Methods for the Treatment of Cystic Fibrosis

1 . A method of treating or lessening the severity of CF, comprising the step of administering to a patient in need an effective amount of

i) a GSNOR inhibitor of Formula I

wherein

m is selected from the group consisting of 0, 1, 2, and 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 thereof, and

ii) one or more secondary active agents selected from the group consisting of CFTR correctors and CFTR potentiators or pharmaceutically acceptable salt(s) thereof.

2 . The method of claim 1 , wherein the GSNOR inhibitor is selected from Formula I wherein R 1 is independently selected from the group consisting of chloro, fluoro, and bromo; 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

X is selected from the group consisting of

3 . The method of claim 1 , wherein the GSNOR inhibitor is selected from Formula I wherein 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 methyl, or alternatively together with the said N form the ring aziridin-1-yl or morpholino.

4 . The method of claim 1 , wherein the GSNOR inhibitor is selected from Formula I 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, hydroxy, methoxy, and N(CH 3 ) 2 .

5 . The method of claim 1 , wherein the GSNOR inhibitor is selected from Formula I wherein X is

6 . The method of claim 1 , wherein the GSNOR inhibitor is selected from Formula I wherein A is COOH.

7 . The method of claim 1 , wherein the GSNOR inhibitor is a compound of Formula I wherein the compound is selected from:

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 1 , wherein the GSNOR inhibitor is selected from the group consisting of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid, 3-fluoro-4-(6-hydroxyquinolin-2-yl)benzoic acid, and 4-(6-hydroxyquinolin-2-yl)-3-methylbenzoic acid.

9 . The method of claim 1 wherein the secondary active agent of the pharmaceutical combination is a CFTR corrector.

10 . The method of claim 1 wherein the secondary active agent is a CFTR potentiator.

11 . The method of claim 1 wherein the secondary active agent is selected from the group consisting of 3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, and 5-{6-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-3-methylpyridin-2-yl}thiophene-3-carboxylic acid.

12 . The method of claim 1 wherein the secondary active agent is N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

13 . The method of claim 1 wherein the secondary active agents are a CFTR corrector and a CFTR potentiator.

14 . The method of claim 13 wherein consists of two secondary active agents wherein the first is the CFTR potentiator N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, and the second is a CFTR corrector selected from the group consisting of 3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide, and 5-{6-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-3-methylpyridin-2-yl}thiophene-3-carboxylic acid.

15 . The method of claim 8 wherein the secondary active agents are N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and 3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid.

16 . The method of claim 8 wherein the secondary active agents are N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and 5-{6-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-3-methylpyridin-2-yl}thiophene-3-carboxylic acid.

17 . The method of claim 8 wherein the secondary active agents are N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide.

18 . The method of claim 15 wherein the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid and the secondary active agents are N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and 3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid.

19 . The method of claim 17 wherein the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid and the secondary active agents are N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide.

20 . The method of claim 11 wherein the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid and the secondary active agent is 3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid.

21 . The method of claim 12 wherein the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid and the secondary active agent is N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

22 . The method of claim 11 wherein the wherein the GSNOR inhibitor is 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid and the secondary active agent is 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide.