Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-9926317-B2
Application number	US-201515323985-A
Country	US
Kind code	B2
Filing date	Jul 9, 2015
Priority date	Jul 14, 2014
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

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:
Z is

X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 4 ) and N, provided that at least one and at most two of X 1 , X 2 , X 3 and X 4 are N;
R 1 is —H, halo, —OH, or —OC 1-3 alkyl;
R 2 is —H, ═O, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 3a is —H, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F;
R 3b is —H or —C 1-3 alkyl, or R 3b is absent when the dashed bond is a double bond;
or R 3a and R 3b are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
each R 4 is independently —H, halo, —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with OH or 1-3 of —F;
R 5 is —H, halo, or —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl;
R 6 is —H or —C 1-3 alkyl;
R 7 is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F, or R 7 is absent when n is zero;
R 8 is —H or —C 1-3 alkyl, or R 8 is absent when n is zero;
or R 7 and R 8 are joined together with the carbon to which they are both attached to form cyclopropyl or cyclobutyl;
R 9 is —H, halo, —OH, —C 1-3 alkyl, —OC 1-3 alkyl or —CH 2 OH;
R 10 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
R 11 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
or R 10 and R 11 are joined together to represent —CH 2 —CH 2 —, —CH 2 —N(CH 3 )—CH 2 — or —CH 2 OCH 2 —;
R 12 , R 13 and R 14 are each independently —H, halo, —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with —OH or 1-3 of —F;
m is zero where R 3b is absent, or one where R 3b is present;
the partially dashed double bond (“ ”) represents a single or double bond wherein:
(i) when m is one, then the dashed bond is a single bond; and
(ii) when m is zero and R 2 is not ═O, then the dashed bond is a double bond; and

n is zero or one.

2. The compound having structural Formula Ia

or a pharmaceutically acceptable salt thereof wherein:
Z is

X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 4 ) and N, provided that at least one and at most two of X 1 , X 2 , X 3 and X 4 are N;
R 1 is —H, halo, —OH, or —OC 1-3 alkyl;
R 2 is —H, ═O, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 3a is —H, —C 3-4 cycloalkyl or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F;
each R 4 is independently —H, halo, —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with OH or 1-3 of —F;
R 5 is —H, halo, or —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl;
R 6 is —H or —C 1-3 alkyl;
R 7 is —H or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 or 1 to 3 of —F, or R 7 is absent when n is zero;
R 8 is —H or —C 1-3 alkyl, or R 8 is absent when n is zero;
R 9 is —H, halo, —OH, —C 1-3 alkyl, —OC 1-3 alkyl or —CH 2 OH;
R 10 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
R 11 is —H, or —C 1-3 alkyl optionally substituted with —OH, —OCH 3 , or 1 to 3 of —F;
R 12 and R 13 are each independently —H, halo, —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with —OH or 1-3 of —F; and
n is zero or one.

3. The compound of claim 1 wherein:
Z is

one of X 1 or X 2 is C(R 4 ) and the other is N;
R 1 is —H, halo, —OH, or —OC 1-3 alkyl;
R 2 is —H, ═O, —OH, —C 1-3 alkyl or —OC 1-3 alkyl;
R 3a is —H or —C 1-3 alkyl optionally substituted with —OCH 3 or 1 to 3 of —F;
each R 4 is independently —H, halo, or —C 1-4 alkyl optionally substituted with OH or 1-3 of —F;
R 5 is —H, halo, or —C 1-3 alkyl optionally substituted with —O—C 1-3 alkyl;
R 6 is —H or —C 1-3 alkyl;
R 7 is —H or —C 1-3 alkyl, or R 7 is absent when n is zero;
R 8 is —H, or R 8 is absent when n is zero;
R 9 is —H, —F, —OH, —C 1-3 alkyl, —OC 1-3 alkyl or —CH 2 OH;
R 10 is —H, or —C 1-3 alkyl;
R 11 is —H, or —C 1-3 alkyl;
R 12 , R 13 and R 14 are each independently —H, halo, —CN, —C 3-6 cycloalkyl, —C(O)OC 1-4 alkyl, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with —OH or 1-3 of —F; and
n is zero or one;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein:
R 1 is —H or halo;
R 2 is —H;
R 3a is —H or —C 1-3 alkyl;
each R 4 is —H;
R 5 is —H, halo, or —C 1-3 alkyl;
R 6 is —H or —C 1-3 alkyl;
R 7 is —H, or R 7 is absent when n is zero;
R 8 is —H, or R 8 is absent when n is zero;
R 9 is —H, —F, —OH, —C 1-3 alkyl, —OC 1-3 alkyl or —CH 2 OH;
R 10 is —H;
R 11 is —H;
R 12 , R 13 and R 14 are each independently —H, halo, —OC 1-4 alkyl, or —C 1-4 alkyl optionally substituted with —OH or 1-3 of —F; and
n is zero or one;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 9 is —OH; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein n is one; or a pharmaceutically acceptable salt thereof.

7. A compound which is:
8-(2-(4-(2H-tetrazol-2-yl)phenyl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
8-(2-(4-(4H-1,2,4-triazol-4-yl)phenyl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
8-(2-(6-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
(S)-8-(2-(4-(2H-tetrazol-2-yl)phenyl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
(S)-8-((S)-2-(4-(2H-tetrazol-2-yl)phenyl)-2-hydroxyethyl)-3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
(S)-8-((R)-2-(4-(2H-tetrazol-2-yl)phenyl)-2-hydroxyethyl)-3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one;
or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 further comprising an additional active agent selected from losartan, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan, amlodipine, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril, amiloride, spironolactone, epleranone or triamterene, or a pro-drug thereof, or a pharmaceutically acceptable salt of any of the foregoing.

10. A method for inhibiting ROMK comprisi

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Pasternak Alexander
• Davies Ian
• Ding Fa-Xiang
• Jiang Jinglong
• Dong Shuzhi
• Gu Xin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title