Inhibitors of the renal outer medullary potassium channel

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

R 1 is —H, —F, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;

R 2 is —H, or C 1-4 alkyl;

R 3 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

R 4 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

or R 3 and R 4 are joined together to form —CH 2 —CH 2 —;

n is 1 or 2;

R 5 is —H, halo, —C 3-6 cycloalkyl or —C 1-3 alkyl;

X 1 is —C(O)—, —CH 2 —, —CR 6 R 7 C(O)—, —CH 2 CR 6 R 7 —, or —CR 6 R 7 CH 2 —;

X 2 is —O—, —OCH 2 — or —N(R);

X 3 is —C(O)—, —CH 2 —, —CR 6 R 7 C(O)—, —CH 2 CR 6 R 7 —, or —CR 6 R 7 CH 2 —;

wherein the ring bearing X1, X2 and X3 is a 5-7 membered ring which results in a (i) 11-13-membered spirocyclic core where n is 1, or a (ii) 12-14-membered spirocyclic core where n is 2;

each R 6 and R 7 is independently —H, halo, —OH, —OC 1-3 alkyl, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

R 8 is —H or —C 1-3 alkyl;

Z is

Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from C(R 9 ) or N;

provided that at most two of Y 1 , Y 2 , Y 3 and Y 4 are N;

each R 9 is independently —H, halo, C 1-4 alkyl optionally substituted with 1-3 of —F, or OC 1-4 alkyl;

R 10 is —H, halo, or C 1-4 alkyl optionally substituted with 1-3 of —F;

R 11 is —H, C 1-4 alkyl optionally substituted with 1-3 of —F, or halo; and

R 12 is —H or C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —H, —F or —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 are —H, or R 3 and R 4 are joined together to form —CH 2 CH 2 —.

4. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

5. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —H, —Cl, —CH 3 or cyclopropyl.

6. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —H.

7. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —CH 3 .

8. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —C(O)—, X 2 is —O— and X 3 is —CH 2 CH 2 —.

9. The compound of any of claim 1 wherein n is 1.

10. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH 2 —, X 2 is —O— and X 3 is —CH 2 CH 2 —.

11. The compound of claim 10 wherein n is 1.

12. The compound of any of claim 1 wherein Z is

wherein each of the variables Y 1 , Y 2 , Y 3 and Y 4 , are as defined in claim 1 .

13. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is

wherein each of the variables R 10 , R 11 and R 12 are as defined in claim 1 .

14. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is

15. A compound which is:

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one dihydrochloride;

9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(S)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.6]dodecan-5-one;

(R)-8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;

8-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;

9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

(R)-5-(1-hydroxy-2-(4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;

4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

(R)-5-(2-(4-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one;

(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-chlorofuran-2(5H)-one;

3-chloro-4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;

9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;

(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-cyclopropylfuran-2(5H)-one;

(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-cyclopropylfuran-2(5H)-one;

3-cyclopropyl-4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

4-(9-(2-hydroxy-2-(2-methyl-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;

4-(9-(2-hydroxy-2-(2-methyl-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

4-(9-(2-(2-fluoro-4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

4-(9-(2-hydroxy-2-(2-methoxy-4-(1H-tetrazol-1-yl)phenyl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-1-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;

(1R,2′R,5S)-8-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4′-(5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;

(R)-3-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-11-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,11-diazaspiro[5.6]dodecan-12-one;

3-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-11-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,11-diazaspiro[5.6]dodecan-12-one;

9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

4-(3-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-7-oxa-3,10-diazaspiro[5.6]dodecan-10-yl)-3-methylfuran-2(5H)-one;

(R)-5-(1-hydroxy-2-(10-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-7-oxa-3,10-diazaspiro[5.6]dodecan-3-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;

(1R,2′R,5S)-8-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;

9-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(1R,2′r,5S)-8-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;

9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(1R,2′R,5S)-8-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;

4-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;

9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(1R,2′r,5S)-8-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)-4′-(5-oxo-2,5-dihydrofuran-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-morpholin]-3′-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-fluoroethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-fluoroethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(R)-9-(2-fluoro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(S)-9-(2-fluoro-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;

(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;

9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;

or a pharmaceutically acceptable salt thereof.

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

17. The pharmaceutical composition of claim 16 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, or trandolapril, amiloride, spironolactone, epleranone or triamterene, or a pro-drug thereof, or a pharmaceutically acceptable salt of any of the foregoing.

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

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

20. 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 one of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.