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

Patent metadata

Field	Value
Publication number	US-10259787-B2
Application number	US-201715784560-A
Country	US
Kind code	B2
Filing date	Oct 16, 2017
Priority date	Oct 14, 2016
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

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 formula (1):

or a pharmaceutically acceptable salt thereof,
wherein;
p is 0, 1 or 2;
q is 0 or 1;
Q 1 is N;
Q 2 is CH;
Q 3 is -(Alk) q -NR 6 , wherein Alk is C 1-4 alkyl;
Q 4 is a 6-membered carbocyclic aromatic ring or a 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, wherein the 6-membered carbocyclic aromatic ring and the 5- or 6-membered heterocyclic aromatic ring are optionally substituted with 1 or more Q 6 ;
Q 5 is H, F, CN, OH, NH 2 or a C 1-9 non-aromatic hydrocarbon group, wherein the C 1-9 non-aromatic hydrocarbon group is optionally substituted with 1, 2, 3, 4, 5 or 6 F and 1, 2 or 3 carbon atoms of the C 1-9 non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from the group consisting of O, N and S;
each Q 6 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 or a C 1-10 non-aromatic hydrocarbon group, wherein the C 1-10 non-aromatic hydrocarbon group is optionally substituted with 1, 2, 3, 4, 5 or 6 F and 1, 2 or 3 carbon atoms of the C 1-10 non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from the group consisting of O, N and S;
R 4 is H or a C 1-6 non-aromatic hydrocarbon group, wherein the C 1-6 non-aromatic hydrocarbon group is optionally substituted with 1, 2, 3, 4, 5 or 6 F and 1 or 2 carbon atoms of the C 1-6 non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from the group consisting of O, N and S;
R 5 is F or a C 1-4 hydrocarbon group;
R 6 is H or a saturated C 1-4 hydrocarbon group;
X 1 is C 1-3 alkylene, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 F;
X 2 is C 1-3 alkylene, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 F;
V is a bond;
W is -Q 3 C(O)YCH 2 R 4 ; and
Y is —CH 2 — or —O—.

2. The compound according to claim 1 , wherein:
(a) p is 0; or
(b) p is 1 and R 5 is F or CH 3 .

3. The compound according to claim 1 , wherein Q is phenyl, pyridyl, imidazolyl or thienyl, each optionally substituted with 1 or more Q 6 .

4. The compound according to claim 1 , wherein Q 5 is H, F, CN, OH, NH 2 , CH 3 , CH 2 CH 3 or OCH 3 .

5. The compound according to claim 1 , wherein each Q 6 is independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , OCH 3 and OCH 2 CH 3 .

6. The compound according to claim 1 , wherein R 4 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH═CH 2 or C≡CCH 3 .

7. The compound according to claim 1 , wherein the compound is selected from the group consisting of;
ethyl [(3S)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]carbamate;
ethyl [(3R)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]carbamate;
ethyl {(3S)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(2-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(3-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(2-methylphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(3-methylphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-(3-chlorophenyl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(3-methoxyphenyl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(pyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(5-fluoropyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[trans-4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3S)-1-[4-cyano-4-(6-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl {(3R)-1-[4-cyano-4-(4-methylpyridin-2-yl)cyclohexyl]pyrrolidin-3-yl}carbamate;
ethyl [(3S)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]methylcarbamate;
ethyl [(3R)-1-(4-cyano-4-phenylcyclohexyl)pyrrolidin-3-yl]methylcarbamate; and
ethyl {(3R)-1-[4-(5-chloropyridin-2-yl)-4-cyanocyclohexyl]pyrrolidin-3-yl}methylcarbamate;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Heptares Therapeutics Ltd

Inventors

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

Classifications

• C07D209/96

  Spiro-condensed ring systems · CPC title

• C07D243/08

  not condensed with other rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D213/57

  Nitriles · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title