Novel amide pyrrole compounds and their use in medicine

Abstract

The present application relates to a novel amide pyrrole compound and its use in medicine, especially as a drug for treating and / or preventing hepatitis B virus infection or diseases caused by hepatitis B virus infection. Specifically, the present application relates to a compound represented by general formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and the use thereof in the preparation of a medicament, especially 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 specification.

Description

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 for the treatment and / or prevention of 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]

[0008] Among them, R 1 C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 cycloalkyl, C 5-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 cycloalkyl, C 5-10 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. w1 replace;

[0009] Each R 2 and R 3 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, methoxy, or ethoxy groups;

[0010] Each R 4 R a R b and R c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups;

[0011] Ring A is

[0012] Where X is N or CR 10 Y is either O or S;

[0013] Each R 11 and R 11a Independently, it can be hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, 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, C 1-4 Halogenated alkyl or C 1-4 Alkoxy;

[0014] Each n1 and n2 is independently 1, 2, 3, or 4;

[0015] Each R 5 R 6 R 7 R 8 R 9 and R 10 Independently, H, deuterium, CN, -C (=O) OR 1a -C(=O)NR 1b R 1c -C(=O)R,C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-10 Aryl or heteroaryl group composed of 5-6 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, 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. w2 replace;

[0016] Each R 1a Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C 1-4 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w1 replace;

[0017] Each R 1b and R 1c Independently hydrogen, deuterium, -S(=O)2C1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 Cycloalkyl or heterocyclic groups consisting of 4-6 ring atoms, or R 1b and R 1c Together with the nitrogen atoms bonded to them, they form a heterocyclic group consisting of 3-7 ring atoms, wherein the -S(=O)2C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 4-6 ring atoms, and heterocyclic groups consisting of 3-7 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R atoms. w3 replace;

[0018] Each R is independently C 1-6 Alkyl, C 3-6 A cycloalkyl group or a heterocyclic group consisting of 3-7 ring atoms, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl groups and heterocyclic groups consisting of 3-7 ring atoms are each independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w4 replace;

[0019] Each R w1 Independently, it can be deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF6, -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(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, C 2-4 Halogenated alkoxy or C 1-4 Alkoxy, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy and ethoxy.

[0020] Each Rw2 R w3 and R w4 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 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, carboxyl group C 1-6 Alkyl, 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, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, carboxyl group C 1-6 Alkyl, 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. w1 replace.

[0021] In some implementation schemes, R 1 C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl groups consisting of 5-6 ring atoms or 7-10 ring atoms, wherein the C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl groups consisting of 5-6 ring atoms and heteroaryl groups consisting of 7-10 atoms are each independently unsubstituted or converted by 1, 2, 3 or 4 R groups. w1 replace;

[0022] Among them, each R w1 This has the meaning described in this invention. In some embodiments, R 1The following are compounds: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purineyl, quinolinyl, or isoquinolinyl, wherein the methyl, ethyl, ... n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, 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] Among them, each R w1 It has the meaning described in this invention.

[0024] In some implementation schemes, each R 5 R 6 R 7 R 8 R 9 and R 10 Independently, H, deuterium, CN, -C (=O) OR 1a -C(=O)NR 1b R 1c-C(=O)R, 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(CF3)2, -CF2CH2CH3, -CH2CH2 CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein... Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CH F2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace;

[0025] Among them, each R 1a R 1b R 1c R and R w2 It has the meaning described in this invention.

[0026] In some implementation schemes, each R 1b and R 1c Independently hydrogen, deuterium, -S(=O)2C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 alkenyl, C 3-6 Cycloalkyl or heterocyclic groups consisting of 4-6 ring atoms, or R 1b and R 1cTogether with the nitrogen atoms bonded to them, they form a heterocyclic group consisting of 3-6 ring atoms, wherein the -S(=O)2C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 alkenyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 4-6 ring atoms, and heterocyclic groups consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 R atoms. w3 replace;

[0027] Among them, each R w3 It has the meaning described in this invention.

[0028] In some implementation schemes, each R 1b and R 1c Independently, it is hydrogen, deuterium, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-n-propyl, -S(=O)2-isopropyl, -S(=O)2-n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazineyl, wherein the -S =O)2-methyl, -S(=O)2-ethyl, -S(=O)2-n-propyl, -S(=O)2-isopropyl, -S(=O)2-n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 Rs. w3 Replace; or R 1b and R 1c Together with the nitrogen atoms attached to them, they form azircyclic propyl, azircyclic butyl, pyrrolidinyl, pyrazolyl, imidazoyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazine, wherein each of the azircyclic propyl, azircyclic butyl, pyrrolidinyl, pyrazolyl, imidazoyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine groups is independently unsubstituted or surrounded by 1, 2, 3, or 4 R atoms. w3 replace;

[0029] Among them, each R w3 It has the meaning described in this invention.

[0030] In some implementation schemes, each R is independently C. 1-4 A heterocyclic group consisting of alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3-6 ring atoms, wherein the C... 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and heterocyclic groups consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 R atoms. w4 replace;

[0031] Among them, each R w4 It has the meaning described in this invention.

[0032] In some embodiments, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinepropyl, aziridinebutyl, oxacyclobutyl, thioheridinebutyl, pyrrolidinyl, pyrazolylyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazineyl, wherein... The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, aziridine, oxazoridine, thiohexacyclic, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine groups are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w4 replace;

[0033] Among them, each R w4 It has the meaning described in this invention.

[0034] In some implementation schemes, each R w2 R w3 and R w4 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. w1 replace;

[0035] Among them, each R w1 It has the meaning described in this invention.

[0036] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients.

[0037] In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] In some other embodiments, the uses described in this invention refer to diseases caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I) or formula (II).

[0052] 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.

[0053] Detailed Description of the Invention

[0054] Definitions and general terms

[0055] 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.

[0056] 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. thEd., 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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), fluorovinyl (-CH=CHF,-CF=CH2), etc.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, etc.

[0068] 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.

[0069] 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 ring system consisting of 3-12 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 4-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 3-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 4-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 3-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group consisting of 5-6 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-10 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group consisting of 8-10 ring atoms; in some embodiments, the heterocyclic group is a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms; in other embodiments, the heterocyclic group... 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073]

[0074] 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.

[0075] 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.

[0076]

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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 document 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.

[0083] It should also be noted that the present invention... R in 11 and R 11a To substitute on the pyrrole ring, i.e., R 11 The substitution can be made at the * position in equation (I-1), R 11a The * sign in equation (I-2) can be replaced:

[0084]

[0085] 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.

[0086] 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.

[0087] 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.

[0088] "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.

[0089] 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.

[0090] 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.

[0091] The term "pharmaceutically acceptable salt" as used in this invention 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, hydrobromic acids, 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.

[0092] 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.

[0093] 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.

[0094] Description of the compounds of the present invention

[0095] The compounds involved in this invention, and their pharmaceutically acceptable compositions, can effectively inhibit HBV infection.

[0096] 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).

[0097]

[0098] Among them, R 1 C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C3-6 cycloalkyl, C 5-10 An aryl group or a heteroaryl group consisting of 5-10 ring atoms, wherein the C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 cycloalkyl, C 5-10 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. w1 replace;

[0099] Each R 2 and R 3 Independently, it can be hydrogen, deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 Halogenated alkyl, methoxy, or ethoxy groups;

[0100] Each R 4 R a R b and R c Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups;

[0101] Ring A is

[0102] Where X is N or CR 10 Y is either O or S;

[0103] Each R 11 and R 11a Independently, it can be hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl, 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, C 1-4 Halogenated alkyl or C 1-4 Alkoxy;

[0104] Each n1 and n2 is independently 1, 2, 3, or 4;

[0105] Each R 5 R 6 R 7 R 8 R 9 and R 10 Independently, H, deuterium, CN, -C (=O) OR 1a-C(=O)NR 1b R 1c -C(=O)R,C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-10 Aryl or heteroaryl group composed of 5-6 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, 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. w2 replace;

[0106] Each R 1a Independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or C 1-4 Halogenated alkyl groups, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C 1-4 The alkyl halide is independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w1 replace;

[0107] Each R 1b and R 1c Independently hydrogen, deuterium, -S(=O)2C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 Cycloalkyl or heterocyclic groups consisting of 4-6 ring atoms, or R 1b and R 1c Together with the nitrogen atoms bonded to them, they form a heterocyclic group consisting of 3-7 ring atoms, wherein the -S(=O)2C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkynyl group, C 2-6 alkenyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 4-6 ring atoms, and heterocyclic groups consisting of 3-7 ring atoms are each independently unsubstituted or converted by 1, 2, 3, or 4 R atoms. w3 replace;

[0108] Each R is independently C 1-6 Alkyl, C 3-6 A cycloalkyl group or a heterocyclic group consisting of 3-7 ring atoms, wherein the C 1-6Alkyl, C 3-6 Cycloalkyl groups and heterocyclic groups consisting of 3-7 ring atoms are each independently unsubstituted or surrounded by 1, 2, 3 or 4 R groups. w4 replace;

[0109] Each R w1 Independently, it can be deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF6, -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(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, phenyl, -OCF3, C 2-4 Halogenated alkoxy or C 1-4 Alkoxy, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy and ethoxy.

[0110] Each R w2 R w3 and R w4 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 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, carboxyl group C 1-6 Alkyl, 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, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, carboxyl group C 1-6Alkyl, 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. w1 replace.

[0111] In some embodiments, the present invention relates to a compound of formula (II) or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II).

[0112]

[0113] Among them, each R a R b R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 11 n1 has the meaning described in this invention.

[0114] In some implementation schemes, R 1 C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl groups consisting of 5-6 ring atoms or 7-10 ring atoms, wherein the C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl groups consisting of 5-6 ring atoms and heteroaryl groups consisting of 7-10 atoms are each independently unsubstituted or converted by 1, 2, 3 or 4 R groups. w1 replace;

[0115] Among them, each R w1 This has the meaning described in this invention. In some embodiments, R 1The following are compounds: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indoleyl, purineyl, quinolinyl, or isoquinolinyl, wherein the methyl, ethyl, ... n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrroleyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, 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;

[0116] Among them, each R w1 It has the meaning described in this invention.

[0117] In some implementation schemes, each R 5 R 6 R 7 R 8 R 9 and R 10 Independently, H, deuterium, CN, -C (=O) OR 1a -C(=O)NR 1b R 1c-C(=O)R, 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(CF3)2, -CF2CH2CH3, -CH2CH2 CH2F, -CH2CH2CHF2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein... Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CH F2, -CH2CH2CF3, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w2 replace;

[0118] Among them, each R 1a R 1b R 1c R and R w2 It has the meaning described in this invention.

[0119] In some implementation schemes, each R 1b and R 1c Independently hydrogen, deuterium, -S(=O)2C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 alkenyl, C 3-6 Cycloalkyl or heterocyclic groups consisting of 4-6 ring atoms, or R 1b and R 1cTogether with the nitrogen atoms bonded to them, they form a heterocyclic group consisting of 3-6 ring atoms, wherein the -S(=O)2C 1-4 Alkyl, C 1-4 Alkyl, C 2-4 alkynyl group, C 2-4 alkenyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 4-6 ring atoms, and heterocyclic groups consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 R atoms. w3 replace;

[0120] Among them, each R w3 It has the meaning described in this invention.

[0121] In some implementation schemes, each R 1b and R 1c Independently, it is hydrogen, deuterium, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2-n-propyl, -S(=O)2-isopropyl, -S(=O)2-n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazineyl, wherein the -S =O)2-methyl, -S(=O)2-ethyl, -S(=O)2-n-propyl, -S(=O)2-isopropyl, -S(=O)2-n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propynyl, propynyl, 1-ynylyl, 2-ynylyl, 3-ynylyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxaziridine, thioaziridine, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 Rs. w3 Replace; or R 1b and R 1c Together with the nitrogen atoms attached to them, they form azircyclic propyl, azircyclic butyl, pyrrolidinyl, pyrazolyl, imidazoyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazine, wherein each of the azircyclic propyl, azircyclic butyl, pyrrolidinyl, pyrazolyl, imidazoyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine groups is independently unsubstituted or surrounded by 1, 2, 3, or 4 R atoms. w3 replace;

[0122] Among them, each R w3 It has the meaning described in this invention.

[0123] In some implementation schemes, each R is independently C. 1-4 A heterocyclic group consisting of alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3-6 ring atoms, wherein the C... 1-4 Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and heterocyclic groups consisting of 3-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 R atoms. w4 replace;

[0124] Among them, each R w4 It has the meaning described in this invention.

[0125] In some embodiments, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinepropyl, aziridinebutyl, oxacyclobutyl, thioheridinebutyl, pyrrolidinyl, pyrazolylyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazineyl, wherein... The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, aziridine, oxazoridine, thiohexacyclic, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazine groups are each independently unsubstituted or substituted by 1, 2, 3, or 4 R groups. w4 replace;

[0126] Among them, each R w4 It has the meaning described in this invention.

[0127] In some implementation schemes, each R w2 R w3 and R w4 Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, or -C(=O)OC. 1-4 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, 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, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. w1 replace;

[0128] Among them, each R w1 It has the meaning described in this invention.

[0129] In some implementation schemes, each R w2 R w3 and R w4Independently, it can be deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)O-methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, -C(=O)O-n-butyl, -C(=O)O-isobutyl, -C(=O)O-sec-butyl, -C(=O)O-tert-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF3, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -C F2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH2F, -OCF3, -OCH2Cl, -OCHF2, -OCHCl2, -OCH2CH2F, -OCH2CH2Cl, -OCH2CHF2, -OCH2CHCl2, -OCHFCH2F, -OCHClCH2Cl, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, 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 1-4Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1- Butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH2F, -OCF3, -OCH2Cl, -OCHF2, -OCHCl2, -OCH2CH2F, -OCH2CH2Cl, -OCH2CHF2, -OCH2CHCl2, -OCHFCH2F, -OCHClCH2Cl, -OCH2CF3, -OCH(CF3)2, -OCF2CH2CH3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, C 2-4 alkenyl, C 2-4 alkynyl group, carboxyl group C 1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophene, pyrazinyl, pyridazinyl, and pyrimidinyl are each independently unsubstituted or surrounded by 1, 2, 3, or 4 R groups. w1 replace;

[0130] Among them, each R w1 It has the meaning described in this invention.

[0131] In another aspect, the present invention comprises a structure of one of the following, or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, or thereof.

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound described herein and pharmaceutically acceptable excipients.

[0153] In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] In some other embodiments, the uses described in this invention refer to diseases caused by hepatitis B virus infection as cirrhosis or hepatocellular carcinoma.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] Other implementations include the method further comprising administering an effective therapeutic dose of another anti-HBV therapeutic agent to a patient requiring treatment.

[0173] 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.

[0174] Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I) or formula (II).

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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 1-4 Alkyl 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.

[0181] Pharmaceutical compositions, formulations, administration, and uses of the compounds and pharmaceutical compositions of the present invention.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides the compounds shown in formula (I) or formula (II).

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] General synthesis methods

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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).

[0210] 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.

[0211] 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), with a G1329A autosampler and a G1315D DAD detector used for analysis, and an ESI source used in the LC-MS spectrometer.

[0212] 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). Gradient elution conditions are shown in Table 1.

[0213] Table 1: Gradient elution conditions

[0214] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0215] The purity of the compounds was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, specifications 2.1 × 30 mm, 4 μm, 10 min, flow rate 0.6 mL / min, 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), and column temperature maintained at 40 °C.

[0216] The following abbreviations are used throughout this invention:

[0217] MeOH, methanol, Pd2(dba)3, tris(dibenzylacetone)dipalladium

[0218] MeOH-d4 / CD3OD Deuterated methanol DMAP 4-Dimethylaminopyridine

[0219] DCM,CH2Cl2 Dichloromethane HATU O-(7-azabenzotriazole-1-

[0220] CDC13 (deuterated chloroformyl)-N,N,N′,N′-tetramethylurea hexafluorophosphate

[0221] TFA (trifluoroacetic acid) h hours

[0222] (Boc)₂O Ditert-butyl dicarbonate (DIPEA) N,N-Diisopropylethylamine

[0223] NBS, N-bromosuccinimide, DMF, and N,N-dimethylformamide

[0224] DDQ 2,3-Dichloro-5,6-dicyanophenyl quinone THF Tetrahydrofuran

[0225] PE, petroleum ether, DMSO, dimethyl sulfoxide

[0226] EtOAc,EA (ethyl acetate) DMSO-d4 (deuterated dimethyl sulfoxide)

[0227] EtOH (ethanol) 1 / 2 half life

[0228] Et3N,TEA Triethylamine AUC Area under the curve

[0229] mL, ml Vss Steady-state apparent volume of distribution

[0230] RT,rt (room temperature), CL,clearance (clearance rate)

[0231] Rt represents retention time F, absolute bioavailability.

[0232] LDA (Lithium diisopropylamino) Dose Dosage

[0233] CDI N,N'-carbonyldiimidazole T max Peak time

[0234] 1 atm 101.325 kPa C max Maximum concentration

[0235] Blood drug concentration * time (hr*ng / mL)

[0236] Synthesis method

[0237] The following synthetic scheme outlines the experimental steps for preparing the compounds disclosed in this invention. Wherein, the A and R rings of each ring... b R 1 R 2 R 3 R 4 R 5 R 6 R 7 X has the meaning as described in this invention.

[0238] Synthesis Scheme 1

[0239]

[0240] The compound shown in formula (A-4) can be prepared by the method described in synthetic 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 (A-4).

[0241] Synthesis Scheme 2

[0242]

[0243] The compound shown in formula (b-4) can be prepared by the method described in synthetic scheme 2. First, compound (b-1) undergoes a ring-closure reaction in the presence of isobutyl chloroformate to generate compound (b-2); then, compound (b-2) is reacted with a reducing agent (such as NaBH4) to generate compound (b-3); finally, compound (b-3) undergoes ring closure under suitable conditions (such as the addition of triethylamine and methanesulfonyl chloride, or DMAP and methanesulfonyl chloride) to obtain compound (b-4).

[0244] Synthesis Scheme 3

[0245]

[0246] The compound shown in formula (C-1) can be prepared by the method described in synthetic scheme 3. First, compound (b-4) is deprotected by the Boc protecting group under suitable conditions (e.g., in the presence of trifluoroacetic acid or hydrochloric acid) to generate compound (b-5) or its salt; then, compound (b-5) or its salt undergoes a condensation reaction with compound (A-3) to obtain compound (C-1). Detailed Implementation

[0247] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0248] Preparation Examples

[0249] 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.

[0250] Synthesis of Example 1

[0251]

[0252] Step 1: Synthesis of Compound 1-1

[0253] Compound F1 (500 mg, 0.99 mmol, prepared according to the synthetic method described in ACS Med. Chem. Lett. 2017, 8, pp. 969-974) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 h, and then evaporated directly to dryness to give the title compound as a brown oil (500 mg, 97%). MS (ESI, pos.ion) m / z: 407.10 [M+H] + .

[0254] Step 2: Synthesis of Compound 1

[0255] Compound F2 (500 mg, 1.49 mmol, prepared according to the synthetic method of compound 42 in WO2017156255A1) and HATU (893 mg, 2.23 mmol) were dissolved in DMF (5 mL), and DIPEA (578 mg, 4.46 mmol) and compound 1-1 (666 mg, 1.64 mmol) were added to the solution. The mixture was stirred at room temperature for 15 h, and then the reaction was quenched with water (50 mL). The mixture was then extracted with dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the title compound as an off-white solid (420 mg, 39%). MS (ESI, pos.ion) m / z: 725.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 9.22 (d, J = 6.4Hz, 1H), 7.95 (d, J = 3.2Hz, 1H) ,7.91–7.86(m,1H),7.84(d,J=3.2Hz,1H),7.50(dd,J=8.6,6.3Hz,1H),7.46–7.37(m,3H ),7.17(td,J=8.4,2.5Hz,1H),6.04(s,1H),4.63–4.55(m,1H),4.46(d,J=5.2Hz,2H),3. 59(s,3H),3.52(s,3H),3.50–3.42(m,1H),3.31–3.25(m,1H),2.39(s,3H),2.20(s,3H).

[0256] Synthesis of Example 2

[0257]

[0258] Step 1: Synthesis of Compound 2-1

[0259] 2-Bromo-4-fluorobenzaldehyde (5.00 g, 24.6 mmol), phenylboronic acid (3.60 g, 29.5 mmol), tri-tert-butylphosphine tetrafluoroborate (736 mg, 2.46 mmol), Pd₂(dba)₃ (1.16 g, 1.23 mmol), cesium carbonate (16.11 g, 49.44 mmol), and 1,4-dioxane (60 mL) were added to the reaction flask, and the mixture was reacted at 95 °C for 12 h under nitrogen protection. Heating was turned off, and the mixture was cooled to room temperature. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was evaporated to dryness, and the residue was added to petroleum ether (50 mL). The mixture was stirred at room temperature for 30 min, filtered, and the filtrate was cooled to 5 °C, filtered, and evaporated to dryness to obtain a brown viscous substance (5.32 g, 100%). MS (ESI, pos.ion) m / z: 201.1 [M+H] + .

[0260] Step 2: Synthesis of Compound 2-2

[0261] F3 (5.30 g, 14.0 mmol, prepared according to the synthesis method of compound 4 in Example 1 of WO2017076286), compound 2-1 (3.36 g, 16.8 mmol), 2-thiazolylformamidin hydrochloride (3.14 g, 18.2 mmol), 4-methylmorpholine (3.53 g, 34.9 mmol), and THF (60 mL) were added sequentially to a dry reaction flask, and the reaction was carried out at 60 °C for 24 h. The heating was turned off and the mixture was cooled to room temperature. The solvent was removed by vacuum distillation, and ethyl acetate (70 mL) and water (50 mL) were added to the residue. The mixture was extracted and separated into layers. The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by vacuum distillation of the filtrate. The crude product was purified by silica gel column chromatography (DCM / CH3OH (V / V) = 30 / 1) to give a yellow solid (3.32 g, 40.9%). MS(ESI,pos.ion)m / z:581.2[M+H] + .

[0262] Step 3: Synthesis of compounds 2-3

[0263] Compound 2-2 (2.02 g, 3.48 mmol), THF (30 mL), and 4-methylmorpholine (711 mg, 7.03 mmol) were added sequentially to a dry reaction flask. The mixture was cooled to 5 °C, and then a solution of isobutyl chloroformate (608 mg, 4.45 mmol) diluted with THF (15 mL) was slowly added dropwise. The reaction was maintained at this temperature for 12 h. Water (30 mL) was then added, followed by extraction with ethyl acetate (30 mL × 2). The organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 1) to give a yellow solid (180 mg, 9.2%). MS (ESI, pos.ion) m / z: 563.2 [M+H] + .

[0264] Step 4: Synthesis of compounds 2-4

[0265] Compounds 2-3 (160 mg, 0.28 mmol) and THF (6 mL) were added sequentially to a dry reaction flask, followed by the addition of NaBH4 (34 mg, 0.86 mmol) under ice bath conditions. After the additions were complete, the reaction mixture was allowed to react at room temperature for 6 h. Ethyl acetate (30 mL) was added, and the organic layer was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow foamy solid (158 mg, 98.05%). MS (ESI, pos.ion) m / z: 567.2 [M+H] + .

[0266] Step 5: Synthesis of compounds 2-5

[0267] Compounds 2-4 (158 mg, 0.28 mmol), DCM (5 mL), and DMAP (103 mg, 0.83 mmol) were added sequentially to a dry reaction flask and stirred until dissolved. Methanesulfonyl chloride (70 mg, 0.60 mmol) was then added under ice bath conditions. The reaction system was transferred to room temperature and reacted for 4 h. Dichloromethane (50 mL) and water (40 mL) were then added to the system, and the layers were extracted and separated. The organic layer was washed sequentially with dilute hydrochloric acid (30 mL, 1 M) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow foamy solid (156 mg, 100%). MS (ESI, pos.ion) m / z: 549.2 [M+H] + .

[0268] Step 6: Synthesis of compounds 2-6

[0269] Compound 2-5 (156 mg, 0.28 mmol), DCM (3 mL), and trifluoroacetic acid (1 mL) were added sequentially to a dry reaction flask. The mixture was stirred at room temperature for 1 h, and then the solvent was removed under reduced pressure to obtain a yellow viscous substance (156 mg, 99.44%). MS (ESI, pos.ion) m / z: 449.4 [M+H] + .

[0270] Step 7: Synthesis of Compound 2

[0271] Compounds 2-6 (156 mg, 0.28 mmol), DMF (5 mL), DIPEA (191 mg, 1.45 mmol), compound F2 (104 mg, 0.31 mmol), and HATU (163 mg, 0.42 mmol) were added sequentially to a dry reaction flask. The mixture was reacted at room temperature for 12 h. Then, ethyl acetate (30 mL) and water (30 mL) were added, and the layers were extracted and separated. The organic layer was washed sequentially with dilute hydrochloric acid (30 mL, 1 M) and saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 3) to give a pale yellow solid (93 mg, 43.7%). MS (ESI, pos.ion) m / z: 767.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.87–7.76 (m, 2H), 7.75–7.65 (m, 1H), 7.58 (d, J = 6.4Hz, 2H), 7.44–7.37 (m, 4H), 7.20–7.10 (m, 2H), 7.04–6.95 (m, 2H) ,5.70(s,1H),4.85–4.66(m,1H),4.50(s,2H),3.62(s,3H),3.60–3.52(m ,1H),3.48(s,3H),3.16(dd,J=18.1,6.2Hz,1H),2.31(d,J=16.4Hz,6H).

[0272] Synthesis of Example 3

[0273]

[0274] Step 1: Synthesis of Compound 3-1

[0275] Compound F1 (613 mg, 1.21 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium hydroxide monohydrate (104 mg, 2.46 mmol) and water (2 mL) were added. The mixture was stirred at 50 °C for 38 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the title compound as a yellow solid (301 mg, 51%). MS (ESI, pos.ion) m / z: 493.20 [M+H] + .

[0276] Step 2: Synthesis of compound 3-2

[0277] Proprynneamine (25 mg, 0.45 mmol) and HATU (225 mg, 0.56 mmol) were dissolved in DMF (5 mL). Compound 3-1 (230 mg, 0.47 mmol) and DIPEA (181 mg, 1.40 mmol) were added to the solution, and the mixture was stirred at room temperature for 19 h. Dichloromethane (20 mL) and water (20 mL) were added, and the mixture was allowed to separate into layers. The organic phase was washed with dilute hydrochloric acid (1 M, 10 mL), saturated sodium bicarbonate (10 mL), water (10 mL), and saturated brine (10 mL), respectively. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound as a yellow solid (180 mg, 73%). MS (ESI, pos.ion): m / z 530.20 [M+H] + .

[0278] Step 3: Synthesis of compound 3-3

[0279] Compound 3-2 (180 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 3 h, and then evaporated directly to dryness to give the title compound as a brown oil (180 mg, 97%). MS (ESI, pos.ion) m / z: 430.10 [M+H] + .

[0280] Step 4: Synthesis of Compound 3

[0281] Compound F2 (100 mg, 0.30 mmol) and HATU (140 mg, 0.35 mmol) were dissolved in DMF (5 mL). Compound 3-3 (180 mg, 0.33 mmol) and DIPEA (116 mg, 0.90 mmol) were added to the solution, and the mixture was stirred at room temperature for 19 h. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL). The organic phase was washed with dilute hydrochloric acid (1 M, 10 mL), saturated sodium bicarbonate solution (10 mL), water (10 mL), and saturated brine (10 mL), respectively. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (EA) to give the title compound as a white solid (120 mg, 54%). MS (ESI, pos.ion): m / z 748.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.39 (s, 1H), 9.20 (d, J = 5.9Hz, 1H), 7.98–7.73 (m, 4H), 7.50–7.30(m,4H),7.16(td,J=8.4,1.7Hz,1H),6.05(s,1H),4.55–4.37(m,2H),4.32( dd,J=11.4,5.8Hz,1H),3.85(dd,J=17.9,3.7Hz,1H),3.72(dd,J=16.8,2.6Hz,1H),3. 57(s,3H),3.42(dd,J=17.1,6.9Hz,1H),3.06–2.96(m,2H),2.35(s,3H),2.17(s,3H).

[0282] Synthesis of Example 4

[0283]

[0284] Step 1: Synthesis of Compound 4-1

[0285] Compound F4 (prepared according to the synthesis method of fragment 4 in Example 1 of WO2017156255A1, 500 mg, 1.97 mmol), DIPEA (0.7 mL, 4 mmol), and HATU (1.027 g, 2.57 mmol) were dissolved in DCM (10 mL). After stirring for ten minutes, compound 1-1 (1.03 g, 1.98 mmol) was added to the reaction system. The reaction mixture was stirred at room temperature for 17 h, then washed with dilute hydrochloric acid (1 M, 10 mL) and sodium hydroxide solution (1 M, 10 mL), respectively. The organic layer was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM / CH3OH (V / V) = 50 / 1) to give a brown solid (400 mg, 31.6%). MS (ESI, pos.ion) m / z: 642.2 [M+H] + .

[0286] Step 2: Synthesis of compound 4-2

[0287] Compound 4-1 (400 mg, 0.62 mmol) was dissolved in ethanol (12 mL) and THF (12 mL), and a solution of sodium hydroxide (99 mg, 2.48 mmol) in water (4 mL) was added. The mixture was stirred at 70 °C for 2 h. The solvent was evaporated, and water (10 mL) and ethyl acetate (10 mL) were added. The organic phase was discarded, and ethyl acetate (10 mL) was added to the aqueous phase. The pH of the solution was adjusted to approximately 3-4 with 1 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give the title compound as a brown solid (225 mg, 59%). MS (ESI, pos.ion): m / z 614.10 [M+H] + .

[0288] Step 3: Synthesis of Compound 4

[0289] Compound 4-2 (225 mg, 0.38 mmol), DIPEA (0.1 mL, 0.60 mmol), and HATU (450 mg, 1.12 mmol) were dissolved in DCM (6 mL). After stirring for 10 min, propyneamine (61 mg, 1.11 mmol) was added to the system, and the reaction was stirred at room temperature for 16 h. The reaction system was washed with dilute hydrochloric acid (1 M, 10 mL), sodium hydroxide solution (1 M, 10 mL), and saturated brine (10 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated from the filtrate. The residue was purified by silica gel column chromatography (DCM / CH3OH (V / V) = 50 / 1) to give a yellow solid (12 mg, 5%). MS (ESI, pos.ion) m / z: 651.15 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.19 (d, J = 6.5 Hz, 1H), 8.58 (t, J = 5.7 Hz, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7. 86(d,J=3.2Hz,1H),7.49(dd,J=8.7,6.3Hz,1H),7.40(dd,J=8.9,2.6Hz,1H),7.17(td,J=8.5,2.6Hz, 1H),6.02(s,1H),4.61–4.53(m,1H),4.44(d,J=5.1Hz,2H),4.01(dd,J=5.6,2.4Hz,2H),3.52(s,3H) ,3.45(s,3H),3.40–3.35(m,1H),3.30–3.25(m,1H),3.13(t,J=2.4Hz,1H),2.33(s,3H),2.15(s,3H).

[0290] Synthesis of Example 5

[0291]

[0292] Step 1: Synthesis of Compound 5-1

[0293] Compound F3 (11.70 g, 30.8 mmol), 2-chloro-4-fluorobenzaldehyde (5.24 g, 32.4 mmol), thiazolamidine hydrochloride (6.13 g, 35.4 mmol), and N-methylmorpholine (8.6 mL, 77 mmol) were dissolved in tetrahydrofuran (100 mL) and reacted at 60 °C for 24 h. After the reaction was complete, the solution was cooled to room temperature and used directly in the next reaction.

[0294] Step 2: Synthesis of Compound 5-2

[0295] The reaction solution from the previous step (i.e., the tetrahydrofuran solution of compound 5-1) was cooled to 5°C, and a THF solution of isobutyl chloroformate (4.95 mL, 37.4 mmol) in 20 mL was slowly added dropwise. The reaction was maintained at this temperature for 1 h, and then water (100 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated. The resulting oily substance was dissolved in tetrahydrofuran (3.56 mL) and ethyl acetate (21.9 mL), and n-heptane (66.4 mL) was slowly added dropwise. A solid precipitated slowly. After the addition was complete, the mixture was cooled to 15°C and stirred for 10 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to obtain the title compound as a yellow solid (3.75 g, 23.1%). MS(ESI,pos.ion)m / z:521.0[M+H] + .

[0296] Step 3: Synthesis of compound 5-3

[0297] Sodium borohydride (0.15 g, 3.8 mmol) was dissolved in water (2 mL). A THF solution of compound 5-2 (1.00 g, 1.92 mmol) in 10 mL was added dropwise under ice bath conditions. After the addition was complete, the reaction was stirred at this temperature for 16 h. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL), washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (0.67 g, 66%). MS (ESI, pos.ion) m / z: 525.20 [M+H] + .

[0298] Step 4: Synthesis of Compound 5-4

[0299] Compound 5-3 (0.67 g, 1.3 mmol) and DMAP (0.47 g, 3.8 mmol) were dissolved in DCM (10 mL). Methanesulfonyl chloride (0.2 mL, 3 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was slowly heated to 35 °C and stirred for 4 h. The reaction was stopped, and the mixture was washed with dilute hydrochloric acid (1 M, 20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 4 / 1) to give the title compound as a yellow solid (0.28 g, 43%). MS (ESI, pos.ion) m / z: 507.20 [M+H] + .

[0300] Step 5: Synthesis of compound 5-5

[0301] Compound 5-4 (0.28 g, 0.55 mmol) was dissolved in DCM (10 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was evaporated to dryness to give the title compound as a brown oil (280 mg, 97%). MS (ESI, pos.ion) m / z: 407.10 [M+H] + .

[0302] Step 6: Synthesis of Compound 5

[0303] Compound 5-5 (0.29 g, 0.56 mmol) was dissolved in DMF (10 mL), followed by the addition of DIPEA (0.20 g, 1.6 mmol), compound F2 (0.22 g, 0.65 mmol), and HATU (0.25 g, 0.66 mmol). The mixture was stirred at room temperature for 6 h. Then, ethyl acetate (20 mL) and water (50 mL) were added. The aqueous phase was extracted with ethyl acetate (20 mL), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 2) to give the title compound as a white solid (160 mg, 40%). MS (ESI, pos.ion) m / z: 725.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.83 (d, J = 3.2Hz, 1H), 7.76–7.69 (m, 1H), 7.44 (s, 1H), 7 .41(d,J=3.2Hz,1H),7.34(dd,J=8.6,6.1Hz,1H),7.22–7.12(s,4H),7.03(td,J=8. 3,2.6Hz,1H),6.21(s,1H),4.78–4.72(m,1H),4.62–4.53(m,2H),3.74(s,3H),3.65 (s,3H),3.63–3.58(m,1H),3.38(dd,J=18.2,6.6Hz,1H),2.44(s,3H),2.41(s,3H).

[0304] Synthesis of Example 6

[0305]

[0306] Step 1: Synthesis of Compound 6-1

[0307] Compound F3 (2.50 g, 6.59 mmol, prepared according to the synthesis method of compound 4 in Example 1 of WO2018196805), aqueous acetaldehyde solution (2.18 g, 19.80 mmol, 40%), thiazolamidine hydrochloride (1.19 g, 7.27 mmol), 4-methylmorpholine (1.68 g, 16.40 mmol), and isopropanol (30 mL) were added to the reaction flask. The reaction mixture was reacted at 80 °C for 6 h, cooled to room temperature, and evaporated to dryness to give the title compound as a yellow oil (2.77 g, 99%). MS (ESI, pos.ion) m / z: 425.2 [M+H] + .

[0308] Step 2: Synthesis of Compound 6-2

[0309] Compound 6-1 (2.70 g, 6.36 mmol) and 4-methylmorpholine (1.29 g, 12.80 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to 5 °C, and isobutyl chloroformate (1.01 g, 7.61 mmol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. Then, ethyl acetate (50 mL) and water (50 mL) were added. The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc (V / V = 3 / 1)) to give the title compound as a yellow solid (0.83 g, 32%). MS (ESI, pos.ion) m / z: 407.2 [M+H] + .

[0310] Step 3: Synthesis of Compound 6-3

[0311] Sodium borohydride (232 mg, 5.89 mmol) was dissolved in water (1 mL). A tetrahydrofuran solution (10 mL) of compound 6-2 (800 mg, 1.97 mmol) was added under ice-water bath conditions. After the addition was complete, the reaction was allowed to proceed for 1 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (650 mg, 81%). MS (ESI, pos.ion) m / z: 411.3 [M+H] + .

[0312] Step 4: Synthesis of compound 6-4

[0313] Compound 6-3 (550 mg, 1.34 mmol) and triethylamine (406 mg, 4.01 mmol) were dissolved in dichloromethane (10 mL). Methylsulfonyl chloride (308 mg, 2.69 mmol) was added under ice-water bath conditions. The mixture was then heated to 35 °C and reacted for 2 h. After cooling and concentration under reduced pressure, the title compound was given as a yellow solid (410 mg, 78%). MS (ESI, pos.ion) m / z: 393.2 [M+H] + .

[0314] Step 5: Synthesis of Compounds 6-5

[0315] Compound 6-4 (200 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 h, and then evaporated to dryness to obtain the title compound as a brown oil (200 mg, 97%).

[0316] Step 6: Synthesis of Compound 6

[0317] Compound F2 (182 mg, 0.54 mmol) and HATU (236 mg, 0.59 mmol) were dissolved in DMF (5 mL). DIPEA (191 mg, 1.47 mmol) and compound 6-5 (200 mg, 0.49 mmol) were added sequentially, and the mixture was stirred at room temperature for 22 h. Ethyl acetate (20 mL) and water (20 mL) were added. The organic phase was washed sequentially with 1 M hydrochloric acid (20 mL), saturated sodium bicarbonate (20 mL), and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to give the title compound as a white solid (108 mg, 36%). MS (ESI, pos.ion) m / z: 611.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.96 (d, J = 3.2Hz, 1H), 7.91–7.83 (m, 2H), 7.46–7.37 (m, 2H), 4.61–4.54 (m, 1H), 4.52–4.44 (m, 1H), 4.39 (d, J=5.8Hz,2H),3.65(s,3H),3.58(s,3H),3.31–3.23(m,2H),3.11(dd,J=17.7,5.7Hz,1H),2.37(s,3H),2.18(s,3H),1.16(d,J=6.4Hz,3H).

[0318] Synthesis of Example 7

[0319]

[0320] Step 1: Synthesis of Compound 7-1

[0321] Compound 3-1 (150 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of tetrahydropyrrole (25 mg, 0.35 mmol), HATU (140 mg, 0.37 mmol), and DIPEA (120 mg, 0.93 mmol). The mixture was stirred at room temperature for 4 h, then extracted with dichloromethane (20 mL) and hydrochloric acid (1 M, 20 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the title compound as a yellow solid (160 mg, 96%). MS (ESI, pos.ion) m / z: 546.2 [M+H] + .

[0322] Step 2: Synthesis of Compound 7-2

[0323] Compound 7-1 (160 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.1 mL) was added. The mixture was stirred at room temperature for 12 h, and the solvent was removed by rotary evaporation. The residue was used for the next reaction.

[0324] Step 3: Synthesis of Compound 7

[0325] Compound 7-2 (160 mg, 0.29 mmol) was dissolved in DMF (5 mL), and compound F2 (120 mg, 0.36 mmol), HATU (130 mg, 0.34 mmol), and DIPEA (110 mg, 0.85 mmol) were added. The mixture was stirred at room temperature for 26 h, and then ethyl acetate (25 mL) and water (50 mL) were added. The mixture was extracted separately, and the aqueous phase was back-extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filter cake was purified by thin-layer chromatography (PE / EA (V / V) = 1 / 6) to give a white solid (30 mg, 13%). MS (ESI, pos.ion) m / z: 764.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.67 (s, 1H), 7.87 (d, J = 3.2Hz, 1H), 7.82–7.72 (m, 1H), 7.63 (d, J = 7 .6Hz,1H),7.43(d,J=3.1Hz,1H),7.37(d,J=8.8Hz,1H),7.32–7.29(m,1H),7.15–7.07(m,2H), 6.98(td,J=8.4,2.4Hz,1H),6.10(s,1H),4.76–4.69(m,1H),4.61–4.53(m,1H),4.48–4.41(m, 1H),3.65(s,3H),3.30(s,3H),3.05–2.91(m,2H),2.35(s,3H),2.31(s,3H),1.89–1.69(m,5H).

[0326] Synthesis of Example 8

[0327]

[0328] Example 8 was prepared using the same synthesis method as in Example 7, and was a grayish-white solid (70 mg, 33.50%). MS (ESI, pos.ion) m / z: 724.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.20 (d, J = 5.9 Hz, 1H), 7.92 (d, J = 3. 2Hz,1H),7.91–7.83(m,1H),7.80(d,J=3.2Hz,1H),7.47–7.39(m,4H),7.18(td, J=8.5,2.5Hz,1H),6.06(s,1H),4.52–4.39(m,2H),4.37–4.27(m,1H),3.58(s,3 H),3.50–3.42(m,2H),3.08–2.95(m,1H),2.52(s,3H),2.37(s,3H),2.17(s,3H).

[0329] Synthesis of Example 9

[0330]

[0331] Example 9 was prepared using the same synthesis method as in Example 7, and was a yellow solid (110 mg, 96.48%). MS (ESI, pos.ion) m / z: 780.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.28 (s, 1H), 7.87 (d, J = 3.2Hz, 1H), 7.78–7.66 (m, 1H), 7.58 (d, J = 7.5Hz, 1H),7.44(d,J=3.2Hz,1H),7.34–7.29(m,2H),7.20–7.09(m,2H),6.99(td,J=8.3,2.5Hz,1H),6.09( s,1H),4.77–4.69(m,1H),4.63–4.53(m,1H),4.53–4.45(m,1H),3.66(s,3H),3.55–3.40(m,4H),3.3 9–3.14(m,4H),2.91(dd,J=16.4,6.8Hz,1H),2.75(dd,J=16.3,5.1Hz,1H),2.36(s,3H),2.32(s,3H).

[0332] Synthesis of Example 10

[0333]

[0334] Step 1: Synthesis of Compound 10-1

[0335] Compound F6 (5.00 g, 11.1 mmol, obtained according to the synthesis method of compound 3 in Example 1 of WO2017076286) and ethyl D-lactic acid (2.63 g, 22.26 mmol) were dissolved in toluene (30 mL), reacted at 100 °C for 12 h, and concentrated under reduced pressure to give a brown oil (5.10 g, 99%). MS (ESI, pos.ion) m / z: 366.2 [M-Boc+H] + .

[0336] Step 2: Synthesis of compound 10-2

[0337] Compound 10⁻¹ (6.00 g, 12.9 mmol), 2-chloro-4-fluorobenzaldehyde (2.15 g, 13.6 mmol), thiazolamidine hydrochloride (2.53 g, 14.8 mmol), 4-methylmorpholine (3.6 mL, 32 mmol), and tetrahydrofuran (50 mL) were added to the reaction flask. The mixture was reacted at 60 °C for 23 h, and then cooled to room temperature for use in the next step. MS (ESI, pos.ion) m / z: 625.2 [M+H] + .

[0338] Step 3: Synthesis of compound 10-3

[0339] The reaction solution was cooled to 5°C, and isobutyl chloroformate (2.10 g, 15.4 mmol) was added dropwise. After the addition was complete, the reaction was continued at 5°C for 14 h. Ethyl acetate (100 mL) and water (100 mL) were added. The organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 1) to give the title compound as a yellow solid (2.15 g, 18%). MS (ESI, pos.ion) m / z: 607.3 [M+H] + .

[0340] Step 4: Synthesis of compound 10⁻⁴

[0341] Sodium borohydride (130 mg, 3.30 mmol) was dissolved in water (0.5 mL). A tetrahydrofuran solution (5 mL) containing 10⁻³ (1.00 g, 1.65 mmol) of compound 10⁻³ was added under ice-water bath conditions. After the addition was complete, the reaction was continued under ice bath conditions for 1 h. Ethyl acetate (10 mL) and water (10 mL) were added. The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (900 mg, 89%). MS (ESI, pos.ion) m / z: 611.1 [M + H] + .

[0342] Step 5: Synthesis of compound 10-5

[0343] Compound 10⁻⁴ (900 mg, 1.47 mmol) and triethylamine (450 mg, 4.45 mmol) were dissolved in dichloromethane (10 mL). Methylsulfonyl chloride (338 mg, 2.95 mmol) was added under ice-water bath conditions. After addition, the mixture was heated to 35 °C and reacted for 3 h. The reaction solution was washed successively with 1 M hydrochloric acid (10 mL) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (620 mg, 71%). MS (ESI, pos.ion) m / z: 593.2 [M + H₂] + .

[0344] Step 6: Synthesis of compound 10-6

[0345] Compound 10-5 (250 mg, 0.42 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to obtain a brown oily substance (250 mg, 98%) containing the title compound.

[0346] Step 7: Synthesis of Compound 10

[0347] Compound F2 (112 mg, 0.37 mmol) and HATU (150 mg, 0.37 mmol) were dissolved in DMF (5 mL). DIPEA (120 mg, 0.93 mmol) and compound 10⁻⁶ (250 mg, 0.41 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 h. The solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL). The organic phase was washed sequentially with 1 M hydrochloric acid (20 mL), saturated sodium bicarbonate aqueous solution (20 mL), and saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the title compound as a yellow solid (140 mg, 57%). MS (ESI, pos.ion) m / z: 811.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.81(d,J=3.2Hz,1H),7.77–7.67(m,2H),7.47–7.37(m,2H),7.35 –7.29(m,1H),7.21–7.11(m,3H),6.95(td,J=8.3,2.5Hz,1H),6.24(s,1H),4.96(q,J=7.0Hz,1H) ,4.85–4.74(m,1H),4.65–4.49(m,2H),4.23–4.09(m,2H),3.78–3.70(m,1H),3.69(s,3H),3.32 (dd,J=18.3,6.3Hz,1H),2.39(s,3H),2.34(s,3H),1.34(d,J=7.1Hz,3H),1.23(t,J=7.1Hz,3H).

[0348] Synthesis of Example 11

[0349]

[0350] Step 1: Synthesis of Compound 11-1

[0351] Compound F3 (3.00 g, 7.91 mmol), 2-chloro-4-fluorobenzaldehyde (1.32 g, 8.32 mmol), cyclopropylformamidin hydrochloride (1.05 g, 8.71 mmol), 4-methylmorpholine (2.2 mL, 20 mmol), and isopropanol (30 mL) were added to a reaction flask. The mixture was stirred at 80 °C for 16 h, and then concentrated under reduced pressure to give the title compound as a brown oil (3.88 g, 98.9%). MS (ESI, pos.ion) m / z: 496.2 [M+H] + .

[0352] Step 2: Synthesis of compound 11-2

[0353] Compound 11-1 (3.88 g, 7.82 mmol) and 4-methylmorpholine (1.58 g, 15.60 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to 5 °C, and isobutyl chloroformate (1.28 g, 9.37 mmol) was slowly added. After the addition was complete, the mixture was reacted at 5 °C for 32 h. The mixture was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 4 / 1) to give the title compound as a yellow solid (1.11 g, 30%).

[0354] MS(ESI,pos.ion)m / z:478.1[M+H] + .

[0355] Step 3: Synthesis of Compound 11-3

[0356] Sodium borohydride (165 mg, 4.19 mmol) was dissolved in water (1 mL). A tetrahydrofuran solution (10 mL) of compound 11-2 (1.00 g, 2.09 mmol) was added under ice-water bath conditions. After the addition was complete, the reaction was continued under ice bath conditions for 1.5 h. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (720 mg, 71%). MS (ESI, pos.ion) m / z: 482.2 [M+H] + .

[0357] Step 4: Synthesis of compound 11-4

[0358] Compound 11-3 (700 mg, 1.45 mmol) and triethylamine (440 mg, 4.35 mmol) were dissolved in dichloromethane (10 mL). Methylsulfonyl chloride (333 mg, 2.91 mmol) was added under ice-water bath conditions. After addition, the mixture was heated to 35 °C and reacted for 19 h. The mixture was then cooled to room temperature. The reaction solution was washed successively with 1 M hydrochloric acid (10 mL), water (10 mL), and saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (520 mg, 77%). MS (ESI, pos.ion) m / z: 464.2 [M+H] + .

[0359] Step 5: Synthesis of Compound 11-5

[0360] Compound 11-4 (200 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure to obtain a brown oily substance (200 mg, 97%) containing the title compound.

[0361] Step 6: Synthesis of Compound 11

[0362] Compound F2 (152 mg, 0.45 mmol) and HATU (199 mg, 0.50 mmol) were dissolved in DMF (5 mL). DIPEA (160 mg, 1.23 mmol) and compound 11-5 (150 mg, 0.41 mmol) were added, and the mixture was stirred at room temperature for 11 h. The solution was diluted with water (20 mL), extracted with dichloromethane (20 mL), and the organic phase was washed successively with 1 M hydrochloric acid (20 mL), saturated sodium bicarbonate aqueous solution (20 mL), and saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 1 / 1) to give the title compound as a yellow solid (110 mg, 39%). MS (ESI, pos.ion) m / z: 682.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.59 (s, 1H), 8.09–7.98 (m, 1H), 7.77–7.68 (m, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.17–7.0 9(m,2H),7.06(dd,J=8.5,2.3Hz,1H),6.88(td,J=8.4,2.2Hz,1H),5.81(s,1H),4.89–4.75(m,1H),4.33–4.21( m,1H),3.96–3.86(m,1H),3.66(s,3H),3.64–3.58(m,1H),3.55(s,3H),3.23(dd,J=18.2,6.9Hz,1H),2.38(s,3 H),2.32(s,3H),1.59–1.50(m,1H),1.16–1.08(m,1H),0.86–0.79(m,1H),0.78–0.71(m,1H),0.60–0.51(m,1H).

[0363] Synthesis of Example 12

[0364]

[0365] Example 12 was prepared using the same synthesis method as in Example 6, and was a yellow solid (150 mg, 55.6%). MS (ESI, pos.ion) m / z: 718.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.49 (s 1H),7.89(d,J=6.5Hz,1H),7.67–7.58(m,1H),7.43–7.31(m,5H),7.30–7.25(m,1H), 7.19(d,J=8.9Hz,1H),7.12–7.02(m,2H),6.96(td,J=8.3,2.4Hz,1H),5.92(d,J=30.2 Hz,1H),4.68–4.57(m,1H),3.85–3.75(m,1H),3.69–3.61(m,1H),3.60(s,3H),3.57( s,3H),3.51(t,J=9.1Hz,1H),3.40(dd,J=18.4,4.5Hz,1H),2.33(s,3H),2.28(s,3H).

[0366] Synthesis of Example 13

[0367]

[0368] Example 13 was prepared using the same synthesis method as in Example 6, and was a yellow solid (150 mg, 55.7%). MS (ESI, pos.ion) m / z: 719.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.63 (s, 2H), 8.05–7.96 (m, 1H), 7.76–7.65 (m, 2H), 7 .53(d,J=6.3Hz,1H),7.37–7.30(m,2H),7.19–7.09(m,3H),6.98(td,J=8.3,2.5 Hz,1H),6.12(s,1H),4.72–4.67(m,1H),3.98–3.90(m,1H),3.68(s,3H),3.62(s ,3H),3.60–3.50(m,2H),3.41(dd,J=18.4,4.8Hz,1H),2.37(s,3H),2.30(s,3H).

[0369] Synthesis of Example 14

[0370]

[0371] Example 14 was prepared using the same synthesis method as in Example 11, and was a yellow solid (181 mg, 80.4%). MS (ESI, pos.ion) m / z: 682.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)8.06(d,J=7.9Hz,1H),7.77–7.67(m,1H),7.52(d,J=4.8Hz,1H),7.33–7.26(m,1H),7.2 1(d,J=8.7Hz,1H),7.17–7.11(m,1H),7.08(dd,J=8.6,2.4Hz,1H),6.96–6.89(m,1H),5.92(s,1H),4.70(d,J=4.7Hz ,1H),4.19–4.12(m,1H),4.09(d,J=10.6Hz,1H),3.69(s,3H),3.59(s,3H),3.49(d,J=18.2Hz,1H),3.39(dd,J=18.5 ,6.7Hz,1H),2.40(s,3H),2.36(s,3H),1.60–1.51(m,1H),1.19–1.10(m,1H),0.88–0.79(m,2H),0.78–0.67(m,1H).

[0372] Synthesis of Example 15

[0373]

[0374] Example 15 was prepared using the same synthesis method as in Example 6, and was a yellow solid (130 mg, 60.3%). MS (ESI, pos.ion) m / z: 718.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ(ppm)7.79(s,1H),7.71–7.62(m,1H),7.45–7.26(m,7H),7.18–7.09(m,3H),7.04–6.96(m,1H),6.13(s,1H),4.58(s,1H), 3.89–3.79(m,1H),3.68(s,3H),3.61(s,3H),3.60–3.51(m,1H),3.48(d ,J=6.7Hz,1H),3.42(dd,J=18.1,2.5Hz,1H),2.38(s,3H),2.32(s,3H).

[0375] Synthesis of Example 16

[0376]

[0377] Example 16 was prepared by referring to the synthesis method of Example 7 and was a white solid (35 mg, 14.46%).

[0378] MS(ESI,pos.ion)m / z:764.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.17 (d, J = 5.5Hz, 1H), 7.93 (d, J = 3.1Hz, 1H), 7.91 –7.83(m,1H),7.81(d,J=3.0Hz,1H),7.65(s,1H),7.48–7.40(m,2H),7.38(dd,J=8.8,2.4Hz,1 H),7.23–7.14(m,1H),6.03(s,1H),4.44(d,J=9.1Hz,1H),4.35–4.25(m,1H),3.58(s,3H),3.2 8(d,J=7.6Hz,1H),2.92(d,J=15.6Hz,1H),2.38(s,3H),2.17(s,3H),1.11(s,3H),0.41(s,3H).

[0379] Synthesis of Example 17

[0380]

[0381] Example 17 was prepared using the same synthesis method as in Example 7, and was a white solid (90 mg, 25.7%). MS (ESI, pos.ion) m / z: 858.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.75–8.29 (m, 1H), 7.86 (d, J = 3.0Hz, 1H), 7.72–7.65 (m, 1H), 7.42 (d, J = 3.1Hz, 3 H),7.37(s,1H),7.25–7.15(m,2H),7.14–7.06(m,1H),7.06–6.99(m,1H),6.96–6.88(m,1H),6.84–6.69(m, 1H),6.67–6.53(m,1H),6.00(s,1H),4.52(d,J=4.3Hz,1H),3.64(s,3H),3.58–3.46(m,1H),2.94–2.80(m,1 H),2.34(s,3H),2.32(s,1H),2.30(s,3H),2.19(s,1H),2.04(s,1H),1.90–1.80(m,2H),1.79–1.67(m,4H).

[0382] Synthesis of Example 18

[0383]

[0384] Example 18 was prepared using the same synthesis method as in Example 7, and was a pale yellow solid (90 mg, 22%). MS (ESI, pos.ion) m / z: 806.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.43 (s, 1H), 9.18 (d, J = 5.7Hz, 1H), 7.97–7.92 (m, 1H), 7.88–7.79 (m, 2H), 7.51–7.46 (m,1H),7.46–7.42(m,1H),7.38(dd,J=8.9,2.4Hz,1H),7.23–7.14(m,2H),6.08(s,1H),4.44(d,J=10.6Hz,2H),4.37 –4.27(m,1H),3.58(s,3H),3.45–3.41(m,1H),3.32–3.26(m,1H),3.04–2.93(m,1H),2.39(s,3H),2.16(s,3H),1.66– 1.51(m,3H),1.46(d,J=12.8Hz,1H),1.20–1.15(m,1H),1.14–1.02(m,2H),0.90–0.83(m,1H),0.79(d,J=6.5Hz,3H).

[0385] Synthesis of Example 19

[0386]

[0387] Example 19 was prepared using the same synthesis method as in Example 7, and was a white solid (70 mg, 20%). MS (ESI, pos.ion) m / z: 856.30 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.43 (s, 1H), 7.85 (d, J = 3.0Hz, 1H), 7.77–7.69 (m, 1H), 7.66 (d, J = 7.5Hz, 1H), 7.42 (d, J = 3.0Hz, 1 H),7.37–7.31(m,1H),7.27(s,2H),7.22(d,J=2.4Hz,2H),7.11–6.98(m,2H),6.93(t,J=7.1Hz,1H),6.04(s,1H),5.30(s,1H) ,4.71(s,1H),4.62–4.52(m,1H),4.45–4.37(m,1H),4.33(d,J=11.5Hz,1H),3.88(d,J=9.5Hz,1H),3.78–3.67(m,1H),3.64( s,3H),3.61–3.53(m,2H),2.99(t,J=11.8Hz,1H),2.92–2.80(m,1H),2.75(dd,J=15.8,4.6Hz,1H),2.34(s,3H),2.33(s,3H).

[0388] Synthesis of Example 20

[0389]

[0390] Example 20 was prepared using the same synthesis method as in Example 7, and was a white solid (70 mg, 20%). MS (ESI, pos.ion) m / z: 856.30 [M+H] + ; 1H NMR (400MHz, CDCl3) δ (ppm) 8.26 (s, 1H), 7.85 (d, J = 3.1Hz, 1H), 7.80–7.71 (m, 1H), 7. 43(d,J=3.2Hz,1H),7.39–7.32(m,3H),7.31–7.27(m,4H),7.20–7.08(m,2H),7.00(t ,J=6.8Hz,1H),6.18(s,1H),5.62(br,1H),4.71–4.61(m,1H),4.60–4.53(m,1H),4.4 7–4.35(m,2H),3.72–3.55(m,5H),3.45–3.35(m,1H),3.27–3.17(m,2H),2.75–2.55(m 3H),2.36(s,3H),2.34(s,3H).

[0391] Synthesis of Example 21

[0392]

[0393] Example 21 was prepared using the same synthesis method as in Example 7, and was a white solid (0.16 g, 48%). MS (ESI, pos.ion) m / z: 750.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 9.18 (d, J = 5.5Hz, 1H), 7.93 (d, J = 3.1Hz, 1H), 7.91–7.83 (m, 1H) ,7.81(d,J=3.1Hz,1H),7.55(d,J=3.5Hz,1H),7.48–7.41(m,2H),7.39(dd,J=8.8,2.3Hz,1H),7.19(td,J=8. 4,2.3Hz,1H),6.06(s,1H),4.45(d,J=9.2Hz,2H),4.37–4.20(m,1H),3.58(s,3H),2.95(d,J=14.8Hz,1H),2 .53(d,J=8.8Hz,2H),2.38(s,3H),2.17(s,3H),0.52(d,J=6.9Hz,2H),0.42–0.28(m,1H),0.29–0.19(m,1H).

[0394] Synthesis of Example 22

[0395]

[0396] Example 22 was prepared using the same synthesis method as in Example 6, and was a yellow solid (210 mg, 75.2%). MS (ESI, pos.ion) m / z: 719.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 9.33 (d, J = 4.6Hz, 1H), 8.82 (d, J = 4.0Hz, 1H), 8.77 (s, 1H ),8.10(d,J=7.7Hz,1H),7.90–7.81(m,1H),7.77–7.68(m,1H),7.63(dd,J=7.8,4.9Hz,1H),7.50–7. 36(m,3H),7.13(td,J=8.4,2.4Hz,1H),6.16(s,1H),4.49(d,J=1.5Hz,1H),4.15–4.08(m,1H),3.79( d,J=11.2Hz,2H),3.59(s,3H),3.57(s,3H),3.35(dd,J=18.1,6.3Hz,1H),2.34(s,3H),2.18(s,3H).

[0397] Synthesis of Example 23

[0398]

[0399] Example 23 was prepared using the same synthesis method as in Example 6, and was a white solid (180 mg, 59.9%). MS (ESI, pos.ion) m / z: 611.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 9.21 (d, J = 5.6Hz, 1H), 7.98 (d, J = 3.2Hz, 1H), 7.8 8(d,J=3.2Hz,1H),7.87–7.82(m,1H),7.49–7.36(m,2H),4.55(q,J=6.3Hz,1H),4.50–4.43(m, 1H),4.40(d,J=11.7Hz,1H),4.34(dd,J=11.8,5.2Hz,1H),3.65(s,3H),3.58(s,3H),3.28(d, J=17.9Hz,1H),3.14(dd,J=18.0,6.7Hz,1H),2.38(s,3H),2.20(s,3H),1.16(d,J=6.4Hz,3H).

[0400] Synthesis of Example 24

[0401]

[0402] Example 24 was prepared using the same synthesis method as in Example 6, and was a white solid (150 mg, 52.2%). MS (ESI, pos.ion) m / z: 673.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.22 (d, J = 6.2Hz, 1H), 7.96 (d ,J=3.2Hz,1H),7.92–7.81(m,2H),7.48–7.40(m,2H),7.37–7.29(m,4H),7. 27–7.20(m,1H),5.62(s,1H),4.57–4.41(m,3H),3.59(s,3H),3.56(s,3H), 3.34–3.31(m,1H),3.23(dd,J=18.0,4.9Hz,1H),2.38(s,3H),2.19(s,3H).

[0403] Synthesis of Example 25

[0404]

[0405] Example 25 was prepared using the same synthesis method as in Example 6, and was a white solid (530 mg, 73.8%). MS (ESI, pos.ion) m / z: 673.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.38(s,1H),9.24(d,J=4.5Hz,1H),8.12(d,J=5.2Hz,2H),7.92–7.81(m,1H),7.49–7.37(m,4H),7.31–7.22(m,3H),5 .65(s,1H),4.52(d,J=10.6Hz,2H),4.42(dd,J=11.8,5.2Hz,2H),3.60(s, 3H),3.53(s,3H),3.26(dd,J=17.9,6.3Hz,1H),2.28(s,3H),2.18(s,3H).

[0406] Synthesis of Example 26

[0407]

[0408] Example 26 was prepared using the same synthesis method as in Example 6, and was a yellow solid (120 mg, 39.5%). MS (ESI, pos.ion) m / z: 597.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.46 (s, 1H), 9.20 (d, J = 6.1Hz, 1H), 7.97 (d, J = 3.2Hz, 1H), 7.92–7.83 (m, 2H), 7.48–7.3 7(m,2H),4.50–4.40(m,2H),4.38–4.27(m,3H),3.64(s,3H),3.58(s,3H),3.20–3.14(m,2H),2.38(s,3H),2.20(s,3H).

[0409] Synthesis of Example 27

[0410]

[0411] Example 27 was prepared using the same synthesis method as in Example 6, and was a white solid (112 mg, 53.80%). MS (ESI, pos.ion) m / z: 663.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.45 (s, 1H), 9.21 (d, J = 6.4Hz, 1H), 7.97 (d, J = 3.2Hz, 1H), 7.92–7.81 (m, 2H), 7.52 (d, J = 15.6Hz, 2H), 7.44 (d, J = 5.5Hz, 2H),6.42(s,1H),5.56(s,1H),4.59–4.38(m,3H),3.63(s,3H),3.58(s,3H) ,3.44–3.39(m,1H),3.15(dd,J=17.6,5.8Hz,1H),2.38(s,3H),2.19(s,3H).

[0412] Synthesis of Example 28

[0413]

[0414] Example 28 was prepared using the same synthesis method as in Example 6, and was a white solid (136 mg, 65.3%). MS (ESI, pos.ion) m / z: 663.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ(ppm)10.42(s,1H),9.19(d,J=4.6Hz,1H),7.99(d,J=3.1Hz,1H),7.93– 7.83(m,2H),7.54(s,1H),7.48(d,J=9.8Hz,1H),7.46–7.37(dd,J=16.6,7.3Hz,2H),6.47(s,1H) ,5.55(s,1H),4.52(d,J=11.6Hz,1H),4.48–4.42(m,1H),4.38(dd,J=11.6,5.1Hz,1H),3.63(s,3 H),3.56(s,3H),3.43(d,J=18.1Hz,1H),3.20(dd,J=18.0,6.5Hz,1H),2.30(s,3H),2.19(s,3H).

[0415] Synthesis of Example 29

[0416]

[0417] Example 29 was prepared using the same synthesis method as in Example 6, and was a white solid (153 mg, 76.1%). MS (ESI, pos.ion) m / z: 663.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.40 (s, 1H), 9.21 (d, J = 4.6Hz, 1H), 7.98 (d, J = 3.2Hz, 1H), 7. 92–7.80(m,2H),7.47(s,1H),7.45–7.37(m,2H),6.31(d,J=2.8Hz,1H),6.24(d,J=3.0Hz,1H) ,5.67(s,1H),4.54(d,J=11.6Hz,1H),4.45(d,J=5.0Hz,1H),4.37(dd,J=11.6,5.3Hz,1H),3. 61(s,3H),3.56(s,3H),3.45(d,J=18.0Hz,1H),3.28–3.13(m,1H),2.34(s,3H),2.20(s,3H).

[0418] Synthesis of Example 30

[0419]

[0420] Example 30 was prepared using the same synthesis method as in Example 6, and was a white solid (53 mg, 60.1%). MS (ESI, pos.ion) m / z: 663.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.22 (d, J = 6.1 Hz, 1H), 7.97 (d, J = 3.2 Hz,1H),7.91–7.83(m,2H),7.54(s,1H),7.47–7.39(m,2H),6.39–6.33(m,1H),6.2 3(d,J=3.1Hz,1H),5.70(s,1H),4.60–4.38(m,3H),3.60(s,3H),3.58(s,3H),3.4 1(dd,J=16.9,5.8Hz,1H),3.22(dd,J=17.9,4.8Hz,1H),2.37(s,3H),2.18(s,3H).

[0421] Synthesis of Example 31

[0422]

[0423] Example 31 was prepared using the same synthetic method as in Example 3, and was a white solid (70 mg, 25%) (compounds 31-5 were prepared using the same synthetic method as compound 3-1). MS (ESI, pos.ion) m / z: 650.20 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ (ppm) 10.39 (s, 1H), 9.15 (d, J = 6.0Hz, 1H), 7.94 (d, J = 3.2Hz, 1H), 7.90–7.82(m,2H),7.46–7.40(m,2H),5.76(s,1H),4.52(q,J=6.3Hz,1H),4.42–4.36(m, 2H),4.33–4.25(m,2H),3.57(s,3H),3.42(d,J=2.4Hz,2H),2.91(dd,J=16.2,6.4Hz,1H) ,2.59–2.55(m,1H),2.36(s,3H),2.16(s,3H),1.92–1.69(m,4H),1.16(d,J=6.5Hz,3H).

[0424] Synthesis of Example 32

[0425]

[0426] Example 32 was prepared using the same synthesis method as in Example 3, and was a white solid (85 mg, 21%). MS (ESI, pos.ion) m / z: 650.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 10.41 (s, 1H), 9.19 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 3. 1Hz,1H),7.91–7.82(m,2H),7.48–7.37(m,2H),4.50–4.32(m,3H),4.22(d,J=9 .3Hz,1H),3.59(s,3H),3.38(s,4H),2.81(dd,J=16.1,6.3Hz,1H),2.72–2.65( m,1H),2.40(s,3H),2.23(s,3H),1.80(d,J=6.6Hz,4H),1.19(d,J=6.4Hz,3H).

[0427] Synthesis of Example 33

[0428]

[0429] Example 33 was prepared using the same synthesis method as in Example 7, and was a white solid (74 mg, 26%). MS (ESI, pos.ion) m / z: 666.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.40 (s, 1H), 9.17 (d, J = 6.2Hz, 1H), 7.94 (d, J = 3.2Hz, 1H), 7. 90–7.85(m,1H),7.83(d,J=3.2Hz,1H),7.46–7.41(m,2H),4.47(q,J=6.3Hz,1H),4.44–4.37 (m,1H),4.36–4.25(m,2H),3.60(s,2H),3.58(d,J=5.8Hz,6H),3.48–3.41(m,2H),2.86(dd, J=16.1,6.5Hz,1H),2.54(d,J=3.3Hz,1H),2.35(s,3H),2.16(s,3H),1.18(d,J=6.5Hz,3H).

[0430] Synthesis of Example 34

[0431]

[0432] Example 34 was prepared using the same synthesis method as in Example 7, and was a white solid (90 mg, 22%). MS (ESI, pos.ion) m / z: 666.20 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.21 (d, J = 5.7Hz, 1H), 7.95 (d, J = 3.0Hz ,1H),7.91–7.81(m,2H),7.47–7.39(m,2H),4.48–4.31(m,3H),4.22(d,J=10.6Hz,1H ),3.59(s,3H),3.57(s,4H),3.55–3.51(m,2H),3.50–3.44(m,2H),2.80(dd,J=16.1, 6.2Hz,1H),2.65(d,J=15.5Hz,1H),2.40(s,3H),2.23(s,3H),1.21(d,J=6.4Hz,3H).

[0433] Synthesis of Example 35

[0434]

[0435] Step 1: Synthesis of Compound 35-1

[0436] Compound 3-1 (150 mg, 0.86 mmol) was dissolved in DMF (5 mL), and DIPEA (445 mg, 3.44 mmol) and HATU (491 mg, 1.29 mmol) were added. After stirring for 20 min, ammonium chloride (68 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 23 h. Dichloromethane (20 mL) was added, followed by washing with water (10 mL × 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 2) to give the title compound as a yellow solid (371 mg, 88%). MS (ESI, pos.ion) m / z: 492.3 [M+H] + .

[0437] Step 2: Synthesis of compound 35-2

[0438] Compound 35-1 (357 mg, 0.73 mmol) was dissolved in DMF (5 mL), and pyridine (462 mg, 5.84 mmol) and TFAA (613 mg, 2.92 mmol) were added. The mixture was stirred at room temperature for 2 h, and ethyl acetate (15 mL) was added. The mixture was then washed with water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to give the title compound as a pale brown solid (216 mg, 62%). MS (ESI, pos.ion) m / z: 474.2 [M+H] + .

[0439] Step 3: Synthesis of compound 35-3

[0440] Compound 35-2 (216 mg, 0.46 mmol) was dissolved in ethyl acetate (2 mL), and ethyl hydrochloride solution (3 mL, 4 mol / L) was added. The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure to give the title compound as a brownish-yellow solid (190 mg, 100%). MS (ESI, pos.ion) m / z: 374.1 [M+H] + .

[0441] Step 4: Synthesis of Compound 35

[0442] Compound F2 (153 mg, 0.46 mmol) and HATU (213 mg, 0.56 mmol) were dissolved in DMF (10 mL), followed by the addition of DIPEA (179 mg, 1.38 mmol). After stirring at room temperature for 10 min, compound 35-3 (190 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 21 h, diluted with ethyl acetate (20 mL), and washed with water (10 mL × 5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the title compound as a grayish-white solid (131 mg, 41%). MS (ESI, pos.ion) m / z: 692.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.31 (d, J = 5.8Hz, 1H), 8.01 (d, J = 3.2Hz, 1H), 7.92 ( d,J=3.2Hz,1H),7.91–7.83(m,1H),7.67–7.58(m,1H),7.51(dd,J=8.7,2.7Hz,1H),7.48–7.38( m,2H),7.32(td,J=8.5,2.6Hz,1H),5.92(s,1H),4.55(d,J=10.3Hz,2H),4.52–4.45(m,1H),3.6 0(s,3H),3.23(dd,J=16.9,6.6Hz,1H),2.90(dd,J=17.0,2.9Hz,1H),2.41(s,3H),2.22(s,3H).

[0443] Synthesis of Example 36

[0444]

[0445] Step 1: Synthesis of Compound 36-1

[0446] (3R)-4-benzyloxy-3-(tert-butoxycarbonylamino)-4-oxobutyric acid (2.00 g, 6.19 mmol) was dissolved in 10 mL of DCM, and DMAP (1.19 g, 9.25 mmol) was added. After stirring at room temperature for 10 min, Michaelis-Menten acid (0.94 g, 6.5 mmol) was added, and the mixture was cooled to 0 °C. Then, a 10 mL solution of EDCI (1.87 g, 9.27 mmol) in DCM was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 15 h. The reaction solution was washed successively with 1 M hydrochloric acid (10 mL × 3) and saturated brine (10 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow liquid (2.78 g, 100%). MS (ESI, pos.ion) m / z: 472.05 [M + Na] + .

[0447] Step 2: Synthesis of compound 36-2

[0448] Compound 36-1 was dissolved in methanol (3 mL) and toluene (8 mL), heated to 70 °C and stirred for 23 h, concentrated under reduced pressure, and the residue was used directly in the next reaction.

[0449] Step 3: Synthesis of compound 36-3

[0450] Compound 36-2 (2.35 g, 6.19 mmol), 2-chloro-4-fluorobenzaldehyde (1.05 g, 6.49 mmol), 2-thiazolylformamidin hydrochloride (1.23 g, 7.11 mmol, 94.6%), THF (20 mL), and NMM (1.7 mL, 15 mmol) were added to the reaction flask. The mixture was stirred at 60 °C for 5 h, then cooled to room temperature and used directly in the next reaction step.

[0451] Step 4: Synthesis of compound 36-4

[0452] The reaction solution from the previous step was cooled to 5°C, and a THF solution of 0.98 mL (7.4 mmol) in THF (5 mL) was added dropwise. After the addition was complete, the reaction was carried out at 5°C with stirring for 2 h. Ethyl acetate (30 mL) was added for dilution, and the mixture was washed successively with water (30 mL × 1) and saturated brine (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to give the title compound as a yellow solid (0.7 g, 22%). MS (ESI, pos.ion) m / z: 521.20 [M+H] + .

[0453] Step 5: Synthesis of compound 36-5

[0454] Sodium borohydride (0.11 g, 2.8 mmol) was dissolved in water (2 mL). A THF solution of compound 36-4 (0.70 g, 1.3 mmol) in 10 mL was added dropwise under ice bath conditions, and the reaction was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (0.64 g, 91%). MS (ESI, pos.ion) m / z: 525.00 [M+H] + .

[0455] Step 6: Synthesis of compound 36-6

[0456] Compound 36-5 (0.64 g, 1.2 mmol) and DMAP (0.45 g, 3.7 mmol) were dissolved in DCM (10 mL). Methanesulfonyl chloride (0.19 mL, 2.5 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was slowly heated to 35 °C and stirred for 20 h. The reaction solution was washed successively with 1 M hydrochloric acid (20 mL), water (20 mL), and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid (0.6 g, 97%). MS (ESI, pos.ion) m / z: 507.00 [M+H]+ .

[0457] Step 7: Synthesis of Compounds 36-7

[0458] Compound 36-7 (0.20 g, 0.39 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1.5 h, concentrated under reduced pressure, and the residue was used directly in the next reaction.

[0459] Step 8: Synthesis of Compound 36

[0460] Compound 36-7 (0.21 g, 0.40 mmol) was dissolved in DMF (5 mL), and DIPEA (0.10 g, 0.77 mmol), compound F2 (0.16 g, 0.48 mmol), and HATU (0.18 g, 0.47 mmol) were added. The mixture was stirred at room temperature for 24 h. The solution was diluted with dichloromethane (20 mL) and water (50 mL). The aqueous phase was back-extracted with dichloromethane (20 mL), and the organic phases were combined. The organic phases were washed successively with 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL), and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a white solid (90 mg, 30%). MS (ESI, pos.ion) m / z: 724.90 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.19 (t, J = 30.4Hz, 1H), 7.97 (d, J = 3.2 Hz,1H),7.91–7.83(m,2H),7.56–7.47(m,1H),7.47–7.37(m,3H),7.18(td,J=8.5,2 .6Hz,1H),6.02(s,1H),4.65–4.53(m,1H),4.46(d,J=5.2Hz,2H),3.57(s,3H),3.52 (s,3H),3.49–3.41(m,1H),3.28(dd,J=17.8,4.7Hz,1H),2.39(s,3H),2.20(s,3H).

[0461] Synthesis of Example 37

[0462]

[0463] Example 37 was prepared using the same synthesis method as in Example 36, and was a white solid product (0.28 g, 94%). MS (ESI, pos.ion) m / z: 724.90 [M+H]+ ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.39 (s, 1H), 9.31 (d, J = 5.0Hz, 1H), 7.97 (d, J = 3.2Hz, 1 H),7.91–7.83(m,2H),7.53(dd,J=8.6,6.4Hz,1H),7.46–7.38(m,3H),6.98(td,J=8.4, 2.5Hz,1H),6.01(s,1H),4.56(d,J=11.7Hz,1H),4.53–4.45(m,1H),4.34(dd,J=11.7, 5.2Hz,1H),3.62–3.46(m,7H),3.28(dd,J=18.0,6.6Hz,1H),2.36(s,3H),2.22(s,3H).

[0464] Synthesis of Example 38

[0465]

[0466] Example 38 was prepared using the same synthesis method as in Example 6, and was a pale yellow solid (206 mg, 62.39%). MS (ESI, pos.ion) m / z: 715.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.84 (d, J = 18.0Hz, 2H), 7.77–7.66 (m, 1H), 7.59–7.38 (m, 2H), 7.26–7.08 (m, 2H), 4.71 (s, 2H), 4.60–4.38 (m, 2H), 3.73 ( s,3H),3.62(s,3H),3.22–3.06(m,1H),2.35(s,3H),2.28(s,3H),2.17–2 .04(m,2H),1.87(d,J=13.1Hz,1H),1.77–1.56(m,5H),1.46–1.30(m,2H).

[0467] Synthesis of Example 39

[0468]

[0469] Example 39 was prepared using the same synthesis method as in Example 6, and was a white solid (134 mg, 35.14%). MS (ESI, pos.ion) m / z: 637.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.17 (d, J = 6.3 Hz, 1H), 7.96 (d, J =3.2Hz,1H),7.91–7.82(m,2H),7.48–7.38(m,2H),4.45–4.33(m,3H),4.27(d ,J=6.7Hz,1H),3.66(s,3H),3.58(s,3H),3.40–3.35(m,1H),3.11(dd,J=17.7 ,5.5Hz,1H),2.38(s,3H),2.18(s,3H),1.09–0.94(m,1H),0.45–0.19(m,4H).

[0470] Synthesis of Example 40

[0471]

[0472] Example 40 was prepared using the same synthesis method as in Example 6, and was a white solid (173 mg, 57.31%). MS (ESI, pos.ion) m / z: 637.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.43 (s, 1H), 9.21 (d, J = 5.2Hz, 1H), 7.98 (d, J = 3.2 Hz,1H),7.91–7.81(m,2H),7.47–7.36(m,2H),4.49–4.40(m,2H),4.39–4.31(m,1H ),4.16(d,J=7.2Hz,1H),3.66(s,3H),3.58(s,3H),3.42–3.36(m,1H),3.15(dd,J= 18.0,6.7Hz,1H),2.40(s,3H),2.22(s,3H),1.10–0.98(m,1H),0.47–0.23(m,4H).

[0473] Synthesis of Example 41

[0474]

[0475] Example 41 was prepared using the same synthesis method as in Example 6, and was a white solid (168 mg, 57.02%). MS (ESI, pos.ion) m / z: 679.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.21 (d, J = 6.2Hz, 1H), 7.97 (d, J = 3 .2Hz,1H),7.91–7.82(m,2H),7.48–7.39(m,3H),7.28(d,J=2.2Hz,1H),7.09(d, J=5.0Hz,1H),5.71(s,1H),4.59–4.39(m,3H),3.62(s,3H),3.58(d,J=10.0Hz, 3H),3.45–3.37(m,1H),3.18(dd,J=17.7,5.4Hz,1H),2.39(s,3H),2.20(s,3H).

[0476] Synthesis of Example 42

[0477]

[0478] Example 42 was prepared using the same synthesis method as in Example 6, and was a white solid (157 mg, 53.28%). MS (ESI, pos.ion) m / z: 679.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 9.18 (d, J = 4.6Hz, 1H), 7.99 (d, J = 3.2Hz, 1H), 7.9 2–7.82(m,2H),7.47–7.39(m,2H),7.37–7.34(m,1H),7.32(s,1H),7.12(d,J=4.9Hz,1H),5.69 (s,1H),4.54(d,J=11.6Hz,1H),4.49–4.42(m,1H),4.38(dd,J=11.7,5.2Hz,1H),3.62(s,3H) ,3.55(s,3H),3.45(d,J=17.9Hz,1H),3.22(dd,J=18.0,6.6Hz,1H),2.29(s,3H),2.18(s,3H).

[0479] Synthesis of Example 43

[0480]

[0481] Example 43 was prepared using the same synthesis method as in Example 6, and was a pale yellow solid (69 mg, 8.3%). MS (ESI, pos.ion) m / z: 715.1 [M+H] + ; 1H NMR(400MHz, CDCl3)δ(ppm)7.86(s,1H),7.78–7.64(m,1H),7.54(s,1H),7.46(s,1H) ,7.21–7.05(m,3H),4.87–4.75(m,1H),4.75–4.64(m,1H),4.61–4.40(m,2H),3.76(s ,3H),3.71(s,3H),3.46(d,J=18.1Hz,1H),3.34–3.18(m,1H),2.40(s,3H),2.37(s,3 H),2.22–2.08(m,2H),1.90(d,J=12.0Hz,1H),1.81–1.68(m,5H),1.46–1.41(m,1H).

[0482] Synthesis of Example 44

[0483]

[0484] Example 44 was prepared using the same synthesis method as in Example 6, and was a light yellow solid (93 mg, 57.45%). MS (ESI, pos.ion) m / z: 677.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 9.05 (d, J = 6.2Hz, 1H), 8.80 (s, 1H), 7.90 (d, J = 3.2Hz, 1H), 7.7 1–7.62(m,1H),7.49(d,J=3.2Hz,1H),7.32-7.27(m,1H),7.14–7.05(m,2H),6.14(s,1H),4 .84–4.76(m,1H),4.65(d,J=12.6Hz,1H),4.55(dd,J=12.6,4.7Hz,1H),4.13(s,3H),3.86 (d,J=13.3Hz,1H),3.73(s,3H),3.59(s,3H),3.23–3.15(m,2H),2.37(s,3H),2.31(s,3H).

[0485] Synthesis of Example 45

[0486]

[0487] Add compound 1 (i.e., compound 1 of embodiment 1) (500 mg, 0.69 mmol), methanol (4 mL), tetrahydrofuran (4 mL), sodium hydroxide (82.8 mg, 2.07 mmol) in water (2 mL) to a reaction flask, and heat to 80 °C for 16 h. Rotate the reaction mixture to dryness, dilute with dichloromethane (50 mL) and 1 M hydrochloric acid (50 mL), separate the layers, back-extract the aqueous phase with dichloromethane (20 mL × 2), combine the organic phases, wash with saturated brine (50 mL), dry to anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 2 / 3) to give a white solid (75 mg, 15.1%). MS (ESI, pos.ion) m / z: 711.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 7.97 (s, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.40 (s, 1H), 7.28 (s, 2H), 7.24–7.18 (m, 1H), 7.13 (d, J=7.5Hz, 1H), 6.93(t,J=10.0Hz,1H),6.05(s,1H),4.82(s,1H),4.62(d,J=5.5Hz,1H),3.68(d,J=19.2Hz,2H),3.61(s,2H),2.35(s,3H),2.28(s,3H).

[0488] Synthesis of Example 46

[0489]

[0490] Example 46 (using Example 36 as the raw material) was prepared by referring to the synthesis method of Example 45 and was a white solid (46 mg, 24.32%). MS (ESI, pos.ion) m / z: 711.20 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm) 8.03 (br, 2H), 7.82 (d, J = 2.7Hz, 1H), 7.73–7.65 (m ,1H),7.40(d,J=2.6Hz,1H),7.26–7.18(m,2H),7.18–7.07(m,2H),6.93(t,J= 8.0Hz,1H),6.01(s,1H),4.87(s,1H),4.64(d,J=6.3Hz,2H),3.70(dd,J=20.6 ,10.3Hz,1H),3.56(s,3H),3.23(d,J=12.2Hz,1H),2.32(s,3H),2.25(s,3H).

[0491] Synthesis of Example 47

[0492]

[0493] Step 1: Synthesis of Compound 47-1

[0494] Compound F5 (240 mg, 0.49 mmol, which can be prepared by referring to the synthesis method of compound 3-1), ammonium chloride (27.52 mg, 0.51 mmol), HATU (224 mg, 0.59 mmol), DIPEA (127 mg, 0.98 mmol), and DMF (6 mL) were added to the reaction flask and stirred at room temperature for 5 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (25 mL). The aqueous phase was extracted with dichloromethane (10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 2 / 3) to give a yellow solid product (220 mg, 91.3%). MS (ESI, pos.ion) m / z: 492.3 [M+H] + .

[0495] Step 2: Synthesis of Compound 47-2

[0496] Compound 47-1 was dissolved in 1,4-dioxane (4 mL), and a 1,4-dioxane solution of HCl (4 mL, 4.01 M / L) was added. The mixture was stirred at room temperature for 17 h, and the reaction solution was evaporated to dryness and used directly in the next step. MS (ESI, pos.ion) m / z: 392.0 [M+H] + .

[0497] Step 3: Synthesis of Compound 47

[0498] Compound 47-2 (0.19 g, 0.44 mmol), compound F2 (0.15 g, 0.44 mmol), HATU (0.20 g, 0.53 mmol), DIPEA (0.11 g, 0.88 mmol), and DMF (10 mL) were added to a reaction flask and stirred at room temperature for 7 h. The mixture was diluted with 1 M hydrochloric acid (50 mL), then extracted with ethyl acetate (20 mL). The aqueous phase was further extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 2) to give a pale yellow solid (44 mg, 13.2%). MS (ESI, pos.ion) m / z: 710.0 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 9.21 (d, J = 5.9Hz, 1H), 7.92 (d, J = 3.1Hz, 1 H),7.86(dd,J=13.1,7.7Hz,1H),7.80(d,J=3.1Hz,1H),7.49–7.36(m,4H),7.26–7.16 (m,1H),6.86(s,2H),6.06(s,1H),4.53–4.38(m,2H),4.33(dd,J=11.8,5.9Hz,1H),3. 58(s,3H),3.49–3.44(m,1H),3.05(dd,J=17.1,3.0Hz,1H),2.37(s,3H),2.18(s,3H).

[0499] Synthesis of Example 48

[0500]

[0501] Compound 48-6 (0.37 g, 0.51 mmol, prepared according to the synthesis method in Example 6) was dissolved in methanol (9 mL) and THF (6 mL), and a solution of sodium hydroxide (0.10 g, 2.55 mmol) in water (3 mL) was added. The mixture was stirred at room temperature for 6 h, and the reaction solution was evaporated to dryness. The solution was diluted with 50 mL of water and then extracted with dichloromethane (50 mL). The aqueous phase was then extracted again with dichloromethane (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was added to ethyl acetate (10 mL), and the mixture was stirred for 19 h. The residue was filtered, and the filter cake was washed with ethyl acetate (5 mL) and dried by rotary evaporation at 50 °C to give a yellow solid (37 mg, 9.47%). MS (ESI, pos.ion) m / z: 717.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.48 (s, 1H), 9.30 (d, J = 6.4Hz, 1H), 8.11–8.0 5(m,2H),7.92(d,J=8.1Hz,2H),7.90–7.85(m,1H),7.55(d,J=8.1Hz,2H),7.4 8–7.39(m,2H),5.76(s,1H),4.65–4.58(m,1H),4.52–4.42(m,2H),3.59(s,6H ),3.50–3.44(m,1H),3.26(dd,J=17.8,5.2Hz,1H),2.39(s,3H),2.20(s,3H).

[0502] Synthesis of Example 49

[0503]

[0504] Example 49 was prepared using the same synthesis method as Example 48, and was a pale yellow solid (67 mg, 16.07%). MS (ESI, pos.ion) m / z: 717.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.37 (s, 1H), 9.24 (d, J = 4.6Hz, 1H), 7.99 (d, J = 3.0Hz, 1H) ,7.89(d,J=2.9Hz,1H),7.83(d,J=8.0Hz,2H),7.51(d,J=8.1Hz,2H),7.45–7.37(m,2H), 5.69(s,1H),4.56(d,J=11.7Hz,1H),4.51–3.43(m,1H),4.38(dd,J=11.6,5.1Hz,1H),3. 58(s,3H),3.55(s,3H),3.46–3.43(m,1H),3.29–3.25(m,1H),2.31(s,3H),2.21(s,3H).

[0505] Synthesis of Example 50

[0506]

[0507] Step 1: Synthesis of Compound 50-1

[0508] Compound 3-1 (500 mg, 1.01 mmol), dichloromethane (15 mL), methanesulfonamide (383 mg, 4.03 mmol), EDCI (290 mg, 1.52 mmol), and DMAP (185 mg, 1.52 mmol) were added to a reaction flask. The reaction mixture was stirred at room temperature for 13 h. The reaction solution was washed with 0.5 M hydrochloric acid (15 mL), and the aqueous phase was back-extracted with dichloromethane (10 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 20 / 1) to give a pale yellow solid (325 mg, 56.45%). MS (ESI, pos.ion) m / z: 570.3 [M+H] + .

[0509] Step 2: Synthesis of Compound 50-2

[0510] Compound 50-1 (325 mg, 0.57 mmol), ethyl acetate (3 mL), and an ethyl acetate solution of hydrogen chloride (6 mL, 4 mol / L) were added to the reaction flask. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed by concentration to obtain a yellow foamy solid (310 mg, 100%).

[0511] Step 3: Synthesis of Compound 50

[0512] Compound 50-2 (192 mg, 0.57 mmol), HATU (260 mg, 0.68 mmol), DMF (10 mL), and DIPEA (223 mg, 1.73 mmol) were added to a reaction flask and stirred at room temperature for 10 min. Then, compound F2 (310 mg, 0.57 mmol) was added, and the reaction mixture was allowed to react at room temperature for 16 h. The mixture was diluted with EA (20 mL) and washed with saturated NaCl solution (20 mL × 5). The organic phase was concentrated, and the residue was purified by thin-layer chromatography (DCM / MeOH (V / V) = 10 / 1) to give a light khaki solid (57 mg, 12.7%). MS (ESI, pos.ion) m / z: 788.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.17 (s, 1H), 10.46 (s, 1H), 9.25 (d, J = 6.2Hz, 1H), 8.00–7.76 (m, 3H), 7.56–7.32 (m, 4H), 7.20 (t, J = 8.7Hz, 1H),6.14(s,1H),4.59–4.33(m,3H),3.59(s,3H),3.54–3.47(m,1H),3.36(s,3H),3.16(dd,J=17.4,4.3Hz,1H),2.38(s,3H),2.19(s,3H).

[0513] Synthesis of Example 51

[0514]

[0515] Step 1: Synthesis of Compound 51-1

[0516] Formic acid (23 mL, 609.60 mmol) was added to the reaction flask, followed by slow addition of triethylamine (42 mL, 303 mmol) under an ice-water bath. After stirring until homogeneous, 4-formylbenzonitrile (10.00 g, 76.26 mmol) and McFarland acid (10.99 g, 76.26 mmol) were added, and the mixture was heated to approximately 100 °C and reacted for about 16.5 h. The heating was then turned off. The reaction system was cooled to approximately 5 °C, and water (120 mL) was slowly added, precipitating a white solid. The solid was acidified with hydrochloric acid (6 M, 45 mL) to pH 1–2, and stirring was continued at approximately 5 °C for 4 h. The mixture was filtered, and the filter cake was washed with water (20 mL) and dried by rotary evaporation at 50 °C for 1 h to obtain the title compound as a white solid (11.21 g, 83.91%). MS (ESI, pos.ion) m / z: 176.1 [M+H] + .

[0517] Step 2: Synthesis of compound 51-2

[0518] Compound 51-1 (12.77 g, 72.90 mmol), formic acid (135 mL), water (45 mL), and Raney nickel (12.80 g, 149.44 mmol) were added to a reaction flask. The mixture was stirred and heated to 105 °C for approximately 1.3 h, then cooled to room temperature. The mixture was filtered, and the filter cake was washed successively with methanol (100 mL) and water (50 mL). The filtrate was concentrated until a large amount of solid precipitated. The residue was diluted with water (150 mL), and the mixture was stirred at room temperature for another 4 h. The mixture was then filtered, and the filter cake was washed with water (100 mL) and dried under vacuum at 60 °C for 5 h to give a white solid (9.43 g, 72.6%). MS (ESI, pos.ion) m / z: 179.2 [M+H] + .

[0519] Step 3: Synthesis of compound 51-3

[0520] Compound 51-2 (3.00 g, 16.84 mmol) and MeOH (15 mL) were added to a reaction flask. Thionyl chloride (3.1 mL, 42.73 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was heated to 70 °C and reacted for 1 h. The mixture was then cooled to room temperature, and the solvent was concentrated to give a brown oily substance (3.36 g, 103.8%). MS (ESI, pos.ion) m / z: 193.3 [M+H] + .

[0521] Step 4: Synthesis of compound 51-4

[0522] Compound 51-3 (3.36 g, 17.48 mmol), compound F3 (6.73 g, 17.13 mmol), 2-thiazolylformamidin hydrochloride (3.95 g, 19.21 mmol, purity 79.6%), isopropanol (15 mL), and 4-methylmorpholine (4.42 g, 43.66 mmol) were added to a reaction flask. The mixture was stirred and heated to 80 °C for 5.5 h. Heating was then stopped, and the mixture was cooled to room temperature. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 20 / 1) to give a yellow solid (7.06 g, 70.5%). MS (ESI, pos.ion) m / z: 573.2 [M+H]

[0523] Step 5: Synthesis of compound 51-5

[0524] Compound 51-4 (7.06 g, 12.33 mmol), THF (30 mL), and 4-methylmorpholine (2.49 g, 24.66 mmol) were added to a reaction flask. The mixture was cooled to approximately 5 °C, and a solution of isobutyl chloroformate (2.02 g, 14.80 mmol) in THF (10 mL) was added dropwise. After the addition was complete, the reaction was continued for 0.5 h. The mixture was then concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a yellow solid (1.77 g, 25.9%). MS (ESI, pos.ion) m / z: 555.5 [M+H] + .

[0525] Step 6: Synthesis of Compounds 51-6

[0526] NaBH4 (0.24 g, 6.38 mmol) and water (5 mL) were added to the reaction flask. A THF solution of compound 51-5 (1.77 g, 3.19 mmol) in 10 mL was added with stirring in an ice bath. After the addition was complete, the reaction was continued in an ice bath for approximately 30 min. Ethyl acetate (20 mL) and water (10 mL) were added. The aqueous phase was discarded, and the organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous Na2SO4, and filtered. The filter cake was washed with ethyl acetate (10 mL), and the filtrate was concentrated to give a yellow solid (1.59 g, 89.2%). MS (ESI, pos.ion) m / z: 559.1 [M+H] + .

[0527] Step 7: Synthesis of Compounds 51-7

[0528] Compound 51-6 (1.59 g, 2.85 mmol), dichloromethane (20 mL), and NMM (1 mL, 9.10 mmol) were added to a reaction flask. MsCl (0.65 g, 5.67 mmol) was added under ice-water bath conditions, and the mixture was heated to 35 °C and reacted for 4 h. The reaction solution was washed successively with 1 M hydrochloric acid (20 mL), water (20 mL), and saturated brine (20 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 3 / 1) to give a light brown solid (518 mg, 33.6%). MS (ESI, pos.ion) m / z: 541.1 [M+H] + .

[0529] Step 8: Synthesis of compounds 51-8

[0530] Compound 51-7 (518 mg, 0.96 mmol) and 1,4-dioxane hydrochloride (6 mL, 4 M) were added to a reaction flask and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with 1,4-dioxane (5 mL) and dried by rotary evaporation at 50 °C for 1 h to give a light brown solid (437 mg, 95.4%). MS (ESI, pos.ion) m / z: 441.3 [M+H] + .

[0531] Step 9: Synthesis of compounds 51-9

[0532] Compound F2 (333 mg, 0.99 mmol), HATU (452 ​​mg, 1.19 mmol), DMF (10 mL), and DIPEA (0.5 mL, 3.02 mmol) were added to a reaction flask and stirred at room temperature for 10 min. Compound 51-8 (437 mg, 0.99 mmol) was then added, and the reaction proceeded for approximately 4.5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated NaCl (20 mL × 5). The organic phase was concentrated, and the residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a brownish-yellow solid (496 mg, 66.0%). MS (ESI, pos.ion) m / z: 759.0 [M+H] + .

[0533] Step 10: Synthesis of Compound 51

[0534] Compound 51-9 (200 mg, 0.26 mmol), THF (3 mL), and MeOH (3 mL) were added to a reaction flask, followed by a solution of NaOH (13 mg, 0.33 mmol) in water (3 mL). The mixture was stirred at room temperature for 4 h, diluted with water (10 mL), and washed with petroleum ether (10 mL). The aqueous phase was acidified with 6 M hydrochloric acid to pH 6–7, and stirred at room temperature for 30 min. The mixture was then filtered, and the filter cake was transferred to a reaction flask. The mixture was stirred at room temperature for 1 h with petroleum ether (6 mL) and ethyl acetate (3 mL), filtered, and washed with a mixture of petroleum ether and ethyl acetate (3 mL, V / V = 2 / 1). Finally, the mixture was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give a light brown solid (84 mg, 43.4%). MS (ESI, pos.ion) m / z: 745.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.46 (s, 1H), 9.22 (d, J = 6.3Hz, 1H), 7.96 (d, J = 3.2Hz, 1H),7.93–7.82(m,2H),7.49–7.37(m,2H),7.23(d,J=7.8Hz,2H),7.16(d,J=7.9Hz,2H ),5.59(s,1H),4.59–4.39(m,3H),3.59(s,3H),3.57(s,3H),3.43–3.40(m,1H),3.25 –3.19(m,1H),2.77(t,J=7.7Hz,2H),2.48(t,J=7.9Hz,2H),2.38(s,3H),2.20(s,3H).

[0535] Synthesis of Example 52

[0536]

[0537] Example 52 was prepared using the same synthesis method as Example 51, and was a white solid (113 mg, 58.36%). MS (ESI, pos.ion) m / z: 745.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 9.23 (d, J = 4.9Hz, 1H), 7.98 (d, J = 3.3Hz, 1H), 7.91–7.8 0(m,2H),7.47–7.36(m,2H),7.28(d,J=7.7Hz,2H),7.08(d,J=7.8Hz,2H),5.57(s,1H),4.56(d,J=11 .7Hz,1H),4.50–4.42(m,1H),4.41–4.32(m,1H),3.57(s,3H),3.56(s,3H),3.46(d,J=18.0Hz,1H),3 .24(dd,J=18.2,6.9Hz,1H),2.77(t,J=7.6Hz,2H),2.48(t,J=7.9Hz,2H),2.34(s,3H),2.22(s,3H).

[0538] Synthesis of Example 53

[0539]

[0540] Example 53 was prepared using the same synthesis method as in Example 3, and was a white solid (43 mg, 36.41%). MS (ESI, pos.ion) m / z: 622.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.42 (s, 1H), 9.11 (d, J = 5.6Hz, 1H), 7.99–7.73 (m, 3H), 7.50–7.33 (m, 2H), 6.90 (s, 2H), 4.47–4.24 (m ,4H),3.57(s,3H),3.43–3.39(m,1H),2.94(dd,J=17.3,5.1Hz,1H),2.35(s,3H),2.17(s,3H),1.07–0.89(m,1H),0.45–0.19(m,4H).

[0541] Synthesis of Example 54

[0542]

[0543] Example 54 was prepared using the same synthesis method as in Example 35, and was a brown solid (88 mg, 49.92%). MS (ESI, pos.ion) m / z: 630.5 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.39 (s, 1H), 9.26 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 3. 0Hz,1H),7.90(d,J=3.0Hz,1H),7.86(dd,J=12.5,7.4Hz,1H),7.65(s,1H),7.46– 7.36(m,2H),6.44(d,J=7.0Hz,2H),5.66(s,1H),4.60–4.42(m,3H),3.58(s,3H) ,3.26(dd,J=16.5,5.4Hz,1H),2.91(d,J=16.8Hz,1H),2.39(s,3H),2.20(s,3H).

[0544] Synthesis of Example 55

[0545]

[0546] Example 55 was prepared using the same synthesis method as Example 45, and was a white solid (91 mg, 15.8%). MS (ESI, pos.ion) m / z: 623.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.55 (s, 1H), 9.66 (s, 1H), 8.39 (s, 1H), 7.95 (d, J = 3.1Hz, 1H), 7.90–7.80 (m, 2H), 7.48–7.29 (m, 2H), 5.73(s,1H),4.43–4.31(m,3H),4.23(d,J=6.9Hz,2H),3.48(s,3H),2.18(s,3H),2.04(s,3H),1.00-0.86(m,1H),0.36–0.16(m,4H).

[0547] Synthesis of Example 56

[0548]

[0549] Example 56 was prepared using the same synthesis method as Example 51, and was a light brown solid (527 mg, 74.68%). MS (ESI, pos.ion) m / z: 759.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.40 (s, 1H), 9.20 (d, J = 6.3Hz, 1H), 7.96 (d, J = 3.2Hz, 1H), 7 .92–7.81(m,2H),7.51–7.37(m,2H),7.25(d,J=7.7Hz,2H),7.17(d,J=7.8Hz,2H),5.60(s, 1H),4.61–4.39(m,3H),3.60(s,3H),3.58(s,6H),3.42(dd,J=17.7,6.5Hz,1H),3.22(dd,J =18.0,3.6Hz,1H),2.82(t,J=7.7Hz,2H),2.61(t,J=7.7Hz,2H),2.39(s,3H),2.21(s,3H).

[0550] Synthesis of Example 57

[0551]

[0552] Example 57 was prepared using the same synthesis method as Example 51, and was a light brown solid (379 mg, 66.60%). MS (ESI, pos.ion) m / z: 759.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 9.21 (d, J = 4.8Hz, 1H), 8.07–7.94 (m, 1H), 7.93–7 .77(m,2H),7.42(d,J=6.2Hz,2H),7.28(d,J=7.6Hz,2H),7.07(d,J=7.7Hz,2H),5.57(s,1H),4 .56(d,J=11.6Hz,1H),4.51–4.42(m,1H),4.41–4.31(m,1H),3.56(s,9H),3.47(d,J=18.3Hz,1 H),3.28–3.18(m,1H),2.80(t,J=7.6Hz,2H),2.58(t,J=7.9Hz,2H),2.33(s,3H),2.22(s,3H).

[0553] Synthesis of Example 58

[0554]

[0555] Example 58 was prepared using the same synthesis method as Example 48, and was a pale yellow solid (97 mg, 40.22%). MS (ESI, pos.ion) m / z: 731.1 [M+H]+ ; 1 H NMR(400MHz, DMSO-d6)δ(ppm)10.39(s,1H),9.20(d,J=6.3Hz,1H),8.02–7.81(m,5H),7.50(d,J=8.0Hz,2H),7.47–7.37(m,2H),5.73(s,1H),4 .64–4.40(m,3H),3.84(s,3H),3.59(s,3H),3.57(s,3H),3.43(dd,J=17 .8,7.0Hz,1H),3.24(dd,J=18.1,5.0Hz,1H),2.39(s,3H),2.21(s,3H).

[0556] Synthesis of Example 59

[0557]

[0558] Example 59 was prepared using the same synthesis method as Example 49, and was a pale yellow solid (193 mg, 53.90%). MS (ESI, pos.ion) m / z: 731.5 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.32 (s, 1H), 9.19 (d, J = 4.9Hz, 1H), 7.99 (d, J = 3.2Hz ,1H),7.92–7.78(m,4H),7.54(d,J=7.9Hz,2H),7.46–7.34(m,2H),5.69(s,1H),4.56 (d,J=11.8Hz,1H),4.47(d,J=6.7Hz,1H),4.43–4.35(m,1H),3.82(s,3H),3.57(s,3H ),3.55(s,3H),3.48(d,J=18.6Hz,1H),3.29–3.21(m,1H),2.31(s,3H),2.19(s,3H).

[0559] Synthesis of Example 60

[0560]

[0561] Example 60 was prepared using the same synthesis method as in Example 6, and was a yellow solid (180.9 mg, 81.31%). MS (ESI, pos.ion) m / z: 727.10 [M+H] + ; 1H NMR(400MHz, CDCl3)δ7.93-7.91(m,1H),7.75–7.71(m,1H),7.62(s,1H),7.57–7 .54(m,1H),7.37–7.35(m,1H),7.18–7.15(m,1H),6.99–6.96(m,1H),6.06(s,1H) ,4.82–4.75(m,1H),4.73–4.68(m,1H),4.62–4.55(m,1H),3.70(s,3H),3.68(s,3 H),3.64–3.60(m,1H),3.39–3.33(m,1H),3.34(s,1H),2.40(s,3H),2.36(s,3H).

[0562] Synthesis of Example 61

[0563]

[0564] Example 61 was prepared using the same synthesis method as in Example 6, and was a pale yellow solid (265.7 mg, 85.74%). MS (ESI, pos.ion) m / z: 727.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 3.2Hz, 1H), 7.76–7.68 (m, 1H), 7.46 (s, 1H), 7.44 (d,J=3.2Hz,1H),7.21–7.17(m,1H),7.16-7.10(m,2H),6.98(dd,J=16.7,8.1Hz, 1H),6.02(s,1H),4.80–4.72(m,1H),4.65–4.54(m,2H),3.73(s,3H),3.68(s,3H) ,3.51(d,J=18.3Hz,1H),3.34(dd,J=18.3,6.6Hz,1H),2.43(s,3H),2.40(s,3H).

[0565] Synthesis of Example 62

[0566]

[0567] Example 62 was prepared using the same synthesis method as in Example 6, and was a pale yellow solid (267.1 mg, 90.42%). MS: (ESI, pos.ion) m / z: 773.10 [M+H] + ; 1H NMR(400MHz, CDCl3) δ7.81(d,J=3.1Hz,1H),7.64(d,J=8.9Hz,2H),7.55(s,1H) ,7.40(d,J=3.1Hz,1H),7.27–7.22(m,2H),7.16(dd,J=8.6,2.4Hz,1H),6.96(t, J=8.2Hz,1H),6.19(s,1H),4.82–4.75(m,1H),4.64–4.54(m,2H),3.73(s,3H),3 .68(d,J=7.4Hz,1H),3.63(s,3H),3.33–3.27(m,1H),2.42(s,3H),2.39(s,3H).

[0568] Synthesis of Example 63

[0569]

[0570] Example 63 was prepared using the same synthesis method as in Example 6, and was a light yellow solid (116.6 mg, 76.32%). MS (ESI, pos.ion) m / z: 773.50 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 3.2Hz, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 7.40 ( d,J=3.5Hz,2H),7.19–7.14(m,2H),7.07–7.02(m,1H),6.99–6.93(m,1H),6. 20(s,1H),4.80–4.75(m,1H),4.63–4.56(m,2H),3.74(s,3H),3.68(d,J=7.8 Hz,1H),3.63(s,3H),3.31(dd,J=18.0,6.3Hz,1H),2.43(s,3H),2.41(s,3H).

[0571] Synthesis of Example 64

[0572]

[0573] Example 64 was prepared using the same synthesis method as in Example 6, and was a yellowish-brown solid (95.4 mg, 83.88%). MS (ESI, pos.ion) m / z: 732.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ9.24(d,J=6.7Hz,1H),8.55(d,J=8.4Hz,1H),8.24–8.2 0(m,1H),7.95(d,J=3.4Hz,2H),7.85(d,J=3.2Hz,1H),7.58–7.46(m,2H),7.43– 7.39(m,1H),7.21–7.15(m,1H),6.03(s,1H),4.61–4.57(m,1H),4.48–4.44(m, 2H),3.60(s,3H),3.52(s,3H),3.44(d,J=7.3Hz,1H),2.40(s,3H),2.21(s,3H).

[0574] Synthesis of Example 65

[0575]

[0576] Example 65 was prepared using the same synthesis method as in Example 6, and was a yellowish-brown solid (152.3 mg, 51.90%). MS (ESI, pos.ion) m / z: 815.00 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ10.67(s,1H),9.29(d,J=6.5Hz,1H),8.44(s,1H),7.96–7.92(m,2H ),7.84(d,J=3.2Hz,1H),7.63–7.59(m,2H),7.50(dd,J=8.6,6.3Hz,1H),7.40(dd,J=8.9,2. 6Hz,1H),7.17(td,J=8.5,2.6Hz,1H),6.03(s,1H),4.63–4.58(m,1H),4.46(d,J=5.4Hz,2H) ,3.61(s,3H),3.51(s,3H),3.49–3.44(m,1H),3.32–3.26(m,1H),2.40(s,3H),2.23(s,3H).

[0577] Synthesis of Example 66

[0578]

[0579] Example 66 was prepared using the same synthesis method as in Example 6, and was a yellowish-brown solid (211.8 mg, 75.19%). MS (ESI, pos.ion) m / z: 741.45 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ10.40(s,1H),9.24(d,J=5.9Hz,1H),8.02(d,J=4.7Hz,1H ),7.95(d,J=2.0Hz,1H),7.84(s,1H),7.61(br,1H),7.53–7.47(m,1H),7.44–7.3 8(m,2H),7.18(t,J=7.0Hz,1H),6.04(s,1H),4.59(d,J=4.5Hz,1H),4.47(s,2H), 3.59(s,3H),3.52(s,3H),3.47(dd,J=17.8,7.0Hz,1H),2.40(s,3H),2.20(s,3H).

[0580] Synthesis of Example 67

[0581]

[0582] Example 67 was prepared using the same synthesis method as in Example 6, and was a pale yellow solid (184.3 mg, 65.48%). MS (ESI, pos.ion) m / z: 689.3 [M+H] + ;1H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.22(d,J=6.5Hz,1H),7.95(d,J=3.2Hz,1H),7.84(d,J=3.2Hz, 1H),7.70(d,J=7.9Hz,2H),7.49(dd,J=8.6,6.3Hz,1H),7.40(dd,J=8.9,2.5Hz,1H),7.34(t,J=7.9Hz ,2H),7.18(td,J=8.4,2.5Hz,1H),7.10(t,J=7.4Hz,1H),6.03(s,1H),4.62–4.55(m,1H),4.46(d,J=5 .1Hz,2H),3.59(s,3H),3.51(s,3H),3.49–3.40(m,1H),3.32–3.25(m,1H),2.39(s,3H),2.20(s,3H).

[0583] Biological tests

[0584] Evaluation of the inhibitory activity of the compound on HBV DNA replication (qPCR method) and cytotoxicity of the compound in HepAD38 cells.

[0585] HBV cell line and culture conditions

[0586] 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).

[0587] In vitro cytotoxicity assay

[0588] 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.

[0589] 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%.

[0590] 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 The experimental results are shown in Table 2.

[0591] In vitro anti-HBV activity assay

[0592] After HepAD38 cells were revived and in 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, G418 at a final concentration of 400 μg / mL, and 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.

[0593] 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). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) 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%.

[0594] HBV DNA QPCR

[0595] qPCR 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 used for qPCR. 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 were added to each well of the qPCR plate (experimental group, control group, standard curve group). Viral DNA copy number was obtained for each well after qPCR. 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 2.

[0596] Table 2: Results of in vitro anti-HBV activity and cytotoxicity experiments of the compounds of this invention

[0597]

[0598]

[0599] Note: N / A indicates no detection.

[0600] Conclusion: Experimental results show that the compound of the present invention has good inhibitory activity against HBV and low cytotoxicity.

Claims

1. A compound, which is a compound of Formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt of the compound of Formula (I), Formula (I) wherein X is N; each n1 is 1, 2, 3, or 4; each n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n3 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n5 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n6 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n7 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n8 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n9 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n10 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n11 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n12 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n13 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n14 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n15 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n16 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n17 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n18 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n19 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n20 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n21 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n22 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n23 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n24 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n25 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n26 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n27 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n28 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n29 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n30 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n31 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n32 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n33 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n34 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n35 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n36 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n37 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n38 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n39 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n40 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n41 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n42 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n43 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n44 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n45 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n46 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n47 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n48 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n49 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n50 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n51 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n52 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n53 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each n54 is 0 wherein R 1 is ethynyl, propargyl, propynyl or phenyl, wherein the phenyl is unsubstituted or substituted by 1, 2 or 3 R w1 substituents, wherein the R w1 is F, CI, CN, methyl, CF3or -OCF3; each R 2 and R 3 independently methyl; each R a and R b independently hydrogen or deuterium; ring A is ​ Each R 11 It is hydrogen or deuterium; ​ R 5 H, deuterium, CN, -C(=0)OR 1a , -C(=0)NR 1b R 1c or -C(=0)R; R 6 H, deuterium, methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, imidazole, thienyl, pyrrolyl, pyrazolyl, oxazolyl, or isoxazolyl, wherein each of said cyclopropyl, phenyl, and imidazole is independently unsubstituted or substituted with 1, 2, or 3 R w2 substituents; R w2 For deuterium, F, Cl, Br, -COOH, -C(=O)OC 1-4 Alkyl, methyl, ethyl, or phenyl, wherein the methyl and ethyl groups are each independently unsubstituted or surrounded by one R group. w1 Replace, wherein, the R w1 -COOH; R 7 is cyclopropyl, phenyl, thiazolyl or pyridinyl; each R 1a independently hydrogen, deuterium, methyl or ethyl, wherein each of said methyl and ethyl is independently unsubstituted or substituted with 1 R w1 substituent, wherein said R w1 is -C(=O)O-ethyl; R 1b is hydrogen or deuterium; R 1c is hydrogen, deuterium, methyl, ethyl, ethynyl, propargyl, propynyl or cyclopropyl, wherein said cyclopropyl is unsubstituted or substituted by 1 or 2 R w3 substituents; R w3 is CHF2, methyl or ethyl; each R is independently pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein each of said pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl is independently unsubstituted or substituted with 1 R w4 substituents; R w4 is deuterium or phenyl, wherein said phenyl is unsubstituted or substituted by 1, 2 or 3 R w1 substituents, wherein said R w1 is F, CI or Br. ​ or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. ​ ​ ​ ​ ​

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