| 摘要 |
In one aspect, the invention relates to compounds having the formula:;
where R1, R2a, R2b, R3—R6, a, b, Z, and X 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 processes and intermediates for preparing such compounds. |
| 主权项 |
1. A compound of formula 1:where R1 is selected from the group consisting of —OR7 and —NR8R9;
R2a is selected from the group consisting of —OH, —OP(O)(OH)2, and —OC(O)CH(R37)NH2, and R2b is —CH3; or R2a and R2b are taken together to form —CH2—CH2—; or R2a is taken together with R7 to form —OCR18R19— or is taken together with R8 to form —OC(O)—; Z is selected from the group consisting of —CH— and —N—; a is 0 or 1; R5 is selected from the group consisting of halo, —CH3, —CF3, and —CN; b is 0 or an integer from 1 to 3; each R6 is independently selected from the group consisting of halo, —OH, —CH3, —OCH3, and —CF3; R7 is selected from the group consisting of H; —C1-8alkyl; —C1-3alkylene-C6-10aryl; —C1-3alkylene-C1-9heteroaryl; —C3-7cycloalkyl; —[(CH2)2O]1-3CH3; —C1-6alkylene-OC(O)R10; —C1-6alkylene-NR12R13; —C 1-6alkylene-C(O)R31; —C0-6alkylenemorpholinyl; —C1-6alkylene-SO2—C1-6alkyl; R10 is selected from the group consisting of —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR12R13, —CH[CH(CH3)2]—NH2, —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3; and R12 and R13 are independently selected from the group consisting of H, —C1-6alkyl, and benzyl, or R12 and R13 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2O(CH2)2—; R31 is selected from the group consisting of —O—C1-6alkyl, —O-benzyl, and —NR12R13; and R32 is —C1-6alkyl or —C0-6alkylene-C6-10aryl; R8 is selected from the group consisting of H, —OH, —OC(O)R14, —CH2COOH, —O-benzyl, pyridyl, and —OC(S)NR15R16; R14 is selected from the group consisting of H, —C1-6alkyl, —C6-10aryl, —OCH2—C6-10aryl, —CH2O—C6-10aryl, and —NR15R16; and R15 and R16 are independently selected from the group consisting of H and —C1-4alkyl; R9 is selected from the group consisting of H, —C1-6alkyl, and —C(O)R17; and R17 is selected from the group consisting of H, —C1-6alkyl, —C3-7cycloalkyl, —C6-10aryl, and —C1-9heteroaryl; R18 and R19 are independently selected from the group consisting of H, —C1-6alkyl, and —O—C3-7cycloalkyl, or R18 and R19 are taken together to form ═O; R37 is selected from the group consisting of H, —CH(CH3)2, phenyl, and benzyl; each alkyl group in R1 is optionally substituted with 1 to 8 fluoro atoms; and; the methylene linker on the biphenyl is optionally substituted with one or two —C1-6alkyl groups or cyclopropyl; and P1 is H or an amino-protecting group selected from the group consisting of t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl; or a salt thereof. |
