| 主权项 |
1. A process for preparing a compound of formula I:or a pharmaceutically acceptable salt thereof, comprising the step of coupling a compound of formula 1 with a compound of formula 2:to produce the compound of formula I; where
R1 is selected from —OR7 and —NR8R9; R2 is H or —P(O)(OH)2 or R2 is taken together with R7 to form —CR18R19— or is taken together with R8 to form —C(O)—; X is a —C1-9heteroaryl; R3 is absent or is selected from H; halo; —C0-5alkylene-OH; —NH2; —C1-6alkyl; —CF3; —C3-7cycloalkyl; —C0-2alkylene-O—C1-6alkyl; —C(O)R20; —C0-1alkylene-COOR21; —C(O)NR22R23; —NHC(O)R24; ═O; —NO2; —C(CH3)═N(OH); phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF3, —OCH3, —HC(O)CH3, and phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazole optionally substituted with methyl; thiophenyl optionally substituted with methyl or halo; furanyl; and —CH2-morpholinyl; and R3, when present, is attached to a carbon atom; R4 is absent or is selected from H; —OH; —C1-6alkyl; —C1-2alkylene-COOR35; —CH2OC(O)CH(R36)NH2; —OCH2OC(O)CH(R36)NH2; —OCH2OC(O)CH3; —CH2OP(O)(OH)2; —CH2CH(OH)CH2OH; —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl; pyridinyl; and phenyl or benzyl optionally substituted with one or more groups selected from halo, —COOR35, —OCH3, —OCF3, and —SCF3; and R4, when present, is attached to a carbon or nitrogen atom; or R3 and R4 are taken together to form -phenylene-O—(CH2)1-3— or -phenylene-O—CH2—CHOH—CH2—; a is 0 or 1; R5 is selected from halo, —CH3, —CF3, and —CN; b is 0 or an integer from 1 to 3; each R6 is independently selected from halo, —OH, —CH3, —OCH3, and —CF3; R7 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-NR12R13, —C1-6alkylene-C(O)R31, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,R10 is selected from —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 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—; and R31 is selected from —O—C1-6alkyl, —O-benzyl, and —NR12R13; R32 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
R8 is selected from H, —OH, —OC(O)R14, —CH2COOH, —O-benzyl, pyridyl, and —OC(S)NR15R16; R14 is selected from H, —C1-6alkyl, —C6-10aryl, —OCH2—C6-10aryl, —CH2O—C6-10aryl, and —NR15R16; and R15 and R16 are independently selected from H and —C1-4alkyl; R9 is selected from H, —C1-6alkyl, and —C(O)R17; and R17 is selected from H, —C1-6alkyl, —C3-7cycloalkyl, —C6-10aryl, and —C1-9heteroaryl; R18 and R19 are independently selected from H, —C1-6alkyl, and —O—C3-7cycloalkyl, or R18 and R19 are taken together to form ═O; R20 is selected from H and —C1-6alkyl; R21 and R35 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)R25, —C1-6alkylene-NR27R28, —C1-6alkylene-C(O)R33, —C0-6alkylenemorpholinyl, —C1-6alkylene-SO2—C1-6alkyl,R25 is selected from —C1-6alkyl, —O—C1-6alkyl, —C3-7cycloalkyl, —O—C3-7cycloalkyl, phenyl, —O-phenyl, —NR27R28, —CH[CH(CH3)2]—NH2, —CH[CH(CH3)2]—NHC(O)O—C1-6alkyl, and —CH(NH2)CH2COOCH3; R27 and R28 are independently selected from H, —C1-6alkyl, and benzyl; or R27 and R28 are taken together as —(CH2)3-6—, —C(O)—(CH2)3—, or —(CH2)2O(CH2)2—; R33 is selected from —O—C1-6alkyl, —O-benzyl, and —NR27R28; and R34 is —C1-6alkyl or —C0-6alkylene-C6-10aryl;
R22 and R23 are independently selected from H, —C1-6alkyl, —CH2COOH, —(CH2)2OH, —(CH2)2OCH3, —(CH2)2SO2NH2, —(CH2)2N(CH3)2, —C0-1alkylene-C3-7cycloalkyl, and —(CH2)2-imidazolyl; or R22 and R23 are taken together to form a saturated or partially unsaturated —C3-5heterocycle optionally substituted with halo, —OH, —COOH, or —CONH2; and optionally containing an oxygen atom in the ring; R24 is selected from —C1-6alkyl; —C0-1alkylene-O—C1-6alkyl; phenyl optionally substituted with halo or —OCH3; and —C1-9heteroaryl; and R36 is selected from H, —CH(CH3)2, phenyl, and benzyl;where each alkyl group in R1, R3, and R4 is optionally substituted with 1 to 8 fluoro atoms; and;where the methylene linker on the biphenyl is optionally substituted with one or two —C1-6alkyl groups or cyclopropyl;P1 is H or an amino-protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl; and where the process further comprises deprotecting the compound of formula 1 when P1 is an amino protecting group. |
