N-[2-(1 -benzylpiperidin-4-yl)ethyl]-4-(pyrazin-2-yl)-piperazine-1 -carboxamide derivatives and related compounds as muscarinic receptor 4 (m4) antagonists for treating neurological diseases

Abstract

Provided herein are small molecule compounds of the following formula (I): or a stereoisomer, tautomer, solvate, ester or pharmaceutically acceptable salt thereof, wherein A, B, C, L i , L 2 , R i , R 2 , R 3 , R 4 , R 5 , w, x, y and z are as defined herein. Methods for treating diseases/disorders by antagonizing muscarinic receptors, including specifically antagonizing muscarinic receptor 4 (M4), are also disclosed. Such diseases/disorders are e.g. neurological diseases/disorders such as e.g. Alzheimer's Disease, Lewy Body Dementia and the cognitive deficits associated with schizophrenia, Parkinson's Disease, drug induced Parkinsonism, dyskinesias, dystonia, chorea, levodopa induced dyskinesia, cerebral palsy, progressive supranuclear palsy, and Huntington's disease. Preferred compounds are e.g. N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(pyrazin-2-yl)-piperazine-1-carboxamide derivatives and related compounds wherein the pyrazine has been replaced by e.g. pyridazine, pyrimidine, pyridine or phenyl.

1 - 61 . (canceled) 
     
     
         62 . A pharmaceutical composition comprising a compound selected from:
 (2R,6R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide;   (2S,6R)—N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide;   (2R,6R)—N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide;   (2R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide;   (2R,6R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide; and   (2R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxamide;   or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.   
     
     
         63 . A method for treating a neurological disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from:
 (2R,6R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide;   (2S,6R)—N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide;   (2R,6R)—N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide;   (2R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide;   (2R,6R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide; and   (2R)—N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxamide;   or a pharmaceutically acceptable salt thereof, wherein the neurological disease or disorder is selected from the group consisting of Alzheimer's Disease, Lewy body dementia, a cognitive deficit associated with schizophrenia, Parkinson's disease, drug induced Parkinsonism, dyskinesia, dystonia, chorea, cerebral palsy, progressive supranuclear palsy, and Huntington's disease.