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

Patent metadata

Field	Value
Publication number	US-10759751-B2
Application number	US-201916295364-A
Country	US
Kind code	B2
Filing date	Mar 7, 2019
Priority date	Oct 14, 2016
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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 (1a):

or a pharmaceutically acceptable salt thereof,
wherein:

p is 0, 1 or 2;
R 1 is H, (CH 2 ) 0-2 C(O)OR 7 , (CH 2 ) 0-2 C(O)NR 7 R 8 , (CH 2 ) 0-2 S(O) 2 R 7 , or a C 1-6 non-aromatic hydrocarbon group, wherein 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 2 is H, halogen, CN, OH, NH 2 , or a C 1-4 non-aromatic hydrocarbon group, wherein the C 1-4 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 1-4 non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from the group consisting of O, N and S;
R 2 is H, halogen, CN, OH, NH 2 , or a C 1-4 non-aromatic hydrocarbon group, wherein the C 1-4 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 1-4 non-aromatic hydrocarbon group may optionally be replaced by a heteroatom selected from the group consisting of O, N and S;
R 3 is H or oxo;
each R 5 is independently F or a C 1-4 hydrocarbon group;
R 7 is H or a C 1-4 hydrocarbon group;
R 8 is H or a C 1-4 hydrocarbon group;
V is a bond, —NH—, —N(C 1-3 alkyl)-, —NHCH 2 —, or —N(C 1-3 alkyl)CH 2 —;

is a monocyclic or bicyclic ring;
Q 1 is —CH— or —N—;
Q 2 is —CH— or —N—;
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 a 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 a C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 F;
W is a 5- or 6-membered heterocyclic aromatic ring containing 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S, optionally substituted with 1 or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , and 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; or
W is -Q 3 C(O)YCH 2 R 4 ;
Q 3 is a bond or -(Alk) q -NR 6 , wherein Alk is C 1-4 alkyl;
q is 0 or 1;
Y is —CH 2 — or —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 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; and
R 6 is H or a saturated C 1-4 hydrocarbon group;
with the provisos that:
(1) at least one of Q 1 or V has a nitrogen atom;
(2) when W is an optionally substituted 5- or 6-membered heterocyclic aromatic ring, Q 2 is —CH—;
(3) when Q 2 is —N— and Q 3 is -(Alk) q -NR 6 , there are at least 2 carbons between Q 2 and NR 6 ;
(4) when Q 3 is a bond, Q 2 is —N—; and
(5) 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 thereof, wherein:

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

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, C(O)OCH 2 CH 3 , CH 2 C(O)NH 2 , S(O) 2 CH 3 , or CH 3 .

5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is H, F, Cl, CN, CH 3 , or OCH 3 ; and
R 2 is H, F, Cl, CN, CH 3 , or OCH 3 .

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is oxo.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
V is a bond; and
Q 1 is —N—.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is A, F, L, M, Q, S, T, CC, 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 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted 1,2,4-oxadiazolyl.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
W is -Q 3 C(O)YCH 2 R 4 ;
Q 3 is a bond, —NH—, or —NCH 3 —;
Y is —O—; and
R 4 is H, CH 3 , or CH 2 CH 3 .

12. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt ther

Assignees

• Heptares Therapeutics Ltd

Inventors

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

Classifications

• C07D243/08

  not condensed with other rings · CPC title

• C07D401/08

  linked by a carbon chain containing alicyclic rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D271/06

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