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 .- 45 . (canceled)
46 . 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;
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.
47 . The compound of claim 46 , wherein R 1 is C 3 cycloalkyl substituted with halogen.
48 . The compound of claim 47 , wherein R 1 is C 3 cycloalkyl substituted with fluoro.
49 . The compound of claim 46 , wherein R 1 is C 1 -C 6 haloalkyl.
50 . The compound of claim 46 , wherein R 1 is C 1 -C 6 alkyl.
51 . The compound of claim 46 , wherein X is —C 1 -C 6 alkyl-.
52 . The compound of claim 46 , wherein L is absent.
53 . The compound of claim 46 , wherein L is —C 1 -C 6 alkyl-.
54 . The compound of claim 46 , wherein n is 1.
55 . The compound of claim 46 , wherein n is 2.
56 . The compound of claim 46 , wherein Ar 1 is phenyl optionally substituted with one or more halogen.
57 . The compound of claim 46 , wherein T is phenyl optionally substituted with one or more halogen.
58 . The compound of claim 46 , wherein the compound is of Formula (I-a) or (I-b):
or a pharmaceutically acceptable salt thereof.
59 . The compound of claim 46 , 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.
60 . The compound of claim 46 , 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.
61 . The compound or salt of claim 46 , 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.
62 . The compound of claim 46 , wherein the compound of Formula (III) is selected from:
or a pharmaceutically acceptable salt thereof.
63 . The compound of claim 46 , wherein the compound of Formula (III) is selected from:
or a pharmaceutically acceptable salt thereof.
64 . A pharmaceutical composition comprising the compound of claim 46 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
65 . 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 46 , or a pharmaceutically acceptable salt thereof.