# US 9,751,881 B2 · Inhibitors of the renal outer medullary potassium channel

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- Number: US 9,751,881 B2
- Document ID: US9751881B2
- Status: Granted
- Kind: B2
- Application number: 14/908,222
- Filed: 2014-07-28
- Published: 2016-07-21
- Granted: 2017-09-05
- Earliest claimed: 2013-07-31
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Haifeng Tang; Barbara Pio; Jinlong Jiang; Alexander Pasternak; Shuzhi Dong; Ronald Dale Ferguson, II; Zack Zhiqiang Guo; Harry Chobanian; Jessica Frie; Yan Guo; Zhicai Wu; Yang Yu; Ming Wang
- Web page: https://patentgrep.com/patent/US9751881B2

## CPC

- C07D 471/10: Spiro-condensed systems
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 451/00: 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
- C07D 493/04: Ortho-condensed systems
- C07D 498/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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

### Claim 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;
R1 is H, alkyl, —F, —OR, or —N(R13)(R14);
R2 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R3 is H or alkyl;
R4 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R5 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
or R4 and R5 are joined together to represent —CH2CH2-, —CH2NCH2-, —CH2N(CH3)CH2- or —CH2OCH2-;
R6 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
or R6 and R1 are joined together to represent —CH2CH2O—;
R7 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
R8 is independently H or alkyl;
R8′ is H or alkyl;
R9 is —CN, tetrazolyl, or —S(O)2R13;
R10 is halo, —OR, alkyl optionally substituted by 1-5 halogen atoms or —OR, —S-alkyl, —N-alkyl or —O-cyclopropyl;
R11 is —CN, —S(O)2R13, or optionally substituted heteroaryl wherein the optional substituent is halogen or alkyl;
R12 is H, halo, alkyl, cycloalkyl, or —OR;
R13 is H, alkyl, allyl or cycloalkyl;
R14 is H, alkyl or cycloalkyl;
R15 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.

### Claim 2 (depends on 1)

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;
R1 is H, alkyl, —F, —OR, or —N(R13)(R14);
R2 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R3 is H or alkyl;
R4 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
R5 is H or alkyl optionally substituted by 1-5 halogen atoms or —OR;
or R4 and R5 are joined together to represent —CH2CH2-, —CH2NCH2-, —CH2N(CH3)CH2- or —CH2OCH2-;
R6 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
or R6 and R1 are joined together to represent —CH2CH2O—;
R7 is H, halo, alkyl optionally substituted by 1-5 halogen atoms or —OR, cycloalkyl or —OR;
R8 is independently H or alkyl;
R8′ is H or alkyl;
R9 is —CN, tetrazolyl, or —S(O)2R13;
R10 is halo, —OR, alkyl optionally substituted by 1-5 halogen atoms or —OR, —S-alkyl, —N-alkyl or —O-cyclopropyl;
R11 is —CN, —S(O)2R13, or optionally substituted heteroaryl, wherein the optional subsitutent is halogen or alkyl;
R12 is H, halo, alkyl, cycloalkyl, or —OR;
R13 is H, alkyl, allyl or cycloalkyl;
R14 is H, alkyl or cycloalkyl;
R15 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.

### Claim 3 (depends on 1)

The compound as defined in claim 1, which has the formula
or a pharmaceutically acceptable salt thereof
wherein:
Z is

### Claim 4 (depends on 1)

The compound as defined in claim 1, which has the formula:
or a pharmaceutically acceptable salt thereof
wherein:
Ra 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.

### Claim 5 (depends on 1)

The compound as defined in claim 1, which has the formula
or a pharmaceutically acceptable salt thereof
wherein
Ra 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.

### Claim 6 (depends on 1)

The compound as defined in claim 1, which has the formula:
or a pharmaceutically acceptable salt thereof
wherein:
Ra 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.

### Claim 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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 1)

A method for inhibiting ROMK comprising administering in a patient in need thereof an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof.