Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Patent metadata

Field	Value
Publication number	US-9630978-B2
Application number	US-201615089342-A
Country	US
Kind code	B2
Filing date	Apr 1, 2016
Priority date	Apr 2, 2015
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

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, A′, R 1 and R 2 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 a 4 to 7 membered monocyclic heterocyclyl saturated or partially unsaturated and optionally substituted with 1 to 5 R 3 groups;
each R 3 is independently selected from the group consisting of C 1-4 alkyl, halogen and oxo; or two R 3 connected to the same or adjacent carbon atoms form a spiro or fused C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring;
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 C 1-4 alkyl, halogen and oxo; 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 phenyl optionally substituted with 1 to 5 R 5 groups;
each R 5 is independently selected from the group consisting of halogen and C 1-3 alkyl; and
R 2 is selected from the group consisting of H, C 1-3 haloalkyl and C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 5 or 6 membered monocyclic heterocyclyl saturated or partially unsaturated and optionally substituted with 1 to 5 R 3 groups.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl and thiazolidinyl; each of which is optionally substituted with 1 to 5 R 3 groups.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl and thiazolidinyl; each of which is optionally substituted with one or two R 3 groups; wherein R 3 is C 1-4 alkyl; or two R 3 connected to the same or adjacent carbon atoms form a spiro or fused C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of oxazolidinyl, piperidinyl, 3,4-unsaturated piperidinyl, pyrrolidinyl, tetrahydro-1,3-oxazinyl and thiazolidinyl; each of which is optionally substituted with methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of C 5-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl; wherein each C 5-6 monocyclic cycloalkyl and 5 to 6 membered monocyclic heterocyclyl is optionally substituted with 1 to 5 R 4 groups.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally substituted with 1 to 5 R 4 groups.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of cyclopentyl, tetrahydrofuranyl, cyclohexyl 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 C 1-4 alkyl, halogen and oxo; or two R 2 connected to the same or adjacent carbon atoms form a spiro or fused C 3-6 cycloalkyl or 4 to 6 membered heterocyclyl ring.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally fused with a C 3-6 cycloalkyl ring.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from the group consisting of cyclopentyl, tetrahydrofuranyl, cyclohexyl and tetrahydropyranyl; each of which is optionally fused with a cyclopropyl group.

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

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

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

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

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

20. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt

Assignees

• Gilead Sciences Inc

Inventors

• Cai Zhenhong R
• Jin Haolun
• Lazerwith Scott E
• Pyun Hyung-Jung

Classifications

• C07D513/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title

• C07D491/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61P31/18

  for HIV · CPC title