Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-9839629-B2
Application number	US-201415101481-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 24, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

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.

First claim

What is claimed is:

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-o

Assignees

• Merck Sharp & Dohme

Inventors

• Dong Shuzhi
• Pasternak Alexander
• Gu Xin
• Fu Qinghong
• Jiang Jinlong
• Ding Fa-Xiang
• Tang Haifeng
• Dejesus Reynalda K
• Suzuki Takao

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title