Inhibitors of the Renal Outer Medullary Potassium Channel

摘要

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 act as diuretics and natriuretics and are valuable pharmaceutically active compounds for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension and conditions resulting from excessive salt and water retention.

主权项

1. A compound having structural Formula I: or a pharmaceutically acceptable salt thereof wherein: Z1 is wherein the dashed bonds represent the optional presence of —C1-2alkanediyl- which, when present, forms a 5 to 6 membered carbocyclic ring which is fused to the aryl ring; Z2 is R1 is —H, —CH3, —CF3, —CHF2, —CH2F or —CH2OH; R2 is —H, oxo (═O) or —C1-6alkyl; R4 is —H, —OH, oxo or —C1-6alkyl;
provided that when R4 is —OH or oxo, then R2 is not oxo; R3 and R5 are each independently —H or —C1-6alkyl; provided that R3 is absent when R2 is oxo, and R5 is absent when R4 is oxo; R1a is —H, halo or —C1-3alkyl; R1b is —H, halo, —C1-3alkyl, —O—C1-3alkyl or —COOC1-3alkyl; one of R2a and R2b is —CN and the other is —H or —C1-3alkyl; one of R2c and R2d is —SO2—C1-3alkyl and the other is —H or —C1-3alkyl; X1, X2, X3 and X4 are each independently CH or N, provided that only one of X1, X2, X3 or X4 is N; X5, X6 and X7 are each independently CH or N, provided that only one of X5, X6 or X7 is N; and Ra and Rb are each independently —H, halo, —C1-3alkyl, —O—C1-3 alkyl or —COOC1-3alkyl.