Macrocyclic Heterocyclic Compound for Inhibiting Hepatitis C Virus and Preparation and Use Thereof

摘要

The present invention discloses a class of novel macro-heterocyclic compounds represented by the formula Ia or Ib, and their intermediates, preparation methods and the uses. The macro-heterocyclic compounds of the present invention have good inhibitory activities against hepatitis C virus (HCV), and can be used to treat HCV infection effectively by its excellent inhibition against HCV, low toxicity and side effects.;

主权项

1. A macro-heterocyclic compound of formula Ia or Ib, or its stereoisomer, tautomer, esterification or amidation prodrug, pharmaceutically acceptable salt or a mixture thereof: wherein: m=1 or 2; n=0, 1 or 2; “” is a single bond or double bond; E is oxygen, —NRa—, —CRbRc-, ethylidene, propylidene, C1-C6 alkoxyl, carbonyl, amino carbonyl or carbonyl amino group; Ra is selected from hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C2-C20 heterocyclic aryl, C1-C20 alkylcarbonyl, C1-C20 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C20 heterocyclic oxycarbonyl, aminocarbonyl, C1-C20 alkylaminocarbonyl, C1-C20 alkylaminosulfonyl, C2-C20 heterocyclic aminosulfonyl, or C6-C20 aryl-aminosulfonyl group; Rb and Rc are each independently selected from hydrogen, halogen atom, cyano, nitro, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxyl, C1-C20 alkylthio, C1-C20 alkoxycarbonyl, C6-C20 aryloxy, C6-C20 aryloxycarbonyl, C2-C20 heterocyclic-oxycarbonyl, C2-C20 heterocyclic aryl, C1-C20 alkylamino, C2-C20 heterocyclic amino, C6-C20 arylamino, aminocarbonyl, C1-C20 alkylaminocarbonyl, carbonylamino, C1-C20 alkylcarbonylamino, C1-C20 alkylsulfonamido, C2-C20 heterocyclic sulfonamido, C6-C20 arylsulfonamido or C1-C20 alkylamino-sulfonamido group; G is selected from oxygen, sulfur, sulfone, —NRa—, —OC(Rb)(Rc)-, —SC(Rb)(Rc)-, —N(Ra)C(Rb)(Rc)-, C1-C20 alkoxyl, C1-C20 alkylamino, C1-C20 alkyl-oxygen, C1-C20 alkyl, C1-C20 alkoxycarbonyl, carbonyl, carbonylamino or C1-C20 alkylcarbonylamino group; when R7 and R8 or R8 and R9 are connected each other as a cyclic structure, G is methylene or does not exist (i.e., “” connected directly with the phenyl group of polyheterocyclic group); wherein the definition of the Ra, Rb and Rc are the same as that in E; L and L1 are each independently selected from oxygen, sulfur, C2-C20 alkenyl, C1-C20 alkyl, C3-C20 cycloalkyl, C2-C20 heterocyclic, C6-C20 aryl, C3-C20 heterocyclic aryl, C1-C20 alkylthio, C1-C20 alkoxyl, C3-C20 cycloalkoxyl, C2-C20 heterocyclic oxyl, C1-C20 alkylamino, C1-C20 alkoxycarbonyl, C6-C20 aryl, or C6-C20 aryloxy group; U is selected from carbonyl, sulfoxide (—SO—), sulfone (—SO2—), —P(O)(ORd)- or —B(ORe)-; Wherein Rd and Re are independently selected from hydrogen (H), C1-C20 alkyl, C3-C20 cycloalkyl, C2-C20 heterocyclic, C6-C20 aryl, or C3-C20 heterocyclic alkyl group; W is selected from oxygen or sulfur; X is selected from oxygen, sulfur, nitrogen or —NRa—; wherein the definition of Ra is the same as that in E and G; Y is selected from nitrogen or CH; Z is selected from hydrogen (H), hydroxyl (OH), amino (NH2), C1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyl, C3-C20 cycloalkoxyl, C1-C20 alkylamino, C3-C20 cycloalkylamino, C2-C20 heterocyclic amino, C6-C20 aryl, C6-C20 arylamino, C3-C20 heterocyclic arylamino, C1-C20 alkylsulfonamido, C3-C20 cycloalkylsulfonamido, C6-C20 arylsulfonamido, C1-C20 alkylaminosulfonamido, C3-C20 cycloalkylaminosulfonamido, C6-C20 aryloxysulfonamido, C1-C20 alkylaminosulfonamido, C3-C20 cycloalkylaminosulfonamido, C6-C20 arylaminosulfonamido, uramido, C1-C20 alkyluramido, or C1-C20 alkylthiouramido group; R1 is selected from hydrogen (H), C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C3-C20 heterocyclic aryl, C1-C20 alkylsulfonamido, C2-C20 heterocyclic sulfonamido, or C1-C20 alkoxylcarbonylamino group; R2 is selected from hydrogen (H), C1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyl, C3-C20 cycloalkoxyl, C6-C20 aryl, C3-C20 heterocyclic aryl, C6-C20 aryloxycarbonyl, C1-C20 alkylsulfonyl, C3-C20 cycloalkylsulfonyl, C1-C20 alkoxysulfonyl, C3-C20 cycloalkoxysulfonyl, C6-C20 arylsulfonyl, C6-C20 aryloxysulfonyl, C1-C20 alkylaminosulfonyl, C3-C20 cycloalkylaminosulfonyl, or C6-C20 arylaminosulfonyl group; R3, R4, R5 and R6 are each independently selected from hydrogen, halogen atom, hydroxyl, cyano, nitro, C1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyl, C1-C20 alkylamino, C2-C20 heterocyclic amino, C6-C20 aryl, C6-C20 arylamino, C1-C20 alkylsulfonamido, C2-C20 heterocyclic sulfonamido, C6-C20 arylsulfonamido or C1-C20 aminosulfonamido group; wherein the R3 and R4 can be connected as a cyclic structure; R7, R8 and R9 are each independently selected from hydrogen, halogen atom, cyano, nitro, trifluoromethyl, C1-C20 alkyl, C1-C20 alkoxyl, C1-C20 alkylthio, C1-C20 alkoxylcarbonyl, aminocarbonyl, C1-C20 alkylaminocarbonyl, carbonylamino, C1-C20 alkylcarbonylamino, C2-C20 heterocyclicoxyl carbonyl, C6-C20 aryl, C6-C20 aryloxy, C6-C20 aryloxycarbonyl or C2-C20 heterocyclic group; wherein R7 and R8 or R8 and R9 can be connected each other as a cyclic structure; R10 is selected from hydrogen, halogen atom, cyano, nitro, trifluoromethyl, C1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyl, C1-C20 alkylthio, C1-C20 alkoxylcarbonyl, C1-C20 alkylaminocarbonyl, C1-C20 alkylcarbonylamino, C6-C20 aryl, C6-C20 aryloxy, C6-C20 aryloxycarbonyl or C2-C20 heterocyclic group; and R11 is selected from hydrogen (H), C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C6-C12 aryl, C3-C12 heterocyclic aryl group.