| 主权项 |
1. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I: or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof, wherein: A is a bond, —O—, —S(O)n—, —NH—, —N((C1-C4)alkyl)- or (C1-C2)alkylene; A1 is —CR9═CR9—, wherein B is arylene, heteroarylene, cycloalkylene or heterocycloalkylene; A2 is —CH(R8)-arylene, —CH(R8)-heteroarylene, —CH(R8)-heterocycloalkylene, —CH(R8)-cycloalkylene, arylene, heteroarylene or cycloalkylene, wherein A2 is optionally substituted with one or more substituents selected from the group consisting ofoxo, —OR9, —SR9, —S(O)R9, —S(O)2R9, —N(R9)2, halo, halo(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, halo(C1-C4)alkoxy, cyano and (C1-C8)alkyl;
X1 is a bond, —O—, —NH—, —N((C1-C4)alkyl)- or heterocycloalkylene; R1 and R2 are independently H, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, halo, cyano or (C1-C4)alkanoyl; or R1 and R2, when taken together with the carbon to which they are both attached, form —C(═O)—, —C(═S)— or —C(═N(C1-C4)alkyl)-; R3 is H or (C1-C4)alkyl which is optionally substituted with halo, cyano, hydroxy or (C1-C8)alkoxy; R4a and R4b are independently H, (C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, heterocycloalkyl, heterocycloalkyl(C1-C4)alkyl, cycloalkyl or cycloalkyl(C1-C4)alkyl, wherein each of R4a and R4b is optionally substituted with one or more substituent selected from the group consisting of cyano, (C1-C8)alkoxy, —COOH, —C(O)O—(C1-C8)alkyl, halo, hydroxyl, amino, mono(C1-C8)alkylamino, di(C1-C8)alkylamino, —C(O)-mono(C1-C8)alkylamino, —C(O)-di(C1-C8)alkylamino, —C(O)-heterocycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein each substituent is optionally substituted with one or more halo, heterocycloalkyl or aryl; R5a and R5b are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, aryl, heterocycloalkyl, cycloalkyl, aryl(C1-C4)alkyl, cycloalkyl(C1-C4)alkyl or heterocycloalkyl(C1-C4)alkyl, wherein R5a and R5b are independently optionally substituted with one or more substituent selected from the group consisting of —N3, cyano, —COOH, halo, hydroxyl, amino, mono(C1-C8)alkylamino, di(C1-C8)alkylamino, aryl and heteroaryl, or R5a and R5b together form a spirocycle having Formula (a): wherein one or more carbon ring atoms of Formula (a) is optionally replaced by a nitrogen, oxygen or sulfur atom, and wherein a ring atom of Formula (a) is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, —NH2, —C(O)O—(C1-C8)alkyl, —C(O)-di(C1-C8)alkylamino, —C(O)—(C1-C8)alkyl, —C(O)-heterocycloalkyl, —S(O)2R10, —OSi(R10)3, (C1-C4)alkyl, cyano(C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C8)alkanoyl and aryl(C1-C4)alkyl; R6a, R6b, R7a and R7b are independently H, hydroxyl, cyano, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, —CH2CH2CR9(═N(C1-C4)alkoxy), aryl, heterocycloalkyl, cycloalkyl, —SR9, —S(O)R9, —S(O)2R9 or —N(R9)2, wherein each of R6a, R6b, R7a and R7b is optionally substituted with one or more substituent selected from the group consisting of halo, hydroxyl, cyano, (C1-C4)alkyl, (C1-C8)alkoxy, aryl, cycloalkyl, heterocycloalkyl, mono(C1-C8)alkylamino, di(C1-C8)alkylamino, —NHS(O)R9, —NHC(O)R9, —OC(O)—(C1-C8)alkyl-C(O)O—(C1-C8)alkyl and (C1-C8)alkanoyl, wherein each —OC(O)C1-C8)alkyl or (C1-C8)alkoxy is optionally substituted with one or more amino, —OC(O)O—(C1-C8)alkyl or —Si(R10)3; or R6a and R6b together form a spirocycle having Formula (a); each R8 is independently H, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, wherein R8 is optionally substituted with —OR, —N(R9)2, —CON(R9)2 or cyano; each R9 is independently H, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl; each R10 is independently H, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, cycloalkyl(C1-C4)alkyl or aryl, wherein R10 is optionally substituted with one or more halo; each n is independently 0, 1 or 2; and m is 1, 2, 3, 4 or 5. |
