Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
This invention relates to compounds that are agonists of the muscarinic M 1 receptor or M 1 and M 4 receptors and which are useful in the treatment of muscarinic M 1 or M 1 /M 4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula wherein Q 4 , Q 5 , R 5 , p, V, Q 1 , Q 2 , X 1 , X 2 and W are defined herein.
1. A compound of the formula (1):
or a pharmaceutically acceptable salt thereof, wherein:
p is 0;
V is selected from a bond, NH, and NH—CH 2 ;
Q 1 is N or CH;
Q 2 is N or CH;
provided that at least one of Q 1 or V comprises a nitrogen atom;
W is —C(O)OCH 2 R 4 or oxadiazolyl, wherein the oxadiazolyl is optionally substituted with methyl, ethyl, or trifluoromethyl, wherein when W is oxadiazolyl optionally substituted with methyl, ethyl, or trifluoromethyl, then Q 2 is CH;
X 1 and X 2 are saturated hydrocarbon groups which together contain a total of one to nine carbon atoms and which link together such that the moiety:
forms a monocyclic ring or bicyclic ring system;
Q 4 is phenyl, wherein the phenyl is optionally substituted with F, methoxy, or methyl;
or Q 4 is pyridyl, wherein the pyridyl is optionally substituted with F, methoxy, or methyl;
Q 5 is cyano; and
R 4 is hydrogen or methyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q 4 is phenyl, wherein the phenyl is optionally substituted with F, methoxy, or methyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q 4 is phenyl.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is a bond and Q 1 is N.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is NH.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is NH—CH 2 .
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is 1 oxa-2,4-diazolyl, wherein the 1-oxa-2,4-diazolyl is optionally substituted with methyl, ethyl, or trifluoromethyl.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety:
is selected from groups A to GG below:
where “a” indicates the point of attachment to the cyclohexane ring and “b” indicates the point of attachment to the W group.
10. The compound according to claim 1 , which is selected from:
ethyl 5-(4-cyano-4-phenylcyclohexyl)-1,5-diazocane-1-carboxylate;
ethyl 2-(4-cyano-4-phenylcyclohexyl)-2,6-diazaspiro[3.4]octane-6-carboxylate;
ethyl 7-(4-cyano-4-phenylcyclohexyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate;
ethyl 8-(4-cyano-4-phenylcyclohexyl)-2,8-diazaspiro[4.5]decane-2-carboxylate;
ethyl 7-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-3-carboxylate;
ethyl 5-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;
ethyl 1-(4-cyano-4-phenylcyclohexyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate;
ethyl 3-(4-cyano-4-phenylcyclohexyl)-3,7-diazabicyclo[4.2.0]octane-7-carboxylate;
ethyl (4aS,7aS)-1-(4-cyano-4-phenylcyclohexyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate;
4-{[(1R,3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-(pyridin-2-yl)cyclohexanecarbonitrile;
4-{[(1R,3S)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopentyl]amino}-1-phenylcyclo hexanecarbonitrile;
1-phenyl-4-{6-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-2-azaspiro[3.3] hept-2-yl}cyclohexanecarbonitrile;
4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-phenylcyclo hexanecarbonitrile;
1-(2-fluorophenyl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile;
1-(5-fluoropyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile;
1-(5-methoxypyridin-2-yl)-4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]cyclohexanecarbonitrile;
4-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-6-yl]-1-(5-methylpyridin-2-yl)cyclohexanecarbonitrile;
4-({[2-(3-ethyl-1,2,4-oxadiazol-5-yl)cyclopropyl]methyl}amino)-1-phenylcyclohexanecarbonitrile;
1-(5-fluoropyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile; and
1-(5-methylpyridin-2-yl)-4-({(1R,3S)-3-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]cyclopentyl}amino)cyclohexanecarbonitrile;
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. A method of treating a disease selected from Alzheimer's Disease, dementia with Lewy bodies, and schizophrenia in a patient in need thereof, comprising administering to the patient a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.