Inhibitors of the renal outer medullary potassium channel

1. A method for the treatment of one or more disorders selected from hypertension, acute heart failure, chronic heart failure or pulmonary arterial hypertension in a patient in need thereof by administering to the patient a therapeutically effective amount of a compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein:

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

m is an integer selected from zero (R 3b is absent) and 1 (R 3b is present);

n is an integer selected from 1 or 2;

R 2 is independently selected at each occurrence from —H, ═O (oxo), —OH, —C 1-3 alkyl or —OC 1-3 alkyl, provided that when n is 2, then at least one R 2 is —H;

R 3a is —H, ═O, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F, provided that only one of R 2 or R 3a can be ═O,

R 3b is —H or —C 1-3 alkyl, or R 3b is absent when R 3a is ═O or when the dashed bond is a double bond or an aromatic bond;

R 4 is —H or ═O;

R 5 is (a) —H, (b) halo, (c) —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl, or (d) —C 3-6 cycloalkyl;

R 6 is —H or —C 1-3 alkyl;

R 7a is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

R 7b is —H or —C 1-3 alkyl;

R 8 is —H, halo or —C 1-3 alkyl;

R 9 is —H, —F, —OH, —OC 1-3 alkyl, —CH 2 OH, —NH—R 13 or

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

or R 9 is —O —and is joined together with R 10 to represent —CH 2 —CH 2 —O —;

R 11 is —H, —CH 2 OH, —CH 2 OCH 3 , or —C 1-3 alkyl optionally substituted with 1 to 3 of —F;

R 12 is —H, —CH 2 OH, —CH 2 OCH 3 , or —C 1-3 alkyl optionally substituted with 1 to 3 of —F;

or R 11 and R 12 are joined together to represent —CH 2 —CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —CH 2 OCH 2 —;

R 13 is —H, —(CH 2 ) 0-2 —C 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 1-3 alkyl, —(CH 2 ) 1-2 —CN,—C(O)OC 1-3 alkyl, —SO 2 CH 3 or —C 1-3 alkyl optionally substituted with one to three of —F; and

the dashed bond (“- - -”) represents a single, double or aromatic bond, provided that

(A) when n is 2, then the dashed bond is a single bond and m is 1; and

(B) when n is 1 and

(i) m is 1, or

(ii) R 3a is ═O and m is zero,

then the dashed bond is a single bond; and

(C) when n is 1, m is zero, R 2 is not ═O and R 3a is not ═O, then the dashed bond is a double bond.

2. The method of claim 1 wherein the compound has structural Formula II or III or a pharmaceutically acceptable salt thereof:

3. The method of claim 2 wherein: R 3a is —H or —CH 3 ; R 4 is ═O; R 5 is —H or —CH 3 ; R 7a is —H or CH 3 ; R 9 is

—H, —OH, —OCH 3 or —NH 2 ; and R 10 is —H or —CH 3 .

4. The method of claim 3 wherein R 9 is —OH; and R 10 is —CH 3 .

5. The method of claim 1 wherein the compound has structural Formula IV or a pharmaceutically acceptable salt thereof:

6. The method of claim 5 wherein: R 3a is —H or —CH 3 ; R 4 is ═O; R 5 is —H or —CH 3 ; R 7a is —H or CH 3 ; R 9 is —H, —OH, —OCH 3 or —NH 2 ; and R 10 is —H or —CH 3 .

7. The method of claim 6 wherein R 9 is —OH; and R 10 is —CH 3 .

8. The method of claim 1 wherein the compound is:

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

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

8-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

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

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

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

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

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

8-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-9-azoniaspiro[5.5]undecane;

5-{(1R)-1-hydroxy-2-[2(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]dec-8-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

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

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

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

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

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

(1R,3r,5S)-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1′-(5-oxo-2,5-dihydrofuran-3-yl)-2 ′H-spiro[8-azabicyclo[3.2.1]octane-3,3′-pyrrolidin]-2 ′-one;

(1R,3r,5S)-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2 ′H-spiro[8-azabicyclo[3.2.1]octane-3,3′-pyrrolidin]-2′-one;

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

8-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1-oxo-2-aza-8-azoniaspiro [4.5]decane;

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-9-azoniaspiro [5.5]undecane;

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2(5-oxo-2,5-dihydrofuran-3-yl)-2-aza-9-azoniaspiro[5.5]undecane;

2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

6-hydroxy-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

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

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

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

4-hydroxy-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

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

8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4-dioxo-2-aza-8-azoniaspiro[4.5]decane;

8-[(2S)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

8-[(2R)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

(1R,3r,5S)-8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-5′-methyl-1-(5-oxo-2,5-dihydrofuran-3-yl)-2′H-spiro[8-azabicyclo[3.2.1]octane-3,3′-pyrrolidin]-2′-one;

(1R,3r,5S)-8-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-5′-methyl-1′-(5-oxo-2,5-dihydrofuran-3-yl)-2′H-spiro [8-azabicyclo[3.2.1]octane-3,3′-pyrrolidin]-2′-one;

8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]dec-3-ene;

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

(1R,3′s,5S)-9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-ypethyl]-7-methyl-1′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2′H-spiro[7,9-diazabicyclo[3.3.1]nonane-3,3′-pyrrolidin]-2′-one;

(1R,3′s,5S)-9-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-7-methyl-1′-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2′H-spiro[7,9-diazabicyclo[3.3.1]nonane-3,3′-pyrrolidin]-2′-one;

8-[(2R)-2-fluoro-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

8-[(2S)-2-fluoro-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

8-[(2R)-2-methoxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2-aza-8-azoniaspiro[4.5]decane;

8-[(2R)-2-ethoxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

8-[(2R)-2-methoxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-8-[(3-oxo-3,6,8,9-tetrahydro-1H-furo[3,4-f]isochromen-6-yl)methyl]-2-aza-8-azoniaspiro[4.5]decane;

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

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

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

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

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

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

3-((1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-(2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethyl)amino)propanenitrile;

8-[2-(methylamino)-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

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

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

Methyl {(1R)-1-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-[2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]dec-8-yl]ethyl}carbamate;

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

1′-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-oxo-1-(5-oxo-2,5-dihydrofuran-3-yl)-1,2-dihydrospiro[indole-3,4′-piperidinium];

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

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

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

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

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

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

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

8-(2-(4-cyclopropyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

8-(2-(4-chloro-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

8-(2-(4-fluoro-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

(1R,3′R,5S)-9-((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-oxa-9-azaspiro[bicyclo [3.3.1]nonane-7,3′-pyrrolidin]-2′-one;

8-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-6-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;

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

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

(S)-8-(1-hydroxy-2-methyl-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one; and

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

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 further comprising administering an 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, and triamterene, or a pro-drug thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. A method for inhibiting ROMK in a patient comprising administering to the patient a ROMK-inhibitory effective amount of a compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein:

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

m is an integer selected from zero (R 3b is absent) and 1 (R 3b is present);

n is an integer selected from 1 or 2;

R 2 is independently selected at each occurrence from —H, ═O (oxo), —OH, —C 1-3 alkyl or —OC 1-3 alkyl, provided that when n is 2, then at least one R 2 is —H;

R 3a is —H, ═O —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F, provided that only one of R 2 or R 3 a can be ═O,

R 3b is —H or —C 1-3 alkyl, or R 3b is absent when R 3a is ═O or when the dashed bond is a double bond or an aromatic bond;

R 4 is —H or ═O;

R 5 is (a) —H, (b) halo, (c) —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl, (d) —C 3-6 cycloalkyl or (e) heterocycle optionally substituted with —C 1-3 alkyl or halo;

R 6 is —H or —C 1-3 alkyl;

R 7a is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

R 7b is —H or —C 1-3 alkyl;

R 8 is —H, halo or —C 1-3 alkyl;

R 9 is —H, —F, —OH, —OC 1-3 alkyl, —CH 2 OH, —NH—R 13 or

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

or R 9 is —O— and is joined together with R 10 to represent—CH 2 —CH 2 —O—;

R 11 is —H, —CH 2 OH, —CH 2 OCH 3 , or—C 1-3 alkyl optionally substituted with 1 to 3 of —F;

R 12 is —H, —CH 2 OH, —CH 2 OCH 3 , or—C 1-3 alkyl optionally substituted with 1 to 3 of —F;

or R 11 and R 12 are joined together to represent —CH 2 —CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —CH 2 OCH 2 —;

R 13 is —H, —(CH 2 ) 0-2 —C 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 1-3 alkyl, —(CH 2 ) 1-2 —CN, —C(O)OC 1-3 alkyl, —SO 2 CH 3 or —C 1-3 alkyl optionally substituted with one to three of —F; and

the dashed bond (“- - -”) represents a single, double or aromatic bond, provided that

(A) when n is 2, then the dashed bond is a single bond and m is 1; and

(B) when n is 1 and

(i) m is 1, or

(ii) R 3a is ═O and m is zero,

then the dashed bond is a single bond; and

(C) when n is 1, m is zero, R 2 is not ═O and R 3a is not ═O, then the dashed bond is a double bond

to a patient in need thereof.

11. The method of claim 1 wherein the disorder is selected from hypertension or heart failure.

12. A method for causing diueresis, natriuresis or both, in a patient in need thereof by administering to the patient a therapeutically effective amount of a compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein:

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

m is an integer selected from zero (R 3 b is absent) and 1 (R 3 b is present);

n is an integer selected from 1 or 2;

R 2 is independently selected at each occurrence from —H, ═O (oxo), —OH, —C 1-3 alkyl or —OC 1-3 alkyl, provided that when n is 2, then at least one R 2 is —H;

R 3a is —H, ═O, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F, provided that only one of R 2 or R 3a can be ═O,

R 3b is —H or —C 1-3 alkyl, or R 3b is absent when R 3a is ═O or when the dashed bond is a double bond or an aromatic bond;

R 4 is —H or ═O;

R 5 is (a) —H, (b) halo, (c) —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl, (d) —C 3-6 cycloalkyl or (e) heterocycle optionally substituted with —C 1-3 alkyl or halo;

R 6 is —H or —C 1-3 alkyl;

R 7 a is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;

R 7b is —H or —C 1-3 alkyl;

R 8 is —H, halo or —C 1-3 alkyl;

R 9 is —H, —F, —OH, —OC 1-3 alkyl, —CH 2 OH, —NH—R 13 or

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

or R 9 is —O— and is joined together with R 1O to represent—CH 2 —CH 2 —O—;

R 11 is —H, —CH 2OH, —CH 2OCH 3 , or —C 1-3 alkyl optionally substituted with 1 to 3 of —F;

R 12 is —H, —CH 2OH, —CH 2OCH 3 , or —C 1-3 alkyl optionally substituted with 1 to 3 of —F;

or R 11 and R 12 are joined together to represent —CH 2 -CH 2 —,—CH 2 —N(CH 3 )—CH 2 — or —CH 2 OCH 2 —;

R 13 is —H, —(CH 2 ) 0-2 —C 3-6 cycloalkyl, —(CH 2 ) 1-2 —O C 3-6 cycloalkyl, —(CH 2 ) 1-2 —OC 1-3 alkyl, —(CH 2 ) 1-2 —CN, —C(O)OC 1-3 alkyl, —SO 2 CH 3 or —C 1-3 alkyl optionally substituted with one to three of —F; and

the dashed bond (“- - -”) represents a single, double or aromatic bond, provided that

(A) when n is 2, then the dashed bond is a single bond and m is 1; and

(B) when n is 1 and

(i) m is 1, or

(ii) R 3a is ═O and m is zero,

then the dashed bond is a single bond; and

(C) when n is 1, m is zero, R 2 is not ═O and R 3a is not ═O, then the dashed bond is a double bond.