Benzothiazole macrocycles as inhibitors of human immunodeficiency virus replication

Patent metadata

Field	Value
Publication number	US-9944656-B2
Application number	US-201515115790-A
Country	US
Kind code	B2
Filing date	Feb 11, 2015
Priority date	Feb 12, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 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 (R 7 )-piperazinyl or Ar 1 ;
R 5 is absent or Ar 2 ;
or R 5 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and oxetanyl;
R 6 is cycloalkyl or Ar 3 ;
R 7 is hydrogen or alkyl;
Ar 1 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl, triazolyl, or quinolinyl, and is substituted with 0-3 alkyl substituents;
Ar 2 is phenyl, pyridinyl, ((R 7 )-piperazinyl)pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl, pyrazolopyridinyl, benzotriazolyl, quinolinyl, or aminoquinolinyl, and is substituted with 0-3 alkyl substituents;
Ar 3 is phenyl, chromanyl, or dihydrobenzoxazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
X 1 is CH, CH 2 , O, S, or NR 7 ;
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 Ar 1 ; R 6 is chromanyl; X 1 is CH 2 , O, or NR 7 ; X 2 is alkylene; and X 3 is CH 2 ; or a pharmaceutically acceptable salt thereof.

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

4. A compound of claim 1 where R 4 is Ar 1 .

5. A compound of claim 1 where R 5 is Ar 2 .

6. A compound of claim 1 where R 5 is (R 7 )-piperazinyl.

7. A compound of claim 1 where Ar 3 is chromanyl.

8. A compound of claim 1 where X 1 is CH 2 , O, or NR 7 ; X 2 is alkylene; and X 3 is CH 2 .

9. A compound of claim 1 selected from the group consisting of
(2S)-2-(tert-Butoxy)-2-[(22S)-4,17,22-trimethyl-21,30-dioxa-8-thia-37-azaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36), 11,13,15(20),16,18,31,34-tridecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,19,21,25-tetramethyl-24,33-dioxa-8-thia-19,20,40-triazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 18 , 22 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),10(39),11,13,15(23),16,18(22),20,34,37-tetradecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,20,25-trimethyl-24,33-dioxa-8-thia-12,19,20,39,40-pentaazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 17 , 21 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),10(39),11,13,15(23),16,18,21,34,37-tetradecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(22S)-4,22-dimethyl-18-(4-methylpiperazin-1-yl)-21,30-dioxa-8-thia-13,19,37-triazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,15(20),16,18,31,34-tridecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,20,25-trimethyl-24,33-dioxa-8-thia-13,16,19,20,40-pentaazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 17 , 21 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),10(39),11,13,15(23),16,18,21,34,37-tetradecaen-3-yl]acetic acid;
(2S)-2-[(26S)-20-Amino-4,26-dimethyl-25,34-dioxa-8-thia-13,17,41-triazaoctacyclo[29.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 24 .0 18 , 23 .0 35 , 39 ]hentetraconta-1(37),2,4,6,9(41),10(40),11,13,15(24),16,18(23),19,21,35,38-pentadecaen-3-yl]-2-(tert-butoxy)acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,20,25-trimethyl-24,33-dioxa-8-thia-12,13,19,20,40-pentaazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 17 , 21 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),10(39),11,13,15(23),16,18,21,34,37-tetradecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-18-(propan-2-yl)-30-oxa-8-thia-13,15,18,36,37-pentaazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,18-dimethyl-26-oxa-8-thia-14,15,16,34-tetraazaheptacyclo[21.6.2.2 10 , 13 .1 6 , 9 .0 2 , 7 .0 12 , 16 .0 27 , 31 ]tetratriaconta-1(29),2,4,6,9(34),10,12,14,27,30,32-undecaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[(24S)-4,14,24-trimethyl-23,32-dioxa-8-thia-14,15,20,40-tetraazaoctacyclo[27.6.2.2 10 , 13 .1 6 , 9 .0 2 , 7 .0 12 , 16 .0 17 , 22 .0 33 , 37 ]tetraconta-1(35),2,4,6,9(40),10,12,15,17(22),18,20,33,36,38-tetradecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,14,20,23-tetramethyl-29-oxa-8-thia-14,15,17,20,38-pentaazaoctacyclo[24.6.2.2 10 , 13 .1 6 , 9 .1 17 , 21 .0 2 , 7 .0 12 , 16 .0 30 , 34 ]octatriaconta-1(32),2,4,6,9(38),10,12,15,30,33,36-undecaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,14,20,24-tetramethyl-31-oxa-8-thia-14,15,17,20,39-pentaazaoctacyclo[26.6.2.2 10 , 13 1 6 , 9 .0 2 , 7 .0 12 , 16 .0 17 , 22 , 32 , 36 ]nonatriaconta-1(34),2,4,6,9(39),10,12,15,32,35,37-undecaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,13,19,25-tetramethyl-24,33-dioxa-8-thia-10,13,19,20,40-pentaazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 18 , 22 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),15(23),16,18 (22),20,34,37-undecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,18,22-trimethyl-30-oxa-8-thia-12,15,18,36,37-pentaazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-18-(propan-2-yl)-30-oxa-8-thia-15,18,36,37-tetraazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-18-(oxetan-3-yl)-30-oxa-8-thia-15,18,36,37-tetraazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,18-dimethyl-19,28-dioxa-8-thia-13,15,36,37-tetraazaheptacyclo[23.6.2.2 15 , 18 .1 6 , 9 .1 10 , 14 .0 2 , 7 .0 29 , 33 ]heptatriaconta-1(31),2,4,6,9(37),10(36),11,13,29,32-decaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,18-dimethyl-27-oxa-8-thia-13,15,18,34,35-pentaazaheptacyclo[22.6.2.1 6 , 9 .1 10 , 14 .1 15 , 17 .0 2 , 7 .0 28 , 32 ]pentatriaconta-1(30),2,4,6,9(35),10(34),11,13,28,31-decaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,19-dimethyl-29-oxa-8-thia-13,15,19,37,38-pentaazaheptacyclo[24.6.2.2 15 , 18 .1 6 , 9 .1 10 , 14 .0 2 , 7 .0 30 , 34 ]octatriaconta-1(32),2,4,6,9(38),10(37),11,13,30,33-decaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-18-(oxetan-3-yl)-30-oxa-8-thia-13,15,18,36,37-pentaazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,18,22-trimethyl-30-oxa-8-thia-13,15,18,36,37-pentaazaheptacyclo[25.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 20 .0 31 , 35 ]heptatriaconta-1(33),2,4,6,9(37),10(36),11,13,31,34-decaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[(25S)-4,20,25-trimethyl-24,33-dioxa-8-thia-13,19,20,40-tetraazaoctacyclo[28.6.2.1 6 , 9 .1 10 , 14 .0 2 , 7 .0 15 , 23 .0 18 , 22 .0 34 , 38 ]tetraconta-1(36),2,4,6,9(40),10(39),11,13,15(23),16,18,21,34,37-tetradecaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,21-dimethyl-18-(propan-2-yl)-29-oxa-8-thia-15,18,36,37-tetraazaheptacyclo[24.6.2.2 6 , 9 .1 10 , 14 .1 15 , 19 .0 2 , 7 .0 30 , 34 ]heptatriaconta-1(32),2,4,6,9(37),10(36),11,13,30,33-decaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-18-(propan-2-yl)-30-oxa-8-thia-1

Assignees

• Viiv Healthcare Uk No 5 Ltd

Inventors

• Naidu B Narasimhulu
• Patel Manoj

Classifications

• C07D515/22

  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

• C07D513/16

  Peri-condensed systems · CPC title