Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-10351546-B2
Application number	US-201615749584-A
Country	US
Kind code	B2
Filing date	Aug 10, 2016
Priority date	Aug 12, 2015
Publication date	Jul 16, 2019
Grant date	Jul 16, 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.

First claim

We claim:

1. A compound of Formula I

wherein:
R 1 is selected from hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxy)alkoxyalkyl, ((cycloalkyl)alkoxy)alkyl, (cycloalkoxy)alkyl, haloalkoxyalkyl, (haloalkoxy)alkoxyalkyl, ((halocycloalkyl)alkoxy)alkyl, (halocycloalkoxy)alkyl, (halophenoxy)alkyl, (Ar 1 )alkyl, (Ar 2 )alkyl, ((R 10 )(R 11 )N)alkyl, (trialkylammonium)alkyl, (R 6 )alkyl, alkenyl, (alkoxy)alkenyl, hydroxy, alkoxy, (Ar 1 )alkoxy, (R 10 )(R 11 )N, CO 2 R 10 , CON(R 10 )(R 11 ), ((Ar 1 )alkyl)imidazolyl, or halobenzimidazolyl;
provided that when R 1 is hydrogen R 5 is not alkyl;
R 2 is selected from halo, phenyl or tetrahydroisoquinolinyl and is substituted with 1 R 7 substituent and with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
provided that when R 2 is halo, R 1 and R 5 are not simultaneously alkyl;
R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or homopiperidinyl substituted with 0-3 halo or alkyl substituents;
R 4 is selected from alkyl or haloalkyl;
R 5 is selected from hydrogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, (alkoxy)alkoxyalkyl, (((alkoxy)alkoxy)alkoxy)alkyl, ((benzyloxy)alkoxy)alkyl, ((R 10 )(R 11 )N)alkyl, or (R 6 )alkyl;
provided that R 1 and R 5 are not simultaneously alkyl;
R 6 is selected from (oxetanyl)alkyl, ((oxetanyl)alkoxy)alkyl, (tetrahydropyranyloxy)alkyl, (tetrahydropyranyl)alkoxy)alkyl, ((pyrrolidinonyl)alkoxy)alkyl, (Ar 1 O)alkyl, ((Ar 1 )alkoxy)alkyl, ((Ar 2 )alkoxy)alkyl, (oxetanyl)oxy, ((R 8 )(R 9 )N)alkoxy, alkylthio, alkylsulfonyl, or (R 8 )(R 9 )N;
R 7 is selected from (Ar 1 )alkyl, (Ar 1 )alkoxy, N-alkoxycarbonyl, or ((Ar 1 )alkyl)HNCO;
or R 7 is selected from pyrimidinyl, benzofuropyrimidinyl, or pyrazolopyrimidinyl substituted with 0-1 alkyl substituents;
R 8 is selected from hydrogen, alkyl, (cycloalkyl)alkyl, alkoxyalkyl, (tetrahydropyanyl)alkyl, tetrahydropyanyl, or alkoxyphenyl;
R 9 is selected from hydrogen or alkyl;
or (R 8 )(R 9 )N taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, (spirocyclobutyl)piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxidothiomorpholinyl, and is substituted with 0-3 alkyl or alkoxycarbonyl substituents;
R 10 is selected from hydrogen, alkyl, or alkoxyalkyl;
R 11 is selected from hydrogen, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, (oxetanyl)alkyl, (tetrahydropyanyl)alkyl, (Ar 1 )alkyl, (Ar 2 )alkyl, (((Ar 1 )alkyl)carbonyl)alkyl, oxetanyl, Ar 1 , formyl, alkylcarbonyl, (Ar 2 )carbonyl, (dialkylamino)oxoacetyl, or alkylsulfonyl;
or (R 10 )(R 11 )N taken together is selected from azetidinyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, [3.1.1]diazabicycloheptanyl, [3.2.1]diazabicyclooctanyl, or tetrhydroquinolinyl and is substituted with 0-3 halo, alkyl, haloalkyl, benzyl, hydroxy, alkoxy, or haloalkoxy substituents and with 0-1 (C 3-7 )spiroalkylenyl substituents;
Ar 1 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and
Ar 2 is selected from pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or pyridinyl and is substituted with 0-3 halo or alkyl substituents;
or a pharmaceutically acceptable salt thereof.

2. A compound or salt of claim 1 wherein R 1 is hydrogen and R 5 is hydrogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxy)alkoxyalkyl, (((alkoxy)alkoxy)alkoxy)alkyl, ((benzyloxy)alkoxy)alkyl, ((R 10 )(R 11 )N)alkyl, or (R 6 )alkyl.

3. A compound or salt of claim 1 wherein R 1 is alkyl and R 5 is hydrogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, (alkoxy)alkoxyalkyl, (((alkoxy)alkoxy)alkoxy)alkyl, ((benzyloxy)alkoxy)alkyl, ((R 10 )(R 11 )N)alkyl, or (R 6 )alkyl.

4. A compound or salt of claim 1 wherein R 2 is phenyl substituted with 1 R 7 substituent and with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

5. A compound or salt of claim 1 wherein R 2 is tetrahydroisoquinolinyl and is substituted with 1 R 7 substituent.

6. A compound or salt of claim 1 wherein R 3 is piperidinyl substituted with 0-3 halo or alkyl substituents.

7. A compound of or salt claim 1 wherein one of R 1 or R 5 are alkyl.

8. A compound or salt of claim 1 wherein R 2 is halo.

9. A compound or salt of claim 8 wherein one of R 1 or R 5 are alkyl.

10. A compound or salt of claim 1 wherein R 7 is selected from (Ar 1 )alkyl, (Ar 1 )alkoxy, N-alkoxycarbonyl, or ((Ar 1 )alkyl)HNCO.

11. A compound or salt of claim 1 wherein R 7 is selected from pyrimidinyl, benzofuropyrimidinyl, or pyrazolopyrimidinyl substituted with 0-1 alkyl substituents.

12. A compound or salt of claim 1 wherein R 9 is selected from hydrogen or alkyl.

13. A compound or salt of claim 1 wherein (R 8 )(R 9 )N taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, (spirocyclobutyl)piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxidothiomorpholinyl, and is substituted with 0-3 alkyl or alkoxycarbonyl substituents.

14. A compound or salt of claim 1 wherein R 11 is selected from hydrogen, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, alkoxyalkyl, (oxetanyl)alkyl, (tetrahydropyanyl)alkyl, (Ar 1 )alkyl, (Ar 2 )alkyl, (((Ar 1 )alkyl)carbonyl)alkyl, oxetanyl, Ar 1 , formyl, alkylcarbonyl, (Ar 2 )carbonyl, (dialkylamino)oxoacetyl, or alkylsulfonyl.

15. A compound or salt of claim 1 wherein (R 10 )(R 11 )N taken together is selected from azetidinyl, bicyclo[1.1.1]pentanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, [3.1.1]diazabicycloheptanyl, [3.2.1]diazabicyclooctanyl, or tetrhydroquinolinyl and is substituted with 0-3 halo, alkyl, haloalkyl, benzyl, hydroxy, alkoxy, or haloalkoxy substituents and with 0-1 (C 3-7 )spiroalkylenyl substituents.

16. A pharmaceutical composition comprising a compound or salt of claim 1 .

17. The pharmaceutical composition of claim 16 further comprising dolutegravir.

18. A method for treating HIV infection comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

19. The method of claim 18 further comprising administration of dolutegravir.

Assignees

• Viiv Healthcare Uk No 5 Ltd

Inventors

• Eastman Kyle J
• Kadow John F
• Naidu B Narasimhulu
• Parcella Kyle E
• Patel Manoj
• Sivaprakasam Prasanna
• Tu Yong

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P31/18

  for HIV · CPC title