Inhibitors of the renal outer medullary potassium channel

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

X is O or NH;

p is an integer selected from 1 (one) or 2 (two), and q is an integer selected from 1 (one) or 2 (two), provided that only one of p and q can be 2;

Z 1 is

R 1 is —H or —C 1-4 alkyl;

R 2 is —H, —F, —Cl, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 3 is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl, OC 1-4 alkyl or N-tetrazolyl optionally substituted with —CH 3 ;

R 4 is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl, —OC 1-4 alkyl or N-tetrazolyl optionally substituted with —CH 3 ;

or R 3 and R 4 are joined together with the phenyl ring to which they are attached to form a bicyclic ring system that is:

 wherein R is —H or —C 1-4 alkyl;

R 5 is —H, —F, —Cl, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

provided that when R 3 and R 4 are not joined together, then either

(a) one of R 3 , R 4 or R 5 is —CN and the others are not —CN, or

(b) one of R 3 or R 4 is N-tetrazolyl optionally substituted with —CH 3 and the other is not N-tetrazolyl optionally substituted with —CH 3 ;

R 6 is —H or —C 1-6 alkyl;

Z 2 is

n is an integer selected from 1 (one) or 2 (two);

m is an integer selected from 1 (one) or 2 (two);

R 2a is —H, —F, —Cl, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 3a is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl, —OC 1-4 alkyl or N-tetrazolyl optionally substituted with —CH 3 ;

R 4a is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl, —OC 1-4 alkyl or N-tetrazolyl optionally substituted with —CH 3 ;

or R 3a and R 4a are joined together with the phenyl ring to which they are attached to form:

 wherein R a is —H or —C 1-4 alkyl;

R 5a is —H, —F, —Cl, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

provided that when R 3a and R 4a are not joined together, then either

(a) only one of R 3a , R 4a or R 5a is —CN and the others are not —CN, or

(b) only one of R 3a or R 4a is N-tetrazolyl optionally substituted with —CH 3 and the other is not N-tetrazolyl optionally substituted with —CH 3 ;

R 7 is independently at each occurrence —H or —C 1-3 alkyl;

R 8 is —H, —F, —Cl, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 9 is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 10 is —H or —CH 3 ; and

R 11 is —H or —CH 3 .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H or —CH 3 ; and R 7 is —H or —CH 3 .

3. The compound of claim 2 having structural Formula II, III, IV or V:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein Z 1 is

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein R 3 and R 4 are joined together with the phenyl ring to which they are attached to form a bicyclic ring system that is:

wherein R is —H or —C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 4 wherein one of R 3 , R 4 or R 5 is —CN and the others are not —CN; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 4 wherein one of R 3 or R 4 is N-tetrazolyl optionally substituted with —CH 3 and the other is not N-tetrazolyl optionally substituted with —CH 3 ; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 wherein Z 1 is

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is:

4-methyl-5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

4-methyl-5-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

3-((3R,9aS)-8-((R)-5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-indene-1carbonyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile and

3-((3R,9aS)-8-((S)-5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-indene-1carbonyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile;

2-fluoro-5-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-fluoro-5-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

4-{2-[(3R,9aS)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-oxoethyl}-2,5-difluorobenzonitrile;

4-{2-[(3R,9aS)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-oxoethyl}-2-methoxybenzonitrile;

5-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

5-fluoro-2-methoxy-4-{2-oxo-2-[(3S,9aS)-3-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]ethyl}benzonitrile;

5-fluoro-2-methoxy-4-{2-oxo-2-[(3R,9aS)-3-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8 (1H)-yl]ethyl}benzonitrile;

5-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

5-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

4-methyl-5-[(3R,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

4-methyl-5-[(3S,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

6-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

5-fluoro-2-methoxy-4-{2-[(3S,9aS)-3-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-oxoethyl}benzonitrile;

5-fluoro-2-methoxy-4-{2-[(3R,9aS)-3-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-oxoethyl}benzonitrile;

2-methoxy-4-[(3S,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methoxy-4-[(3R,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

4-chloro-5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

4-chloro-5-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

6-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

6-fluoro-2-methyl-3-{(3S,9aS)-8-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]octahydropyrazino[2,1-c][1,4]oxazin-3-yl}benzonitrile;

6-fluoro-2-methyl-3-{(3R,9aS)-8-[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]octahydropyrazino[2,1-c][1,4]oxazin-3-yl}benzonitrile;

2-fluoro-6-methoxy-3-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-methoxy-2-methyl-3-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

4-fluoro-2-methoxy-5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methoxy-4-{2-oxo-2-[(3S,9aR)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]ethyl}benzonitrile;

2-methoxy-4-{2-oxo-2-[(3R,9aS)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]ethyl}benzonitrile;

5-fluoro-2-methoxy-4-{2-oxo-2-[(3R,9aS)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]ethyl}benzonitrile;

5-fluoro-2-methoxy-4-{2-oxo-2-[(3S,9aR)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]ethyl}benzonitrile;

6-fluoro-2-methoxy-3-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methoxy-3-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-chloro-2-methyl-3-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl)]benzonitrile;

6-chloro-2-methyl-3-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-chloro-2-methyl-3-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-chloro-2-methyl-3-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-fluoro-4-methyl-5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

3-methyl-4-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

3-methyl-4-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

6-methyl-5-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

2-methyl-3-[(3R,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methyl-3-[(3S,9aS)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-2-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3R,9aS)-8-{2-[4-(1H-tetrazol-1-yl)phenyl]propanoyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aS)-8-{[3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3R,9aS)-8-{[3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3R,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

4-methyl-5-(9-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-1H-[1,4]oxazino[4,3-a][1,4]diazepin-3-yl)-2-benzofuran-1(3H)-one;

4-methyl-5-(8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-1H-[1,4]oxazino[4,3-d][1,4]diazepin-3-yl)-2-benzofuran-1(3-H)-one;

3-[(3R,9aS)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aR)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aR)-8-{[2,5-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aS)-8-{[2,5-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

6-fluoro-2-methyl-3-[(3R,9aR)-8-{[3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{[3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-3-[(3S,9aR)-8-{[2-fluoro-5-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-methylbenzonitrile;

6-fluoro-3-[(3R,9aR)-8-{[2-fluoro-5-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-methylbenzonitrile;

6-fluoro-2-methyl-3-[(3R,9aR)-8-{[2-methyl-3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{[2-methyl-3-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl)]benzonitrile;

6-methoxy-2-methyl-3-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-methoxy-2-methyl-3-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methoxy-4-[(3R,9aR)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methoxy-4-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

2-methoxy-4-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

3-[(3R,9aS)-8-{[2-cyano-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aR)-8-{[2-cyano-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aR)-8-{[2-chloro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3R,9aS)-8-{[2-chloro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-fluoro-2-methylbenzonitrile;

4-methyl-5-[(3S,9aS)-8-{3-[3(1H-tetrazol-1-yl)phenyl]propanoyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

6-fluoro-2-methyl-3-[(3R,9aS)-8-{3-[3-(1H-tetrazol-1-yl)phenyl]propanoyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{3-[3-(1H-tetrazol-1-yl)phenyl]propanoyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

(3S,9aS)-3-(4-methyl-2,1,3-benzoxadiazol-5-yl)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazine;

(3R,9aS)-3-(4-methyl-2,1,3-benzoxadiazol-5-yl)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazine;

(3R,9aS)-3-(2,1,3-benzoxadiazol-5-yl)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazine;

(3R,9aS)-3-(2,1,3-benzoxadiazol-5-yl)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazine;

5-[(3R,9aR)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-4-methyl-2-benzofuran-1(3H)-one;

(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}-3-[3(1H-tetrazol-1-yl)phenyl]octahydropyrazino[2,1-c][1,4]oxazin;

4-methyl-5-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

3-methyl-4-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

3-methyl-4-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

(3R)-3-methyl-6-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

(3R)-3-methyl-6-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

6-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

6-[(3R,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

4-methyl-5-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

4-methyl-5-[(3R,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-2-benzofuran-1(3H)-one;

6-[(3R,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]-3,4-dihydro-1H-isochromen-1-one;

6-fluoro-2-methyl-3-[(3R,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3R,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3R,9aR)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

3-methyl-4-[(3R,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

3-methyl-4-[(3S,9aS)-8-{[6-(1H-tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]thiophene-2-carbonitrile;

6-fluoro-2-methyl-3-[(3S,9aS)-8-{[5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]carbonyl}octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile;

3-((4R,9aR)-8-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)octahydro-1H-pyrazino[1,2-a]pyrazin-3-yl)-6-fluoro-2-methylbenzonitrile;

4-methyl-5-[(3S,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]-2-benzofuran-1(3H)-one;

6-fluoro-2-methyl-3-[(3S,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]benzonitrile;

3-[(3R,9aR)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]-6-fluoro-2-methylbenzonitrile;

3-[(3S,9aR)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]-6-fluoro-2-methylbenzonitrile;

(3R)-3-methyl-6-[(3R,9aR)-8-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]-3,4-dihydro-1H-isochromen-1-one; or

(3R)-6-[(3R,9aR)-8-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl]-3-methyl-3,4-dihydro-1H-isochromen-1-one.

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

11. The pharmaceutical composition of claim 10 further comprised of one or more of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a neutral endopeptidase inhibitor, a dual inhibitors of angiotensin converting enzyme (ACE) and neutral endopeptidase, carbonic anhydrase inhibitor, an aldosterone antagonist, aldosterone synthase inhibitor, a renin inhibitor, an endothelin receptor antagonist, a vasodilator, a calcium channel blocker, a potassium channel activator, a diuretic, a sympatholitic, a beta-adrenergic blocking drug, an alpha adrenergic blocking drug, a central alpha adrenergic agonist, a peripheral vasodilator, an HMG-CoA reductase inhibitor, a cholesterol absorption inhibitor, niacin, niacin in combination with a prostaglandin D2 receptor 1 antagonist, a niacin receptor agonist, a niacin receptor partial agonist, an insulin sensitizing agent, an alpha glucosidase inhibitor, a dipeptidyl peptidase inhibitor, phosphodiesterase-5 inhibitor, or metformin.

12. The pharmaceutical composition of claim 10 further comprising an additional active agent selected from losartan, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, azilsartan, 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, and optionally hydrochlorothiazide, or a pharmaceutically acceptable salt thereof.