IP Library › Granted Patent US 9,951,052

Granted Patent B2

US 9,951,052 · App. 15/032,174 · Granted Apr 24, 2018

Inhibitors of the renal outer medullary potassium channel

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Quick Facts

Patent No.: US 9,951,052
App. No.: 15/032,174
Granted: Apr 24, 2018
Kind: B2

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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.

Claims (79)

1. A compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein R 1 is:

wherein each heterocyclic ring is optionally substituted on an available ring carbon with —C 1-3 alkyl, —OC 1-3 alkyl, —C 3-4 cycloalkyl, —OC 3-4 cycloalkyl or —CN; and

R i is selected from —H or phenyl optionally substituted with C 1-3 alkyl or halo;

R 2 is —H or —C 1-6 alkyl;

R 3 is —H, —OH, —F or —NH 2 ;

R 4 is —H, —OH, oxo, —F or —C 1-6 alkyl;

R 5 is —H, halo or —C 1-3 alkyl optionally substituted with one to three of —F;

R 6 is —H, halo, —O—C 1-3 alkyl, —C(O)OC 1-3 alkyl or —C 1-3 alkyl optionally substituted with one to three of —F; and

the dashed line “- - -” represents the presence or absence of a bond.

2. A compound having structural Formula I

or a pharmaceutically acceptable salt thereof wherein;

R 1 is

R 2 is —H or —C 1-3 alkyl;

R 3 is —H, —F or —NH 2 ;

R 4 is —H or —OH;

R 5 is —H, halo, —CH 3 or —CF 3 ;

R 6 is —H;

R 7 is —H, —C 1-3 alkyl or —OC 1-3 alkyl;

R 8 is —H, —C 1-3 alkyl or —OC 1-3 alkyl; and

the dashed line “- - -” represents the presence or absence of a bond.

3. The compound of claim 1 selected from:

N-(4-cyano-1-(4-fluorophenyl)-1H-pyrrol-2-yl)-1-(2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidine-4-carboxamide;

1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isoxazol-4-yl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-4-yl)piperidine-4-carboxamide;

(R)-N-(4-cyanothiazol-2-yl)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazolo[4,3-c]pyridin-3-yl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxamide;

(R)-N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methylisothiazol-5-yl)piperidine-4-carboxamide;

(R)-4-hydroxy-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-5-yl)piperidine-4-carboxamide;

(R)-4-hydroxy-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methylisothiazol-5-yl)piperidine-4-carboxamide;

(R)-4-hydroxy-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)piperidine-4-carboxamide;

1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)-N-methylpiperidine-4-carboxamide;

1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)-N-trideuteromethylpiperidine-4-carboxamide;

(R)-N-ethyl-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-5-yl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-methyl-N-(3-methylisothiazol-5-yl)piperidine-4-carboxamide;

(R)-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-N-methylpiperidine-4-carboxamide;

4-amino-1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)piperidine-4-carboxamide;

4-fluoro-1-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)piperidine-4-carboxamide;

(R)-4-fluoro-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methylisothiazol-5-yl)piperidine-4-carboxamide;

(R)-5-(2-(4-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carbonyl)-4-fluoropiperidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1 (3H)-one;

(R)-4-fluoro-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-4-yl)piperidine-4-carboxamide;

(R)-4-fluoro-1-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(1,2,3-thiadiazol-5-yl)piperidine-4-carboxamide;

3-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-N-(isothiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methylisothiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-4-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(isothiazol-5-yl)-N-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide; or

3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-methyl-N-(3-methyl-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

4. A compound selected from:

(R)-1-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)piperidine-4-carboxamide;