Inhibitors of the renal outer medullary potassium channel
View Patent ↗Novel spirocyclic compounds of formula I: and pharmaceutically acceptable salts thereof are disclosed as inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention. Pharmaceutical compositions and methods of treatment are also included.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is
R is H, or C 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
R′ is H, or C 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
R 1 is OH, H, C 1-6 alkyl, OC 1-6 alkyl, CH 2 OH, or C 1-6 alkylOC 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
or
X and R 1 together form
m is 0, 1, 2, 3, or 4,
n is 0, or 1,
R 2 and R 3 are each independently H or C 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, or R 2 and R 3 together form oxo,
Y is CH 2 or O,
R 4 is H, C 1-6 alkyl, or oxo, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
R 5 is H, OH, C 1-6 alkyl, OC 1-6 alkyl, OC 1-6 alkylOC 1-6 alkyl, or halo, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
Z is
R a is H, F, Cl, CH 3 , cyclopropyl, phenyl, or pyridyl, wherein CH 3 , cyclopropyl, phenyl, or pyridyl substituents are further optionally substituted with 1-3 halogen substituents,
R b is H, C 1-6 alkyl, or OC 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents,
R c is C 1-6 alkyl, or 3-to 6-membered cycloalkyl, wherein alkyl or cycloalkyl substituents are further optionally substituted with 1-4 halogen substituents, and
each R d is independently halo, C 1-6 alkyl, tetrazolyl, CN, or OC 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
X is
and
R 1 is OH, H, C 1-6 alkyl, OC 1-6 alkyl, CH 2 OH, or C 1-6 alkylOC 1-6 alkyl, wherein alkyl substituents are further optionally substituted with 1-4 halogen substituents, and R d , m, R and R′ are as defined in claim 1 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R and R′ are independently H or CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1, or 2.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each H, or R 2 and R 3 together form oxo.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R c is CH 3 , CH 2 CH 3 , or cyclopropyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is
R a , R b and R c are as defined in claim 1 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R b is H, CH 3 , or OCH 2 CH 3 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
m is 1,
n is 1,
R 1 is OH,
R 2 , R 3 , R 4 , and R 5 are each independently is H,
R d is tetrazolyl, and
Y is CH 2 .
12. A compound which is:
5-{2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;
4-methyl-5-{2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;
3-methyl-4-(9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;
(R)-3-(9-(2-methoxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
5-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
5-{(1R)-1-hydroxy-2-[9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
6-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methoxypyridine-3-carbonitrile;
(3R)-6-{1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;
(3S)-6-{(1R)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;
(3S)-6-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;
4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridazin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridazin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2R)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;
9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;
9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;
9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;
(R)-9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;
5-{(1R)-1-hydroxy-2-[8-methyl-9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[8-methyl-9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-2-[(7R)-7-fluoro-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-2-[(7S)-7-fluoro-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
4-{9-[2-(4-bromophenyl)-2-hydroxyethyl]-3,9-diazaspiro[5.5]undec-3-yl}-3-methylfuran-2(5H)-one;
5-{(1R)-1-hydroxy-2-[9-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-2-[9-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
3-fluoro-4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
5-{(1R)-2-[9-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[9-(5-oxo-4-phenyl-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[9-(5-oxo-4-pyridin-4-yl-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
3-cyclopropyl-4-(9-{2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
5-{(1R)-2-[9-(4-cyclopropyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-hydroxy-1-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{2-hydroxy-1-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[3-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[3-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyridin-4-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyridin-4-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyrazin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyrazin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2R)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
4-(9-{(2S)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;
3-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;
3-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;
5-{(1R)-1-hydroxy-2-[9-(3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
3-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;
3-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;
3-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;
5-{(1R)-1-hydroxy-2-[9-(2-methyl-3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
3-(9-{(2R)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;
3-{9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl}-3,9-diazaspiro[5.5]undec-3-yl]-4-methylcyclobut-3-ene-1,2-dione;
(R)-3-ethyl-4-(9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;
(R)-3-cyclopropyl-4-(9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;
(R)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(S)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(S)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(R)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(S)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(R)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(S)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(R)-3-(9-(2-hydroxy-2-(tetrazolo[1,5-a]quinolin-7-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
(S)-3-(9-(2-hydroxy-2-(tetrazolo[1,5-a]quinolin-7-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;
5-{(1S)-1-methoxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-methoxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-2-[9-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[9-(6-oxo-3,6-dihydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[(7R)-7-hydroxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[(7R)-7-(methoxymethoxy)-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[(7S)-7-(methoxymethoxy)-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[(7R)-7-methoxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
5-{(1R)-1-hydroxy-2-[(7S)-7-methoxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;
4-(9-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{[5-fluoro-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{[3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]carbonyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-(9-{[2,5-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;
4-methyl-5-{2-oxo-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;
4-(9-{[5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one; or
a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprised of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 further comprising an additional active agent selected from losartan, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, 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, or a pharmaceutically acceptable salt of any of the foregoing.
15. 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.
16. A method for the treatment of one or more disorders selected from hypertension, acute heart failure, chronic heart failure, or pulmonary arterial 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.