Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists

Patent metadata

Field	Value
Publication number	US-11834407-B2
Application number	US-202117306390-A
Country	US
Kind code	B2
Filing date	May 3, 2021
Priority date	Oct 14, 2016
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Congreve Miles Stuart
• Pickworth Mark
• Tehan Benjamin Gerald

Classifications

• C07D207/14 Primary

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D209/96

  Spiro-condensed ring systems · CPC title

• C07D213/57

  Nitriles · CPC title

• C07D243/08

  not condensed with other rings · CPC title

• C07D271/06

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title