Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-9850245-B2
Application number	US-201515505277-A
Country	US
Kind code	B2
Filing date	Oct 26, 2015
Priority date	Oct 31, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are 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.

First claim

What is claimed is:

1. A compound having structural Formula I:

or a pharmaceutically acceptable salt thereof wherein:
R 1 is —H, —F, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 2 is —H, or C 1-4 alkyl;
R 3 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;
R 4 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;
or R 3 and R 4 are joined together to form —CH 2 —CH 2 —;
n is 1 or 2;
R 5 is —H, halo, —C 3-6 cycloalkyl or —C 1-3 alkyl;
X 1 is —C(O)—, —CH 2 —, —CR 6 R 7 C(O)—, —CH 2 CR 6 R 7 —, or —CR 6 R 7 CH 2 —;
X 2 is —O—, —OCH 2 — or —N(R);
X 3 is —C(O)—, —CH 2 —, —CR 6 R 7 C(O)—, —CH 2 CR 6 R 7 —, or —CR 6 R 7 CH 2 —;
wherein the ring bearing X1, X2 and X3 is a 5-7 membered ring which results in a (i) 11-13-membered spirocyclic core where n is 1, or a (ii) 12-14-membered spirocyclic core where n is 2;
each R 6 and R 7 is independently —H, halo, —OH, —OC 1-3 alkyl, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F;
R 8 is —H or —C 1-3 alkyl;
Z is

Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from C(R 9 ) or N;
provided that at most two of Y 1 , Y 2 , Y 3 and Y 4 are N;
each R 9 is independently —H, halo, C 1-4 alkyl optionally substituted with 1-3 of —F, or OC 1-4 alkyl;
R 10 is —H, halo, or C 1-4 alkyl optionally substituted with 1-3 of —F;
R 11 is —H, C 1-4 alkyl optionally substituted with 1-3 of —F, or halo; and
R 12 is —H or C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —H, —F or —OH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 are —H, or R 3 and R 4 are joined together to form —CH 2 CH 2 —.

4. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

5. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —H, —Cl, —CH 3 or cyclopropyl.

6. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —H.

7. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —CH 3 .

8. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —C(O)—, X 2 is —O— and X 3 is —CH 2 CH 2 —.

9. The compound of any of claim 1 wherein n is 1.

10. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is —CH 2 —, X 2 is —O— and X 3 is —CH 2 CH 2 —.

11. The compound of claim 10 wherein n is 1.

12. The compound of any of claim 1 wherein Z is

wherein each of the variables Y 1 , Y 2 , Y 3 and Y 4 , are as defined in claim 1 .

13. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is

wherein each of the variables R 10 , R 11 and R 12 are as defined in claim 1 .

14. The compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is

15. A compound which is:
9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one dihydrochloride;
9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4,9-triazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-3-methylfuran-2(5H)-one;
(R)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(S)-9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-(2-(4-(1H-tetrazol-1-yl)phenyl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methyl-4-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
9-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.6]dodecan-5-one;
(R)-8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
8-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-5-one;
(R)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(S)-4-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
4-(9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)furan-2(5H)-one;
(R)-5-(1-hydroxy-2-(4-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-4,9-diazaspiro

Assignees

• Merck Sharp & Dohme
• Pasternak Alexander
• Ding Fa-Xiang
• Dong Shuzhi
• Jiang Jinlong
• Tang Haifeng
• Gu Xin
• Dejesus Reynalda K
• Frie Jessica
• Fu Qinghong
• Suzuki Takao
• Pu Zhifa

Inventors

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

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K31/499

  Spiro-condensed pyrazines or piperazines · CPC title