IP Library › Granted Patent US 7,939,545
Granted Patent B2
US 7,939,545 · App. 11/746,303 · Granted May 10, 2011

Inhibitors of human immunodeficiency virus replication

Assignee: Boehringer Ingelheim International GmbH
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Quick Facts
Patent No.
US 7,939,545
App. No.
11/746,303
Granted
May 10, 2011
Kind
B2
Abstract

Compounds of formula I: wherein a, b, c, X, R 2 , R 3 , R 4 , R 6 and R 7 are defined herein, are useful as inhibitors of HIV replication.

Claims (783)

1. A compound of the formula (I),

wherein:

bond a is a double bond and bond b is a single bond or

bond a is a single bond and bond b is a double bond;

X is NR 1 when bond a is a single bond;

or X is N when bond a is a double bond;

R 1 is H, (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl- or Het-(C 1-6 )alkyl-;

wherein each of the (C 1-6 )alkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl- and Het-(C 1-6 )alkyl- is optionally substituted with —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl or —N((C 1-6 )alkyl) 2 ;

R 2 is H, (C 1-6 )alkyl or —O(C 1-6 )alkyl when bond b is a single bond;

or R 2 is O when bond b is a double bond;

R 3 is (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- or —Y—R 31 , and bond c is a single bond; or

R 3 is (C 1-6 )alkylidene and bond c is a double bond;

wherein Y is O or S and R 31 is (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl, aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl- or Het-(C 1-6 )alkyl-;

wherein each of the (C 1-6 )alkylidene, (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- and —Y—R 31 is optionally substituted with 1 to 3 substituents each independently selected from (C 1-6 )alkyl, halo, cyano, oxo and —O(C 1-6 )alkyl;

R 4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ; wherein the (C 1-6 )alkyl is optionally substituted with hydroxy, cyano or oxo;

R 6 and R 7 are each independently selected from H, halo, (C 1-6 )alkyl and (C 1-6 )haloalkyl;

with the proviso that when

bond a is a single bond and bond b is a double bond; and

X is NR 1 ; R 1 is H; and R 2 is O; and

R 4 is unsubstituted phenyl; R 6 is Cl; R 7 is H; and

bond c is a double bond; then

R 3 is not ═CH—CH(CH 3 ) 2 ; and

wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S;

or a salt, ester or tautomer thereof.

2. A compound according to claim 1 , wherein X is NR 1 and bond a is a single bond.

3. A compound according to claim 1 , wherein X is N and bond a is a double bond.

4. A compound according to claim 1 wherein R 4 is naphthyl or phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo.

5. A compound according to claim 4 , wherein R 4 is phenyl optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo.

6. A compound according to claim 1 , wherein R 4 is Het optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ; wherein the (C 1-6 )alkyl is optionally substituted with hydroxy, cyano or oxo.

7. A compound according to claim 6 , wherein R 4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-6 )alkyl and —O(C 1-6 )alkyl;

wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N, O and S.

8. A compound according to claim 1 of formula (Ia):

wherein

X is NR 1 ;

R 1 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, or Het-(C 1-6 )alkyl-;

wherein Het is a 4- to 7-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S;

and wherein each of the (C 1-6 )alkyl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-, and Het-(C 1-6 )alkyl- is optionally substituted with —OH, —O(C 1-3 )alkyl, —NH 2 , —NH(C 1-3 )alkyl or —N((C 1-3 )alkyl) 2 ;

R 2 is O;

R 3 is (C 1-6 )alkyl or (C 2-6 )alkenyl; and

bond c is a single bond;

R 4 is naphthyl or phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo;

R 6 is H, halo, (C 1-3 )alkyl or (C 1-3 )haloalkyl;

R 7 is H or F;

or a salt or ester thereof.

9. A compound according to claim 8 , wherein R 4 is phenyl optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo.

10. A compound according to claim 8 , wherein R 4 is a group of formula:

wherein R 41 is selected from halo, (C 1-4 )alkyl and (C 1-4 )haloalkyl.

11. A compound according to claim 9 , wherein R 6 is H, Cl or Br and R 7 is H.

12. A compound according to claim 1 of formula (Id):

wherein

R 2 is (C 1-6 )alkyl or —O(C 1-6 )alkyl;

R 3 is (C 1-6 )alkyl, (C 2-6 )alkenyl, —O—(C 1-6 )alkyl, —O—(C 1-6 )haloalkyl, —O—(C 2-6 )alkenyl, —O—(C 2-6 )alkynyl, —O—(C 3-7 )cycloalkyl, —O-aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-O—, aryl-(C 1-6 )alkyl-O— or Het-(C 1-6 )alkyl-O—;

wherein each of the —O—(C 1-6 )alkyl, —O—(C 2-6 )alkenyl, —O—(C 2-6 )alkynyl, —O—(C 3-7 )cycloalkyl, —O-aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-O—, aryl-(C 1-6 )alkyl-O— and Het-(C 1-6 )alkyl-O— is optionally substituted with 1 to 3 substituents each independently selected from (C 1-6 )alkyl, halo, cyano, oxo and —O(C 1-6 )alkyl; and

bond c is a single bond; or

R 3 is (C 1-6 )alkylidene and bond c is a double bond;

R 4 is naphthyl or phenyl, wherein the phenyl is optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo; or

R 4 is Het optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-6 )alkyl, —SH, —S(C 1-6 )alkyl, —NH 2 , —NH(C 1-6 )alkyl and —N((C 1-6 )alkyl) 2 ; wherein the (C 1-6 )alkyl is optionally substituted with hydroxy, cyano or oxo;

R 6 is H, halo, (C 1-3 )alkyl or (C 1-3 )haloalkyl; and

R 7 is H or F;

or a salt or ester thereof.

13. A compound according to claim 12 , wherein R 7 is H and R 6 is H, Cl or Br.

14. A compound according to claim 12 , wherein R 2 is (C 1-6 )alkyl.

15. A compound according to claim 14 , wherein R 2 is CH 3 .

16. A compound according to claim 12 , wherein R 3 is —O—(C 1-6 )alkyl, —O—(C 1-6 )haloalkyl, —O—(C 2-6 )alkenyl, —O—(C 2-6 )alkynyl, —O—(C 3-7 )cycloalkyl, —O-aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-O—, aryl-(C 1-6 )alkyl-O— or Het-(C 1-6 )alkyl-O—;

wherein each of the —O—(C 1-6 )alkyl, —O—(C 2-6 )alkenyl, —O—(C 2-6 )alkynyl, —O—(C 3-7 )cycloalkyl, —O-aryl, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-O—, aryl-(C 1-6 )alkyl-O— and Het(C 1-6 )alkyl-O— is optionally substituted with 1 to 3 substituents each independently selected from (C 1-6 )alkyl, halo, cyano, oxo and —O(C 1-6 )alkyl; and

bond c is a single bond.

17. A compound according to claim 12 , wherein R 4 is phenyl optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, —OH, —O(C 1-4 )alkyl, —SH, —S(C 1-4 )alkyl, —NH 2 , —NH(C 1-4 )alkyl and —N((C 1-4 )alkyl) 2 ; wherein the (C 1-4 )alkyl is optionally substituted with hydroxy, cyano or oxo.

18. A compound according to claim 12 , wherein R 4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-6 )alkyl and —O(C 1-6 )alkyl;

wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N, O and S.

19. A compound according to claim 1 of the formula:

Cpd

R 2

R 3

R 4

R 6

R 7

1001

CH 3

Br

H

1002

CH 3

Br

H

1003

CH 3

Br

H

1004

CH 3

Br

H

1005

CH 3

Cl

H

1006

CH 3

Br

H

1007

CH 3

Br

H

1008

CH 3

Cl

H

1009

—OCH 3

Br

H

1010

—CH(CH 3 ) 2

Br

H

1011

CH 3

H

H

1012

CH 3

Cl

H

1013

CH 3

Cl

H

1014

CH 3

Cl

H

1015

CH 3

Cl

H

1016

CH 3

Cl

H

1017

CH 3

Cl

H

1018

CH 3

Cl

H

1019

CH 3

Cl

H

1020

CH 3

Br

H

1021

CH 3

Cl

H

1022

CH 3

Br

H

1023

CH 3

Br

H

1024

CH 3

Cl

H

1025

CH 3

Br

H

1026

CH 3

Br

H

1027

CH 3

Br

H

1028

CH 3

Br

H

1029

CH 3

Cl

H

1030

CH 3

Cl

H

1031

CH 3

Cl

H

1032

CH 3

Br

H

1033

CH 3

H

H

1034

CH 3

Cl

H

1035

CH 3

Br

H

1036

CH 3

Cl

H

1037

CH 3

Cl

H

1038

CH 3

Br

H

1039

CH 3

Br

H

1040

CH 3

Br

H

1041

CH 3

Br

H

1042

CH 3

Br

H

1043

CH 3

Br

H

1044

CH 3

Br

H

1045

CH 3

Br

H

1046

CH 3

Br

H

1047

CH 3

Br

H

1048

CH 3

Br

H

1049

CH 3

Br

H

1050

CH 3

Br

H

1051

CH 3

Br

H

1052

CH 3

Br

H

1053

CH 3

F

F

1054

CH 3

Cl

H

1055

CH 3

Br

H

1056

CH 3

Cl

H

1057

CH 3

Cl

H

1058

CH 3

Cl

H

1059

CH 3

Cl

H

1060

CH 3

Cl

H

1061

CH 3

Cl

H

1062

CH 3

Cl

H

1063

CH 3

Cl

H

1064

CH 3

Cl

H

1065

CH 3

Cl

H

1066

CH 3

Cl

H

1067

CH 3

Cl

H

1068

CH 3

Cl

H

1069

CH 3

Cl

H

1070

CH 3

Cl

H

1071

CH 3

Cl

H

1072

CH 3

Cl

H

1073

CH 3

Cl

H

1074

CH 3

Cl

H

1075

CH 3

Cl

H

1076

CH 3

Cl

H

1077

CH 3

Cl

H

1078

CH 3

Cl

H

1079

CH 3

Br

H

1080

CH 3

Cl

H

1081

CH 3

Cl

H

1082

CH 3

H

H

1083

CH 3

Cl

H

1084

CH 3

Cl

H

1085

CH 3

Cl

H

1086

CH 3

Cl

H

1087

CH 3

Cl

H

1088

CH 3

Cl

H

1089

CH 3

Cl

H

1090

CH 3

Cl

H

1091

CH 3

Cl

H

1092

CH 3

Cl

H

1093

CH 3

Cl

H

1094

CH 3

Cl

H

1095

CH 3

Cl

H

1096

CH 3

Cl

H

1097

CH 3

Cl

H

1098

CH 3

Cl

H

1099

CH 3

Cl

H

1100

CH 3

Cl

H

1101

—CH 2 CH 3

Cl

H

1102

CH 3

Cl

H

1103

CH 3

Cl

H

1104

CH 3

Cl

H

1105

CH 3

Cl

H

1106

CH 3

Br

H

1107

CH 3

Cl

H

1108

CH 3

Cl

H

1109

CH 3

Cl

H

1110

CH 3

Cl

H

1111

CH 3

Cl

H

1112

CH 3

Cl

H

1113

CH 3

Cl

H

1114

CH 3

Cl

H

1115

CH 3

Cl

H

1116

CH 3

Cl

H

1117

CH 3

Cl

H

1118

CH 3

Cl

H

1119

CH 3

Cl

H

1120

CH 3

Cl

H

1121

CH 3

Cl

H

1122

CH 3

Cl

H

1123

CH 3

Cl

H

1124

CH 3

Cl

H

1125

CH 3

Cl

H

1126

CH 3

Cl

H

1127

CH 3

Cl

H

1128

CH 3

Cl

H

1129

CH 3

Cl

H

1130

CH 3

Cl

H

1131

CH 3

Cl

H

1132

CH 3

Cl

H

1133

CH 3

Cl

H

1134

CH 3

Cl

H

1135

CH 3

Cl

H

1136

CH 3

Cl

H

1137

CH 3

Cl

H

1138

CH 3

Cl

H

1139

CH 3

Cl

H

1140

CH 3

Cl

H

1141

CH 3

Cl

H

1142

CH 3

Cl

H

1143

CH 3

Cl

H

1144

CH 3

Cl

H

1145

CH 3

Cl

H

1146

CH 3

Cl

H

1147

CH 3

Cl

H

1148

CH 3

Cl

H

1149

CH 3

Cl

H

1150

CH 3

Cl

H

1151

CH 3

Cl

H

1152

CH 3

H

H

1153

CH 3

Cl

H

1154

CH 3

H

H

1155

CH 3

Cl

H

1156

CH 3

Cl

H

1157

CH 3

H

H

1158

CH 3

H

H

1159

CH 3

H

H

1160

CH 3

H

H

1161

CH 3

H

H

1162

CH 3

Cl

H

1163

CH 3

H

H

1164

CH 3

Br

H

1165

CH 3

Cl

H

1166

CH 3

Cl

H.

20. A compound according to claim 1 of the formula:

Cpd

R 1

R 3

R 4

R 6

2001

H

Cl

2002

Cl

2003

Cl

2004

H

Br

2005

H

H

2006

H

Br

2007

Cl

2008

Cl

2009

CH 3

Cl

2010

Cl

2011

 Cl.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable carriers.

22. The pharmaceutical composition as defined in claim 21 additionally comprising at least one other antiviral agent.

23. The pharmaceutical composition as defined in claim 22 wherein the at least one antiviral agent comprises at least one NNRTI.

24. The pharmaceutical composition as defined in claim 22 , wherein the at least one antiviral agent comprises at least one NRTI.

25. The pharmaceutical composition as defined in claim 22 , wherein the at least one antiviral agent comprises at least one protease inhibitor.

26. The pharmaceutical composition as defined in claim 22 , wherein the at least one antiviral agent comprises at least one entry inhibitor.

27. The pharmaceutical composition as defined in claim 22 , wherein the at least one antiviral agent comprises at least one integrase inhibitor.

28. A method of treating an HIV infection in an infected human, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined in claim 1 .

29. The method of claim 28 , wherein there is also administered at least one other antiviral agent.

30. A method of inhibiting the replication of HIV comprising exposing the virus to an effective amount of the compound of formula (I) as defined in claim 1 , or a salt or ester thereof, under conditions where replication of HIV is inhibited.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 29, 2012
From: GILEAD SCIENCES LIMITED
To: GILEAD SCIENCES, INC.
Reel/Frame 027786/0155 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 16, 2012
From: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
To: GILEAD SCIENCES LIMITED
Reel/Frame 027716/0349 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 22, 2008
From: TSANTRIZOS, YOULA S.; BOES, MICHAEL; BROCHU, CHRISTIAN; FENWICK, CRAIG; MASON, STEPHEN; PESANT, MARC; MALENFANT, ERIC
To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Reel/Frame 021562/0535 →
Continuity (2)
Provisional Application 60747311 · May 16, 2006
Related Publication 20080221159A1 · Sep 11, 2008