Inhibitors of the renal outer medullary potassium channel

1. A compound of the formula:

wherein X is N or CR b ;

Z is O or CH 2 ;

A is

or a six-membered aromatic ring containing one or two nitrogen atoms which is optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl;

R 1 is H, OH or O(C 1-3 alkyl);

R 2 is H or C 1-3 alkyl;

R 4 is H or C 1-3 alkyl;

R 5 is H or C 1-3 alkyl;

R 6 is H or C 1-3 alkyl;

R 7 is H, C 1-3 alkyl or O(C 1-3 alkyl);

R a is H or C 1-3 alkyl;

R b is H, OH, C 1-3 alkyl or (C═O)OC 1-3 alkyl;

R x is H, halo, C 1-3 alkyl or O(C 1-3 alkyl);

n is 0, 1 or 2;

- - - - is an optional bond;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 of the formula

wherein

A is

or a six-membered aromatic ring containing one or two nitrogen atoms which is optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl;

R 1 is H, OH or O(C 1-3 alkyl);

R 2 is H or C 1-3 alkyl;

R 4 is H or C 1-3 alkyl;

R 5 is H or C 1-3 alkyl;

R 6 is H or C 1-3 alkyl;

R 7 is H or O(C 1-3 alkyl);

R a is H or C 1-3 alkyl;

R b is H, OH, C 1-3 alkyl or (C═O)OC 1-3 alkyl;

R x is H, halo, C 1-3 alkyl or O(C 1-3 alkyl);

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein A is

pyridinyl, pyrazinyl or pyridazinyl, wherein said pyridinyl, pyrazinyl or pyridazinyl are optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 1 is OH, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 2 is H or methyl; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein R 4 is H or methyl; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 selected from:

3-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyrrolidin-2-one;

1-((3S,4S)-1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-((3R,4R)-1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one,

3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

(R)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

(S)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

4-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

4-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

4-(3-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyrrolidin-2-one;

1-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(3-oxocyclopent-1-en-1-yl)imidazolidin-2-one;

(R)-1-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

(R)-1-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;

1-(1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;

1-(3-fluoro-1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methoxypiperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3-methoxypiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;

1-(1-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

3-(4-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(4-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)piperazin-1-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

(R)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;

(S)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;

3-(1-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methyl-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-methyl-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-methyl-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-hydroxypiperidin-4-yl)-1-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyrrolidin-2-one;

1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methyl-3-(5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-methyl-3-(5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-methyl-3-(5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-methyl-3-(5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

ethyl 1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)-2-oxooxazolidin-5-yl)piperidine-4-carboxylate;

ethyl 1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2-oxooxazolidin-5-yl)piperidine-4-carboxylate;

3-(4-hydroxy-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyrrolidin-2-one;

1′-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-[3,4′-bipiperidin]-2-one;

4-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-methyl-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;

3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-methyl-1-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyrrolidin-2-one;

1-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-4-ethyl-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

4-ethyl-1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-hydroxy-2-(tetrazolo[1,5-a]quinolin-7-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-Tetrazol-1-yl)pyridin-2-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

(R)-1-(1-(2-methoxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

(R)-1-(1-(2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

(R)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-methoxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(6-(1H-Tetrazol-1-yl)pyridin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-(1-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((1R,2R)-1-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((1R,2S)-1-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((1S,2R)-1-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

1-(1-((1S,2S)-1-hydroxy-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)piperidin-4-yl)-3-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)imidazolidin-2-one;

(R)-5-(1-hydroxy-2-(4-(4-methyl-5-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(5-(4-methyl-5-oxo-2, 5-dihydrofuran-3-yl)pyridin-2-yl)piperidin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(5-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(5-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(4-methoxy-5-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(3-methoxy-5-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-5-(1-hydroxy-2-(4-(1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-4-(3-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1H-1,2,4-triazol-1-yl)-3-methylfuran-2(5H)-one

(S)-4-(3-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1H-1,2,4-triazol-1-yl)-3-methylfuran-2(5H)-one;

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 further comprising an additional active agent selected from losartan, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, amlodipine, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, amiloride, spironolactone, epleranone, triamterene, riociguat or vericiguat, or a pro-drug thereof, or a pharmaceutically acceptable salt of any of the foregoing.

12. A method for inhibiting ROMK comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a ROMK-inhibitory effective amount to a patient in need thereof.

13. A method for causing diueresis, natriuresis or both, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.

14. A method for the treatment of one or more disorders selected from hypertension, acute heart failure, chronic heart failure, pulmonary arterial hypertension, cardiovascular disease, diabetes, endothelial dysfunction, diastolic dysfunction, stable and unstable angina pectoris, thromboses, restenosis, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, hepatic cirrhosis, ascitis, pre-eclampsia, cerebral edema, nephropathy, nephrotic syndrome, acute kidney insufficiency, chronic kidney disease, hypercalcemia, Dent's disease, Meniere's disease, or edematous states comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.