Inhibitors of the renal outer medullary potassium channel

Patent metadata

Field	Value
Publication number	US-9751881-B2
Application number	US-201414908222-A
Country	US
Kind code	B2
Filing date	Jul 28, 2014
Priority date	Jul 31, 2013
Publication date	Sep 5, 2017
Grant date	Sep 5, 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

The invention claimed is:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof,

wherein:
Z is

 where is a single or double bond;
R is independently H, alkyl or haloalkyl;
R 1 is H, alkyl, —F, —OR, or —N(R 13 )(R 14 );
R 2 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R 3 is H or alkyl;
R 4 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R 5 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
or R 4 and R 5 are joined together to represent —CH 2 CH 2 -, —CH 2 NCH 2 -, —CH 2 N(CH 3 )CH 2 - or —CH 2 OCH 2 -;

R 6 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
or R 6 and R 1 are joined together to represent —CH 2 CH 2 O—;

R 7 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
R 8 is independently H or alkyl;
R 8′ is H or alkyl;
R 9 is —CN, tetrazolyl, or —S(O) 2 R 13 ;
R 10 is halo, —OR, alkyl optionally substituted by 1-5 halogen atoms or —OR, —S-alkyl, —N-alkyl or —O-cyclopropyl;
R 11 is —CN, —S(O) 2 R 13 , or optionally substituted heteroaryl wherein the optional substituent is halogen or alkyl;
R 12 is H, halo, alkyl, cycloalkyl, or —OR;
R 13 is H, alkyl, allyl or cycloalkyl;
R 14 is H, alkyl or cycloalkyl;
R 15 independently oxo, —F, —CN, alkyl optionally substituted by 1-5 fluroine atoms or —OR, cycloalkyl, heteroaryl optionally substituted by halogen, —CN, alkyl or haloalkyl;
a is 1 or 2; and
n is 0, 1 or 2.

2. The compound as defined in claim 1 ,
or a pharmaceutically acceptable salt thereof,

wherein:
Z is

 where is a single or double bond;
R is independently H, alkyl or haloalkyl;
R 1 is H, alkyl, —F, —OR, or —N(R 13 )(R 14 );
R 2 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R 3 is H or alkyl;
R 4 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R 5 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
or R 4 and R 5 are joined together to represent —CH 2 CH 2 -, —CH 2 NCH 2 -, —CH 2 N(CH 3 )CH 2 - or —CH 2 OCH 2 -;

R 6 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
or R 6 and R 1 are joined together to represent —CH 2 CH 2 O—;

R 7 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
R 8 is independently H or alkyl;
R 8′ is H or alkyl;
R 9 is —CN, tetrazolyl, or —S(O) 2 R 13 ;
R 10 is halo, —OR, alkyl optionally substituted by 1-5 halogen atoms or —OR, —S-alkyl, —N-alkyl or —O-cyclopropyl;
R 11 is —CN, —S(O) 2 R 13 , or optionally substituted heteroaryl, wherein the optional subsitutent is halogen or alkyl;
R 12 is H, halo, alkyl, cycloalkyl, or —OR;
R 13 is H, alkyl, allyl or cycloalkyl;
R 14 is H, alkyl or cycloalkyl;
R 15 independently oxo, —F, —CN, alkyl optionally substituted by 1-5 fluorine atoms or —OR, cycloalkyl, heteroaryl optionally substituted by halogen, —CN, alkyl or haloalkyl;
a is 1; and
n is 0, 1 or 2.

3. The compound as defined in claim 1 , which has the formula

or a pharmaceutically acceptable salt thereof
wherein:
Z is

4. The compound as defined in claim 1 , which has the formula:

or a pharmaceutically acceptable salt thereof

wherein:
R a is H, —F, —CN, alkyl optionally substituted by 1-5 fluorine atoms or —OR, or cycloalkyl; and
Z is

 where is a single or double bond.

5. The compound as defined in claim 1 , which has the formula

or a pharmaceutically acceptable salt thereof

wherein
R a is H, —F, —CN, alkyl optionally substituted by 1-5 fluorine atoms or —OR, or cycloalkyl; and
Z is

 where is a single or double bond.

6. The compound as defined in claim 1 , which has the formula:

or a pharmaceutically acceptable salt thereof

wherein:
R a is H, —F, —CN, alkyl optionally substituted by 1-5 fluorine atoms or —OR, or cycloalkyl; and
Z is

 where is a single or double bond.

7. A compound which is:
(R)-5-(1-Hydroxy-2-(2-(5-(methylsulfonyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;
(R)-5-(1-Hydroxy-2-(2-(5-(methylsulfonyl)pyrazin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)ethyl)-4-methylisobenzofuran-1(3H)-one;
(R)-8-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(5-(methylsulfonyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-3-one;
(R)-8-(2Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisbenzofuran-5-yl)ethyl)-2-(5-(methylsulfonyl)pyrazin-2-yl)-2,8-diazaspiro[4.5]decan-3-one;
(R)-6-(9-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-4-methoxynicotinonitrile;
(R)-8-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(5-(methylsulfonyl)pyrazin-2-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;
(R)-6-(8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2,8-diazaspiro[4.5]decan-2-yl)nicotinonitrile;
(R)-5-(8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2,8-diazaspiro[4.5]decan-2-yl)pyrazine-2-carbonitrile;
(R)-6-(9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyrimidine-4-carbonitrile;
or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition as defined in claim 8 , which further comprises a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of 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 pharmaceutically acceptable salt of any of the foregoing.

10. A method for inhibiting ROMK comprising administering in a patient in ne

Assignees

• Merck Sharp & Dohme

Inventors

• Tang Haifeng
• Pio Barbara
• Jiang Jinlong
• Pasternak Alexander
• Dong Shuzhi
• Ferguson Ii Ronald Dale
• Guo Zack Zhiqiang
• Chobanian Harry
• Frie Jessica
• Guo Yan
• Wu Zhicai
• Yu Yang
• Wang Ming

Classifications

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• C07D451/00

  Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title