Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections

Patent metadata

Field	Value
Publication number	US-9732092-B2
Application number	US-201615349934-A
Country	US
Kind code	B2
Filing date	Nov 11, 2016
Priority date	Dec 21, 2012
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

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

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , X, W, Y 1 , Y 2 , Z 1 , and Z 4 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

What is claimed is:

1. A compound having Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
X is —O—;
W is —CHZ 2 —;
Z 1 and Z 2 , taken together, form -L- wherein L is —C(R a ) 2 C(R a ) 2 —;
Z 4 is —CH 2 —;
Y 1 and Y 2 are each independently hydrogen, C 1-3 alkyl or C 1-3 haloalkyl;

R 1 is phenyl substituted with one, two or three halogens; and
each R a is independently hydrogen, halo, hydroxy or C 1-4 alkyl.

2. The compound of claim 1 , wherein R 1 is substituted with one halogen.

3. The compound of claim 2 , wherein R 1 is 4-fluorophenyl or 2-fluorophenyl.

4. The compound of claim 1 , wherein R 1 is substituted with two halogens.

5. The compound of claim 4 , wherein R 1 is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

6. The compound of claim 5 , wherein R 1 is 2,4-difluorophenyl.

7. The compound of claim 1 , wherein R 1 is substituted with three halogens.

8. The compound of claim 7 , wherein R 1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

9. The compound of claim 8 , wherein R 1 is 2,4,6-trifluorophenyl.

10. The compound of claim 1 , wherein Y 1 and Y 2 are each independently hydrogen, methyl or trifluoromethyl.

11. The compound of claim 1 , having Formula (II-A):

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

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

14. RAE pharmaceutical composition of claim 13 , further comprising one or more additional therapeutic agents.

15. The pharmaceutical composition of claim 14 , wherein the one or more one additional therapeutic agents is an anti-human immunodeficiency virus agent.

16. The pharmaceutical composition of claim 15 , wherein the one or more additional therapeutic agents is selected from the group consisting of a human immunodeficiency virus protease inhibitor, a human immunodeficiency virus non-nucleoside inhibitor of reverse transcriptase, a human immunodeficiency virus nucleoside inhibitor of reverse transcriptase and a human immunodeficiency virus nucleotide inhibitor of reverse transcriptase, or a combination thereof.

Assignees

• Gilead Sciences Inc

Inventors

• Jin Haolun
• Lazerwith Scott E
• Pyun Hyung-Jung
• Bacon Elizabeth M
• Morganelli Philip Anthony
• Ji Mingzhe

Classifications

• A61P31/18

  for HIV · CPC title

• A61P43/00

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

• A61P31/12

  Antivirals · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07D471/22

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