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 compound of the Formula (I):
or an enantiomer, diastereomer, tautomer, or isotopic variant thereof;
or a pharmaceutically acceptable salt thereof;
wherein:
Z is O;
X is CR 1 and Y is CR 2 ;
R 1 is a pyrazolyl attached through any available carbon atom on the pyrazolyl and is optionally substituted with 1 to 2 C 1-6 alkyl groups;
R 2 is halo;
R 3 is H;
R 4 is H;
R 5 is a pyridyl attached through any available carbon atom on the pyridyl and is optionally substituted with halo or alkyl; and
n is 1.
2. The compound of claim 1 , wherein R1 is substituted with one or two methyl.
3. The compound of claim 1 , wherein R 2 is F, Cl, or Br.
4. The compound of claim 1 , wherein R 5 is substituted with F, Cl, or Br.
5. The compound of claim 1 , wherein R 5 is substituted with alkyl.
6. The compound of claim 5 , wherein R 5 is substituted with alkyl which is substituted with one or more halogen.
7. The compound of claim 6 , wherein R 5 is substituted with trifluoromethyl.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable excipient.
9. The compound of claim 1 , wherein one or more hydrogen comprises an unnatural proportion of deuterium.
10. The compound of claim 1 , wherein one or more carbon comprises an unnatural proportion of 13 C.
11. The compound of claim 1 , wherein one or more nitrogen comprises an unnatural proportion of 15 N.