Benzodiazepine derivatives as GABA a GAMMA1 PAM

Patent metadata

Field	Value
Publication number	US-12344614-B2
Application number	US-202217938000-A
Country	US
Kind code	B2
Filing date	Oct 4, 2022
Priority date	Oct 6, 2021
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The invention provides novel heterocyclic compounds having the general formula (I) or (II), and pharmaceutically acceptable salts thereof, wherein the variables are as described herein.Further provided are pharmaceutical compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as medicaments, in particular methods of using the compounds for the treatment or prevention of acute neurological disorders, chronic neurological disorders and/or cognitive disorders.

First claim

What is claimed is:

1. A compound selected from:
6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one;
6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one;
3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-4-fluoro-phenol;
3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluorophenol;
(5S)-8,9-dichloro-7-(2-fluoro-5-hydroxyphenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one;
8,9-dichloro-7-(2-fluoro-5-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one;
[7,8-dichloro-6-(2-fluoro-5-hydroxy-phenyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone;
6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one;
3-[7-chloro-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol;
3-[7-chloro-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol;
3-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-4-fluoro-phenol;
8-chloro-7-(2-fluoro-5-hydroxy-phenyl)-9-(trifluoromethyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one;
6,7-dichloro-5-(2,6-difluoro-3-hydroxy-phenyl)-1-methyl-3H-1,4-benzodiazepin-2-one;
3-(7,8-dichloro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl)-2,4-difluoro-phenol;
8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one;
3-[(4S)-7,8-dichloro-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-2,4-difluoro-phenol;
[7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone;
(5S)-8,9-dichloro-7-(2,6-difluoro-3-hydroxy-phenyl)-5-methyl-5H-pyrimido[1,2-a][1,4]benzodiazepin-3-one;
[7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]-(3-methoxyazetidin-1-yl)methanone; 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol;
[(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-fluoroazetidin-1-yl)methanone;
5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-6-yl]pyridin-2-ol;
6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol;
6-[(10S)-6-chloro-10-methyl-5-(trifluoromethyl)-1,9,12-triazatetracyclo[9.6.0.02,7.013,17]heptadeca-2,4,6,8,11,13(17)-hexaen-8-yl]-5-fluoro-pyridin-2-ol; 6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]-5-fluoropyridin-2-ol;
5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol;
5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol;
6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol;
5-chloro-6-[(4S)-7-chloro-2,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-6-yl]pyridin-2-ol; azetidin-1-yl-[(4S)-7-chloro-6-(3-fluoro-6-hydroxypyridin-2-yl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-2-yl]methanone;
(4S)-7-chloro-N-cyclopropyl-6-(3-fluoro-6-hydroxy-2-pyridyl)-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide; and
(4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
6,7-dichloro-5-(2-fluoro-5-hydroxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one;
6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one;
6-chloro-5-(2-fluoro-5-hydroxy-phenyl)-1-methyl-7-(trifluoromethyl)-3H-1,4-benzodiazepin-2-one;
[7-chloro-6-(2-fluoro-5-hydroxy-phenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a][1,4]benzodiazepin-2-yl]-(3-methoxyazetidin-1-yl)methanone;
6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol; and
5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol.

3. A pharmaceutical composition comprising the compound according to 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

4. A method for treating or preventing autism spectrum disorder (ASD), said method comprising administering an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

5. A compound 6-chloro-5-(2-fluoro-5-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one, or a pharmaceutically acceptable salt thereof.

6. A compound (4S)-7-chloro-6-(3-fluoro-6-hydroxy-2-pyridyl)-N-isopropyl-4-methyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

7. A compound 6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]-5-fluoro-pyridin-2-ol, or a pharmaceutically acceptable salt thereof.

8. A compound 5-chloro-6-[(4S)-7-chloro-1,4-dimethyl-8-(trifluoromethyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-6-yl]pyridin-2-ol, or a pharmaceutically acceptable salt thereof.

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Cecere Giuseppe
• Gobbi Luca
• Hernandez Maria-Clemencia
• Humm Roland
• Olivares Morales Andrés Miguel
• Patiny-Adam Angélique
• Runtz-Schmitt Valerie
• Schnider Christian

Classifications

• C07D243/24 Primary

  Oxygen atoms · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title

• A61K47/10 Primary

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K9/4866

  Organic macromolecular compounds · CPC title

• A61K9/4858

  Organic compounds · CPC title