Neprilysin inhibitors

A compound of formula I:

• where:
• R1 is —OR16 or —NR60R70;
• R2 is H or —OR20;
• R3 is selected from H, Cl, F, —CH3, and —CF3;
• X is a —C1-10heteroaryl or a partially unsaturated —C2-12heterocycle, with the proviso that X is not pyrazole;
• R4 is absent or is selected from H;
• halo;
• —C0-5alkylene-OH;
• —NH2;
• —C1-6 alkyl;
• —CF3;
• —C3-7cycloalkyl;
• —C0-2alkylene-O—C1-6alkyl;
• —C(O)R40;
• —C0-1alkylene-C(O)OR41;
• —C(O)NR42R43;
• —NHC(O)R44;
• ═O;
• —NO2;
• furan;
• pyrazine;
• naphthalene;
• pyridine;
• pyrazole optionally substituted with methyl;
• thiophene optionally substituted with methyl;
• and phenyl optionally substituted with one group selected from halo, —OH, —CF3, —OCH3, —NHC(O)CH3, and phenyl;
• and R4, when present, is attached to a carbon atom;
• and R4 can also be phenyl substituted with —C(O)OR41 when X is pyridazine, pyrazine, or pyridine;
• R5 is absent or is selected from H;
• —C1-6 alkyl;
• —C0-3 alkylene-OH;
• —[(CH2)2O]1-3CH3;
• —C1-3 alkylene-C(O)OR50;
• —CH2—C(O)NR51R52;
• —C0-2alkylene-pyridine optionally substituted with halo;
• —CH2-isoxazole optionally substituted with methyl;
• —CH2-pyrimidine optionally substituted with —O—C1-6alkyl;
• —C2alkylene-phenyl;
• and R5, when present, is attached to a nitrogen atom;
• R6 is absent or is selected from H, halo, —OH, —C1-6alkyl, and —O—C1-6 alkyl;
• and R6, when present, is attached to a carbon atom;
• R10, R41 and R50 are independently selected from H, —C1-6alkyl, —C1-3alkylene-C6-10aryl, —C1-3alkylene-C1-9heteroaryl, —C3-7cycloalkyl, —[(CH2)2O]1-3CH3, —C1-6alkylene-OC(O)R13, —C1-6alkylene-NR14R15, —C1-6alkylene-C(O)R17, —C0-6alkylenemorpholine, —C1-6alkylene-SO2—C1-6alkyl,
• R13 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR14R15, and —CH(NH2)CH2COOCH3;
• R14 and R15 are independently selected from H, —C1-6alkyl, and benzyl, or R14 and R15 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2—O—(CH2)2—;
• R16 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
• R17 is selected from —O—C1-6alkyl, —O-benzyl, and —NR14R15;
• R20 is H or is taken together with R10 to form —CR21R22— or is taken together with R60 to form —C(O)—;
• R21 and R22 are independently selected from H, —C1-6alkyl, and —O—C3-7cycloalkyl, or R21 and R22 are taken together to form ═O;
• R40 is H or —C1-6alkyl;
• R42, R43, R51, and R52 are independently selected from H, —C1-6alkyl, —CH2COOH, —(CH2)2OH, —(CH2)2OCH3, —(CH2)2SO2NH2, —(CH2)2N(CH3)2, —C3-7cycloalkyl, and —(CH2)2-imidazole;
• or R42 and R43 or R52 and R53 are taken together to form a saturated or partially unsaturated —C3-5heterocycle optionally substituted with —OH, —COOR41, or —CONH2, and optionally containing an oxygen atom in the ring;
• R44 is selected from —C1-6alkyl;
• —C0-1alkylene-O—C1-6alkyl;
• phenyl optionally substituted with halo or —OCH3;
• and —C1-9heteroaryl;
• and
• R53, R54, R55, R56, and R57 are independently selected from H, halo, —C1-6alkyl, —O—C1-6alkyl, and —S—C1-6alkyl, where each —C1-6alkyl is optionally substituted with 1-5 fluoro atoms;
• R60 is selected from H, —OH, —OC(O)R61, —CH2COOH, —O-benzyl, pyridyl, and —OC(S)NR62R63;
• where R61 is selected from H, —C1-6alkyl, —C6-10aryl, —OCH2—C6-10aryl, —CH2O—C6-10aryl, and —NR62R63;
• R62 and R63 are independently H or —C1-4alkyl;
• R70 is selected from H, —C1-6alkyl, and —C(O)R71;
• R71 is selected from H, —C1-6alkyl, —C3-7cycloalkyl, —C6-10aryl, and —C1-9heteroaryl;
• or a pharmaceutically acceptable salt thereof.