MEDIUM- OR MACRO-CYCLIC BENZYL-SUBSTITUTED HETEROCYCLE DERIVATIVES AND THEIR USES AS OREXIN-2 RECEPTOR AGONISTS
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 (I′);
or a pharmaceutically acceptable salt thereof, wherein:
X is —O—, —NH—, —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
L is absent, —O—, —NH—, —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —((C 1 -C 6 alkyl)-O) nl —, —(O—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-O) nl —, —(O—(C 2 -C 6 alkenyl)) nl -, —((C 1 -C 6 alkyl)-NH) nl —, —(NH—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-NH) nl —, or —(NH—(C 2 -C 6 alkenyl)) nl -, wherein the —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —((C 1 -C 6 alkyl)-O) nl —, —(O—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-O) nl —, —(O—(C 2 -C 6 alkenyl)) nl -, —((C 1 -C 6 alkyl)-NH) nl —, —(NH—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-NH) nl —, or —(NH—(C 2 -C 6 alkenyl)) nl - is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ; and n1 is an integer ranging from 1 to 6;
Y is —O—, —NH—, —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl, wherein the —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, or C 2 -C 6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy;
n is an integer ranging from 0 to 3;
R a and R b each independently are H, halogen, —CN, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the —O(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R S ; or R a and R b , together with the atom they attach to, form C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R S ;
each R S independently is halogen, —CN, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;
Z is —O— or —NR Z —; wherein R Z is H or C 1 -C 6 alkyl;
R 1 is —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —SH, —S(C 1 -C 6 alkyl), —S(C 6 -C 10 aryl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 6 -C 10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C 3 -C 10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C 6 -C 10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(C 1 -C 6 alkyl), —S(C 6 -C 10 aryl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 6 -C 10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C 3 -C 10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C 6 -C 10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C 3 -C 10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl) is optionally substituted with one or more R 1S ;
each R 1S independently is oxo, halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —S(C 1 -C 6 alkyl), —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
Ar 1 is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R A1 ;
each R A1 independently is Ar 2 , halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
T is absent or Ar 2 ;
each Ar 2 independently is C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R A2 ; and
each R A2 independently is halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
2 . The compound of claim 1 , being of Formula (I):
or a pharmaceutically acceptable salt thereof.
3 . The compound of any one of the preceding claims, wherein X is —O—.
4 . The compound of any one of the preceding claims, wherein X is —NH— or —N(C 1 -C 6 alkyl)-, wherein the —N(C 1 -C 6 alkyl)- is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.
5 . The compound of any one of the preceding claims, wherein X is —NH— or —N(CH 3 )—.
6 . The compound of any one of the preceding claims, wherein X is C 1 -C 6 alkyl optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.
7 . The compound of any one of the preceding claims, wherein X is azetidinyl optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.
8 . The compound of any one of the preceding claims, wherein L is absent.
9 . The compound of any one of the preceding claims, wherein L is —O—, —NH—, —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —((C 1 -C 6 alkyl)-O) nl —, —(O—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-O) nl -, —(O—(C 2 -C 6 alkenyl)) nl -, —((C 1 -C 6 alkyl)-NH) nl —, —(NH—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-NH) nl —, or —(NH—(C 2 -C 6 alkenyl)) nl -, wherein the —N(C 1 -C 6 alkyl)-, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —((C 1 -C 6 alkyl)-O) nl —, —(O—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-O) nl —, —(O—(C 2 -C 6 alkenyl)) nl -, —((C 1 -C 6 alkyl)-NH) nl —, —(NH—(C 1 -C 6 alkyl)) nl -, —((C 2 -C 6 alkenyl)-NH) nl —, or —(NH—(C 2 -C 6 alkenyl)) nl - is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
10 . The compound of any one of the preceding claims, wherein L is —O—.
11 . The compound of any one of the preceding claims, wherein L is —NH— or —N(C 1 -C 6 alkyl)-, wherein the —N(C 1 -C 6 alkyl)- is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
12 . The compound of any one of the preceding claims, wherein L is C 1 -C 6 alkyl or C 2 -C 6 alkenyl, wherein the C 1 -C 6 alkyl or C 2 -C 6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
13 . The compound of any one of the preceding claims, wherein L is —((C 1 -C 6 alkyl)-O) nl — or —(O—(C 1 -C 6 alkyl)) nl -, wherein the —((C 1 -C 6 alkyl)-O) nl — or —(O—(C 1 -C 6 alkyl)) nl - is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
14 . The compound of any one of the preceding claims, wherein L is —((C 1 -C 6 alkyl)-NH) nl — or —(NH—(C 1 -C 6 alkyl)) nl -, wherein the —((C 1 -C 6 alkyl)-NH) nl — or —(NH—(C 1 -C 6 alkyl)) nl - is optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 .
15 . The compound of any one of the preceding claims, wherein n1 is an integer ranging from 1 to 3.
16 . The compound of any one of the preceding claims, wherein Y is —O—.
17 . The compound of any one of the preceding claims, wherein Y is —NH—.
18 . The compound of any one of the preceding claims, wherein Y is C 1 -C 6 alkyl optionally substituted with one or more halogen, —CN, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.
19 . The compound of any one of the preceding claims, wherein n is 1.
20 . The compound of any one of the preceding claims, wherein n is 2.
21 . The compound of any one of the preceding claims, wherein R a and R b each independently are H or halogen; or R a and R b , together with the atom they attach to, form C 3 -C 7 cycloalkyl optionally substituted with one or more R S .
22 . The compound of any one of the preceding claims, wherein one of R a and R b is H, and one of R a and R b is halogen.
23 . The compound of any one of the preceding claims, wherein R a and R b , together with the atom they attach to, form cyclopropyl.
24 . The compound of any one of the preceding claims, wherein Z is —O—.
25 . The compound of any one of the preceding claims, wherein Z is —NH—.
26 . The compound of any one of the preceding claims, wherein R 1 is C 1 -C 6 alkyl optionally substituted with one or more R 1S .
27 . The compound of any one of the preceding claims, wherein R 1 is methyl or ethyl.
28 . The compound of any one of the preceding claims, wherein R 1 is C 3 -C 7 cycloalkyl optionally substituted with one or more R 1S .
29 . The compound of any one of the preceding claims, wherein R 1 is cyclopropyl optionally substituted with one or more R 1S .
30 . The compound of any one of the preceding claims, wherein at least one R 1S is halogen.
31 . The compound of any one of the preceding claims, wherein Ar 1 is C 6 -C 10 aryl optionally substituted with one or more R A1 .
32 . The compound of any one of the preceding claims, wherein Ar 1 is 5- to 10-membered heteroaryl optionally substituted with one or more R A1 .
33 . The compound of any one of the preceding claims, wherein at least one R A1 is Ar 2 .
34 . The compound of any one of the preceding claims, wherein at least one R A1 is C 6 -C 10 aryl optionally substituted with one or more R A2 .
35 . The compound of any one of the preceding claims, wherein at least one R A1 is halogen.
36 . The compound of any one of the preceding claims, wherein T is absent.
37 . The compound of any one of the preceding claims, wherein T is Ar 2 .
38 . The compound of any one of the preceding claims, wherein at least one R A1 is Ar 2 , and T is absent.
39 . The compound of any one of the preceding claims, wherein Ar 1 is
and T is absent.
40 . The compound of any one of the preceding claims, wherein Ar 1 is
and T is Ar 2 .
41 . The compound of any one of the preceding claims, wherein Ar 1 is
and T is Ar 2 .
42 . The compound of any one of the preceding claims, wherein at least one Ar 2 is C 6 -C 10 aryl optionally substituted with one or more R A2 .
43 . The compound of any one of the preceding claims, wherein at least one Ar 2 is 5- to 10-membered heteroaryl optionally substituted with one or more R A2 .
44 . The compound of any one of the preceding claims, wherein at least one R A2 is halogen.
45 . The compound of any one of the preceding claims, wherein the compound is of Formula (I′-a), (I′-b), (IA′), (IA′-a), (IA′-b), (IB′), (IB′-a), (IB′-b), (II), (II′-a), (II′-b), (IIA′), (IIA′-a), (IIA′-b), (IIB′), (IIB′-a), (IIB′-b), (IIIA′), (IIIA′-a), (IIIA′-b), (IIIB′), (IIIB′-a), or (IIIB′b), (IVA′), (IVA′-a), (IVA′-b), (VA′), (VA′-a), or (VA′-b):
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.
46 . The compound of any one of the preceding claims, wherein the compound is of Formula (I-a), (1-b), (IA), (IA-a), (IA-b), (IB), (IB-a), (IB-b), (II), (II-a), (II-b), (IIA), (IIA-a), (IIA-b), (IIB), (IIB-a), (IIB-b), (IIIA), (IIIA-a), (IIIA-b), (IIIB), (IIIB-a), or (IIIB-b), (IVA), (IVA-a), (IVA-b), (VA), (VA-a), or (VA-b):
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.
47 . The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table A1 and pharmaceutically acceptable salts thereof.
48 . The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table A2 and pharmaceutically acceptable salts thereof.
49 . The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table B1 and pharmaceutically acceptable salts thereof.
50 . The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table B2 and pharmaceutically acceptable salts thereof.
51 . A compound obtainable by, or obtained by, a method described herein;
optionally, the method comprises one or more steps described in Schemes 1-5.
52 . A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
53 . The pharmaceutical composition of any one of the preceding claims, wherein the compound is selected from the compounds described in Tables A1, A2, B1, and B2.
54 . A method of modulating orexin-2 receptor activity, comprising contacting a cell with an effective amount of the compound of any one of the preceding claims; optionally the activity is in vitro or in vivo.
55 . A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of any one of the preceding claims.
56 . The compound or pharmaceutical composition of any one of the preceding claims for use in modulating orexin-2 receptor activity; optionally, the activity is in vitro or in vivo.
57 . The compound or pharmaceutical composition of any one of the preceding claims for use in treating or preventing a disease or disorder.
58 . Use of the compound of any one of the preceding claims in the manufacture of a medicament for modulating orexin-2 receptor activity; optionally, the activity is in vitro or in vivo.
59 . Use of the compound of any one of the preceding claims in the manufacture of a medicament for treating or preventing a disease or disorder.
60 . The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is associated with an implicated orexin-2 receptor.
61 . The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a neurological disorder, a symptom of a rare genetic disorder, a psychiatric disorder, a mental health disorder, a circadian rhythm disorder, a metabolic syndrome, osteoporosis, cardiac failure, coma, or facilitating emergence from anesthesia.
62 . The method, compound, pharmaceutical composition, or use of any one of the preceding claims, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia.