New amide pyrrole compound and use thereof in drugs

Abstract

The present invention relates to a new amide pyrrole compound and the use thereof in drugs, particularly the use as a drug for treating and / or preventing hepatitis B virus infection or diseases caused by hepatitis B virus infection. Specifically, the present invention relates to a compound as represented by general formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the use thereof in the preparation of a drug, particularly the use as a drug for treating and / or preventing hepatitis B virus infection or diseases caused by hepatitis B virus infection, wherein each variable is as defined in the description.

Description

Novel amide-pyrrole compounds and their uses in pharmaceuticals Technical Field

[0001] This invention belongs to the pharmaceutical field. Specifically, it relates to a novel amide-pyrrole compound and its use as a medicine, particularly as a medicine for treating and / or preventing hepatitis B virus infection or diseases caused by hepatitis B virus infection. This invention also relates to compositions comprising the novel amide-pyrrole compound and / or other antiviral agents, and their use for treating and / or preventing hepatitis B virus (HBV) infection or diseases caused by hepatitis B virus infection. Background Technology

[0002] Hepatitis B virus (HBV) belongs to the Hepatoviridae family. It can cause acute and / or progressively chronic diseases. HBV can also cause many other pathological and clinical manifestations—especially chronic inflammation of the liver, cirrhosis, and hepatocellular carcinoma. The World Health Organization estimates that 2 billion people worldwide have been infected with HBV, with approximately 350 million chronically infected, and about 1 million people die annually from liver failure, cirrhosis, and hepatocellular carcinoma (HCC) caused by HBV infection.

[0003] Currently, the main treatment for chronic hepatitis B (CHB) is antiviral therapy. Interferon-alpha (IFN-α), pegylated IFN-α, and five nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate) have been approved by the U.S. Food and Drug Administration (FDA) for clinical treatment. Interferon was the first anti-HBV drug approved by the FDA. It primarily works by directly inhibiting the virus and inducing an immune response to clear the virus. However, its application is limited due to its low response rate, various side effects, high cost, and limited treatment options. Nucleoside (acid) analogs against HBV share the characteristic of specifically targeting viral DNA polymerase, exhibiting a strong inhibitory effect on viral replication. Patients tolerate these drugs better than with interferon. However, the widespread and long-term use of nucleoside (acid) analogs can induce DNA polymerase mutations, leading to drug resistance and the emergence of resistant strains, making treatment far from achieving ideal efficacy.

[0004] Therefore, there is still a need for new drugs that can be effectively used to treat and / or prevent hepatitis B. Summary of the Invention

[0005] This invention relates to novel amide-pyrrole compounds and their use in the preparation of medicaments for the treatment and / or prevention of HBV infection or diseases caused by HBV infection. In particular, this invention relates to a novel amide-pyrrole compound and pharmaceutically acceptable compositions thereof, which possess advantages such as good solubility, good stability, minimal induction of hepatic drug-metabolizing enzymes, and low toxicity, and especially excellent pharmacokinetic properties. The compounds of this invention can effectively inhibit HBV infection and show great promise for anti-HBV applications.

[0006] On one hand, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0007] Among them, each R 1 and R 2 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, -OH, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, methoxy, or ethoxy groups;

[0008] R 3 The radicals are hydrogen, deuterium, F, Cl, Br, I, CN, -OH, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C. 1-4 Halogenated alkyl, methoxy, or ethoxy groups;

[0009] Each R 4 R a R b R c R d R e R f R g R h R j and R k Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl, or R e R f Together with the carbon atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups;

[0010] R is -L1-CO-NR b R 6 -CHR 1a -C(=O)-NR c R 7 -CR eR f -L2-C(=O)-NR g R 8a , -CH(C(=O)-NH2)-C(=O)-NH2, -CHR 1b CHR 1c -C(=O)-NR d R 8 -L3-R 11 -CHR 1d -C(=O)-R 9 -L4-C(=O)-NR k R 12 -L5-CR 1e R 1f -C(=O)-NR j R 13 or -CHR 1h CHR 1j -C(=O)-R 14 ;

[0011] L4 is C 2-8 Alkylene, wherein, the C shown 2-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 replace;

[0012] Each of L1, L2, L3, and L5 is independently C 3-6 cycloalkyl, C 4-8 Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 3-6 cycloalkyl, C 4-8 Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w1 replace;

[0013] R 6 For H, methyl, -C(=NH)NH2, C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 replace;

[0014] R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-7 ring atoms, or heteroaryl group consisting of 5-12 ring atoms, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, and heteroaryl groups consisting of 5-12 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 replace;

[0015] Each R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 replace;

[0016] Each R 9 R 11 and R 14 Independently for C 3-6Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 replace;

[0017] Each R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the -(CH2) m -R 10 -(CH2) m -、C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 replace;

[0018] R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-6Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6 replace;

[0019] Each R w1 R w2 R w3 R w4 R w5 R w6 R w7 and R w8 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 An aryl group or a heteroaryl group composed of 5-6 ring atoms, wherein the amino group, -C(=O)OC 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w replace;

[0020] Each R wIndependently, it can be deuterium, F, Cl, Br, CN, =O, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, C 2-4 Halogenated alkoxy or C 1-4 Alkyl groups;

[0021] Each n and m is independently 1, 2, 3, 4 or 5.

[0022] In some embodiments of the present invention, each of L1, L2, L3 and L5 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w1 replace.

[0023] In some embodiments of the present invention, the R 6For H, methyl, -C(=NH)NH2, C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 replace.

[0024] In some embodiments of the present invention, the R 6H, methyl, -C(=NH)NH2, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, alkyne Propyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indole, purine, quinolinyl or isoquinolinyl, and their The terms ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl propynyl, 1-ynylbutyl, 2-ynylbutyl 3-Alynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace.

[0025] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHRh -C(=O)-NHR 9a C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 ring atoms, or heteroaryl group consisting of 5-10 ring atoms, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, and heteroaryl groups consisting of 5-10 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0026] In some embodiments of the present invention, the respective R 8a R 8 R 9a R 13 and R 12 Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 Replacement, where each R w7 It has the meaning described in this invention.

[0027] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9aMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl 1-Oynylbutyl, 2-Oynylbutyl, 3-Oynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinebutyl, oxaziridinebutyl, thioheridinebutyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydropyranyl, tetrahydrothiopheneyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiopheneyl, pyrazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl, purine, quinolinyl or isoquinolinyl, wherein the methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylbutyryl, 2-ynylbutyryl 3-Alynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrroleyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0028] In some embodiments of the present invention, the respective R8a R 8 R 9a R 13 and R 12 Independently, -C(=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, Propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl or isoquinolinyl, wherein the -C (=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ethynylbutyl, 2 -Oynyl butyl, 3-Oynyl butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine butyl, oxaziridine, thioaziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups.w7 Replacement, where each R w7 It has the meaning described in this invention.

[0029] In some embodiments of the present invention, the respective R 9 R 11 and R 14 Independently for C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0030] In some embodiments of the present invention, the respective R 9 R 11 and R 14 Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, thiohexyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioheridine, pyrrolylalkyl, pyrazolylalkyl, imidazolealkyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0031] In some embodiments of the present invention, the respective R 1a R 1b R1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the -(CH2) m -R 10 -(CH2) m -、C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 Replacement, where each m and R 10 R w5 It has the meaning described in this invention.

[0032] In some embodiments of the present invention, the R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6Replacement, where each R w6 It has the meaning described in this invention.

[0033] In some embodiments of the present invention, the respective R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the -(CH2) m -R 10 -(CH2) m-, Methyl, Ethyl, n-propyl, Isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, Vinyl, Propylene, Allyl, Ethynyl, Propylene propynyl, Propylene, 1-Eynylbutyl, 2-Eynylbutyl, 3-Eynylbutyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w5 Replacement, where each m and R 10 R w5 It has the meaning described in this invention.

[0034] In some embodiments of the present invention, the R 10-SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, methyl thio, ethyl thio, n-propyl thio, isopropyl thio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thiohexyl, pyrrolidinyl, pyrazolylyl Imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazine, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indole, purine, quinoline The amino group or isoquinolinyl group, wherein the amino group, methylthio, ethylthio, n-propylthio, isopropylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydro Thionyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazine, pyridazine, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indole, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 R groups. w6 Replacement, where each R w6 It has the meaning described in this invention.

[0035] In some embodiments of the present invention, L4 is C 3-8 Alkylene, wherein, the C shown 3-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0036] In some embodiments of the present invention, L4 is C 3-6 Alkylene, wherein, the C shown 3-6 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0037] In some embodiments of the present invention, L4 is -(CH2)2-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, or -(CH2)4-, wherein -(CH2)2-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, and -(CH2)4- are each independently unsubstituted or not substituted by 1, 2, 3, or 4 Rs. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0038] In some embodiments of the present invention, the respective R w1 R w2 R w3 R w4 R w5 R w6 and R w7 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-4 Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2F, -CH2Cl, -C HF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)C F3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, etc.), azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein the amino group, -C(=O)OC 1-4 Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2 , -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3 , -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, etc.), azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w Replacement, where each R w It has the meaning described in this invention.

[0039] In some embodiments of the present invention, the compound is a compound of formula (II) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0040] Among them, each R, R 1R 2 R 3 R 4 and R a It has the meaning described in this invention.

[0041] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients.

[0042] In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0043] In some embodiments, the pharmaceutical composition of the present invention includes, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

[0044] In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simvastatin, clavudine, emtricitabine, famciclovir, interferon, bacalanol CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, roximate, cizonan, eufovac, ampridin, phosphazid, heplisav, interferon α-2b, levamisole, or propanthenium.

[0045] On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or relief of viral diseases in patients.

[0046] In some embodiments, the use described in this invention refers to the viral disease as hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0047] In some other embodiments, the uses described in this invention refer to diseases caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0048] On the other hand, the present invention relates to the use of the compound or pharmaceutical composition described herein in the preparation of a medicament for the prevention, treatment or relief of hepatitis B in patients, including administering to patients an effective therapeutic dose of the compound or pharmaceutical composition described herein.

[0049] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.

[0050] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable and effective dose.

[0051] Another aspect of the present invention relates to the use of a compound of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of these symptoms.

[0052] Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compounds of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of those symptoms.

[0053] Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a dose of the compound or pharmaceutical composition of the present invention capable of effectively inhibiting HBV. In some further embodiments, the method further comprises contacting the cells with other anti-HBV therapeutic agents.

[0054] Another aspect of the present invention relates to a treatment method for HBV disease in patients, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment. In some further embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV drug to a patient requiring treatment.

[0055] Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment. In some further embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV drug to a patient requiring treatment.

[0056] Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I) or formula (II).

[0057] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0058] Detailed Description of the Invention

[0059] Definitions and general terms

[0060] This invention will list in detail the relevant literature for the specific details described herein, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usages of terms, described techniques, or the scope controlled as defined in this application.

[0061] This invention will apply the following definitions unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75. th Ed., 1994, defines it. Additionally, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, and all of the above are incorporated herein by reference.

[0062] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and class of compounds included in this invention as described in the embodiments.

[0063] In various parts of this specification, the substituents of the compounds of the present invention are disclosed according to the type or scope of the groups. In particular, the present invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C" 1-6 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0064] As used in this invention, the term "alkyl" includes a monovalent hydrocarbon group consisting of a saturated straight-chain or branched chain of 1-20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Some embodiments have an alkyl group containing 1-12 carbon atoms, others have an alkyl group containing 1-10 carbon atoms, still others have an alkyl group containing 1-8 carbon atoms, still others have an alkyl group containing 1-6 carbon atoms, still others have an alkyl group containing 1-4 carbon atoms, and still others have an alkyl group containing 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH 2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)) 2) 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)C H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc.

[0065] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position of C and D is sp. 2The double bond, wherein the alkenyl group may be independently unsubstituted or substituted by one or more substituents described in this invention, including "cis", "trans" or "Z", "E" isomers, wherein specific examples include, but are not limited to, vinyl (-CH=CH2), propenyl (-CH=CHCH3), allyl (-CH2CH=CH2), etc., wherein the alkenyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0066] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one C-C position is an sp triple bond. Specific examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), propynyl (-C≡C-CH3), 1-alkynylbutyryl (-CH2CH2C≡CH), 2-alkynylbutyryl (-CH2C≡CCH3), 3-alkynylbutyryl (-C≡CCH2CH3), etc., wherein the alkynyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0067] The term "haloalkyl" or "haloalkoxy" means alkyl, wherein alkyl and alkoxy have the meanings described in this invention. Such examples include, but are not limited to, difluoroethyl (-CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (-CH2CF3,-CF2CH2F,-CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), etc.

[0068] The term "carboxyalkyl" means that an alkyl group is replaced by one or two carboxyl substituents, wherein "carboxyl" is -COOH and alkyl has the meaning described in this invention. Such examples include, but are not limited to, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, etc.

[0069] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in still other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0070] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0071] The term "alkathio" indicates that an alkyl group is attached to the remainder of the molecule by a sulfur atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkathio group contains 1-12 carbon atoms. In some embodiments, the alkathio group contains 1-8 carbon atoms; in other embodiments, the alkathio group contains 1-6 carbon atoms; in still other embodiments, the alkathio group contains 1-4 carbon atoms; and in yet another embodiment, the alkathio group contains 1-3 carbon atoms. The alkathio group may optionally be substituted by one or more substituents described in this invention. Examples of alkathio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, etc.

[0072] The term "composed of M-M1 ring atoms" or "composed of M-M1 atoms" indicates that the cyclic group is composed of M-M1 ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "a heteroaryl composed of 6-10 atoms" means that it comprises a heteroaryl group consisting of 6, 7, 8, 9, or 10 ring atoms.

[0073] The terms “carbocyclic,” “carbocyclic group,” or “carbocyclic” are used interchangeably herein to refer to a non-aromatic carbocyclic system containing 3-14 ring carbon atoms, saturated or containing one or more unsaturated units. In some embodiments, the number of carbon atoms is 3-12; in others, 3-10; in still others, 3-8; in yet others, 3-6; in still others, 5-6; in still others, 5-8; and in still others, 6-8. This “carbocyclic group” includes monocyclic, bicyclic, or polycyclic fused, spirocyclic, or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbon ring may be fused with one or more non-aromatic carbon rings or heterocycles or one or more aromatic rings or combinations thereof, wherein the connecting atomic groups or points are on the carbon ring. Bicyclic carbocyclic groups include bridged bicyclic carbocyclic groups, fused bicyclic carbocyclic groups, and spirobicyclic carbocyclic groups. A "fused" bicyclic ring system comprises two rings sharing two adjacent ring atoms. A bridged bicyclic group comprises two rings sharing three or four adjacent ring atoms. A spirocyclic ring system shares one ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Bridging carbocyclic groups include, but are not limited to, bicyclic [2.2.2]octyl, bicyclic [2.2.1]heptyl, bicyclic [3.3.1]nonyl, bicyclic [3.2.3]nonyl, etc.

[0074] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring carbon atoms, with one or more linkages to the rest of the molecule, including monocyclic, bicyclic, or polycyclic fused, spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl group is a spirobicycloalkyl group consisting of 6-10 atoms; in other embodiments, the cycloalkyl group is a fused bicycloalkyl group consisting of 6-10 atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-7 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 5-8 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-6 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and said cycloalkyl groups may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0075] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein, referring to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms, and the ring system has one or more bonding sites connected to the remainder of the molecule. The term "heterocyclic group" includes monocyclic heterocyclic groups, bicyclic or polycyclic fused heterocyclic groups, spirocyclic or bridged heterocyclic heterocyclic groups, and also includes polycyclic ring systems in which the heterocycle may be fused with one or more non-aromatic carbocyclic or heterocyclic or one or more aromatic rings or combinations thereof, wherein the bonding group or site is on the heterocycle. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. Unless otherwise stated, the -CH2- group of the heterocyclic group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic group is a heterocyclic group composed of 3-12 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 4-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 3-10 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 3-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 4-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 3-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 5-6 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 7-10 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 8-10 ring atoms; in some embodiments, the heterocyclic group is a bridged bicyclic heterocyclic group composed of 6-10 ring atoms. In some other embodiments, the heterocyclic group is a ring system consisting of 3-8 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 3-6 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 5-7 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 5-8 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 6-8 ring atoms; the heterocyclic group is a ring system consisting of 3 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 4 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 5 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 6 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 7 ring atoms; in some other embodiments, the heterocyclic group is a ring system consisting of 8 ring atoms.

[0076] Examples of heterocycles include, but are not limited to, pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, piperazinyl, homopiperazinyl, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, homopiperidinyl, oxacyclopropyl, azirroheptanyl, oxacycloheptanyl, thioheptanyl, oxazazolyl, diazazolyl, thioazazolyl, 2-pyrrolinyl, 3- Pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 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-dioxothiomorpholino; wherein examples of carbon atoms on the ring being replaced by oxo (=O) groups include, but are not limited to, pyrimidinidone, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-keto, etc.; wherein examples of carbon atoms on the ring being replaced by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thiono, 1,3,4-oxadiazole-2(3H)-thiono. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0077] The terms “spirocyclic,” “spirocyclic,” “spirobicyclic,” or “spirobicyclic” are used interchangeably here to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system in which one ring originates from a specific ring carbon atom on the other ring, and the two rings share only one atom.

[0078] For example, as described in formula a-1 below, a saturated ring system (rings B and B′) is called a “fused bicyclic”, while rings A′ and B share a single carbon atom and are called a “spirocyclic” or “spirobicyclic”. Each ring in a fused bicyclic or spirobicyclic group can be a carbocyclic or heterocyclic group, and each ring may optionally be substituted by one or more substituents described in this invention.

[0079] The term "fused bicyclic heterocyclic group" refers to a monovalent, saturated or partially unsaturated, non-aromatic fused-ring system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or aromatic heterocyclic ring (although aromatics can act as substituents thereon). Each ring in the ring system comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-10 ring atoms; in some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 8-10 ring atoms. Examples of such groups include, but are not limited to, 3-aza-fused [3.1.0]hexane, 3-aza-bicyclic [3.3.0]octane, hexahydro-furan [3,4-c]pyrrole, hexahydro-thiophene [3,4-c]pyrrole, 3,4,5,6-tetrahydro-cyclopentane [c]thiophene, etc. The fused bicyclic heterocyclic group is optionally substituted by one or more substituents described in this invention.

[0080] The term "bridged carbocyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic or polycyclic carbon system, wherein each ring contains 3-7 carbon atoms. Examples of such systems include, but are not limited to, [list of examples]. The carbocyclic bridged cyclogroup may optionally be replaced by one or more substituents described in this invention.

[0081] The term "bridged bicyclic group" refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula b, where rings A1 and A2 share a common alkane chain or a heteroalkane chain, where j is 1, 2, 3, or 4. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or aryl ring (although aromatics can be used as substituents thereon). Each ring, such as A1 or A2, contains 3-7 atoms; examples include, but are not limited to, bicyclic [2.2.1]heptyl, 2-methyl-diazabicyclo[2.2.1]heptyl, etc. The bridged bicyclic group may optionally be substituted with one or more substituents described in this invention.

[0082] The term "bridged bicyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic system, wherein each ring contains 3-7 carbon atoms. Examples of such systems include, but are not limited to, bicyclic [2.2.1]heptyl groups. The bridged bicyclic group may optionally be substituted by one or more substituents described in this invention.

[0083] The term "bridged bicyclic heterocyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic system, wherein each ring comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the bridged bicyclic heterocyclic group is a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms. Examples of such groups include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, and 2-methyl-2,5-diazabicyclo[2.2.1]heptyl. The bridged bicyclic heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0084] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 carbon atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 carbon atoms and has one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic cyclic ring," as aryl can include phenyl, naphthyl, and anthracene. The aryl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0085] The term "heteroaryl" can be used alone or as a subset of "heteroarylalkyl" or "heteroarylalkoxy" to refer to a monocyclic, bicyclic, or tricyclic system containing 5-16 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system comprises a ring of 5-7 ring atoms and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring" or "heteroaryl compound." In some embodiments, a heteroaryl is a heteroaryl comprising 5-14 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, a heteroaryl is a heteroaryl comprising 5-12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In still other embodiments, a heteroaryl is a heteroaryl comprising 5-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 7-10 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0086] Other embodiments include, but are not limited to, the following monocyclic groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl. 3-Pyridinyl, 4-Pyridinyl, 2-Pyrimidinyl, 4-Pyrimidinyl, 5-Pyrimidinyl, Pyridazinyl (e.g., 3-pyridazinyl), 2-Thiazolyl, 4-Thiazolyl, 5-Thiazolyl, Tetrazolyl (e.g., 5H-Tetrazolyl, 2H-Tetrazolyl), Triazolyl (e.g., 2-Triazolyl, 5-Triazolyl, 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-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including The following bicyclic or tricyclic groups, but not limited to: benzimidazolyl, benzofuranyl, benzothiopheneyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathioyl, dibenzimidazolyl, dibenzofuranyl, or dibenzothiopheneyl, etc. The heteroaryl group may optionally be substituted by one or more substituents described in this invention.

[0087] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases “each and each is independently”, “each and each is independently”, and “each and each is independently” used throughout this section are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0088] It should also be noted that the present invention... R in 1 It can be substituted at any position on the benzene ring, where n represents R. 1 Substitution can occur at one position on the benzene ring, or at two, three, four, or five positions; when R 1 When substitution occurs at two or more positions, the R values ​​at different positions... 1 The substituents can be the same or different.

[0089] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers (e.g., enantiomers, diastereomers), or mixtures of geometric isomers (or conformational isomers) of the compounds of this invention are within the scope of this invention.

[0090] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I) or (II) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0091] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0092] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0093] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is levorotatory, while (-) or l indicates that the compound is levorotatory, and the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and mixtures of enantiomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lacks optical activity.

[0094] The terms "tautomer" or "tautomer form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0095] As used in this invention, "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8Sulfonates and aromatic sulfonates.

[0096] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0097] The term "protecting group" or "Pg" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, a "protecting group for an amino group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, and so on. For a general description of protecting groups, please refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0098] Description of the compounds of the present invention

[0099] The compounds involved in this invention, and their pharmaceutically acceptable compositions, can effectively inhibit HBV infection.

[0100] On one hand, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0101] Among them, each n, R, R 1 R 2 R 3 R 4 and R a It has the meaning described in this invention.

[0102] In some embodiments of the present invention, the respective R 1 and R 2 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, -OH, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, methoxy, or ethoxy.

[0103] In some embodiments of the present invention, the R 3 The radicals are hydrogen, deuterium, F, Cl, Br, I, CN, -OH, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C. 1-4 Halogenated alkyl, methoxy, or ethoxy.

[0104] In some embodiments of the present invention, the respective R 4 R a R b R c R d R e R f R g R h R j and R k Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups.

[0105] In some embodiments of the present invention, the respective R 4 R a R b R c R d R e R f R g R h R j and R k Independently, it is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3.

[0106] In some embodiments of the present invention, R is -L1-CO-NR. b R 6 -CHR 1a -C(=O)-NR c R 7 -CR e R f -L2-C(=O)-NR g R 8a , -CH(C(=O)-NH2)-C(=O)-NH2, -CHR 1b CHR 1c -C(=O)-NR d R 8 -L3-R 11 -CHR 1d -C(=O)-R 9 -L4-C(=O)-NR k R 12 -L5-CR 1e R 1f -C(=O)-NR j R 13 or -CHR 1h CHR 1j -C(=O)-R 14 Among them, each L1, L 2、 L3, L4, L5, R b R 6 R 1a R c R 7 R 1b R 1c R d R e R f R g R 8a R 8 R 1d R 9 R 11 R k R 12 R 1e R 1f R 1h R 1j R j R 13 and R 14 It has the meaning described in this invention.

[0107] In some embodiments of the present invention, each L1, L2, L3 and L5 is independently C. 3-6 cycloalkyl, C 4-8Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 3-6 cycloalkyl, C 4-8 Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w1 Replacement, where each R w1 It has the meaning described in this invention.

[0108] In some embodiments of the present invention, L4 is C 2-8 Alkylene, wherein, the C shown 2-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0109] In some embodiments of the present invention, the R 6 For H, methyl, -C(=NH)NH2, C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 Replacement, where each R w2 It has the meaning described in this invention.

[0110] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-7 ring atoms, or heteroaryl group consisting of 5-12 ring atoms, wherein the C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, and heteroaryl groups consisting of 5-12 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0111] In some embodiments of the present invention, the respective R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 Replacement, where each R w7 It has the meaning described in this invention.

[0112] In some embodiments of the present invention, the respective R 9 R 11 and R 14 Independently for C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0113] In some embodiments of the present invention, the respective R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the -(CH2) m -R 10 -(CH2) m -、C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 Replacement, where each m and R 10 and R w5 It has the meaning described in this invention.

[0114] In some embodiments of the present invention, the R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6 Replacement, where each R w6 It has the meaning described in this invention.

[0115] In some embodiments of the present invention, the respective R w1 R w2 R w3 R w4 R w5 R w6 R w7 and R w8 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-6 Alkyl, C 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 An aryl group or a heteroaryl group composed of 5-6 ring atoms, wherein the amino group, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w Replacement, where each R w It has the meaning described in this invention.

[0116] In some embodiments of the present invention, the respective R wIndependently, it can be deuterium, F, Cl, Br, CN, =O, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, C 2-4 Halogenated alkoxy or C 1-4 Alkyl group.

[0117] In some embodiments of the present invention, the respective R w Independently, it is deuterium, F, Cl, Br, CN, =O, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, carboxymethyl, carboxyethyl, carboxyn-n-propyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF 3. -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, -OCH2CH2F, -OCH2CH2Cl, -OCH2CHF2, -OCH2CHCl2, -OCHFCH2F, -OCHClCH2Cl, -OCH2CF3, -OCH(CH3)CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, methoxy, ethoxy, n-propoxy, isopropoxy, or tert-butoxy.

[0118] In some embodiments of the present invention, each of n and m is independently 1, 2, 3, 4 or 5.

[0119] In some embodiments of the present invention, each L1, L2, L3, and L5 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C4-carbon bridged cycloyl group, C5-carbon bridged cycloyl group, C6-carbon bridged cycloyl group, C7-carbon bridged cycloyl group, C8-carbon bridged cycloyl group, heterocyclic group composed of 3 ring atoms, heterocyclic group composed of 4 ring atoms, heterocyclic group composed of 5 ring atoms, heterocyclic group composed of 6 ring atoms, phenyl, naphthyl, heteroaryl group composed of 5 ring atoms, heteroaryl group composed of 6 ring atoms, heteroaryl group composed of 7 ring atoms, heteroaryl group composed of 8 ring atoms, heteroaryl group composed of 9 ring atoms, or heteroaryl group composed of 10 ring atoms. Among them, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C4-carbon bridged cycloyl group, C5-carbon bridged cycloyl group, C6-carbon bridged cycloyl group, C7-carbon bridged cycloyl group, C8-carbon bridged cycloyl group, heterocyclic group composed of 3 ring atoms, heterocyclic group composed of 4 ring atoms, heterocyclic group composed of 5 ring atoms, heterocyclic group composed of 6 ring atoms, phenyl, naphthyl, heteroaryl group composed of 5 ring atoms, heteroaryl group composed of 6 ring atoms, heteroaryl group composed of 7 ring atoms, heteroaryl group composed of 8 ring atoms, heteroaryl group composed of 9 ring atoms, or heteroaryl group composed of 10 ring atoms are each independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. w1 replace.

[0120] In some embodiments of the present invention, each of L1, L2, L3 and L5 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w1 replace.

[0121] In some embodiments of the present invention, the R 6 For H, methyl, -C(=NH)NH2, C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 replace.

[0122] In some embodiments of the present invention, the R 6 For H, methyl, -C(=NH)NH2, C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein the C... 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, and 10 ring atoms, each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace.

[0123] In some embodiments of the present invention, the R 6H, methyl, -C(=NH)NH2, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, alkyne Propyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indole, purine, quinolinyl or isoquinolinyl, and their The terms ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl propynyl, 1-ynylbutyl, 2-ynylbutyl 3-Alynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace.

[0124] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHRh -C(=O)-NHR 9a C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 ring atoms, or heteroaryl group consisting of 5-10 ring atoms, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, and heteroaryl groups consisting of 5-10 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0125] In some embodiments of the present invention, the respective R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 A heteroaryl group composed of aryl or 5-10 ring atoms, wherein -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 Replacement, where each R w7 It has the meaning described in this invention.

[0126] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a C 1-4 Alkyl, C 1-4 Haloalkyl, C2-4 alkenyl, C 2-4 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein the C... 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, and 10 ring atoms, each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0127] In some embodiments of the present invention, the respective R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkyne, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, and 10 ring atoms, each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w7 Replacement, where each R w7 It has the meaning described in this invention.

[0128] In some embodiments of the present invention, the R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9aMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl 1-Oynylbutyl, 2-Oynylbutyl, 3-Oynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinebutyl, oxaziridinebutyl, thioheridinebutyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydropyranyl, tetrahydrothiopheneyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiopheneyl, pyrazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl, purine, quinolinyl or isoquinolinyl, wherein the methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylbutyryl, 2-ynylbutyryl 3-Alynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrroleyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w3 Replacement, where each R h R w3 and R 9a It has the meaning described in this invention.

[0129] In some embodiments of the present invention, the respective R8a R 8 R 9a R 13 and R 12 Independently, -C(=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, Propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl or isoquinolinyl, wherein the -C (=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ethynylbutyl, 2 -Oynyl butyl, 3-Oynyl butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine butyl, oxaziridine, thioaziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups.w7 Replacement, where each R w7 It has the meaning described in this invention.

[0130] In some embodiments of the present invention, the respective R 9 R 11 and R 14 Independently for C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0131] In some embodiments of the present invention, the respective R 9 R 11 and R 14 Independently comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein the cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, and 10 ring atoms, each independently unsubstituted or substituted by 1, 2, 3, or 4 R atoms. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0132] In some embodiments of the present invention, the respective R 9 R 11 and R 14Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, thiohexyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioheridine, pyrrolylalkyl, pyrazolylalkyl, imidazolealkyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w4 Replacement, where each R w4 It has the meaning described in this invention.

[0133] In some embodiments of the present invention, the respective R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the -(CH2) m -R 10 -(CH2) m -、C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 Replacement, where each m and R 10 R w5 It has the meaning described in this invention.

[0134] In some embodiments of the present invention, the respective R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, H, deuterium, F, Cl, Br, -(CH2)-R 10 -(CH2)2-R 10 -(CH2)3-R 10 -(CH2)4-R 10 C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C9 carbon-bridged cycloyl, C 10 Carbon ring bridged ring group, C 11 Carbon-linked bridged ring groups, heterocyclic groups composed of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups composed of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein the -(CH2)-R 10 -(CH2)- and -(CH2)2-R 10 -(CH2)2- and -(CH2)3-R 10 -(CH2)3- and -(CH2)4-R 10 -(CH2)4-, C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C9 carbon-bridged cycloyl, C10 Carbon ring bridged ring group, C 11 Carbocyclic bridged cyclic groups, heterocyclic groups with 3 ring atoms, heterocyclic groups with 4 ring atoms, heterocyclic groups with 5 ring atoms, heterocyclic groups with 6 ring atoms, phenyl, naphthyl, heteroaryl groups with 5 ring atoms, heteroaryl groups with 6 ring atoms, heteroaryl groups with 7 ring atoms, heteroaryl groups with 8 ring atoms, heteroaryl groups with 9 ring atoms, and heteroaryl groups with 10 ring atoms are all independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. w5 Replacement, where each m and R 10 R w5 It has the meaning described in this invention.

[0135] In some embodiments of the present invention, the respective R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein the -(CH2) m -R 10 -(CH2) m-, Methyl, Ethyl, n-propyl, Isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, Vinyl, Propylene, Allyl, Ethynyl, Propylene propynyl, Propylene, 1-Eynylbutyl, 2-Eynylbutyl, 3-Eynylbutyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w5 Replacement, where each m and R 10 R w5 It has the meaning described in this invention.

[0136] In some embodiments of the present invention, the R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6 Replacement, where each R w6 It has the meaning described in this invention.

[0137] In some embodiments of the present invention, the R10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, heterocyclic groups consisting of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, or 10 ring atoms, wherein the amino group, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, heterocyclic groups consisting of 3, 4, 5, 6 ring atoms, phenyl, naphthyl, heteroaryl groups consisting of 5, 6, 7, 8, 9, and 10 ring atoms, each independently unsubstituted or occupied by 1, 2, 3, or 4 R atoms. w6 Replacement, where each R w6 It has the meaning described in this invention.

[0138] In some embodiments of the present invention, the R 10-SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, methyl thio, ethyl thio, n-propyl thio, isopropyl thio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thiohexyl, pyrrolidinyl, pyrazolylyl Imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazine, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indole, purine, quinoline The amino group or isoquinolinyl group, wherein the amino group, methylthio, ethylthio, n-propylthio, isopropylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydro Thionyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazine, pyridazine, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indole, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 R groups. w6 Replacement, where each R w6 It has the meaning described in this invention.

[0139] In some embodiments of the present invention, L4 is C 3-8 Alkylene, wherein, the C shown 3-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0140] In some embodiments of the present invention, L4 is C 3-6 Alkylene, wherein, the C shown 3-6 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0141] In some embodiments of the present invention, L4 is C 2-6 Alkylene, wherein, the C shown2-6 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0142] In some embodiments of the present invention, L4 is C 2-4 Alkylene, wherein, the C shown 2-4 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0143] In some embodiments of the present invention, L4 is -(CH2)2-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, or -(CH2)4-, wherein -(CH2)2-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, and -(CH2)4- are each independently unsubstituted or not substituted by 1, 2, 3, or 4 Rs. w8 Replacement, where each R w8 It has the meaning described in this invention.

[0144] In some embodiments of the present invention, the respective R w1 R w2 R w3 R w4 R w5 R w6 and R w7 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-4Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2F, -CH2Cl, -C HF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)C F3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkyl groups (such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OC(CH3)3, etc.), C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, etc.), azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein the amino group, -C(=O)OC 1-4Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2 , -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3 , -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkyl groups (such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OC(CH3)3, etc.), C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, etc.), azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w Replacement, where each R w It has the meaning described in this invention.

[0145] In some embodiments of the present invention, the compound is a compound of formula (II) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0146] Among them, each R, R 1 R 2 R 3 R4 and R a It has the meaning described in this invention.

[0147] In some embodiments of the present invention, the compounds of the present invention comprise one of the following structures:

[0148] Or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0149] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients.

[0150] In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0151] In some embodiments, the pharmaceutical composition of the present invention includes, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

[0152] In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simvastatin, clavudine, emtricitabine, famciclovir, interferon, bacalanol CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, rofloxacin-A, cizonan, eufovac, amprigin, phosphazid, heplisav, interferon α-2b, levamisole, or propafenone.

[0153] On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or relief of viral diseases in patients.

[0154] In some embodiments, the use described in this invention refers to the viral disease as hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0155] In some other embodiments, the uses described in this invention refer to diseases caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0156] On the other hand, the compounds or pharmaceutical compositions described in this invention are used to prepare remedies for the prevention, treatment, or relief of viral diseases in patients.

[0157] In some embodiments, the use of the compound or pharmaceutical composition of the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0158] In other embodiments, the use of the compound or pharmaceutical composition of the present invention, wherein the disease caused by the hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

[0159] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable and effective dose.

[0160] In some embodiments, the method of the present invention refers to a viral disease as hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0161] In some other embodiments, the method of the present invention refers to the disease caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0162] On the other hand, the present invention relates to the use of the aforementioned compound or pharmaceutical composition in the preparation of a medicine for the prevention, treatment or relief of hepatitis B in patients.

[0163] Another aspect of the present invention relates to a method for preventing, treating, or alleviating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.

[0164] Another aspect of the present invention relates to the use of a compound of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of these symptoms.

[0165] Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compounds of the present invention to prepare a medicament for the prevention or treatment of HBV symptoms in patients and to reduce the severity of those symptoms.

[0166] In some embodiments, the patient is a mammal; in others, the patient is a human. Still other embodiments further include contact between cells and an anti-HBV therapeutic agent.

[0167] Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a dose of the compound or pharmaceutical composition of the present invention capable of effectively inhibiting HBV. In some further embodiments, the method further comprises contacting the cells with other anti-HBV therapeutic agents.

[0168] Another aspect of the present invention relates to a treatment method for HBV disease in patients, the method comprising administering an effective therapeutic dose of the compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment.

[0169] Other implementations include the method further comprising administering an effective therapeutic dose of another anti-HBV therapeutic agent to a patient requiring treatment.

[0170] Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient requiring treatment. In some further embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV therapeutic agent to a patient requiring treatment.

[0171] Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I) or formula (II).

[0172] This invention also relates to the use of the compounds of this invention and their pharmaceutically acceptable salts in the production of pharmaceutical products to effectively inhibit HBV infection, and the use of the compounds of this invention in the production of medicaments for effectively inhibiting HBV infection. The compounds of this invention are also used in the production of a pharmaceutical product to alleviate, prevent, control, or treat symptoms of hepatitis B in patients.

[0173] Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are within the scope of this invention.

[0174] Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically appropriate in relation to the other components of the formulation and the mammal intended for treatment.

[0175] The salts of the compounds of the present invention also include salts for the preparation or purification of intermediates of the compounds of formula (I) or (II) or for the isolation of enantiomers of the compounds of formula (I) or (II), but are not necessarily pharmaceutically acceptable salts.

[0176] If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, etc. Alternatively, organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc., or combinations thereof, can be used.

[0177] If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, such as using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N2, etc. + (R 14 Salts of 4 and alkaline earth metal hydroxides, etc. 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 ammonia, N... + (R 14 )4 salts, such as R 14 It is H, C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-4Alkyl groups, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium salts, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C. 1-8 Sulfonates and aromatic sulfonates.

[0178] Pharmaceutical compositions, formulations, administration, and uses of the compounds and pharmaceutical compositions of the present invention.

[0179] According to another aspect, the pharmaceutical compositions of the present invention are characterized by comprising compounds represented by formula (I) or formula (II), compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable excipients. The compounds in the pharmaceutical compositions of the present invention are effective in inhibiting hepatitis B virus and are suitable for the treatment of viral diseases, especially acute and chronic persistent HBV infection. Chronic HBV-induced viral diseases can lead to severe pathological changes, and chronic hepatitis B virus infection can lead to cirrhosis and / or hepatocellular carcinoma in many cases.

[0180] For the compounds of the present invention, the areas of disease treatment that may be mentioned include, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, such as hepatitis B virus infection. The compounds of the present invention are particularly suitable for treating chronic hepatitis B infection and acute and chronic hepatitis B virus infection.

[0181] The present invention includes pharmaceutical preparations containing one or more compounds of formula (I) of the present invention or pharmaceutical compositions thereof, in addition to non-toxic, inert, pharmaceutically suitable excipients.

[0182] The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides the compounds shown in formula (I) or formula (II).

[0183] The compounds of the present invention exist in free form or as suitable, 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 adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0184] As described in this invention, the pharmaceutical compositions of this invention comprise any compound of formula (I) or formula (II) of this invention, and further comprise pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, solid excipient, diluent, binder, disintegrant, other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0185] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides 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; polyacrylates; waxes; 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 carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients 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; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0186] The pharmaceutical compositions of the compounds of the present invention can be administered in any of the following ways: oral administration, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administration via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0187] The compounds or pharmaceutical compositions thereof of this invention can be administered in unit doses. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders for injection, inclusion complexes, implants, patches, and liniments.

[0188] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0189] Oral liquids can be formulated as hydrated oil suspensions, solutions, emulsions, syrups, or elixirs, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous excipients (which may contain edible oils such as almond oil), fats such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0190] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0191] For external administration, liquid dosage forms are typically made from a compound and a sterilized excipient. Water is the preferred excipient. Depending on the excipient and drug concentration, the compound can be either dissolved in the excipient or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0192] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more excipients. Excipients that may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Excipients that may be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0193] Generally, it has been proven advantageous, in both human and veterinary medicine, that the total dosage of the active compound of the present invention is about 0.5-500 mg / kg body weight per 24 hours, preferably 1-100 mg / kg body weight, administered in multiple single doses if appropriate, to achieve the desired effect. The amount of active compound in a single dose is preferably about 1-80 mg / kg body weight, more preferably 1-50 mg / kg body weight, but may not follow the above dosages, depending on the type and weight of the patient, the nature and severity of the disease, the type of formulation and the route of administration, and the dosing cycle or time interval.

[0194] The pharmaceutical composition provided by this invention further comprises an anti-HBV drug. The anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or interferon.

[0195] The anti-HBV drugs mentioned include lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simmointerleukin, clavudine, emtricitabine, faprovir, interferon, bacalanol CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, roximate, cizonan, eufovac, amprigin, phosphazid, heplisav, interferon α-2b, levamisole, or propafenone, etc.

[0196] Another aspect of this invention relates to the use of a compound or pharmaceutical composition of the invention in the preparation of a medicament for the prevention, treatment, or relief of hepatitis B disease in a patient, including administering the medication to the patient in a pharmaceutically acceptable and effective dose. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute hepatitis B virus infection can be asymptomatic or present with symptoms of acute hepatitis. Patients with chronic viral infection have active disease that can progress to cirrhosis and liver cancer.

[0197] Anti-HBV drugs can be administered separately from compositions comprising the compounds of the present invention as part of a multiple-dose regimen. Alternatively, those drugs can be part of a single-dose formulation, mixed with the compounds of the present invention to form a single composition. If administration is part of a multiple-dose regimen, the two active agents can be delivered simultaneously and continuously or over a period of time to achieve the target agent activity.

[0198] The amount of compounds and pharmaceutical compositions that can be combined with excipients to produce single-dose formulations (those comprising a single pharmaceutical composition as described in this invention) varies depending on the indication and specific dosing regimen. Normally, the amount of the pharmaceutical compositions of this invention will not exceed the amount normally administered in a composition containing only one active agent. On the other hand, the amounts of the pharmaceutical compositions disclosed herein range from approximately 50% to 100% of the normal amounts in existing pharmaceutical compositions, containing an agent as the sole active therapeutic agent. In those compositions, the composition will act synergistically with the compounds of this invention.

[0199] The compounds of this invention exhibit potent antiviral activity. These compounds possess unexpected antiviral activity against HBV, making them suitable for treating various viral diseases, particularly those caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity; chronic hepatitis B virus infection is well known to cause cirrhosis and / or hepatocellular carcinoma.

[0200] Examples of indications for treatment with the compounds of the present invention include acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Chronic hepatitis B infection and acute hepatitis B virus infection are particularly preferred.

[0201] The present invention also relates to the use of the compounds and pharmaceutical compositions of the present invention in the preparation of medicaments for the treatment and prevention of viral diseases, particularly hepatitis B.

[0202] General synthesis methods

[0203] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I) or formula (II). The following synthetic schemes and examples are provided to further illustrate the content of the present invention.

[0204] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0205] In the examples described below, all temperatures are specified in degrees Celsius (°C) unless otherwise stated. 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 stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0206] Silica gel columns were used, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets were observed, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartets), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet). The coupling constant J was expressed in Hertz (Hz).

[0207] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0208] Low-resolution mass spectrometry (MS) data were also determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0209] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Compound purity was evaluated using an Agilent 1100 series high-performance liquid chromatography (HPLC) system with UV detection at 210 nm and 254 nm, using a Zorbax SB-C18 column, 2.1 × 30 mm, 4 μm, for 10 minutes, at a flow rate of 0.6 mL / min, with 5-95% (0.1% formic acid acetonitrile solution) and (0.1% formic acid aqueous solution) at a column temperature maintained at 40 °C.

[0210] The following abbreviations are used throughout this invention: MeOH (methanol), Pd2(dba)3 (tris(dibenzylacetone)dipalladium), MeOH-d4 / CD3OD (deuterated methanol), DMAP (4-dimethylaminopyridine), DCM, CH2Cl2 (dichloromethane), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetradecanoic acid), CDCl3 (deuterated chloroform), methylurea hexafluorophosphate (TFA), trifluoroacetic acid (H), Boc)2O (ditert-butyl dicarbonate), DIPEA (N,N-diisopropylethylamine), NBS (N-bromosuccinimide), DMF (N,N-dimethylformamide), DDQ (2,3-dichloro-5,6-dicyanophenyl quinone), THF (tetrahydrofuran), PE (petroleum ether), DMSO (dimethyl sulfoxide), EtOAc, EA (ethyl acetate), DMSO-d4 (deuterated dimethyl sulfoxide), EtOH (ethanol). 1 / 2 Half-life (Et3N, TEA), Triethylamine (AUC), Area under the curve (mL, ml), Vss, Steady-state apparent volume of distribution (RT, rt), Room temperature (CL, clearance), Clearance (Rt), Retention time (F, absolute bioavailability), LDA, Diisopropylaminolithium (Dose), CDI, N,N'-Carbonyldiimidazole (T) max Peak time 1 atm 101.325 kPa C max Maximum concentration hr* ng / mL blood drug concentration * time

[0211] Synthesis method

[0212] The following synthetic scheme outlines the experimental steps for preparing the compounds disclosed in this invention. Wherein, each R, R... a R 1 R 2 R 3 R 4 And n has the meaning as described in this invention.

[0213] Synthesis Scheme 1

[0214] Compound (I) can be prepared by the method described in Synthesis Scheme 1. First, compound (A-1) is deprotected by the Boc protecting group under suitable conditions (e.g., in the presence of trifluoroacetic acid or hydrochloric acid) to generate compound (A-2) or its salt; then, compound (A-2) or its salt undergoes a condensation reaction with compound (A-3) to obtain compound (I). The specific reaction time, temperature, and other reaction conditions can be adjusted according to the technical knowledge in the field. Detailed Implementation

[0215] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0216] Preparation Examples

[0217] In the following preparation examples, the inventors have described in detail the preparation process of the compounds of the present invention using some of the compounds of the present invention as examples.

[0218] Synthesis of intermediates

[0219] Synthesis of compound F1

[0220] Step 1: Synthesis of compound F1-1

[0221] In a dry reaction flask, ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10 g, 59.81 mmol) and DMF (120 mL) were added sequentially. After complete dissolution by stirring at room temperature, the mixture was cooled to 0 °C, and then NaH (3.11 g, 77.75 mmol) was added, resulting in the release of a large amount of gas. Subsequently, iodomethane (11.04 g, 77.75 mmol) was added. After the addition was complete, the reaction mixture was transferred to room temperature and stirred for 30 min. Then, NaH (7.18 g, 179.43 mmol) was added, and the mixture was stirred until homogeneous. 3,4-difluoroaniline (11.58 g, 89.72 mmol) was added, and the mixture was stirred until homogeneous. The mixture was then heated to 30 °C and stirred for 12 h. The heating was turned off, and the mixture was cooled to room temperature. Water (150 mL) was added to quench the reaction, resulting in the precipitation of a large amount of solid. The mixture was stirred at room temperature for 20 min. The mixture was filtered, and the filter cake was washed with water (200 mL) to obtain a gray crude solid. Isopropanol (70 mL) was added to the crude product, and the mixture was stirred at room temperature for 23 h. The mixture was then filtered, and the filter cake was washed with isopropanol (70 mL) and dried under vacuum at 50 °C for 8 h to obtain the title compound as a grayish-white solid (14.37 g, 90.91%). MS (ESI, pos.ion) m / z: 265.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H), 7.88–7.81 (m, 1H), 7.44–7.33 (m, 2H), 5.74 (s, 1H), 3.56 (s, 3H), 2.17 (d, J = 4.0Hz, 6H).

[0222] Step 2: Synthesis of compound F1-2

[0223] Compound F1-1 (45 g, 170.28 mmol) and DCM (450 mL) were added sequentially to a dry reaction flask. The mixture was stirred at room temperature until completely dissolved. The temperature was lowered to 0 °C, and oxaloyl chloride monomethyl ester (96.78 g, 766.26 mmol) was slowly added dropwise over 15-20 min. After the addition was complete, stirring was continued for 5 min. Anhydrous aluminum trichloride (68.80 g, 510.84 mmol) was then added in portions. After the addition was complete, the mixture was transferred to room temperature and stirred for 12 h. Oxaloyl chloride monomethyl ester (26.6 g, 217 mmol) was added as needed. The reaction was continued at room temperature for 6 h. Oxaloyl chloride monomethyl ester (26.6 g, 217 mmol) was added as needed. The reaction was continued at room temperature for 19 h. The mixture was cooled in an ice bath, and ice water (500 g) was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was stirred until completely dissolved. The layers were separated, and the aqueous layer was extracted with DCM (200 mL). The organic phases were combined. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution (400 mL), saturated ammonium chloride aqueous solution (400 mL), and saturated sodium chloride aqueous solution (400 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was diluted with isopropanol (200 mL) and stirred at room temperature for 12 h. The mixture was filtered, and the resulting filter cake was washed with isopropanol (100 mL) and dried under vacuum at 50 °C for 8 h to give the title compound as a white solid (44.7 g, 74.9%). MS (ESI, pos.ion) m / z: 351.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.77–7.70 (m, 1H), 7.64 (s, 1H), 7.20–7.16 (m, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H).

[0224] Step 3: Synthesis of compound F1

[0225] Compound F1-2 (40 g, 114.18 mmol), methanol (300 mL), and THF (100 mL) were added sequentially to a dry reaction flask and stirred until homogeneous. Sodium hydroxide (23.79 g, 570.90 mmol) was dissolved in water (200 mL) and added dropwise to the reaction system. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.5 h. A portion of the solvent (approximately 200 mL) was removed under reduced pressure. The pH of the remaining mixture was adjusted to 1–2 with concentrated hydrochloric acid while stirring, resulting in the precipitation of a large amount of solid. Stirring was continued at room temperature for 30 min, followed by filtration. The resulting filter cake was dried under vacuum at 60 °C for 8 h to obtain a pale pink solid (38.4 g, 100%). MS (ESI, pos.ion) m / z: 337.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 7.91–7.83 (m, 1H), 7.47–7.40 (m, 2H), 3.60 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H).

[0226] Synthesis of compound F2

[0227] Replacing 3,4-difluoroaniline in the synthetic route of compound F1 with 5-amino-2-fluorobenzonitrile, and following the same synthetic method as compound F1, yielded a white solid (1.8 g, 66.0%). MS (ESI, pos.ion) m / z: 344.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.21(dd,J=5.7,2.5Hz,1H),8.02–7.90(m,1H),7.54(t,J=9.1Hz,1H),3.61(s,3H),2.46(s,3H),2.27(s,3H).

[0228] Synthesis of compound F3

[0229] Replacing 3,4-difluoroaniline with 3-chloro-4-fluoroaniline in the synthetic route of compound F1, and following the same synthetic method as compound F1, yielded a white solid (1.65 g, 89.1%). MS (ESI, pos.ion) m / z: 353.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.01 (dd, J=6.8, 2.5Hz, 1H), 7.62 (ddd, J= 8.9,4.1,2.7Hz,1H),7.44-7.37(m,1H),3.61(s,3H),2.46(s,3H),2.27(s,3H).

[0230] Synthesis of compound F4

[0231] Replacing 3,4-difluoroaniline with 3,4,5-trifluoroaniline in the synthetic route of compound F1, and following the same synthetic method as compound F1, yielded a white solid (7.8 g, 68%). MS (ESI, pos.ion) m / z: 355.1 [M+H] + ;

[0232] Synthesis of compound F5

[0233] Replacing 3,4-difluoroaniline with 4-fluoro-3-methylaniline in the synthetic route of compound F1, and following the same procedure as compound F1, yielded a white solid (7.2 g, 71%). MS (ESI, pos.ion) m / z: 333.2 [M+H] + ;

[0234] Synthesis of compound F6

[0235] Replacing 3,4-difluoroaniline in the synthetic route of compound F1 with 4-fluoro-3-trifluoromethylaniline, and following the same synthetic method as compound F1, yielded a white solid (4.8 g, 66%). MS (ESI, pos.ion) m / z: 387.2 [M+H] + ;

[0236] Example 1: Synthesis of Compound 1

[0237] Step 1: Synthesis of Compound 1-1

[0238] Compound 1-0 (1.0 g, 4.92 mmol), isopropylamine (1.45 g, 24.6 mmol), HATU (2.24 g, 5.90 mmol), and DMF (15 mL) were added sequentially to a dry reaction flask. After complete dissolution by stirring at room temperature, DIPEA (2.44 mL, 14.76 mmol) was added. The reaction mixture was reacted at 40 °C for 12 h under nitrogen protection. The reaction solution was diluted with EA (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure. The crude product was purified by column chromatography (PE / EA (V / V = 1 / 1)) to give a white solid (0.65 g, 54.07%). MS (ESI, pos.ion) m / z: 245.20 [M+H] + .

[0239] Step 2: Synthesis of Compounds 1-2

[0240] Compound 1-1 (0.2 g, 0.82 mmol) and 1,4-dioxane (4 mL) were added sequentially to a dry reaction flask and stirred at room temperature until completely dissolved. A solution of 1,4-dioxane in HCl (0.60 g, 16.4 mmol, 4 M) was added, and the system became clear. The reaction mixture was stirred at room temperature for 12 h. Most of the solvent was removed by vacuum distillation, and the remaining solvent was removed by azeotropic distillation using DCM (10 mL × 2) to give a colorless oil (0.18 g, 100%). MS (ESI, pos.ion) m / z: 145.20 [M + H] + .

[0241] Step 3: Synthesis of Compound 1

[0242] Compounds 1-2 (0.18 g, 0.83 mmol), compound F1 (0.28 g, 0.83 mmol), HATU (0.38 g, 1.0 mmol), and DMF (8 mL) were added sequentially to a dry reaction flask. After complete dissolution by stirring at room temperature, DIPEA (0.43 g, 3.32 mmol) was added. The reaction mixture was reacted at 40 °C for 12 h under nitrogen protection. The heating was turned off, and the mixture was cooled to room temperature. The reaction solution was diluted with EA (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give a white solid (0.3 g, 78.28%). MS (ESI, pos.ion) m / z: 462.80 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.59(d,J=8.0Hz,1H),7.91–7.83(m,1H),7.76(d,J=7.6Hz,1H),7.47–7.38(m,2H),4.29–4.16(m,1H),3.8 9–3.78(m,1H),3.59(s,3H),2.39(s,3H),2.37–2.32(m,1H),2.24(s,3H ),2.22–2.16(m,1H),1.12(d,J=6.6Hz,3H),1.04(dd,J=6.5,2.6Hz,6H).

[0243] Example 2: Synthesis of Compound 2

[0244] Replacing isopropylamine in step 1 of Example 1 with propargylamine, and following the same synthesis method as in Example 1, yielded a white solid (0.39 g, 82.43%). MS (ESI, pos.ion) m / z: 458.80 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.61 (d, J = 8.0Hz, 1H), 8.38 ( t,J=5.4Hz,1H),7.91–7.84(m,1H),7.47-7.37(m,2H),4.29–4.18(m,1H),3 .86(dd,J=5.4,2.4Hz,2H),3.59(s,3H),3.09(t,J=2.4Hz,1H),2.46–2.40( m,1H),2.39(s,3H),2.30–2.25(m,1H),2.24(s,3H),1.13(d,J=6.6Hz,3H).

[0245] Example 3: Synthesis of Compound 3

[0246] Replacing compound 1-0 in step 1 of Example 1 with compound 3-0, and following the same synthesis method as in Example 1, yielded a white solid (0.35 g, 88.10%). MS (ESI, pos.ion) m / z: 448.80 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.74 (d, J = 7.7Hz, 1H), 7.91–7.81 (m, 2H), 7.47–7.38 (m, 2H), 4.36 (p, J =7.0Hz,1H),3.88–3.77(m,1H),3.59(s,3H),2.38(s,3H),2.23(s,3H),1.26(d,J=7.0Hz,3H),1.07(t,J=6.3Hz,6H).

[0247] Example 4: Synthesis of Compound 4

[0248] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compound 3-0 and propargylamine respectively, and following the same synthesis method as in Example 1, yielded a white solid (0.34 g, 84.65%). MS (ESI, pos.ion) m / z: 444.80 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.85 (d, J = 7.5Hz, 1H), 8.47 (t, J = 5.1Hz, 1H), 7.87 (dd, J = 11.8, 7.8Hz, 1H), 7.41 (dd, J = 17.9, 7.8Hz,2H),4.42(dd,J=14.3,7.1Hz,1H),3.89(d,J=2.9Hz,2H),3.59(s,3H),3.13(s,1H),2.38(s,3H),2.23(s,3H),1.28(d,J=7.0Hz,3H).

[0249] Example 5: Synthesis of Compound 5

[0250] Replacing compound 1-0 in step 1 of Example 1 with compound 5-0, and following the same synthesis method as in Example 1, yielded a white solid (0.19 g, 35.36%). MS (ESI, pos.ion) m / z: 511.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 9.31 (d, J = 8.6Hz, 1H), 8.77 (dd, J = 4.4, 1.2Hz, 1H ),8.54(dd,J=8.4,1.3Hz,1H),8.28(d,J=7.5Hz,1H),7.90–7.82(m,1H),7.52(dd,J=8.4,4.4H z,1H),7.48(d,J=7.2Hz,2H),7.36(t,J=7.4Hz,2H),5.60(d,J=8.6Hz,1H),3.82(dq,J=13.4,6 .6Hz,1H),3.57(s,3H),2.32(s,3H),2.15(s,3H),1.10(d,J=6.5Hz,3H),0.98(d,J=6.6Hz,3H).

[0251] Example 6: Synthesis of Compound 6

[0252] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compound 6-0 and propargylamine respectively, and following the same synthesis method as in Example 1, yielded a gray solid (0.23 g, 67.14%). MS (ESI, pos.ion) m / z: 431.20 [M+H] + ;

[0253] 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.88 (t, J = 5.9Hz, 1H), 8.45 (t, J = 5.3Hz, 1H), 7.93–7.80 (m, 1H), 7.48–7.37 (m,2H),3.91(dd,J=5.2,2.3Hz,2H),3.84(d,J=5.9Hz,2H),3.59(s,3H),3.13(t,J=2.3Hz,1H),2.40(s,3H),2.24(s,3H).

[0254] Example 7: Synthesis of Compound 7

[0255] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compound 7-0 and propyne respectively, and following the same synthesis method as in Example 1, yielded a gray solid (0.24 g, 75.69%). MS (ESI, pos.ion) m / z: 473.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.77 (d, J = 8.7Hz, 1H), 8.57 (t, J = 5.4Hz, 1H), 7.90–7.83 (m, 1H), 7.46–7.36 (m, 2H), 4.17 (t, J=8.4Hz,1H),3.96–3.82(m,2H),3.58(s,3H),3.10(t,J=2.3Hz,1H),2.37(s,3H),2.22(s,3H),2.06–1.97(m,1H),0.91(t,J=6.1Hz,6H).

[0256] Example 8: Synthesis of Compound 8

[0257] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compound 8-0 and propargylamine respectively, and following the valid procedure of Example 1 for the remaining steps, yielded a white solid (0.24 g, 75.69%). MS (ESI, pos.ion) m / z: 473.20 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 8.77 (d, J = 8.7Hz, 1H), 8.57 (t, J = 5.4Hz, 1H), 7.91–7.82 (m, 1H), 7.46–7.36 (m, 2H), 4.17 (t, J=8.4Hz,1H),3.96–3.82(m,2H),3.58(s,3H),3.10(t,J=2.2Hz,1H),2.37(s,3H),2.22(s,3H),2.08–1.96(m,1H),0.91(t,J=6.1Hz,6H).

[0258] Example 9: Synthesis of Compound 9

[0259] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 3-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.24 g, 82.63%) was obtained. MS (ESI, pos.ion) m / z: 510.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.90(d,J=7.3Hz,1H),8.63(d,J=8.9Hz,1H),8.21(dd,J=5.7,2.5Hz,1H),8.01–7.93(m,1H),7.54(t, J=9.1Hz,1H),4.66–4.54(m,1H),4.46(p,J=7.0Hz,1H),3.60(s,3H),2.39(s,3H),2.24(s,3H),1.30(d,J=7.1Hz,3H),1.27(d,J=7.1Hz,3H).

[0260] Example 10: Synthesis of Compound 10

[0261] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 3-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.25 g, 86.07%). MS (ESI, pos.ion) m / z: 510.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.93(d,J=7.5Hz,1H),8.65(d,J=8.8Hz,1H),8.21(d,J=3.1Hz,1H),8.02–7.87(m,1H),7.54(t,J =9.1Hz,1H),4.64–4.52(m,1H),4.50–4.40(m,1H),3.59(s,3H),2.37(s,3H),2.23(s,3H),1.30(d,J=6.9Hz,3H),1.25(d,J=6.9Hz,3H).

[0262] Example 11: Synthesis of Compound 11

[0263] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.24 g, 84.04%) was obtained. MS (ESI, pos.ion) m / z: 572.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.56(d,J=8.6Hz,1H),9.06(d,J=8.9Hz,1H),8.21(dd,J=5.5,2.4Hz,1H),8.00–7.92(m,1H),7.53(dd,J =18.1,8.5Hz,3H),7.42–7.30(m,3H),5.74(d,J=8.6Hz,1H),4.64–4.4 9(m,1H),3.58(s,3H),2.32(s,3H),2.17(s,3H),1.16(d,J=7.0Hz,3H).

[0264] Example 12: Synthesis of Compound 12

[0265] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.24 g, 84.04%) was obtained. MS (ESI, pos.ion) m / z: 572.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.46(d,J=8.2Hz,1H),8.95(d,J=8.7H z,1H),8.20(d,J=3.0Hz,1H),7.96(d,J=3.3Hz,1H),7.53(t,J=9.0Hz,1H),7. 46(d,J=7.2Hz,2H),7.40–7.30(m,3H),5.72(d,J=8.2Hz,1H),4.62(dd,J=14 .7,7.4Hz,1H),3.58(s,3H),2.33(s,3H),2.17(s,3H),1.29(d,J=6.8Hz,3H).

[0266] Example 13: Synthesis of Compound 13

[0267] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 13-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.077 g, 23.04%). MS (ESI, pos.ion) m / z: 578.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.79(d,J=24.0Hz,2H),8.21(s,1H),7.97(s,1H),7.54(s,1H),4.60(s,1H),4 .29(s,1H),3.59(s,3H),2.38(s,3H),2.23(s,3H),1.69(s,3H),1.59(s,3H),1.24(s,3H),1.14(s,3H),1.00(s,2H).

[0268] Example 14: Synthesis of Compound 14

[0269] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 3-0 and 4-cyanoperpiperidine, respectively, and following the synthetic method of Example 1, a white solid (0.18 g, 61%) was obtained. MS (ESI, pos.ion) m / z: 507.05 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.47(d,J=8.9Hz,1H),8.22(dd,J=5.7,2.6Hz,1H), 8.00–7.94(m,1H),7.55(t,J=9.1Hz,1H),4.63–4.50(m,1H),4.39–4.30(m,1H),3.61(s,3H ),3.52(d,J=12.8Hz,1H),3.13(t,J=12.9Hz,1H),2.91–2.77(m,1H),2.46(s,3H),2.27(s, 3H),1.87–1.78(m,1H),1.76–1.66(m,1H),1.57-1.44(m,2H),1.23(dd,J=6.9,4.0Hz,3H).

[0270] Example 15: Synthesis of Compound 15

[0271] Replacing compound 1-0 in step 1 of Example 1 with compound 15-0, and following the synthetic method of Example 1, yielded a white solid (0.23 g, 88.84%). MS (ESI, pos.ion) m / z: 532.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.90(d,J=8.5Hz,1H),8.20(dd,J=5.6, 2.5Hz,1H),7.98–7.93(m,2H),7.54(t,J=9.1Hz,1H),7.32-7.24(m,4H),7.23 -7.16(m,1H),4.61–4.54(m,1H),3.87-3.77(m,1H),3.54(s,3H),2.99–2.86( m,2H),2.13(s,3H),2.08(s,3H),1.06(d,J=6.5Hz,3H),0.98(d,J=6.5Hz,3H).

[0272] Example 16: Synthesis of Compound 16

[0273] Replacing compound 1-0 in step 1 of Example 1 with compound 16-0, and following the synthetic method of Example 1, yielded a white solid (0.22 g, 84.97%). MS (ESI, pos.ion) m / z: 532.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.22(d,J=8.4Hz,1H),8.21(dd,J=5.5,2.3Hz ,1H),8.04–7.86(m,1H),7.70(d,J=7.6Hz,1H),7.53(t,J=9.1Hz,1H),7.43–7.29(m, 4H),7.28-7.21(m,1H),5.33(q,J=7.6Hz,1H),3.82-3.70(m,1H),3.57(s,3H),2.65– 2.53(m,2H),2.29(s,3H),2.16(s,3H),0.98(d,J=6.5Hz,3H),0.91(d,J=6.5Hz,3H).

[0274] Example 17: Synthesis of Compound 17

[0275] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 17-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.22 g, 59.00%). MS (ESI, pos.ion) m / z: 522.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.98(s,1H),8.22(dd,J=5.6,2.4Hz,1H),8.03(d,J=8.9Hz,1H),8.00–7.94(m,1H),7.54(t,J=9.1Hz,1 H),4.80–4.51(m,1H),3.61(s,3H),2.38(s,3H),2.24(s,3H),1.43–1. 35(m,2H),1.26(d,J=7.0Hz,3H),1.13–1.07(m,1H),1.06–1.00(m,1H).

[0276] Example 18: Synthesis of Compound 18

[0277] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 18-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a yellow solid (0.17 g, 48.98%). MS (ESI, pos.ion) m / z: 550.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.77(d,J=7.5Hz,1H),8.43(d,J=8.9Hz,1H),8.21( dd,J=5.6,2.5Hz,1H),8.05–7.89(m,1H),7.53(t,J=9.1Hz,1H),4.59(dq,J=15.4,7.5Hz, 1H),423–4.08(m,1H),3.60(s,3H),2.81–2.68(m,1H),2.40(s,3H),2.25(s,3H),2.18–2. 07(m,1H),1.95–1.81(m,2H),1.80–1.65(m,2H),1.65–1.54(m,1H),1.23(d,J=7.0Hz,3H).

[0278] Example 19: Synthesis of Compound 19

[0279] Replacing compound 1-0 in step 1 of Example 1 with compound 19-0, and following the synthetic method of Example 1, yielded a white solid (0.095 g, 54.62%). MS (ESI, pos.ion) m / z: 498.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 8.73 (d, J = 8.4Hz, 1H), 8.19 (dd, J = 5.9, 2. 7Hz,1H),7.94(q,J=8.3,7.4Hz,2H),7.53(t,J=8.4Hz,1H),4.35(q,J=7.1Hz,1H) ,3.82(dt,J=13.7,6.8Hz,1H),3.57(s,3H),2.36(s,3H),2.21(s,3H),1.62–1.5 2(m,2H),1.47–1.40(m,1H),1.04(t,J=7.3Hz,6H),0.88(dd,J=10.4,6.5Hz,6H).

[0280] Example 20: Synthesis of Compound 20

[0281] Replacing compound 1-0 in step 1 of Example 1 with compound 20-0, and following the synthetic method of Example 1, yielded a white solid (0.12 g, 55.20%). MS (ESI, pos.ion) m / z: 498.10 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.67(d,J=8.9Hz,1H),8.18(s,1H),7.96(t,J=12.0Hz,2H),7.50(t,J=10.7Hz,1H),4.14( d,J=9.0Hz,1H),3.82(s,1H),3.56(s,3H),3.14(s,1H),2.34(s,3H),2.19(s,3H),1.55–1.44(m,2H),1.02(s,6H),0.83(s,6H).

[0282] Example 21: Synthesis of Compound 21

[0283] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and R(+)-α-methylbenzylamine, respectively, and following the synthetic method of Example 1, a white solid (0.32 g, 61.89%) was obtained. MS (ESI, pos.ion) m / z: 546.05 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.73(d,J=8.9Hz,1H),8.60(d,J=8.0Hz,1H),8.21(dd, J=5.6,2.5Hz,1H),8.03–7.92(m,1H),7.54(t,J=9.1Hz,1H),7.35–7.26(m,4H),7.23–7.18(m, 1H),4.94(p,J=7.0Hz,1H),4.25(t,J=8.4Hz,1H),3.60(s,3H),2.38(s,3H),2.24(s,3H),2.0 0(dq,J=13.6,6.7Hz,1H),1.36(d,J=7.0Hz,3H),0.85(d,J=6.7Hz,3H),0.80(d,J=6.7Hz,3H).

[0284] Example 22: Synthesis of Compound 22

[0285] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and S(-)-α-phenylethylamine, respectively, and following the synthetic method of Example 1, a white solid (0.16 g, 28.77%) was obtained. MS (ESI, pos.ion) m / z: 546.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.73(d,J=8.8Hz,1H),8.55(d,J=8.0Hz,1H),8.21(dd, J=5.6,2.5Hz,1H),8.01–7.92(m,1H),7.55(t,J=9.1Hz,1H),7.30(q,J=7.5Hz,4H),7.17(t,J =6.9Hz,1H),4.95(p,J=7.0Hz,1H),4.23(t,J=8.5Hz,1H),3.56(s,3H),2.29(s,3H),2.16(s, 3H), 2.02 (dq, J=13.6, 6.7Hz, 1H), 1.36 (d, J=6.9Hz, 3H), 1.25 (d, J=6.5Hz, 3H), 0.94 (s, 3H).

[0286] Example 23: Synthesis of Compound 23

[0287] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compound 5-0 and propargylamine respectively, and following the synthesis method of Example 1, a grayish-white solid (0.22 g, 76.17%) was obtained. MS (ESI, pos.ion) m / z: 514.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),9.42(d,J=8.4Hz,1H),8.84(t,J=5.0Hz,1H),8.19(d,J=3.2Hz,1H),8.02–7.83(m,1H),7.6 1–7.40(m,3H),7.39-7.26(m,3H),5.64(d,J=8.4Hz,1H),3.96-3.81(m,2H),3.56(s,3H),3.12(s,1H),2.30(s,3H),2.15(s,3H).

[0288] Example 24: Synthesis of Compound 24

[0289] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 24-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a yellow solid (0.12 g, 13.84%) was obtained. MS (ESI, pos.ion) m / z: 586.20 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ10.52(s,1H),9.27(d,J=7.9Hz,1H),8.80(d,J=8.6H z,1H),8.21(d,J=2.8Hz,1H),7.99–7.95(m,1H),7.88(d,J=7.9Hz,2H),7.56 -7.47(m,3H),5.16–5.06(m,1H),4.93-4.83(m,1H),3.59(s,3H),2.34(s,3H),2.20(s,3H),1.46(d,J=6.8Hz,3H),1.37(d,J=6.9Hz,3H).

[0290] Example 25: Synthesis of Compound 25

[0291] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 25-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthesis method of Example 1, a pink solid (0.36 g, 37.96%) was obtained. MS (ESI, pos.ion) m / z: 586.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),9.29(d,J=8.1Hz,1H),8.86(d,J=8.7Hz ,1H),8.24(dd,J=5.7,2.5Hz,1H),8.07–7.97(m,1H),7.89(d,J=8.2Hz,2H),7 .55–7.47(m,3H),5.10(p,J=7.0Hz,1H),4.84(dq,J=15.3,7.5Hz,1H),3.57(s ,3H),2.32(s,3H),2.19(s,3H),1.44(d,J=7.0Hz,3H),1.36(d,J=7.1Hz,3H).

[0292] Example 26: Synthesis of Compound 26

[0293] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 24-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a yellow solid (0.14 g, 26.10%) was obtained. MS (ESI, pos.ion) m / z: 586.20 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ10.51(s,1H),9.26(d,J=8.1Hz,1H),8.80(d,J=8.7H z,1H),8.20(dd,J=5.6,2.5Hz,1H),8.02–7.92(m,1H),7.88(d,J=8.2Hz,2H) ,7.56–7.48(m,3H),5.15–5.08(m,1H),4.86(dq,J=15.2,7.4Hz,1H),3.59(s ,3H),2.34(s,3H),2.19(s,3H),1.46(d,J=7.0Hz,3H),1.37(d,J=7.1Hz,3H).

[0294] Example 27: Synthesis of Compound 27

[0295] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 25-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a yellow solid (0.34 g, 67.73%) was obtained. MS (ESI, pos.ion) m / z: 586.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.27(d,J=8.1Hz,1H),8.81(d,J=8.8Hz ,1H),8.21(dd,J=5.7,2.6Hz,1H),7.99–7.93(m,1H),7.88(d,J=8.3Hz,2H),7 .57–7.48(m,3H),5.11(p,J=7.0Hz,1H),4.86(dq,J=15.6,7.7Hz,1H),3.59(s ,3H),2.34(s,3H),2.19(s,3H),1.46(d,J=7.0Hz,3H),1.36(d,J=7.1Hz,3H).

[0296] Example 28: Synthesis of Compound 28

[0297] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (S)-3-buten-2-amine hydrochloride, respectively, and following the synthesis method of Example 1, a gray solid (0.17 g, 63.86%) was obtained. MS (ESI, pos.ion) m / z: 530.20 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.36(d,J=8.1Hz,1H),8.42(d,J=7.7Hz,1H), 8.20(d,J=2.4Hz,1H),7.96(s,1H),7.60-7.46(m,3H),7.37(t,J=6.9Hz,2H),7.33- 7.28(m,1H),5.84–5.69(m,1H),5.68(d,J=8.3Hz,1H),4.85(dd,J=34.0,13.8Hz,2H ),4.41-4.30(m,1H),3.58(s,3H),2.32(s,3H),2.17(s,3H),1.18(d,J=6.6Hz,3H).

[0298] Example 29: Synthesis of Compound 29

[0299] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthesis method of Example 1, a gray solid (0.15 g, 60.69%) was obtained. MS (ESI, pos.ion) m / z: 538.15 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.82(d,J=8.5Hz,1H),8.73(d,J=8.7Hz ,1H),8.21(d,J=3.0Hz,1H),8.03–7.90(m,1H),7.54(t,J=9.0Hz,1H),4.68-4 .58(m,1H),4.27(t,J=8.0Hz,1H),3.60(s,3H),2.39(s,3H),2.24(s,3H),2.0 2(dq,J=13.5,6.6Hz,1H),1.26(d,J=6.9Hz,3H),0.91(dd,J=8.7,7.4Hz,6H).

[0300] Example 30: Synthesis of Compound 30

[0301] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 30-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (45 g, 17.08%) was obtained. MS (ESI, pos.ion) m / z: 598.20 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.50(s,1H),8.78(d,J=8.7Hz,1H),8.21(dd,J=5.6,2.5Hz,1H),8.03–7.92(m,1H),7.84(d,J=8.3Hz,2H) ,7.54(t,J=9.1Hz,1H),7.36(d,J=8.3Hz,2H),4.95–4.73(m,1H),3.60( s,3H),2.38(s,3H),2.22(s,3H),1.40–1.32(m,5H),1.31–1.26(m,2H).

[0302] Example 31: Synthesis of Compound 31

[0303] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compound 30-0 and methylamine hydrochloride, respectively, and following the synthesis method of Example 1, a gray solid (0.17 g, 44.20%) was obtained. MS (ESI, pos.ion) m / z: 516.20 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),9.48(s,1H),8.44–8.31(m,1H),8.22(dd,J=5.6,2.5Hz,1H),8.00–7.94(m,1H),7.78(d,J=8.3Hz,2H),7. 54(t,J=9.1Hz,1H),7.32(d,J=8.3Hz,2H),3.60(s,3H),2.79(d,J=4.5H z,3H),2.38(s,3H),2.22(s,3H),1.36–1.31(m,2H),1.31–1.26(m,2H).

[0304] Example 32: Synthesis of Compound 32

[0305] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.26 g, 93.80%) was obtained. MS (ESI, pos.ion) m / z: 538.20 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.86(d,J=8.8Hz,1H),8.74(d,J=8.9Hz ,1H),8.21(dd,J=5.6,2.5Hz,1H),8.01–7.93(m,1H),7.53(t,J=9.1Hz,1H),4 .60(dq,J=15.3,7.5Hz,1H),4.25(t,J=8.5Hz,1H),3.59(s,3H),2.35(s,3H), 2.22(s,3H),2.07–1.96(m,1H),1.24(d,J=6.9Hz,3H),0.92(t,J=7.1Hz,6H).

[0306] Example 33: Synthesis of Compound 33

[0307] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 17-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a yellow solid (14 mg, 2.35%) was obtained. MS (ESI, pos.ion) m / z: 522.10 [M+H] + .

[0308] Example 34: Synthesis of Compound 34

[0309] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 34-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (50 mg, 20.75%) was obtained. MS (ESI, pos.ion) m / z: 552.20 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.76(dd,J=9.3,6.8Hz,2H),8.21(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.9,2.7Hz,1H),7.55 (t,J=9.1Hz,1H),4.67–4.57(m,1H),4.44(d,J=9.7Hz,1H),3.59(s,3H),2.36(s,3H),2.22(s,3H),1.23(d,J=7.0Hz,3H),0.98(s,9H).

[0310] Example 35: Synthesis of Compound 35

[0311] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 35-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.17 g, 68.92%) was obtained. MS (ESI, pos.ion) m / z: 552.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.77(dd,J=9.3,4.9Hz,2H),8.21(dd,J=5.8,2.7Hz,1H),7.96(ddd,J=9.3,4.9,2.7Hz,1H),7.54(d,J= 18.3Hz,1H),4.61(dt,J=15.2,7.7Hz,1H),4.44(d,J=9.6Hz,1H),3.59(s,3H),2.35(s,3H),2.21(s,3H),1.23(d,J=7.0Hz,3H),0.98(s,9H).

[0312] Example 36: Synthesis of Compound 36

[0313] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 35-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.16 g, 64.74%) was obtained. MS (ESI, pos.ion) m / z: 552.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.75(d,J=8.7Hz,1H),8.70(d,J=9.4Hz,1H),8.21(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.3,4.9,2.7Hz,1H ),7.54(t,J=9.2Hz,1H),4.63(p,J=7.6Hz,1H),4.41(d,J=9.3Hz,1H),3. 60(s,3H),2.38(s,3H),2.23(s,3H),1.24(d,J=7.1Hz,3H),0.97(s,9H).

[0314] Example 37: Synthesis of Compound 37

[0315] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.23 g, 85.72%) was obtained. MS (ESI, pos.ion) m / z: 531.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.86(d,J=8.8Hz,1H),8.74(d,J=8.8Hz,1H),7.87(dd,J=12.2,7.5Hz,1H),7.46–7.36(m,2H),4.67– 4.53(m,1H),4.25(t,J=8.5Hz,1H),3.58(s,3H),2.35(s,3H),2.21(s,3H),2.07–1.96(m,1H),1.24(d,J=6.9Hz,3H),0.92(t,J=7.0Hz,6H).

[0316] Example 38: Synthesis of Compound 38

[0317] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 8-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.24 g, 86.09%) was obtained. MS (ESI, pos.ion) m / z: 531.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.82(d,J=8.6Hz,1H),8.73(d,J=8.8Hz,1H),7.92–7.80(m,1H),7.47–7.37(m,2H),4.62(dq,J=14.9 ,7.3Hz,1H),4.27(t,J=8.1Hz,1H),3.59(s,3H),2.38(s,3H),2.22(s,3H),2.08–1.96(m,1H),1.25(d,J=7.0Hz,3H),0.91(t,J=6.6Hz,6H).

[0318] Example 39: Synthesis of Compound 39

[0319] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 34-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (50 mg, 20.75%) was obtained. MS (ESI, pos.ion) m / z: 552.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.75(d,J=8.8Hz,1H),8.70(d,J=9.4Hz,1H),8.21(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.9,2.7Hz,1H),7 .53(t,J=9.1Hz,1H),4.62(dq,J=15.4,7.7Hz,1H),4.41(d,J=9.4Hz,1H), 3.60(s,3H),2.38(s,3H),2.23(s,3H),1.25(d,J=7.1Hz,3H),0.97(s,9H).

[0320] Example 40: Synthesis of Compound 40

[0321] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 18-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.1 g, 20.55%) was obtained. MS (ESI, pos.ion) m / z: 550.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.76(d,J=7.5Hz,1H),8.42(d,J=8.9Hz,1H),8.21(dd ,J=5.7,2.5Hz,1H),8.04–7.90(m,1H),7.53(t,J=9.1Hz,1H),4.58(dq,J=15.4,7.5Hz,1H),4 .25–4.08(m,1H),3.60(s,3H),2.80–2.68(m,1H),2.40(s,3H),2.24(s,3H),2.20–2.10(m,1H ),1.95–1.85(m,1H),1.81(dd,J=14.9,7.5Hz,2H),1.68–1.54(m,2H),1.23(d,J=6.9Hz,3H).

[0322] Example 41: Synthesis of Compound 41

[0323] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 41-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a brown solid (0.32 g, 58.85%) was obtained. MS (ESI, pos.ion) m / z: 536.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.03(s,1H),8.22(d,J=2.9Hz,1H),8.01–7.94(m,1H),7.91(d,J=8.8Hz,1H),7.54(t,J=9.0Hz,1H),4. 72–4.55(m,1H),3.60(s,3H),2.64–2.54(m,1H),2.39(s,3H),2.35–2. 16(m,6H),1.98–1.89(m,1H),1.86–1.76(m,1H),1.25(d,J=6.8Hz,3H).

[0324] Example 42: Synthesis of Compound 42

[0325] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compound 41-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a brown solid (0.28 g, 52.21%) was obtained. MS (ESI, pos.ion) m / z: 536.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.51 (s, 1H), 9.03 (s, 1H), 8.22 (dd, J = 5.6, 2.5Hz, 1H), 8.0 0–7.94(m,1H),7.92(d,J=9.0Hz,1H),7.54(t,J=9.1Hz,1H),4.69–4.57(m,1H),3.6 0(s,3H),2.64–2.57(m,1H),2.55(s,1H),2.39(s,3H),2.35–2.28(m,1H),2.26(s,3 H),2.24–2.17(m,1H),1.98–1.88(m,1H),1.87–1.78(m,1H),1.25(d,J=7.0Hz,3H).

[0326] Example 43: Synthesis of Compound 43

[0327] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (R)-(-)-1-amino-2-propanol, respectively, according to the synthesis method of Example 1, yielded a white solid (53 mg, 22.1%). MS (ESI, pos.ion) m / z: 534.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.33(d,J=8.4Hz,1H),8.33(t,J=5.7Hz,1H),8.19(dd,J=5.8,2. 7Hz,1H),7.96(ddd,J=9.4,4.9,2.8Hz,1H),7.54(d,J=9.1Hz,1H),7.49(d,J=7.1Hz,2H),7.35(t,J=7.4 Hz,2H),7.29(t,J=7.2Hz,1H),5.67(d,J=8.4Hz,1H),4.69(d,J=4.6Hz,1H),3.64–3.60(m,1H),3.57(s ,3H),3.09(dt,J=12.0,5.8Hz,1H),3.00–2.94(m,1H),2.31(s,3H),2.16(s,3H),0.96(d,J=6.2Hz,3H).

[0328] Example 44: Synthesis of Compound 44

[0329] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 44-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (62 mg, 21.50%) was obtained. MS (ESI, pos.ion) m / z: 646.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.76(dd,J=9.3,4.0Hz,2H),8.20(dd,J=5.8,2.7 Hz,1H),7.96(ddd,J=9.3,4.9,2.8Hz,1H),7.54(t,J=9.1Hz,1H),4.60(p,J=7.4Hz,1H) ,4.44(s,1H),4.35(d,J=9.6Hz,1H),3.58(s,3H),2.34(s,3H),2.20(s,3H),2.10(s,2H ),1.59(d,J=11.8Hz,4H),1.52–1.46(m,4H),1.44–1.36(m,4H),1.23(d,J=6.9Hz,3H).

[0330] Example 45: Synthesis of Compound 45

[0331] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 44-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.17 g, 53.74%) was obtained. MS (ESI, pos.ion) m / z: 646.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.71(t,J=9.5Hz,2H),8.20(dd,J=5.8,2 .7Hz,1H),7.96(dt,J=7.8,3.4Hz,1H),7.54(t,J=9.1Hz,1H),4.66–4.56(m,1H) ,4.43(s,1H),4.32(d,J=9.2Hz,1H),3.59(s,3H),2.37(s,3H),2.22(s,3H),2. 09(s,2H),1.53(d,J=9.9Hz,5H),1.44(d,J=11.3Hz,7H),1.23(d,J=7.0Hz,3H).

[0332] Example 46: Synthesis of Compound 46

[0333] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 46-0 and (S)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (62 mg, 22.4%) was obtained. MS (ESI, pos.ion) m / z: 548.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.32(s,1H),8.29(d,J=8.8Hz,1H),8.21(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.8,2.7Hz, 1H),7.54(t,J=9.1Hz,1H),4.57(dt,J=15.6,7.8Hz,1H),3.60(s,3H),2.40(s,3H),2.28(s,6H),2.24(s,3H),1.25(d,J=7.1Hz,3H).

[0334] Example 47: Synthesis of Compound 47

[0335] Replacing compounds 1-0 and isopropylamine in step 1 of Example 1 with compounds 46-0 and (R)-1,1,1-trifluoroisopropylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (65 mg, 23.7%) was obtained. MS (ESI, pos.ion) m / z: 548.20 [M+H] + .

[0336] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.33(s,1H),8.29(d,J=8.9Hz,1H),8.22(dd,J=5.8,2.7Hz,1H),7.98(dq,J=6.6,2.5Hz,1H ),7.54(t,J=9.1Hz,1H),4.58(dq,J=15.6,7.7Hz,1H),3.60(s,3H),2.40(s,3H),2.28(s,6H),2.24(s,3H),1.25(d,J=7.1Hz,3H).

[0337] Example 48: Synthesis of Compound 48

[0338] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.21 g, 80.12%) was obtained. MS (ESI, pos.ion) m / z: 565.1 [M+H] + .

[0339] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.54(d,J=8.6Hz,1H),9.05(d,J=8.8Hz,1H),7.86(dd,J=12.3,7.5Hz,1H),7.50(d,J=7.3Hz,2H) ,7.45–7.29(m,5H),5.74(d,J=8.6Hz,1H),4.56(dq,J=15.0,7.5Hz,1H),3.57(s,3H),2.32(s,3H),2.16(s,3H),1.16(d,J=6.9Hz,3H).

[0340] Example 49: Synthesis of Compound 49

[0341] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 5-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.22 g, 82.36%) was obtained. MS (ESI, pos.ion) m / z: 565.1 [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.44(d,J=8.1Hz,1H),8.94(d,J=8.5Hz,1 H),7.86(dd,J=11.9,7.2Hz,1H),7.50–7.27(m,7H),5.72(d,J=8.1Hz,1H),4.70 4.52(m,1H),3.57(s,3H),2.32(s,3H),2.16(s,3H),1.28(d,J=6.6Hz,3H).

[0343] Example 50: Synthesis of Compound 50

[0344] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 50-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.21 g, 80.2%). MS (ESI, pos.ion) m / z: 572.0 [M+H] + .

[0345] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.54(d,J=8.6Hz,1H),9.05(d,J=8.9Hz, 1H),8.20(dd,J=5.7,2.6Hz,1H),8.02–7.90(m,1H),7.55(d,J=9.1Hz,1H),7.5 2–7.44(m,2H),7.42–7.36(m,2H),7.35–7.30(m,1H),5.73(d,J=8.7Hz,1H),4. 65–4.48(m,1H),3.58(s,3H),2.32(s,3H),2.17(s,3H),1.16(d,J=7.0Hz,3H).

[0346] Example 51: Synthesis of Compound 51

[0347] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 50-0 and (S)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.19 g, 78.4%). MS (ESI, pos.ion) m / z: 572.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.44(d,J=8.3Hz,1H),8.95(d,J=8.8Hz,1H),7.92–7.81(m,1H),7.51–7.41(m,4H),7.38(t,J=7 .4Hz,2H),7.35–7.29(m,1H),5.71(d,J=8.3Hz,1H),4.70–4.53(m,1H),3.57(s,3H),2.32(s,3H),2.16(s,3H),1.28(d,J=7.0Hz,3H).

[0348] Example 52: Synthesis of Compound 52

[0349] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 50-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.22 g, 86.3%). MS (ESI, pos.ion) m / z: 565.2 [M+H] + ;

[0350] Example 53: Synthesis of Compound 53

[0351] Replacing compound 1-0, isopropylamine, and compound F1 in step 1 of Example 1 with compounds 50-0, (R)-1,1,1-trifluoropropane-2-aminohydrochloride, and compound F3, respectively, according to the synthesis method of Example 1, a white solid (0.18 g, 79.3%) was obtained. MS (ESI, pos.ion) m / z: 581.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.32(d,J=8.5Hz,1H),8.27(d,J=7.5Hz,1H),8. 20(dd,J=5.6,2.4Hz,1H),8.05–7.89(m,1H),7.54(t,J=9.1Hz,1H),7.47(d,J=7.3Hz, 2H),7.36(t,J=7.3Hz,2H),7.33–7.27(m,1H),5.59(d,J=8.5Hz,1H),3.87–3.75(m,1H ),3.57(s,3H),2.32(s,3H),2.16(s,3H),1.10(d,J=6.5Hz,3H),0.98(d,J=6.5Hz,3H).

[0352] Example 54: Synthesis of Compound 54

[0353] Replacing compounds 1-0 and F1 in step 1 of Example 1 with compounds 50-0 and F2 respectively, and following the synthesis method of Example 1, a white solid (0.19 g, 80.8%) was obtained. MS (ESI, pos.ion) m / z: 518.2 [M+H] + .

[0354] Example 55: Synthesis of Compound 55

[0355] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compounds 55-0 and (R)-1,1,1-trifluoropropane-2-aminohydrochloride, respectively, according to the synthesis method of Example 1, yielded a white solid (0.15 g, 72.8%). MS (ESI, pos.ion) m / z: 588.1 [M+H] + .

[0356] Example 56: Synthesis of Compound 56

[0357] Replacing compound 1-0 and isopropylamine in step 1 of Example 1 with compound 55-0 and methylamine hydrochloride, respectively, and following the synthetic method of Example 1, a white solid (0.16 g, 74.5%) was obtained. MS (ESI, pos.ion) m / z: 506.2 [M+H] + .

[0358] The compounds in Table 1 below were synthesized using the method described in Example 1 (i.e., compound 1).

[0359] Table 1

[0360] Synthesis of Compound 127

[0361] Step 1: Synthesis of Compound 127-1

[0362] In a dry reaction flask, methyl 4-iodobenzoate (2.51 g, 9.49 mmol), compound 127-0 (3.25 g, 9.47 mmol), potassium carbonate (3.94 g, 28.48 mmol), 1,4-dioxane (15 mL), and water (15 mL) were added sequentially. After stirring thoroughly at room temperature, Pd(PPh3)4 (0.56 g, 0.47 mmol) was added. The reaction mixture was reacted at 80 °C for 3 h under nitrogen protection, then the heating was turned off and the mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give a white solid (2.08 g, 64.07%).

[0363] MS.ESI(pos.ion)m / z:286[M+H-56] + ; 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=8.4Hz,2H),7.81(d,J=8.3Hz,2H),7.69(d,J=8.0Hz,2H),7 .45(t,J=5.9Hz,1H),7.36(d,J=8.1Hz,2H),4.18(d,J=6.0Hz,2H),3.87(s,3H),1.40(s,9H).

[0364] Step 2: Synthesis of Compound 127-2

[0365] Compound 127-1 (2.04 g, 5.98 mmol), methanol (15 mL), and tetrahydrofuran (15 mL) were added sequentially to a dry reaction flask and stirred at room temperature until homogeneous. A solution of sodium hydroxide (0.97 g, 24.16 mmol) in water (10 mL) was added to the above system, and the resulting reaction mixture was stirred at room temperature for 2 h. The solvent was removed by vacuum evaporation, and water (150 mL) was added to the residue. The pH was adjusted to 2-3 with hydrochloric acid aqueous solution (1 N) while stirring. The mixture was filtered, and the solid was collected. The solid was dried under vacuum at 45 °C for 2 h to give a white solid (1.85 g, 99.04%).

[0366] MS.ESI(pos.ion)m / z:272[M+H-56] + ; 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.01(d,J=8.2Hz,2H),7.78(d,J=8.2Hz,2H),7.69(d,J =7.9Hz,2H),7.44(t,J=5.6Hz,1H),7.35(d,J=7.9Hz,2H),4.18(d,J=5.8Hz,2H),1.40(s,9H).

[0367] Step 3: Synthesis of Compound 127-3

[0368] Compound 127-2 (0.5 g, 1.53 mmol), HATU (1.17 g, 3.09 mmol), and DMF (10 mL) were added sequentially to a dry reaction flask and stirred at room temperature until homogeneous. Isopropylamine (0.1 g, 1.62 mmol) and DIPEA (1.02 g, 7.87 mmol) were then added, and the reaction was carried out at 40 °C for 12 h under nitrogen atmosphere. The heating was turned off, and the mixture was cooled to room temperature. The reaction solution was diluted with EA (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. EA (3 mL) was added to the residue, and the mixture was stirred at room temperature for 5 h. After filtration, the solid was washed with EA (3 mL) and dried under vacuum at room temperature for 2 h to obtain a white solid (0.53 g, 93.90%).

[0369] MS.ESI(pos.ion)m / z:369[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=7.7Hz,1H),7.93(d,J=8.2Hz,2H),7.73(d,J=8.1Hz,2H),7.68(d,J=7.9H z,2H),7.45(t,J=5.6Hz,1H),7.34(d,J=7.9Hz,2H),4.27–4.01(m,3H),1.40(s,9H),1.18(d,J=6.5Hz,6H).

[0370] Step 4: Synthesis of Compound 127-4

[0371] Compound 127-3 (0.11 g, 0.30 mmol) and DCM (5 mL) were added sequentially to a dry reaction flask and stirred thoroughly at room temperature. Trifluoroacetic acid (2 mL) was then added, and the mixture was stirred at room temperature for 1 h. The solvent was removed by vacuum distillation to give a pale yellow oil (115 mg, 100%). MS.ESI(pos.ion) m / z: 269 [M+H] + .

[0372] Step 5: Synthesis of Compound 127

[0373] In a dry reaction flask, 127-4 (0.12 g, 0.30 mmol), compound F1 (0.10 g, 0.30 mmol), HATU (0.22 g, 0.59 mmol), and DMF (5 mL) were added sequentially. The mixture was stirred thoroughly at room temperature, and then DIPEA (0.19 g, 1.45 mmol) was added. The reaction mixture was reacted at 40 °C for 4 h under nitrogen protection. The heating was turned off, and the mixture was cooled to room temperature. The reaction solution was diluted with EA (100 mL), washed with saturated sodium chloride aqueous solution (100 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. EA (2 mL) was added to the residue, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, and the solid was washed with EA (2 mL). The solid was dried under vacuum at room temperature for 2 h to give a white solid (83 mg, 47.3%).

[0374] MS:(ESI,neg.ion)m / z:585.2[MH] - ; 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.26(t,J=5.9Hz,1H),8.26(d,J=7.7Hz,1H),7.94(d,J=8.2Hz,2H),7.87(dd,J=11.9,7.8Hz,1H),7. 79–7.70(m,4H),7.49–7.36(m,4H),4.46(d,J=5.9Hz,2H),4.18–4.07(m,1H),3.59(s,3H),2.37(s,3H),2.22(s,3H),1.19(d,J=6.6Hz,6H).

[0375] Compound 128 was prepared using the same synthetic method as compound 127.

[0376] Pale yellow solid (75.2 mg, 69.4%). MS: (ESI, pos.ion) m / z: 601.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.22(d,J=8.0Hz,1H),8.24(d,J=7.5Hz,1 H),7.93(d,J=7.9Hz,2H),7.86(dd,J=12.5,8.2Hz,1H),7.79–7.67(m,4H),7.50 (d,J=7.8Hz,2H),7.45–7.37(m,2H),5.17–5.04(m,1H),4.20–4.06(m,1H),3.57 (s,3H),2.34(s,3H),2.20(s,3H),1.48(d,J=6.6Hz,3H),1.18(d,J=6.3Hz,6H).

[0377] Synthesis of Compound 129

[0378] Step 1: Synthesis of Compound 129-1

[0379] Compound 129-0 (0.1 g, 0.58 mmol) was dissolved in acetonitrile (3 mL) in a single-necked flask. K₂CO₃ (0.24 g, 1.74 mmol) and ethyl bromoacetate (0.12 g, 0.70 mmol) were added, and the mixture was reacted at 40 °C for 12 h. The heating was turned off, and the mixture was cooled to room temperature. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was collected. The organic phase was washed with saturated sodium chloride aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA (V / V) = 0 to 1 / 5) to give a colorless oil (0.13 g, 86.7%). MS (ESI, pos.ion) m / z: 259.2 [M+H] + ;MS(ESI,pos.ion)m / z:203.1(Mt-Bu+H) + .

[0380] Step 2: Synthesis of Compound 129-2

[0381] Compound 129-1 (0.13 g, 0.50 mmol) was dissolved in methanol (15 mL), and a solution of lithium hydroxide monohydrate (0.042 g, 1.0 mmol) in water (5 mL) was added. The reaction was carried out at room temperature for 12 h. The solvent was removed under reduced pressure, and water (10 mL) was added to the residue. The pH was adjusted to 2–3 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness to give a colorless oil (0.096 g, 80.2%). MS (ESI, neg.ion) m / z: 229.4 [MH] - .

[0382] Step 3: Synthesis of Compound 129-3

[0383] Compound 129-2 (0.12 g, 0.52 mmol), isopropylamine (0.031 g, 0.52 mmol), and HATU (0.24 g, 0.62 mmol) were dissolved in DMF (2 mL) in a single-necked flask. DIPEA (0.34 g, 2.6 mmol) was added, and the mixture was reacted at room temperature for 12 h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was collected. The phase was washed with saturated sodium chloride aqueous solution (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA (V / V) = 0 to 1 / 5) to give a white solid (0.084 g, 60.3%). MS (ESI, pos.ion) m / z: 272.2 [M+H] + .

[0384] Step 4: Synthesis of compound 129-4

[0385] Compound 129-3 (0.5 g, 1.84 mmol) was dissolved in methanol (15 mL), and TMSCl (2 g, 18.43 mmol) was added. The reaction was carried out at room temperature for 12 h, and the solvent was removed by vacuum evaporation to give a pale yellow oil (0.32 g, 95.2%). MS (ESI, pos.ion) m / z: 172.1 [M+H] + .

[0386] Step 5: Synthesis of Compound 129

[0387] Compound 129-4 (0.1 g, 0.58 mmol), compound F1 (0.16 g, 0.49 mmol), and HATU (0.22 g, 0.58 mmol) were dissolved in DMF (3 mL) in a single-necked flask. DIPEA (0.31 g, 2.43 mmol) was added, and the mixture was reacted at room temperature for 12 h. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was collected. The mixture was washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give a white solid (0.13 g, 54.7%). MS (ESI, pos.ion) m / z: 490.2 [M+H] + .

[0388] The compounds in Table 2 below were obtained using the same synthetic method as compound 129.

[0389] Table 2

[0390] Performance testing

[0391] Biological tests

[0392] 1. Evaluation of the cytotoxicity and HBV DNA replication inhibition activity of compounds in HepAD38 cells (qPCR method)

[0393] HBV cell line and culture conditions

[0394] HepAD38: Ladner et al. (Ladner, Otto et al. 1997) ligated the tetracycline-sensitive cytomegalovirus (CMV) promoter to the PBR322 plasmid and linked it to ayw subtype HBV DNA to form the ptetHBV plasmid. HepAD38 cell line was obtained by transfecting HepG2 cells. Due to the disruption of the pre-C region gene, the HBV DNA yield was approximately 11 times higher than that of HepG2.2.15 cells. HBV replication can be regulated using tetracycline, and the culture time required is only half that of HepG2.2.15 cells, making it suitable for studying the HBV replication process and intermediates, as well as screening anti-HBV drugs. HepAD38 cells were cultured in DMEM / F-12K medium containing 10% FBS and 1% penicillin antibiotics (also containing 300 ng / mL Tetracycline and 400 μg / mL G418).

[0395] Viral particle DNA secreted by HepAD38 cells can be quantified using qPCR, thereby detecting the effect of compounds on viral replication.

[0396] In vitro cytotoxicity assay

[0397] HepAD38 cells were resuscitated and, after reaching confluence and good condition, digested, counted, and diluted with DMEM / F-12K medium containing 10% FBS and 1% penicillin antibiotics to a concentration of 1×10⁻⁶. 5 Cell suspension was seeded at a rate of 100 μL per well in a 96-well plate (covering the entire plate), and incubated at 37°C in a 5% CO2 incubator for 24 h. After 24 h, the old culture medium was discarded, and 200 μL of fresh DMEM / F-12K medium containing 2% FBS and 1% antibiotics was added.

[0398] Compound preparation and cell treatment in in vitro cytotoxicity assays: The compound was dissolved in DMSO to a final concentration of 20 mM, and then subjected to eight 4-fold dilutions, with the highest concentration being 20 mM. 1 μL of each serially diluted compound was added to each well of the cell plate, with the highest final concentration being 100 μM (200-fold dilution). Staurosporine (Selleck, CAS No. 62996-74-1) was used as a positive control compound, with a maximum concentration of 1 μM. 1 μL of DMSO was added to each negative control well, resulting in a final concentration of 0.5%.

[0399] After 72 hours, the old culture medium was discarded, and culture medium containing 10% CCK8 solution was added. The mixture was incubated for 20-40 minutes, and the OD values ​​were measured using a microplate reader. The data were exported to calculate the inhibition rate. The CCK values ​​of the compounds were then calculated using a nonlinear regression model generated by Graphpad Prism 5 software and a curve was plotted. 50.

[0400] In vitro anti-HBV activity assay

[0401] After resuscitating HepAD38 cells to a good condition, Tetracycline (final concentration 300 ng / ml) and G418 (final concentration 400 μg / ml) were added to the culture medium. Virus expression was inhibited in the presence of Tetracycline. After confluence, the cells were digested, counted, and diluted to a concentration of 2 × 10⁻⁶ cells using DMEM / F-12K medium containing 10% FBS (containing Tetracycline at a final concentration of 300 ng / ml and G418 at a final concentration of 400 μg / ml, plus 1% penicillin antibody). 5 Cell suspension was seeded at a rate of 100 μL per well in a 96-well plate (covering the entire plate), and incubated at 37°C in a 5% CO2 incubator for 24 h. After 24 h, the old culture medium was discarded, and 200 μL of fresh DMEM / F-12K medium containing 2% FBS and 1% antibiotics was added.

[0402] Compound preparation and cell treatment in the antiviral assay: The compound was dissolved in DMSO to 20 mM, further diluted with DMSO to 800 μM, and then subjected to eight 4-fold dilutions, with the highest concentration being 800 μM. 1 μL of each serially diluted compound was added to each well of the cell plate, with the highest final concentration being 4 μM (200-fold dilution). ALG-001075 was used as a positive control compound, with a highest concentration of 4 μM. 1 μL of DMSO was added to each negative control well, resulting in a final concentration of 0.5%.

[0403] HBV DNA Q-PCR

[0404] Quantitative PCR (q-PCR) was performed using the Sansure Biotech 48-sample (PCR-fluorescent probe method) one-step hepatitis B virus nucleic acid quantitative assay kit. 2.5 μL of supernatant was aspirated for q-PCR. Before use, the kit reagents were thawed and vortexed to mix. After centrifugation, the enzyme mixture was placed on ice until ready to use, ensuring subsequent steps were performed on ice. 2.5 μL of sample release agent and 2.5 μL of test sample supernatant (experimental group, control group, standard curve group) were added to each well of the q-PCR plate. Viral DNA copy number was obtained for each well after the q-PCR reaction. The concentration-viral copy number was processed using Graphpad Prism 5 software, and the EC50 of the compound on viral replication was calculated using a four-parameter nonlinear regression model. 50 The experimental results are shown in Table A.

[0405] Table A: EC5 of compounds on viral replication 50 result.

[0406] Conclusion: Experimental results show that the compound of the present invention has good inhibitory activity against HBV.

[0407] 2. Stability tests of the compounds of the present invention in liver microsomes of different species.

[0408] Method for testing the liver microsomal stability of the compounds of this invention in different species:

[0409] Add 30 μL of a mixture of blank solution and liver microsomes to each well of a 96-well plate. Add 15 μL of buffer solution containing the analyte to each well, performing two replicates. After pre-incubation at 37°C for 10 min, add 15 μL of NADPH solution (8 mM) at each time point. The final concentration of the analyte is 1 μM, the concentration of liver microsomes is 0.5 mg / mL, and the final concentration of NADPH is 2 mM. Incubate for 0, 15, 30, and 60 min, respectively. After incubation, add 150 μL of acetonitrile (containing internal standard) to the mixture. Centrifuge the acetonitrile-diluted sample at 4000 rpm for 5 min, and collect 150 μL of the supernatant for LC-MS / MS analysis.

[0410] Table B: Hepatic microsomal stability data of compounds in different species N / A indicates that it was not measured.

[0411] Conclusion: The compounds of this invention exhibit good stability in liver microsomes of different species.

[0412] 3. PK test of the compound of the present invention in SD rats

[0413] Experimental method for PK determination of compounds in SD rats:

[0414] Rats were administered the test compound orally at doses of 2.5 mg / kg or 5 mg / kg, or intravenously at doses of 0.5 mg / kg, 1 mg / kg, or 2 mg / kg.

[0415] Following drug administration, venous blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7, and 24 hours) and collected in anticoagulant tubes containing EDTA-K2. Plasma was prepared by centrifugation. After protein precipitation, the supernatant of the plasma samples was collected, and its concentration was determined by multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model method with WinNonlin 6.3 software.

[0416] Table C: PK data of the compound in SD rats

[0417] Conclusion: Pharmacokinetic data show that the compound of this invention has good pharmacokinetic properties in SD rats and has good application prospects in anti-HBV virus.

[0418] Finally, it should be noted that there are other ways to implement this invention. Accordingly, the embodiments of this invention are described as examples, but are not limited to the content described in this invention. It is understood that the above embodiments are exemplary and should not be construed as limiting the invention. Those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of this invention. These may also be modifications made within the scope of this invention or equivalent content added to the claims. All publications or patents cited in this invention are to be used as references in this invention.

Claims

1. A compound, which is a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I). in, Each R 1 and R 2 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, -OH, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, methoxy, or ethoxy groups; R 3 The radicals are hydrogen, deuterium, F, Cl, Br, I, CN, -OH, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C. 1-4 Halogenated alkyl, methoxy, or ethoxy groups; Each R 4 R a R b R c R d R e R f R g R h R j and R k Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl, or R e R f Together with the carbon atoms they are attached to, they form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups; R is -L1-CO-NR b R 6 , -CHR 1a -C(=O)-NR c R 7 , -CR e R f -L2-C(=O)-NR g R 8a , -CH(C(=O)-NH2)-C(=O)-NH2, -CHR 1b CHR 1c -C(=O)-NR d R 8 , -L3-R 11 , -CHR 1d -C(=O)-R 9 , -L4-C(=O)-NR k R 12 , -L5-CR 1e R 1f -C(=O)-NR j R 13 or -CHR 1h CHR 1j -C(=O)-R 14 ; L4 is C 2-8 Alkylene, wherein, the C shown 2-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 replace; Each of L1, L2, L3, and L5 is independently C 3-6 cycloalkyl, C 4-8 Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 An aryl group or a heteroaryl group composed of 5-10 ring atoms, wherein the C 3-6 cycloalkyl, C 4-8 Carbon-linked bridged ring groups, heterocyclic groups composed of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w1 replace; R 6 For H, methyl, -C(=NH)NH2, C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 2-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 replace; R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-7 ring atoms, or heteroaryl group consisting of 5-12 ring atoms, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, and heteroaryl groups consisting of 5-12 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 replace; Each R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein -C(=NH)NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-7 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 replace; Each R 9 R 11 and R 14 Independently for C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 Aryl or heteroaryl group composed of 5-12 ring atoms, wherein the C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-12 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-12 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 replace; Each R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the -(CH2) m -R 10 -(CH2) m -、C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 8-12 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 replace; R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6 replace; Each R w1 R w2 R w3 R w4 R w5 R w6 R w7 and R w8 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 An aryl group or a heteroaryl group composed of 5-6 ring atoms, wherein the amino group, -C(=O)OC 1-6 Alkyl group, -C(=O)NC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, hydroxyl group C 1-6 Alkyl, carboxyl C 1-6 Alkyl groups, heterocyclic groups consisting of 5-6 ring atoms, C 6-12 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w replace; Each R w Independently, it can be deuterium, F, Cl, Br, CN, =O, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, C 2-4 Halogenated alkoxy or C 1-4 Alkoxy; Each n and m is independently 1, 2, 3, 4 or 5.

2. The compound according to claim 1, wherein each L1, L2, L3 and L5 is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or azacyclobutyl. Oxyheterobutyl, thioheterobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl or isoquinolinyl, wherein, The cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups mentioned above... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w1 replace.

3. The compound according to claim 1 or 2, wherein R 6 For H, methyl, -C(=NH)NH2, C 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 Aryl or heteroaryl groups composed of 5-10 ring atoms, wherein... The C mentioned 2-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w2 replace.

4. The compound according to any one of claims 1-3, wherein R 6 H, methyl, -C(=NH)NH2, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl The following groups are listed: propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purine, quinolinyl, or isoquinolinyl, wherein... The following are listed: ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl 3-Alynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thioheridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace.

5. The compound according to any one of claims 1-4, wherein R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, heterocyclic groups consisting of 3-6 ring atoms, or heteroaryl groups consisting of 5-10 ring atoms, wherein, The C mentioned 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, and heteroaryl groups consisting of 5-10 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w3 replace; Each R 8a R 8 R 9a R 13 and R 12 Independently -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 A heteroaryl group composed of aryl or 5-10 ring atoms, wherein -C(=NH)NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w7 replace.

6. The compound according to any one of claims 1-5, wherein R 7 -C(=NH)NH2, -CHR h -C(=O)-NHR 9a Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, propargyl The following groups are included: alkynyl, 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinebutyl, oxaziridinebutyl, thioheridinebutyl, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purine, quinolinyl, or isoquinolinyl, wherein... The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl propynyl, 1-ethynylbutyl, 2 -Oynylbutyl, 3-Oynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w3 replace; Each R 8a R 8 R 9a R 13 and R 12 Independently, -C(=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, Propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolylalkyl, pyrazolylalkyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl or isoquinolinyl, wherein the -C (=NH)NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ethynylbutyl, 2 -Oynyl butyl, 3-Oynyl butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine butyl, oxaziridine, thioaziridine, pyrrolyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, tetrahydrothiophene, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w7 replace.

7. The compound according to any one of claims 1-6, wherein each R 9 R 11 and R 14 Independently for C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 Aryl or heteroaryl groups composed of 5-10 ring atoms, wherein... The C mentioned 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-10 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w4 replace.

8. The compound according to any one of claims 1-7, wherein each R 9 R 11 and R 14 Independently, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirrobutyl, oxacyclobutyl, thiohexyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purine, quinolinyl, or isoquinolinyl, wherein, The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thiohexyl, pyrrolyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, etc. Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indoleyl, purinyl, quinolinyl, or isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w4 replace.

9. The compound according to any one of claims 1-8, wherein each R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 Aryl or heteroaryl groups composed of 5-10 ring atoms, wherein... The -(CH2) mentioned m -R 10 -(CH2) m -、C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, C 9-11 Carbon-bridged cyclic groups, heterocyclic groups composed of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w5 replace; R 10 For -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the amino group, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-4 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, C 6-10 The aryl group and the heteroaryl group consisting of 5-10 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R groups. w6 replace.

10. The compound according to any one of claims 1-9, wherein each R 1a R 1b R 1c R 1d R 1e R 1f R 1h and R 1j Independently, it can be H, deuterium, F, Cl, Br, or -(CH2). m -R 10 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, or isoquinolinyl, wherein... The -(CH2) mentioned m -R 10 -(CH2) m -, Methyl, Ethyl, n-propyl, Isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, -CH2OH, -CH2CH2OH, -CHOHCH3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, Vinyl, Propylene, Allyl, Ethynyl, Propylene propynyl, Propylene, 1-Eynylbutyl, 2-Eynylbutyl, 3-Eynylbutyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w5 replace; R 10 -SH, -OH, -COOH, -C(=O)NH2, -NH-C(=NH)NH2, amino, methyl thio, ethyl thio, n-propyl thio, isopropyl thio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, thiohexyl, pyrrolidinyl, pyrazolylyl Imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazine, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indole, purine, quinoline The amino group or isoquinolinyl group, wherein the amino group, methylthio, ethylthio, n-propylthio, isopropylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-yntynebutyl, 2-yntynebutyl, 3-yntynebutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydro Thionyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, phenyl, naphthyl, pyrroleyl, pyridinyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazine, pyridazine, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophene, indole, purine, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 R groups. w6 replace.

11. The compound according to any one of claims 1-10, wherein L4 is C 3-8 Alkylene, wherein, C shown 3-8 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replace; or L4 is C 3-6 Alkylene, wherein, the C shown 3-6 The alkylene group is not substituted or is represented by 1, 2, 3 or 4 R groups. w8 Replace; or L4 is -(CH2)2-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, or -(CH2)4-, wherein -(CH2)3-, -(CH2)3-, -CH2C(CH3)2-, -C(CH3)2CH2-, -CH2CH2C(CH3)2-, and -(CH2)4- are each independently unsubstituted or replaced by 1, 2, 3, or 4 R groups. w8 replace.

12. The compound according to any one of claims 1-11, wherein each R w1 R w2 R w3 R w4 R w5 R w6 R w7 and R w8 Independently, it can be deuterium, F, Cl, Br, I, CN, =O, -OH, -SH, -COOH, nitro, amino, or -C(=O)OC. 1-4 Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2F, -CH2Cl, -C HF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)C F3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl Phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein, The amino group, -C(=O)OC 1-4 Alkyl, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)NHCH2CH2CH3, -C(=O)NHCH(CH3)2, -C(=O)NHCH2CH2CH2CH3, -C(=O)NHCH2CH(CH3)2, -C(=O)NHC(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2 , -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CH3)CF3 , -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, carboxyl C 1-4 Alkyl, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl Phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w replace.

13. The compound according to any one of claims 1-12, wherein it is a compound of formula (II) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II). in, Each R, R 1 R 2 R 3 R 4 and R a It has the definition as described in any one of claims 1-11.

14. The compound according to any one of claims 1-13, comprising one of the following structures: Or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.

15. A pharmaceutical composition comprising the compound of any one of claims 1-14, and pharmaceutically acceptable excipients thereof.

16. The pharmaceutical composition of claim 15, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators, or interferons.

17. The pharmaceutical composition of claim 15, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir disoproxil fumarate, entecavir, adefovir disoproxil fumarate, alfaferone, alloferon, simvastatin, clavudine, emtricitabine, famciclovir, bacalin CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, rofloxacin-A, cizonan, eufovac, amplivir, phosphazid, heplisav, interferon α-2b, levamisole, or propafenone.

18. Use of the compound of any one of claims 1-14 or the pharmaceutical composition of any one of claims 15-17 in the preparation of a medicament for the prevention, treatment, or relief of a patient’s viral disease.

19. The use according to claim 18, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

20. The use according to claim 19, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

21. The compound according to any one of claims 1-14 or the pharmaceutical composition according to any one of claims 15-17 is used for the prevention, treatment, or relief of viral diseases in patients.

22. The compound or pharmaceutical composition according to claim 21, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

23. The compound or pharmaceutical composition according to claim 22, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

24. A method for preventing, treating, or alleviating a viral disease in a patient, comprising administering to the patient an effective therapeutic amount of the compound of any one of claims 1-14 or the pharmaceutical composition of any one of claims 15-17.

25. The method of claim 24, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

26. The method according to claim 25, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

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