New cyclopenta-thieno-diazepine derivatives as gaba a gamma1 positive allosteric modulators

Patent metadata

Field	Value
Publication number	US-2024190889-A1
Application number	US-202418429832-A
Country	US
Kind code	A1
Filing date	Feb 1, 2024
Priority date	Aug 2, 2021
Publication date	Jun 13, 2024
Grant date	—

Abstract

The invention provides heterocyclic compounds having the general formula (1), 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. release wednesday

First claim

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

is selected from:

R 1 is selected from hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, amino-C 1 -6-alkyl, 5-14-membered heteroaryl, 3-14-membered heterocycloalkyl, (3-14-membered heterocycloalkyl)-C(O)—, and —C(O)NR 5 R 6 ; wherein said C 3 -C 10 -cycloalkyl, 5-14-membered heteroaryl and 3-14-membered heterocycloalkyl are optionally substituted by 1-3 substituents that are each independently selected from halogen, cyano, hydroxy, oxo, amino, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkoxy;
R 2 is selected from hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy;
R 3 is selected from chloro and fluoro;
R 4 is selected from C 1 -C 6 -alkyl, halo-C 1 -C 2 -alkyl, and cyano; and
R 5 and Re are each independently selected from hydrogen, C 1 -C 6 -alkyl, and hydroxy-C 1 -C 6 -alkyl.

2 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

3 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 3 -Cio-cycloalkyl, 5-14-membered heteroaryl, (3-14-membered heterocycloalkyl)-C(O)—, and —C(O)NR 5 R 6 ; wherein said 3-14-membered heterocycloalkyl is substituted by 2 oxo substituents; R 5 is hydroxy -C 1 -C 6 -alkyl; and R 6 is hydrogen.

4 . The compound of formula (I) according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 -alkyl.

5 . The compound of formula (I) according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

6 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen and C 1 -C 6 -alkyl.

7 . The compound of formula (I) according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 -alkyl.

8 . The compound of formula (I) according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

9 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halo-C 1 -C 6 -alkyl.

10 . The compound of formula (I) according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CHF 2 .

11 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, 5-14-membered heteroaryl, (3-14-membered heterocycloalkyl)-C(O)—, and —C(O)NR 5 R 6 ; wherein said 3-14-membered heterocycloalkyl is substituted by 2 oxo substituents; R 2 is selected from hydrogen and C 1 -C 6 -alkyl; R 5 is hydroxy-C 1 -C 6 -alkyl; and R 6 is hydrogen.

12 . The compound of formula (I) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are both C 1 -C 6 -alkyl; and
R 4 is halo-C 1 -C 6 -alkyl.

13 . The compound of formula (I) according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are both methyl; and R 4 is CHF 2 .

14 . The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from:
(13R)-9-(2-chloro-6-fluoro-phenyl)-3-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene-13-carbonitrile; (13R)-9-(2,6-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene-13-carbonitrile; (13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene; (13R)-9-(2-chloro-6-fluoro-phenyl)-13-(difluoromethyl)-3-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene; (7S,13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-3,7-dimethyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene; (13R)-9-(2-chloro-6-fluoro-phenyl)-3-cyclopropyl-13-(difluoromethyl)-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene; (13R)-3-cyclopropyl-13-(difluoromethyl)-9-(2,6-difluorophenyl)-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S, 13R)-3-cyclopropyl-13-(difluoromethyl)-9-(2,6-difluorophenyl)-7-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011,15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S, 13R)-9-(2-chloro-6-fluoro-phenyl)-13-(difluoromethyl)-3,7-dimethyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-3-pyridazin-3-yl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene: (7S, 13R)-9-(2-chloro-6-fluoro-phenyl)-3-cyclopropyl-13-(difluoromethyl)-7-methyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011,15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S, 13R)-9-(2-chloro-6-fluoro-phenyl)-13-(difluoromethyl)-7-methyl-3-pyridazin-3-yl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S, 13R)-9-(2,6-difluorophenyl)-3,7-dimethyl-13-(trifluoromethyl)-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (4S,8R)-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-8,9-dihydro-4H,7H-cyclopenta [4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine: (13R)-9-(2,6-difluorophenyl)-3,13-dimethyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene: (7S, 13R)-9-(2,6-difluorophenyl)-3,7,13-trimethyl-16-thia-2,4,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S, 13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-4,7-dimethyl-16-thia-2,3,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaene: (7S, 13S)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-4,7-dimethyl-16-thia-2,3,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8,11(15)-pentaene: (7S,13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-N-(2-hydroxyethyl)-7-methyl-16-thia-2,3,5,8-tetrazatetracyclo [8.6.0.02,6.011,15]hexadeca-1(10),3,5,8, 11(15)-pentaene-4-carboxamide: [(7S,13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-7-methyl-16-thia-2,3,5,8-tetrazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaen-4-yl]-(1, 1-dioxo-1,4-thiazinan-4-yl)methanone: (7S, 13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-3,7-dimethyl-16-thia-2,5,8-triazatetracyclo [8.6.0.02,6.011,15]hexadeca-1(10),3,5,8,11(15)-pentaene: [(7S, 13R)-13-(difluoromethyl)-9-(2,6-difluorophenyl)-7-methyl-16-thia-2,5,8-triazatetracyclo [8.6.0.02,6.011, 15]hexadeca-1(10),3,5,8, 11(15)-pentaen-3-yl]methanol: and [(7S,13S)-13-(difluoromethyl)-9-(2,6-dif

Assignees

• Hoffmann La Roche

Inventors

• Cecere Giuseppe
• Gobbi Luca
• Hernandez Maria-Clemencia
• Koblet Andreas
• Olivares Morales Andres Miguel
• Runtz-Schmitt Valerie
• Zorn Nicolas

Classifications

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/22

  Anxiolytics · CPC title