Inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-9938271-B2
Application number	US-201515119465-A
Country	US
Kind code	B2
Filing date	Feb 13, 2015
Priority date	Feb 19, 2014
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The disclosure generally relates to compounds of formula I, including compositions and methods for treating human immunodeficiency virus (HIV) infection. The disclosure provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.

First claim

We claim:

1. A compound of Formula I or Formula II

where:
R 1 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkenyl, Ar 1 , (Ar 1 )alkyl, and (Ar 1 )O;
R 2 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, and phenyl;
or R 2 is cycloalkyl, cycloalkenyl, chromanyl, oxazinyl, or dihydropyranoquinolinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, and phenyl;
R 3 is alkyl or haloalkyl;
R 4 is alkyl;
R 5 is hydrogen or alkyl;
Ar 1 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkenyloxy;
X 1 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, benzimidazolyl, or phenyl;
X 2 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
X 3 is O or absent;
X 4 is alkylene or alkenylene;
X 5 is O or absent; and
X 6 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 halo or alkyl substituents;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 according to Formula I where R 1 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkenyl, Ar 1 , (Ar 1 )alkyl, and (Ar 1 )O; R 2 is piperidinyl substituted with 0-3 alkyl substituents or R 2 is chromanyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, and phenyl; R 3 is alkyl; R 4 is alkyl; R 5 is hydrogen; and Ar 1 is phenyl substituted with 0-3 substituents selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkenyloxy; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 according to Formula II where X 1 is phenyl; X 2 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; X 3 is O or absent; X 4 is alkylene or alkenylene; X 5 is O or absent; and X 6 is piperidinyl substituted with 0-3 alkyl substituents; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 where R 1 is phenyl substituted with 1 Ar 1 substituent.

5. A compound of claim 1 where R 2 is cycloalkyl, cycloalkenyl, chromanyl, oxazinyl, or dihydropyranoquinolinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, and phenyl.

6. A compound of claim 1 where Ar 1 is phenyl substituted with 0-3 substituents selected from halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkenyloxy.

7. A compound of claim 1 where X 1 is phenyl.

8. A compound of claim 1 where X 6 is piperidinyl substituted with 0-3 halo or alkyl substituents.

9. A compound of claim 1 selected from the group consisting of
(2S)-2-(tert-Butoxy)-2-(8-(8-fluoro-5-methylchroman-6-yl)-2-(4′-fluoro-[1,1′-biphenyl]-3-yl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetic acid;
(2S)-2-(tert-Butoxy)-2-(8-(8-fluoro-5-methylchroman-6-yl)-2-(2′-fluoro-[1,1′-biphenyl]-3-yl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetic acid;
(2S)-2-(tert-Butoxy)-2-(2-(2′-fluoro-[1,1′-biphenyl]-3-yl)-8-(2-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetic acid;
(2S)-2-(tert-Butoxy)-2-(8-(8-fluoro-5-methylchroman-6-yl)-6-methyl-2-(2′-methyl-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-7-yl)acetic acid;
(S)-2-(tert-Butoxy)-2-(8-(chroman-6-yl)-2-(2′-fluoro-[1,1′-biphenyl]-3-yl)-6-methylimidazo[1,2-a]pyridin-7-yl)acetic acid;
(S)-2-(tert-Butoxy)-2-(8-(chroman-6-yl)-6-methyl-2-(2′,3′,4′-trifluoro-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-7-yl)acetic acid;
(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,6,8-triazahexacyclo[26.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,20 ]tetratriaconta-2,4,7,9(34),10(33),11,13,15,17,19-decaen-3-yl]acetic acid; and
(2S)-2-(tert-Butoxy)-2-[(22S)-34-tert-butyl-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,6,8-triazahexacyclo[26.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,20 ]tetratriaconta-2,4,7,9(34),10(33),11,13,15,17,19-decaen-3-yl]acetic acid;
or a pharmaceutically acceptable salt thereof.

10. A composition useful for treating HIV infection comprising a therapeutic amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. A method for treating HIV infection comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient.

Assignees

• Viiv Healthcare Uk No 5 Ltd
• Viiv Healthcare Uk No 5 Ltd

Inventors

• Eastman Kyle J
• Kadow John F
• Naidu B Narasimhulu
• Parcella Kyle E
• Peese Kevin

Classifications

• A61P31/18

  for HIV · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/22

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