# US 2025/0145595 A1 · Antagonists of the muscarinic acetylcholine receptor m4

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- Number: US 2025/0145595 A1
- Document ID: US20250145595A1
- Status: Published application
- Kind: A1
- Application number: 18/715,048
- Filed: 2022-12-01
- Published: 2025-05-08
- Earliest claimed: 2021-12-01
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Aaron M. Bender; Matthew Spock; Melissa A. Korkmaz-Vaisys; Cori A. Malinky; P. Jeffrey Conn; Craig W. Lindsley
- Web page: https://patentgrep.com/patent/US20250145595A1

## CPC

- C07D 405/14: containing three or more hetero rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are (6-(4-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine, (6-(4-(difluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine, and (6-(2-(trifluoromethyl)pyridin-3-yl)pyridazin-3-yl)octahydrocyclopenta[c]pyrrol-5-amine compounds, 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 (V):
or a pharmaceutically acceptable salt thereof, wherein:
G1 is
G1a is
R is hydrogen, C1-4alkyl, C3-4cycloalkyl, or —C1-3alkylene-C3-4cycloalkyl;
R1a is hydrogen, C1-4alkyl, C1-4fluoroalkyl, —OC1-4alkyl, —OC1-4fluoroalkyl, —OC3-6cycloalkyl, —OCH2C3-6cycloalkyl, —SO2C1-4alkyl, —SO2C3-6cycloalkyl, phenyl, or C3-6cycloalkyl, wherein the phenyl and each C3-6cycloalkyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4haloalkyl, —OC1-4alkyl, and —OC1-4haloalkyl;
R1b is hydrogen, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, or C3-6cycloalkyl;
or alternatively, R1a and R1b, together with the atoms to which they attach, form a five- or six-membered unsaturated or partially unsaturated carbocyclic or heterocyclic ring, the carbocyclic or heterocyclic ring being unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, C2-4alkenyl, C3-6cycloalkyl, and —C1-3alkylene-C3-4cycloalkyl;
R2 is CF3 or CHF2;
R2a, at each occurrence, is independently halogen, C1-4alkyl, C1-4fluoroalkyl, —OC1-4alkyl, or —OC1-4fluoroalkyl;
n is 0, 1, or 2.
R3 is -L1-G2;
L1 is CH2; and
G2 is

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (V-A):

### Claim 3 (depends on 1, 2)

The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the CH2 at L1 is CD2.

### Claim 4 (depends on 1, 2, 3)

The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein G1 is

### Claim 5 (depends on 1, 2, 3, 4)

The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein G1a is

### Claim 6 (depends on 1, 2, 3, 4)

The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein G1a is

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The compound of any of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein n is 0,

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein G2 is

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein G2 is

### Claim 12 (depends on 1, 2, 3, 4, 5, 7, 8, 9, 10)

The compound of any of claims 1-5 or 7-10, or a pharmaceutically acceptable salt thereof, wherein the compound is

### Claim 13 (depends on 1, 2, 3, 4, 5, 7, 8, 9)

The compound of any of claims 1-5, 7-9, or 11, or a pharmaceutically acceptable salt thereof, wherein the compound is

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, in a form having greater than or equal to 90% enantiomeric excess at a chiral carbon atom.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, in a form that is substantially free of its enantiomer.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, in a form having at least 50% deuterium incorporation at each deuterium label.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

A pharmaceutical composition comprising the compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

A method for antagonizing mAChR M4 in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

A method for treating a disorder in a subject, wherein the subject would benefit from antagonism of mAChR M4, comprising administering to the mammal a therapeutically effective amount of the compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17.

### Claim 20 (depends on 19)

The method of claim 19, wherein the disorder is a neurodegenerative disorder, a movement disorder, or a brain disorder.

### Claim 21 (depends on 20)

The method of claim 20, wherein the disorder is a movement disorder.

### Claim 22 (depends on 20)

The method of claim 20, wherein the disorder is selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

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 any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17.

### Claim 24 (depends on 23)

The method of claim 23, wherein the subject has a disorder selected from Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

A compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, for use in the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)

The use of a compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, for the preparation of a medicament for the treatment of a neurodegenerative disorder, a movement disorder, or a brain disorder.