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US 2017/0283416 A1Published application
Inhibitors of the renal outer medullary potassium channel
AssigneeMerck Sharp & Dohme Corp.
InventorsFa-Xiang Ding, Shuzhi Dong, Jinlong Jiang, Takao Suzuki, Joseph P. Vacca, Shouning Xu
Life of this patent
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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.
Claims19
A compound having structural Formula I:
- or a pharmaceutically acceptable salt thereof wherein:
- R1 is —H, —F, —OH, —C1-3alkyl or —OC1-3alkyl;
- R2 is —H, or C1-4alkyl;
- R3 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F;
- R4 is —H, or —C1-3alkyl optionally substituted with —OH, —OCH3 or 1 to 3 of —F;
- R5 is —H, halo, —C3-6cycloalkyl or —C1-3alkyl;
- R6 is —H or —C1-3alkyl when the dashed bond is absent, or R6 is absent when the dashed bond is a double bond;
- n is zero where R6 is absent, or one where R6 is present;
- Z is
- Y1, Y2, Y3 and Y4 are each independently selected from C(R7) or N;
- provided that at most two of Y1, Y2, Y3 and Y4 are N;
- each R7 is independently —H, halo, C1-4alkyl optionally substituted with 1-3 of —F, or OC1-4alkyl;
- R8 is —H, halo, or C1-4alkyl optionally substituted with 1-3 of —F;
- R9 is —H, C1-4alkyl optionally substituted with 1-3 of —F, or halo;
- and
- R10 is —H or C1-4alkyl.
13 more elements
A compound which is:
- 8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]decan-1-one;
- (R)-8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]decan-1-one;
- 8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]decan-1-one;
- (R)-8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]decan-1-one;
- (S)-8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]decan-1-one;
- 8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]dec-3-en-1-one;
- (R)-8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]dec-3-en-1-one;
- (S)-8-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]dec-3-en-1-one;
- 8-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)-2-hydroxyethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]dec-3-en-1-one;
- 8-(2-(6-(1H-tetrazol-1-yl)pyridazin-3-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,3,8-triazaspiro[4.5]dec-3-en-1-one;
- or a pharmaceutically acceptable salt thereof.
8 more elements
Dependencies are inferred from the claim text.