# US 2024/0199564 A1 · Trpm8 agonists as cooling agents and for the treatment of disease

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- Number: US 2024/0199564 A1
- Document ID: US20240199564A1
- Status: Published application
- Kind: A1
- Application number: 18/546,560
- Filed: 2022-02-16
- Published: 2024-06-20
- Earliest claimed: 2021-02-17
- Assignees: Concentric Analgesics, Inc.
- Applicants: Concentric Analgesics, Inc.
- Inventors: Craig HUSFELD
- Web page: https://patentgrep.com/patent/US20240199564A1

## CPC

- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4465: only substituted in position 4
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/472: Non-condensed isoquinolines, e.g. papaverine
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- C07C 233/62: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C 235/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 237/10: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 213/40: Acylated substituent nitrogen atom
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 295/185: from aliphatic carboxylic acids
- C07C 2601/16: the ring being unsaturated
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate transient receptor potential melastatin 8 receptor (TRPM8) activity.

## Claims

### Claim 1

A compound having the structure of Formula (I):
wherein:
R1 and R2 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R6; or R1 and R2, together with the nitrogen atom to which they are attached, are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R6;
each R3 is independently selected from halogen, —OR9, —N(R9)(R10), —CN, —C(O)OR9, —C(O)N(R9)(R10), —C(O)R11, —S(O)2R11, —S(O)2N(R9)(R10), C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl are optionally substituted by 1, 2, 3, or 4 R7; or an R3 and R1, together with the atoms to which they are attached, are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R7;
R4a, R4b, and R5 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl optionally substituted by 1, 2, 3, or 4 R8;
each R6, each R7, and each R8 are each independently selected from halogen, oxo, —OR9, —N(R9)(R10), —CN, —C(O)OR9, —C(O)N(R9)(R10), —C(O)R11, C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, phenyl, and C2-C9heteroaryl;
each R9 is independently selected from hydrogen, C1-6alkyl, —C1-6alkyl-NH2, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —CH2—C3-6cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, —CH2—C3-6cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R10 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R11 is independently selected C1-6alkyl, —C1-6alkyl-NH2, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
X is a bond or C1-6alkylene;
n is 0 or 1; and
p is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is 0 having the structure of Formula (Ia):

### Claim 3 (depends on 1)

The compound of claim 1, wherein n is 1 having the structure of Formula (Ib):

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

The compound of any one of claims 1-3, wherein R2 is hydrogen or C1-C6alkyl optionally substituted by 1, 2, 3, or 4 R6.

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

The compound of any one of claims 1-3, wherein R2 is hydrogen or C1-C6alkyl unsubstituted by 1, 2, 3, or 4 R6.

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

The compound of any one of claims 1-5, wherein R1 is hydrogen or C1-C6alkyl optionally substituted by 1, 2, 3, or 4 R6.

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

The compound of any one of claims 1-5, wherein R1 is hydrogen or C1-C6alkyl unsubstituted by 1, 2, 3, or 4 R6.

### Claim 8 (depends on 1, 2, 3)

The compound of any one of claims 1-3, wherein R1 and R2 together with the nitrogen atom to which they are attached are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R6.

### Claim 9 (depends on 1, 2, 3)

The compound of any one of claims 1-3, wherein R1 and R2 together with the nitrogen atom to which they are attached are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R6, wherein the C2-C9heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

### Claim 10 (depends on 1, 2, 3)

The compound of any one of claims 1-3, wherein R1 and R2 together with the nitrogen atom to which they are attached are combined to form an unsubstituted C2-C9heterocycloalkyl, wherein the C2-C9heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.

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

The compound of any one of claims 1-10, wherein each R3 is independently selected from halogen, —OR9, —N(R9)(R10), and C1-C6alkyl optionally substituted by 1, 2, 3, or 4 R7.

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

The compound of any one of claims 1-10, wherein p is 0.

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

The compound of any one of claims 1-5, wherein an R3 and R1, together with the atoms to which they are attached, are combined to form a C2-C9heterocycloalkyl optionally substituted by 1, 2, 3, or 4 R7.

### Claim 14 (depends on 1, 2, 3, 4, 5)

The compound of any one of claims 1-5, wherein an R3 and R1, together with the atoms to which they are attached, are combined to form an ubsubstituted C2-C9heterocycloalkyl.

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

The compound of any one of claims 1-14, wherein R4a and R4b are independently selected from hydrogen and C1-C6alkyl optionally substituted by 1, 2, 3, or 4 R8.

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

The compound of any one of claims 1-15, wherein R4a and R4b are independently selected from hydrogen and unsubstituted C1-C6alkyl.

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

The compound of any one of claims 1-16, wherein R4a and R4b are hydrogen.

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

The compound of any one of claims 1-17, wherein R5 is selected from hydrogen and C1-C6alkyl optionally substituted by 1, 2, 3, or 4 R8.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

The compound of any one of claims 1-18, wherein R5 is selected from hydrogen and unsubstituted C1-C6alkyl.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1-19, wherein R5 is hydrogen.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)

The compound of any one of claims 1-20, wherein X is C1-C6alkylene.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)

The compound of any one of claims 1-21, wherein X is —CH2—.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The compound of any one of claims 1-22, wherein X is a bond.

### Claim 24

A compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof, having the structure:

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof as claimed in any one of claims 1-24 and a pharmaceutically acceptable diluent, excipient or binder.

### Claim 26 (depends on 25)

The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is formulated for parenteral administration, oral administration, or topical administration.

### Claim 27 (depends on 25)

The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

A method of treating pain in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 28)

The method of claim 28, wherein the compound of any one of claims 1-24, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof, is administered locally, dermally, transdermally or systemically.