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 salt thereof, wherein: B1—ZB— is B1—CHR1CH2—, B1—CHR1C(O)—, B1—C(O)—, B1—CHR1CH2C(O)—, B1—OCH2C(O)—, or B1—CH(CH2OH)—; —ZA-A1 is CHR21CR2R22-A1, —CH═CR2-A1, —C≡C-A1, —S-A1, —CH2O-A1, —C(O)CHR2-A1, —O-A1, —NHCHR2-A1, —CH2N(CH3)CH2CH(OH)-A1, —CH2N(CH3)CH(CH2OH)-A1, —CH2N(CH3)-A1, —CH2S-A1, —CH2O-A1, CH2S(O)-A1, —CH2S(O2)-A1, or —NH-A1; A1 is B1 is X is O or S; R1 is —H, —C1-6 alkyl, —C3-6 cycloalkyl, CF3, —OH, F, —CH2OH, —C(O)OH, —C(O)OC1-6 alkyl, or R1 may be joined with R13b by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring; R2 is —H, —C1-6 alkyl, —C3-6 cycloalkyl, CF3, —OH, F, —CH2OH, —C(O)OH, —C(O)OC1-6 alkyl, or R2 may be joined with R13a by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring; R4 is H, —OH, F, —O—C1-6 alkyl, or —C1-6 alkyl, or may be joined with R5 by a bond, or by 1-4 carbon atoms, to form a ring; R5 is H, —OH, F, —O—C1-6 alkyl, or —C1-6 alkyl, or may be joined with R4 by a bond, or by 1-4 carbon atoms to form a ring; R6 is H, —C(O)OCH3, C(O)OCH2CH3, —OC(O)CH3—CH2OH, —OH, —CHF3, —N(CH3)2, —CH3, —C6H5, or F; R13a is —H, —C1-6 alkyl, —C3-6 cycloalkyl, -halogen, CF3, —CH2OH, —CO2R16a, —OR16a, —SR16a, —CN, -aryl, -heterocycle, —NR16aR18a, or R13a may be joined with R2 by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring, or R13a may be joined with R14a by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring; R13b is —H, —C1-6 alkyl, —C3-6 cycloalkyl, -halogen, CF3, —CH2OH, —CO2R16b, —OR16b, —SR16b, —CN, -aryl, -heterocycle, —NR16bR18b, or R13b may be joined to R1 by 2-3 carbon atoms or 1-2 carbon atoms and one heteroatom to form a ring, or R13b may be joined to R14b by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring; R14a is —H, —C1-6 alkyl, —C3-6 cycloalkyl, -halogen, CF3, —CH2OH, —CO2R17a, —OR17a, —SR17a, —CN, -aryl, -heterocycle, or R14a may be joined to R13a by 3-4 carbon atoms or 2-3 carbon atoms and one heteroatom to form a ring; R14b is —H, —C1-6 alkyl, —C3-6 cycloalkyl, -halogen, CF3, —CH2OH, —CO2R17b, —OR17b, —SR17b, —CN, -aryl, -heterocycle, or R14b may be joined to R13b by 3-4 carbon atoms or 2-3 carbon atoms and one heteratom to form a ring; R15a is —H, halogen, —C1-6 alkyl, C3-6 cycloalkyl, —OC1-6 alkyl, or —CF3; R15b is —H, halogen, —C1-6 alkyl, C3-6 cycloalkyl, —OC1-6 alkyl, or —CF3; R16a, R16b, R17a, R17b, R18a, and R18b are independently —H, —C1-6 alkyl, or —C3-6 cycloalkyl; R19 and R20 are H, or may be joined by a bond or 1-2 carbon atoms, to form a 4-5-membered ring; and R21 and R22 are H, or, together with carbon atom to which they are attached, form —C3-6 cycloalkyl.