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 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.