# US 11,299,476 B2 · Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof

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- Number: US 11,299,476 B2
- Document ID: US11299476B2
- Status: Granted
- Kind: B2
- Application number: 16/084,093
- Filed: 2017-03-08
- Published: 2020-09-17
- Granted: 2022-04-12
- Earliest claimed: 2016-03-14
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
- Inventors: Amy Hauck Newman; Vivek Kumar; Anver Basha Shaik
- Web page: https://patentgrep.com/patent/US11299476B2

## CPC

- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/36: Opioid-abuse
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein novel dopamine D3 receptor selective antagonists/partial agonists compounds with high affinity and metabolic stability useful for the treatment of psychiatric and neurological disorders and as research and diagnostic tools. Also disclosed are methods of making the compounds.

## Claims

### Claim 1

A compound selected from the group consisting of
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide; and
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, comprising tritium, deuterium, 11C, 13C, 14C, 18F, or a combination thereof.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, further comprising at least one pharmaceutically acceptable carrier.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a capsule, a syrup, an ophthalmic solution, or a transdermal patch.

### Claim 5 (depends on 3)

A package comprising the pharmaceutical composition of claim 3 in a container and further comprising instructions for using the composition in order to treat a patient suffering from a substance use disorder, schizophrenia, depression, a bipolar disorder, or a dyskinesia associated with Parkinson's disease (PD) or treatment of PD with L-DOPA.

### Claim 6 (depends on 1)

A method for treating a substance use disorder, schizophrenia, depression, a bipolar disorder, or a dyskinesia associated with Parkinson's disease (PD) or treatment of PD with L-DOPA in a patient, comprising providing a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

### Claim 7 (depends on 1)

A method for treating a substance use disorder, schizophrenia, depression, a bipolar disorder, or a dyskinesia associated with Parkinson's disease (PD) or treatment of PD with L-DOPA in a patient, comprising providing a therapeutically effective amount of a compound of claim 1 along with at least one pharmaceutically acceptable carrier to a patient in need thereof.

### Claim 8 (depends on 6)

The method of claim 6, wherein the substance of the substance use disorder is an opioid or a cannabinoid.

### Claim 9 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide; and
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide; and
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide; and
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
(R)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide; and
(S)-N-(4-(4-(3-chloro-5-ethyl-2-methoxyphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide; and
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)-1H-indole-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1 selected from the group consisting of
N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
(R)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide; and
(S)-N-(4-(4-(2-chloro-3-ethylphenyl)piperazin-1-yl)-3-fluorobutyl)benzofuran-2-carboxamide;
a radioisotope thereof; or
a pharmaceutically acceptable salt thereof.