Inhibitors of the Renal Outer Medullary Potassium channel

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein the central ring system is a saturated heterocyclic ring, and wherein:

n1 and n2 can be individually either 0 or 1;

a is absent;

b is absent;

c is absent;

R 5 and R 6 together on the same carbon form C 3-6 cycloalkyl optionally substituted with 1-3 of —F;

Z 1 is:

Z 2 is:

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

R 1 and R 2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 3a and R 3b is —CN, tetrazolyl, or —S(O) 2 C 1-3 alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 4a and R 3b is CN, tetrazolyl, or —S(O) 2 C 1-3 alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

R 3c and R 4c are each independently —H, —C 1-6 alkyl or —C 1-6 cycloalkyl;

R a , R aa , R b and R bb are each independently —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F;

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

one of Y 1 or Y 2 is —CH(OH)—; and the other is —CH(OH)—; —C(O)—; —S(O) 2 —; —CH 2 — or absent;

provided that where Y 1 or Y 2 is —C(O)—; —S(O) 2 — or absent, then the adjacent n1 or n2, respectively, is 0; and provided further that where n1 or n2 is 0, the adjacent Y 1 or Y 2 is —C(O)—, —S(O) 2 — or absent.

2. The compound of claim 1 wherein:

Y 1 and Y 2 are both individually —CH(OH)— where n1 and n2 are both individually 1, or one of Y 1 and Y 2 is —CH(OH)— and the other is —C(O)— where the n1 or n2 adjacent —C(O)— is 0 and —CH(OH) is 1;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein:

Z 1 is

Z 2 is

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein:

Z 1 is

or a pharmaceutically acceptable salts thereof.

5. The compound of claim 1 wherein:

Z 1 is

Z 2 is

or a pharmaceutically acceptable salts thereof.

6. The compound of claim 1

or a pharmaceutically acceptable salts thereof wherein the central ring system is a saturated heterocyclic, and wherein:

n1 and n2 can be individually either 0 or 1;

a is absent;

b is absent;

c is absent;

R 5 and R 6 together on the same carbon form C 3-6 cycloalkyl optionally substituted with 1-3 of —F;

Z 1 and Z 2 are selected as follows:

Z 1 is

where W 1 is CH and W 2 is N,

and

Z 2 is

or Z 1 is

and

Z 2 is

where W 1 is CH and W 2 is N,

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

R 1 and R 2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 3a and R 3b is —CN, tetrazolyl, or —S(O) 2 C 1-3 alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

one of R 4a and R 4b is CN, tetrazolyl, or —S(O) 2 C 1-3 alkyl and the other is —H, —F, —Cl, —Br, —S—CH 3 , —NH—CH 3 , —O-cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

R 3c and R 4c are each independently —H, —C 1-6 alkyl or —C 1-6 cycloalkyl;

R a , R aa , R b and R bb are each independently —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F;

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

one of Y 1 or Y 2 is —CH(OH)—; and the other is —CH(OH)—; —C(O)—; —S(O) 2 —; —CH 2 — or absent;

provided that where Y 1 or Y 2 is —C(O)—, —S(O) 2 — or absent, then the adjacent n1 or n2, respectively, is 0; and provided further that where n1 or n2 is 0, the adjacent Y 1 or Y 2 is —C(O)—, —S(O) 2 — or absent.

7. The compound of claim 6 wherein:

Y 1 and Y 2 are both individually —CH(OH)— where n1 and n2 are both individually 1, or one of Y 1 and Y 2 is —CH(OH)— and the other is —CH 2 — where n1 or n2 are both individually 1;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6 wherein:

Z 1 is

Z 2 is

or a pharmaceutically acceptable salts thereof.

9. A compound selected from:

5,5′-{6,9-Diazaspiro[4.5]decane-6,9-diylbis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one);

5,5′-(1R, l′R)-2,2′-(4,7-Diazaspiro[2.5]octane-4,7-diyl)bis(1-hydroxyethane-2,1-diyl)bis(4-methylisobenzofuran-1(3H)-one);

(R)-6-(4-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)nicotinonitrile;

4-[(2R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-1-{2-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine;

(R)-6-(2-(4-((S)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)-3-methylisochroman-1-one;

(R)-6-(2-(4-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)isochroman-1-one;

(S)-6-(2-(4-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)isochroman-1-one;

6-(2-(4-(2-(4-Ethyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-hydroxyethyl)piperazin-1-yl)ethyl)isochroman-1-one;

6-(2-(4-(2-Hydroxy-2-(1-oxo-4-(trifluoromethyl)-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)isochroman-1-one;

(3R)-6-[(1R)-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one;

(3R)-6-[(1S)-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one;

(3S)-6-[(1R)-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one;

(3S)-6-[(1S)-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one;

6-[1-hydroxy-2-[4-[2-hydroxy-2-(3-methyl-1-oxo-isochroman-6-yl)ethyl]piperazin-1-yl]ethyl]-4-methoxy-pyridine-3-carbonitrile hydrochloride;

5-[(1R)-1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one hydrochloride;

5-[(1R)-1-Hydroxy-2-[4-[(2S)-2-hydroxy-2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one hydrochloride;

5-[(1R)-1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-[4-methyl-6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one hydrochloride;

5-[(1R)-1-Hydroxy-2-[4-[(2S)-2-hydroxy-2-[4-methyl-6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-4-methyl-3H-isobenzofuran-1-one hydrochloride;

5-[(1R)-1-hydroxy-2-(4-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one;

5-[(1R)-1-hydroxy-2-(4-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one;

5-[(1R)-2-{4-[(2S)-2-(1,1-dioxido-2,3-dihydro-1-benzothiophen-5-yl)-2-hydroxyethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one;

5-[(1R)-2-{4-[(2R)-2-(1,1-dioxido-2,3-dihydro-1-benzothiophen-5-yl)-2hydroxyethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one;

or a pharmaceutically acceptable salt thereof.

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

11. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein the central ring system is a saturated heterocyclic ring, and wherein:

n1 and n2 are each 1;

a, b and c are absent;

R 5 and R 6 are each —H;

Z 1 is:

Z 2 is:

one of W 1 and W 2 is N and the other is CR b ;

each R 1 is —H, —F, —Cl, —Br, cyclopropyl, —C 1-3 alkyl optionally substituted with 1-3 of —F, or —OC 1-3 alkyl optionally substituted with 1-3 of —F;

R 4a is tetrazolyl;

and R 4b is —H;

R b and R bb are each independently —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F;

each R c is —H, —F, —Cl, —C 1-3 alkyl optionally substituted with 1 to 3 of —F, or —OC 1-3 alkyl optionally substituted with 1 to 3 of —F; and

one of Y 1 or Y 2 is —CH(OH)—; and the other is —CH(OH)— or —CH 2 —.