# US 11,299,481 B2 · Antagonists of the muscarinic acetylcholine receptor M4

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- Number: US 11,299,481 B2
- Document ID: US11299481B2
- Status: Granted
- Kind: B2
- Application number: 16/757,245
- Filed: 2018-10-20
- Published: 2021-06-24
- Granted: 2022-04-12
- Earliest claimed: 2017-10-20
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Craig W. Lindsley; P. Jeffrey Conn; Darren W. Engers; Julie L. Engers; Kayla J. Temple; Aaron M. Bender; Logan A. Baker
- Web page: https://patentgrep.com/patent/US11299481B2

## CPC

- A61P 25/00: Drugs for disorders of the nervous system
- C07D 403/14: containing three or more hetero rings
- A61P 25/16: Anti-Parkinson drugs
- C07D 209/52: condensed with a ring other than six-membered
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 493/08: Bridged systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein are substituted hexahydro-1H-cyclopenta[c]pyrrole compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is an arylene or a five- or six-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from N, O, and S;
Q is selected from NRa, O, and —NRb—C(O)—;
m is 0, 1, or 2;
R1 is aryl;
n is 1 or 2;
each R2 is independently selected from hydrogen, C1-C4 alkyl, halo, and —ORg;
R3 is selected from hydrogen and C1-C4 alkyl;
R4 is selected from —(CRhRi)p—Y′, hydrogen, C1-C8 alkyl, and C2-C8 alkenyl;
R5 is selected from hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy;
Y′ is selected from cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl;
each Ra, Rh, and Rg is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and aryl;
each Rh is independently selected from hydrogen and C1-C4 alkyl;
each Ri is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and aryl; and
p is 0, 1, 2, 3, or 4;
wherein each aryl, heteroaryl, arylene, heteroarylene, cycloalkyl, cycloalkenyl, and heterocycle is independently unsubstituted or substituted with 1-5 substituents.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is selected from:
wherein:
T is selected from O, S and NH;
U, V, W, X, Y and Z are independently selected from N and CRj;
each Rj is independently selected from hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and hydroxy;
Ra and Rb are independently selected from hydrogen and C1-C4 alkyl;
R1 is phenyl or a 9- to 12-membered aryl, and R1 is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, —OR10, —NR10COR10, —CONR10R10, —C1-C3alkylene-OR10, C3-C6 cycloalkyl, and —C1-C3alkylene-C3-C6cycloalkyl;
each R2 is independently selected from hydrogen and C1-C4 alkyl;
R4 is C4-C6 alkyl or —(CRhRi)p—Y′;
Rh is hydrogen;
Ri is hydrogen;
p is 0, 1, 2, or 3;
Y′ is
a) C3-C10 cycloalkyl;
b) C3-C8 cycloalkenyl;
c) a 6- to 12-membered aryl;
d) a 5- to 12-membered heteroaryl; or
e) a 4- to 12-membered heterocyclyl;
wherein Y′ is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR12, —NR12R12, —NR12COR12, and —NR12SO2R13;
R5 is selected from hydrogen and C1-C4 alkyl;
R10, at each occurrence, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl;
R11, at each occurrence, is independently C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl;
R12, at each occurrence, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl; and
R13, at each occurrence, is independently C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein
A is
wherein R1-A- is, respectively,
Ra and Rb are hydrogen;
R2 is hydrogen;
R3 is hydrogen; and
R5 is hydrogen.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl or a 9- to 12-membered aryl, and R1 is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, —OR10, —NR10COR10, —CONR10R10, —C1-C3alkylene-OR10, C3-C6 cycloalkyl, and —C1-C3alkylene-C3-C6cycloalkyl;
R10, at each occurrence, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl; and
R11, at each occurrence, is independently C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein
R4 is C4-C6 alkyl.

### Claim 6 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein
R4 is —(CRhRi)p—Y′;
Rh is hydrogen;
Ri is hydrogen;
p is 0, 1, 2, or 3;
Y′ is
a) C3-C10 cycloalkyl;
b) C3-C8 cycloalkenyl;
c) a 6- to 12-membered aryl;
d) a 5- to 12-membered heteroaryl; or
e) a 4- to 12-membered heterocyclyl;
wherein Y′ is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR12, —NR12R12, —NR12COR12, and —NR12SO2R13;
R12, at each occurrence, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl; and
R13, at each occurrence, is independently C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, or —C1-C3alkylene-C3-C6 cycloalkyl.

### Claim 7 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y′ is a C3-C10 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, and C1-C4 haloalkyl.

### Claim 8 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y′ is a C3-C8 cycloalkenyl.

### Claim 9 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y′ is a phenyl or a 9- to 12-membered aryl, and optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR12, —NR12R12, —NR12COR12, and —NR12SO2R13.

### Claim 10 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Y′ is a 5- to 6-membered monocyclic heteroaryl or an 8- to 12 membered bicyclic heteroaryl, and optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 haloalkyl, —OR12, —NR12R12, —NR12COR12, and —NR12SO2R13.

### Claim 11 (depends on 1)

A method for antagonizing mAChR M4 in a subject, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A method for treating motor symptoms in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 6)

The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein p is 0.

### Claim 15 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Q is NRa and m is 0.

### Claim 16 (depends on 14)

The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Q is NRa and m is 0.

### Claim 17 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Q is NRa and m is 1.

### Claim 18 (depends on 14)

The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Q is NRa and m is 1.

### Claim 19 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Q is O and m is 0.

### Claim 20 (depends on 14)

The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Q is O and m is 0.