 3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl; wherein each C 3-7 monocyclic cycloalkyl and 4 to 7 membered monocyclic heterocyclyl is optionally substituted with 1 to 5 R 4 groups;
each R 4 is independently selected from the group consisting of oxo, methyl, and ethyl; or two R 4 connected to the same or adjacent carbon atoms form a spiro or fused C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;
R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
R 2 is selected from the group consisting of hydrogen, C 1-3 haloalkyl and C 1-3 alkyl;
R 3 is selected from the group consisting of phenyl substituted with at least 3 R 5 groups; and
each R 5 is independently selected from the group consisting of C 1-3 alkyl and halogen.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of cyclohexyl, cyclopentyl, tetrahydrofuranyl and tetrahydropyranyl; each of which is optionally substituted with one or two R 4 groups, wherein each R 4 is independently selected from the group consisting of oxo and methyl; or two R 4 connected to the same or adjacent carbon atoms form a spiro dioxolane or a fused cyclopropyl ring.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is substituted with two R 4 groups, wherein the two R 4 connected to the same or adjacent carbon atoms form a spiro dioxolane or a fused cyclopropyl ring.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, CH 2 CF 3 , CH 2 CHF 2 and cyclopropyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-4 haloalkyl and C 3-6 cycloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, CHF 2 and methyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl and R 2 is hydrogen.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted with three R 5 groups, wherein each R is independently selected from the group consisting of methyl, ethyl, and halogen.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted with three R 5 groups, wherein each R 5 is independently selected from the group consisting of fluoro and chloro.

13. The compound of claim 1 having the Formula (Ib)

or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , and X 3 are each independently selected from the group consisting of CHR 4 , O, C═O and CH 2 CHR 4 ; provided that no more than one of X 1 , X 2 , and X 3 is O or C═O;
each R 4 is independently selected from the group consisting of H and CH 3 ;
R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 haloalkyl and C 3-6 cycloalkyl;
R 2 is selected from the group consisting of hydrogen, C 1-3 haloalkyl and C 1-3 alkyl;
R 3 is selected from the group consisting of phenyl substituted with three R 5 groups;
each R 5 is independently selected from the group consisting of C 1-3 alkyl and halogen.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein X 3 is CHR 4 ; and X 1 and X 2 are each independently O, CHR 4 or C═O.

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

16. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein —X 1 —X 2 —X 3 — is selected from the group consisting of —CH 2 —CH 2 —CH 2 —, —CH 2 —O—CH 2 —, and —O—CH 2 —CH 2 —.

17. The compound of claim j, or a pharmaceutically acceptable salt thereof, wherein one of X 1 and X 3 is CH 2 CHR 4 and the other one of X 1 and X 3 is CHR 4 ; and X 2 is O, CHR 4 or C═O.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —H.

19. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein —X 1 —X 2 —X 3 — is selected from the group consisting of —CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —O—CH—CH 2 —, —CH(CH 3 )—O—CH 2 —CH 2 —, —CH 2 —CH 2 —O—CH 2 —, and —CH 2 —C(O)—CH 2 —CH 2 —.

20. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, methyl and CHF 2 .

21. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 haloalkyl.

22. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

23. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

24. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

25. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

26. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

27. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

Assignees

• Gilead Sciences Inc

Inventors

• Bacon Elizabeth M
• Cai Zhenhong R
• Cottell Jeromy J
• Ji Mingzhe
• Jin Haolun
• Lazerwith Scott E
• Morganelli Philip Anthony
• Pyun Hyung-Jung

Classifications

• A61P31/18

  for HIV · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D491/147 Primary

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title