MEDIUM- OR MACRO-CYCLIC BENZYL-SUBSTITUTED HETEROCYCLE DERIVATIVES AND RELATED USES
The present disclosure relates to compounds of Formula (I′): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating orexin-2 receptor activity and may be used in the treatment of disorders in which orexin-2 receptor activity is implicated, such as narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or facilitating emergence from anaesthesia.
1 . A compound of Formula (III′):
or a pharmaceutically acceptable salt thereof, wherein:
X is —N(C 1 -C 6 alkyl)-, —N(C 1 -C 6 haloalkyl)-, or —C 1 -C 6 alkyl-;
L is absent or —C 1 -C 6 alkyl-;
Y is —O—;
n is 1 or 2;
R a is H or halogen;
R b is halogen or C 1 -C 6 alkyl;
or R a and R b , together with the atom they attach to, form C 3 cycloalkyl;
Z is —NH—;
R 1 is C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 3 cycloalkyl substituted with halogen;
Ar 1 is —C 6 -C 10 aryl- optionally substituted with one or more halogen; and
T is —C 6 -C 10 aryl- optionally substituted with one or more halogen or C 1 -C 6 alkyl,
provided that when X is alkyl, L is absent.
2 . The compound of claim 1 , wherein R 1 is C 3 cycloalkyl substituted with halogen.
3 . The compound of claim 2 , wherein R 1 is C 3 cycloalkyl substituted with fluoro.
4 . The compound of claim 1 , wherein R 1 is C 1 -C 6 haloalkyl.
5 . The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.
6 . The compound of claim 1 , wherein X is —C 1 -C 6 alkyl-.
7 . The compound of claim 1 , wherein L is absent.
8 . The compound of claim 1 , wherein L is —C 1 -C 6 alkyl-.
9 . The compound of claim 1 , wherein n is 1.
10 . The compound of claim 1 , wherein n is 2.
11 . The compound of claim 1 , wherein R b is halogen.
12 . The compound of claim 1 , wherein Ar 1 is phenyl optionally substituted with one or more halogen.
13 . The compound of claim 1 , wherein T is phenyl optionally substituted with one or more halogen.
14 . The compound of claim 1 , wherein the compound is of Formula (II′-a):
or a pharmaceutically acceptable salt thereof, wherein
R A1 is halogen; and
n1 is an integer from 0 to 4.
15 . The compound of claim 1 , wherein the compound is of Formula (IIIA′):
or a pharmaceutically acceptable salt thereof, wherein
R A1 is halogen;
R A2 is halogen or C 1 -C 6 alkyl;
n1 is an integer from 0 to 4; and
n2 is an integer from 0 to 4.
16 . The compound or salt of claim 1 , wherein the compound is of Formula (IIIA′-1):
or a pharmaceutically acceptable salt thereof, wherein:
n1 is an integer ranging from 0 to 4; and
n2 is an integer ranging from 0 to 4.
17 . The compound of claim 1 , wherein the compound of Formula (III′) is selected from:
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 , wherein the compound of Formula (III′) is selected from:
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.