Inhibitors of the renal outer medullary potassium channel

摘要

This invention relates to compounds having structural Formula I:;
and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

主权项

1. A compound having structural Formula I: or a pharmaceutically acceptable salts thereof wherein: represents a heterocyclic ring selected from the group consisting of: Z1 is selected from the group consisting of: Z2 is selected from the group consisting of: X is selected from the group consisting of —H, —OH, —OC1-3alkyl, —F, oxo, NH2, and —CH3; Y is selected from the group consisting of —H, —OH, —OC1-3alkyl, —F, oxo, NH2, and —CH3; X1 and Y1 are each independently selected from the group consisting of —H and —CH3; X2 and Y2 are each —O—; provided that when X is oxo then X1 is absent and when Y is oxo then Y1 is absent; and further provided that when neither X2 nor Y2 is present, then at least one of X and Y is selected from the group consisting of —OH, —OC1-3alkyl, —F and oxo; R1 and R2 are each independently selected from the group consisting of —H, -halo, —C3-C6cycloalkyl, —OR8, —SR8, —SOR8, —SO2R8, —(CH2)nOR8 and C1-C6alkyl optionally substituted with 1-3 of —F; one of R3a and R3b is selected from the group consisting of —CN and —NO2 and the other is Re; one of R4a and R4b is selected from the group consisting of —CN and —NO2 and the other is Rf; R5 and R6 are each independently selected from the group consisting of —H, —C1-6 alkyl, —C3-6 cycloalkyl, —CF3, —CHF2, —CH2F and —CH2OH; R7 is selected from the group consisting of —H, —CH3, —CF3, —CHF2, —CH2F and —CH2OH; Ra and Rb are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C1-6 alkyl optionally substituted with 1-3 of —F, (d) —C3-6 cycloalkyl, (e) —OC1-3alkyl optionally substituted with 1-3 of —F, (f) —OR8, (g) —CO2C1-6alkyl optionally substituted with 1-3 of —F, (h) —(CH2)nOR8, (i) —SR8, (j) —SOR8, (k) —SO2R8, (l) —NHCOR8 and (m) —NHSO2R8; Rc and Rd are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C1-6 alkyl optionally substituted with 1-3 of —F, (d) —C3-6 cycloalkyl, (e) —OC1-3alkyl optionally substituted with 1-3 of —F, (f) —OR8, (g) —CO2C1-6alkyl optionally substituted with 1-3 of —F, (h) —(CH2)nOR8, (i) —SR8, (j) —SOR8, (k) —SO2R8, (l) —NHCOR8 and (m) —NHSO2R8; Re and Rf are each independently selected from the group consisting of (a) —H, (b) halo, (c) —C1-6 alkyl optionally substituted with 1-3 of —F, (d) —C3-6 cycloalkyl, (e) —OC1-3alkyl optionally substituted with 1-3 of —F, (f) —OR8, (g) —CO2C1-6alkyl optionally substituted with 1-3 of —F, (h) —(CH2)nOR8, (i) —SR8, (j) —SOR8, (k) —SO2R8, (l) —NHCOR8 and (m) —NHSO2R8; n is an integer selected from 1, 2 and 3;and R8 is independently selected at each occurrence from the group consisting of —H, —C3-6cycloalkyl and —C1-6alkyl optionally substituted with 1-3 of —F.