Pyrazolopyrimidine macrocycles as inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-9932356-B2
Application number	US-201515115758-A
Country	US
Kind code	B2
Filing date	Feb 10, 2015
Priority date	Feb 12, 2014
Publication date	Apr 3, 2018
Grant date	Apr 3, 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

where:
R 1 is hydrogen, alkyl, or cycloalkyl;
R 2 is hydrogen or alkyl;
R 3 is hydrogen, alkyl or halo;
R 4 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 halo or alkyl substituents;
R 5 is hydrogen or alkyl;
Ar 1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and is substituted with 0-3 alkyl substituents;
X 1 is CH, CH 2 , O, S, or NR 5 ;
X 2 is alkylene or alkenylene; and
X 3 is CH, CH 2 , CH 2 O, O, S, or NR 5 ;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 where R 1 is alkyl; R 2 is alkyl; R 3 is hydrogen; R 4 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl substituted with 0-3 alkyl substituents; Ar 1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and is substituted with 0-3 alkyl substituents; X 1 is CH 2 or O; X 2 is alkylene or alkenylene; and X 3 is CH, CH 2 or O; or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 where R 4 is piperidinyl substituted with 0-1 alkyl substituents; Ar 1 is phenyl; Ar 2 is pyrazolyl, imidazolyl, or thiazolyl substituted with 0-3 alkyl substituents; X 1 is CH 2 or O; X 2 is alkylene or alkenylene; and X 3 is CH, CH 2 or O; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 where R 1 is alkyl, R 2 is alkyl and R 3 is hydrogen.

5. A compound of claim 1 where R 4 is piperidinyl substituted with 0-3 alkyl substituents.

6. A compound of claim 1 where Ar 1 is phenyl.

7. A compound of claim 1 where Ar 2 is pyrazolyl, imidazolyl, or thiazolyl substituted with 0-3 alkyl substituents.

8. A compound of claim 1 X 1 is CH 2 or O; X 2 is alkylene or alkenylene; and X 3 is CH, CH 2 or O.

9. A compound of claim 1 where X 1 is CH 2 ; X 2 is alkylene or alkenylene; and X 3 is CH 2 .

10. A compound of claim 1 selected from the group consisting of
(2S)-tert-Butoxy[(21E)-4,25-dimethyl-24-oxa-1,5,7,8,15,30-hexaazahexacyclo[23.2.2.1 6,9 .1 10,14 .1 15,18 .0 2,7 ]dotriaconta-2,4,6(32),8,10(31),11,13,16,18(30),21-decaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,25-dimethyl-24-oxa-1,5,7,8,15,30-hexaazahexacyclo[23.2.2.1 6,9 .1 10,14 .1 15,18 .0 2,7 ]dotriaconta-2,4,6(32),8,10(31),11,13,16,18(30)-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,25-dimethyl-24-oxa-1,5,7,8,18,30-hexaazahexacyclo[23.2.2.1 6,9 .1 10,14 .1 15,18 .0 2,7 ]dotriaconta-2,4,6(32),8,10(31),11,13,15(30),16-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,24-dimethyl-23-oxa-1,5,7,8,18,29-hexaazahexacyclo[22.2.2.1 6,9 .1 10,14 .1 15,18 .0 2,7 ]hentriaconta-2,4,6(31),8,10(30),11,13,15(29),16-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,17,26-trimethyl-1,5,7,8,15,16-hexaazahexacyclo[24.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]dotriaconta-2,4,6(32),8,10(31),11,13,16,18-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,17,25-trimethyl-1,5,7,8,15,16-hexaazahexacyclo[23.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]hentriaconta-2,4,6(31),8,10(30),11,13,16,18-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,17,26-trimethyl-18-thia-1,5,7,8,16-pentaazahexacyclo[24.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]dotriaconta-2,4,6(32),8,10(31),11,13,15(19),16-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,17,25-trimethyl-18-thia-1,5,7,8,16-pentaazahexacyclo[23.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]hentriaconta-2,4,6(31),8,10(30),11,13,15(19),16-nonaen-3-yl]acetic acid;
(2S)-tert-Butoxy[4,16,17,26-tetramethyl-1,5,7,8,15,18-hexaazahexacyclo[24.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]dotriaconta-2,4,6(32),8,10(31),11,13,16,18,22-decaen-3-yl]acetic acid; and
(2S)-tert-Butoxy[4,16,17,26-tetramethyl-1,5,7,8,15,18-hexaazahexacyclo[24.2.2.1 6,9 .1 10,14 .0 2,7 .0 15,19 ]dotriaconta-2,4,6(32),8,10(31),11,13,16,18-nonaen-3-yl]acetic acid
or a pharmaceutically acceptable salt thereof.

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

12. 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 in need thereof.

Assignees

• Viiv Healthcare Uk No 5 Ltd

Inventors

• Kadow John F
• Langley David R
• Naidu B Narasimhulu
• Peese Kevin
• Wang Zhongyu

Classifications

• C07D471/22

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

• C07D498/22

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

• A61P31/18

  for HIV · CPC title

• C07D513/22 Primary

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