# US 12,215,099 B2 · Quinolinone and benzoxazine derivatives as muscarinic M1 and/or M4 receptor agonists

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- Number: US 12,215,099 B2
- Document ID: US12215099B2
- Status: Granted
- Kind: B2
- Application number: 17/311,212
- Filed: 2019-12-09
- Published: 2022-01-20
- Granted: 2025-02-04
- Earliest claimed: 2018-12-07
- Assignees: Nxera Pharma UK Limited
- Applicants: Nxera Pharma UK Limited
- Inventors: Giles Albert Brown; Miles Stuart Congreve; Benjamin Gerald Tehan; Mark Pickworth
- Web page: https://patentgrep.com/patent/US12215099B2

## CPC

- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07D 413/14: containing three or more hetero rings
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 403/14: containing three or more hetero rings
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D 471/08: Bridged systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention related to compounds having activity as muscarinic M1 or M1 and M4 receptor agonists which are useful in the treatment of diseases mediated by the muscarinic M1 and M4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula (I) where X1; X2; X3; X4; Y; Z; n, R1 and R2 are defined herein.

## Claims

### Claim 1

A compound of the formula (I):
or a salt thereof, wherein:
R1 is:
n is 1, 2, 3 or 4;
X1 is CH2 or O;
Y is N or CH;
X2 and X3 are saturated hydrocarbon groups which together contain a total of four to six carbon atoms and which link together such that the moiety:
represents a monocyclic or bicyclic ring system;
Z is CH2 or CO;
X4 is CH2 or O;
and R2 is F or H.

### Claim 2 (depends on 1)

A compound according to claim 1 of formula (II)
or a salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1 of formula (III)
or a salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein the ring system formed by the moiety:
is the monocyclic ring system:
or is selected from the bicyclic ring systems A or B:

### Claim 5 (depends on 1)

A compound according to claim 1 wherein the ring system formed by the moiety:
is the bicyclic ring system A1:

### Claim 6 (depends on 1)

A compound according to claim 1 which is selected from:
1-[3-[4-[2-(4,5-dihydroisoxazol-3-yloxy) ethyl]-1-piperidyl]propyl]-3,4-dihydroquinolin-2-one,
1-[3-[4-[4-(4,5-dihydroisoxazol-3-yloxy) butyl]-1-piperidyl]propyl]-3,4-dihydroquinolin-2-one,
1-[3-[3-[2-(4,5-dihydroisoxazol-3-yloxy) ethyl]-8-azabicyclo [3.2.1]octan-8-yl]propyl]-3,4-dihydroquinolin-2-one,
1-[3-[3-[3-(4,5-dihydroisoxazol-3-yloxy) propyl]-8-azabicyclo [3.2.1]octan-8-yl]propyl]-3,4-dihydroquinolin-2-one,
1-[3-[(1R,5S)-3-[2-(4,5-dihydroisoxazol-3-yloxy) ethoxy]-8-azabicyclo [3.2.1]octan-8-yl]propyl]-3,4-dihydroquinolin-2-one,
1-[3-[3-[3-(4,5-dihydroisoxazol-3-yloxy) propyl]-3,8-diazabicyclo [3.2.1]octan-8-yl]propyl]-3,4-dihydroquinolin-2-one,
4-[3-[4-[2-(4,5-dihydroisoxazol-3-yloxy) ethyl]-1-piperidyl]propyl]-7-fluoro-1,4-benzoxazin-3-one,
4-[3-[4-[4-(4,5-dihydroisoxazol-3-yloxy) butyl]-1-piperidyl]propyl]-7-fluoro-1,4-benzoxazin-3-one,
3-[3-[8-[3-(3,4-dihydro-2H-quinolin-1-yl) propyl]-8-azabicyclo [3.2.1]octan-3-yl]propoxy]-4,5-dihydroisoxazole,
2-[2-[1-[3-(2-oxo-3,4-dihydroquinolin-1-yl) propyl]-4-piperidyl]ethyl]isoxazolidin-3-one,
2-[4-[1-[3-(2-oxo-3,4-dihydroquinolin-1-yl) propyl]-4-piperidyl]butyl]isoxazolidin-3-one,
2-[5-[1-[3-(2-oxo-3,4-dihydroquinolin-1-yl) propyl]-4-piperidyl]pentyl]isoxazolidin-3-one, and
2-[3-[8-[3-(2-oxo-3,4-dihydroquinolin-1-yl) propyl]-8-azabicyclo [3.2.1]octan-3-yl]propyl]isoxazolidin-3-one,
or a salt thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.

### Claim 8 (depends on 1)

A compound according to claim 1 having muscarinic M1 receptor agonist activity.

### Claim 9 (depends on 1)

A method of treating a cognitive disorder or psychotic disorder or for the treatment or lessening the severity of acute, chronic, neuropathic or inflammatory pain, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

### Claim 10 (depends on 9)

The method according to claim 9 wherein the cognitive disorder is Alzheimers disease.

### Claim 11 (depends on 9)

The method according to claim 9 wherein the cognitive disorder is dementia with Lewy bodies.