US 8,076,349 B2Granted

Spirotropane compounds and methods for the modulation of chemokine receptor activity

AssigneeViroChem Pharma Inc.

InventorsLaval Chan Chun Kong, Christophe Moinet, Marc Courchesne, Louis Vaillancourt, Monica Bubenik

Life of this patent

Estimating the term…

Abstract

Compounds according to formula (I): wherein A, R1 and R2 are as defined herein, and the pharmaceutically acceptable salts, hydrates and solvates thereof are useful for the modulation of CCR5 chemokine receptor activity.

Claims19

Dependent claims

A compound represented by formula (I):

or pharmaceutically acceptable salts, hydrates or solvates thereof,
wherein
R1 is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from a halogen, C1-6 alkyl, C1-6alkyloxy, CF3, COOH, COOC1-6alkyl, cyano, NH2, nitro, NH(C1-6 alkyl), N(C1-6 alkyl)2 and a 3-8 member heterocycle;
R2 is H,
R3 or R4 are each independently methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, any of which is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO3R62, PO3R65R66, CONR63R64, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C7-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(O)C1-6 alkyl, C(O)C2-6 alkenyl, C(O)C2-6 alkynyl, C(O)C6-12 aryl, C(O)C7-12 aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl, oxo, oxime, NR63R64, C(O)OR62, cyano, azido, amidino and guanido;
wherein R62, R65, R66, R63 and R64 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C7-18 aralkyl, or R65 and R66 are taken together with the oxygen atoms to form a 5 to 10 member heterocycle, or R63 and R64 are taken together with the nitrogen atom to form a 3 to 10 member heterocycle;
or
R3 or R4 are each independently oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, CH2-oxetanyl, CH2-tetrahydropyranyl, CH2-tetrahydrofuranyl, any of which can be unsubstituted or substituted by one or more substituents chosen from halogen, C1-6 alkyl, NH2, nitro, C(O)OC1-6 alkyl, COOH, C1-6 alkyloxy, cyano, and azido;
or
R3 or R4 are each independently benzyl unsubstituted or substituted by one or more substituents chosen from halogen, C1-3 alkoxy, SO2C1-3alkyl, difluoromethoxy, trifluoromethoxy, trifluoromethyl, CN and pyrazoyl;
R5 and R′5 are each H;
and
R7 is methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, any of which can be unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO3R62, PO3R65R66, CONR63R64, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C7-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(O)C1-6 alkyl, C(O)C2-6 alkenyl, C(O)C2-6 alkynyl, C(O)C6-12 aryl, C(O)C7-12 aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl, oxo, oxime, NR63R64, C(O)OR62, cyano, azido, amidino, and guanido;
wherein R62, R65, R66, R63 and R64 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C7-18 aralkyl, or R65 and R66 are taken together with the oxygen atoms to form a 5 to 10 member heterocycle, or R63 and R64 are taken together with the nitrogen atom to form a 3 to 10 member heterocycle.

11 more elements

A compound selected from

1
(3S,4S)-3-[3-(4-Methanesulfonylbenzyl)-
bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-
8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid
tert-butyl ester;
2
(3S,4S)-3-[1-Isopropyl-3-methyl-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;
3
(3S,4S)-3-[3-Ethyl-1-isopropyl-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;
4
(3S,4S)-3-[1-Isopropyl-3-(2-methoxy-
ethyl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-
carboxylic acid tert-butyl ester;
5
(3S,4S)-3-[1-Isopropyl-3-
(tetrahydrofuran-3-yl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester;
6
(3S,4S)-3-[1-Isopropyl-3-
(tetrahydropyran-4-yl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester;
7
(3S,4S)-3-[1-Isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester;
8
(3S,4S)-3-[3-Ethyl-1-isopropyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester;
9
(3S,4S)-1-benzyl-3-[3-(2,2-Difluoro-ethyl)-1-isopropyl-
bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-
8-ylmethyl]-4-phenyl-pyrrolidine;
10
(3S,4S)-3-[3-(2,2-Difluoro-ethyl)-1-isopropyl-
bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-
ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-
butyl ester;
11
(3S,4S)-3-[1-Isopropyl-3-(2-methoxy-
ethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-
carboxylic acid tert-butyl ester
12
(3S,4S)-3-[1-Isopropyl-3-
(tetrahydrofuran-3-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester
13
(3S,4S)-3-[1-Isopropyl-3-
(tetrahydropyran-4-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine-1-carboxylic acid tert-butyl ester;
14
(3R,4S)-3-[1-Isopropyl-3-methyl-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
15
(3R,4S)-3-[3-Ethyl-1-isopropyl-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
16
(3R,4S)-3-[3-(2,2-Difluoro-ethyl)-1-isopropyl-
bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-
8-ylmethyl]-4-phenyl-pyrrolidine;
17
(3R,4S)-3-[1-Isopropyl-3-(2-methoxy-
ethyl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
18
(3R,4S)-3-[1-Isopropyl-3-
(tetrahydrofuran-3-yl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
19
(3R,4S)-3-[1-Isopropyl-3-
(tetrahydropyran-4-yl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
20
(3R,4S)-3-[1-Isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
21
(3R,4S)-3-[3-Ethyl-1-isopropyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
22
(3R,4S)-3-[3-(2,2-Difluoro-ethyl)-1-isopropyl-
bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-
ylmethyl]-4-phenyl-pyrrolidine;
23
(3R,4S)-3-[1-Isopropyl-3-(2-methoxy-
ethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
24
(3R,4S)-3-[1-Isopropyl-3-
(tetrahydrofuran-3-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
25
(3R,4S)-3-[1-Isopropyl-3-
(tetrahydropyran-4-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
26
(3S,4S)-1-Cyclopentanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
27
(3S,4S)-1-(1-Trifluoromethyl-cyclobutanecarbonyl)-3-
[1-isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
28
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-ethyl-1-
isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
29
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-ethyl-1-
isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
30
(3S,4S)-1-(1-Trifluoromethyl-cyclobutanecarbonyl)-3-
[3-ethyl-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
31
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
32
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
33
(3S,4S)-1-Cyclopentanecarbonyl-3-[-1-isopropyl-3-(2-
methoxy-ethyl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
34
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-(2-
methoxy-ethyl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
35
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-3-yl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
36
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-4-yl)-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]docdec-8-ylmethyl]-4-phenyl-
pyrrolidine;
37
(3S,4S)-1-Cyclopentanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine
38
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
39
(3S,4S)-1-(1-Trifluoromethyl-cyclobutanecarbonyl)-3-
[1-isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
40
(3S,4S)-1-(2-Cyclopropyl-acetyl)-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
41
(3S,4S)-1-(3-Methyl-butyryl)-3-[1-isopropyl-3-methyl-
bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-
ylmethyl]-4-phenyl-pyrrolidine;
42
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-ethyl-1-
isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
43
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-ethyl-1-
isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
44
(3S,4S)-1-(1-Trifluoromethyl-cyclobutanecarbonyl)-3-
[3-ethyl-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
45
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
46
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
47
(3S,4S)-1-Cyclopentanecarbonyl-3-[-1-isopropyl-3-(2-
methoxy-ethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
48
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-(2-
methoxy-ethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
49
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isobutyl-3-(2-
methoxy-ethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
50
(3S,4S)-1-Cyclopentanecarbonyl-3-[-1-isopropyl-3-
(tetrahydro-furan-3-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
51
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-3-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
52
(3S,4S)-1-Cyclopentanecarbonyl-3-[-1-isopropyl-3-
(tetrahydro-pyran-4-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
53
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-4-yl)-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
54
(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-3-[3-(4-
N,N-dimethyl-benzenesulfonamide)-bicyclo[3.2.1]-2,4-
dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
55
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isobutyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
56
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-
cyclopropylmethyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
57
(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-3-[1,3-
diethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
58
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-ethyl-1-isobutyl-
bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-
8-ylmethyl]-4-phenyl-pyrrolidine;
59
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
60
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-
cyclopropylmethyl-3-methyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
61
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-(3-fluorophenyl)-
pyrrolidine;
62
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-(3-fluorophenyl)-
pyrrolidine;
63
(3S,4S)-1-Cyclopentanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-(3-fluorophenyl)-
pyrrolidine;
64
(3S,4S)-1-Cyclopentanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-(3-fluorophenyl)-
pyrrolidine;
65
(3S,4S)-1-Cyclobutanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
66
(3S,4S)-1-Cyclobutanecarbonyl-3-[1-isopropyl-3-
methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
67
(3S,4S)-1-(1-Methyl-cyclobutanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
68
(3S,4S)-1-(1-Methyl-cyclobutanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
69
(3S,4S)-1-(1-Methyl-cyclopentanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
70
(3S,4S)-1-(1-Methyl-cyclopentanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
71
(3S,4S)-1-(1-Methyl-cyclohexanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
72
(3S,4S)-1-(1-Methyl-cyclohexanecarbonyl)-3-[1-
isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
73
(3S,4S)-1-Cyclobutanecarbonyl-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
74
(3S,4S)-1-Cyclobutanecarbonyl-3-[3-(2,2-difluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
75
(3S,4S)-1-(1-Methyl-cyclobutanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
76
(3S,4S)-1-(1-Methyl-cyclobutanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
77
(3S,4S)-1-(1-Methyl-cyclopentanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
78
(3S,4S)-1-(1-Methyl-cyclopentanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
79
(3S,4S)-1-(1-Methyl-cyclohexanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
80
(3S,4S)-1-(1-Methyl-cyclohexanecarbonyl)-3-[3-(2,2-
difluoro-ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
81
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2-fluoro-ethyl)-
1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
82
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2-fluoro-ethyl)-
1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
83
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2-fluoro-ethyl)-
1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
84
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2-fluoro-ethyl)-
1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
85
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2,2,2-trifluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
86
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2,2,2-trifluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
87
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2,2,2-trifluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
88
(3S,4S)-1-Cyclopentanecarbonyl-3-[3-(2,2,2-trifluoro-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
89
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxetan-2-ylmethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
90
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxetan-2-ylmethyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
91
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxetan-3-ylmethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
92
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxetan-3-ylmethyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
93
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-2-ylmethyl)-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
94
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-2-ylmethyl)-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
95
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-3-ylmethyl)-bicyclo[3.2.1]-2,4-dioxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
96
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-furan-3-ylmethyl)-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
97
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-2-ylmethyl)-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
98
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-2-ylmethyl)-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
99
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-3-ylmethyl)-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
100
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-3-ylmethyl)-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
101
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-4-ylmethyl)-bicyclo[3.2.1]-2,4-
dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-
phenyl-pyrrolidine;
102
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
(tetrahydro-pyran-4-ylmethyl)-bicyclo[3.2.1]-2-oxo-
1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
103
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-furan-2-
ylmethyl-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
104
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-furan-2-
ylmethyl-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
105
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-furan-3-
ylmethyl-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
106
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-furan-3-
ylmethyl-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
107
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxazol-2-ylmethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
108
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-
oxazol-2-ylmethyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
109
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2-ethoxy-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
110
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[3-(2-ethoxy-
ethyl)-1-isopropyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
111
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-(2-
methoxy-propyl)-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-
triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-
pyrrolidine;
112
(3S,4S)-1-(3,3-Dimethyl-butyryl)-3-[1-isopropyl-3-(2-
methoxy-propyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-
spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine;
or pharmaceutically acceptable salts thereof.

507 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/792,577Filed 9 Dec 2005 · us provisional application
Priority: 9 Dec 2004
Published: US 2009/0047238 A119 Feb 2009
Granted: 13 Dec 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 451/02
Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring…:…
A61P 31/18
For RNA viruses: for HIV
C07D
Heterocyclic compounds
A61P
Therapeutic uses of medicines

Family

Application60/634,257Us provisional application · filed 9 Dec 2004
US 2009/0047238 A1Pre-grant publication · published 19 Feb 2009
US 8,076,349 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

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Abstract

A compound represented by formula (I):

or pharmaceutically acceptable salts, hydrates or solvates thereof,
wherein
R1 is unsubstituted phenyl or phenyl substituted with at least one substituent chosen from a halogen, C1-6 alkyl, C1-6alkyloxy, CF3, COOH, COOC1-6alkyl, cyano, NH2, nitro, NH(C1-6 alkyl), N(C1-6 alkyl)2 and a 3-8 member heterocycle;
R2 is H,
R3 or R4 are each independently methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, any of which is unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO3R62, PO3R65R66, CONR63R64, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C7-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(O)C1-6 alkyl, C(O)C2-6 alkenyl, C(O)C2-6 alkynyl, C(O)C6-12 aryl, C(O)C7-12 aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl, oxo, oxime, NR63R64, C(O)OR62, cyano, azido, amidino and guanido;
wherein R62, R65, R66, R63 and R64 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C7-18 aralkyl, or R65 and R66 are taken together with the oxygen atoms to form a 5 to 10 member heterocycle, or R63 and R64 are taken together with the nitrogen atom to form a 3 to 10 member heterocycle;
or
R3 or R4 are each independently oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, CH2-oxetanyl, CH2-tetrahydropyranyl, CH2-tetrahydrofuranyl, any of which can be unsubstituted or substituted by one or more substituents chosen from halogen, C1-6 alkyl, NH2, nitro, C(O)OC1-6 alkyl, COOH, C1-6 alkyloxy, cyano, and azido;
or
R3 or R4 are each independently benzyl unsubstituted or substituted by one or more substituents chosen from halogen, C1-3 alkoxy, SO2C1-3alkyl, difluoromethoxy, trifluoromethoxy, trifluoromethyl, CN and pyrazoyl;
R5 and R′5 are each H;
and
R7 is methyl, ethyl, vinyl, propyl, propenyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, any of which can be unsubstituted or substituted by one or more substituents chosen from halogen, nitro, nitroso, SO3R62, PO3R65R66, CONR63R64, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C7-12 aralkyl, C6-12 aryl, C1-6 alkyloxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C6-12 aryloxy, C(O)C1-6 alkyl, C(O)C2-6 alkenyl, C(O)C2-6 alkynyl, C(O)C6-12 aryl, C(O)C7-12 aralkyl, 3-10 member heterocycle, 4-16 member heteroaralkyl, hydroxyl, oxo, oxime, NR63R64, C(O)OR62, cyano, azido, amidino, and guanido;
wherein R62, R65, R66, R63 and R64 are each independently chosen from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-12 aryl, 3-10 member heterocycle, 4-16 member heteroaralkyl, and C7-18 aralkyl, or R65 and R66 are taken together with the oxygen atoms to form a 5 to 10 member heterocycle, or R63 and R64 are taken together with the nitrogen atom to form a 3 to 10 member heterocycle.

11 more elements

Facts

Application

11/792,577Filed 9 Dec 2005 · us provisional application

Priority

9 Dec 2004

Published

US 2009/0047238 A119 Feb 2009

Granted

13 Dec 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07D 451/02
Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring…:…
A61P 31/18
For RNA viruses: for HIV
C07D
Heterocyclic compounds
A61P
Therapeutic uses of medicines