Inhibitors of the renal outer medullary potassium channel
View Patent ↗This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.
1. A compound having structural Formula I:
and the pharmaceutically acceptable salts thereof wherein:
represents
Z 1 is
Z 2 is selected from the group consisting of:
X is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
Y is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 ;
X 1 and Y 1 are each independently selected from the group consisting of —H and —CH 3 ;
Y 2 is —O—;
provided that when X is oxo then X 1 is absent and when Y is oxo then Y 1 is absent;
and further provided that when Z 2 is z2-i, z2-ii, z2-iii, z2-iv, z2-ix or z2-x, then at least one of X and Y is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo, and when Z 2 is z2-v or z2-vii, then X is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo;
R 1 and R 2 are each independently selected from the group consisting of —H, -halo, —C 3 -C 6 cycloalkyl, —OR 8 , —SR 8 , —SOR 8 , —SO 2 R 8 , —(CH 2 ) n OR 8 and C 1 -C 6 alkyl optionally substituted with 1-3 of —F;
one of R 4a and R 4b is selected from the group consisting of —CN and —NO 2 and the other is R f ;
R 5 and R 6 are each independently selected from the group consisting of —H, —C 1-6 alkyl, —C 3-6 cycloalkyl, —CF 3 , —CHF 2 , —CH 2 F and —CH 2 OH;
R 7 is selected from the group consisting of —H, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F and —CH 2 OH;
R b is selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
R c and R d are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
R f is selected from the group consisting of (a) —H, (b) halo, (c) —C 1-6 alkyl optionally substituted with 1-3 of —F, (d) —C 3-6 cycloalkyl, (e) —OC 1-3 alkyl optionally substituted with 1-3 of —F, (f) —OR 8 , (g) —CO 2 C 1-6 alkyl optionally substituted with 1-3 of —F, (h) —(CH 2 ) n OR 8 , (i) —SR 8 , (j) —SOR 8 , (k) —SO 2 R 8 , (l) —NHCOR 8 and (m) —NHSO 2 R 8 ;
n is an integer selected from 1, 2 and 3; and
R 8 is independently selected at each occurrence from the group consisting of —H, —C 3-6 cycloalkyl and —C 1-6 alkyl optionally substituted with 1-3 of —F.
2. The compound of claim 1 wherein Z 2 is selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
3. The compound of claim 1 wherein X is selected from —H, —OH, —F and —CH 3 , and Y, when present, is selected from —H, —OH, —F and —CH 3 , provided that when Z 2 is z2-i, z2-ii, z2-iii, z2-iv, z2-ix or z2-x, then at least one of X and Y is selected from —OH and —F, and when Z 2 is z2-v or z2-vii, then X is selected from —OH and —F, and the pharmaceutically acceptable salts thereof.
4. The compound of claim 3 wherein Z 2 is selected from the group consisting of z2-i, z2-ii, z2-iv, z2-v and z2-vi, and the pharmaceutically acceptable salts thereof.
5. The compound of claim 4 wherein R 1 is selected from the group consisting of (a) —H, (b) —F, (c) —Cl, (d) —Br, (e) —C 1-3 alkyl optionally substituted with 1-3 of —F, (f) cyclopropyl, (g) —OC 1-3 alkyl optionally substituted with 1-3 of —F, and (h) —(CH2) 1-3 —OH, and R 2 , when present, is selected from the group consisting of (a) —H, (b) —F, (c) —Cl, (d) —Br, (e) —C 1-3 alkyl optionally substituted with 1-3 of —F, (f) cyclopropyl, (g) —OC 1-3 alkyl optionally substituted with 1-3 of —F, and (h) —(CH2) 1-3 —OH; and the pharmaceutically acceptable salts thereof.
6. The compound of claim 5 wherein one of R 4a and R 4b , when present, is —CN and the other is R f , and the pharmaceutically acceptable salts thereof.
7. The compound of claim 6 wherein R f , when present, is selected from the group consisting of —H, —CH 3 , —OCH 3 and —F, and the pharmaceutically acceptable salts thereof.
8. The compound of claim 7 wherein R 5 and R 6 are each independently selected from the group consisting of —H and —CH 3 , and the pharmaceutically acceptable salts thereof.
9. The compound of claim 8 wherein R c is selected from the group consisting of —H, —CH 3 and —OCH 3 ; R d , when present, is selected from the group consisting of —H, —CH 3 and —OCH 3 ; and R b , when present, is selected from the group consisting of —H, —CH 3 and —F; and the pharmaceutically acceptable salts thereof.
10. The compound of claim 1 having a structural Formula VIII:
and the pharmaceutically acceptable salts thereof, wherein
Z 2 is selected from z2-vi and z2-viii,
X is selected from the group consisting of —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 , and —CH 3 and
X 1 is selected from the group consisting of —H and —CH 3 ; or
Z 2 is selected from z2-ix and z2-x, and
at least one of X and Y is selected from the group consisting of —OH, —OC 1-3 alkyl, —F and oxo and the other is selected from —H, —OH, —OC 1-3 alkyl, —F, oxo, NH 2 and —CH 3 .
11. The compound of claim 2 having structural Formula VIIIa:
and the pharmaceutically acceptable salts thereof wherein:
R 1 is selected from the group consisting of —H, —CH 3 and —OCH 3 ; R c is selected from the group consisting of —H and —CH 3 ; Z 2 is selected from the group consisting of
Y is selected from the group consisting of —H, —OH, —F and —CH 3 ; R 2 is selected from the group consisting of —H, —CH 3 and —OCH 3 ; R d is selected from the group consisting of —H and —CH 3 ; and R 4b is selected from the group consisting of —H, —OCH 3 and —F.
12. The compound of claim 2 having structural Formula X
and the pharmaceutically acceptable salts thereof wherein:
R 1 is selected from —H and —CH 3 ;
R c is selected from —H and —CH 3 ; and
Z 2 is selected from z2-ii, z2-iv, z2-v and z2-vi.
13. The compound of claim 1 selected from the group consisting of:
6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-{piperazine-1,4-diylbis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one);
5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(6-methyl-2-benzofuran-1(3H)-one);
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-bromo-2-benzofuran-1(3H)-one);
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-chloro-2-benzofuran-1(3H)-one;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(2-benzofuran-1(3H)-one);
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis[4-(methyloxy)-2-benzofuran-1(3H)-one];
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4,6-dimethyl-2-benzofuran-1(3H)-one);
5,5′-[(2-methylpiperazine-1,4-diyl)bis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-[Piperazine-1,4-diylbis(1-fluorethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one;)
5-(1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-(1-hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-((1R)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-((1S)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-[2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-(methyloxy)ethyl]-4-methyl-2-benzofuran-1(3H)-one;
5-(1-(ethyloxy)-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-(1-fluoro-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one;
4-(1-hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethy2-(methyloxy)-4-oxiran-2-ylbenzonitrile;
5-fluoro-4-(1-hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
5-fluoro-4-(1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
6-fluoro-3-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-methylbenzonitrile;
5-chloro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-5-methyl-2-(methyloxy)benzonitrile;
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
5-fluoro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-3-methyl-2-(methyloxy)benzonitrile;
2-fluoro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;
4-(2-{4-[2-fluoro-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-(methyloxy)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(2-{4-[2-(ethyloxy)-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-2-(methyloxy)benzonitrile;
4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}propyl)-2-(methyloxy)benzonitrile;
5-({4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4,6-dimethyl-2-benzofuran-1(3H)-one;
4-(1-fluoro-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile;
1-({4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-3,4-dihydro-1H-isochromene-5-carbonitrile;
1-({4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-5-(methyloxy)-3,4-dihydro-1H-isochromene-6-carbonitrile;
1-({4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-7-(methyloxy)-3,4-dihydro-1H-isochromene-6-carbonitrile;
6-(1-Hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methoxypyridine-3-carbonitrile;
5-({4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}acetyl)-4-methyl-2-benzofuran-1(3H)-one;
5-(1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-fluoro-1-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-2,3-dihydro-1H-indene-4-carbonitrile;
4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-dimethylethyl)-2-(methyloxy)benzonitrile;
6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)pyridine-3-carbonitrile;
6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methylpyridine-3-carbonitrile;
6-(1-Hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-5-methylpyridine-3-carbonitrile;
6-[1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methyl-pyridine-3-carbonitrile;
5-Chloro-6-[1-hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]pyridine-3-carbonitrile;
4-[1-Hydroxy-2-[4-[2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-fluoro-2-benzofuran-1(3H)-one);
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(7-fluoro-4-methyl-2-benzofuran-1(3H)-one);
5-[(1R)-1-hydroxy-2-{4-[2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one;
5-(2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl)-2-benzofuran-1(3H)-one;
5-[(1R)-2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one;
5-[(1R)-2-{4-[(2S)-2-(2,1,3-benzoxadiazol-5-yl)-2-hydroxyethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one;
5-[(1R)-2-{4-[(2R)-2-(2,1,3-benzoxadiazol-5-yl)-2-hydroxyethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one;
and the pharmaceutically acceptable salts thereof.
14. The compound of claim 1 selected from the group consisting of
and the pharmaceutically acceptable salts thereof.
15. The compound of claim 1 selected from the group consisting of:
(6S)-6-({4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one;
(6R)-6-({4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-8,9-dihydro-1H-furo[3,4-f]isochromen-3(6H)-one;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-{piperazine-1,4-diylbis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one);
5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one);
5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(6-methyl-2-benzofuran-1(3H)-one);
5-((1R)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
5-((1S)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one;
6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one;
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]-4-methoxypyridine-3-carbonitrile
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]-4-methoxypyridine-3-carbonitrile;
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]pyridine-3-carbonitrile;
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]pyridine-3-carbonitrile;
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]-4-methylpyridine-3-carbonitrile;
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]-4-methylpyridine-3-carbonitrile;
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]-2-methylpyridine-3-carbonitrile;
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]-2-methylpyridine-3-carbonitrile;
5-[(1R)-1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one;
5-[(1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one; and
5-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4,6-dimethyl-2-benzofuran-1(3H)-one;
and the pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition comprised of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
17. A method for causing diueresis, natriuresis or both, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.
18. A method for the treatment of hypertension comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.
19. A method for the treatment of one or more disorders selected from the group consisting of hepatic cirrhosis, acute or chronic kidney insufficiency and nephrotic syndrome, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.
20. A method for the treatment of heart failure comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.
21. The method of claim 18 which additionally comprises administering a therapeutically effective amount of losartan, valsartan, candesartan, olmesartan or telmisartan, with or without hydrochlorothiazide.
22. The method of claim 20 which additionally comprises administering a therapeutically effective amount of losartan, valsartan, candesartan, olmesartan or telmisartan, with or without hydrochlorothiazide.
23. The pharmaceutical composition of claim 16 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
24. The compound of claim 1 that is 5,5′-{piperazine-1,4-diylbis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one))
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 1 that is 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]pyridine-3-carbonitrile
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 that is 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]pyridine-3-carbonitrile
or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 that is 5-[(1R)-1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 that is 5-[(1R)-1-hydroxy-2-{4-[(25)-2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 that is 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]-4-methoxypyridine-3-carbonitrile
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 that is 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]-4-methoxypyridine-3-carbonitrile
or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprised of the compound of claim 24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
33. A pharmaceutical composition comprised of the compound of claim 25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
34. The pharmaceutical composition of claim 33 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
35. A pharmaceutical composition comprised of the compound of claim 26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
36. The pharmaceutical composition of claim 35 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
37. A pharmaceutical composition comprised of the compound of claim 27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
39. A pharmaceutical composition comprised of the compound of claim 28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 39 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
41. A pharmaceutical composition comprised of the compound of claim 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
42. The pharmaceutical composition of claim 41 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
43. A pharmaceutical composition comprised of the compound of claim 30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
44. The pharmaceutical composition of claim 43 further comprising losartan, valsartan, candesartan, olmesartan or telmisartan, and which is optionally additionally comprised of hydrochlorothiazide.
45. The pharmaceutical composition of claim 16 further comprising an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker, and optionally additionally comprised of a beta-adrenergic blocker.
46. The pharmaceutical composition of claim 45 wherein the angiotensin converting enzyme inhibitor is alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril; the angiotensin receptor blocker is losartan, valsartan, candesartan, olmesartan or telmisartan; and the optional beta-adrenergic blocker is propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol tartate.
47. The method of claim 17 wherein the patient has one or more of hypertension, heart failure, acute or chronic kidney insufficiency, nephrotic syndrome and hepatic cirrhosis.
48. The method of claim 47 wherein the kidney insufficiency is chronic kidney insufficiency.
49. The compound of claim 24 that is
50. The compound of claim 24 that is a pharmaceutically acceptable salt of
51. The compound of claim 50 which is a mono-HCl salt, di-HCl salt or H 2 SO 4 salt.
52. The compound of claim 1 that is 5,5′-[piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one)
or a pharmaceutically acceptable salt thereof.
53. The compound of claim 1 that is 5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one)
or a pharmaceutically acceptable salt thereof.
54. The compound of claim 1 that is 5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one
or a pharmaceutically acceptable salt thereof.