IP Library › Granted Patent US 12,679,804
Granted Patent B2
US 12,679,804 · App. 18/479,695 · Granted Jul 14, 2026

2-(3-ethynylbenzyl)-substituted heterocycle derivatives and related uses

Inventors: John Andrew Christopher (Cambridge, GB); Karl Gibson (Sandwich, GB); Paul Humphries (Santa Clara, CA); Gordon Saxty (Cambridge, GB); Matthew Spendiff (Cambridge, GB); Wojciech Zawodny (Cambridge, GB)
Assignee: CENTESSA PHARMACEUTICALS (UK) LIMITED
C07D207/14A61K31/40A61K31/4025A61K31/4439A61K31/4523C07D401/14C07D403/06C07D405/06C07D405/10
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Quick Facts
Patent No.
US 12,679,804
App. No.
18/479,695
Filed
Oct 2, 2023
Granted
Jul 14, 2026
Kind
B2
Art Unit
1626
USPC
514/210.18
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-2 receptor activity and may be used in the treatment of disorders in which orexin-2 receptor activity is implicated, such as 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.

Claims (51)

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is —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 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl, 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 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R X1 ;

each R X1 independently is oxo, halogen, —CN, —OH, —O(C 1 -C 6 alkyl), —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 ;

Z is —O— or —NR Z —;

R Z is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

R 1 is —OH, —O(C 1 -C 6 alkyl), —NH 2 , —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 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 —O(C 1 -C 6 alkyl), —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 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, —O(C 1 -C 6 alkyl), —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 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

Ar 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 A ;

each R A 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;

R 2 is C 2 -C 6 alkynyl optionally substituted with one or more Res;

each R 2S independently is oxo, halogen, —CN, —OH, —O(C 1 -C 6 alkyl), —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 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the —O(C 1 -C 6 alkyl), —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 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R 2SS ;

each R 2SS independently is oxo, halogen, —CN, —OH, —NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

R 4a is 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, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

R 4b is 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, C 2 -C 6 alkynyl, or C 1 -C 6 haloalkyl;

R 5a and R 5b 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 5S ; or R 5a and R 5a , 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 5S ;

each R 5S 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; and

n is 0, 1, 2, or 3.

2 . The compound of claim 1 , wherein:

X is —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 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl, 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 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R X1 ;

each R X1 independently is halogen, —OH, or —O(C 1 -C 6 alkyl);

Z is —NH—;

R 1 is —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, or 3- to 7-membered heterocycloalkyl, wherein the —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R 1S ;

each R 1S independently is halogen;

Ar 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 A ;

each R A independently is halogen or —O(C 1 -C 6 alkyl);

R 2 is C 2 -C 6 alkynyl optionally substituted with one or more R 2S ;

each R 2S independently is —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R 2SS ;

each R 2SS independently is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4a is H;

R 4b is H;

R 5a and R 5b each independently are H or halogen; or R 5a and R 5a , together with the atom they attach to, form C 3 -C 7 cycloalkyl; and

n is 1 or 2.

3 . The compound of claim 1 , wherein X is —O(C 1 -C 6 alkyl) optionally substituted with one or more R X1 .

4 . The compound of claim 1 , wherein X is —NH(C 1 -C 6 alkyl) or —N(C 1 -C 6 alkyl) 2 , wherein the —NH(C 1 -C 6 alkyl) or —N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R X1 .

5 . The compound of claim 1 , wherein X is C 1 -C 6 alkyl optionally substituted with one or more R X1 .

6 . The compound of claim 1 , wherein X is C 3 -C 7 cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R X1 .

7 . The compound of claim 1 , wherein X is oxetanyl or azetidinyl, wherein the oxetanyl or azetidinyl is optionally substituted with one or more R X1 .

8 . The compound of claim 1 , wherein Z is —NH—.

9 . The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), or —N(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl, —NH(C 1 -C 6 alkyl) or —N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R 1S .

10 . The compound of claim 1 , wherein R 1 is CH 3 or CH 2 CH 3 .

11 . The compound of claim 1 , wherein Ar is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with one or more R A , wherein at least one R A 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.

12 . The compound of claim 1 , wherein R 2 is ethynyl optionally substituted with one or more R 2S .

13 . The compound of claim 1 , wherein at least one R 2S is —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the —O(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl is optionally substituted with one or more R 2SS .

14 . The compound of claim 1 , wherein at least one Res is C 3 -C 7 cycloalkyl optionally substituted with one or more R 2SS .

15 . The compound of claim 1 , wherein at least one Res is 3- to 7-membered heterocycloalkyl optionally substituted with one or more R 2SS .

16 . The compound of claim 1 , wherein the compound is selected from

17 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

18 . A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with an implicated orexin-2 receptor.

19 . The method of claim 18 , wherein the disease or disorder is 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 a complication in emergence from anesthesia.

20 . The method of claim 18 , wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia.

Assignments (4)
RELEASE OF SECURITY INTEREST Recorded Jun 24, 2026
From: OXFORD FINANCE LLC
To: CENTESSA PHARMACEUTICALS (UK) LIMITED
Reel/Frame 075069/0879 →
SECURITY INTEREST Recorded Dec 31, 2024
From: CENTESSA PHARMACEUTICALS (UK) LIMITED
To: OXFORD FINANCE LLC
Reel/Frame 069708/0039 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 5, 2024
From: OREXIA THERAPEUTICS LIMITED
To: CENTESSA PHARMACEUTICALS (UK) LIMITED
Reel/Frame 069502/0358 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 28, 2024
From: CHRISTOPHER, JOHN ANDREW; GIBSON, KARL; HUMPHRIES, PAUL; SAXTY, GORDAN; SPENDIFF, MATTHEW; ZAWODNY, WOJCIECH
To: OREXIA THERAPEUTICS LIMITED
Reel/Frame 066588/0711 →
Continuity (3)
Continuation PCTEP2022058817 · Apr 1, 2022
Provisional Application 63170099 · Apr 2, 2021
Related Publication 20240239744A1 · Jul 18, 2024
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