Inhibitors of the renal outer medullary potassium channel

• US 9,839,629 B2
• Filed: 12/19/2014
• Issued: 12/12/2017
• Est. Priority Date: 12/24/2013
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Dong, Shuzhi, Pasternak, Alexander, Gu, Xin, Fu, Qinghong, Jiang, Jinlong, Ding, Fa-Xiang, Tang, Haifeng, DeJesus, Reynalda K., Suzuki, Takao
• Primary Examiner(s): Bernhardt, Emily
• Application Number:
  US15/101,481
• Publication Number:
  US 20160324833A1
• Time in Patent Office: 1,089 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 498/10 Spiro-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Novel spirocyclic compounds of formula I: and pharmaceutically acceptable salts thereof are disclosed as 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. Pharmaceutical compositions and methods of treatment are also included.

Claims

1. A compound of the formula I:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

X is

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R and R′

are independently H or CH₃.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, or 2.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are each H, or R² and R³ together form oxo.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH₂.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^c is CH₃, CH₂CH₃, or cyclopropyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Z is

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^b is H, CH₃, or OCH₂CH₃.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

m is 1,

n is 1,

R¹ is OH,

R², R³, R⁴, and R⁵ are each independently is H,

R^d is tetrazolyl, and

Y is CH₂.

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

14. The pharmaceutical composition of claim 13 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 pharmaceutically acceptable salt of any of the foregoing.

15. A method for causing diueresis, natriuresis or both, comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.

16. A method for the treatment of one or more disorders selected from hypertension, acute heart failure, chronic heart failure, or pulmonary arterial hypertension comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a patient in need thereof.

12. A compound which is:

5-{2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;

4-methyl-5-{2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;

3-methyl-4-(9-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;

(R)-3-(9-(2-methoxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

5-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

5-{(1R)-1-hydroxy-2-[9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

6-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methoxypyridine-3-carbonitrile;

(3R)-6-{1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;

(3S)-6-{(1R)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;

(3S)-6-{(1S)-1-hydroxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-3-methyl-3,4-dihydro-1H-isochromen-1-one;

4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridazin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridazin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2R)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;

9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;

9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-hydroxy-2-(2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl)ethyl)-3-(5-oxo-2,5-dihydrofuran-3-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one;

5-{(1R)-1-hydroxy-2-[8-methyl-9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[8-methyl-9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-2-[(7R)-7-fluoro-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-2-[(7S)-7-fluoro-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

4-{9-[2-(4-bromophenyl)-2-hydroxyethyl]-3,9-diazaspiro[5.5]undec-3-yl}-3-methylfuran-2(5H)-one;

5-{(1R)-1-hydroxy-2-[9-(2-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-2-[9-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

3-fluoro-4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

5-{(1R)-2-[9-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[9-(5-oxo-4-phenyl-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[9-(5-oxo-4-pyridin-4-yl-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

3-cyclopropyl-4-(9-{2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

5-{(1R)-2-[9-(4-cyclopropyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

4-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-hydroxyethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-hydroxy-1-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{2-hydroxy-1-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[3-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[3-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyridin-4-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)pyridin-4-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[5-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyrazin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[6-(1H-tetrazol-1-yl)pyrazin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2R)-2-hydroxy-2-[4-(1H-tetrazol-1-yl)pyridin-2-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

4-(9-{(2S)-2-hydroxy-2-[2-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-3-methylfuran-2(5H)-one;

3-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;

3-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;

5-{(1R)-1-hydroxy-2-[9-(3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

3-(9-{2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)cyclopent-2-en-1-one;

3-(9-{(2R)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;

3-(9-{(2S)-2-hydroxy-2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;

5-{(1R)-1-hydroxy-2-[9-(2-methyl-3-oxocyclopent-1-en-1-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

3-(9-{(2R)-2-hydroxy-2-[2-methyl-4-(1H-tetrazol-1-yl)phenyl]ethyl}-3,9-diazaspiro[5.5]undec-3-yl)-2-methylcyclopent-2-en-1-one;

3-{9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl}-3,9-diazaspiro[5.5]undec-3-yl]-4-methylcyclobut-3-ene-1,2-dione;

(R)-3-ethyl-4-(9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;

(R)-3-cyclopropyl-4-(9-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobut-3-ene-1,2-dione;

(R)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(S)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(S)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(R)-3-(9-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(S)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(R)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyrazin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(S)-3-(9-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(R)-3-(9-(2-hydroxy-2-(tetrazolo[1,5-a]quinolin-7-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

(S)-3-(9-(2-hydroxy-2-(tetrazolo[1,5-a]quinolin-7-yl)ethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methylcyclobut-3-ene-1,2-dione;

5-{(1S)-1-methoxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-methoxy-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-2-[9-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[9-(6-oxo-3,6-dihydro-2H-pyran-4-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[(7R)-7-hydroxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[(7R)-7-(methoxymethoxy)-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[(7S)-7-(methoxymethoxy)-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[(7R)-7-methoxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

5-{(1R)-1-hydroxy-2-[(7S)-7-methoxy-9-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one;

4-(9-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{[2,6-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{[5-fluoro-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{[3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl]carbonyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-(9-{[2,5-difluoro-4-(1H-tetrazol-1-yl)phenyl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

4-methyl-5-{2-oxo-2-[9-(5-oxo-2,5-dihydrofuran-3-yl)-3,9-diazaspiro[5.5]undec-3-yl]ethyl}-2-benzofuran-1(3H)-one;

4-(9-{[5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetyl}-3,9-diazaspiro[5.5]undec-3-yl)furan-2(5H)-one;

or

a pharmaceutically acceptable salt thereof.