Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections

Patent metadata

Field	Value
Publication number	US-11548901-B2
Application number	US-202016868119-A
Country	US
Kind code	B2
Filing date	May 6, 2020
Priority date	Dec 21, 2012
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

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 —NZ 3 —;
Z 1 and Z 3 , taken together, form -L-;
L is —C(R a ) 2 —;
each R a is independently H, halogen, OH, or C 1-4 alkyl:
W is —CHZ 2 —;
Z 2 is H or C 1-3 alkyl;
Z 4 is, —CH 2 ;
Y 1 is H, C 1-3 alkyl, or C 1-3 haloalkyl;
Y 2 is H, C 1-3 alkyl, or C 1-3 haloalkyl; and
R 1 is phenyl, wherein the phenyl is substituted with one, two, or three independently selected halogen substituents.

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

3. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one R a is halogen and the other R a is H.

4. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one R a is CH 3 and the other R a is H.

5. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Z 2 is H.

6. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y 1 is H, CH 3 , or CF 3 and Y 2 is H, CH 3 , or CF 3 .

7. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Y 1 is H and Y 2 is H.

8. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with one halogen substituent.

9. The compound of claim 8 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is 4-fluorophenyl or 2-fluorophenyl.

10. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with two independently selected halogen substituents.

11. The compound of claim 10 , or a stereoisomer or pharmaceutically acceptable salt thereof, 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.

12. The compound of claim 11 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is 2,4-difluorophenyl.

13. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with three independently selected halogen substituents.

14. The compound of claim 13 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

15. The compound of claim 14 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is 2,4,6-trifluorophenyl.

16. The compound of claim 1 , wherein the compound has Formula (II-B):

or a stereoisomer or pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

18. 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.

19. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition further comprising one or more additional therapeutic agents.

20. The pharmaceutical composition of claim 19 , wherein the additional therapeutic agent is an anti-human immunodeficiency virus agent.

21. The pharmaceutical composition of claim 20 wherein the one or more additional therapeutic agents is selected from the group consisting of human immunodeficiency virus protease inhibitors, human immunodeficiency virus non-nucleoside inhibitors of reverse transcriptase, human immunodeficiency virus nucleoside inhibitors of reverse transcriptase, human immunodeficiency virus nucleotide inhibitors of reverse transcriptase, and combinations thereof.

Assignees

• Gilead Sciences Inc

Inventors

• Bacon Elizabeth M
• Cai Zhenhong R
• Chen Xiaowu
• Cottell Jeromy J
• Desai Manoj C
• Ji Mingzhe
• Jin Haolun
• Lazerwith Scott E
• Mish Michael R
• Morganelli Philip Anthony
• Pyun Hyung-Jung
• Taylor James G
• Trejo Martin Teresa Alejandra

Classifications

• A61K31/529

  forming part of bridged ring systems · CPC title

• C07D498/18

  Bridged systems · CPC title

• A61K31/537

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61P31/18

  for HIV · CPC title

• C07D471/22

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