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 or stereoisomer thereof,
wherein:
Q 1 is N;
Q 2 is N or CH;
X 1 is a saturated hydrocarbon group, 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 a saturated hydrocarbon group, 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;
W is -Q 3 C(O)YCH 2 R 4 ;
Q 3 is a bond;
Y is —O—;
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 further wherein 1 or 2 —CH 2 — groups of the C 1-6 non-aromatic hydrocarbon group may be optionally and independently replaced by a heteroatom selected from the group consisting of N, O, and S;
Q 4 is a 6-membered carbocyclic aromatic ring, wherein the 6-membered carbocyclic aromatic ring is optionally substituted with 1 or more independently selected Q 6 substituents; or
Q 4 is a 5- or 6-membered heterocyclic aromatic ring, wherein the 5- or 6-membered heterocyclic aromatic ring contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the 5- or 6-membered heterocyclic aromatic ring is optionally substituted with 1 or more independently selected Q 6 substituents;
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 further wherein 1, 2, or 3 —CH 2 — groups of the C 1-9 non-aromatic hydrocarbon group may be optionally and independently replaced by a heteroatom selected from the group consisting of 0 and S;
each Q 6 is independently F, Cl, Br, I, CN, OH, NH 2 , or a C 1-10 non-aromatic hydrocarbon group, wherein each C 1-10 non-aromatic hydrocarbon group is optionally and independently substituted with 1, 2, 3, 4, 5, or 6 F, and further wherein 1, 2, or 3 —CH 2 — groups of the C 1-10 non-aromatic hydrocarbon group may be optionally and independently replaced by a heteroatom selected from the group consisting of N, O, and S;
V is a bond;
R 5 is F or a C 1-4 hydrocarbon group; and
p is 0, 1, or 2;
with the proviso that X 1 and X 2 together contain a total of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is H, CH 3 , CH 2 F, C≡CH, or C≡CCH 3 .
3. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is CH 3 .
4. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Q 4 is phenyl, imidazolyl, thienyl, or pyridyl, wherein the phenyl, imidazolyl, thienyl, and pyridyl are each optionally substituted with 1 or more independently selected Q 6 substituents.
5. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Q 5 is H, CN, or C(O)OCH 3 .
6. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Q 5 is CN.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each Q 6 is independently F, Cl, Br, I, CH 3 , CF 3 , CH 2 CH 3 , OCH 3 , or OCH 2 CH 3 .
8. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
(a) p is 0; or
(b) p is 1; and
R 5 is F or CH 3 .
9. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
is A, B, C, L, M, N, O, P, or DD:
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 , wherein the compound is of formula (4):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 9 is H, F, or OH.
11. The compound according to claim 1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
13. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or stereoisomer thereof.