CN111116577A

CN111116577A - Fused tetracyclic compounds and application thereof in medicines

Info

Publication number: CN111116577A
Application number: CN201911034847.0A
Authority: CN
Inventors: 任青云; 黄建洲; 刘洋; 张英俊; 李中乐
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd; Guangdong HEC Pharmaceutical
Priority date: 2018-10-30
Filing date: 2019-10-29
Publication date: 2020-05-08

Abstract

The invention relates to a condensed tetracyclic compound and application thereof in medicaments, in particular to medicaments for treating and/or preventing hepatitis BThe application of the compound is provided. Specifically, the invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein variables are defined in the specification. The invention also relates to the application of the compound shown in the general formula (I) or the stereoisomer, the tautomer, the nitrogen oxide, the solvate, the metabolite, the pharmaceutically acceptable salt or the prodrug thereof as a medicament, in particular to the application as a medicament for treating and/or preventing hepatitis B.

Description

Fused tetracyclic compounds and application thereof in medicines

Technical Field

The invention belongs to the field of medicines, and relates to a fused tetracyclic compound and application thereof as a medicine, in particular to application of the fused tetracyclic compound as a medicine for treating and/or preventing hepatitis B. The invention also relates to compositions of these fused tetracyclic compounds with other antiviral agents, and their use for the treatment and/or prevention of Hepatitis B Virus (HBV) infection.

Background

Hepatitis b virus belongs to the hepadnaviridae family. It can cause acute and/or persistent progressive chronic disease. Hepatitis b virus also causes many other clinical manifestations in pathological morphology-in particular chronic inflammation of the liver, cirrhosis and canceration of hepatocytes. Estimated by the world health organization, there are 20 million people worldwide infected with HBV, about 3.5 million people with chronic infection, and about 100 million people per year die of liver failure, cirrhosis, and primary hepatocellular carcinoma (HCC) due to HBV infection.

Interferon α (IFN- α), pegylated IFN- α and 5 nucleotide analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir) are approved by the united states Food and Drug Administration (FDA) for clinical treatment.

Therefore, there is still a need for new compounds that can be effectively used as antiviral drugs, especially as drugs for the treatment and/or prevention of hepatitis b in the clinic.

Disclosure of Invention

The invention relates to a novel fused tetracyclic compound and application thereof in preparing medicaments for treating and preventing HBV infection. The inventor finds that the novel condensed tetracyclic compound has the advantages of better pharmacokinetic property, good solubility, small toxicity, good stability of liver microsome, good inhibitory activity on generation or secretion of HBsAg and replication of HBV DNA and the like, and has good application prospect in the aspect of anti-HBV. In particular, the compounds of the present invention, and the pharmaceutically acceptable compositions thereof, are also effective in inhibiting HBV infection.

In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I), or a prodrug thereof,

wherein R is¹Is R^1aO-or R^aR^bN-；

X₁is-CH₂-、-CH₂O-or-CH₂CH₂-；

X is N or CH;

R²is R⁸-(C＝O)-、R^8aO-(C＝O)-、C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl, heterocyclic radical consisting of 3-10 ring atoms, C_6-10Aryl or heteroaryl of 5 to 10 ring atoms, wherein said C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl, heterocyclic radical consisting of 3-10 ring atoms, C_6-10Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w1Substituted;

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-C_1-4Alkylene radical, C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein R is¹⁰-C_1-4C in alkylene_1-4Alkylene radical, C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w2Substituted;

R^8ais hydrogen, deuterium, HO-, C_1-6Alkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl and C_3-6Cycloalkyl is each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R⁸is hydrogen, deuterium, HO-, R^aR^bN-、C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl or heteroaryl of 5 to 10 ring atoms, wherein C is_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R¹⁰is hydrogen,Deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl or heteroaryl of 5 to 10 ring atoms, wherein C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium, F, Cl, Br, C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl, thiazolyl or heterocyclyl consisting of 3 to 10 ring atoms, wherein said C is_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl, thiazolyl and heterocyclyl consisting of 3-10 ring atoms each independently being unsubstituted or substituted with 1,2,3 or 4R^w4Substituted;

each R^1a、R^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_6-10Aryl, heterocyclyl of 3 to 6 ring atoms or heteroaryl of 5 to 10 ring atoms, wherein C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_6-10Aryl, heterocyclyl of 3 to 6 ring atoms and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w5Substituted;

each R^w1、R^w2、R^w3、R^w4And R^w5Independently is deuterium, F, Cl, Br, HO-, HOOC-, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_3-7Cycloalkyl, wherein said amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl and C_3-7Cycloalkyl is independently of one another unsubstituted or substituted by 1,2,3 or 4 substituents selected from the group consisting of F, Cl, Br, CN, HO-, -O, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy or C_1-6Substituted by alkylamino;

n is 0,1, 2,3 or 4.

In some embodiments, R is described herein²Is R⁸-(C＝O)-、R^8aO-(C＝O)-、C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein said C is_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w1Substituted;

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-C_1-3Alkylene radical, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein R is¹⁰-C_1-3C in alkylene_1-3Alkylene radical, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w2Substituted;

wherein each R is⁸、R^8a、R¹⁰、R^w1And R^w2Have the meaning as described in the present invention.

In some embodiments, R is described herein²Is R⁸-(C＝O)-、R^8aO-(C＝O)-、C_2-4Alkenyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C is C_2-4Alkenyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R^w1Substituted;

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-CH₂-、R¹⁰-(CH₂)₂-、R¹⁰-(CH₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyriOxazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein R is¹⁰-CH₂-CH of (A-O-)₂-、R¹⁰-(CH₂)₂In- (CH)₂)₂-、R¹⁰-(CH₂)₃In- (CH)₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w2Substituted;

In some embodiments, R is described herein^8aIs hydrogen, deuterium, HO-, C_1-4Alkyl or C_3-6Cycloalkyl, wherein said C_1-4Alkyl and C_3-6Cycloalkyl is each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R⁸is hydrogen, deuterium, HO-, R^aR^bN-、C_1-4Alkyl radical, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl or heteroaryl consisting of 5 to 6 ring atoms, wherein said C_1-4Alkyl radical, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl and heteroaryl consisting of 5 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R¹⁰is hydrogen, deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein C is_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium, F, Cl, Br, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl, thiazolyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein said C is_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl, thiazolyl and heterocyclyl consisting of 3-6 ring atoms each independently being unsubstituted or substituted by 1,2,3 or 4R^w4Substituted;

wherein each R is^a、R^b、R^w3And R^w4Have the meaning as described in the present invention.

In some embodiments, R is described herein^8aIs hydrogen, deuterium, HO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R⁸is hydrogen, deuterium, HO-, R^aR^bN-, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinylPyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, and the like, Piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R^w3Substituted;

R¹⁰is hydrogen, deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, thiazyl, and the like, Pyridazinyl or pyrimidinyl wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxyYl, 2-methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently of the others being unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C is_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w4Substituted;

In some embodiments, each R described herein^1a、R^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, phenyl, heterocyclyl consisting of 3 to 6 ring atoms, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein said C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, phenyl, heterocyclyl consisting of 3 to 6 ring atoms, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w5Substituted;

each R^w1、R^w2、R^w3、R^w4And R^w5Independently is deuterium, F, Cl, Br, HO-, HOOC-, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_2-4Alkenyl radical, C_2-4Alkynyl, phenyl or C_3-6Cycloalkyl, wherein said amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylamino radical, C_2-4Alkenyl radical, C_2-4Alkynyl, phenyl and C_3-6Cycloalkyl is independently of one another unsubstituted or substituted by 1,2,3 or 4 substituents selected from the group consisting of F, Cl, Br, CN, HO-, -O, amino, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Haloalkoxy or C_1-4Substituted by alkylamino.

In some embodiments, each R described herein^1a、R^aAnd R^bEach independently of the others hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, and the like,Imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothionyls, Tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4R^w5Substituted;

each R^w1、R^w2、R^w3、R^w4And R^w5Independently deuterium, F, Cl, Br, HO-, HOOC-, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, C_1-3Alkylthio radical, C_1-3Alkylamino, ethenyl, propenyl, allyl, ethynyl, propargyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein said amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, C_1-3Alkylthio radical, C_1-3Alkylamino, ethenyl, propenyl, allyl, ethynyl, propargyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, HO-, ═ O, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Alkylthio group、C_1-3Haloalkoxy or C_1-3Substituted by alkylamino.

In another aspect, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant or a combination of said adjuvants.

In some embodiments, the pharmaceutical composition of the present invention further comprises an additional anti-HBV agent.

In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

In some embodiments, the pharmaceutical composition of the invention, wherein the other anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, famciclovir, interferon, calamine CP, intefine, interferon α -1b, interferon α, interferon α -2a, interferon β -1a, interferon α -2, interleukin-2, mevoxil, nitazoxanide, peginterferon α -2a, ribavirin, roscovitine-a, cezopyran, Euforavac, ampril, Phosphazid, heplav, interferon α -2b, levamisole, or propafegermanium.

In another aspect, the invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease in a patient.

In some embodiments, the use of the invention, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.

In still other embodiments, the use of the present invention, wherein the disease caused by hepatitis b virus infection is liver cirrhosis or hepatocellular carcinoma.

In another aspect, the invention also provides the use of said compound or said pharmaceutical composition in the manufacture of a medicament for inhibiting the production or secretion of HBsAg, and/or for inhibiting the production of HBV DNA.

In another aspect, the invention relates to the use of said compound or pharmaceutical composition in the manufacture of a medicament for the prevention, treatment or alleviation of hepatitis b disease in a patient.

Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount of a compound of the invention.

Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV disorders in a patient, said method comprising administering to the patient a pharmaceutically acceptable effective amount of a pharmaceutical composition comprising a compound of the present invention.

Another aspect of the present invention pertains to the use of a compound of the present invention in the manufacture of a medicament for the prevention, treatment, or treatment of an HBV condition in a patient, and for lessening the severity of the HBV condition in the patient.

Another aspect of the present invention relates to the use of a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for preventing or treating HBV conditions in a patient and reducing the severity thereof.

Another aspect of the present invention relates to a method of inhibiting HBV infection comprising contacting a cell with a compound or composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with an additional anti-HBV agent.

Another aspect of the present invention pertains to methods for treating HBV disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises administering an additional HBV treatment.

Another aspect of the present invention pertains to a method for inhibiting HBV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises administering an additional HBV treatment.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75,^thed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley Chemistry&Sons, New York, 2007, all of which are hereby incorporated by reference.

The compounds of the invention may be substituted with one or more substituents as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be selected from a particular groupSubstituted with one or more substituents, the substituents may be substituted at various positions, identically or differently. In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 12 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) 2-methylpropyl or isobutyl (i-Bu, -CH)₂CH(CH₃)₂) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl group(-CH₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) 3, 3-dimethyl-butyl (-CH)₂CH₂C(CH₃)₃) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains. The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein alkyl has the meaning described herein. In some of these embodiments, the haloalkyl group contains 1 to 12 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 10 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 8 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 6 carbon atoms; in other embodiments, haloThe alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the haloalkyl group contains 1 to 3 carbon atoms. Examples include, but are not limited to, trifluoromethyl, trifluoroethyl, and the like.

The term "carboxy", whether used alone or in combination with other terms (e.g., "carboxyalkyl"), means-CO₂H or-COOH.

The term "carbonyl", whether used alone or in combination with other terms (such as "aminocarbonyl" or "acyloxy"), denotes- (C ═ O) -.

The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two C_1-12Alkyl groups. Wherein in some embodiments, alkylamino is one or two C_1-12Lower alkylamino radical in which the alkyl group is attached to the nitrogen atom, in some embodiments, alkylamino is C_1-6In some embodiments, alkylamino is C_1-4Lower alkylamino groups of (a). In some embodiments, alkylamino is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-propylamino, N-dipropylamino, and the like, wherein the alkylamino groups can independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms, in other embodiments 1 to 6 carbon atoms, in other embodiments 1 to 4 carbon atoms, and in other embodiments 1 to 3 carbon atoms. In other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)₂-), ethylene (II) and (III)-CH₂CH₂-, propylene (-CH)₂CH₂CH₂-) isopropylidene (-CH (CH)₃)CH₂-) butylene (-CH)₂CH₂CH₂CH₂-) pentylene (-CH)₂CH₂CH₂CH₂CH₂-) and hexylene (-CH₂CH₂CH₂CH₂CH₂CH₂-) heptylene (-CH₂CH₂CH₂CH₂CH₂CH₂CH₂-) octylene (-CH)₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂-) and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein C-C in at least one position is sp²Double bonds, wherein the alkenyl groups may be independently unsubstituted or substituted with one or more substituents as described herein, include the "cis", "trans" or "Z", "E" isomers, specific examples of which include, but are not limited to, vinyl (-CH ═ CH)₂) Propenyl (-CH ═ CHCH)₃) Allyl (-CH)₂CH＝CH₂) And the like, wherein the alkenyl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position of the C-C is a sp triple bond, and wherein the alkynyl radical may independently be unsubstituted or substituted with one or more substituents as described herein, specific examples include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C ≡ CH), propynyl (-C ≡ C-CH)₃) 1-alkynylbutyl (-CH)₂CH₂C ≡ CH), 2-alkynylbutyl (-CH)₂C≡CCH₃) 3-alkynylbutyl (-C [ identical to ] CCH₂CH₃) And the like, wherein the alkynyl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms, some examples of which are alkoxy groups containing 1 to 12 carbon atoms, other examples of which are alkoxy groups containing 1 to 8 carbon atoms, other examples of which are alkoxy groups containing 1 to 6 carbon atoms, other examples of which are alkoxy groups containing 1 to 4 carbon atoms, and other examples of which are alkoxy groups containing 1 to 3 carbon atoms.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH))₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH)₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And the like, wherein the alkoxy groups may independently be unsubstituted or substituted with one or more of the groups described hereinSubstituted with the substituent(s).

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein alkoxy has the meaning described herein. In some of these embodiments, the haloalkoxy group contains 1 to 12 carbon atoms; in still other embodiments, the haloalkoxy group contains 1 to 10 carbon atoms; in still other embodiments, the haloalkoxy group contains 1 to 8 carbon atoms; in still other embodiments, the haloalkoxy group contains 1 to 6 carbon atoms; in other embodiments, the haloalkoxy group contains 1 to 4 carbon atoms, and in other embodiments, the haloalkoxy group contains 1 to 3 carbon atoms. Examples include, but are not limited to, trifluoromethoxy and the like.

The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms that is saturated, having one or more points of attachment to the rest of the molecule. In some of these embodiments, cycloalkyl is a ring system containing from 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 8 ring carbon atoms; in other embodiments, cycloalkyl groups are ring systems containing from 3 to 7 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 5 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 6 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, and wherein the ring system has one or more attachment points to the remainder of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes those in which a heterocyclic ring may be joined to one or more nonaromatic carbocyclic or heterocyclic ringsOr a polycyclic ring system fused to one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocycle. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. Unless otherwise indicated, -CH on heterocyclyl₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-12 ring atoms; in some embodiments, heterocyclyl is a ring system of 3-10 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 3 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, azepinyl, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithienylalkyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1, 1-dioxothiomorpholinyl; examples of the group in which the carbon atom on the ring is substituted with an oxo (═ O) group include, but are not limited to, pyrimidinedione group, 1,2, 4-thiadiazol-5 (4H) -one group, 1,2, 4-oxadiazol-5 (4H) -one group, 1H-1,2, 4-triazol-5 (4H) -one group and the like; examples in which the carbon atom on the ring is substituted with an ═ S group include, but are not limited to, 1,2, 4-oxadiazol-5 (4H) -thioketo, 1,3, 4-oxadiazol-2 (3H) -thioketo, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "M-M₁"consisting of one ring atom" means that the cyclic group consists of M-M₁And the ring atoms comprise carbon atoms and/or heteroatoms such as O, N, S, P. For example, "heteroaryl of 6 to 10 ring atoms" means that it includes heteroaryl of 6, 7, 8,9 or 10 ring atoms.

The term "heteroatom" means one or more of O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R representing a substituent as described herein).

The term "halogen" or "halogen atom" refers to F, Cl, Br or I.

The term "unsaturated" as used herein means that the moiety contains one or more degrees of unsaturation.

The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 carbon atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to a monocyclic, bicyclic, or tricyclic aromatic system containing 5 to 16 ring atoms, with at least one ring system containing one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 ring atoms with one or more attachment points attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl consisting of 5 to 14 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 12 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 7 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 to 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is heteroaryl consisting of 5 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, or dibenzothienyl, and the like. The heteroaryl group is optionally substituted with one or more substituents described herein.

The terms "heteroarylalkyl" and "heteroarylalkylene" are used interchangeably herein to mean an alkyl group substituted with one or more identical or different heteroaryl groups, wherein alkylene, alkyl and heteroaryl groups have the meaning described herein, and examples include, but are not limited to, pyridine-2-ethyl, thiazole-2-methyl, imidazole-2-ethyl, pyrimidine-2-propyl, and the like.

The term "alkylthio" includes C_1-12A linear or branched alkyl group is attached to a divalent sulfur atom, wherein the alkyl group has the meaning as described herein. In some of these embodiments, the alkylthio group is a lower C_1-6Alkylthio radicals, in other embodiments, alkylthioRadical being lower C_1-4Alkylthio, in other embodiments, the alkylthio is lower C_1-3Alkylthio groups, and such examples include, but are not limited to, methylthio (CH)₃S-), ethylthio, and the like.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers): for example, the R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformers.

As used herein, "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent (e.g., hydrogen peroxide) or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14of the A.C.S.Sympossium Series, Edward B.Roche, ed., Bioreverted arrays in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7,255 and 270, and S.J.Herr et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51, 2328 and 2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50: 50 is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., tautomers of proton transfer) include interconversion by proton migration, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbic acidSalts, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, caproates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and so on. If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N⁺(R¹⁴)₄Salts and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary, N⁺(R¹⁴)₄Salts, e.g. R¹⁴Is H, C_1-4Alkyl radical, C_6-10Aryl radical, C_6-10Aryl radical C_1-4Alkyl, etc., and cyclic amines such as piperidine, morpholine, piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。

Description of the Compounds of the invention

The compound and the pharmaceutically acceptable composition thereof can effectively inhibit HBV infection.

wherein R is¹Is R^1aO-or R^aR^bN-；

X₁is-CH₂-、-CH₂O-or-CH₂CH₂-；

X is N or CH;

R¹⁰is hydrogen, deuterium,HO-、R^aR^bN-、R¹¹-S(＝O)₂-、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl or heteroaryl of 5 to 10 ring atoms, wherein C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^w1、R^w2、R^w3、R^w4And R^w5Independently is deuterium, F, Cl, Br, HO-, HOOC-, amino, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl or C_3-7Cycloalkyl, wherein said amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl and C_3-7Cycloalkyl is independently of one another unsubstituted or substituted by 1,2,3 or 4 substituents selected from the group consisting of F, Cl, Br, CN, HO-, -O, amino, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy or C_1-6Substituted by alkylamino;

n is 0,1, 2,3 or 4.

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-CH₂-、R¹⁰-(CH₂)₂-、R¹⁰-(CH₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinylA group selected from the group consisting of imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl, wherein R is¹⁰-CH₂-CH of (A-O-)₂-、R¹⁰-(CH₂)₂In- (CH)₂)₂-、R¹⁰-(CH₂)₃In- (CH)₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w2Substituted;

R⁸is hydrogen, deuterium, HO-, R^aR^bN-, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazoleAlkyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, piperidyl, thiomorpholinyl, piperazinyl, thiomorpholinyl, and the like are mentioned, Phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R¹⁰is hydrogen, deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, thiazyl, and the like, Pyridazinyl or pyrimidinyl wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-Methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted with 1,2,3 or 4R^w3Substituted;

In some embodiments, each R described herein^1a、R^aAnd R^bEach independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazole, and so onAlkyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, Tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted with 1,2,3 or 4R^w5Substituted;

each R^w1、R^w2、R^w3、R^w4And R^w5Independently deuterium, F, Cl, Br, HO-, HOOC-, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, C_1-3Alkylthio radical, C_1-3Alkylamino, ethenyl, propenyl, allyl, ethynyl, propargyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein said amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, C_1-3Alkylthio radical, C_1-3Alkylamino, ethenyl, propenyl, allyl, ethynyl, propargyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3 or 4 substituents selected from F, Cl, Br, CN, HO-, ═ O, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Alkylthio radical, C_1-3Haloalkoxy or C_1-3Substituted by alkylamino.

In some embodiments, the present invention relates to compounds, or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of one of the following, but in no way limited to these compounds:

unless otherwise specified, stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof of the compounds of formula (I) are included within the scope of the present invention.

In another aspect, the present invention also provides a pharmaceutical composition comprising the compound of the present invention, optionally further comprising a pharmaceutically acceptable adjuvant or a combination of said adjuvants.

In other embodiments, the pharmaceutical composition of the invention, wherein the anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

In some embodiments, the anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, famciclovir, interferon, calamine CP, intefine, interferon α -1b, interferon α, interferon α -2a, interferon β -1a, interferon α -2, interleukin-2, mevoxil, nitazoxanide, peginterferon α -2a, ribavirin, roscovitine-a, cezopyran, Euforavac, ampril, Phosphazid, heplav, interferon α -2b, levamisole, or propafegermanium.

In another aspect, the invention also provides the use of said compound or said pharmaceutical composition in the manufacture of a medicament for inhibiting HBsAg production or secretion, and/or for inhibiting HBV DNA production or replication.

Another aspect of the invention relates to a method of preventing, treating or ameliorating HBV disorders in a patient, comprising administering to the patient a pharmaceutically acceptable effective amount of a pharmaceutical composition comprising a compound of the invention.

Another aspect of the invention relates to the use of a compound of the invention in the manufacture of a medicament for the prevention, treatment or treatment of HBV disorders in a patient and for lessening the severity thereof.

Another aspect of the invention relates to a method of inhibiting HBV infection comprising contacting a cell with a compound or composition of the invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with an additional anti-HBV agent.

Another aspect of the present invention relates to a method of treating HBV disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises administering an additional HBV treatment.

Another aspect of the present invention relates to a method of inhibiting HBV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises administering an additional HBV treatment.

The invention also encompasses the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product effective in inhibiting HBV infection, including those described herein: the application of the compound of the invention in the production of the drugs for effectively inhibiting HBV infection. The compounds of the invention are also useful in the manufacture of a medicament for alleviating, preventing, controlling or treating a condition of hepatitis b in a patient. The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I) in combination with at least one pharmaceutically acceptable excipient.

The invention also encompasses a method of effectively inhibiting HBV-infected diseases, or susceptibility to such conditions, which comprises treating a patient with a therapeutically effective amount of a compound represented by formula (I).

Unless otherwise indicated, all stereoisomers, tautomers, nitric oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of the compounds of the invention are within the scope of the invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.

The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or salts of formula (I) or isomers thereof, but are not necessarily pharmaceutically acceptable salts.

The term "pharmaceutically acceptable" refers to a substance that is acceptable from a toxicological standpoint for pharmaceutical use and does not adversely interact with the active ingredient.

If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like, or using organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, malic, 2-hydroxypropionic, citric, oxalic, glycolic and salicylic acids, pyranonic acids such as glucuronic and galacturonic acids, α -hydroxy acids such as citric and tartaric acids, amino acids such as aspartic and glutamic acids, aromatic acids such as benzoic and cinnamic acids, sulfonic acids such as p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, trifluoromethanesulfonic and the like, or combinations thereof.

If the compound of the invention is acidic, the desired salt can be prepared by a suitable method, and the inorganic base is lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ferric salt, ferrous salt, manganese salt, manganous salt, copper salt, zinc salt, ammonium salt and the like of the compound shown in the formula (I); organic bases, such as salts of compounds of formula (I) with methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylamino ethanol, pyridine, picoline, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazolium salts, lysine, arginine, L-arginine, histidine, N-methylglucamine, dimethylglucamine, ethylglucamine, dicyclohexylamine, 1, 6-hexanediamine, ethylenediamine, glucamine, sarcosine, serinol, aminopropanediol, 1-amino-2, 3, 4-butanetriol, L-lysine, ornithine, and the like.

Pharmaceutical compositions, formulations, administration of the compounds of the invention and uses of the compounds and pharmaceutical compositions

The pharmaceutical composition comprises a compound with a structure shown in a formula (I) or a compound with a structure shown in an embodiment, or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and pharmaceutically acceptable auxiliary materials. The compound in the composition can effectively inhibit the hepatitis B virus and is suitable for treating diseases caused by the virus, particularly acute and chronic persistent HBV virus infection.

The compounds of the invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.

The invention encompasses pharmaceutical preparations which, in addition to nontoxic, inert, pharmaceutically suitable adjuvants, also contain one or more compounds (I) or compositions according to the invention.

The above pharmaceutical preparation may also contain other active pharmaceutical ingredients than compound (I).

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I) of the present invention, and further comprises pharmaceutically acceptable excipients, which, for example, as used herein, include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, suitable for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21stedition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Endencyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Anscholar 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.

Substances that may serve as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.

Pharmaceutical compositions of the compounds of the present invention may be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrapulmonary, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administration via an explanted reservoir. Preferred modes of administration are oral, intramuscular, intraperitoneal or intravenous.

The compounds of the present invention or compositions containing them which are pharmaceutically acceptable may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.

Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.

Oral liquids may be prepared as suspensions, solutions, emulsions, syrups or elixirs in water and oil, or as dry products, supplemented with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous vehicles (which may include edible oils), such as almond oil, fats and oils such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired.

Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, the liquid dosage form is usually prepared from the compound and a sterile excipient. The auxiliary material is preferably water. According to different selected adjuvants and drug concentrations, the compound can be dissolved in adjuvants or made into suspension solution, and can be dissolved in water for injection, filtered, sterilized and filled into sealed bottle or ampoule.

When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in ointment formulations including, but not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams adjuvants that may be used include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In general, it has proven advantageous, both in human medicine and in veterinary medicine, to administer the active compounds according to the invention in a total amount of from about 0.01 to 500mg/kg of body weight, preferably from 0.01 to 100mg/kg of body weight, if appropriate in multiple single doses, per 24 hours in order to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1 to 80mg/kg body weight, more preferably 1 to 50mg/kg body weight, but may be varied from the above-mentioned dose, i.e., depending on the kind and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, and the period or interval of administration.

The pharmaceutical composition provided by the invention also comprises an anti-HBV medicament. Wherein the anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, an interferon or other novel anti-HBV agent such as an HBV RNA replication inhibitor, an HBsAg secretion inhibitor, an HBV capsid inhibitor, an antisense oligomer, an siRNA, an HBV therapeutic vaccine, an HBV prophylactic vaccine, an HBV antibody therapy (monoclonal or polyclonal), and an agonist for treating or preventing HBV.

anti-HBV drugs include lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, alfafenone, Alloferon, simon interleukin, cladribine, emtricitabine, faprivir, interferon, calamine CP, intefine, interferon α -1b, interferon α, interferon α -2a, interferon β -1a, interferon α -2, interleukin-2, mefenate, nitazoxanide, peginterferon α -2a, ribavirin, roscovellin-A, cizopyran, Euforavac, anidol, fosphazid, heplisv, interferon α -2b, levamisole or propafege.

In one aspect, the compound or pharmaceutical composition of the invention is used for preparing a medicament for preventing, treating or alleviating hepatitis b disease in a patient. Hepatitis B disease refers to liver diseases caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute hepatitis b virus infection may be asymptomatic or manifest as acute hepatitis symptoms. Patients with chronic viral infections have active disease and can develop cirrhosis and liver cancer.

The compound or the pharmaceutical composition of the invention can be used for inhibiting the generation or secretion of HBsAg, and comprises the step of administering an effective dose which is acceptable in pharmacy to a patient.

The compound or the pharmaceutical composition of the invention can be used for inhibiting HBV DNA generation, and comprises the step of administering an effective dose which is pharmaceutically acceptable to a patient to the patient.

In one aspect, the compound or pharmaceutical composition of the present invention can be used for inhibiting the expression of HBV genes, comprising administering to a patient a pharmaceutically acceptable effective amount.

Other anti-HBV agents may be administered separately from compositions comprising compounds of the present invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other simultaneously, sequentially or over a period of time, to achieve the desired agent activity.

The amount of compound and composition that can be combined with an adjuvant material to produce a single dosage form (those containing a composition like that described herein) will vary depending on the indication and the particular mode of administration. Normally, the amount of the composition of the invention will not exceed the amount of the composition normally administered containing as the only active agent.

The compound of the invention shows stronger antiviral effect. The compounds have unexpected antiviral activity on HBV, and are suitable for treating various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity, and chronic hepatitis b virus infection is known to cause cirrhosis and/or hepatocellular carcinoma.

Examples of indications that can be treated with the compounds of the invention are: acute and chronic viral infections, such as hepatitis b virus infections, which can lead to infectious hepatitis are treated. Particularly preferred are the treatment of chronic hepatitis B virus infection and the treatment of acute hepatitis B virus infection.

The invention also relates to the use of the compounds and compositions of the invention for the preparation of medicaments for the treatment and prophylaxis of viral diseases, in particular hepatitis b.

General synthetic methods

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following synthetic schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (. degree. C.). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance IIIHD 600 NMR spectrometer, in CDCl₃、DMSO-d₆、CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), s, s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), ddd (doublets of doublets, doublets), dt (doublets of triplets, doublets), ddt (doublets of doublets, doublets), td (triplets of doublets, triplets), br. Coupling constant J, monoBits are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by Agilent6320 series LC-MS spectrometer equipped with G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), G1329A autosampler and G1315B DAD detector applied for analysis, ESI source applied to LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were measured by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

table 1: gradient elution conditions

Time (min)	A(CH₃CN,0.1％HCOOH)	B(H₂O,0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The following acronyms are used throughout the invention:

synthesis method

The following synthetic schemes set forth the synthetic procedures for preparing the compounds disclosed in the present invention. Wherein each R is²、R³、R⁴、R⁵、R⁶、R⁹And X₁Having the meaning as described in the present invention, X is halogen. R^1aIs C_1-6Alkyl or C_3-6A cycloalkyl group.

Synthesis scheme 1

Formula (II)(a-6)The compounds shown can be prepared by the methods described in scheme 1. First, the compound(a-1)And compounds(a-2)Or a compound(a-3)Cyclizing in a suitable solvent (such as isopropanol, ethanol, DMSO, etc.) to give compound(a-4). Compound (I)(a-4)With chloranil, dehydrogenating in proper solvent (DME, etc.) to produce compound(a-5). Chemical combinationArticle (A)(a-5)Hydrolyzing to obtain the compound(a-6)。

Synthesis scheme 2

When R is^1aWhen it is tert-butyl, formula(a-6)The compounds shown may also be prepared by(a-4)With tetrachlorobenzoquinone in a suitable solvent (such as DME, etc.).

Synthesis scheme 3

The compounds of formula (b-13) can be prepared by the methods described in FIG. 3. Reacting the compound (b-1) with the compound (b-2) under the alkaline condition (such as potassium carbonate, sodium carbonate and the like) and in a proper solvent (such as acetonitrile, DMF and the like) to obtain a compound (b-3); reacting the compound (b-3) in an acidic condition (such as trifluoroacetic acid and the like) and a suitable solvent (such as DCM and the like) to obtain a compound (b-4); the compound (b-4) and the compound (b-5) generate a compound (b-6) under the action of concentrated sulfuric acid; reacting the compound (b-6) with the compound (b-7) under the condition of alkalinity (such as potassium carbonate, sodium carbonate and the like) and in a proper solvent (such as acetonitrile and the like) to obtain a compound (b-8); subjecting the compound (b-8) to intermolecular coupling reaction in a Pd catalyst (such as palladium bromide and the like), a base (such as potassium acetate and the like) and a suitable solvent (such as DMA and the like) to obtain a compound (b-9); removing a benzyl protecting group from the compound (b-9) to obtain a compound (b-10), reacting the compound (b-10) with N-phenylbis (trifluoromethanesulfonyl) imide to generate a compound (b-11), and finally, performing a coupling reaction on the compound (b-11) and the compound (b-12) in a palladium catalyst (such as bis (triphenylphosphine) palladium dichloride and the like) and a proper solvent (such as 1,4 dioxane and the like) to generate a compound (b-13).

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Preparation examples

In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.

Example 1: 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,5, 9-tetrahydro-2H-furan And [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Step 1: 1- (2- (allyloxy) -4-bromophenyl) ethanone

A reaction flask was charged with compound 1- (4-bromo-2-hydroxyphenyl) ethanone (10g,46.50mmol), allyl bromide (8mL,92.45mmol), DMF (100mL) and potassium carbonate (12.8g,92.6mmol), and allowed to warm to 80 deg.C for 4 h. After completion of TLC detection, the reaction was poured into water (200mL), extracted with ethyl acetate (200 mL. times.2), the organic phases were combined, washed with saturated sodium chloride (200 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was dried to give the title compound as a yellow solid (11g,43.12mmol, 93%). MS (ESI, pos. ion) m/z: 255.0[ M + H]⁺。

Step 2: 1- (3-allyl-4-bromo-2-hydroxyphenyl) ethanone

1- (2- (allyloxy) -4-bromophenyl) ethanone (11g,43.119mmol) and N-methylpyrrolidone (25mL) were added to a reaction flask, and the mixture was heated to 200 ℃ under nitrogen protection to react for 8 h. After completion of the TLC detection reaction, the reaction solution was cooled to room temperature, then poured into water (100mL), extracted with ethyl acetate (100mL × 2), the organic phases were combined, washed with saturated sodium chloride (100mL × 2), dried over anhydrous sodium sulfate, the solvent was dried by spinning, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 20/1) to give the title compound as a pale yellow oily product (10g,39.20mmo, 91%). MS (ESI, pos).ion)m/z：256.9[M+H]⁺。

And step 3: 1- (4-bromo-2- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-yl) ethanone

The compound 1- (3-allyl-4-bromo-2-hydroxyphenyl) ethanone (10g,39.199mmol) and chloroform (150mL) were added to a reaction flask, cooled to 0 deg.C, and then m-CPBA (13.5g,78.2mmol) was added and reacted at 0 deg.C for 30 min. After TLC detection of the reaction completion, the reaction was quenched by addition of saturated aqueous sodium thiosulfate (100mL) and saturated sodium bicarbonate (100mL), extracted with dichloromethane (200 mL. times.2), the organic phases combined and the solvent was dried by rotary evaporation. To the resulting residue were added MeOH (150mL) and potassium carbonate (14.6g,106mmol), followed by stirring at room temperature for 2 h. The reaction was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a white solid product (7g,25.82mmol, 66%). MS (ESI, pos. ion) m/z: 271.0[ M + H ]]⁺。

And 4, step 4: 4-bromo-7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran-2-methanol

The compound 1- (4-bromo-2- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-yl) ethanone (5.9g,22mmol), chloroform (50mL), trimethyl orthoformate (6.9g,65mmol), ethylene glycol (4.1g,66mmol) and p-toluenesulfonic acid (0.37g,2.1mmol) were added to a reaction flask, and the temperature was raised to 50 ℃ for 20 h. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate (150mL), extracted with dichloromethane (100mL × 2), the organic phases were combined, and concentrated by column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a colorless oily product (4.2g,13mmol, 61%). MS (ESI, pos. ion) m/z: 315.3[ M + H]⁺。

And 5: 4-bromo-2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran

The compound 4-bromo-7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran-2-methanol (5.0g,16mmol) and DMF (40mL) were added to a reaction flask, cooled to 0 ℃ under nitrogen, added with 60% sodium hydride solution (1.3g,33mmol), stirred for 20min, added with iodomethane (4.5g,32mmol), and warmed to room temperature for 2 h. After completion of the TLC detection reaction, the reaction solution was quenched by addition of saturated aqueous ammonium chloride (100mL) under ice bath, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride (50mL × 3), and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a colorless oily product (3.3g,10mmol, 63%). MS (ESI, pos. ion) m/z: 331.0[ M + H]⁺。

Step 6:1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran- 4-yl) -3-methylbutan-2-one

To a reaction flask was added the compound 4-bromo-2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran (3.2g,9.7mmol), methyl isopropyl ketone (1.7g,20mmol), 1, 4-dioxane (30mL), Xantphos (0.56g,0.97mmol), Pd₂(dba)₃(0.45g,0.49mmol) and t-BuONa (1.9g,20mmol), after addition, the reaction mixture was reacted at 70 ℃ for 8h with nitrogen substitution three times. After completion of the TLC detection, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 2/1) to give the title compound as a pale yellow oil (2.3g,6.9mmol, 71%). MS (ESI, pos. ion) m/z: 335.1[ M + H]⁺。

And 7: 1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran- 4-yl) -3-methylbutan-2-amine

The compound 1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran-4-yl) -3-methylbutan-2-one (2.2g,6.6mmol), methanol (20mL) and ammonium acetate (5.1g,66mmol) were added to a reaction flask and stirred at room temperature for 1 h. The temperature is reduced to 0 ℃, sodium cyanoborohydride (0.83g,13mmol) is added in batches, and after the addition is finished, the mixture is warmed to room temperature and stirred for 24 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure to remove methanol, and a saturated aqueous solution of sodium hydrogencarbonate (50mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with a saturated solution of sodium chloride (50mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent to give the title compound as a yellow oil (2.2g,6.6mmol, 100%). MS (ESI, pos. ion) m/z: 336.3[ M + H ]]⁺。

And 8: n-1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran Pyran-4-yl) -3-methylbutan-2-yl) carboxamides

1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran-4-yl) -3-methyl-2-butylamine (2.2g,6.6mmol) and ethyl formate (20mL) were added to a reaction flask, and the reaction was refluxed at elevated temperature for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give the title compound as a pale yellow solid (2.4g,6.6mmol, 100%). MS (ESI, pos. ion) m/z: 364.2[ M + H]⁺。

And step 9: 1- (8-isopropyl-2- (methoxymethyl) -1,2,8, 9-tetrahydrofuro [3, 2-f)]Isoquinoline-4- Alkyl) ethanones

Into a reaction flask were added N-1- (2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran-4-yl) -3-methylbutan-2-yl) carboxamide (2.4g,6.6mmol) and acetonitrile (30mL), and POCl was added under ice bath₃(0.92mL,9.9mmol), the reaction was refluxed at elevated temperature for 3 h. After the TLC monitoring reaction is completed, the reaction solution is dried by spinning, and residues are remainedThe reaction mixture was diluted with ethyl acetate (100mL), and the organic layer was washed successively with a saturated sodium bicarbonate solution (100mL × 2) and a saturated sodium chloride solution, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 2/1) to give the title compound as a yellow oily product (0.65g,2.2mmol, 33%). MS (ESI, pos. ion) m/z: 302.2[ M + H]⁺。

Step 10: 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,4,9,10,10 a-hexahydro- 5H-furo [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester

Adding 8-isopropyl-2- (methoxymethyl) -1,2,8, 9-tetrahydrofuran [3,2-f ] into a reaction bottle]Isoquinolin-4-yl) ethanone (0.65g,2.2mmol), ethyl 2- (ethoxymethylene) -3-oxobutanoate (8.5g,45.5mol) and ethanol (10mL), and the reaction was refluxed at elevated temperature for 12 h. TLC monitors the reaction to be complete, and the reaction solution is decompressed and distilled to remove the solvent, and then the next reaction is directly carried out. MS (ESI, pos. ion) m/z: 442.2[ M + H]⁺。

Step 11: 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furan And [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester

Adding 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,4,9,10,10 a-hexahydro-5H-furo [3,2-f ] into a reaction bottle]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester (0.95g,2.2mmol), chloranil (0.63g,2.6mmol) and ethylene glycol dimethyl ether (10mL) are heated and refluxed for reaction for 8 hours. After TLC check reaction was complete, the reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 10/1) to afford the title compound as a brown solid (0.46g,1.0mmol, 49%). MS (ESI, pos. ion) m/z: 440.3[ M + H]⁺。

Step 12: 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,5, 9-tetrahydro-2H-furan And [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Adding the compound 12-acetyl-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3, 2-f)]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester (450mg,1.024mmol), methanol (5mL) and LiOH (0.21g,5.0mmol) were reacted at room temperature for 8 h. The reaction was adjusted to pH 2-3 with 1M HCl, extracted with dichloromethane (10mL × 2), the organic phases were combined, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 10/1), the crude product was slurried with methanol (10mL), filtered, and the filter cake was dried to give the title compound as a white solid (170mg,0.43mmol, 67%). MS (ESI, pos. ion) m/z: 412.2[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.79(d,J＝2.3Hz,1H),8.12(d,J＝4.5Hz,1H),7.25(d,J＝6.1Hz,1H),5.37–5.19(m,1H),4.59–4.46(m,1H),3.76–3.56(m,2H),3.33(s,3H),3.31–3.26(m,2H),3.21–3.14(m,1H),3.10–2.95(m,1H),2.58(s,3H),1.64–1.45(m,1H),0.94–0.62(m,6H)。

Example 2: 5-isopropyl-12- (methoxycarbonyl) -2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro- 2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Step 1: 2- (allyloxy) -4-bromobenzoic acid methyl ester

Methyl 4-bromo-2-hydroxybenzoate (15g,64.92mmol), allyl bromide (15.8g,131mmol), DMF (100mL) and potassium carbonate (18g,130.242mmol) were added to a reaction flask and the temperature was raised to 80 ℃ for 4 h. After completion of the TLC detection, the reaction mixture was poured into water (200mL), extracted with ethyl acetate (200 mL. times.2), and the combined organic phases were saturated with waterSodium chloride solution (200 mL. times.3) was washed, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid product (17g,62.70mmol, 97%). MS (ESI, pos. ion) m/z: 271.0[ M + H ]]⁺。

Step 2: 3-allyl-4-bromo-2-hydroxybenzoic acid methyl ester

Methyl 2- (allyloxy) -4-bromobenzoate (17g,62.705mmol) and N-methylpyrrolidone (40mL) were added to a reaction flask, and the mixture was heated to 200 ℃ under nitrogen atmosphere for 12 h. After completion of the TLC detection reaction, the reaction was cooled to room temperature, then poured into water (100mL), extracted with ethyl acetate (100mL × 2), the combined organic phases were washed with saturated sodium chloride solution (100mL × 2), dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 20/1) to afford the title compound as a pale yellow oily product (11.9g,43.9mmol, 70.0%). MS (ESI, pos. ion) m/z: 271.1[ M + H]⁺。

And step 3: 4-bromo-2- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester

Methyl 3-allyl-4-bromo-2-hydroxybenzoate (11g,40.574mmol) and chloroform (150mL) were added to a reaction flask, cooled to 0 deg.C, and m-CPBA (14g,81.12mmol) was added and the reaction mixture reacted at 0 deg.C for 30 min. After TLC detection of the reaction was complete, the reaction was quenched by addition of saturated sodium thiosulfate (100mL) and saturated sodium bicarbonate solution (100mL), extracted with dichloromethane (200 mL. times.2), the organic phases combined, concentrated under reduced pressure, and the residue diluted with MeOH (150mL) and potassium carbonate (14.6g,106 mmol). The resulting mixture was stirred at room temperature for 2h, then filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a white solid product (9g,31.347mmol, 77.25%). MS (ESI, pos. ion) m/z: 288.0[ M + H]⁺。

And 5: 4-bromo-2- (A)Oxymethyl) -2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester

Methyl 4-bromo-2- (hydroxymethyl) -2, 3-dihydrobenzofuran-7-carboxylate (5.0g,17mmol) and DMF (40mL) were added to a reaction flask, cooled to 0 ℃ under nitrogen, 60% sodium hydride (1.3g,33mmol) was added, and after stirring for 20min, methyl iodide (4.8g,34mmol) was added, and the mixture was allowed to warm to room temperature for 2 h. After completion of the TLC detection reaction, the reaction solution was quenched by addition of saturated aqueous ammonium chloride (100mL) under ice bath, followed by extraction with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated aqueous sodium chloride (50 mL. times.3), and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a colorless oily product (5.0g,16mmol, 96%). MS (ESI, pos. ion) m/z: 301.1[ M + H]⁺。

Step 6: 2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid

To a reaction flask was added methyl 4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-carboxylate (9.2g,31mmol), methyl isopropyl ketone (5.3g,62mmol), 1, 4-dioxane (100mL), xanthphos (1.8g,3.1mmol), Pd₂(dba)₃(1.4g,1.5mmol) and t-BuONa (5.9g,61mmol), after addition, the reaction was carried out three times with nitrogen and at 70 ℃ for 8 hours. LCMS check reaction complete. The reaction mixture was poured into water (300mL), ethyl acetate (200mL) was added, the organic phase was separated, the organic phase was discarded, the aqueous phase was adjusted to pH 2-3 with HCl, and then extracted with ethyl acetate (200mL × 2), the organic phases were combined, the organic phase was dried over sodium sulfate, and the solvent was dried to directly carry out the next reaction. MS (ESI, pos. ion) m/z: 293.2[ M + H]⁺。

Step 6: 2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester Esters

2 + is added into the reaction bottle(Methoxymethyl) -4-(3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid (8.5g,29mmol), methanol (25mL) and tetrahydrofuran (25mL), cooled to 0 deg.C, trimethylsilyldiazomethane (30mL,60mmol,2mol/L) was added dropwise, and after addition, warmed to room temperature and stirred for 1 h. LCMS check reaction complete. The reaction was quenched by the addition of acetic acid (5mL), the solvent was dried by spinning, and the residue was dissolved in ethyl acetate (200mL), then washed successively with saturated aqueous sodium bicarbonate (100mL × 2) and saturated aqueous sodium chloride (100mL), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 10/1) to give the title compound as a pale yellow oily product (1.3g,4.2mmol, 15%). MS (ESI, pos. ion) m/z: 307.2[ M + H]⁺。

And 7: 4- (2-amino-3-methylbutyl) -2- (methoxymethyl) -2-3-dihydrobenzofuran-7-carboxylic acid methyl ester Esters

2-adding in the reaction bottle(Methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester (1.3g,4.2mmol), methanol (15mL) and ammonium acetate (2.3g,30mmol) were stirred at room temperature for 1 h. The temperature was reduced to 0 ℃ and sodium cyanoborohydride (0.53g,8.4mmol) was added in portions and after addition was allowed to warm to room temperature and stirred for 24 h. After completion of the TLC detection reaction, the reaction solution was evaporated under reduced pressure to remove methanol, the reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL. times.2), extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent to give the title compound as a yellow oily product (1.3g,4.2mmol, 100%). MS (ESI, pos. ion) m/z: 308.2[ M + H]⁺。

And 8: 4- (2-carboxamido-3-methylbutyl) -2- (methoxymethyl) -2-3-dihydrobenzofuran-7-carboxylic acid methyl ester Acid methyl ester

Methyl 4- (2-amino-3-methylbutyl) -2- (methoxymethyl) -2-3-dihydrobenzofuran-7-carboxylate (1.2g,3.9mmol) and ethyl formate (20mL) were added to a reaction flask, and the mixture was refluxed at elevated temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give the title compound as a pale yellow solid product (1.3g,3.9mmol, 99%). MS (ESI, pos. ion) m/z: 336.2[ M + H ]]⁺。

And step 9: 8-isopropyl-2- (methoxymethyl) -1,2, 8-9-tetrahydrofuro [3,2-f]Isoquinoline-4-carboxylic acid Methyl ester

To a reaction flask were added methyl 4- (2-carboxamido-3-methylbutyl) -2- (methoxymethyl) -2-3-dihydrobenzofuran-7-carboxylate (1.2g,3.6mmol) and acetonitrile (15mL), and POCl was further added under ice bath₃(0.5mL,5mmol), the reaction was refluxed at elevated temperature for 3 h. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50mL), then washed with saturated aqueous sodium bicarbonate (50mL × 2) and saturated aqueous sodium chloride (50mL), and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a yellow oily product (0.8g,3mmol, 70%). MS (ESI, pos. ion) m/z: 318.5[ M + H]⁺。

Step 10: 5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,4,9,10,10 a-hexahydro-5H-furo [3,2-f]Pyridine [2,1-a ]]Isoquinoline-12-methoxycarbonyl-8-carboxylic acid tert-butyl ester

Adding 8-isopropyl-2-(Methoxymethyl) -1,2, 8-9-tetrahydrofuro [3,2-f]Methyl isoquinoline-4-carboxylate (0.2g,0.6mmol), tert-butyl 2- ((dimethylamino) methyleneene) -3-oxobutyrate (0.5g,2.7mol) and tert-butanol 10mL, and the reaction was refluxed at elevated temperature for 24 h. TLC monitoring reaction completion, reaction liquid decreaseConcentrated under pressure and the residue purified by thin layer chromatography (PE/EA (V/V) ═ 1/2) to afford the title compound as a brown oil (0.22g,0.45mmol, 70%). MS (ESI, pos. ion) m/z: 486.8[ M + H]⁺。

Step 11: 5-isopropyl-12- (methoxycarbonyl) -2- (methoxymethyl) -9-oxo-2, 3,4, 9-tetrahydro-5H-fural Pyrano [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Adding 5-isopropyl-2- (methoxymethyl) -9-oxo-2, 3,4,9,10,10 a-hexahydro-5H-furo [3,2-f ] into a reaction bottle]Pyridine [2,1-a ]]Isoquinoline-12-methoxycarbonyl-8-carboxylic acid tert-butyl ester (0.2g,0.4mmol), tetrachlorobenzoquinone (0.2g,0.8mmol) and ethylene glycol dimethyl ether (10mL), and the reaction is carried out under reflux at elevated temperature for 8 h. After TLC check reaction was complete, the reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 15/1) to afford the title compound as off-white solid product (60mg,0.1404mmol, 30%). MS (ESI, pos. ion) m/z: 428.1[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.79(s,1H),8.19(s,1H),7.23(s,1H),5.23(s,1H),4.58–4.43(m,1H),3.83(s,3H),3.75–3.54(m,2H),3.31(overlap,5H),3.18–3.01(m,2H),1.67–1.44(m,1H),0.78(dd,J＝48.3,6.5Hz,6H)。

Example 3: 5-isopropyl-2- (methoxymethyl) -9-oxo-12-propionyl-3, 4,5, 9-tetrahydro-2H-furan And [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

The title compound was obtained as a white solid by the synthesis method of reference example 1 using 1- (4-bromo-2-hydroxyphenyl) -1-propanone as a starting material. MS (ESI, pos. ion) m/z: 426.2[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.75(d,J＝2.2Hz,1H),8.10(d,J＝4.5Hz,1H),7.30(d,J＝6.1Hz,1H),5.38–5.30(m,1H),4.48–4.36(m,1H),3.86–3.90(m,2H),3.35(s,3H),3.37–3.30(m,2H),3.24–3.15(m,1H),3.19–2.75(m,1H),2.58(q,J＝13.39Hz,2H),1.64–1.45(m,1H),1.22(t,J＝13.39Hz,3H),0.98–0.65(m,6H)。

Example 4: 5-isopropyl-2- (methoxymethyl) -12- (3-methylbutyryl) -9-oxo-3, 4,5, 9-tetra-n-butyl hydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Step 1: 4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-carboxylic acid

4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester (3.0g,10mmol), methanol (30mL), water (10mL) and LiOH. H.H.₂O (504mg,12mmol), stirred at rt for 3h, TLC checked for completion, adjusted pH 2-3 with 1M aqueous HCl, extracted with ethyl acetate (200mL × 2), combined organic phases dried over sodium sulfate, and solvent distilled off under reduced pressure to afford the title compound as a white solid (2.8g,10mmol, 100%) which was used directly in the next reaction.

Step 2: 4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide

To the flask were added 4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-carboxylic acid (2.8g,10mmol), DMF (30mL), DIPEA (1.78mL,10.2mmol), dimethylhydroxylamine hydrochloride (1.2g,12mmol), and HATU (4.6g,12mmol) in that order. The reaction mixture was stirred at room temperature for 24h, pH was adjusted to 5 by addition of 1M hydrochloric acid, ethyl acetate (20mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as a colorless oil (2.6g,8mmol, 80%). MS (ESI, pos. ion) m/z: 330.1/332.2[M+H]⁺。

and step 3: 1- (4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-yl) -3-methylbutan-1-one

4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide (2.6g,8mmol) and THF (30mL) were added sequentially to the two-necked flask, nitrogen was replaced three times, the mixture was cooled to 0 ℃ and isobutylmagnesium bromide THF solution (9.6mL,9.6mmol,1mol/mL) was added dropwise, stirred at 0 ℃ for 1h, warmed to room temperature and stirred for 4 h. And (3) post-treatment: the reaction was quenched by the addition of saturated ammonium chloride 20mL, extracted with ethyl acetate (3 × 20mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/EA (V/V) ═ 10/1) to give the title compound as a colorless oil (1.6g,4.8mmol, 60%). MS (ESI, pos. ion) m/z: 327.2/329.3[ M + H]⁺。

And 4, step 4: 4-bromo-7- (2-isobutyl-1, 3-dioxolan-2-yl) -2- (methoxymethyl) -2, 3-dihydrobenzo Furan compounds

Starting from 1- (4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-7-yl) -3-methylbutan-1-one, the title compound was obtained as a colorless oil by the synthesis method of reference example 1, step 4. MS (ESI, pos. ion) m/z: 371.1/373.1[ M + H ]]⁺。

And 5: 5-isopropyl-2- (methoxymethyl) -12- (3-methylbutyryl) -9-oxo-3, 4,5, 9-tetrahydro- 2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-7- (2-isobutyl-1, 3-dioxolan-2-yl) -2- (methoxymethyl) -2, 3-dihydrobenzofuran, reference is made to the procedure of example 1The synthesis of step 6 to step 12 gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 454.2[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.79(d,J＝2.2Hz,1H),8.12(d,J＝4.5Hz,1H),7.31(d,J＝6.1Hz,1H),5.40–5.29(m,1H),4.49–4.35(m,1H),3.90–3.83(m,2H),3.34(s,3H),3.34–3.30(m,2H),3.25–3.16(m,1H),3.19–2.75(m,1H),2.3–2.1(m,1H),1.64–1.45(m,1H),2.88(d,J＝12.73Hz,2H),0.98–0.60(m,12H)。

Example 5: 12-isobutyryl-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo Pyrano [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide and isopropylmagnesium bromide, the title compound was obtained as a white solid by the synthetic methods of reference example 4, steps 3 to 5. MS (ESI, pos. ion) m/z: 440.2[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ8.80(d,J＝2.3Hz,1H),8.13(d,J＝4.5Hz,1H),7.28(d,J＝6.1Hz,1H),5.35–5.20(m,1H),4.58–4.47(m,1H),3.78–3.54(m,2H),3.33(s,3H),3.32–3.24(m,1H),3.23–3.15(m,1H),3.11–2.94(m,2H),1.66–1.40(m,1H),1.02–0.52(m,12H).

Example 6: 12- (Cyclopropylformyl) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro- 2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide and cyclopropylmagnesium bromide, the title compound was obtained as a white solid with reference to the synthesis methods of steps 3 to 5 of example 4. MS (ESI, pos. ion) m/z: 438.2[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.79(d,J＝2.3Hz,1H),8.12(d,J＝4.5Hz,1H),7.25(d,J＝6.1Hz,1H),5.37–5.19(m,1H),4.59–4.46(m,1H),3.76–3.56(m,2H),3.33(s,3H),3.31–3.26(m,2H),3.21–3.14(m,1H),3.10–2.95(m,2H),1.64–1.45(m,1H),0.94–0.62(m,10H)。

Example 7: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (4,4, 4-trifluorobutanoyl) -3,4,5,9- tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide and (3,3, 3-trifluoropropyl) magnesium bromide, the title compound was obtained as a white solid in reference example 4, steps 3 to 5. MS (ESI, pos. ion) m/z: 494.3[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.80(d,J＝2.4Hz,1H),8.20(d,J＝4.6Hz,1H),7.26(d,J＝6.0Hz,1H),5.36–5.20(m,1H),4.60–4.50(m,1H),3.77–3.58(m,2H),3.35(s,3H),3.32–3.25(m,2H),3.20–3.15(m,3H),3.11–2.96(m,3H),1.65–1.44(m,1H),1.01–0.72(m,6H)。

Example 8: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (2-phenylacetyl) -3,4,5, 9-tetrakis hydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-N-methoxy-2- (methoxymethyl) -N-methyl-2, 3-dihydrobenzofuran-7-carboxamide and benzylmagnesium bromide, the title compound was obtained as a white solid in reference example 4, steps 3 to 5. MS (ESI, pos. ion) m/z: 488.3[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.75(d,J＝2.2Hz,1H),8.13(d,J＝4.6Hz,1H),7.55–6.80(m,6H),5.36–5.19(m,1H),4.60–4.47(m,1H),3.78–3.57(m,2H),3.34(s,3H),3.31–3.26(m,2H),3.23–3.24(m,1H),3.16–2.99(m,1H),2.60(s,2H),1.60–1.55(m,1H),1.05–0.65(m,6H)。

Example 9: 12- (ethoxyformyl) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro- 2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Step 1: 2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid ethyl ester Esters

2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid (2g,6.8mmol) and ethanol (20mL) were added to the flask, cooled to 0 ℃, thionyl chloride (0.75mL,10.2mmol) was added, and after stirring for 10min, the mixture was heated to reflux and stirred overnight. The solvent was distilled off under reduced pressure, diluted with water (20mL), extracted with ethyl acetate (30 mL. times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give the title compound as a colorless oil (1.95g,6.12mmol, 90%). MS (ESI, pos. ion) m/z: 321.2[ M + H]⁺。

Step 2: 12- (ethoxyformyl) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H- Furo [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Using ethyl 2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylate as a starting material, the title compound was obtained as a white solid by the synthesis methods of reference example 2, step 7 to step 11. MS (ESI, pos. ion) m/z: 442.3[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.89(s,1H),8.12(s,1H),7.26(s,1H),5.13(s,1H),4.60–4.45(m,1H),3.84(s,3H),3.77–3.56(m,2H),3.42–3.26(m,4H),3.20–3.11(m,2H),1.68–1.45(m,1H),0.98–0.55(m,9H)。

Example 10: 12- (Isopropoxycarbonyl) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5,9- tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 2- (methoxymethyl) -4- (3-methyl-2-oxobutyl) -2, 3-dihydrobenzofuran-7-carboxylic acid, the title compound was obtained as a white solid by the synthesis method of reference example 9. MS (ESI, pos. ion) m/z: 456.3[ M + H]⁺；¹HNMR(400MHz,DMSO-d₆)δ(ppm)8.80(s,1H),8.21(s,1H),7.20(s,1H),5.30(s,1H),4.60–4.44(m,1H),3.82(s,3H),3.77–3.56(m,2H),3.50–3.25(m,3H),3.20–3.31(m,2H),1.57–1.46(m,1H),0.97–0.56(m,12H)。

Example 11: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro- 2H-Furan [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Step 1: 12- (benzyloxy) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furan And [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

First, (7- (benzyloxy) -4-bromo-2, 3-dihydrobenzofuran-2-yl) methanol was obtained by the synthesis method of steps 1 to 3 of reference example 1 starting from 2- (benzyloxy) -5-bromophenol and allyl bromide, and then, (7- (benzyloxy) -4-bromo-2, 3-dihydrobenzofuran-2-yl) methanol was obtained as a brown solid by the synthesis method of steps 5 to 11 of reference example 1. MS (ESI, pos. ion) m/z: 504.3[ M + H]⁺。

Step 2: 12-hydroxy-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 45, 9-tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester

Reacting 12- (benzyloxy) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid (2.5g,6.05mmol), Pd/C (0.64g, 10%), THF (12mL), and methanol (4mL) were added to a single-necked flask and the reaction mixture was stirred under hydrogen atmosphere overnight. After the reaction was complete, the reaction mixture was filtered through a pad of celite, the filter cake was washed with DCM (50mL), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 10/1) to give the title compound as a gray solid (1.9g,4.6mmol, 99%). MS (ESI, pos. ion) m/z: 414.2[ M + H]⁺。

And step 3: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (((trifluoromethyl) sulfonyl) oxy) -3,4, 5, 9-tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester

Adding 12-hydroxy-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3,2-f ] to a single-neck flask]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester (1g,2.4mmol), TEA (3.1mL,7.2mmol), and DCM (10 mL). The reaction mixture was cooled to 0 ℃, N-phenylbis (trifluoromethanesulfonyl) imide (1.02g,2.88mmol) was added, warmed to room temperature and stirred overnight. After completion of the reaction, the reaction system was washed with 1M hydrochloric acid (20mL) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (DCM/CH)₃OH (V/V) ═ 50/1 to 30/1) purified to give the title compound as a grey powder solid (1.18g,2.16mmol, 90%). MS (ESI, pos. ion) M/z 546.5[ M + H ]]⁺。

And 4, step 4: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro-2H- Furo [3,2-f ]]Pyrido [2,1-a ]]IsoquineQuinoline-8-carboxylic acid ethyl ester

Adding 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (((trifluoromethyl) sulfonyl) oxy) -3,4,5, 9-tetrahydro-2H-furo [3,2-f ] to a single-neck flask]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester (550mg,1.0mmol), bis triphenylphosphine palladium dichloride (70mg,0.1mmol), 2-tributylstannyl thiazole (448.8mg,1.2mmol), and dioxane (5 mL). The reaction mixture was purged with nitrogen 3 times, then heated to 100 ℃ and stirred for 12 hours. After completion of the reaction, the reaction mixture was concentrated in solvent under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 10/1) to give the title compound as a brown solid (408mg, 85%). MS (ESI, pos. ion) M/z 481.6[ M + H ]]⁺。

And 5: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro-2H- Furan [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Adding 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro-2H-furan [3,2-f ] into a single-neck bottle]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester (400mg,0.88mmol), lithium hydroxide monohydrate (110.9mg,2.64mmol), methanol (4mL) and water (1mL), the mixture was stirred at room temperature for 8 hours, then 1M hydrochloric acid was added to adjust pH to 5, DCM was extracted (30mL × 3), the organic phases were combined, the solvent was distilled off under reduced pressure and the residue was chromatographed on a silica gel column to give the title compound as a pale yellow solid (198mg, 50%). MS (ESI, pos.ion) M/z 453.6[ M + H ]]⁺；¹HNMR(400MHz,CDCl₃)δ16.21(s,1H),8.93(s,1H),8.49(s,1H),8.02(d,J＝3.2Hz,1H),7.48(d,J＝3.2Hz,1H),7.01(s,1H),5.38–5.18(m,1H),4.60–4.47(m,1H),3.77–3.58(m,2H),3.35(s,3H),3.32–3.27(m,2H),3.22–3.15(m,1H),3.12–2.95(m,1H),1.66–1.45(m,1H),0.98–0.61(m,6H)。

Example 12: 5-isopropyl group-2- (methoxymethyl) -9-oxo-12- (thien-2-yl) -3,4,5, 9-tetrahydro- 2H-Furan [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

By 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (((trifluoromethyl) sulfonyl) oxy) -3,4,5, 9-tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid ethyl ester and tributyl (thiophen-2-yl) tin as starting materials, and the title compound was obtained as a white solid from step 4 to step 5 of reference example 11. MS (ESI, pos.ion) M/z 452.1[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)δ16.05(br,1H),8.50(s,1H),8.03(s,1H),7.61(d,J＝2.8Hz,1H),7.45(d,J＝4.2Hz,1H),7.23(s,1H),7.33–7.15(m,1H),6.92(s,1H),5.36–5.20(m,1H),4.58–4.42(m,1H),3.86–3.76(m,2H),3.56(s,3H),3.45–3.26(m,2H),3.32–3.04(m,1H),3.15–2.90(m,1H),1.65–1.41(m,1H),0.92–0.63(m,6H)。

Example 13: 12-acetyl-5-cyclopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-fural Pyrano [3,2-f ]]Pyrido [2,1-a ]]Isoquinoline-8-carboxylic acid

Starting from 4-bromo-2- (methoxymethyl) -7- (2-methyl-1, 3-dioxan-2-yl) -2, 3-dihydrobenzofuran and cyclopropylmethyl ketone, the title compound was obtained as a white solid by the synthesis methods of reference example 1, step 6 to step 12. MS (ESI, pos.ion) M/z 410.1[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.60(d,J＝2.4Hz,1H),8.32(d,J＝4.7Hz,1H),7.24(d,J＝6.2Hz,1H),5.46–5.09(m,1H),4.35–4.24(m,1H),3.86–3.57(m,2H),3.42(s,3H),3.32–3.20(m,2H),3.20–3.15(m,1H),3.11–2.96(m,1H),2.57(s,3H),1.70–1.42(m,1H),0.89–0.24(m,4H)。

Example 14: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro- 2H-furo [3,2-f]A pyrido [ 2] group having a structure,1-a]phthalazine-8-carboxylic acid

Step 1: 2- ((dimethylamino) methylene) -3-oxobutanoic acid tert-butyl ester

The compound tert-butyl acetoacetate (30g,189.63mmol), DMF-DMA (45g,377.64mmol) and 1, 4-dioxane (200mL) were added to a reaction flask and the reaction was stirred at room temperature for 12 h. The reaction solution was removed of the solvent under reduced pressure, and the residue was diluted with ethyl acetate (200 mL. times.3), then washed with water (200 mL. times.3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spinning to give the title compound as a brown oil (40g,187.56mmol, 98.90%). MS (ESI, pos. ion) m/z: 214.3[ M + H]⁺。

Step 2: 4-oxo-4H-pyran-3-carboxylic acid tert-butyl ester

Tert-butyl 2- ((dimethylamino) methylene) -3-oxobutyrate (20g,93.778mmol), tetrahydrofuran (200mL) and ethyl formate (14g,189.0mmol) were charged to a reaction flask, sodium tert-butoxide (24g,242.2mmol) was added under ice bath, after the addition was completed, the temperature was raised to room temperature and stirred for 12h, HCl (500mL,1M) was added to the reaction solution to quench, followed by extraction with ethyl acetate (200mL × 3), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (300mL × 2) and saturated aqueous sodium chloride (300mL × 1), the organic phase was dried, and the residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/1) to give the title compound as a yellow solid product (10g,50.97mmol, 54.35%). MS (ESI, pos. ion) m/z: 141.2[ M-56+1 ]]⁺。

And step 3: 1- ((tert-Butoxycarbonyl) amino) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid tert-butyl ester

To a reaction flask were added tert-butyl 4-oxo-4H-pyran-3-carboxylate (18g,91.743mmol), tert-butyl carbazate (24.3g,184mmol), and 180mL of ethanol, and the reaction was refluxed at elevated temperature for 12 hours. After completion of the TLC detection, the reaction was concentrated and the residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 1/2) to afford the title compound as an orange solid (28g,90.24mmol, 98.36%). MS (ESI, pos. ion) m/z: 311.1[ M + H]⁺。

And 4, step 4: 1- ((tert-Butoxycarbonyl) (isopropyl) amino) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid tert-butyl ester

To a reaction flask was added tert-butyl 1- ((tert-butoxycarbonyl) amino) -4-oxo-1, 4-dihydropyridine-3-carboxylate (28g,90.24mmol), acetonitrile (300mL), potassium carbonate (25g,180.89mmol) and 2-bromopropane (22g,178.87mmol), and after the addition was complete, the temperature was raised to 80 ℃ for 12 h. The reaction solution is filtered, the filtrate is dried by spinning, and the residue is directly subjected to the next reaction without purification. MS (ESI, pos. ion) m/z: 353.3[ M + H]⁺。

And 5: 1- (isopropylamino) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid

Tert-butyl 1- ((tert-butoxycarbonyl) (isopropyl) amino) -4-oxo-1, 4-dihydropyridine-3-carboxylate was dissolved in dichloromethane (200mL), trifluoroacetic acid (100mL,1323mmol) was added slowly under ice bath, and after addition was complete, the mixture was warmed to room temperature and stirred for 12 h. The solvent of the reaction solution was spin-dried, and the residue was directly subjected to the next reaction without purification. MS (ESI, pos. ion) m/z: 197.2[ M + H]⁺。

Step 6:1- (isopropylamino) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid methyl ester

1- (isopropylamino) -4-oxo-1, 4-dihydropyridine-3-carboxylic acid, MeOH (200mL), and concentrated sulfuric acid (5mL,90.90mmol,18.18mol/L) were added to a reaction flask, and after the addition was complete, the reaction was refluxed for 24 h. After solid sodium bicarbonate was slowly added to the reaction solution in ice bath until no bubbles were generated, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (EA) to obtain the title compound as a dark red solid (10g,47.57mmol, three-step yield: 53%). MS (ESI, pos. ion) m/z: 211.1[ M +1 ]]⁺。

And 7: 7- (benzyloxy) -2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-carbaldehyde

7- (benzyloxy) -4-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran (20.0g,57.4mmol) and anhydrous THF (200mL) were sequentially added to a two-necked flask, the flask was purged with nitrogen three times, and after stirring at-78 ℃ for 30 minutes, a n-hexane solution of n-BuLi (27.5mL,2.50M) was slowly added. After the addition, stirring was continued for 1 h. DMF (4.4mL) was added, and the reaction was continued for 7h by warming to room temperature. Saturated ammonium chloride (1000mL) was added, stirring was continued for 15 minutes, and after ethyl acetate extraction (100mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) ═ 5/1) to give the title compound as a yellow solid (8.00g,31.5mmol, 45.70%). MS (ESI, pos. ion) m/z: 299.1[ M +1 ]]⁺。

And 7: 7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-carbaldehyde

To a reaction flask were added 7- (benzyloxy) -2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-carbaldehyde (1g,3.35mmol), DMF (10mL) and NBS (655.9mg,3.68mmol), and stirred at room temperature for 2 h. The LC-MS detection reaction is complete. Water (50mL) was added to the reaction mixture, followed by EAExtraction (30mL × 3), combined organic phases, washed with saturated sodium chloride (50mL × 3), concentrated under reduced pressure, and the residue purified by silica gel column chromatography (PE/EA (V/V) ═ 3/1) to give the title compound as a pale yellow solid product (1.08g,2.88mmol, 85%). MS (ESI, pos. ion) m/z: 377.1[ M +1 ]]⁺。

And 8: (7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-yl) -methanol

To a reaction flask were added 7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-carbaldehyde (1g,2.88mmol) and methanol (10mL), and sodium borohydride (29mg,2.9mmol) was added under ice bath, and after completion of the addition, the reaction solution was warmed to room temperature and reacted for 3 h. The reaction solution was quenched by addition of water (200mL), extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to the next reaction without purification.

And step 9: 7- (benzyloxy) -5-bromo-4- (chloromethyl) -2- (methoxymethyl) -2, 3-dihydrobenzofuran

(7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-yl) -methanol was dissolved in dichloromethane (10mL), sulfoxide chloride (0.26mL,3.45mmol) was added under ice bath, after completion of addition, the mixture was warmed to room temperature and stirred for 3h, concentrated by distillation under reduced pressure, and the residue was directly subjected to the next reaction.

Step 10: 1- (((7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-yl) methyl) Methyl (isopropyl) amino) -4-yl) methyl (isopropyl) amino) -oxo-1, 4-dihydropyridine-3-carboxylate

The reaction product of 7- (benzyloxy) -5-bromo-4- (chloromethyl) -2- (methyl) benzeneOxymethyl) -2, 3-dihydrobenzofuran (1.14g,2.88mmol) was dissolved in acetonitrile (10mL), and methyl 1- (isopropylamino) -4-oxo-1, 4-dihydropyridine-3-carboxylate (604mg,2.7mmol), potassium carbonate (1.1g,8.6mmol) and potassium iodide (166mg,1mmol) were added, followed by warming to 80 ℃ for reaction overnight. The reaction was filtered and the filtrate was concentrated to give the title compound as a brown oil (1.31g,2.3mmol, 80%) which was directly subjected to the next reaction without purification. MS (ESI, pos. ion) m/z: 571.1/573.1[ M +1 ]]⁺。

Step 11: 12- (benzyloxy) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furan Pyrano [3,2-f ]]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester

To a dry reaction flask was added methyl 1- (((7- (benzyloxy) -5-bromo-2- (methoxymethyl) -2, 3-dihydrobenzofuran-4-yl) methyl) (isopropyl) amino) -oxo-1, 4-dihydropyridine-3-carboxylate (1.3g,2.3mmol), N-dimethylacetamide (10mL), palladium bromide (55mg,0.21mmol) and potassium acetate (450mg,4.6mmol), after addition N₂Heating to 130 ℃ under protection and reacting for 12 h. The reaction was concentrated and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 15/1) to afford the title compound as a brown oil (360mg,0.73mmol, 32%). MS (ESI, pos. ion) m/z: 491.1[ M +1 ]]⁺。

Step 12: 12-hydroxy-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester

Adding 12- (benzyloxy) -5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3,2-f ] to the reaction flask]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester (350mg,0.73mmol), methanol (10mL), and Pd/C (40mg,10 mass%), displaced with hydrogen three times, and the reaction was stirred at room temperature for 12 h. Filtering the reaction solution, and spin-drying the filtrate to obtain the titleThe compound was a grey solid (233mg,0.58mmol, 80%) and was directly subjected to the next reaction. MS (ESI, pos. ion) m/z: 401.2[ M +1 ]]⁺。

Step 13: 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (((trifluoromethyl) sulfonyl) oxy) -3, 4,5, 9-tetrahydro-2H-furo [3,2-f]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester

Adding 12-hydroxy-5-isopropyl-2- (methoxymethyl) -9-oxo-3, 4,5, 9-tetrahydro-2H-furo [3,2-f ] into a reaction bottle]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester (233mg,0.58mmol), then DBU (180mg,1.18mmol) and N-phenylbis (trifluoromethanesulfonyl) imide (310mg,0.87mmol) were added under ice-bath, and after the addition was complete, the reaction was warmed to room temperature for 12 h. The reaction was quenched by addition of HCl (50mL,1M), then extracted with DCM (30mL × 3), the organic phases were combined and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 15/1) to afford the title compound as a brown solid (185g,0.35mmol, 60%). MS (ESI, pos. ion) m/z: 533.4[ M +1 ]]⁺。

Step 14: 5-isopropyl-2- (methyl-methyl) -9-oxo-12- (thiazol-2-yl) -3,4,5, 9-tetrahydro-2H-furan Pyrano [3,2-f ]]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid

Adding 5-isopropyl-2- (methoxymethyl) -9-oxo-12- (((trifluoromethyl) sulfonyl) oxy) -3,4,5, 9-tetrahydro-2H-furo [3, 2-f)]Pyrido [2,1-a ]]Phthalazine-8-carboxylic acid methyl ester (180mg,0.35mmol), 2-tributylstannyl thiazole (157mg,0.42mmol), palladium (28mg,0.04mmol) and 1, 4-dioxane (5mL) were reacted for 12h under nitrogen protection at 110 ℃. The reaction was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) ═ 15/1) to give the title compound as a pale yellow solid product (80mg, 52%). MS (ESI, pos.ion) M/z 454.1[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)δ16.71(s,1H),9.02(s,1H),8.68(s,1H),8.07(d,J＝3.2Hz,1H),7.60(d,J＝3.2Hz,1H),7.02(s,1H),5.56–5.30(m,1H),4.59–4.45(m,1H),3.87–3.74(m,2H),3.66(s,3H),3.46–3.26(m,2H),3.33–3.06(m,1H),3.20–2.91(m,1H),0.91–0.64(m,6H)。

Biological activity assay

HBV cell line

HepG2.2.15 cells (SELLS, PNAS,1987 and SELLS, JV,1988) have the entire HBV genome integrated into their chromosomes and stably express viral RNA and viral proteins. HepG2.2.15 cells secrete mature hepatitis B virus particles and HBsAg into the culture medium. Virion DNA and HBsAg secreted by HepG2.2.15 cells can be quantified by qPCR and ELISA methods and the effect of compounds on viral replication and HBsAg secretion is thereby detected.

Test 1: inhibition of HBV DNA replication by Compounds of the invention

The experimental method comprises the following steps:

HepG2.2.15 cells 8,000 cells per well were seeded into 96-well cell culture plates in duplicate and cultured for 3 days until the cells grew to full well. Cells were treated with 4-fold serial dilutions of compounds for 10 days, dosed every other day with a final concentration of 0.5% DMSO in all wells and DMSO was used as no drug control. Supernatants were harvested on day 11 for quantitative detection of HBV DNA.

The qPCR method is used for detecting the virus genome DNA, and HBV primers are as follows:

HBV-For-202，CAGGCGGGGTTTTTCTTGTTGA(SEQ ID NO:1)；

HBV-Rev-315，GTGATTGGAGGTTGGGGACTGC(SEQ ID NO:2)。

using SYBR Premix Ex Taq II-Takara DRR081S kit, 1. mu.L of cell culture supernatant was used as a template, a standard curve was made with a plasmid containing HBV genome, and the virus copy number was calculated from the standard curve. Concentration-viral copy number was processed with Graphpad Prism 5 software and IC for compound inhibition of viral replication was calculated by a four-parameter non-linear regression model₅₀。

And (4) conclusion: the inhibition experiment of the compound of the invention on HBV virus replication shows that the compound of the invention has the function of HBV DNA replicationVery good inhibitory activity, wherein IC of the inventive compounds on the replication inhibitory activity of HBV DNA₅₀IC of replication inhibitory Activity of most Compounds on HBV DNA less than 0.1. mu.M₅₀Less than 0.05. mu.M.

The inhibitory activity of some compounds of the present invention on HBV DNA replication is shown in Table 2.

Table 2: replication inhibitory Activity of partial Compounds of the present invention on HBV DNA

And (3) testing 2: inhibition of HBsAg secretion by Compounds of the invention

The experimental method comprises the following steps:

HepG2.2.15 cells 8,000 cells per well were seeded into 96-well cell culture plates in duplicate and cultured for 3 days until the cells grew to full well. Cells were treated with 4-fold serial dilutions of compounds for 10 days, dosed every other day with a final concentration of 0.5% DMSO in all wells and DMSO was used as no drug control. Supernatants were harvested on day 11 for HBsAg quantification.

The level of HBsAg secreted by cells after compound treatment was measured using ELISA method using hepatitis B surface antigen diagnostic kit (Shanghai Kowa bioengineering, Inc. S10910113). 25 μ L of test supernatant (diluted to 75 μ L in PBS) was added to each well of the ELISA plate, and a positive control and a negative control of the kit were set. After blocking the ELISA plates with mounting paper, incubation was carried out at 37 ℃ for 60 minutes. The ELISA plate was removed, the mounting was removed and 50. mu.L of enzyme conjugate was added to each well. The plate was shaken on a shaker for 10 seconds, sealed with mounting paper and incubated at 37 ℃ for 30 minutes. The ELISA plate was removed, the mounting paper was torn off, and the washing was repeated 5 times: discarding liquid in the holes each time, adding washing liquid to fill each hole, standing for 60 seconds, spin-drying, and patting dry liquid residues on absorbent paper. Immediately after washing, a freshly prepared mixture of developer a and developer B was added to all wells: 100 μ L per well. After blocking the ELISA plates with mounting paper with shaking on a shaker for 10 seconds, incubation was carried out at 37 ℃ for 30 minutes. Add 50. mu.L stop solution to all wells. Read at a wavelength of 450nm on an Envision plate reader. With GrapThe hpad Prism 5 software processes the concentration-HBsAg OD450 value data, and calculates the IC of the compound for inhibiting HBsAg secretion by a four-parameter nonlinear regression model₅₀。

And (4) conclusion: the experiment for inhibiting the secretion of the HBsAg by the compound shows that the compound has good inhibitory activity to the secretion of the HBsAg, wherein the IC of the compound has the inhibitory activity to the secretion of the HBsAg₅₀IC of inhibitory Activity of most Compounds on HBsAg secretion less than 0.1. mu.M₅₀Less than 0.05. mu.M.

The inhibitory activity of the partial compounds of the present invention against HBsAg secretion is the result shown in Table 3.

Table 3: inhibitory Activity of partial Compounds of the present invention against HBsAg secretion

And (3) testing: pharmacokinetic experiments of the compounds of the invention in beagle dogs, mice and rats

(1) Beagle PK test experiment

PK assay experiment of the compound of the present invention in beagle dogs (body weight 10-12kg, male, age 10-12 months, 3 per group orally, 3 per group intravenously)

The experimental method comprises the following steps:

beagle dogs were administered 2.5mg/kg or 5mg/kg by oral gavage or 1mg/kg or 2mg/kg by intravenous injection of the test compound.

Blood was collected intravenously at time points (0.083, 0.25, 0.5, 1,2,4, 6, 8 and 24 hours) after administration and collected at the time of EDTA-K addition₂In the anticoagulation tube. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.3 software.

And (4) conclusion: the pharmaceutical experiment data show that the compound has better pharmacokinetic property in beagle dogs and has good application prospect in the aspect of anti-HBV.

(2) Mouse PK test experiment

PK assay experiment of the compound of the present invention in mice (weight 20-25g, male, age 45-60 days, 3 per group orally, 3 per group intravenously) was conducted

The experimental method comprises the following steps:

ICR mice were orally gavaged with 10mg/kg or injected via the tail vein with 2mg/kg or 10mg/kg of the test compound. Blood was collected at time points (0.083, 0.25, 0.5, 1,2,4, 6, 8 and 24 hours) from the orbital vein after administration and collected by adding EDTA-K₂In the anticoagulation tube. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.3 software.

And (4) conclusion: the data of the drug-induced experiment show that the compound has better pharmacokinetic property in mice and has good application prospect in the aspect of anti-HBV.

(3) SD rat PK test experiment

PK assay experiment of the compound of the present invention in SD rats (body weight 200-

The experimental method comprises the following steps:

SD rats were dosed either 2.5mg/kg or 5mg/kg per oral gavage or 1mg/kg per intravenous injection of the test compound. Blood was collected intravenously at time points (0.083, 0.25, 0.5, 1,2,5, 7 and 24 hours) after administration and collected by adding EDTA-K₂In the anticoagulation tube. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.3 software.

And (4) conclusion: the pharmaceutical experiment data show that the compound has better pharmacokinetic property in SD rats and has good application prospect in the aspect of anti-HBV.

And (4) testing: stability testing of Compounds of the invention in liver microsomes of different species

The experimental method comprises the following steps:

30. mu.L of a mixed solution of the blank solution and the liver microsomes was added to a 96-well plate, and 15. mu.L of a buffer containing the compound to be detected was added to each well, and two samples were prepared in parallel. After pre-incubation at 37 ℃ for 10min, 15. mu.L of NADPH solution (8mM) was added at 0min, 15min, 20min and 60min, the final concentration of the test compound was 1. mu.M, the concentration of liver microsomes was 0.1mg/mL, and the final concentration of NADPH was 2 mM. Incubate for 0, 15, 30, 60min, respectively, and add 150 μ L acetonitrile (containing internal standard) to the mixed system after incubation. The acetonitrile diluted sample was centrifuged at 4000rpm for 5min and 150. mu.L of the supernatant was taken to LC-MS/MS for analysis.

And (4) conclusion: the stability experiment data of the liver microsome shows that the compound has better stability in different types of liver microsomes.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound represented by formula (I), or a prodrug thereof,

wherein R is¹Is R^1aO-or R^aR^bN-；

X₁is-CH₂-、-CH₂O-or-CH₂CH₂-；

X is N or CH;

R¹⁰is hydrogen, deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl or heteroaryl of 5 to 10 ring atoms, wherein C is_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl, heterocyclic radical consisting of 3-6 ring atoms, C_6-10Aryl and heteroaryl of 5 to 10 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium,F、Cl、Br、C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl, thiazolyl or heterocyclyl consisting of 3 to 10 ring atoms, wherein said C is_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy radical, C_2-6Alkynyl, C_2-6Alkenyl radical, C_3-7Cycloalkyl, phenyl, thiazolyl and heterocyclyl consisting of 3-10 ring atoms each independently being unsubstituted or substituted with 1,2,3 or 4R^w4Substituted;

n is 0,1, 2,3 or 4.

2. The compound of claim 1, wherein R is²Is R⁸-(C＝O)-、R^8aO-(C＝O)-、C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein said C is_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w1Substituted;

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-C_1-3Alkylene radical, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein R is¹⁰-C_1-3C in alkylene_1-3Alkylene radical, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl and heterocyclyl consisting of 3 to 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w2And (4) substituting.

3. The compound of claim 1 or 2, wherein R is²Is R⁸-(C＝O)-、R^8aO-(C＝O)-、C_2-4Alkenyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrakismorpholinylOxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C is_2-4Alkenyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R^w1Substituted;

R³is hydrogen, deuterium, F, Cl, Br, R¹⁰-CH₂-、R¹⁰-(CH₂)₂-、R¹⁰-(CH₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein R is independently selected from the group consisting of¹⁰-CH₂-CH of (A-O-)₂-、R¹⁰-(CH₂)₂In- (CH)₂)₂-、R¹⁰-(CH₂)₃In- (CH)₂)₃-, methyl, ethyl, n-propyl, isopropyl, C_1-3Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, ethynyl, propynyl, propargyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinylIndependently of one another, the radicals, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are unsubstituted or substituted by 1,2,3 or 4R^w2And (4) substituting.

4. The compound of claim 1 or 2, wherein R is^8aIs hydrogen, deuterium, HO-, C_1-4Alkyl or C_3-6Cycloalkyl, wherein said C_1-4Alkyl and C_3-6Cycloalkyl is each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium, F, Cl, Br, C_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl, thiazolyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein said C is_1-4Alkyl radical, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl radical, C_3-6Cycloalkyl, phenyl, thiazolyl and heterocyclyl consisting of 3-6 ring atoms each independently being unsubstituted or substituted by 1,2,3 or 4R^w4And (4) substituting.

5. The compound of claim 1 or 2, wherein R is^8aIs hydrogen, deuterium, HO-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R⁸is hydrogen, deuterium, HO-, R^aR^bN-, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolinylEach of which is independently unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

R¹⁰is hydrogen, deuterium, HO-, R^aR^bN-、R¹¹-S(＝O)₂-, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, thiazyl, and the like, Pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, and the like, Thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being unsubstituted or substituted by 1,2,3 or 4R^w3Substituted;

each R^3a、R⁴、R⁵、R⁶、R⁷、R⁹And R¹¹Independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C is_1-4Alkylamino radical, C_1-4Alkoxy radical, C_2-4Alkynyl, C_2-4Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thiazolyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted by 1,2,3 or 4R^w4And (4) substituting.

6. The compound of claim 1 or 2, wherein each R is^1a、R^aAnd R^bIndependently of one another is hydrogen, deuterium, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, phenyl, heterocyclyl consisting of 3 to 6 ring atoms, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein said C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, phenyl, heterocyclyl consisting of 3 to 6 ring atoms, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms are each independently unsubstituted or substituted by 1,2,3 or 4R^w5Substituted;

7. The compound of claim 1 or 2, wherein each R is^1a、R^aAnd R^bEach independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl is substituted with one or more substituents selected from the group consisting of alkyl, pyridyl, pyrazolyl, pyridyl, isopropyl, methoxy, ethoxy, 1-propoxy, 2-propoxy, vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxadiazolyl, oxadiazinyl, and the likeOxazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4R^w5Substituted;

8. A compound according to claim 1 or 2, comprising a compound of one of:

or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt thereof, or prodrug thereof.

9. A pharmaceutical composition comprising a compound of any one of claims 1-8; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant or a combination of said adjuvants.

10. The pharmaceutical composition according to claim 9, further comprising other anti-HBV agents.

11. The pharmaceutical composition according to claim 10, wherein the other anti-HBV agent is an HBV polymerase inhibitor, an immunomodulator or an interferon.

12. The pharmaceutical composition of claim 11, wherein the other anti-HBV agent is lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simon interleukin, cladribine, emtricitabine, famciclovir, interferon, calamin CP, intefine, interferon α -1b, interferon α, interferon α -2a, interferon β -1a, interferon α -2, interleukin-2, mevoxil, nitazoxanide, peginterferon α -2a, ribavirin, roscovitine-a, cezopyran, Euforavac, april, phosziphad, hepisiva, interferon α -2b, levamisole, or propafege.

13. Use of a compound of any one of claims 1-8 or a pharmaceutical composition of any one of claims 9-12 in the manufacture of a medicament for preventing, treating or ameliorating a viral disease in a patient.

14. The use of claim 13, wherein the viral disease is hepatitis b virus infection or a disease caused by hepatitis b virus infection.

15. The use according to claim 14, wherein the disease caused by hepatitis b virus infection is cirrhosis or hepatocellular carcinoma.

16. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 12 in the manufacture of a medicament for inhibiting the production or secretion of HBsAg, and/or for inhibiting the production of HBV DNA.