# US 9,433,618 B2 · Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors

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- Number: US 9,433,618 B2
- Document ID: US9433618B2
- Status: Granted
- Kind: B2
- Application number: 15/097,378
- Filed: 2016-04-13
- Published: 2016-08-04
- Granted: 2016-09-06
- Earliest claimed: 2010-10-08
- Assignees: Nivalis Therapeutics, Inc.
- Applicants: Nivalis Therapeutics, Inc.
- Inventors: Xicheng Sun; Jian Qiu; Adam Stout
- Web page: https://patentgrep.com/patent/US9433618B2

## CPC

- C07D 215/20: Oxygen atoms
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/00: Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D 215/42: attached in position 4
- C07D 215/46: with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
- C07D 215/54: attached in position 3
- C07D 215/60: N-oxides
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to novel quinoline compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.

## Claims

### Claim 1

A method of inhibiting the activity of the enzyme S-nitrosoglutathione reductase (GSNOR) comprising the step of contacting said enzyme with a compound of formula I:
wherein
m is selected from the group consisting of 0, 1, 2, or 3;
R1 is independently selected from the group consisting of chloro, fluoro, bromo, cyano, and methoxy;
R2b and R2c are independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano, C1-C3 alkoxy, and N(CH3)2;
X is selected from the group consisting of
n is selected from the group consisting of 0, 1, and 2;
R3 is independently selected from the group consisting of halogen, C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano, C1-C3 alkoxy, and NR4R4′ where R4 and R4′ are independently selected from the group consisting of C1-C3 alkyl, or R4 when taken together with R4′ form a ring with 3 to 6 members; and
A is selected from the group consisting of
or a pharmaceutically acceptable salt, stereoisomer, or N-oxide thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein
R1 is independently selected from the group consisting of chloro, fluoro, and bromo;
X is selected from the group consisting of
and
R3 is independently selected from the group consisting of halogen, C1-C3 alkyl, fluorinated C1-C3 alkyl, cyano, C1-C3 alkoxy, and NR4R4′ where R4 and R4′ are independently selected from the group consisting of C1-C3 alkyl, or R4 when taken together with R4′ form a ring with 3 to 6 members.

### Claim 3 (depends on 1)

The method of claim 1 wherein m is selected from the group consisting of 0 and 1; R2b and R2c are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH3)2; n is selected from the group consisting of 0 and 1; and R3 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, cyano, methoxy, and N(CH3)2.

### Claim 4 (depends on 3)

The method of claim 3 wherein X is

### Claim 5 (depends on 4)

The method of claim 4 wherein A is COOH.

### Claim 6 (depends on 1)

The method of claim 1 wherein the compound is selected from the group consisting of
4-(6-hydroxy-3-methylquinolin-2-yl)benzoic acid;
2-(4-(1H-tetrazol-5-yl)phenyl)-3-methylquinolin-6-ol;
4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-(4-(1H-tetrazol-5-yl)phenyl)quinolin-6-ol;
1-(6-hydroxyquinolin-2-yl)piperidine-4-carboxylic acid;
(1r,4r)-4-(6-hydroxyquinolin-2-yl)cyclohexanecarboxylic acid;
(1s,4s)-4-(6-hydroxyquinolin-2-yl)cyclohexanecarboxylic acid;
3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-(4-(2H-tetrazol-5-yl)phenyl)-4-chloroquinolin-6-ol;
3-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-oxadiazol-5(2H)-one;
3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid;
5-(6-hydroxyquinolin-2-yl)thiophene-2-carboxylic acid;
4-(6-hydroxyquinolin-2-yl)cyclohex-3-enecarboxylic acid;
4-(3-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-chloro-3-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(3-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
3-(2-fluoro-4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one;
3-(3-fluoro-4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one;
4-(4-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)quinolin-6-ol;
5-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one;
3-(dimethylamino)-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid;
4-(3-chloro-6-hydroxyquinolin-2-yl)-3-fluorobenzoic acid;
3-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-thiadiazol-5(2H)-one;
4-(6-hydroxyquinolin-2-yl)-3-(trifluoromethyl)benzoic acid;
4-(6-hydroxy-3-(trifluoromethyl)quinolin-2-yl)benzoic acid;
2-(4-carboxyphenyl)-6-hydroxyquinoline 1-oxide;
5-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,3,4-thiadiazol-2(3H)-one;
5-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-oxadiazol-3(2H)-one;
(1r,4r)-4-(3-chloro-6-hydroxyquinolin-2-yl)cyclohexanecarboxylic acid;
(1s,4s)-4-(3-chloro-6-hydroxyquinolin-2-yl)cyclohexanecarboxylic acid;
3-chloro-4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
2-(5-(2H-tetrazol-5-yl)thiophen-2-yl)quinolin-6-ol;
5-(4-(6-hydroxyquinolin-2-yl)phenyl)-1,2,4-thiadiazol-3(2H)-one;
3-fluoro-4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
1-(6-hydroxy-3-(trifluoromethyl)quinolin-2-yl)piperidine-4-carboxylic acid;
4-(5-chloro-6-hydroxyquinolin-2-yl)benzoic acid;
(1r,4r)-4-(6-hydroxy-3-(trifluoromethyl)quinolin-2-yl)cyclohexanecarboxylic acid;
(1s,4s)-4-(6-hydroxy-3-(trifluoromethyl)quinolin-2-yl)cyclohexanecarboxylic acid;
4-(5-bromo-6-hydroxyquinolin-2-yl)benzoic acid;
3-bromo-4-(6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-(dimethylamino)-6-hydroxyquinolin-2-yl)benzoic acid;
4-(4-fluoro-6-hydroxyquinolin-2-yl)-3-methoxybenzoic acid;
3-cyano-4-(6-hydroxyquinolin-2-yl)benzoic acid;
2-(4-carboxy-2-chlorophenyl)-6-hydroxyquinoline 1-oxide;
4-(3-cyano-6-hydroxyquinolin-2-yl)benzoic acid;
4-(5-fluoro-6-hydroxyquinolin-2-yl)benzoic acid;
4-(8-fluoro-6-hydroxyquinolin-2-yl)benzoic acid; and
3-fluoro-4-(5-fluoro-6-hydroxyquinolin-2-yl)benzoic acid.

### Claim 7 (depends on 6)

The method of claim 6 wherein the compound is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid.

### Claim 8 (depends on 6)

The method of claim 6 wherein the compound is 3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid.

### Claim 9 (depends on 6)

The method of claim 6 wherein the compound is 4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid.