Oxexin 1 receptor antagonists

Patent metadata

Field	Value
Publication number	US-12240825-B2
Application number	US-202017426301-A
Country	US
Kind code	B2
Filing date	Jan 28, 2020
Priority date	Jan 28, 2019
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

The disclosures herein relate to novel compounds of formula (1) and salts thereof, wherein V; W; X; Y; Z; R 1 ; R 2 ; R 3 ; R 4 and R 5 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of neurological or psychiatric disorders associated with orexin receptors.

First claim

The invention claimed is:

1. A compound of formula (1):

or a salt thereof, wherein
V is N, CH or CF;
W is N, CH or CF;
X is N, CH or CF;
Y is CH 2 ;
Z is N, CH or CF;
R 1 is selected from the group consisting of H, C(O)R 6 , and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens or hydroxy groups;
R 2 is a 5 or 6-membered heteroaryl ring containing two or three nitrogen atoms, and is optionally substituted with one or more fluorine atoms;
R 3 is H or C 1-3 alkyl;
R 4 is H or a halogen;
R 5 is H or a halogen;
R 6 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl, each of which is optionally substituted with —OMe or one or more fluorine atoms.

2. The compound according to claim 1 , wherein the compound is of formula (2):

or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , V, W, X, Y, and Z are as defined in claim 1 .

3. The compound according to claim 1 , wherein V is CH.

4. The compound according to claim 1 , wherein W is CH.

5. The compound according to claim 1 , wherein X is N.

6. The compound according to claim 1 , wherein Z is CH.

7. The compound according to claim 1 , wherein R 1 is selected from H; C(O)OMe; C(O)CH 3 ; C(O)CHF 2 ; C(O)cyclopropyl; C(O)CH 2 OMe;
CH 2 CHF 2 or CH 2 CH 2 OH.

8. The compound according to claim 7 , wherein R 1 is C(O)OMe or C(O)CH 3 .

9. The compound according to claim 1 , wherein R 2 is selected from the group consisting of:

10. The compound according to claim 9 , wherein R 2 is

11. The compound according to claim 1 , wherein R 3 is H.

12. The compound according to claim 1 , wherein R 4 is H.

13. The compound according to claim 1 , wherein R 5 is F.

14. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
5-acetamido-3-fluoro-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-2-(triazol-2-yl)benzamide;
3-acetamido-2-fluoro-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-6-pyrimidin-2-yl-benzamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-amino-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-N-methyl-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-chlorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-N-isopropyl-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[dideuterio-(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(3,4-difluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
methyl N-[6-[[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]carbamoyl]-5-(triazol-2-yl)-2-pyridyl]carbamate;
6-[(2,2-difluoroacetyl)amino]-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-amino-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-pyrimidin-2-yl-pyridine-2-carboxamide;
6-(cyclopropanecarbonylamino)-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-pyrimidin-2-yl-pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-chlorophenoxy)methyl]cyclopentyl]-3-pyrimidin-2-yl-pyridine-2-carboxamide;
N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-6-[(2-methoxyacetyl)amino]-3-pyrimidin-2-yl-pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(2,4-difluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-N-methyl-3-pyrimidin-2-yl-pyridine-2-carboxamide;
6-(2,2-difluoroethylamino)-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide;
N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-6-(2-hydroxyethylamino)-3-(triazol-2-yl)pyridine-2-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(5-fluoropyrimidin-2-yl)pyridine-2-carboxamide;
6-amino-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-3-(5-fluoropyrimidin-2-yl)pyridine-2-carboxamide;
2-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-5-(triazol-2-yl)pyridine-4-carboxamide;
2-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-5-pyrimidin-2-yl-pyridine-4-carboxamide;
5-acetamido-N-[(1S,2S)-2-[(4-fluorophenoxy)methyl]cyclopentyl]-2-(triazol-2-yl)pyridine-3-carboxamide;
6-acetamido-N-[(1S,2S)-2-[(5-fluoro-2-pyridyl)oxymethyl]cyclopentyl]-3-(triazol-2-yl)pyridine-2-carboxamide,
or a pharmaceutically acceptable salt thereof.

15. A pharmaceutically acceptable salt of a compound according to claim 1 .

16. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable excipient.

17. The compound according to claim 1 , wherein the compound is an antagonist of the orexin OX 1 receptor.

18. A method for treating neurological or psychiatric disorders in a subject having the disorders, comprising administering an effective amount of the compound of claim 1 to the subject.

19. A method of treating a disorder in a subject having the disorder, comprising administering an effective amount of the compound of claim 1 to the subject, wherein the disorder is selected from the group consisting of:
substance related disorders, addictive disorders, opioid use disorder, opioid intoxication, opioid withdrawal, opioid induced disorder, unspecified opioid related disorder, stimulant use disorder, stimulant intoxication, stimulant withdrawal, stimulant induced disorders, unspecified stimulant related disorder, caffeine related disorders, caffeine intoxication, caffeine withdrawal, unspecified caffeine related disorders, tobacco related disorders, tobacco use disorder, tobacco withdrawal, other tobacco induced disorders, unspecified tobacco related disorder, alcohol use disorder, alcohol intoxication, alcohol withdrawal, unspecified alcohol related disorder, cannabis related disorders, cannabis use disorder, cannabis intoxication, cannabis withdrawal, unspecified cannabis related disorders, hallucinogen related disorders, phencyclidine use disorder, phencyclidine intoxication, hallucinogen use disorder, hallucinogen persisting perception disorder, unspecified hallucinogen related disorder, inhalant related disorders, inhalant use disorder, inhalant intoxication, inhalant induced disorders, unspecified inhalant related disorder, sedative, hypnotic or anxiolytic related disorders, use disorder, intoxication, or withdrawal), gambling disorder, internet gaming disorder, addiction to sex or internet use), anxiety disorders, separation anxiety disorder, specific phobia disorder, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance/medication induced anxiety disorder, anxiety disorder due to another medical condi

Assignees

• Heptares Therapeutics Ltd
• Nxera Pharma Uk Ltd

Inventors

• Brown Giles Albert
• Congreve Miles Stuart
• Christopher John Andrew
• Swain Nigel Alan
• Bucknell Sarah Joanne
• Stephenson Anne Mary
• Tehan Benjamin Gerald
• Jones Geraint
• Mills Mark
• Patel Anil
• Phillips Andrew William

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/24

  Antidepressants · CPC title