Inhibitors of the renal outer medullary potassim channel

Patent metadata

Field	Value
Publication number	US-2016304515-A1
Application number	US-201415101467-A
Country	US
Kind code	A1
Filing date	Dec 16, 2014
Priority date	Dec 18, 2013
Publication date	Oct 20, 2016
Grant date	—

Abstract

The present invention provides compounds of Formula (I) (Formula (I)) including 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 having structural Formula I

or a pharmaceutically acceptable salt thereof wherein:
X is CHR 4 or a bond;
R 1 and R 2 are each independently of one another H, —OH, halogen, —C 1-4 alkyl optionally substituted with 1-9 halogens, —C 3-4 cycloalkyl, or —OC 1-4 alkyl optionally substituted with 1-9 halogens;
R 3 is H or —C 1-4 alkyl;
R 4 is H, —C 1-4 alkyl, or —OC 1-4 alkyl;
R 5 is —H, —OH, oxo, fluoro or —C 1-4 alkyl which is optionally substituted with 1-9 halogens;
Y is —CH 2 — or a bond;
The dashed line between rings A and B represents an optional double bond where rings A and B are fused;
A is a 6 or 7-membered heterocyclic ring having 1 or 2-N-atoms and optionally 1 double bond;
Z is a nitrogen atom or a carbon atom, where the carbon atom is unsubstituted when the A and B rings are fused by a double bond, or the carbon atom is substituted with —H when the A and B rings are fused by a single bond;
R 6 represents optional substituent groups on ring A which are each independently selected from the group consisting of —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
R 7 represents optional substituent groups on ring B which are each independently selected from the group consisting of -halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens
a and b are each independently 0 or an integer from 1-3;
B is a 5- or 6-membered heterocyclic, heteroaromatic or phenyl ring fused to ring A, wherein ring B optionally comprises 1-3 heteroatoms selected from O and N, including Z if Z is N, and wherein ring B optionally comprises one oxo group, and optionally comprises 1-3 double bonds including the optional double bond between rings A and B;
C is a cyclic or bicyclic group selected from
(a) Phenyl substituted with one group —CN or -tetrazole and optionally with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
(b) Pyridyl, pyrimidyl, pyrazinyl, pyridazolyl or thiazolyl substituted with one group —CN or -tetrazole, and optionally substituted with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
(c)

which is optionally substituted with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens;
(d)

which is optionally substituted with 1-3 groups independently selected from halogen, —C 1-3 alkyl optionally substituted with 1-7 halogens, and —OC 1-3 alkyl optionally substituted with 1-7 halogens; and
(e)

optionally substituted with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen.

2 . The compound of claim 1 having Formula II

or a pharmaceutically acceptable salt thereof wherein:
X is CHR 4 or a bond;
R 1 and R 2 are each independently H, F, —C 1-2 alkyl optionally substituted with 1-5 F, or —OC 1-2 alkyl optionally substituted with 1-5 F;
R 3 is H or —C 1-2 alkyl;
R 4 is H or —CH 3 ;
R 5 is —H, —OH, F or —CH 3 ;
Y is —CH 2 — or a bond;
The dashed line between rings A and B represents an optional double bond where rings A and B are fused;
A is a 6 or 7-membered heterocyclic ring having 1 or 2-N-atoms and optionally one double bond;
Z is a nitrogen atom or a carbon atom, wherein the carbon atom is unsubstituted when the A and B rings are fused by a double bond, or the carbon atom is substituted with —H, when the A and B rings are fused by a single bond;
B is a 5- or 6-membered heterocyclic, heteroaromatic or phenyl ring fused to ring A, wherein ring B optionally comprises 1-3 heteroatoms selected from O and N, including Z if Z is N, and ring B optionally comprises one oxo group, and optionally comprises 1-3 double bonds including the optional double bond between rings A and B; and
C is a cyclic or bicyclic group selected from
(a) Phenyl substituted with one group —CN or -tetrazole, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(b) Pyridyl substituted with one group —CN or -tetrazole and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(c)

optionally substituted on the phenyl ring with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen;
(d)

optionally substituted on the lactone ring with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen; and
(e)

optionally substituted with 1-2 groups selected from —CH 3 , —OCH 3 , and halogen.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 3 are each H or —CH 3 ; R 2 is H; R 4 is H or —CH 3 ; R 5 is —H or —OH; A is a 6 or 7-membered heterocyclic ring having 1 or 2-N-atoms and optionally one double bond; and C is a cyclic or bicyclic group selected from
(a) Phenyl substituted with one group —CN or -tetrazole, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(b) Pyridyl substituted with one group —CN, and optionally with 1-2 groups independently selected from —CH 3 , —OCH 3 , and halogen;
(c)

optionally substituted on the phenyl ring with one group selected from —CH 3 , —OCH 3 , and halogen;
(d)

optionally substituted on the lactone ring with one group —CH 3 ; and
(e)

optionally substituted with one group —CH 3 .

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, pyrimidine, pyrazole, imidazole, imidazoline, 1,2,4-triazole, 1,2,4-triazolone, 1,3-oxazole, oxazolidinone, pyrrolidine, pyridine, pyrazine, pyridazine, piperidine, piperazine, isoxazole, and pyrrolidinone optionally having a double bond.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, pyrimidine, pyrazole, imidazole, 1,2,4-triazole, 1,2,4-triazolone, 1,3-oxazole, oxazolidinone, pyrrolidine, and pyrrolidinone optionally having a double bond.

6 . The compound of claim 1 having a st

Assignees

• Chobanian Harry
• Pio Barbara
• Guo Yan
• Ding Fa-Xiang
• Dong Shuzhi
• Walsh Shawn P
• Jiang Jinlong
• Kim Dooseop
• Merck Sharp & Dohme

Inventors

• Chobanian Harry
• Pio Barbara
• Guo Yan
• Ding Fa-Xiang
• Dong Shuzhi
• Walsh Shawn P
• Jiang Jinlong
• Kim Dooseop

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/585

  containing lactone rings, e.g. oxandrolone, bufalin · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• A61K31/401

  Proline; Derivatives thereof, e.g. captopril · CPC title