Substituted 2-azabicycles and their use as orexin receptor modulators
The present invention is directed to compounds of Formula I: wherein X is N or CR 1 ; Y is N or CR 2 ; R 1 is H, alkoxy, halo, triazolyl, pyrimidinyl, oxazolyl, isoxazole, oxadiazolyl, or pyrazolyl; R 2 is H, alkyl, alkoxy, or halo; Z is NH or O; R 3 is H, alkyl, alkoxy, halo, or triazolyl; R 4 is H or alkyl; or R 3 and R 4 , together with the atoms to which they are attached, form a 6- membered aryl ring or a 5- or 6-membered heteroaryl ring; R 5 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.
1. A method of treating a subject suffering from or diagnosed with depression, manic depression, anxiety, stress, post-traumatic stress disorder, panic disorders, or addiction, said method 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 CR 1 ;
Y is N or CR 2 ;
R 1 is H, alkoxy, halo, triazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrazolyl;
R 2 is H, alkyl, alkoxy, or halo;
Z is NH or O;
R 3 is H, alkyl, alkoxy, halo, or triazolyl;
R 4 is H or alkyl;
or R 3 and R 4 , together with the atoms to which they are attached, form a 6-membered aryl ring or a 5- or 6-membered heteroaryl ring;
R 5 is pyridyl, pyrazinyl, or pyrimidinyl, wherein the pyridyl, pyrazinyl, or pyrimidinyl is optionally substituted with halo or alkyl; and
n is 1 or 2.
2. The method of claim 1 , wherein the subject is suffering from or diagnosed with post-traumatic stress disorder or panic disorders.
3. The method of claim 1 , wherein Z is O.
4. The method of claim 1 , wherein X is CR 1 and Y is CR 2 .
5. The method of claim 1 , wherein R 1 is alkoxy, halo, triazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrazolyl.
6. The method of claim 5 , wherein R 1 is alkoxy, halo, triazolyl, or pyrimidinyl.
7. The method of claim 1 , wherein R 2 is H, alkyl, or halo.
8. The method of claim 1 , wherein R 2 is H.
9. The method of claim 1 , wherein R 3 is H.
10. The method of claim 1 , wherein R 4 is H.
11. The method of claim 1 , wherein R 5 is pyridyl, optionally substituted with halo or alkyl.
12. The method of claim 11 , wherein alkyl is trihaloalkyl.
13. The method of claim 1 , wherein n is 1.
14. The method of claim 1 , wherein n is 2.
15. A method of treating a subject suffering from or diagnosed with depression, manic depression, anxiety, stress, post-traumatic stress disorder, panic disorders, or addiction, said method comprising administering to the subject an effective amount of a compound selected from the group consisting of
and pharmaceutically acceptable salts thereof.