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US 2023/0141603 A1Published application
Benzodiazepine derivatives as gaba a gamma1 pam
AssigneeHoffmann-La Roche Inc.
InventorsGiuseppe CECERE, Luca GOBBI, Maria-Clemencia HERNANDEZ, Frédéric KNOFLACH, Andreas KOBLET, Eoin Cornelius O'CONNOR, Andres Miguel OLIVARES MORALES, Valerie RUNTZ-SCHMITT, Jaclyn WAMSTEEKER CUSULIN, Nicolas ZORN
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Abstract
The invention provides novel compounds having the general formula (I) wherein R1, R3, R4, R5 and X are as described herein, compositions including the compounds and methods of using the compounds for treatment of CNS disorders.
Claims19
A compound of formula (I)
- wherein
- R1 is selected from
- i) H,
- ii) C1-6-alkyl,
- iii) C1-6-alkoxy,
- iv) C1-6-alkoxy-C1-6-alkyl,
- v) hydroxy,
- vi) hydroxy-C1-6-alkyl,
- vii) C3-8-cycloalkyl optionally substituted by R7, R8 and R9,
- viii) amino-C1-6-alkyl
- ix) heteroaryl optionally substituted by R7, R8 and R9, and
- x) heterocycloalkyl optionally substituted by R7, R8 and R9;
- R3 is selected from
- i) Cl, and
- ii) F;
- X is selected from
- i) CR6, and
- ii) N;
- R6 is selected from
- i) H,
- ii) Cl, and
- iii) F;
- R4 is selected from
- i) Br, and
- ii) Cl;
- R5 is selected from
- i) C1-6-alkyl,
- ii) C1-6-alkoxy,
- iii) halogen,
- iv) halo-C1-6-alkyl,
- v) cyano, and
- vi) C3-8-cycloalkyl;
- R7, R8 and R9 are independently selected from
- i) C1-6-alkyl, and
- ii) C1-6-alkoxy;
- or pharmaceutically acceptable salts.
33 more elements
A compound selected from:
- 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-8-cyclopropyl-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2-fluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;
- 7,8-dichloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-tetrahydropyran-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2,6-difluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;
- 7-chloro-6-(2,6-difluorophenyl)-8-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2-fluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-(2-methoxyethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-1,8-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2-fluorophenyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;
- 7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- [8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol;
- 7-chloro-6-(2,6-difluorophenyl)-8-iodo-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- [8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanamine hydrochloride;
- 7-chloro-6-(2,6-difluorophenyl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dibromo-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dibromo-6-(2,6-difluorophenyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(3-chloro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2-chloro-6-fluoro-phenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(2,6-difluorophenyl)-8-methoxy-1-(3-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyrimidin-4-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(3-fluoro-2-pyridyl)-1-(1-methylpyrazol-4-yl)-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(3-fluoro-2-pyridyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(3-fluoro-2-pyridyl)-1-pyridazin-3-yl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-6-(3-fluoro-2-pyridyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7-chloro-1-cyclopropyl-6-(2,6-difluorophenyl)-8-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 7,8-dichloro-6-(2,6-difluorophenyl)-1-methoxy-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- trans-7,8-dichloro-6-(2,6-difluorophenyl)-1-(3-methoxycyclobutyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- 8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
- or pharmaceutically acceptable salts thereof.
63 more elements
The method of claim 12, wherein the disease or condition is Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and/or cognitive symptoms associated with schizophrenia, bipolar disorders, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-X disorder, Angelman syndrome, Alzheimer's disease, negative and/or cognitive symptoms associated with schizophrenia.
Dependencies are inferred from the claim text.