Neprilysin inhibitors

A method of treating hypertension, heart failure, or renal disease in a subject in need thereof, comprising administering to the subject an AT1 receptor antagonist and an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from H, —C1-8alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R10, —C1-6alkylene-NR11R12, —C1-6alkylene-C(O)R13, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,
• R10 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O— phenyl, —NR11R12, —CH(R15)—NH2, —CH(R15)—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3;
• R11 and R12 are independently selected from H, —C1-6alkyl, and benzyl;
• or R11 and R12 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2O(CH2)2—;
• R13 is selected from —O—C1-6alkyl, —O-benzyl, and —NR11R12;
• R14 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
• R15 is H, —CH3, —CH(CH3)2, phenyl, or benzyl;
• R2 is —OR21 or —CH2OR21;
• and R3 is H or —CH3;
• wherein R21 is H, —C(O)—C1-6alkyl, —C(O)—CH(R22)—NH2, —C(O)—CH(R22)—NHC(O)O—C1-6alkyl, or —P(O)(OR23)2;
• R22 is H, —CH3, —CH(CH3)2, phenyl, or benzyl;
• R23 is H, —C1-6alkyl, or phenyl;
• or
• R2 is taken together with R1 to form —OCR15R16— or —CH2O—CR15R16—, and R3 is selected from H and —CH3, wherein R15 and R16 are independently selected from H, —C1-6alkyl, and —O-C3-7cycloalkyl, or R15 and R16 are taken together to form ═O;
• or
• R2 is taken together with R3 to form —CH2—O—CH2— or —CH2—CH2—;
• or
• R2 and R3 are both —CH3;
• Z is selected from —CH— and —N—;
• R4 is selected from H, —C1-8alkyl, —C1-3alkylene-O—C1-8alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-O—C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R40, —C1-6alkylene-NR41R42, —C1-6alkylene-C(O)R43, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,
• R40 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR41R42, —CH(R45)—NH2, —CH(R45)—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3;
• R41 and R42 are independently selected from H, —C1-6alkyl, and benzyl;
• or R41 and R42 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2O(CH2)2—;
• R43 is selected from —O—C1-6alkyl, —O— benzyl, and —NR41R42;
• R44 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
• R45 is H, —CH3, —CH(CH3)2, phenyl, or benzyl;
• a is 0 or 1;
• R5 is selected from halo, —CH3, —CF3, and —CN;
• b is 0 or an integer from 1 to 3;
• and each R6 is independently selected from halo, —OH, —CH3, —OCH3, —CN, and —CF3;
• wherein each alkyl group in R1 and R4 is optionally substituted with 1 to 8 fluoro atoms;
• and
• wherein the methylene linker on the biphenyl is optionally substituted with one or two —C1-6alkyl groups or cyclopropyl.