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
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.
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.