Inhibitors of the renal outer medullary potassium channel

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:

represents:

R 7 is selected from —H, —F, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OH, cyclopropyl or —CH 2 C(═O)O—CH 3 , or R 7 represents di-substitution on a single carbon with two of —F or two of —CH 3 ;

Z 1 is selected from:

Z 2 is selected from:

one of W 1 and W 2 is N and the other is CH;

R 1 and R 2 are each independently selected from —H, —F, —Cl, —Br, —C 3 —C 6 cycloalkyl, —OR 8 , —SR 8 , —SOR 8 , —SO 2 R 8 , —(CH 2 ) n OR 8 or —C 1-6 alkyl optionally substituted with 1-3 of —F;

one of R 3a and R 3b is selected from —CN, —NO 2 or tetrazoly, and the other is R 3c wherein R 3c selected from —H, —F, —Cl, —Br, —CH 3 , —S—CH 3 , —NH—CH 3 , —O-cyclopropyl or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 4a and R 4b is selected from CN, —NO 2 or tetrazolyl, and the other is R 4c wherein R 4c is selected from —H, —F, —Cl, —Br, —CH 3 , —S—CH 3 , —NH—CH 3 , —O-cyclopropyl or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

R a , R aa , R b and R bb are each independently selected from —H, —F, —Cl, —CH 3 optionally substituted with 1 to 3 of —F, or —OCH 3 optionally substituted with 1 to 3 of —F;

R c and R d are each independently selected from —H, —F, —Cl, —C 1-6 alkyl optionally substituted with 1 to 3 of —F, —C 3-6 cycloalkyl or —OC 1-6 alkyl optionally substituted with 1 to 3 of —F;

R e and R f are each independently selected from —H or —CH 3 ;

X and X 1 are each independently selected from —H or —C 1-6 alkyl,

or X 1 is joined together with Z 1 and the carbon to which both are attached to form a fused ring system selected from:

Y and Y 1 are each independently selected from —H or —C 1-6 alkyl,

or Y 1 is joined together with Z 2 and the carbon to which both are attached to form a fused ring system selected from

R 5 and R 6 are each independently selected from —H, —C 1-6 alkyl or —C(O)OC 1-3 alkyl;

and

R 8 is selected from —C 1-6 alkyl or —C 3-6 cycloalkyl.

2. The compound of claim 1 wherein:

Z 1 is selected from:

Z 2 is selected from:

X and X 1 are each independently selected from —H or —C 1-6 alkyl;

Y and Y 1 are each independently selected from —H or —C 1-6 alkyl,

or Y 1 is joined together with Z 2 and the carbon to which both are attached to form a fused ring system selected from:

R 5 is selected from —H, —CH 3 , —C 1-6 alkyl or —C(O)OC 1-3 alkyl; and

R 6 is selected from —H, —CH 3 , —C 1-6 alkyl or —C(O)OC 1-3 alkyl,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein

R 7 is —H;

R 1 and R 2 are independently selected from —H or —CH 3 ;

R a and R b are each independently selected from —H, —F, —Cl, —CH 3 optionally substituted with 1 to 3 of —F, or —OCH 3 optionally substituted with 1 to 3 of —F;

R aa and R bb are each independently selected from —H or —F

R c and R d are each independently selected from —H, —F, —Cl, —CH 3 optionally substituted with 1 to 3 of —F, or —OCH 3 optionally substituted with 1 to 3 of —F;

R 5 is selected from —H or —CH 3 ;

R 6 is selected from —H or —CH 3 ;

X, X 1 and Y are each —H; and

Y 1 is —H, or Y 1 is joined together with Z 2 and the carbon to which both are attached to form a fused ring system as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 selected from:

1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one);

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one

2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Fluoro-2-methoxy-3-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Methyl-5-(1-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)propan-2-yl)isobenzofuran-1(3H)-one;

2-Methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2,2-Dimethyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile;

4-(2-{4-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)naphthalene-1-carbonitrile;

4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

(3S,3'S)-6,6′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(3-methyl-3,4-dihydro-1H-isochromen-1-one);

2-(Methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Fluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2-(Cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Chloro-2-fluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile; or

4-Fluoro-2-methoxy-3-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 selected from:

1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine;

4,4′-(Piperazine-1,4-diyldiethane-2,1-diyl)dibenzonitrile;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one);

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one;

2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Fluoro-2-methoxy-3-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Methyl-5-(1-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)propan-2-yl)isobenzofuran-1(3H)-one; or

4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A compound selected from:

1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine;

1-[2-(4-Nitrophenyl)ethyl]-4-[2-(5-nitropyridin-2-yl)ethyl]piperazine;

4-(2-{4-[2-(4-Nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-(Fluoromethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

4,4′-(Piperazine-1,4-diyldiethane-2,1-diyl)dibenzonitrile;

2-Methyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

Methyl(2S)-3-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}propanoate;

2,2-Dimethyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

2-Cyclopropyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

2-(Difluoromethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;

{1,4-Bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl}methanol;

1-[2-(4-Nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propyl]piperazine;

1-[2-(4-Nitrophenyl)ethyl]-4-{2-[4-nitro-2-(trifluoromethyl)phenyl]ethyl}piperazine;

1-[1-Methyl-2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine;

1,4-Bis[1-methyl-2-(4-nitrophenyl)ethyl]piperazine;

Methyl {1,4-bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl}acetate;

2-Methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2,6-Difluoro-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Fluoro-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

1-((4-(2-(1-Oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)methyl)-2,3-dihydro-1H-indene-4-carbonitrile;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-({4-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-7-carbonitrile;

5-({4-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-5,6,7,8-tetrahydronaphalene-2-carbonitrile;

2-Fluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2,5-Difluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2-Bromo-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

5-[2-[4-[2-[6-(Tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one;

4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one;

2-Methoxy-4-[1-methyl-2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2-Methoxy-4-[1-methyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile;

4-[1,1-Dimethyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methoxy-benzonitrile;

2-Methoxy-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile;

2-(Difluoromethoxy)-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;

5-Fluoro-3-({4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-7-carbonitrile;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile;

5-Fluoro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

5-Fluoro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4,4′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(5-fluoro-2-methoxybenzonitrile);

2-Methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

(3 S,3′S)-6,6′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(3-methyl-3,4-dihydro-1H-isochromen-1-one);

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one);

2-(Methylthio)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile:

5-Chloro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-(Methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-(Difluoromethoxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-(Cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

5-(2-{4-[2-(4-Nitrophenyl)ethyl]piperazin-1-yl}ethyl)-2-benzofuran-1(3H)-one;

5,5′-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one;

2-Trifluoromethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Trifluoromethoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Chloro-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Chloro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Fluoro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Fluoro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-(2-{4-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)naphthalene-1-carbonitrile;

2,3,5-Trifluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Ethoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

5-Chloro-2-fluoro-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

5-Chloro-2-fluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

5-Chloro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Fluoro-3-methyl-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Fluoro-3-methyl-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-3-methyl-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

2-Methoxy-3-methyl-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Chloro-2-fluoro-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Chloro-2-fluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Chloro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

3-Chloro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Fluoro-2-methoxy-3-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-Fluoro-2-methoxy-3-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

4-({4-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-7-carbonitrile;

5-Fluoro-3-({4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-7-carbonitrile;

5,5′-(Piperazine-1,4-diyldipropane-1,3-diyl)bis(4-methyl-2-benzofuran-1(3H-one);

4-Methyl-5-(1-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)propan-2-yl)isobenzofuran-1(3H)-one;

4-(2-{4-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;

or a pharmaceutically acceptable salt thereof.