US 12,503,475 B2 · Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists

Abstract

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 receptor activity and may be used in the treatment of disorders in which orexin 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 a complication in emergence from anaesthesia.

A compound of Formula (I″):

or a pharmaceutically acceptable salt thereof, wherein:
X is —C(RX1)3, —ORX2, or —N(RX2)2;
Y is —CH2—, —CH2—O—, —O—CH2—, —CF2—, —CH2—NH—, —NH—CH2—, —CH2—N(CH2CF3)—, or —N(CH2—CF3)—CH2—;
Z is —O— or —NRZ—;
each RX1 independently is H, halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl-C1-C6 alkoxy, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl,
or two RX1 together with the atom to which they are attached form a C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with oxo, halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy,
or three RX1 together with the atom to which they are attached form a C4-C10 cycloalkyl, wherein the cycloalkyl is optionally substituted with halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy;
each RX2 independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl,
or two RX2 together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-C6 alkoxy;
each RZ is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl;
Ar1 is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R3;
R1 is —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —N(C1-C6 alkyl)(C3-C10 cycloalkyl), —S(C1-C6 alkyl), —S(C6-C10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C6-C10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C3-C10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C6-C10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C3-C10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R1S;
each R1S independently is oxo, halogen, —CN, —OH, —O—(CH2)2—OC1—C6 alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(C1-C6 alkyl), —SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
R2 is halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SH, —S(C1-C6 alkyl), —SO2(C1-C6 alkyl), —S(C6-C10 aryl), —SO2(C6-C10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C6-C10 aryl), —O-(5- to 10-membered heteroaryl), —O—(C3-C10 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), —NH—(C6-C10 aryl), —NH-(5- to 10-membered heteroaryl), —NH—(C3-C10 cycloalkyl), or —NH-(3- to 7-membered heterocycloalkyl), wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R2S;
each R2S independently is oxo, halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —S(C1-C6 alkyl), —SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
each R3 independently is halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-6 alkoxy;
R4a is H, halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-6 alkoxy;
R4b is H, halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, or C1-6 alkoxy;
and
n is 0, 1, 2, or 3.

17 more elements

Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists

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Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists

Life of this patent

Abstract

Claims20