Pyrazolopyrimidine Macrocycles as Inhibitors of Human Immunodeficiency Virus Replication

Patent metadata

Field	Value
Publication number	US-2015232481-A1
Application number	US-201514619728-A
Country	US
Kind code	A1
Filing date	Feb 11, 2015
Priority date	Feb 19, 2014
Publication date	Aug 20, 2015
Grant date	—

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 making and using these compounds in the treatment of HIV infection.

First claim

We claim:

1 . A compound of Formula I

where:
R 1 is alkyl or haloalkyl;
R 2 is hydrogen or alkyl;
R 3 is hydrogen, halo, or alkyl;
R 4 is hydrogen, alkyl, or cycloalkyl;
R 5 is hydrogen, alkyl, or (Ar 4 )alkyl;
Ar 1 is phenyl or naphthyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 2 is pyrrolyl, pyrazolyl, or triazolyl substituted with 0-2 alkyl substituents;
Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 4 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
X 1 is alkylene, alkenylene, —CH 2 O—, —CH 2 OCH 2 —, —CH 2 N(R 4 )CH 2 —, or —CH 2 CON(R 4 )—;
X 2 is —O—, —Ar 1 —, —Ar 2 —, —CON(R 5 )—, —(Ar 3 )CH—, -((benzyloxy)CH 2 )CH—,)-, —O(Ar 3 )CH—, —CH 2 CON(R 5 )—, or —N(R 5 )COCON(R 5 )—;
X 3 is absent, —O—, alkyloxy, cycloalkyloxy, cycloalkyl, Ar 3 , (Ar 3 )O—, or ((Ar 3 )alkyl)O—;
X 4 is alkylene, alkenylene, alkyleneoxy, or alkenyleneoxy;
X 5 is absent or —O—; 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 where R 1 is alkyl or haloalkyl; R 2 is hydrogen or alkyl; R 3 is hydrogen, halo, or alkyl; R 4 is hydrogen, alkyl, or cycloalkyl; R 5 is hydrogen, alkyl, or (Ar 4 )alkyl; Ar 1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar 3 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar 4 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; X 1 is alkylene, alkenylene, —CH 2 O—, —CH 2 OCH 2 —, —CH 2 N(R 4 )CH 2 —, or —CH 2 CON(R 4 )—; X 2 is —O—, —Ar 1 —, —CON(R 5 )—, —(Ar 3 )CH—, -((benzyloxy)CH 2 )CH—,)-, —O(Ar 3 )CH—, —CH 2 CON(R 5 )—, or —N(R 5 )COCON(R 5 )—; X 3 is absent, —O—, alkyloxy, cycloalkyloxy, cycloalkyl, Ar 3 , (Ar 3 )O—, or ((Ar 3 )alkyl)O—; X 4 is alkylene, alkenylene, alkyleneoxy, or alkenyleneoxy; X 5 is absent or —O—; and X 6 is piperidinyl substituted with 0-3 halo or alkyl substituents; or a pharmaceutically acceptable salt thereof.

3 . A compound of claim 1 where X 2 is Ar 1 .

4 . A compound of claim 1 where X 3 is absent or —O—; X 4 is alkylene or alkenylene; and X 5 is —O—.

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

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

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

8 . A compound of claim 1 selected from the group consisting of
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27),18-heptaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,22-dimethyl-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27)-hexaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,15,15,22-tetramethyl-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27),19-heptaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,15,15,22-tetramethyl-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27),17-heptaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,28-dimethyl-22,27-dioxa-1,5,7,8,11,12,13-heptaazahexacyclo[26.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 .0 15 , 20 ]tetratriaconta-2,4,6(34),8,12,14(33),15(20),16,18-nonaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,26-dimethyl-20,25-dioxa-1,5,7,8,11,12,13-heptaazahexacyclo[24.2.2.1 6 , 9 .1 11 , 14 .1 15 , 19 .0 2 , 7 ]tritriaconta-2,4,6(33),8,12,14(32),15(31),16,18-nonaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4′,22′-dimethyl-16′,21′-dioxa-1′,5′,7′,8′,11′,12′,13′-heptaazaspiro[cyclohexane-1,15′-pentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosane]-2′,4′,6′(28′),8′,12′,14′(27′), 19′-heptaen-3′-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4′,22′-dimethyl-16′,21′-dioxa-1′,5′,7′,8′,11′,12′,13′-heptaazaspiro[cyclohexane-1,15′-pentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosane]-2′,4′,6′(28′),8′,12′,14′(27′)-hexaen-3′-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-15-(propan-2-yl)-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27),19-heptaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-15-(propan-2-yl)-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27)-hexaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,22-dimethyl-15-(2-methylpropyl)-16,21-dioxa-1,5,7,8,11,12,13-heptaazapentacyclo[20.2.2.1 6 , 9 .1 11 , 14 .0 2 , 7 ]octacosa-2,4,6(28),8,12,14(27)-hexaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,24-dimethyl-12-oxo-23-oxa-1,5,7,8,11-pentaazapentacyclo[22.2.2.1 6 , 9 .0 2 , 7 .0 13 , 18 ]nonacosa-2,4,6(29),8,13(18),14,16,20-octaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,24-dimethyl-12-oxo-23-oxa-1,5,7,8,11-pentaazapentacyclo[22.2.2.1 6 , 9 .0 2 , 7 .0 13 , 18 ]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,26-dimethyl-12-oxo-20,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.1 6 , 9 .0 2 , 7 .0 14 , 19 ]hentriaconta-2,4,6(31),8,14(19),15,17,23-octaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,26-dimethyl-12-oxo-20,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.1 6 , 9 .0 2 , 7 .0 14 , 19 ]hentriaconta-2,4,6(31),8,14(19),15,17-heptaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[14-[(4-fluoro-3-methylphenyl)methyl]-4,20-dimethyl-12,13-dioxo-19-oxa-1,5,7,8,11,14-hexaazatetracyclo[18.2.2.1 6 , 9 .0 2 , 7 ]pentacosa-2,4,6(25),8,16-pentaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{14-[(4-fluoro-3-methylphenyl)methyl]-4,20-dimethyl-12,13-dioxo-19-oxa-1,5,7,8,11,14-hexaazatetracyclo[18.2.2.1 6 , 9 .0 2 , 7 ]pentacosa-2,4,6(25),8-tetraen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[(18Z)-4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 12 , 17 ]octacosa-2,4,6(28),8,12(17),13,15,18-octaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(20Z)-4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 12 , 17 ]octacosa-2,4,6(28),8,12(17),13,15,20-octaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-[(19Z)-4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 12 , 17 ]octacosa-2,4,6(28),8,12(17),13,15,19-octaen-3-yl]acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 13 , 18 ]octacosa-2,4,6(28),8,13(18),14,16-heptaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.1 6 , 9 .0 2 , 7 .0 13 , 18 ]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-{4,23-dimethyl-22-oxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 13 , 18 ]octacosa-2,4,6(28),8,13(18),14,16-heptaen-3-yl}acetic acid;
(2S)-2-(tert-Butoxy)-2-[4,23-dimethyl-16-(trifluoromethyl)-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.1 6 , 9 .0 2 , 7 .0 13 , 1

Assignees

• Bristol Myers Squibb Co

Inventors

• Naidu B Narasimhulu
• Walker Michael A
• Sorenson Margaret E
• Patel Manoj
• Zheng Zhizhen Barbara
• Kadow John F
• Zheng Bin
• Eastgate Martin D
• Chen Ke
• Gonzalez-Bobes Francisco

Classifications

• A61P31/18

  for HIV · CPC title

• C07D498/22 Primary

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

• C07D211/48

  having an acyclic carbon atom attached in position 4 · CPC title