Neprilysin inhibitors

摘要

In one aspect, the invention relates to compounds having the formula:;
where R1, R2, R3, R4, and R5 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

主权项

1. A compound of formula (Ib-1):where:
R1 is —OR10 or —NR60R70; R3 is selected from H, Cl, F, —CH3, and —CF3; R4 is selected from H; —C1-6alkyl; —C2-3alkylene-OH; —[(CH2)2O]1-3CH3; —C1-3alkylene-C(O)OR40; —CH2—C(O)NR41R42; —C0-2alkylene-pyridine optionally substituted with halo; —CH2-isoxazole optionally substituted with methyl; —CH2-pyrimidine optionally substituted with —O—C1-6 alkyl; —C2 alkylene-phenyl; R5 is selected from H; halo; —C0-5alkylene-OH; —NH2; —C1-6alkyl; —CF3; —C3-7cycloalkyl; —C0-2alkylene-O—C1-6alkyl; —C(O)R50; —C0-1alkylene-C(O)OR51; —C(O)NR52R53; —NHC(O)R54; —NO2; furan; pyrazine; naphthalene; pyridine; pyrazole optionally substituted with methyl; thiophene optionally substituted with methyl; and phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF3, —OCH3, —NHC(O)CH3, and phenyl; R10, R40, and R51 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, —C1-6 alkylene-NR14R15, —C1-6 alkylene-C(O)R17, —C0-6alkylenemorpholine, —C1-6 alkylene-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)2O(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; R41, R42, R52, and R53 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 R41 and R42 or R52 and R53 are taken together to form a saturated or partially unsaturated —C3-5heterocycle optionally substituted with —OH, —COOR40, or —CONH2, and optionally containing an oxygen atom in the ring; R43, R44, R45, R46, and R47 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; R50 is H or —C1-6alkyl; and R54 is selected from —C1-6alkyl; —C0-1alkylene-O—C1-6alkyl; phenyl optionally substituted with halo or —OCH3; and —C1-9heteroaryl; R60 is selected from H, —OH, —OC(O)R61, —CH2COOH, —O-benzyl, pyridyl, and —OC(S)NR62R63; R61 is selected from H, —C1-6alkyl, —C6-10aryl, —OCH2—C6-10aryl, —CH2O—C6-10aryl, and —NR62R63; R62 and R63 are independently selected from H and —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.