Substituted pyridines as inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-10189816-B2
Application number	US-201615749176-A
Country	US
Kind code	B2
Filing date	Aug 10, 2016
Priority date	Aug 11, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Disclosed are compounds of Formula (I), including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS. In the compounds of formula (I), R 1 is selected from hydrogen, alkyl, or cycloalkyl; R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents; R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; R 4 is selected from alkyl or haloalkyl; R 5 is alkyl; R 6 is selected from Ar 1 , (Ar 1 )alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl; and Ar 1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl.

First claim

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl;
R 2 is tetrahydroisoquinolinyl, substituted with 1 R 6 substituent and optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo and C 1-6 alkyl;
R 3 is piperidinyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cyano, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
R 4 is C 1-6 alkyl or C 1-6 haloalkyl;
R 5 is C 1-6 alkyl;
R 6 is (Ar 1 )C 1-6 alkyl; and
Ar 1 is phenyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of cyano, hydroxy, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, (hydroxy)C 1-6 alkoxy, (C 1-6 alkoxy)C 1-6 alkoxy, phenoxy, benzyloxy, carboxy, C 3-7 cycloalkyl, (cyano)C 3-7 cycloalkyl and phenyl.

2. A compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent selected from the group consisting of a nucleoside human immunodeficiency virus reverse transcriptase inhibitor, a non-nucleoside human immunodeficiency virus reverse transcriptase inhibitor, a human immunodeficiency virus protease inhibitor, a human immunodeficiency virus integrase inhibitor, a human immunodeficiency virus fusion inhibitor, a human immunodeficiency virus attachment inhibitor, a human immunodeficiency virus budding inhibitor, a human immunodeficiency virus maturation inhibitor, a C—C chemokine receptor type 5 inhibitor and a C—X—C chemokine receptor type 4 inhibitor.

5. The pharmaceutical composition of claim 4 , wherein the at least one additional therapeutic agent is dolutegravir.

6. A method for treating a human immunodeficiency virus infection in a patient, comprising administering to a patient in need thereof, a compound of claim 2 , or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 , wherein the method further comprises administering at least one additional therapeutic agent selected from the group consisting of a nucleoside human immunodeficiency virus reverse transcriptase inhibitor, a non-nucleoside human immunodeficiency virus reverse transcriptase inhibitor, a human immunodeficiency virus protease inhibitor, a human immunodeficiency virus integrase inhibitor, a human immunodeficiency virus fusion inhibitor, a human immunodeficiency virus attachment inhibitor, a human immunodeficiency virus budding inhibitor, a human immunodeficiency virus maturation inhibitor, a C—C chemokine receptor type 5 inhibitor and a C—X—C chemokine receptor type 4 inhibitor.

8. The method of claim 7 , wherein the at least one additional therapeutic agent is dolutegravir.

Assignees

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

Inventors

• Eastman Kyle J
• Kadow John F
• Parcella Kyle E
• Naidu B Narasimhulu
• Wang Tao
• Yin Zhiwei
• Zhang Zhongxing

Classifications

• A61P31/18

  for HIV · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/5365

  ortho- or peri-condensed with heterocyclic ring systems · CPC title