Compounds of formulas (VII), (VIII), (IX), (XI), (XII), (XIII), and (XIV) as muscarinic receptor 4(M4) antagonists for treating neurological diseases
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 1 , L 2 , R 2 , R 3 , R 4 , R 3 , 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derivatives and related compounds wherein the pyrazine has been replaced by e.g. pyridazine, pyrimidine, pyridine or phenyl.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. A compound having the structure of the following formula (VII):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl,
R 1 is, at each occurrence, H, C 1-4 alkyl, C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl),—N(C 1-4 alkyl) 2,
—C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3; and
L 1 is selected from
2. A compound having the structure of the following formula (VIII):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl;
R 1 is, at each occurrence, H, C 1-4 alkyl, C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl),—N(C 1-4 alkyl) 2,
—C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3; and
L 1 is selected from
3. A compound having the structure of the following formula (IX):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl,
R 1 is, at each occurrence, H, C 1-4 alkyl, C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl),—N(C 1-4 alkyl) 2,
—C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3; and
L 1 is selected from:
4. A compound having the structure of the following formula (XI):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A, B and C are each independently a carbocyclyl or heterocyclyl;
R 1 is, at each occurrence, H, C 1-4 alkyl, C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 ,—NH(C 1-4 alkyl) 2 ,
—C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3.
5. A compound having the structure of the following formula (XII):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl;
R 1 is, at each occurrence, H, c 1-4alkyl , C(═O)OC 1-4alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3.
6. A compound having the structure of the following formula (XIII):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl;
R 1 is, at each occurrence, H, C 1-4 alkyl, C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl) 2 , —N(C 1-4 alkyl) 2 , —C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2, 3, wherein at least one of y or z is 1, 2, or 3.
7. A compound having the structure of the following formula (XIV):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
A and C are each independently a carbocyclyl or heterocyclyl;
R 1 is, at each occurrence, C 1-4 alkyl,C(═O)OC 1-4 alkyl or aryl;
R 2 , R 3 , R 4 and R 5 are each independently —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 —C≡N, —C(═O)NH 2 , halo, C 1-4 alkyl, C 1-4 alkyl—OH, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy; and
w, x, y and z are each independently 0, 1, 2 or 3, wherein at least one of y or z is 1, 2 or 3.
8. A pharmaceutical composition comprising a compound of any one of claims 1 - 7 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
9. A method for antagonizing a muscarinic receptor of a cell comprising contacting the cell with a compound of any one of claims 1 - 7 , or a stereoisomer, solvate or pharmaceutically acceptable salt thereof.
10. A method for treating or a neurological disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 7 , or a stereoisomer, solvate or 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 Huntinoton's disease.
11. The method of claim 10 , wherein the.
12. A compound, which is:
(2R, 6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.
13. A compound, which is:
(2R,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.
14. A compound, which is:
(2R,6R)-N-(2-4-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.
15. A compound, which is:
(2S,6R)-N-(2-(1-benzylpiperidin-4-yl)ethyl)-4-(5-cyanopyrimidin-2-yl)-2,6-dimethylpiperazine- 1-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.
16. A compound, which is:
(2R)-N[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethyl-4-]5-(trifluoromethyl)pyrazin-2-yl]-1-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.
17. A compound, which is:
(2R)-N-[2-1-benzylpiperidin-4-yl)ethyl]-4-(3-cyano-5fluorophenyl)-2-methylpiperazine-carboxamide, or a solvate or pharmaceutically acceptable salt thereof.