# US 2025/0084064 A1 · 2-amino-n-heteroaryl-nicotinamides as nav1.8 inhibitors

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- Number: US 2025/0084064 A1
- Document ID: US20250084064A1
- Status: Published application
- Kind: A1
- Application number: 18/960,010
- Filed: 2024-11-26
- Published: 2025-03-13
- Earliest claimed: 2018-11-02
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC
- Inventors: Ashok Arasappan; Ian M. Bell; Michael J. Breslin; Christopher James Bungard; Christopher S. Burgey; Harry R. Chobanian; Jason M. Cox; Anthony T. Ginnetti; Deodial Guy Guiadeen; Kristen L.G. Jones; Mark E. Layton; Hong Liu; Jian Liu; James J. Perkins; Shawn J. Stachel; Linda M. Suen-Lai; Zhe Wu
- Web page: https://patentgrep.com/patent/US20250084064A1

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 401/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Nav1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Nav1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

## Claims

### Claim 1

A composition comprising:
a) a first compound selected from:
1) (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;
2) (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;
3) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-nicotinamide;
4) 2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)nicotinamide;
5) 5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
6) 5-chloro-6-cyclobutyl-2-((2S,6R)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
7) 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
8) 2-(4,4-difluoroazepan-1-yl)-6-(difluoromethyl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
9) 2-(4,4-difluoropiperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
10) 2-(4,4-difluoropiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl) nicotinamide;
11) 5-chloro-6-cyclobutyl-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)nicotinamide;
12) 4-(2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)nicotinamido)picolinamide;
13) 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydro-pyridin-4-yl)nicotinamide; and
14) 2-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide;
or a pharmaceutically acceptable salt thereof;
b) a second compound selected from a calcium channel antagonist, or a pharmaceutically acceptable salt thereof, and
c) a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The composition according to claim 1 wherein the first compound is (S)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The composition according to claim 1 wherein the first compound is (R)-2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)-nicotinamide; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The composition according to claim 1 wherein the first compound is 5-chloro-6-cyclobutyl-2-((2R,6S)-2-methyl-6-(trifluoromethyl)morpholino)-N-(2-sulfamoyl-pyridin-4-yl)-nicotinamide; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The composition according to claim 1 wherein the first compound is 2-(4,4-difluoro-piperidin-1-yl)-5-fluoro-6-methyl-N-(2-sulfamoylpyridin-4-yl)nicotinamide; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The composition according to claim 1 wherein the first compound is 5-chloro-6-cyclopropyl-2-(4,4-difluoroazepan-1-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)nicotinamide; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The composition according to claim 1 wherein the second compound is a calcium channel antagonist selected from:
1) amlodipine;
2) diltiazem;
3) felodipine;
4) gabapentin;
5) isradipine;
6) nicardipine;
7) nifedipine;
8) nisoldipine;
9) pregabalin;
10) verapamil; and
11) ziconitide;
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

The composition according to claim 7 wherein the second compound is gabapentin or pregabalin; or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A method of treating a disorder, condition or disease that is responsive to the inhibition of Nav1.8 channel activity in a patient in need thereof comprising administration of the composition according to claim 1, wherein the disorder is a pain disorder, a cough disorder, an acute itch disorder or a chronic itch disorder.

### Claim 10 (depends on 9)

The method of claim 9 wherein the disorder is a pain disorder.

### Claim 11 (depends on 10)

The method of claim 10 wherein the pain disorder is selected from: acute pain, inflammatory pain, or neuropathic pain.