Substituted macrocyclic compounds and related methods of treatment
The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.
1. A compound of Formula I-A or a pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
n is 1, 2, or 3;
T is CR 1 R 2 or O;
W is CR 4 R 5 or O;
U is CR 6 R 7 ;
X is CR 8 R 9 ;
V is CR 3 or N;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R is halogen or deuterium; and
p is 0, 1, 2, 3, or 4;
and further wherein:
m is 1, 2, 3, or 4;
R 1 , R 2 , R 4 , and R 5 are each, independently, selected from the group consisting of H, halogen, and deuterium;
or, alternatively, R 2 and R 5 together with the carbon atoms to which they are attached, form a single bond;
R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
or, alternatively, R 3 and R 1 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl;
or, alternatively, R 3 and R 4 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl;
R 6 , R 7 , R 8 , R 9 , and R 11 are each, independently, selected from the group consisting of H, halogen, and deuterium;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms; and
each R 12 and R 13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen atoms.
2. The compound of claim 1 , wherein n is 1 or 2.
3. The compound of claim 1 , wherein ring A is phenyl.
4. The compound of claim 1 , wherein ring A is pyridinyl.
5. The compound of claim 1 , wherein Y is O.
6. The compound of claim 1 , wherein Y is absent.
7. The compound of claim 1 , wherein Tis CR 1 R 2 .
8. The compound of claim 1 , wherein Tis O.
9. The compound of claim 1 , wherein W is CR 4 R 5 .
10. The compound of claim 1 , wherein W is O.
11. The compound of claim 1 , wherein V is CR 3 .
12. The compound of claim 1 , wherein m is 1 or 2.
13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
15. A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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