# US 2024/0199591 A1 · Selective ligands for modulation of girk channels

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- Number: US 2024/0199591 A1
- Document ID: US20240199591A1
- Status: Published application
- Kind: A1
- Application number: 18/392,203
- Filed: 2023-12-21
- Published: 2024-06-20
- Earliest claimed: 2018-06-11
- Assignees: Northeastern University; Indiana University Research and Technology Corporation
- Applicants: Northeastern University; Indiana University Research and Technology Corporation
- Inventors: Ganeshsingh A. THAKUR; Diomedes E. LOGOTHETIS; Lucas CANTWELL; Yu XU; Anantha SHEKHAR
- Web page: https://patentgrep.com/patent/US20240199591A1

## CPC

- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- A61K 31/415: 1,2-Diazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/22: Anxiolytics
- C07D 231/40: Acylated on said nitrogen atom
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

Selective small molecule regulators of GIRK potassium channels are provided, which are effective in treatment of post-traumatic stress disorder and other medical conditions.

## Claims

### Claim 1

A method of treating a neurological or cardiovascular disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound having a structure according to Formula I:
wherein R1 is chosen from hydrogen, halo, methyl, halomethyl, deuteromethyl, cyclopropyl, and cyclopropylmethyl;
wherein R2 is —(CH2)—RC or —RC; RC can be piperidine, thiane, tetrahydropyran, cyclohexyl, or phenyl optionally substituted with one RD, one carbon atom of the phenyl optionally replaced with N, S, or O, wherein RD can be C1-C6 alkyl, halogen, or CF3;
wherein R3 is chosen from —RE—RG, —RF—RG, —RH, and —RI; RE is C2 alkene with trans configuration; RF is cyclopropyl or oxirane; RG is a 5 or 6 membered aromatic ring optionally comprising one or two N, S, or O in place of one or two carbon atoms, the 5 or 6 membered aromatic ring can be optionally substituted with RH; RH can be halogen, CF3, or CD3; RI is a substituted or unsubstituted ring or ring system chosen from thiophene, benzo[b]thiophene, 4,5,6,7-tetrahydrobenzo[b]thiophene, pyrimidine, isoxazole, thiazole, adamantane, benzo[d][1,3]dioxole, and isoquinoline; and wherein RI is optionally substituted with one or more functional groups chosen from halo, and C1-C6 branched or unbranched alkyl optionally substituted with one or more halogens;
or a pharmaceutically-acceptable salt thereof, wherein the compound is a modulator of a GIRK channel.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound has a structure according to Formula V:
wherein R3 is chosen from —RE—RG, —RF—RG, —RH, and —RI; RE is C2 alkene with trans configuration; RF is cyclopropyl or oxirane; RG is a 5 or 6 membered aromatic ring optionally having one or two carbon atoms replaced with N, S, or O, the 5 or 6 membered aromatic ring can be optionally substituted with RH; RH can be halogen, CF3, or CD3; RI is a substituted or unsubstituted ring or ring system chosen from thiophene, benzo[b]thiophene, 4,5,6,7-tetrahydrobenzo[b]thiophene, pyrimidine, isoxazole, thiazole, adamantane, benzo[d][1,3]dioxole, and isoquinoline; and wherein R1 is optionally substituted with one or more functional groups chosen from halo, and C1-C6 branched or unbranched alkyl optionally substituted with one or more halogens;
or a pharmaceutically-acceptable salt thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound is selected from the group consisting of:
and pharmaceutically-acceptable salts thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound activates GIRK1/2 channels.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound activates GIRK1/4 channels.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound does not activate GIRK1/4 channels at physiologically-relevant levels.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is administered as a pharmaceutical composition comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, and an excipient.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound stimulates GIRK1/2 channels and wherein a neurologic disease or disorder is treated, the disease or disorder selected from the group consisting of post-traumatic stress disorder (PTSD), epilepsy, stroke, general anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, pain, chronic pain, neuropathic pain, cancer-related pain, headache, pain related to traumatic brain injury, inflammatory pain, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

### Claim 9 (depends on 8)

The method of claim 8, wherein PTSD is treated.

### Claim 10 (depends on 8)

The method of claim 8, wherein general anxiety disorder, panic disorder, or social anxiety disorder is treated.

### Claim 11 (depends on 8)

The method of claim 8, wherein epilepsy is treated.

### Claim 12 (depends on 8)

The method of claim 8, wherein obsessive-compulsive disorder is treated.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound inhibits GIRK1/4 channels, and wherein a cardiac arrhythmia is treated.

### Claim 14 (depends on 1)

A method of selectively modulating a GIRK channel, the method comprising contacting a cell with a compound of claim 1.

### Claim 15 (depends on 14)

The method of claim 14, wherein the modulation is agonism, partial agonism, allosteric agonism, antagonism, partial antagonism, or allosteric antagonism.