# US 2012/0083500 A1 · Oxazolone and pyrrolidinone-substituted arylamides as p2x3 and p2x 2/3 antagonists

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2012/0083500 A1
- Document ID: US20120083500A1
- Status: Published application
- Kind: A1
- Application number: 13/314,529
- Filed: 2011-12-08
- Published: 2012-04-05
- Earliest claimed: 2009-06-22
- Assignees: Roche Palo Alto LLC
- Inventors: Li CHEN; Michael Patrick DILLON; Lichun FENG; Minmin YANG
- Web page: https://patentgrep.com/patent/US20120083500A1

## CPC

- A61K 31/497: containing further heterocyclic rings
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/30: for treating abuse or dependence
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 39/02: Antidotes
- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 233/32: One oxygen atom
- C07D 263/20: attached in position 2
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 407/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.

## Claims

### Claim at position 1

1-22. (canceled)

### Claim 23

A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is:
C1-6alkyl; or
halo;
R2 is:
C1-6cycloalkyl;
C1-6alkoxy-C1-6alkyl;
hydroxy-C1-6alkyl; or
heteroaryl-C1-6alkyl;
R3 is:
hydrogen;
halo;
C1-6alkyl; or
C1-6alkoxy-carbonyl;
R4 is:
hydrogen;
halo;
C1-6alkyl;
or R3 and R4 together with the atoms to which they are attached may form a fused 6-membered aromatic ring that optionally includes one or two nitrogens;
or R3 and R4 together with the atom to which they are attached may form C3-6cycloalkyl;
R5, R6 and R7 each independently is fluoro or hydrogen.
X is: —CRa− wherein Ra is C1-6alkyl or halo; and
Y is: —O—; —CHRb—; or —NRc—; wherein Rb and Rc each independently is hydrogen or C1-6alkyl.

### Claim 24 (depends on 23)

The compound of claim 23, wherein R5, R6 and R7 are hydrogen.

### Claim 25 (depends on 24)

The compound of claim 24 wherein R1 is methyl.

### Claim 26 (depends on 24)

The compound of claim 24 wherein R2 is: cyclopropyl; 2-methoxy-1-methyl-ethyl; 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; 1-pyrazin-2-yl-ethyl; pyrimidin-5-yl-methyl; 6-methyl-pyridazin-3-yl-methyl; pyridazin-3-yl-methyl; 5-methyl-pyrimidin-2-yl-methyl; or 2-methyl-pyrimidin-5-yl-methyl.

### Claim 27 (depends on 24)

The compound of claim 24, wherein R2 is 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; or 1-pyrazin-2-yl-ethyl.

### Claim 28 (depends on 24)

The compound of claim 24, wherein R3 is C1-6alkyl.

### Claim 29 (depends on 24)

The compound of claim 24, wherein R3 is ethyl or isopropyl.

### Claim 30 (depends on 24)

The compound of claim 24, wherein R4 is hydrogen.

### Claim 31 (depends on 24)

The compound of claim 24, wherein R3 and R4 together with the atoms to which they are attached form a fused phenyl ring.

### Claim 32 (depends on 24)

The compound of claim 24, wherein Ra is hydrogen or halo.

### Claim 33 (depends on 24)

The compound of claim 24, wherein Ra is hydrogen.

### Claim 34 (depends on 24)

The compound of claim 24, wherein Ra is halo.

### Claim 35 (depends on 24)

The compound of claim 24, wherein Y is —O—.

### Claim 36 (depends on 24)

The compound of claim 24, wherein Y is —CHRb—.

### Claim 37 (depends on 24)

The compound of claim 24, wherein Y is —NRc—.

### Claim 38 (depends on 31)

The compound of claim 31, wherein said compound is of formula III:
wherein:
n is from 0 to 2;
Y is: —O—; —CH2— or —NH—
R8 is:
C1-6alkyl;
C1-6alkoxy;
C1-6alkyl-sulfonyl;
halo-C1-6alkyl; or
halo;
and X, R1 and R2 are as recited in claim 31.

### Claim 39 (depends on 1)

The compound of claim 1, wherein said compound is selected from:
4′-Methyl-5-(2-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
4′-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
4′-Methyl-5-(2-methyl-5-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
(S)-1-[5-(2-Methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-5-oxo-pyrrolidine-2-carboxylic acid methyl ester;
5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;
5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid cyclopropylamide;
5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid cyclopropylamide;
5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid
((S)-2-hydroxy-1-methyl-ethyl)-amide;
5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;
5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;
2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid cyclopropylamide;
4′-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
4′-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;
4′-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
4′-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;
4′-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide; and
4′-Methyl-5-(8-oxo-7,8-dihydro-purin-9-yl)-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide.

### Claim 40 (depends on 1)

A pharmaceutical composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) a compound of claim 1.

### Claim 41

A method for treating a pain condition selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury, or pain associated with irritable bowel syndrome, said method