Substituted quinoline compounds as S-nitrosoglutathione reductase inhibitors

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;

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.

2. 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.

3. 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 .

4. The method of claim 3 wherein X is

5. The method of claim 4 wherein A is COOH.

6. 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.

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

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

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