Inhibitors of the renal outer medullary potassium channel

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

m is the integer zero or 1;

n is the integer zero or 1;

one of the dashed lines a, b or c represents a —CH 2 — or —CH 2 —CH 2 — bridge, and the other dashed lines are absent;

R 1 is —H, —OC 1-3 alkyl or —OH;

R 2 is —H or —C 1-3 alkyl;

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

or, when n is zero, R 2 and R 3 are joined together to represent —(CH 2 ) (q) — and form a 4-6 member ring with the nitrogen and carbon to which each is attached;

q is the integer 2, 3 or 4;

R 4 and R 5 are each independently —H or —C 1-3 alkyl, or R 4 and R 5 are joined together with the carbon to which they are attached to form C 3-6 cycloalkyl;

R 6 is —H, —C 1-3 alkyl, —OH, —OC 1-3 alkyl or —F, or is di-fluoro that replaces two hydrogens on the carbon to which it is attached;

R 7 is —H, —C 1-3 alkyl, —OH, —OC 1-3 alkyl or —F, or is di-fluoro that replaces two hydrogens on the carbon to which it is attached;

Z 1 is

R is —H or —C 1-4 alkyl;

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

R 9 is —H, —F, —Cl, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-6 alkyl; or when R 10 is —H, then R 9 can be 1H-tetrazol-1-yl;

R 10 is —H, —Cl, —F, —CN, —C 1-6 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 11 is —H, —Cl, —F, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

R 11a is —H, —Cl, —F, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl;

provided that R 9 and R 10 are not both —H; and

provided that one and only one of R 9 , R 10 or R 11a is —CN;

Z 2 is

X 1 , X 2 , X 3 and X 4 are each independently C(R a ) or N, provided that one or two of X 1 , X 2 , X 3 and X 4 must be N and the others are C(R a );

each R a is independently —H or —C 1-3 alkyl;

G is —OC 1-3 alkyl, —CN or a 5-membered heteroaryl;

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

R 12 is —H, —C 1-3 alkyl, —OC 1-3 alkyl, —SO 2 C 1-3 alkyl or halo;

R 13 is —H, —C 1-3 alkyl, —OC 1-3 alkyl, halo, —NO 2 , —CN or a 5-membered heteroaryl;

R 14 is —H, —C 1-3 alkyl, —OC 1-3 alkyl, halo, —NO 2 , —CN or a 5-membered heteroaryl;

provided that only one of R 13 and R 14 is —CN, —NO 2 or the 5-membered heteroaryl and the other is —H, —C 1-3 alkyl, —OC 1-3 alkyl or halo;

R 15 is —H, —C 1-3 alkyl, —OC 1-3 alkyl, —SO 2 C 1-3 alkyl or halo;

R 15a is —H, —C 1-3 alkyl, —OC 1-3 alkyl, —SO 2 C 1-3 alkyl or halo;

or R 2 and R 15 are joined together and represent —CH 2 — to form the bicyclic fused ring system

 and

R 16 is —H, —Cl, —F, —CN, —C 1-4 alkyl, —C 3-6 cycloalkyl or —OC 1-4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H or —OH, R 2 is —H or —CH 3 and R 3 is —H, —C 1-3 alkyl or phenyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein R 6 is —H, —F or —OCH 3 and R 7 is —H, —F or —OCH 3 .

4. The compound of claim 1 having structural Formula II or a pharmaceutically acceptable salt thereof:

5. The compound of claim 2 having structural Formula lla or a pharmaceutically acceptable salt thereof:

wherein R 1 is —H or —OH;

R 2 is —H or —CH 3 , or R 2 and R 15 are joined together and represent —CH 2 — to form the bicyclic fused ring system

 and R 3 is —H or —C 1-3 alkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein: Z 2 is

G is —CN or 1H-tetrazol-1-yl; when R 2 and R 15 are joined together and represent —CH 2 —then R 14 is —NO 2 ; and when R 2 and R 15 are not joined together, then one of R 13 and R 14 is —CN or a 5-membered heteroaryl and the other is —H, —C 1-3 alkyl, —OC 1-3 alkyl or halo.

7. The compound of claim 1 having structural Formula III or a pharmaceutically acceptable salt thereof:

wherein p is an integer selected from 0 (zero) or 1 (one).

8. The compound of claim 7 having structural Formula IIIa or a pharmaceutically acceptable salt thereof:

wherein R 3 is —H, —C 1-3 alkyl or phenyl; R 4 and R 5 are each independently —H or —C 1-3 alkyl, or R 4 and R 5 are joined together with the carbon to which they are attached to form C 3-6 cycloalkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein

Z 2 is;

 and G is 1H-tetrazol-1-yl.

10. A compound or a pharmaceutically acceptable salt thereof that is:

N-Methyl-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-oxo-1,3-dihydroisobenzofuran-5-carboxamide;

N-(1-(2-(4-Methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-(1H -tetrazol-1-yl)nicotinamide;

(S)-N-(1-(2-(3-methyl-1-oxoisochroman-6-yl)ethyl)piperidin-4-yl)-1-oxo-1,3-dihydroisobenzofuran-5-carboxamide;

4-Cyano-3-methoxy-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-oxo-1,3-dihydroisobenzofuran-5-carboxamide;

4-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin -4-yl)-3-methoxybenzamide;

3-Cyano-4-methoxy-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

3-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin -4-yl)-4-methoxybenzamide;

4-Cyano-3-fluoro-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

N-(1-(2-(3-Cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperidin-4-yl)-1-oxo-1,3-dihydroisobenzofuran-5-carboxamide;

4-Cyano-N-(1-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;

N-(1-(2-(4-Methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-2-(1H -tetrazol-1-yl)isonicotinamide;

4-Cyano-3-fluoro-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

5-Cyano-4-fluoro-2-methoxy-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

5-Cyano-2-fluoro-4-methyl-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

5-Cyano-4-methyl-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin -4-yl)picolinamide;

(R)-5-Cyano-4-fluoro-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-2-methoxybenzamide;

(S)-5-Cyano-4-fluoro-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-2-methoxybenzamide;

(R)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methylpicolinamide;

(S)-5-cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methylpicolinamide;

(R)-6-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)nicotinamide;

(R)-4-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-methylbenzamide;

(R)-4-Cyano-2-ethoxy-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

(R)-4-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

(R)-5-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)picolinamide;

4-Cyano-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-2-(methylsulfonyl)benzamide;

N-(1-(2-(4-Methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(1H -tetrazol-1-yl)benzamide;

N-(1-(2-(4-Methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(1H -pyrazol-1-yl)benzamide;

4-Cyano-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)thiophene-2-carboxamide;

5-Cyano-N-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(1H-tetrazol-1-yl)benzamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(isoxazol-3-yl)benzamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(1H-tetrazol-1-yl)benzamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(1H-pyrazol-1-yl)benzamide;

5-Cyano-N-((trans)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(1H-pyrazol-3-yl)benzamide;

(R)-5-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)picolinamide;

(R)-5-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-methylpicolinamide;

(R)-4-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)isoquinoline-1-carboxamide;

5-Cyano-N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)picolinamide;

5-Cyano-N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-methylpicolinamide;

(R)-4-Cyano-2-fluoro-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

6-Cyano-N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)nicotinamide;

4-Cyano-N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-methylbenzamide;

5-Cyano-N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methylpicolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-((cis)-3-Fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

(R)-5-(2-(1-(6-(1H-Tetrazol-1-yl)picolinoyl)-1,7-diazaspiro[3.5]nonan-7-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((cis)-1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methoxypiperidin-4-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

(R)-5-(2-(1-(5-(1H-Tetrazol-1-yl)picolinoyl)-1,7-diazaspiro[3.5]nonan-7-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one;

N-(3-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(1H-tetrazol-1-yl)picolinamide;

(R)-4-Cyano-N-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-methoxybenzamide;

N-((cis)-3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-methyl-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((S)-1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin -3-yl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((R)-1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin -3-yl)-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)-4-methyl-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-5-(1H-tetrazol-1-yl)pyrazine-2-carboxamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-(1H-tetrazol-1-yl)pyridazine-3-carboxamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpiperidin-3-yl)methyl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-phenylpyrrolidin-3-yl)methyl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpyrrolidin-3-yl)methyl)-5-(1H-tetrazol-1-yl)picolinamide;

N-(1-(1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)cyclobutyl)-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)-6-(1H-tetrazol-1-yl)pyridazine-3-carboxamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)-5-(1H-tetrazol-1-yl)pyrazine-2-carboxamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-6-(1H-pyrazol-1-yl)nicotinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(1H-1,2,4-triazol-1-yl)benzamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-4-(thiazol-2-yl)benzamide;

N-(8-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-(1H-tetrazol-1-yl)picolinamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-methylpiperidin-4-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-methyl-4-(1H-tetrazol-1-yl)benzamide;

(R)-N-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-8-(1H-tetrazol-1-yl)quinoline-5-carboxamide;

N-(2-(1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-3-yl)propan-2-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-phenylpyrrolidin-3-yl)methyl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-(8-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpiperidin-3-yl)methyl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methylpyrrolidin-3-yl)methyl)-6-(1H-tetrazol-1-yl)nicotinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)methyl)-4-methyl-5-(1H-tetrazol-1-yl)picolinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)methyl)-5-(1H-tetrazol-1-yl)picolinamide;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)methyl)-6-(1H-tetrazol-1-yl)picolinamide;

(R)-2-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-5-nitroisoindolin-1-one;

N-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)methyl)benzo[c][1,2,5]oxadiazole-5-carboxamide;

N-(1-(1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin -3-yl)cyclobutyl)-6-(1H-tetrazol-1-yl)nicotinamide;

(R)-2-(1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-5-(1H-tetrazol-1-yl)isoindolin-1-one;

or a stereisomer thereof.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof that is

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

13. A compound of claim 1 of Formula I wherein Z 2 is

wherein R a is —H, —CH 3 , or —C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

14. A compound that is:

N-(1 -(2-(4-Methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 -yl)ethyl)piperidin-4-yl)-1 -oxo-1,3-dihydroisobenzofuran-5-carboxamide;

N-(1 -(2-(4-Methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzo[c][1,2,5]oxadiazole-5-carboxamide; or

3-Cyano-4-fluoro-N-(1-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)benzamide;

or a pharmaceutically acceptable salt thereof.