Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-2018016263-A1
Application number	US-201615545891-A
Country	US
Kind code	A1
Filing date	Feb 8, 2016
Priority date	Feb 12, 2015
Publication date	Jan 18, 2018
Grant date	—

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

1 . A compound of the formula:

wherein X is N or CR b ;
Z is O or CH 2 ;

A is

or a six-membered aromatic ring containing one or two nitrogen atoms which is optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl;
R 1 is H, OH or O(C 1-3 alkyl);
R 2 is H or C 1-3 alkyl;
R 4 is H or C 1-3 alkyl;
R 5 is H or C 1-3 alkyl;
R 6 is H or C 1-3 alkyl;
R 7 is H, C 1-3 alkyl or O(C 1-3 alkyl);
R a is H or C 1-3 alkyl;
R b is H, OH, C 1-3 alkyl or (C═O)OC 1-3 alkyl;
R x is H, halo, C 1-3 alkyl or O(C 1-3 alkyl);
n is 0, 1 or 2;
- - - - is an optional bond;
or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 wherein

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 of the formula

wherein

A is

or a six-membered aromatic ring containing one or two nitrogen atoms which is optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl;
R 1 is H, OH or O(C 1-3 alkyl);
R 2 is H or C 1-3 alkyl;
R 4 is H or C 1-3 alkyl;
R 5 is H or C 1-3 alkyl;
R 6 is H or C 1-3 alkyl;
R 7 is H or O(C 1-3 alkyl);
R a is H or C 1-3 alkyl;
R b is H, OH, C 1-3 alkyl or (C═O)OC 1-3 alkyl;
R x is H, halo, C 1-3 alkyl or O(C 1-3 alkyl);
or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 wherein A
is

pyridinyl, pyrazinyl or pyridazinyl, wherein said pyridinyl, pyrazinyl or pyridazinyl are optionally substituted with one or two substituents independently selected from the group consisting of tetrazolyl and C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 wherein R 1 is OH, or a pharmaceutically acceptable salt thereof.
The compound of any of claims 1 to 6 wherein R 2 is H or methyl; or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 wherein R 2 is H or methyl; or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 1 wherein R 4 is H or methyl; or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 selected from:
3-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
1-((3S,4S)-1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-((3R,4R)-1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one,
3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
3-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
3-(1-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
3-(1-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
(R)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
(S)-1-(1-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
4-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
4-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
4-(3-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-1-1-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)pyrrolidin-2-one;
1-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-((R)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-((S)-2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(3-oxocyclopent-1-en-1-yl)imidazolidin-2-one;
(R)-1-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
(R)-1-(1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;
1-(1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;
1-(3-fluoro-1-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(3-fluoro-1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-methoxypiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3-methoxypiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3-fluoropiperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)imidazolidin-2-one;
1-(1-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)piperidin-4-yl)-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)tetrahydropyrimidin-2(1H)-one;
1-(1-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxy

Assignees

• Pasternak Alexander
• Frie Jessica
• Dong Shuzhi
• Suzuki Takao
• Xu Shouning
• Merck Sharp & Dohme

Inventors

• Pasternak Alexander
• Frie Jessica
• Dong Shuzhi
• Suzuki Takao
• Xu Shouning

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title