US 2015/0174129 A1 · SUBSTITUTED 2-AZABICYCLES AND THEIR USE AS OREXIN RECEPTOR MODULATORS

Abstract

The present invention is directed to compounds of Formula I: wherein X is N or CR1; Y is N or CR2; R1 is H, alkoxy, halo, triazolyl, pyrimidinyl, oxazolyl, isoxazole, oxadiazolyl, or pyrazolyl; R2 is H, alkyl, alkoxy, or halo; Z is NH or O; R3 is H, alkyl, alkoxy, halo, or triazolyl; R4 is H or alkyl; or R3 and R4, together with the atoms to which they are attached, form a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring; R5 is pyridyl, pyrazinyl, or pyrimidinyl, wherein the pyridyl, pyrazinyl, or pyrimidinyl is optionally substituted with halo or alkyl; and n is 1 or 2. Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

Claims17

Dependent claims

1-40. (canceled)

A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, comprising administering to the subject an effective amount of a compound of formula I

or an enantiomer or diastereomer thereof;
or a pharmaceutically acceptable salt thereof;
wherein
X is N or CR1;
Y is N or CR2;
R1 is H, alkoxy, halo, triazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrazolyl;
R2 is H, alkyl, alkoxy, or halo;
Z is NH or O;
R3 is H, alkyl, alkoxy, halo, or triazolyl;
R4 is H or alkyl;
or R3 and R4, together with the atoms to which they are attached, form a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring;
R5 is pyridyl, pyrazinyl, or pyrimidinyl, wherein the pyridyl, pyrazinyl, or pyrimidinyl is optionally substituted with halo or alkyl;
and
n is 1 or 2.

11 more elements

Ex.
No.
Compound
Compound Name
1
(R/S)-(2-(2H-1,2,3-triazol-2- yl)phenyl)(6-((5- (trifluoromethyl)pyrazin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
2
(R/S)-(6-methyl-3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl)(6-((5- (trifluoromethyl)pyrazin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
3
(R/S)-(3-ethoxyisoquinolin-4- yl)((5-(trifluoromethyl)pyrazin-2- yl)oxy)-2-azabicyclo[2.2.1]heptan- 2-yl)methanone
4
(R/S)-5-methyl-3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl)(6-((5- (trifluoromethyl)pyrazin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
7
(R/S)-(2-(2H-1,2,3-triazol-2- yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
8
(R/S)-(3-ethoxyisoquinolin-4- yl)(6-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
9
(R/S)-(5-methyl-3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
10
(R/S)-(7-ethoxyquinolin-8-yl)(6- ((5-(trifluoromethyl)pyridin-2- yl)oxy)-2-azabicyclo[2.2.1]heptan- 2-yl)methanone
11
(R/S)-(3-fluoro-2-(pyrimidin-2- yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
12
(R/S)-(4-methoxy-2-(pyrimidin-2- yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
13
(R/S)-4-methoxy-2-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
14
(R/S)-(5-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
15
(R/S)-2-methoxy-6-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
16
(R/S)-(3-fluoro-2-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
17
(R/S)-(3-methyl-2-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
18
(R/S)-(2-fluoro-6-(2H-1,2,3- triazol-2-yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
19
(R/S)-(5-fluoro-2-(pyrimidin-2- yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
20
(R/S)-(4-fluoro-2-(pyrimidin-2- yl)phenyl)(-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
21
(R/S)-(2-(4H-1,2,4-triazol-4- yl)phenyl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
22
(R/S)-(6-methyl-3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl)(6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
23
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1R,4S,6S)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
24
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
25
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
26
(4-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
27
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
28
(5-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
29
(6-methyl-2-(2H-1,2,3-triazol-2- yl)pyridin-3-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
30
(3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
31
(3-fluoro-2- methoxyphenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
32
(3-methyl-2-(oxazol-2- yl)phenyl((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
33
(3-fluoro-2-(1H-1,2,3-triazol-1- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
34
(6-methyl-2-(1H-1,2,3-triazol-1- yl)pyridin-3-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
35
(3-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
36
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
37
(3-ethoxy-6-methylpyridin-2- yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
38
(2-fluoro-6-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
39
(2-methoxy-6-(1H-pyrazol-5- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
40
(2-methoxy-6-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]hepan-2- yl)methanone
41
(2-(1,4-dimethyl-1H-pyrazol-5- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
42
(1H-indol-7-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
43
(5-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
44
(4-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
45
(2-bromo-3- fluorophenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
46
(2-fluoro-6-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
47
((1S,4R,6R)-6-((5-bromopyridin-2- yl)oxy)-2-azabicyclo[2.2.1]heptan- 2-yl)(2-fluoro-6-(pyrimidin-2- yl)phenyl)methanone
48
((1S,4R,6R)-6-((5-bromopyridin-2- yl)oxy)-2-azabicyclo[2.2.1]heptan- 2-yl)(3-fluoro-2-(pyrimidin-2- yl)phenyl)methanone
49
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((5- bromopyridin-2-yl)oxy)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
50
((1S,4R,6R)-6-((5-bromopyridin-2- yl)oxy)-2-azabicyclo[2.2.1]heptan- 2-yl)(6-methyl-3-(2H-1,2,3-triazol- 2-yl)pyridin-2-yl)methanone
51
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4R,6R)-6-((3- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
52
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((3- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
53
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
54
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
55
(3-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
56
(7-ethoxyquinolin-8- yl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
57
(5-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
58
(5-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
59
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
60
(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
61
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
62
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
63
(4-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
64
(4-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
65
(4-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
66
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
67
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
68
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
69
(2-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
70
(3-fluoro-2-(3-methyl-1,2,4- oxadiazol-5- yl)phenyl)((1S,4S,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.1]heptan-2- yl)methanone
71
(3-fluoro-2-(3-methyl-1,2,4- oxadiazol-5- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- azabicyclo[2.2.1]heptan-2- yl)methanone
72
(3-fluoro-2-(3-methyl-1,2,4- oxadiazol-5- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.1]heptan-2- yl)methanone
73
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.2]octan-2- yl)methanone
74
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrazin-2-yl)oxy)- 2-azabicyclo[2.2.2]octan-2- yl)methanone
75
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)oxy)-2-azabicyclo[2.2.2]octan- 2-yl)methanone
76
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2-yl)oxy)- 2-azabicyclo[2.2.2]octan-2- yl)methanone
77
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrazin-2-yl)oxy)- 2-azabicyclo[2.2.2]octan-2- yl)methanone
78
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)oxy)-2-azabicyclo[2.2.2]octan- 2-yl)methanone
79
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone
80
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone
81
(3-fluoro-2-(pyrimidin-2- yl)phenyl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone
82
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyridin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone
83
(6-methyl-2-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrazin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone
84
(6-methyl-3-(2H-1,2,3-triazol-2- yl)pyridin-2-yl)((1S,4R,6R)-6-((5- (trifluoromethyl)pyrimidin-2- yl)amino)-2- azabicyclo[2.2.2]octan-2- yl)methanone

165 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/605,387Filed 26 Jan 2015

Priority

13 Mar 2013

Published

25 Jun 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4709
Quinolines; Isoquinolines: non-condensed quinolines and containing further heterocyclic rings

Family

Application61/780,378Us provisional application · filed 13 Mar 2013

Application14/206,722Division · filed 12 Mar 2014

Application14/605,387Division

US 2014/0275118 A1Published application

US 8,969,352 B2Related patent

US 9,447,117 B2Related patent

US 2015/0174129 A1This patent

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

Substituted 2-azabicycles and their use as orexin receptor modulators

Life of this patent

Substituted 2-azabicycles and their use as orexin receptor modulators

Life of this patent

Abstract

Claims17