Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors

1. A method of treatment of a disorder selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and inflammatory diseases, which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I)

wherein

m is selected from the group consisting of 0, 1, 2, or 3;

R 1 is independently selected from the group consisting of chloro, fluoro, bromo, cyano, and methoxy;

R 2b and R 2c are independently selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and N(CH 3 ) 2 ;

X is selected from the group consisting of

n is selected from the group consisting of 0, 1, and 2;

R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ 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,

and

wherein the compound is administered with a secondary active agent administered for treatment of same said disorder.

2. The method of claim 1 wherein the secondary active agent is selected from the group consisting of an NO donor, other NO bioactivity generating compounds, an NO releaser, a chemotherapeutic agent, an agent that imposes nitrosative or oxidative stress, a phosphodiesterase inhibitor, a β-agonist, a steroid, an anti-muscarinics, or a leukotriene antagonist (LTD-4).

3. The method of claim 1 wherein

R 1 is independently selected from the group consisting of chloro, fluoro, and bromo;

X is selected from the group consisting of

and

R 3 is independently selected from the group consisting of halogen, C 1 -C 3 alkyl, fluorinated C 1 -C 3 alkyl, cyano, C 1 -C 3 alkoxy, and NR 4 R 4′ where R 4 and R 4′ are independently selected from the group consisting of C 1 -C 3 alkyl, or R 4 when taken together with R 4′ form a ring with 3 to 6 members.

4. The method of claim 1 wherein m is selected from the group consisting of 0 and 1; R 2b and R 2c are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 ; n is selected from the group consisting of 0 and 1; and R 3 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, cyano, methoxy, and N(CH 3 ) 2 .

5. The method of claim 4 wherein X is

6. The method of claim 5 wherein A is COOH.

7. The method of claim 1 wherein the compound of Formula I 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.

8. The method of claim 7 wherein the compound is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid.

9. The method of claim 7 wherein the compound is 3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid.

10. The method of claim 7 wherein the compound is 4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid.

11. The method of claim 1 wherein the disorder is selected from the group consisting of pulmonary disorders, inflammatory diseases, and functional bowel disorders.

12. The method of claim 11 wherein the pulmonary disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.

13. The method of claim 12 wherein the pulmonary disorder is cystic fibrosis.

14. The method of claim 11 wherein the inflammatory disorder is inflammatory bowel disease (IBD).