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 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 conditions associated with excessive salt and water retention.

主权项

1. A compound having structural Formula I:or a pharmaceutically acceptable salt thereof wherein:
X is O or NH; p is an integer selected from 1 (one) or 2 (two), and q is an integer selected from 1 (one) or 2 (two), provided that only one of p and q can be 2; Z1 is R1 is —H or —C1-4alkyl; R2 is —H, —F, —Cl, —C1-6alkyl, —C3-6cycloalkyl or —OC1-4alkyl; R3 is —H, —F, —Cl, —CN, —C1-6alkyl, —C3-6cycloalkyl, OC1-4alkyl or N-tetrazolyl optionally substituted with —CH3; R4 is —H, —F, —Cl, —CN, —C1-6alkyl, —C3-6cycloalkyl, —OC1-4alkyl or N-tetrazolyl optionally substituted with —CH3; or R3 and R4 are joined together with the phenyl ring to which they are attached to form a bicyclic ring system that is:  wherein R is —H or —C1-4alkyl; R5 is —H, —F, —Cl, —CN, —C1-4alkyl, —C3-6cycloalkyl or —OC1-4alkyl; provided that when R3 and R4 are not joined together, then either
(a) one of R3, R4 or R5 is —CN and the others are not —CN, or(b) one of R3 or R4 is N-tetrazolyl optionally substituted with —CH3 and the other is not N-tetrazolyl optionally substituted with —CH3; R6 is —H or —C1-6alkyl; Z2 is n is an integer selected from 1 (one) or 2 (two); m is an integer selected from 1 (one) or 2 (two); R2a is —H, —F, —Cl, —C1-6alkyl, —C3-6cycloalkyl or —OC1-4alkyl; R3a is —H, —F, —Cl, —CN, —C1-6alkyl, —C3-6cycloalkyl, —OC1-4alkyl or N-tetrazolyl optionally substituted with —CH3; R4a is —H, —F, —Cl, —CN, —C1-6alkyl, —C3-6cycloalkyl, —OC1-4alkyl or N-tetrazolyl optionally substituted with —CH3; or R3a and R4a are joined together with the phenyl ring to which they are attached to form:  wherein Ra is —H or —C1-4alkyl; R5a is —H, —F, —Cl, —CN, —C1-4alkyl, —C3-6cycloalkyl or —OC1-4alkyl; provided that when R3a and R4a are not joined together, then either
(a) only one of R3a, R4a or R5a is —CN and the others are not —CN, or(b) only one of R3a or R4a is N-tetrazolyl optionally substituted with —CH3 and the other is not N-tetrazolyl optionally substituted with —CH3; R7 is independently at each occurrence —H or —C1-3alkyl; R8 is —H, —F, —Cl, —C1-6alkyl, —C3-6cycloalkyl or —OC1-4alkyl; R9 is —H, —F, —Cl, —CN, —C1-6alkyl, —C3-6cycloalkyl or —OC1-4alkyl; R10 is —H or —CH3; and R11 is —H or —CH3.