Aminothiophene compound and preparation method and application thereof

Abstract

The invention relates to an aminothiophene compound as well as a preparation method and application thereof. The structure of the compound is shown as a formula (I). The compound disclosed by the invention is a brand new anti-HBV (Hepatitis B Virus) compound. The invention also relates to a pharmaceutical composition containing the compound as an active component, and the pharmaceutical composition can be used for treating and / or preventing HBV infection and has important application value. # imgabs0 #

Description

Aminothiophene compounds, preparation methods and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to an aminothiophene compound for treating HBV infection, a preparation method thereof and uses thereof. Background Art

[0002] Hepatitis B virus (HBV), which causes hepatitis B, remains one of the most concerning viruses worldwide. Currently, over 250 million people worldwide are carriers of HBV, putting them at increased risk for serious liver diseases including cirrhosis, permanent scarring of the liver, liver failure, and cancer. The World Health Organization estimates that over 780,000 people die from HBV each year. According to the Hepatitis B Foundation, HBV accounts for 80% of liver cancer risk, and the five-year survival rate for liver cancer patients is typically only 15%.

[0003] Despite the availability of effective vaccines, vaccination coverage remains unsatisfactory in areas where HBV is endemic. [1] Currently, there are two main types of drugs approved for the treatment of chronic hepatitis B. One type is interferon (IFN-α) and its pegylated form (Peg-IFN-α). IFN-α is an immunomodulator that can induce the expression of interferon-stimulated genes (ISGs) in a non-specific manner. This gene encodes constitutive or secreted proteins with direct or indirect antiviral properties, thereby promoting the differentiation or activation of immune cells. [2] After 48 weeks of subcutaneous IFN-α administration, the efficacy rate in HBV patients was only 25%. [3]In addition to its low response rate, IFN-α also has other shortcomings, such as the need for injection, adverse reactions such as severe flu-like symptoms, and contraindications for patients with compensated cirrhosis, severe hepatitis, and concurrent autoimmune and psychological diseases. Another class of approved drugs is nucleoside analogs (NAs). Currently, there are five approved NAs, including Lamivudine (LMV), Telbivudine (Ldt), Adefovir dipivoxil (ADV), Tenofovir (TFV), and Entecavir (ETV). NAs directly inhibit the activity of HBV polymerase, leading to a reduction in viral particles, thereby interrupting the cycle of nucleocapsids to the nucleus of infected cells, and theoretically reducing the expression of cccDNA. However, NAs treatment is unable to inhibit the de novo synthesis of cccDNA in newly infected cells. This suggests that residual viral particles during antiviral treatment can lead to new cell infection and the reconstruction of the cccDNA reservoir. If patients stop taking the medication on their own, virological rebound may occur. Therefore, chronic hepatitis B virus infection rarely achieves a functional cure, and most patients require lifelong medication. However, long-term use of NAs can easily cause viral mutations and the development of drug resistance.

[0004] Based on the inadequacy of current therapies, some drugs targeting the HBV replication cycle or enhancing the human immune response are being developed and have entered the clinical research stage. Among them, the core protein in the HBV replication process is crucial for the packaging and reverse transcription of HBV pgRNA. The molecules developed for this protein are called core protein allosteric modulators or capsid assembly modulators (CpAMs). According to the mechanism of action of CpAMs, they can be divided into two categories: Class I CpAMs represented by heteroaryldihydropyrimidines (HAPs), whose mechanism of action is to enhance the kinetics of nucleocapsid formation, leading to the incorrect assembly of nucleocapsids; Class II CpAMs represented by phenylacrylamides (PPAs) and sulfonylbenzamides (SBAs) structural types, whose mechanism of action is to accelerate nucleocapsid assembly and form nucleocapsids with normal morphology but lacking viral pgRNA and HBV polymerase. [4] .

[0005] Antiviral studies of nucleocapsid inhibitors BAY41-4109 (HAP) and JNJ-632 (SBA) with different mechanisms in human primary hepatocytes revealed that CpAMs not only inhibited HBV replication, but also inhibited HBV RNA transcription and antigen production, suggesting that CpAMs have a dual mechanism of action in inhibiting both early and late stages of the virus. [5-6]NVR3-778 (SBA), an early-stage CpAMs molecule, exhibited strong anti-HBV activity, with an EC50 of 0.4 μM in HepG2.2.15 cells. Similarly, it also demonstrated effective anti-HBV activity in a humanized liver mouse model of HBV infection. [7] With the advancement of science and technology, drug developers have designed and screened molecular structures with in vitro anti-HBV activity as high as nM level, such as GLP-26 and RG7907.

[0006] Currently, most anti-HBV drugs demonstrate good in vitro anti-HBV activity. However, upon entering clinical practice, some have failed due to low efficacy and adverse reactions such as elevated ALT and relapse after drug discontinuation. Therefore, despite the current availability of numerous drugs and methods for treating HBV, molecules with new structural types and novel mechanisms of action to achieve a cure for hepatitis B remain urgently needed in the HBV treatment field.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by formula (I), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0009] wherein R1 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Deuterated alkoxy, halogen, cyano, amino;

[0010] R2 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl acyl, C 1-3 Haloalkyl acyl, C 2-3 Alkenyl, C 2-3 Alkynyl;

[0011] R3 is selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; the C 6-10 The substituents of aryl and 5-10 membered heteroaryl are independently selected from halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano;

[0012] R4 is selected from substituted or unsubstituted C1-10 Alkyl, substituted or unsubstituted C 3-10 Heteroalkyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 4-14 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 2-8 Alkynyl,

[0013] The C 1-10 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-8 Alkoxy, C 2-8 Alkynyl, -NR a R b 、-COOR a 、-C(O)NR a R b , substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; the -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; the substituents of the 5-6 membered heteroaryl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; the substituents of the 5-6 membered heterocycloalkyl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-8 Hydroxyalkyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl;

[0014] The C 3-10 The heteroalkyl group contains 1 to 4 heteroatoms selected from N, O and S; 3-10 The substituents of heteroalkyl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl.

[0015] The C 3-14 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-14 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 Alkynyl, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Heteroalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Carbonyl, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-8 Halogenated alkyl, C 1-8 Alkyl; the C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S;

[0016] The -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-14 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Carbonyl, C 2-8 Alkynyl, -C(O)NR a R b 、-C(O)R a 、-NR a R b 、-COOR a , -S(O)2CH3, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl substituted with halogen; the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S;

[0017] The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-10 membered heteroaryl group are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a Rb 、-COOR a 、-C(O)NR a R b ;

[0018] The C 6-10 The substituents of the aryl group are selected from halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl, -COOR a 、-C(O)NR a R b ;

[0019] R a 、R b are each independently selected from hydrogen, C 1-4 alkyl;

[0020] R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-8 Alkyl, amino; m is selected from 0 or 1;

[0021] Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

[0022] In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, halogen, cyano, amino.

[0023] In a preferred embodiment, R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, halogen, cyano, amino.

[0024] In a more preferred embodiment, R1 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, halogen, cyano, amino.

[0025] In a still further preferred embodiment, R1 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, -CF3, -CH2F, -CHF2, -CD3, haloethyl, halopropyl, deuterated ethyl, deuterated propyl, fluorine, chlorine, bromine, cyano, and amino.

[0026] In a preferred embodiment, R1 is selected from methyl, -CF3, -CD3, fluoro, chloro, bromo, cyano, and amino.

[0027] In a preferred embodiment, R1 is selected from methyl and chlorine.

[0028] In a most preferred embodiment, R1 is selected from methyl.

[0029] In one embodiment, in the above-mentioned compound, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methylacyl, ethylacyl, propylacyl, isopropylacyl, halomethylacyl, haloethylacyl, halopropylacyl, haloisopropylacyl, vinyl, propenyl, ethynyl, and propynyl.

[0030] In a preferred embodiment, R2 is selected from the group consisting of methyl, ethyl, propyl, methylacyl, ethylacyl, and propylacyl.

[0031] In a more preferred embodiment, R2 is selected from hydrogen, methyl, ethyl, methylacyl, ethylacyl.

[0032] In a preferred embodiment, R2 is selected from hydrogen, methyl, methylacyl.

[0033] In a most preferred embodiment, R2 is selected from hydrogen.

[0034] In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl and pyridyl groups are independently selected from halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, cyano.

[0035] In a preferred embodiment, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl and pyridyl groups are independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano.

[0036] In a more preferred embodiment, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl group are selected from fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, cyano; the substituent of the pyridyl group is selected from fluorine, chlorine, bromine, C 1-4 alkyl.

[0037] In a still more preferred embodiment, R3 is selected from

[0038] In a still more preferred embodiment, R3 is selected from

[0039] In a still more preferred embodiment, R3 is selected from

[0040] In a preferred embodiment, R3 is selected from

[0041] In a most preferred embodiment, R3 is selected from

[0042] In one embodiment, R3 is selected from

[0043] In one embodiment, R3 is selected from substituted or unsubstituted phenyl; the substituents of the phenyl group are selected from fluorine, chlorine, bromine, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano.

[0044] In one embodiment, R3 is selected from

[0045] In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R4 is selected from substituted or unsubstituted C 1-10 Alkyl, C 3-10 Heteroalkyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 4-14 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 2-8 Alkynyl,

[0046] The C 1-10 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-8 Alkoxy, C 2-8 Alkynyl, -NR a R b , substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-8 Alkyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-8 hydroxyalkyl;

[0047] The C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S;

[0048] The C 3-14 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-14 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 Alkynyl, C 1-8 Alkyl, C 3-10 Heteroalkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-8 Halogenated alkyl, C 1-8 Alkyl; the C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S;

[0049] The -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-14 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8Hydroxyalkyl, -C(O)R a , -S(O)2CH3;

[0050] The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-10 membered heteroaryl group are selected from halogen, C 1-8 Alkyl, C 1-8 alkyl halide;

[0051] The C 6-10 The substituents of the aryl group are selected from halogen, cyano, C 1-8 Alkyl, C 1-8 alkyl halide;

[0052] R a 、R b are each independently selected from hydrogen, C 1-4 alkyl;

[0053] R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-8 Alkyl, amino; m is selected from 0 or 1;

[0054] Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

[0055] In a preferred embodiment, R4 is selected from substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, C 3-8 Heteroalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 5-8 membered heteroaryl, C 2-6 Alkynyl,

[0056] The C 1-8 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 2-6 Alkynyl, -NR a R b , substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-6 Alkyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-6 hydroxyalkyl;

[0057] The C3-8 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S;

[0058] The C 3-10 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-10 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 3-8 Heteroalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-6 Halogenated alkyl, C 1-6 Alkyl; the C 3-8 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0059] The -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-12 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)R a , -S(O)2CH3;

[0060] The 5-8 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-8 membered heteroaryl group are selected from halogen, C 1-6 Alkyl, C 1-6 alkyl halide;

[0061] The C 6-8 The substituents of the aryl group are selected from halogen, cyano, C 1-6 Alkyl, C 1-6 alkyl halide;

[0062] R a 、R b are each independently selected from hydrogen, C 1-3 alkyl;

[0063] R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-6 Alkyl, amino; m is selected from 0 or 1;

[0064] Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

[0065] In a more preferred embodiment, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, C 3-6 heteroalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 2-4 Alkynyl,

[0066] The C 1-6 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkoxy, C 2-4 Alkynyl, -NR a R b , substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-4 Alkyl; the C 3-5 The substituents of the cycloalkyl group are selected from C 1-3 hydroxyalkyl;

[0067] The C 3-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0068] The C 3-8 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-8 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 3-6 Heteroalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR aR b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-4 Halogenated alkyl, C 1-4 Alkyl; the C 3-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0069] The -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-12 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -C(O)R a , -S(O)2CH3;

[0070] The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl group are selected from halogen, C 1-4 Alkyl, C 1-4 alkyl halide;

[0071] The substituents of the phenyl group are selected from halogen, cyano, C 1-4 Alkyl, C 1-4 alkyl halide;

[0072] R a 、R b are each independently selected from hydrogen, C 1-3 alkyl;

[0073] R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-4 Alkyl, amino; m is selected from 0 or 1;

[0074] Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

[0075] In a still more preferred embodiment, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, C 4-6 Heteroalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 2-4 Alkynyl,

[0076] The C 1-6The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methoxy, ethoxy, propoxy, ethynyl, propynyl, -NR a R b , substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, methyl, ethyl, propyl; the C 3-5 The substituents of the cycloalkyl group are selected from methylhydroxy, ethylhydroxy, and propylhydroxy;

[0077] The C 4-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0078] The C 3-8 Cycloalkyl includes spiro ring, bridged ring and fused ring; said C 3-8 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-8 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, propynyl, methyl, ethyl, propyl, heteropropyl, heterobutyl, heteropentyl, fluoromethyl, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituent of the 5-6 membered heteroaryl is selected from methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl; the heteropropyl, heterobutyl and heteropentyl contain 1 to 3 heteroatoms selected from N, O and S;

[0079] The 4-12 membered heterocycloalkyl group includes a spiro ring, a bridged ring and a condensed ring; the -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 4-12 membered heterocycloalkyl group are selected from hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(O)R a , -S(O)2CH3;

[0080] The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl group are selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl;

[0081] The substituent of the phenyl group is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl;

[0082] R a 、R b Each is independently selected from hydrogen, methyl, ethyl, propyl;

[0083] R5 is selected from hydrogen, deuterium, and hydroxyl; R6 is selected from hydrogen, deuterium, methyl, ethyl, propyl, and amino; m is selected from 0 or 1;

[0084] Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

[0085] In a preferred embodiment, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, propynyl, butynyl,

[0086] The C 1-6 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from fluorine, chlorine, bromine, hydroxyl, cyano, methoxy, ethoxy, propoxy, ethynyl, propynyl, N,N-dimethylamino, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, The substituents of the cyclopropyl and cyclobutyl groups are each independently selected from hydroxymethyl, hydroxyethyl, and hydroxypropyl;

[0087] The C 3-8 Cycloalkyl includes spiro ring, bridge ring or fused ring; said C 3-8 The substituents of the cycloalkyl group are selected from fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, propynyl, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, amino, -C(O)NH2, -C(O)NHCH3, -C(O)OCH3, -COOH, -C(O)CH3,

[0088] The 4-12 membered heterocycloalkyl group includes a spiro ring, a bridged ring or a condensed ring; the 4-12 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O and S; the substituents of the 4-12 membered heterocycloalkyl group are selected from hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, -CF3, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(O)CH3, -S(O)2CH3;

[0089] The 5-6 membered heteroaryl group is selected from pyridyl, thiazolyl, isoxazolyl, and pyrazolyl; the substituent of the pyridyl group is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, -CF3, fluoroethyl, and fluoropropyl; the substituents of the thiazolyl, isoxazolyl, and pyrazolyl groups are each independently selected from methyl, ethyl, and propyl;

[0090] The substituents of the phenyl group are selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, -CF3, fluoroethyl, and fluoropropyl.

[0091] In a preferred embodiment, R4 is selected from C 1-6 Alkyl, substituted C 1-6 Alkyl, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, substituted C 3-8 cycloalkyl, substituted or unsubstituted 4-11 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, propynyl, butynyl,

[0092] The C 1-6 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from fluorine, hydroxyl, and methoxy;

[0093] The C 1-3 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-3 The substituents of the alkyl group are selected from cyano, ethynyl, N,N-dimethylamino, cyclopropyl substituted with hydroxymethyl;

[0094] The C 3-8 Cycloalkyl includes spiro ring, bridge ring or fused ring; said C 3-8 The substituents of the cycloalkyl group are selected from fluorine, cyano, hydroxy, ethynyl, methyl, ethyl, -CF3, hydroxymethyl, methoxy, amino, -C(O)NH2, -C(O)NHCH3, -C(O)OCH3, -COOH, -C(O)CH3,

[0095] The 4-11 membered heterocycloalkyl group includes a spiro ring, a bridged ring or a condensed ring; the 4-11 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O and S; the substituent of the 4-11 membered heterocycloalkyl group is selected from hydroxyl, methyl, ethyl, isopropyl, -CF3, ethynyl, hydroxymethyl, -C(O)CH3, -S(O)2CH3;

[0096] The 5-6 membered heteroaryl group is selected from pyridyl, thiazolyl, isoxazolyl, pyrazolyl; the substituent of the pyridyl group is selected from fluorine and -CF3; the substituents of the thiazolyl, isoxazolyl, pyrazolyl are each independently selected from methyl;

[0097] The substituents of the phenyl group are selected from fluorine, chlorine, bromine, cyano, methyl, and -CF3.

[0098] In a preferred embodiment, R4 is selected from methyl, ethyl, propyl, isopropyl,

[0099] In one embodiment, R4 is selected from

[0100] In one embodiment, R4 is selected from

[0101] In one embodiment, R4 is selected from

[0102] In one embodiment, R4 is selected from

[0103] In one embodiment, R4 is selected from

[0104] In a most preferred embodiment, R4 is selected from

[0105] In one embodiment, the compound of formula (I) has the structure of formula (II) as described above, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer:

[0106] The definitions of R3 and R4 refer to the above definitions.

[0107] In one embodiment, the compound of formula (I) has the structure of formula (II) as described above, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer:

[0108] wherein R3 is selected from unsubstituted or substituted by one or more R m Substituted C 6-10 Aryl, unsubstituted or substituted with one or more R n Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; each R m 、R n are independently selected from the same or different halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano, hydroxy;

[0109] R4 is selected from adamantyl, unsubstituted or substituted by one or more R c Substituted C 1-8 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-8 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-8 Cycloalkyl or unsubstituted or substituted by one or more R f Substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S; R7 is selected from C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; each R c 、R d 、R e 、R f 、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-8 Alkyl, C 1-8 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl.

[0110] In one embodiment, in the above compounds, or their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers, R3 is selected from unsubstituted or substituted with one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano, hydroxy.

[0111] In one embodiment, R3 is selected from unsubstituted or substituted with one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, amino, cyano, hydroxy.

[0112] In one embodiment, R3 is selected from unsubstituted or substituted with one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, amino, cyano, hydroxy.

[0113] In one embodiment, R3 is selected from unsubstituted or substituted with one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n Each is independently selected from the same or different F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, fluoromethyl, fluoroethyl, amino, cyano, and hydroxyl.

[0114] In one embodiment, R3 is selected from unsubstituted or substituted with one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R nEach is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl.

[0115] In one embodiment, R3 is selected from unsubstituted or substituted with 1, 2 or 3 R m Substituted phenyl, unsubstituted or substituted by 1, 2 or 3 R n Substituted pyridyl; each R m 、R n Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl.

[0116] In one embodiment, R3 is unsubstituted or replaced by 1, 2 or 3 R m Substituted phenyl; each R m Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl.

[0117] In one embodiment, R3 is selected from

[0118] In one embodiment, R3 is selected from

[0119] In one embodiment, in the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, R4 is selected from adamantyl, C 1-8 Alkyl, 1 or more R c Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-6 Cycloalkyl or unsubstituted or substituted by one or more R f Substituted 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S; R7 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-membered heteroaryl, the 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; each R c 、R d 、R e 、R f、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl.

[0120] In one embodiment, R4 is selected from adamantyl, C 1-8 Alkyl, 1 or more R c Substituted C 1-4 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-6 Cycloalkyl or unsubstituted or substituted by one or more R f Substituted 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S; R7 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1-3 heteroatoms selected from N; each R c 、R d 、R e 、R f 、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 1-4 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl.

[0121] In one embodiment, R4 is selected from C 1-2 Alkyl, C 3-8 Alkyl, substituted by one or more halogen or ethynyl or C 1-2 Alkoxy-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 1 or more hydroxyl groups or C 1-2 Alkoxy-substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form a C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O; R7 is selected from methyl, ethyl, fluoromethyl, fluoroethyl, ethynyl, propynyl, -C(O)NR i R j , unsubstituted or triazolyl substituted by one or more methyl, ethyl or isopropyl groups; R i 、R j Each is independently selected from H, methyl, and ethyl.

[0122] In one embodiment, R4 is selected from C 1-2 Alkyl, C 3-6 Alkyl, C substituted with 1, 2 or 3 F 1-4 Alkyl, C substituted with 1 ethynyl 1-4 Alkyl, C substituted with 1 methoxy or ethoxy 1-4 Alkyl, C 3-6 Cycloalkyl, C substituted by 1 hydroxyl or methoxy or ethoxy 4-6 Cycloalkyl, R8, R9 and the carbon to which they are attached are combined to form a cyclopropyl, a cyclobutyl, a cyclobutyl substituted by 1 or 2 Fs, or a 4-6 membered heterocycloalkyl containing 1 O; R7 is selected from methyl, ethyl, -CF3, ethynyl, -C(O)NH2, -C(O)NH(CH3), a triazolyl which is unsubstituted or substituted by 1 methyl, ethyl or isopropyl.

[0123] In one embodiment, R4 is selected from

[0124] In one embodiment, R4 is selected from

[0125] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, the compound of formula (I) has the structure of formula (III-1), (III-2) or (III-3):

[0126] The definition of R4 refers to the above definition.

[0127] In one embodiment, the compound of formula (I) has the structure shown in formula (III-1) in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer:

[0128] The definition of R4 refers to the above definition.

[0129] In one embodiment, the compound of formula (I) has the structure shown in formula (III-2) in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer:

[0130] The definition of R4 refers to the above definition.

[0131] In one embodiment, the compound of formula (I) has the structure shown in formula (III-3) in the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer:

[0132] The definition of R4 refers to the above definition.

[0133] In one embodiment, the above compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, is selected from the following compounds:

[0134] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application. The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction processes based on the existing embodiments.

[0135] An important consideration in the planning of synthetic routes in this area is to select a suitable protecting group for a reactive functional group (such as an amino group in this application), for example, see Chem. Commun., 2019, 55, 7331--7334. All references cited in this application are incorporated herein as a whole, or synthetic methods known in the art and the methods described herein are used in combination. The product obtained by each step of the reaction is obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized according to the literature (such as provided by Scifinder) or purchased.

[0136] In some embodiments, the compounds of the general formula (I) of the present application can be prepared by those skilled in the art of organic synthesis using the following routes and standard methods in the art:

[0137] Method 1:

[0138] Step 1: The compound represented by Formula 1-a reacts with TFAA to obtain the compound represented by Formula 1-b by adding a protective group;

[0139] Step 2: The compound represented by Formula 1-b undergoes an ester exchange reaction with the compound represented by Formula 1-c under alkaline conditions (such as LiHMDS) to obtain the compound represented by Formula 1-d;

[0140] Step 3: The compound represented by Formula 1-d undergoes a Friedel-Crafts reaction with the compound represented by Formula 1-e under Lewis acidic conditions (such as AlCl 3 ) to obtain the compound represented by Formula 1-f;

[0141] Step 4: The compound represented by Formula 1-f undergoes a condensation reaction with the compound represented by Formula 1-g to obtain the compound represented by Formula 1-h;

[0142] Step 5: Deprotecting the compound represented by Formula 1-h under acidic conditions (such as HCl) to obtain the compound represented by Formula 1;

[0143] Method 2:

[0144] Step 1: The compound represented by Formula 1-h undergoes a coupling reaction with the compound represented by Formula 2-a to obtain the compound represented by Formula 2-b;

[0145] Step 2: Deprotecting the compound represented by Formula 2-b under acidic conditions to obtain the compound represented by Formula 2-c;

[0146] Step 3: Deprotecting the compound represented by Formula 2-c under alkaline conditions to obtain the compound represented by Formula 2;

[0147] Wherein, R1, R3 and R4 are as defined in the present invention.

[0148] The present invention also provides a pharmaceutical composition comprising a compound represented by the above formula (I), (II), (III-1), (III-2) or (III-3), its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer and pharmaceutically acceptable auxiliary ingredients.

[0149] The present invention also provides the use of the compounds represented by the above formula (I), (II), (III-1), (III-2) or (III-3), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or the above pharmaceutical compositions in the preparation of drugs for anti-HBV infection.

[0150] The present invention also provides the use of the compounds represented by the above formula (I), (II), (III-1), (III-2) or (III-3), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or the above pharmaceutical compositions in the preparation of drugs for treating, preventing and / or reducing HBV infection.

[0151] The present invention also provides a method for combating HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by the above formula (I), (II), (III-1), (III-2) or (III-3), its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the above pharmaceutical composition.

[0152] The present invention also provides a method for treating, preventing and / or reducing HBV infection, by administering to a patient in need thereof a therapeutically effective amount of a compound represented by the above formula (I), (II), (III-1), (III-2) or (III-3), its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer or the above pharmaceutical composition.

[0153] The present invention also provides compounds represented by the above formula (I), (II), (III-1), (III-2) or (III-3), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or the above pharmaceutical compositions, which are used for anti-HBV infection.

[0154] The present invention also provides compounds represented by the above formula (I), (II), (III-1), (III-2) or (III-3), their prodrugs, solvates, crystal forms, pharmaceutically acceptable salts, stereoisomers or tautomers or the above pharmaceutical compositions, which are used to treat, prevent and / or reduce HBV infection.

[0155] Technical terms of the present invention:

[0156] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, it will be understood by those skilled in the art that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and claims, the word "comprise" and its variations, such as "comprises" and "comprising", should be interpreted as open-ended inclusive meaning, i.e., "including but not limited to". In addition, the headings provided herein are for convenience only and are not intended to explain the scope or meaning of the claimed invention.

[0157] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in a sense including "and / or" unless the context clearly dictates otherwise.

[0158] According to the common practice in this field, The bonds used in the formulae herein to describe the points of attachment of the moiety or substituent to the parent core or structure.

[0159] In the present invention, the term "substituted" means that an atom or a group of atoms formally replaces hydrogen and is connected to another group as a "substituent". Unless otherwise noted, the term "substituted" refers to any degree of substitution in the case where such substitution is allowed, such as mono-, di-, tri-, tetra- or penta-substitution. Substituents are selected independently, and substitution can be at any chemically accessible position. It should be understood that the substitution on the specified atom is subject to atomic valence restrictions. It should be understood that the substitution on the specified atom produces a chemically stable molecule.

[0160] In the present invention, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be a straight chain or a branched chain. 1-10"Alkyl" refers to an alkyl group having 1 to 10 carbon atoms. Alkyl formally corresponds to an alkane with one C-H bond replaced as the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-3 carbon atoms, or 1-2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-butyl, tert-butyl, isobutyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0161] In the present invention, the term "heteroalkyl" used alone or in combination with other terms refers to an alkyl group in which CH2 is replaced by different heteroatoms, wherein the heteroatoms are selected from N, O, and S, wherein the term "alkyl" is as defined above. For example, C 3-10 Heteroalkyl refers to an alkyl group containing 3-10 carbon atoms, wherein CH2 is substituted by 1-4 heteroatoms selected from N, O, and S. In some embodiments, heteropropyl refers to an alkyl group containing 3 carbon atoms, wherein one CH2 is substituted by 1 heteroatom selected from N, O, and S.

[0162] In the present invention, the term "halo" or "halogen" used alone or in combination with other terms refers to F, Cl, Br and I. In some embodiments, the term "halo" refers to a halogen atom selected from F, Cl or Br.

[0163] In the present invention, the term "haloalkyl" used alone or in combination with other terms refers to an alkyl group substituted by one or more halogens, wherein the terms "halogen" and "alkyl" are as defined above.

[0164] In the present invention, the term "hydroxyalkyl" used alone or in combination with other terms refers to an alkyl group substituted by one or more hydroxy groups, wherein the term "alkyl" is as defined above.

[0165] In the present invention, the term "heteroatom" used alone or in combination with other terms includes S, O and N.

[0166] In the present invention, the term "alkenyl" used alone or in combination with other terms refers to an optionally substituted straight-chain or optionally substituted branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in a cis or trans conformation around the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this document, terms such as "C2‐6 The numerical ranges for "alkenyl" and "alkenyl" all mean that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the term "alkenyl" appearing without specifying a numerical range. Unless otherwise specifically stated in the present specification, the alkenyl group can be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0167] In the present invention, the term "alkynyl" used alone or in combination with other terms refers to an optionally substituted straight-chain or optionally substituted branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears in this document, a radical such as "C 2-6 The numerical ranges for "alkynyl" and "alkynyl" all mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the term "alkynyl" appearing without specifying a numerical range. Unless otherwise specifically stated in the present specification, the alkynyl group can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.

[0168] In the present invention, the term " alkoxy " used alone or in combination with other terms refers to a group of formula -OR, wherein R is an alkyl group as defined above. Unless specifically indicated otherwise in this specification, alkoxy can be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. Replacement. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH, -OMe, -NH or -NO Replacement. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0169] In the present invention, the term "haloalkoxy" used alone or in combination with other terms refers to an alkoxy group substituted by one or more halogens, wherein the terms "halogen" and "alkoxy" are as defined above.

[0170] In the present invention, the term "aryl" used alone or in combination with other terms refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (for example, having two fused rings). 6-10 "Aryl" refers to an aromatic radical having 6 to 10 ring carbon atoms. Aryl radicals include, for example, phenyl, naphthyl, indanyl, indenyl, and the like. In some embodiments, an aryl radical has 6 carbon atoms. In some embodiments, an aryl radical has 10 carbon atoms. In some embodiments, an aryl radical is phenyl. In some embodiments, an aryl radical is naphthyl.

[0171] In the present invention, the term "heteroaryl" used alone or in combination with other terms refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from S, O and N, wherein the heteroatom can be on any ring or on multiple (e.g., two or three) rings at the same time. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl group has 5 to 14 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, the heteroaryl group has 5 to 10 ring atoms, including carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from S, O and N. In some embodiments, the heteroaryl group has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from S, O and N. In some embodiments, the heteroaryl group is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an eight-membered, nine-membered, or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolyl, isoquinolyl, naphthyridinyl (including 1,2-naphthyridine, 1,3-naphthyridine, 1,4-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,3-naphthyridine, and 2,6-naphthyridine), indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0172] In the present invention, the term "cycloalkyl" used alone or in combination with other terms refers to a saturated ring system (monocyclic, bicyclic or polycyclic), polycyclic (such as bicyclic or tricyclic) including fused rings, spiro rings, bridged rings, including cyclized alkyl. 3-8 Cycloalkyl" or "C 3-14"Cycloalkyl" refers to a cycloalkyl group having 3-8 or 3-14 ring member carbon atoms, respectively. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring member carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-12 ring members, 3-10 ring members, 3-8 ring members, 3-6 ring members, 3-5 ring members, or 3-4 ring members. In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group is a monocyclic ring or a bicyclic ring. In some embodiments, the cycloalkyl group is C 3-8 Monocyclic cycloalkyl. The ring carbon atoms of the cycloalkyl group may be optionally oxidized to form an oxo or sulfide group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0173] In the present invention, unless otherwise stated, the term "heterocycloalkyl" used alone or in combination with other terms refers to a saturated ring system (monocycle, bicycle or polycycle), polycycle (such as bicycle or tricycle) includes fused ring, spirocycle, bridged ring, it has at least one heteroatom ring member independently selected from N, S and O, and it has 4-14 ring members, 4-12 ring members, 4-10 ring members or 4-8 ring members, heteroatoms can be on any ring thereof, it is also possible to be on multiple (such as two or three) rings simultaneously. The term "heterocycloalkyl" includes monocyclic 4 yuan, 5 yuan, 6 yuan and 7 yuan heterocycloalkyl. In some embodiments, heterocycloalkyl is a monocyclic group with 1,2 or 3 heteroatoms independently selected from N, S and O. In some embodiments, heterocycloalkyl is a spirocycle with 1,2 or 3 heteroatoms independently selected from N, S and O. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) , N-oxides, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected via a ring-forming carbon atom or a ring-forming heteroatom.

[0174] In the present invention, the term "optional" means that it can be selected or not. For example, "-CH2- on the ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-" means that the -CH2- can be replaced by -C(=O)-, -C(=S)-, and / or -S(=O)2-, or it can not be replaced by -C(=O)-, -C(=S)-, and / or -S(=O)2-.

[0175] As used herein, the term "therapeutically effective amount" alone or in combination with other terms refers to an amount of a compound administered to a mammal and / or subject as a single dose or as part of a series of doses that is effective to produce the desired therapeutic effect.

[0176] Beneficial effects of the present invention:

[0177] The compound and pharmaceutical composition provided by the present invention show good anti-HBV infection activity and can be used as drugs for preventing and / or improving and / or treating diseases related to this activity. Specific implementation plan

[0178] Unless otherwise defined, all technical and scientific terms used in this invention have the same meanings as those commonly understood by those skilled in the art. Various other modifications, substitutions, or variations may be made in accordance with common technical knowledge and customary means in the art without departing from the basic technical principles of this invention.

[0179] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and they should also be considered as the scope of protection of the present invention.

[0180] Example 1 Preparation of Compound 1

[0181] Step 1: Synthesis of compound 1-b

[0182] 1-a (10 g, 54.00 mmol) was added to a single-necked flask and dissolved in dichloromethane (100 mL). Acetyl chloride (19.27 mL, 269.98 mmol) was then added under an ice-water bath. The mixture was stirred overnight at room temperature under nitrogen. The reaction solution was slowly poured into ice water (200 mL) to quench the mixture. After stirring for 5 minutes, the aqueous phase was extracted with dichloromethane (100 mL). The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (100 mL), and then washed with saturated brine (100 mL). The mixture was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-b (11 g, 48.39 mmol) as a brown solid. MS m / z (ESI): 228.15 [M+H] + .

[0183] Step 2: Synthesis of compound 1-d

[0184] 1-b (11 g, 48.39 mmol) and 1-c (9.9 g, 72.59 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (200 mL). Under nitrogen, the mixture was stirred in an ice-water bath for five minutes. Lithium bistrimethylsilylamide (435.51 mL, 435.51 mmol) was slowly added dropwise in an ice-water bath. After completion of the addition, the mixture was allowed to react at 25°C for 1 hour. The reaction solution was quenched with ice water (200 mL), saturated brine (200 mL) was added, and the layers were separated. The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A small amount of ethyl acetate was added to the resulting solid, slurried, filtered, and washed with a small amount of ethyl acetate. The filter cake was evaporated to dryness to obtain compound 1-d (10 g, 65.1 mmol) as a white solid. MS m / z (ESI): 318.08 [M+H] + .

[0185] Step 3: Synthesis of compound 1-e

[0186] 1-d (4 g, 12.61 mmol) was placed in a single-necked flask, followed by a 2M ethanolic hydrochloric acid solution (30 mL). The mixture was heated to 80°C under nitrogen and stirred for 1 hour. The reaction solution was concentrated, and a small amount of ethyl acetate was added to the resulting solid to slurry. The solid was filtered and washed with a small amount of ethyl acetate. The filter cake was evaporated to dryness to obtain compound 1-e (2 g, 3.63 mmol) as a white solid. MS m / z (ESI): 276.10 [M+H] + .

[0187] Step 4: Synthesis of compound 1-f

[0188] 1-e (2 g, 2.63 mmol) was added to a single-necked flask, along with trifluoroacetic anhydride (20 mL). The mixture was heated to 50°C under nitrogen and stirred for 3 hours. The reaction solution was concentrated and purified on a C18 column using an eluent ratio of 55% acetonitrile:45% 0.05% formic acid in water. The purified product was collected and concentrated under reduced pressure to afford compound 1-f (530 mg, 1.43 mmol) as an off-white solid. MS m / z (ESI): 372.07 [M+H] + .

[0189] Step 5: Synthesis of compound 1-h

[0190] 1-f (0.53 g, 1.43 mmol) was added to a reaction flask, followed by dichloromethane (20 mL). 1-g (5.59 mL, 49.96 mmol) was slowly added under an ice-water bath, followed by aluminum chloride (6.7 g, 49.96 mmol) in portions. Under nitrogen, the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (40 mL) and then slowly poured into ice water (100 mL) for quenching. The reaction solution was extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield 1-h (0.6 g, 1.35 mmol) as an off-white solid. MS m / z (ESI): 442.0 [MH] - .

[0191] Step 6: Synthesis of compound 1-j

[0192] 1-h (150 mg, 0.34 mmol) and 1-i (61 mg, 0.41 mmol) were added to a reaction flask. N,N-dimethylformamide (5 mL) was added to dissolve the mixture. N,N-diisopropylethylamine (0.23 mL, 1.36 mmol) was then added. After stirring in an ice-water bath for 1 minute, HATU (154 mg, 0.41 mmol) was added and stirred in an ice-water bath for 20 minutes. The reaction solution was directly purified by C18 column using an eluent ratio of 55% (acetonitrile): 45% (0.05% formic acid in water). The purified product was collected and concentrated under reduced pressure to obtain compound 1-j (100 mg, 0.19 mmol) as a yellow solid. MS m / z (ESI): 537.11 [MH] - .

[0193] Step 7: Synthesis of Compound 1

[0194] 1-j (50 mg, 0.09 mmol) was added to a sealed tube, followed by a 2M ethanolic hydrochloric acid solution (5 mL). The tube was sealed and heated to 80°C under nitrogen and stirred for 1 hour. The reaction solution was concentrated and purified by HPLC to obtain compound 1 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 443.04 [M+H] + .

[0195] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.33(d,J=9.2Hz,1H),8.22(dd,J=6.0,2.8Hz,1H),7.97-7.9 3(m,1H),7.80(s,2H),7.55(t,J=9.2Hz,1H),4.68-4.61(m,1H),2.55(s,3H),1.36(d,J=6.8Hz,3H).

[0196] Example 2 Preparation of Compound 2

[0197] Step 1: Synthesis of compound 2-b

[0198] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i was replaced with 2-a (50 mg, 0.41 mmol), and 90 mg of yellow solid product compound 2-b was obtained. MS m / z (ESI): 513.08 [M+H] + .

[0199] Step 2: Synthesis of compound 2

[0200] 2-b (50 mg, 0.10 mmol) was added to a single-necked flask and dissolved in methanol (5 mL). Potassium phosphate (207 mg, 0.98 mmol) was then added. Under nitrogen, the mixture was heated to 80°C and refluxed for 1.5 hours. The reaction solution was concentrated and purified by HPLC to obtain compound 2 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 417.10 [M+H] + .

[0201] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.31(s,1H),8.23(dd,J=5.8,2.8Hz,1H),7.98-7.93(m,1H),7.7 4(s,2H),7.56(t,J=9.2Hz,1H),4.69(d,J=6.4Hz,2H),4.35(d,J=6.4Hz,2H),2.57(s,3H),1.57(s,3H).

[0202] Example 3 Preparation of Intermediate 1-h

[0203] Step 1: Synthesis of compound 3-a

[0204] 1-a (10 g, 54 mmol) was added to a single-necked flask, followed by trifluoroacetic anhydride (50 mL), heated to 50°C, and stirred for 3 hours. The reaction solution was concentrated and washed sequentially with water (100 mL), saturated sodium carbonate solution (50 mL), and brine (50 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an off-white solid compound 3-a (14 g, 49.79 mmol). MS m / z (ESI): 282.15 [M+H] + .

[0205] Step 2: Synthesis of compound 1-f

[0206] 3-a (3 g, 10.67 mmol) and 1-c_ (1.7 g, 12.80 mmol) were added to a three-necked flask, and tetrahydrofuran (40 mL) was added to dissolve the mixture. Under nitrogen protection, the mixture was stirred in an ice-water bath for five minutes. Lithium bis(trimethylsilyl)amide (53.35 mL, 53.35 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was reacted at room temperature for 1 hour. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, and the liquid was separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with a mixed solvent of PE / EA = 1 / 2, filtered, washed, and the filter cake was evaporated to dryness to obtain a dark brown solid compound 1-f (3.9 g, 10.50 mmol). MS m / z (ESI): 372.05 [M+H] + .

[0207] Step 3: Synthesis of compound 1-h

[0208] 1-f (3.9 g, 10.50 mmol) was added to a reaction flask, followed by dichloromethane (100 mL). 1-g (41.13 mL, 367.63 mmol) was slowly added in an ice-water bath, followed by aluminum chloride (49.0 g, 367.63 mmol) in portions. The mixture was stirred overnight at room temperature under nitrogen. The reaction solution was diluted with ethyl acetate (150 mL) and then slowly poured into ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield compound 1-h (4.5 g, 10.15 mmol) as a dark yellow solid. MS m / z (ESI): 442.0 [MH] - .

[0209] Example 4 Preparation of Compound 4

[0210] Step 1: Synthesis of compound 4-b

[0211] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i was replaced with 4-a (60.1 mg, 0.41 mmol) to obtain yellow solid compound 4-b (60 mg, 0.09 mmol). MS m / z (ESI): 537.11 [MH] - .

[0212] Step 2: Synthesis of compound 4

[0213] The operation steps were the same as those for the synthesis of compound 1, except that 1-j was replaced with 4-b (50 mg, 0.09 mmol) to obtain yellow solid compound 4 (8 mg, 0.02 mmol). MS m / z (ESI): 443.23 [M+H] + .

[0214] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.34(d,J=9.2Hz,1H),8.22(dd,J=5.8,2.6Hz,1H),7.97-7.9 3(m,1H),7.80(s,2H),7.55(t,J=9.2Hz,1H),4.70-4.60(m,1H),2.55(s,3H),1.35(d,J=6.8Hz,3H).

[0215] Example 5 Preparation of Compound 5

[0216] Step 1: Synthesis of compound 5-b

[0217] 3-a (4 g, 14.22 mmol) and 5-a (2.2 g, 17.07 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (40 mL). Under nitrogen protection, the mixture was stirred in an ice-water bath for five minutes. Lithium bistrimethylsilylamide (42.66 mL, 42.66 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, and the liquid was separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with a mixed solvent of PE / EA = 1 / 2. Filtered, washed, and the filter cake was evaporated to dryness to obtain an off-white solid compound 5-b (5 g, 17.32 mmol). MS m / z (ESI): 365.21 [M+H] + .

[0218] Step 2: Synthesis of compound 5-c

[0219] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) was replaced with 5-b (1 g, 2.74 mmol) to obtain dark yellow solid compound 5-c (1.1 g, 2.52 mmol). MS m / z (ESI): 435.00 [MH] - .

[0220] Step 3: Synthesis of compound 5-d

[0221] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) was replaced with 5-c (150 mg, 0.34 mmol) to obtain yellow solid compound 5-d (100 mg, 0.19 mmol). MS m / z (ESI): 532.07 [M+H] + .

[0222] Step 4: Synthesis of compound 5

[0223] The operation steps were the same as those for the synthesis of compound 2, except that 2-b (50 mg, 0.10 mmol) was replaced with 5-d (50 mg, 0.09 mmol) to obtain yellow solid compound 5 (15 mg, 0.03 mmol). MS m / z (ESI): 436.18 [M+H] + .

[0224] 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 9.33 (d, J = 8.8Hz, 1H), 7.91-7.86 (m, 1H), 7.7 7(s,2H),7.47-7.41(m,2H),4.68-4.60(m,1H),2.54(s,1H),1.35(d,J=6.8Hz,3H).

[0225] Example 6 Preparation of Compound 6

[0226] Step 1: Synthesis of compound 6-a

[0227] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 2-a (68 mg, 1.2 mmol) to obtain yellow solid compound 6-a (115 mg, 0.23 mmol). MS m / z (ESI): 506.08 [M+H] + .

[0228] Step 2: Synthesis of compound 6

[0229] 6-a (115 mg, 0.23 mmol) was added to a single-necked flask and dissolved in methanol (20 mL). Potassium phosphate (976.6 mg, 4.60 mmol) was then added and heated to 70°C with reflux stirring for 1.5 hours. The reaction solution was concentrated and purified by HPLC to obtain compound 6 (10 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 410.07 [M+H] + .

[0230] 1 H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.27(s,1H),7.89-7.83(m,1H),7.67(s,2H),7.4 4-7.38(m,2H),4.67(d,J=6.4Hz,2H),4.33(d,J=6.4Hz,2H),2.54(s,3H),1.54(s,3H).

[0231] Example 7 Preparation of Compound 7

[0232] Step 1: Synthesis of compound 7-b

[0233] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 7-a (45.7 mg, 0.55 mmol) to obtain yellow solid compound 7-b (140 mg, 0.28 mmol). MS m / z (ESI): 502.10 [M+H] + .

[0234] Step 2: Synthesis of compound 7

[0235] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 7-b (120 mg, 0.24 mmol) to obtain yellow solid compound 7 (13 mg, 0.03 mmol). MS m / z (ESI): 406.11 [M+H] + .

[0236] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),8.53(s,1H),7.89-7.83(m,1H),7.70(s,2H),7.42-7.38(m,2H),3.21(s,1H),2.52(s,3H),1.56(s,6H).

[0237] Example 8 Preparation of Compound 8

[0238] Step 1: Synthesis of compound 8-b

[0239] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 8-a (37.9 mg, 0.69 mmol) to obtain yellow solid compound 8-b (100 mg, 0.21 mmol). MS m / z (ESI): 474.06 [M+H] + .

[0240] Step 2: Synthesis of compound 8

[0241] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 8-b (100 mg, 0.21 mmol) to obtain yellow solid compound 8 (5 mg, 0.01 mmol). MS m / z (ESI): 378.08 [M+H] + .

[0242] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.18(t,J=6.0Hz,1H),7.89-7.83(m,1H),7.70(s, 2H),7.44-7.38(m,2H),3.93(dd,J=6.4,2.8Hz,2H),3.13(t,J=2.8Hz,1H),2.52(s,3H).

[0243] Example 9 Preparation of Compound 9

[0244] Step 1: Synthesis of compound 9-a

[0245] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 4-a (37.9 mg, 81.2 mmol) to obtain yellow solid compound 9-a (120 mg, 0.23 mmol). MS m / z (ESI): 532.03 [M+H] + .

[0246] Step 2: Synthesis of compound 9

[0247] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 9-a (120 mg, 0.23 mmol) to obtain yellow solid compound 9 (15 mg, 0.03 mmol). MS m / z (ESI): 436.05 [M+H] + .

[0248] 1H NMR (400MHz, DMSO-d6) δ10.23 (s, 1H), 9.31 (d, J = 9.2Hz, 1H), 7.90-7.82 (m, 1H), 7.7 5(s,2H),7.46-7.34(m,2H),4.66-4.60(m,1H),2.52(s,3H),1.33(d,J=6.8Hz,3H).

[0249] Example 10 Preparation of Compound 10

[0250] Step 1: Synthesis of compound 10-b

[0251] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 10-a (64.7 mg, 0.55 mmol) to obtain yellow solid compound 10-b (130 mg, 0.26 mmol). MS m / z (ESI): 500.02 [M+H] + .

[0252] Step 2: Synthesis of compound 10

[0253] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 10-b (80 mg, 0.16 mmol) to obtain yellow solid compound 10 (5 mg, 0.01 mmol). MS m / z (ESI): 404.10 [M+H] + .

[0254] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.36(s,1H),7.91-7.85(m,1H),7.72(s,2H), 7.44-7.40(m,2H),3.05(s,1H),2.55(s,3H),1.17-1.14(m,2H),1.09-1.06(m,2H).

[0255] Example 11 Preparation of Compound 11

[0256] Step 1: Synthesis of compound 11-b

[0257] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 11-a (110.4 mg, 0.55 mmol) to obtain yellow solid compound 11-b (140 mg, 0.24 mmol). MS m / z (ESI): 583.08 [M+H] + .

[0258] Step 2: Synthesis of compound 11

[0259] 11-b (100 mg, 0.17 mmol) was placed in a single-necked flask and dissolved in methanol (20 mL). Potassium phosphate (729.1 mg, 3.43 mmol) was then added, heated to 70°C, and stirred under reflux for 1.5 hours. The mixture was cooled to room temperature, and ethyl acetate (20 mL), water (2 mL), and saturated brine (20 mL) were added. The liquids were separated, and the organic phase was concentrated and purified by HPLC to obtain compound 11 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 487.11 [M+H] + .

[0260] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.49(s,1H),7.91-7.86(m,1H),7.83-7.81(m,1H), 7.68(s,2H),7.57-7.38(m,2H),3.25-3.14(m,2H),3.04-2.99(m,2H),2.60-2.59(m,6H).

[0261] Example 12 Preparation of Compound 12

[0262] Step 1: Synthesis of compound 12-b

[0263] The operation steps were the same as those for the synthesis of compound 5-d, except that 1-i was replaced with 12-a (52.3 mg, 0.55 mmol) to obtain yellow solid compound 12-b (100 mg, 0.19 mmol). MS m / z (ESI): 514.09 [M+H] + .

[0264] Step 2: Synthesis of compound 12

[0265] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 12-b (80 mg, 0.16 mmol) to obtain yellow solid compound 12 (10 mg, 0.02 mmol). MS m / z (ESI): 418.28 [M+H] + .

[0266] 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.22(s,1H),7.89-7.83(m,1H),7.68(s,2H), 7.44-7.38(m,2H),3.28(s,1H),2.52(s,3H),2.43-2.37(m,4H),1.99-1.86(m,2H).

[0267] Example 13 Preparation of Compound 13

[0268] Step 1: Synthesis of compound 13-b

[0269] The operation steps were the same as those for the synthesis of compound 5-b, except that 5-a (2.2 g, 17.07 mmol) was replaced with 13-a (2.5 g, 17.06 mmol) to obtain an off-white solid compound 13-b (4.6 g, 12.03 mmol). MS m / z (ESI): 383.01 [M+H] + .

[0270] Step 2: Synthesis of compound 13-c

[0271] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) was replaced with 13-b (1 g, 2.62 mmol) to obtain dark yellow solid compound 13-c (1.0 g, 2.2 mmol). MS m / z (ESI): 453.0 [MH] - .

[0272] Step 3: Synthesis of compound 13-d

[0273] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) was replaced with 13-c (150 mg, 0.33 mmol) to obtain yellow solid compound 13-d (120 mg, 0.22 mmol). MS m / z (ESI): 550.00 [M+H] + .

[0274] Step 4: Synthesis of compound 13

[0275] The operation steps were the same as those for the synthesis of compound 2, except that 2-b was replaced with 13-d (120 mg, 0.22 mmol) to obtain yellow solid compound 13 (20 mg, 0.04 mmol). MS m / z (ESI): 454.05 [M+H] + .

[0276] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.32(d,J=9.2Hz,1H),7.78(s,2H),7.59(dd,J=10.4,6.4Hz,2H),4.66-4.58(m,1H),1.33(d,J=6.8Hz,3H).

[0277] Example 14 Preparation of Compound 14

[0278] Step 1: Synthesis of compound 14-a

[0279] The operation steps were the same as those for the synthesis of compound 13-d, except that 1-i was replaced with 4-a (52.3 mg, 0.55 mmol) to obtain yellow solid compound 14-a (150 mg, 0.27 mmol). MS m / z (ESI): 550.03 [M+H] + .

[0280] Step 2: Synthesis of compound 14

[0281] The operation steps were the same as those for the synthesis of compound 2, except that 2-b was replaced with 14-a (150 mg, 0.27 mmol) to obtain yellow solid compound 14 (30 mg, 0.07 mmol). MS m / z (ESI): 454.03 [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6) δ10.37 (s, 1H), 9.33 (d, J = 9.2Hz, 1H), 7.80 (s, 2H), 7.61 (dd,J=10.4,6.4Hz,2H),4.69-4.60(m,1H),3.33(s,3H),1.35(d,J=6.8Hz,3H).

[0283] Example 15 Preparation of Compound 15

[0284] Step 1: Synthesis of compound 15-b

[0285] Dissolve 15-a (1.2 g, 7.5 mmol) in methanol (20 mL), add Pd / C (220 mg, 5% wet), and stir overnight at room temperature under a hydrogen atmosphere. Filter and concentrate the filtrate to obtain compound 15-b (955 mg, 7.34 mmol) as an orange solid, which is used directly in the next step. MS m / z (ESI): 131.00 [M+H] + .

[0286] Step 2: Synthesis of compound 15-c

[0287] The operation steps were the same as those for the synthesis of compound 5-b, except that 5-a (2.2 g, 17.07 mmol) was replaced with 15-b (950 mg, 7.30 mmol) to obtain yellow solid compound 15-c (1.7 g, 4.65 mmol). MS m / z (ESI): 366.04 [M+H] + .

[0288] Step 3: Synthesis of compound 15-d

[0289] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) was replaced with 15-c (500 mg, 1.37 mmol) to obtain yellow solid compound 15-d (300 mg, 0.69 mmol). MS m / z (ESI): 436.0 [MH] - .

[0290] Step 4: Synthesis of compound 15-e

[0291] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) was replaced with 15-d (300 mg, 0.69 mmol) to obtain yellow solid compound 15-e (280 mg, 0.53 mmol). MS m / z (ESI): 533.13 [M+H] + .

[0292] Step 5: Synthesis of compound 15

[0293] 15-e (80 mg, 0.15 mmol) was added to a single-necked flask and dissolved in methanol (20 mL). Potassium phosphate (638 mg, 3.01 mmol) was then added, heated to 70°C, and stirred under reflux for half an hour. The mixture was cooled to room temperature, and ethyl acetate (20 mL), water (2 mL), and saturated brine (20 mL) were added. The liquids were separated, and the organic phase was concentrated and purified by high-performance liquid chromatography to obtain compound 15 (8 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 437.08 [M+H] + .

[0294] 1 H NMR (400MHz, DMSO-d6) δ10.46 (s, 1H), 9.30 (d, J = 9.2Hz, 1H), 8.34-8.28 (m, 1H), 8.2 6-8.25(m,1H),7.80(s,2H),4.66-4.60(m,1H),2.54(s,3H),1.33(d,J=6.8Hz,3H).

[0295] Example 16 Preparation of Compound 17

[0296] Step 1: Synthesis of compound 17-b

[0297] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i (61 mg, 0.41 mmol) was replaced with 17-a (55 mg, 0.54 mmol) to obtain yellow solid compound 17-b (89 mg, 0.17 mmol). MS m / z (ESI): 527.13 [M+H] + .

[0298] Step 2: Synthesis of compound 17

[0299] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 17-b (89 mg, 0.17 mmol) to obtain yellow solid compound 17 (8 mg, 0.02 mmol). MS m / z (ESI): 431.15 [M+H] + .

[0300] 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.26-8.14(m,2H),7.93m,1H),7.66(s,2H),7 .52(t,J=9.2Hz,1H),3.72(m,1H),2.53(s,3H),1.05(d,J=6.8Hz,3H),0.87(s,9H).

[0301] Example 17 Preparation of Compound 20

[0302] Step 1: Synthesis of compound 20-b

[0303] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i (61 mg, 0.41 mmol) was replaced with 20-a (47 mg, 0.54 mmol) to obtain yellow solid compound 20-b (153 mg, 0.28 mmol). MS m / z (ESI): 541.24 [M+H] + .

[0304] Step 2: Synthesis of compound 20

[0305] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 20-b (153 mg, 0.28 mmol) to obtain yellow solid compound 20 (27 mg, 0.06 mmol). MS m / z (ESI): 445.10 [M+H] + .

[0306] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.21(dd,J=5.6,2.4Hz,1H),8.12(s,1H),7.97-7.92(m,1H),7.69(s,2H),7.54( t,J=9.2Hz,1H),3.65-3.60(m,2H),3.53-3.47(m,2H),2.55(s,3H),2.17-2.14(m,2H),1.60-1.53(m,2H),1.36(s,3H).

[0307] Example 18 Preparation of Compound 23

[0308] Step 1: Synthesis of compound 23-a

[0309] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i (61 mg, 0.41 mmol) was replaced with 7-a (45 mg, 0.54 mmol) to obtain yellow solid compound 23-a (80 mg, 0.16 mmol). MS m / z (ESI): 507.14 [MH] - .

[0310] Step 2: Synthesis of compound 23

[0311] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 23-a (80 mg, 0.16 mmol) to obtain yellow solid compound 23 (13 mg, 0.03 mmol). MS m / z (ESI): 413.09 [M+H] + .

[0312] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.54(s,1H),8.30-8.16(m,1H),8.02-7.90( m,1H),7.74(s,2H),7.55(t,J=9.2Hz,1H),3.22(s,1H),2.54(s,3H),1.59(s,6H).

[0313] Example 19 Preparation of Compound 24

[0314] Step 1: Synthesis of compound 24-b

[0315] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i (61 mg, 0.41 mmol) was replaced with 24-a (37 mg, 0.54 mmol) to obtain yellow solid compound 24-b (140 mg, 0.28 mmol). MS m / z (ESI): 493.32 [MH] - .

[0316] Step 2: Synthesis of compound 24

[0317] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 24-b (140 mg, 0.28 mmol) to obtain yellow solid compound 24 (5 mg, 0.01 mmol). MS m / z (ESI): 399.09 [M+H] + .

[0318] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.14(d,J=8.2Hz,1H),8.25-8.19(m,1H),7.99-7.91(m,1H),7.74(s ,2H),7.55(t,J=9.2Hz,1H),4.73-4.61(m,1H),3.22(d,J=2.4Hz,1H),2.54(s,3H),1.39(d,J=7.0Hz,3H).

[0319] Example 20 Preparation of Compound 25

[0320] Step 1: Synthesis of compound 25-a

[0321] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i (61 mg, 0.41 mmol) was replaced with 10-a (43.8 mg, 0.54 mmol) to obtain yellow solid compound 25-a (130 mg, 0.26 mmol). MS m / z (ESI): 505.09 [MH] - .

[0322] Step 2: Synthesis of compound 25

[0323] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 25-a (130 mg, 0.26 mmol) to obtain yellow solid compound 25 (6 mg, 0.01 mmol). MS m / z (ESI): 411.06 [M+H] + .

[0324] 1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),9.34(s,1H),8.25-8.15(m,1H),7.99-7.91(m,1H),7.74 (s,2H),7.55(t,J=9.2Hz,1H),3.04(s,1H),2.54(s,3H),1.18-1.12(m,2H),1.11-1.05(m,2H).

[0325] Example 21 Preparation of Compound 26

[0326] Step 1: Synthesis of compound 26-b

[0327] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i was replaced with 26-a (30 mg, 0.41 mmol), and 90 mg of yellow solid product compound 26-b was obtained. MS m / z (ESI): 499.10 [M+H] + .

[0328] Step 2: Synthesis of compound 26

[0329] 26-b (90 mg, 0.13 mmol) was added to a single-necked flask and dissolved in methanol (5 mL). Potassium phosphate (274 mg, 1.3 mmol) was then added. Under nitrogen, the mixture was heated to 80°C and refluxed for 1.5 hours. The reaction solution was concentrated and purified by HPLC to obtain compound 26 (8 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 403.10 [M+H] + .

[0330] 1 H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.20(dd,J=5.8,2.6Hz,1H),8.00(s,1H),7.94(dd d,J=9.0,4.8,2.6Hz,1H),7.68(s,2H),7.52(t,J=9.2Hz,1H),2.52(s,3H),1.34(s,9H).

[0331] Example 22 Preparation of Compound 27

[0332] Step 1: Synthesis of compound 27-b

[0333] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i was replaced with 27-a (80 mg, 0.30 mmol), and 115 mg of yellow solid product compound 27-b was obtained. MS m / z (ESI): 553.07 [M+H] + .

[0334] Step 2: Synthesis of compound 27

[0335] 27-b (115 mg, 0.21 mmol) was added to a single-necked flask and dissolved in methanol (5 mL). Potassium phosphate (445 mg, 2.1 mmol) was then added. Under nitrogen, the mixture was heated to 80°C and refluxed for 1.5 hours. The reaction solution was concentrated and purified by HPLC to obtain compound 27 (15 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 457.09 [M+H] + .

[0336] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.50(s,1H),8.19(dd,J=5.8,2.8Hz,1H),7.93(dd d,J=9.0,5.0,2.8Hz,1H),7.76(s,2H),7.52(t,J=9.2Hz,1H),2.55(s,3H),1.58(s,6H).

[0337] Example 23 Preparation of Compound 29

[0338] Step 1: Synthesis of compound 29-a

[0339] 1-h (63 g, 133.64 mmol) and DMF (200 mL) were added to a reaction flask, followed by 10% aqueous sodium hydroxide solution (200 mL, 500.12 mmol). The reaction was stirred at room temperature for 3 hours, quenched with water (500 mL), and extracted with EA (500 mL). The aqueous solution was collected, the pH was adjusted to 2-3, and the mixture was extracted with EA / MeOH = 2:1 (500 mL). The organic phase was collected and concentrated under reduced pressure to obtain 11 g of crude product. The crude product was thoroughly dissolved in EA (200 mL), filtered, and the solid was collected to obtain compound 29-a (9.0 g, 25.53 mmol) as a yellow solid. MS m / z (ESI): 348.08 [M+H] + .

[0340] Step 2: Synthesis of compound 29-c

[0341] Compound 29-b (10 mg, 0.04 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (10 mg, 0.09 mmol) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 1 hour. The palladium-carbon was removed by filtration, and the filtrate was concentrated to give compound 29-c (5 mg, 0.04 mmol). MS m / z (ESI): 136.12 (M+H) + .

[0342] Step 3: Synthesis of compound 29

[0343] 29-c (5.00 mg, 0.04 mmol) and 29-a (16.7 mg, 0.05 mmol) were added to a reaction flask and dissolved in N,N-dimethylformamide (1.0 mL). N,N-diisopropylethylamine (0.02 mL, 0.11 mmol) and HATU (21.1 mg, 0.06 mmol) were then added and allowed to react at room temperature for 20 minutes. The reaction solution was purified to obtain compound 29 (8.3 mg, 0.02 mmol) as a pale yellow solid. MS m / z (ESI): 465.18 [M+H] + .

[0344] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.07(s,1H),8.19(dd,J=5.6,2.8Hz,1H),7.98-7.89(m,1H),7.69(s,2H),7.5 2(t,J=9.2Hz,1H),2.98-2.87(m,2H),2.72-2.64(m,2H),2.54(s,3H),1.83(q,J=7.2Hz,2H),0.79(t,J=7.2Hz,3H).

[0345] Example 24 Preparation of Compound 30

[0346] Step 1: Synthesis of compound 30

[0347] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 30-a (10.2 mg, 0.06 mmol) to obtain 4.2 mg of a yellow product, compound 30. MS m / z (ESI): 471.07 [M+H] + .

[0348] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.94(s,1H),8.22(dd,J=6.0,2.8Hz,1H),7.99-7.91(m,1H) ),7.81(s,2H),7.55(t,J=9.2Hz,1H),4.87(d,J=8.4Hz,2H),4.74(d,J=8.4Hz,2H),2.58(s,3H).

[0349] Example 25 Preparation of Compound 31

[0350] Step 1: Synthesis of compound 31-b

[0351] The operation steps were the same as those for the synthesis of compound 1-f, except that 1-c was replaced with 31-a (1.2 g, 8.53 mmol) to obtain yellow solid compound 31-b (2.1 g, 5.52 mmol). MS m / z (ESI): 378.70 [MH] - .

[0352] Step 2: Synthesis of compound 31-c

[0353] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f was replaced with 31-b (2 g, 5.25 mmol) to obtain yellow solid compound 31-c (2.2 g, 4.86 mmol). MS m / z (ESI): 451.01 [MH] - .

[0354] Step 3: Synthesis of compound 31-d

[0355] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h was replaced with 31-c (400 mg, 0.88 mmol) to obtain yellow solid compound 31-d (480 mg, 0.88 mmol). MS m / z (ESI): 546.05 [MH] - .

[0356] Step 4: Synthesis of compound 31

[0357] The operation steps were the same as those for the synthesis of compound 11, except that 11-b was replaced with 31-d (480 mg, 0.88 mmol) to obtain yellow solid compound 31 (20 mg, 0.04 mmol). MS m / z (ESI): 452.02 [M+H] + .

[0358] 1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.31(d,J=9.2Hz,1H),8.06-8.01(m,1H),7.77(s,2H),7 .63-7.55(m,1H),7.42(t,J=9.2Hz,1H),4.75-4.59(m,1H),2.55(s,3H),1.36(d,J=7.0Hz,3H).

[0359] Example 26 Preparation of Compound 32

[0360] Step 1: Synthesis of compound 32-b

[0361] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-i was replaced with 32-a (69 mg, 0.30 mmol), and 109 mg of yellow solid product compound 32-b was obtained. MS m / z (ESI): 517.09 [M+H] + .

[0362] Step 2: Synthesis of compound 32

[0363] 32-b (109 mg, 0.22 mmol) was added to a single-necked flask and dissolved in methanol (5 mL). Potassium phosphate (446 mg, 2.2 mmol) was then added. Under nitrogen, the mixture was heated to 80°C and refluxed for 1.5 hours. The reaction solution was concentrated and purified by HPLC to obtain compound 32 (13 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 421.11 [M+H] + .

[0364] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.19-8.20(m,1H),8.15(s,1H),7.93(ddd,J=9.2,5.0,2.8 Hz,1H),7.71(s,2H),7.52(t,J=9.2Hz,1H),4.57(s,1H),4.45(s,1H),2.53(s,3H),1.32(s,6H).

[0365] Example 27 Preparation of Compound 33

[0366] Step 1: Synthesis of compound 33

[0367] The procedure was the same as for the synthesis of compound 1-j, except that 1-h was replaced with 29-a (52 mg, 0.15 mmol) and 1-i was replaced with 33-a (47 mg, 0.18 mmol). The reaction was continued for 30 min until the starting materials were consumed. High-performance liquid chromatography (HPLC) yielded 24 mg of compound 33 as a yellow solid. MS m / z (ESI): 455.07 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.50(s,1H),8.19(dd,J=5.8,2.6Hz,1H),7.93(ddd,J=9.0,4. 8, 2.6Hz, 1H), 7.76 (s, 2H), 7.52 (t, J = 9.2Hz, 1H), 1.31-1.27 (m, 2H), 2.52 (s, 3H), 1.13-1.08 (m, 2H).

[0369] Example 28 Preparation of Compound 34

[0370] Step 1: Synthesis of compound 34-b

[0371] Compounds 3-a (2 g, 7.11 mmol) and 34-a (1.1 g, 9.24 mmol) were added to a three-necked flask and dissolved in tetrahydrofuran (30 mL). Under nitrogen, the mixture was stirred in an ice-water bath for five minutes. Lithium bis(trimethylsilyl)amide (21.33 mL, 21.33 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, and the liquid was separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with a mixed solvent of PE / EA = 1 / 2. The mixture was filtered, washed, and the filter cake was evaporated to dryness to obtain an off-white solid compound 34-b (2.5 g, 6.94 mmol). MS m / z (ESI): 361.06 [M+H] + .

[0372] Step 2: Synthesis of compound 34-c

[0373] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) was replaced with 34-b (2.5 g, 6.94 mmol) to obtain dark yellow solid compound 34-c (2.6 g, 6.01 mmol). MS m / z (ESI): 433.04 [MH] - .

[0374] Step 3: Synthesis of compound 34-d

[0375] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) was replaced with 34-c (150 mg, 0.34 mmol) to obtain yellow solid compound 34-d (100 mg, 0.19 mmol). MS m / z (ESI): 528.07 [M+H] + .

[0376] Step 4: Synthesis of compound 34

[0377] The operation steps were the same as those for the synthesis of compound 2, except that 2-b (50 mg, 0.10 mmol) was replaced with 34-d (100 mg, 0.19 mmol) to obtain yellow solid compound 34 (15 mg, 0.03 mmol). MS m / z (ESI): 432.09 [M+H] + .

[0378] 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 9.27 (d, J = 9.0Hz, 1H), 7.69 (s, 2H), 7.61 (dd, J = 7.0, 2.2Hz, 1H), 7.55-7. 34(m,1H),7.09(t,J=9.2Hz,1H),4.73-4.54(m,1H),2.54(s,3H),2.22(d,J=1.2Hz,3H),1.33(d,J=7.0Hz,3H).

[0379] Example 29 Preparation of Compound 37

[0380] Step 1: Synthesis of compound 37

[0381] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 37-a (7 mg, 0.07 mmol) to obtain yellow solid compound 37 (15 mg, 0.03 mmol). MS m / z (ESI): 427.07 [M+H] + .

[0382] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.84(s,1H),8.23(dd,J=5.8,2.6Hz,1H),8.02-7.89(m,1H),7.7 9(s,2H),7.56(t,J=9.2Hz,1H),4.78(d,J=6.6Hz,2H),4.72(d,J=6.6Hz,2H),3.61(s,1H),2.58(s,3H).

[0383] Example 30 Preparation of Compound 38

[0384] Step 1: Synthesis of compound 38

[0385] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 38-a (27.4 mg, 0.23 mmol) to obtain yellow solid compound 38 (9 mg, 0.02 mmol). MS m / z (ESI): 413.15 [M+H] + .

[0386] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.25(s,1H),8.22(dd,J=5.8,2.6Hz,1H),7.95(ddd,J=9 .2,4.8,2.6Hz,1H),7.70(s,2H),7.55(t,J=9.2Hz,1H),2.54(s,3H),2.47(s,1H),2.07(s,6H).

[0387] Example 31 Preparation of Compound 39

[0388] Step 1: Synthesis of compound 39

[0389] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 39-a (23.7 mg, 0.23 mmol) to obtain yellow solid compound 39 (6 mg, 0.01 mmol). MS m / z (ESI): 433.10 [M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ10.33 (s, 1H), 8.21 (dd, J = 5.8, 2.6Hz, 1H), 7.92-7.98 (m, 2H), 7 .72(s,2H),7.54(t,J=9.2Hz,1H),3.42(s,2H),3.32(s,3H),2.54(s,3H),1.32(s,6H).

[0391] Example 32 Preparation of Compound 40

[0392] Step 1: Synthesis of compound 40

[0393] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 40-a (15 mg, 0.09 mmol) to obtain yellow solid compound 40 (4 mg, 0.01 mmol). MS m / z (ESI): 461.07 [M+H] + .

[0394] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.68(s,1H),8.21(dd,J=5.9,2.7Hz,1H),7.95(ddd,J=9.2, 4.8, 2.6Hz, 1H), 7.77 (s, 2H), 7.55 (t, J = 9.2Hz, 1H), 3.46 (s, 1H), 3.23-3.06 (m, 4H), 2.55 (s, 3H).

[0395] Example 33 Preparation of Compound 41

[0396] Step 1: Synthesis of compound 41-b

[0397] The operation steps were the same as those for the synthesis of compound 5-b, except that 5-a (2.2 g, 17.07 mmol) was replaced with 41-a (1.6 g, 8.53 mmol) to obtain an off-white solid compound 41-b (2.95 g, 6.54 mmol). MS m / z (ESI): 427.00 [M+H] + .

[0398] Step 2: Synthesis of compound 41-c

[0399] The operation steps were the same as those for the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) was replaced with 41-b (1 g, 2.35 mmol) to obtain dark yellow solid compound 41-c (1.0 g, 2.01 mmol). MS m / z (ESI): 496.93 [M+H] + .

[0400] Step 3: Synthesis of compound 41-d

[0401] The operation steps were the same as those for the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) was replaced with 41-c (900 mg, 1.81 mmol) to obtain yellow solid compound 41-d (600 mg, 1.01 mmol). MS m / z (ESI): 594.12 [M+H] + .

[0402] Step 4: Synthesis of compound 41

[0403] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 41-d (200 mg, 0.34 mmol) to obtain yellow solid compound 41 (38 mg, 0.08 mmol). MS m / z (ESI): 498.00 [M+H] + .

[0404] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),9.31(d,J=9.2Hz,1H),8.16(dd,J=6.6,2.6Hz,1H),7.76(s,2 H),7.65-7.61(m,1H),7.38(t,J=8.8Hz,1H),4.73–4.57(m,1H),2.55(s,3H),1.36(d,J=7.2Hz,3H).

[0405] Example 34 Preparation of Compound 42

[0406] Step 1: Synthesis of compound 42-a

[0407] 41-d (413 mg, 0.7 mmol) was added to a sealed tube, followed by tert-butyl carbamate (816 mg, 6.97 mmol), cesium carbonate (681 mg, 2.09 mmol), and BrettPhos Pd G3 (126 mg, 0.14 mmol). 1,4-dioxane (10 mL) was added, the atmosphere was replaced with nitrogen, the tube was sealed, and the mixture was heated to 100°C and stirred overnight. The mixture was concentrated and purified on a silica gel column (PE / EA = 3 / 1) to obtain compound 42-a (200 mg, 0.32 mmol) as a yellow solid. MS m / z (ESI): 573.00 [M-56+H] + .

[0408] Step 2: Synthesis of compound 42-b

[0409] 42-a (200 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by C18 column with an eluent ratio of 55% (acetonitrile): 45% (0.05% formic acid in water). The purified product was collected and concentrated under reduced pressure to obtain compound 42-b (150 mg, 0.28 mmol) as a yellow solid. MS m / z (ESI): 529.06 [M+H] + .

[0410] Step 3: Synthesis of compound 42

[0411] The operation steps were the same as those for the synthesis of compound 6, except that 6-a was replaced with 42-b (200 mg, 0.34 mmol) to obtain yellow solid compound 42 (17 mg, 0.04 mmol). MS m / z (ESI): 433.06 [M+H] + .

[0412] 1 H NMR (400MHz, DMSO-d6) δ9.76(s,1H),9.27(d,J=9.2Hz,1H),7.66(s,2H),7.22(dd,J=8.4,2.6Hz,1H),6.92(dd,J= 11.2,8.6Hz,1H),6.80(dq,J=8.6,2.8Hz,1H),5.14(s,2H),4.71–4.58(m,1H),2.54(s,3H),1.35(d,J=7.0Hz,3H).

[0413] Preparation of Compounds 43 and 44 in Examples 35 and 36

[0414] Step 1: Synthesis of Intermediate 43-b

[0415] The operation steps were the same as those for the synthesis of compound 29, except that 29-c was replaced with 43-a (60.2 mg, 0.35 mmol) to obtain yellow solid compound 43-b (100 mg, 0.02 mmol). MS m / z (ESI): 504.09 [M+H] + .

[0416] Step 2: Synthesis of compounds 43, 44

[0417] Compound 43-b (20 mg, 0.04 mmol) was dissolved in 2 mL of DMF, and potassium carbonate (11 mg, 0.08 mmol) and iodomethane (6.8 mg, 0.05 mmol) were added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase chromatography (acetonitrile:water = 60%:40%) to give compound 43 (3 mg, 0.01 mmol) as a yellow solid; MS m / z (ESI): 517.85 [M+H] + .

[0418] 1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.74(s,1H),8.21(dd,J=5.8,2.8Hz,1H),7.99–7.8 9(m,2H),7.72(s,2H),7.54(t,J=9.2Hz,1H),4.03(s,3H),3.30–3.17(m,4H),2.55(s,3H).

[0419] 44(2mg,0.01mmol);MS m / z(ESI):517.85[M+H] +

[0420] 1 H NMR (400MHz, DMSO-d6) δ10.35 (s, 1H), 9.78 (s, 1H), 8.22 (dd, J = 5.7, 2.6Hz, 1H), 8.01–7. 91(m,1H),7.73(s,2H),7.65–7.49(m,2H),4.14(s,3H),3.27–3.16(m,4H),2.62(s,3H).

[0421] Example 37 Preparation of Compound 45

[0422] Step 1: Synthesis of compound 45

[0423] The operation steps were the same as those for the synthesis of compound 43, except that iodomethane was replaced with iodoethane (7.8 mg, 0.05 mmol) to obtain yellow solid compound 45 (2 mg, 0.01 mmol). MS m / z (ESI): 532.09 [M+H] + .

[0424] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.78(s,1H),8.21(dd,J=5.8,2.6Hz,1H),8.01–7.90(m,1H),7.73(s,2H) ,7.63(s,1H),7.54(t,J=9.2Hz,1H),4.42(q,J=7.4Hz,2H),3.28–3.12(m,4H),2.54(s,3H),1.62–1.34(m,3H).

[0425] Example 38: In vitro anti-HBV activity experiment of HepG2.2.15 cells

[0426] 1. Compound Dilution: Dilution Method ①: Dilute the 20μM compound stock solution 10-fold with DMSO to obtain a 2μM concentration of the compound. Then, dilute the 20μM and 2μM compounds 200-fold with culture medium to obtain final concentrations of 100nM and 10nM, respectively. Dilution Method ②: Dilute the 20μM compound stock solution 10-fold and 100-fold with DMSO to obtain 2μM and 0.2μM concentrations of the compound. Then, dilute the 2μM and 0.2μM compounds 200-fold with culture medium to obtain final concentrations of 10nM and 1nM, respectively. Dilution method ③: first use DMSO to dilute the 400μM compound stock solution 4-fold to 8 concentration points to obtain 400μM, 100μM, 25.0μM, 6.25μM, 1.56μM, 0.391μM, 0.0977μM and 0.0244μM gradient diluted compounds, and then use culture medium to further dilute the gradient diluted compounds 200-fold to the final concentrations of 2000nM, 500nM, 125nM, 31.3nM, 7.81nM, 1.95nM, 0.488nM and 0.122nM.

[0427] 2. Experimental operation: On the first day, HepG2.2.15 cells (Wuhan Institute of Virology, Chinese Academy of Sciences) (1×10 5 Cells / well) were plated into 96-well cell culture plates and cultured overnight at 37°C, 5% CO2. Wells without cells and containing only culture medium were set as culture medium controls. On the second day, culture medium with different final concentrations of compounds in step 1 was added to the cell culture plate, and 3 replicate wells were set for each concentration. The final concentration of DMSO in the cell culture medium was 0.5%, and the final volume in the culture wells was 200 μl. Wells without compounds with a final concentration of 0.5% DMSO were set as DMSO controls. Culture was continued until the fifth day, and fresh culture medium with the same treatment as above was replaced in the compound-treated wells and control wells. On the eighth day, the cell supernatant in the culture wells was collected, and part of the sample was taken to detect the content of HBV DNA. A plasmid containing the full-length sequence of type D HBV DNA was used as a standard for qPCR, and the standard range was 10 7 -10 1 HBV DNA content in all samples was determined by qPCR. After collecting the supernatant, Cell Titer-Glo reagent was added to the cell culture wells and incubated at room temperature for 10 minutes. The chemiluminescence values ​​in all wells were then read using a microplate reader to calculate cell proliferation activity.

[0428] 3. Data analysis: Calculate the inhibition percentage using the following formula:

[0429] HBV DNA inhibition rate (%) = (1-DNA copy number in compound sample / DNA copy number in DMSO control) × 100%.

[0430] Cell Viability %=(luminescence value in compound sample−luminescence value of medium control) / (luminescence value of DMSO control−luminescence value of medium control)×100%.

[0431] The EC value of the compound's anti-HBV replication activity was obtained based on the HBV DNA inhibition rate (%) for the compound tested according to the dilution method ①②. 50 Range; According to the dilution method ③, the compounds tested were fitted with the four-parameter method [log (agonist) vs. response--Variable slope] of HBV DNA inhibition rate (%) and compound concentration using GraphPad Prism software to obtain the EC value of the compound's anti-HBV replication activity. 50 Exact value.

[0432] Using the above experimental method, the anti-HBV activities of some compounds of the present invention are shown in Table 1 below.

[0433] Table 1.HepG2.2.15 cell HBV DNA inhibition

[0434] Among them, the dilution method of compound 1 in Table 1 adopts method ③, and the EC of compound 1 is 50 The range is summarized by the exact value obtained; the dilution method for compounds 10, 12-14, 17, 20, 23-27, 29-34, and 37-45 adopts method ②, and the dilution method for the remaining compounds adopts method ①. As shown in Table 1, the compounds of the present invention have excellent anti-HBV activity.

[0435] Example 39: Liver Microsome Stability Study (MMS)

[0436] Experimental materials, methods and results analysis:

[0437] Human liver microsomes (BIOIVT) were used in the experiment;

[0438] Reagent preparation:

[0439] PBS: 0.1 M KH2PO4 and K2HPO4 buffer, pH 7.4.

[0440] MgCl2: Weigh a certain amount of MgCl2 and prepare a 16 mM MgCl2 solution with PBS.

[0441] NADPH: Weigh a certain amount of NADPH and prepare NADPH to 4 mM with 16 mM MgCl2 solution, and the final incubation concentration is 1 mM.

[0442] Compounds: The test compounds were diluted to 4 mM in PBS, with a final incubation concentration of 1 mM.

[0443] Liver microsomes: Dilute liver microsomes to 1 mg / ml with PBS, and the final incubation concentration is 0.5 mg / ml.

[0444] Experimental steps:

[0445] Add the test compound to the test tube, followed by the prepared NADPH, mix well, and pre-incubate in a 37°C, 220 rpm incubator. After 5 minutes of pre-incubation, add liver microsomes to initiate the reaction and perform the procedure in duplicate.

[0446] After a certain reaction time, a certain volume of glacial acetonitrile solution containing an internal standard was added to precipitate the protein. The mixture was vortexed for 5 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was collected in a 96-well plate and analyzed by LC-MS / MS (Shimadzu LC-30A, AB API 4500).

[0447] The concentration (peak area ratio) of the example compound was determined by LC-MS / MS, and the rate constant was obtained by plotting "Ln (compound residual amount %)" against "incubation time" in Excel. The half-life and intrinsic clearance of the drug were then calculated to provide a basis for the prediction of in vivo clearance.

[0448] Data analysis: CL int =(0.693 / t 1 / 2 , microsomes) × [incubation medium volume (ml) / microsomal protein mass (mg)] × [microsomal protein mass (mg) / liver mass (g)] × [liver mass (g) / body weight (kg)] [8] CL H =CL int ×f u ×Q h / (CL int ×f u +Q h )

[0449] In the formula

[0450] CL int --Intrinsic clearance (ml / min / kg)

[0451] CL H --Hepatic clearance (ml / min / kg)

[0452] f u --The plasma unbound fraction is 1

[0453] Q h --Hepatic blood flow

[0454] Table 2

[0455] It can be seen from Table 2 that the compounds of the present invention have a longer half-life.

[0456] Example 40: PK experiment in rats and mice

[0457] Materials and methods

[0458] The experimental animals were healthy adult SD male rats and BALB / c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[0459] Rat medication and sample collection:

[0460] SD male rats were given a single intravenous dose (1 mg / kg, 5% DMSO + 5% Solutol + 90% saline) (DMSO: AR 500 ml, Cologne; Solutol: 42966-1KG, BASF; saline: 100 ml / bag, Sichuan Meida Kangjiale Pharmaceutical Co., Ltd.) or oral administration (10 mg / kg, 0.5% CMC-Na) (CMC-Na, 419273-100G, Sigma). 200 μL of whole blood was collected from the fundus venous plexus of the rats at different time points at 0.083 (intravenous only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration, and the plasma was obtained by centrifugation at 4000 rpm for 6 min.

[0461] Mouse medication and sample collection:

[0462] BALB / c female mice were given a single intravenous dose (1 mg / kg, 5% DMSO + 5% Solutol + 90% saline) (DMSO: AR 500 ml, Cologne; Solutol: 42966-1 kg, BASF; saline: 100 ml / bag, Sichuan Meida Kangjiale Pharmaceutical Co., Ltd.) or oral administration (10 mg / kg, 0.5% CMC-Na) (CMC-Na, 419273-100G, Sigma). Whole blood (60 μL) was collected from the fundus venous plexus of the mice at different time points at 0.083 (intravenous only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration, and the blood was centrifuged at 4000 rpm for 6 min to obtain plasma.

[0463] Sample analysis:

[0464] 10 μL of mouse and rat plasma samples were collected and protein precipitated with a specific volume of acetonitrile solution containing an internal standard. The samples were vortexed for 10 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was collected and transferred to a 96-well plate for analysis using a Shimadzu LC-MS / MS system (Shimadzu LC-30A, AB API 4500).

[0465] The LC-MS / MS method was used to determine the drug concentrations in the plasma of mice at different times after a single intravenous and oral administration of the example compound, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in mice and evaluate its pharmacokinetic characteristics.

[0466] The pharmacokinetic data of Compound 1 are shown in Tables 3 and 4 below.

[0467] Table 3 Rat full-PK data

[0468] Table 4 Full-PK data in mice

[0469] As can be seen from Tables 3 and 4 above, the compounds of the present invention have good pharmacokinetic properties.

[0470] Example 41: Tissue distribution study in mice and rats

[0471] Experimental materials, methods and results analysis:

[0472] The experimental animals were healthy adult SD male rats and BALB / c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[0473] Rat medication and sample collection:

[0474] Male SD rats were gavage-administered 15 mg / kg of 0.2% Tween 80 + 99.8% 0.5% CMC-Na (CMC-Na, 419273-100G, Sigma). Plasma, brain, liver, heart, and kidney samples were collected at 0.5, 2, 6, 24, and 48 hours after administration. 200 μL of whole blood was collected from the retinal venous plexus and centrifuged at 4000 rpm for 6 minutes to obtain plasma. The peritoneal cavity was opened and the heart was perfused with normal saline. Brain, liver, heart, and kidney tissues were then collected and wiped clean with filter paper. The samples were weighed, homogenized with a proportional amount of normal saline, and then placed in EP tubes.

[0475] Mouse medication and sample collection:

[0476] BALB / c female mice were gavage-administered 30 mg / kg of 0.5% CMC-Na (CMC-Na, 419273-100G, Sigma). Plasma, brain, liver, heart, and kidney samples were collected at 1, 4, 8, 24, and 28 hours after administration. 60 μL of whole blood was collected from the retinal venous plexus and centrifuged at 4000 rpm for 6 minutes to obtain plasma. The peritoneal cavity was opened and the heart was perfused with normal saline. Brain, liver, heart, and kidney tissues were collected and wiped clean of moisture with filter paper. The samples were weighed and a proportional amount of normal saline was added. The homogenized samples were then placed in EP tubes.

[0477] Sample analysis:

[0478] 10 μL of mouse and rat plasma and tissue samples were collected and protein precipitated with a specific volume of acetonitrile containing an internal standard. The samples were vortexed for 10 minutes and then centrifuged at 4000 rpm for 10 minutes. The supernatant was collected and transferred to a 96-well plate for analysis using a Shimadzu LC-MS / MS system (Shimadzu LC-30A, AB API 4500).

[0479] The LC-MS / MS method was used to determine the drug concentrations in plasma and various tissues at different times after oral administration of the example compounds to mice, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compounds in mice and evaluate their pharmacokinetic characteristics.

[0480] Table 5 Tissue distribution data of compound 1 in rats

[0481] Table 6 Tissue distribution data of compound 1 in mice

[0482] As can be seen from Tables 5 and 6 above, the exposure of the compound of the present invention in the target organ, the liver, is maintained at a high and stable level, indicating that the compound of the present invention can better exert its effect in the target organ.

[0483] Example 42: hERG inhibition studies

[0484] 1.1 hERG inhibition studies

[0485] Using Predictor TM hERG Fluorescence Polarization Assay Kit (ThermoFisher Scientific PV5365) was used for hERG inhibition assay. TM hERG Tracer Red and 4×E-4031 positive controls. In a 384-well plate, add 5 μL of Predictor to the blank well of the assay. TMhERG FP Assay Buffer and 5μL Predictor TM hERG Membrane. Add 2.5 μL Predictor to each of the negative control, positive control, and test compound wells. TM hERG FP Assay Buffer, 2.5 μL 4×E-4031 Positive Control, 2.5 μL 4×test compound, and then 5 μL Predictor TM hERG Membrane and 2.5 μL 4×Predictor TM hERG Tracer Red. Incubate at room temperature (25°C) in the dark for 3.5 hours. After the reaction, measure fluorescence polarization using a microplate reader; the G factor is 2.14.

[0486] 1.2 Calculation of inhibition rate

[0487] The inhibition rate of the compound or positive control was calculated using the following formula.

[0488] Inhibition rate % = (mP negative control - mP compound) / (mP negative control - mP positive control) * 100%

[0489] Using the above experimental method, the hERG inhibition test results of some compounds of the present invention are shown in Table 7 below.

[0490] Table 7 hERG inhibition test results

[0491] Industrial applicability

[0492] The compound of the present invention has excellent anti-HBV activity and can be used as a drug for treating or preventing diseases related to this activity.

[0493] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

[0494] References:

[0495] [1]Villain P, Gonzalez P, Almonte M, et al. European Code against Cancer 4th Edition: Infections and Cancer[J]. Cancer Epidemiology, 2015.

[0496] [2]Samuel,E C.Antiviral actions of interferons[Table of Contents][J].Clinical Microbiology Reviews,2001,14(4):778-809.

[0497] [3]A R G G,B B G,C C L L,et al.Chronic hepatitis B:Virology,natural history,current management and a glimpse at future opportunities-ScienceDirect[J].Antiviral Research,2015,121:47-58.

[0498] [4]Elias S,Smith C I,Ghany M G.Hepatitis B:Current Status of Therapy and Future Therapies[J].Gastroenterology clinics of North America,2021.

[0499] [5]Berke,Martin J,Dehertogh,et al.Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus.

[0500] [6]Berke J M,Dehertogh P,Vergauwen K,et al.Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus[J].Antimicrob Agents Chemother,2017:AAC.00560-17.

[0501] [7]Angela,M,Lam,et al.Preclinical Characterization of NVR 3-778,a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus.[J].Antimicrobial Agents & Chemotherapy,2018.

[0502] [8]Davies B,Morris T.Physiological parameters in laboratory animals and humans.Pharm Res.1993;10:1093-5.

Claims

1. A compound represented by formula (I), or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof: in, R1 is selected from hydrogen, C 1-8 Alkyl, C 3-8 Cycloalkyl, C 1-8 Halogenated alkyl, C 1-8 Deuterated alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy, C 1-8 Deuterated alkoxy, halogen, cyano, amino; R2 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl acyl, C 1-3 Haloalkyl acyl, C 2-3 Alkenyl, C 2-3 Alkynyl; R3 is selected from substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; the C 6-10 The substituents of aryl and 5-10 membered heteroaryl are independently selected from halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano; R4 is selected from substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 3-10 Heteroalkyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 4-14 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 2-8 Alkynyl, The C 1-10 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-8 Alkoxy, C 2-8 Alkynyl, -NR a R b 、-COOR a 、-C(O)NR a R b , substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; the -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; the substituents of the 5-6 membered heteroaryl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; the substituents of the 5-6 membered heterocycloalkyl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-8 Hydroxyalkyl, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; The C 3-10 The heteroalkyl group contains 1 to 4 heteroatoms selected from N, O and S; 3-10 The substituents of heteroalkyl are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b , cyano, hydroxyl; The C 3-14 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-14 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 Alkynyl, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-10 Heteroalkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 1-8 Carbonyl, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-8 Halogenated alkyl, C 1-8 Alkyl; the C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S; The -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-14 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Carbonyl, C 2-8 Alkynyl, -C(O)NR a R b 、-C(O)R a 、-NR a R b 、-COOR a , -S(O)2CH3, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl substituted with halogen; the 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-10 membered heteroaryl group are selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, -NR a R b 、-COOR a 、-C(O)NR a R b ; The C 6-10 The substituents of the aryl group are selected from halogen, cyano, C 1-8 Alkyl, C 1-8 Haloalkyl, -COOR a 、-C(O)NR a R b ; R a 、R b are each independently selected from hydrogen, C 1-4 alkyl; R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-8 Alkyl, amino; m is selected from 0 or 1; Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S.

2. The compound according to claim 1, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkoxy, halogen, cyano, amino; Preferably, R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, halogen, cyano, amino; More preferably, R1 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, halogen, cyano, amino; Still more preferably, R1 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, -CF3, -CH2F, -CHF2, -CD3, haloethyl, halopropyl, deuterated ethyl, deuterated propyl, fluorine, chlorine, bromine, cyano, amino; Preferably, R1 is selected from methyl, -CF3, -CD3, fluorine, chlorine, bromine, cyano, amino; Preferably, R1 is selected from methyl, chlorine; Most preferably, R1 is selected from methyl.

3. The compound according to claim 1 or 2, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R2 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methylacyl, ethylacyl, propylacyl, isopropylacyl, halomethylacyl, haloethylacyl, halopropylacyl, haloisopropylacyl, vinyl, propenyl, ethynyl, propynyl; Preferably, R2 is selected from hydrogen, methyl, ethyl, propyl, methylacyl, ethylacyl, propylacyl; More preferably, R2 is selected from hydrogen, methyl, ethyl, methylacyl, ethylacyl; Preferably, R2 is selected from hydrogen, methyl, methylacyl; Most preferably, R2 is selected from hydrogen.

4. The compound according to any one of claims 1 to 3, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl and pyridyl groups are independently selected from halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, cyano; Preferably, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl and pyridyl groups are independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano; More preferably, R3 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, The substituents of the phenyl group are selected from fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, cyano; the substituent of the pyridyl group is selected from fluorine, chlorine, bromine, C 1-4 alkyl; Still more preferably, R3 is selected from Still more preferably, R3 is selected from Still more preferably, R3 is selected from Still more preferably, R3 is selected from Preferably, R3 is selected from substituted or unsubstituted phenyl; the substituent of the phenyl is selected from fluorine, chlorine, bromine, hydroxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano; Preferably, R3 is selected from Preferably, R3 is selected from Most preferably, R3 is selected from 5. The compound according to any one of claims 1 to 4, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R4 is selected from substituted or unsubstituted C 1-10 Alkyl, C 3-10 Heteroalkyl, substituted or unsubstituted C 3-14 Cycloalkyl, substituted or unsubstituted 4-14 membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 2-8 Alkynyl, The C 1-10 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-8 Alkoxy, C 2-8 Alkynyl, -NR a R b , substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-8 Alkyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-8 hydroxyalkyl; The C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S; The C 3-14 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-14 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 Alkynyl, C 1-8 Alkyl, C 3-10 Heteroalkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-8 Halogenated alkyl, C 1-8 Alkyl; the C 3-10 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S; The -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-14 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Hydroxyalkyl, -C(O)R a , -S(O)2CH3; The 5-10 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-10 membered heteroaryl group are selected from halogen, C 1-8 Alkyl, C 1-8 alkyl halide; The C 6-10 The substituents of the aryl group are selected from halogen, cyano, C 1-8 Alkyl, C 1-8 alkyl halide; R a 、R b are each independently selected from hydrogen, C 1-4 alkyl; R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-8 Alkyl, amino; m is selected from 0 or 1; Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; Preferably, R4 is selected from substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, C 3-8 Heteroalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted C 6-8 Aryl, substituted or unsubstituted 5-8 membered heteroaryl, C 2-6 Alkynyl, The C 1-8 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkoxy, C 2-6 Alkynyl, -NR a R b , substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-6 Alkyl; the C 3-8 The substituents of the cycloalkyl group are selected from C 1-6 hydroxyalkyl; The C 3-8 Heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S; The C 3-10 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-10 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 3-8 Heteroalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-6 Halogenated alkyl, C 1-6 Alkyl; the C 3-8 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S; The -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-12 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)R a , -S(O)2CH3; The 5-8 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-8 membered heteroaryl group are selected from halogen, C 1-6 Alkyl, C 1-6 alkyl halide; The C 6-8 The substituents of the aryl group are selected from halogen, cyano, C 1-6 Alkyl, C 1-6 alkyl halide; R a 、R b are each independently selected from hydrogen, C 1-3 alkyl; R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-6 Alkyl, amino; m is selected from 0 or 1; Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; More preferably, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, C 3-6 heteroalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 2-4 Alkynyl, The C 1-6 The substituents of the alkyl group are selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkoxy, C 2-4 Alkynyl, -NR a R b , substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-4 Alkyl; the C 3-5 The substituents of the cycloalkyl group are selected from C 1-3 hydroxyalkyl; The C 3-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S; The C 3-8 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-8 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 3-6 Heteroalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl are selected from C 1-4 Halogenated alkyl, C 1-4 Alkyl; the C 3-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S; The -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; the substituents of the 4-12 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, -C(O)R a , -S(O)2CH3; The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl group are selected from halogen, C 1-4 Alkyl, C 1-4 alkyl halide; The substituents of the phenyl group are selected from halogen, cyano, C 1-4 Alkyl, C 1-4 alkyl halide; R a 、R b are each independently selected from hydrogen, C 1-3 alkyl; R5 is selected from hydrogen, deuterium, hydroxyl; R6 is selected from hydrogen, deuterium, C 1-4 Alkyl, amino; m is selected from 0 or 1; Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; Still preferably, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, C 4-6 Heteroalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, C 2-4 Alkynyl, The C 1-6 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methoxy, ethoxy, propoxy, ethynyl, propynyl, -NR a R b , substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl; -CH2- on the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; the substituent of the 5-6 membered heterocycloalkyl is selected from hydroxyl, methyl, ethyl, propyl; the C 3-5 The substituents of the cycloalkyl group are selected from methylhydroxy, ethylhydroxy, and propylhydroxy; The C 4-6 Heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S; The C 3-8 Cycloalkyl includes spiro ring, bridged ring and fused ring; said C 3-8 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the C 3-8 The substituents of the cycloalkyl group are selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, propynyl, methyl, ethyl, propyl, heteropropyl, heterobutyl, heteropentyl, fluoromethyl, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, -C(O)NR a R b 、-C(O)R a 、-COOR a 、-NR a R b , substituted or unsubstituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; the substituent of the 5-6 membered heteroaryl is selected from methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl; the heteropropyl, heterobutyl and heteropentyl contain 1 to 3 heteroatoms selected from N, O and S; The 4-12 membered heterocycloalkyl group includes a spiro ring, a bridged ring and a condensed ring; the -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, or -S(=O)2-; the 4-12 membered heterocycloalkyl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 4-12 membered heterocycloalkyl group are selected from hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(O)R a , -S(O)2CH3; The 5-6 membered heteroaryl group contains 1 to 3 heteroatoms selected from N, O and S; the substituents of the 5-6 membered heteroaryl group are selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl; The substituent of the phenyl group is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl; R a 、R b Each is independently selected from hydrogen, methyl, ethyl, propyl; R5 is selected from hydrogen, deuterium, and hydroxyl; R6 is selected from hydrogen, deuterium, methyl, ethyl, propyl, and amino; m is selected from 0 or 1; Ring A is selected from 5-6 membered heteroaryl and phenyl; the 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; Preferably, R4 is selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 Heteroaryl, propynyl, butynyl, The C 1-6 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from fluorine, chlorine, bromine, hydroxyl, cyano, methoxy, ethoxy, propoxy, ethynyl, propynyl, N,N-dimethylamino, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, The substituents of the cyclopropyl and cyclobutyl groups are each independently selected from hydroxymethyl, hydroxyethyl, and hydroxypropyl; The C 3-8 Cycloalkyl includes spiro ring, bridge ring or fused ring; said C 3-8 The substituents of the cycloalkyl group are selected from fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, propynyl, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, amino, -C(O)NH2, -C(O)NHCH3, -C(O)OCH3, -COOH, -C(O)CH3, The 4-12 membered heterocycloalkyl group includes a spiro ring, a bridged ring or a condensed ring; the 4-12 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O and S; the substituents of the 4-12 membered heterocycloalkyl group are selected from hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, -CF3, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(O)CH3, -S(O)2CH3; The 5-6 membered heteroaryl group is selected from pyridyl, thiazolyl, isoxazolyl, and pyrazolyl; the substituent of the pyridyl group is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, -CF3, fluoroethyl, and fluoropropyl; the substituents of the thiazolyl, isoxazolyl, and pyrazolyl groups are each independently selected from methyl, ethyl, and propyl; The substituents of the phenyl group are selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl; Further, R4 is selected from C 1-6 Alkyl, substituted C 1-6 Alkyl, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, substituted C 3-8 cycloalkyl, substituted or unsubstituted 4-11 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, propynyl, butynyl, The C 1-6 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-6 The substituents of the alkyl group are selected from fluorine, hydroxyl, and methoxy; The C 1-3 The alkyl group includes a straight chain or branched chain alkyl group; the C 1-3 The substituents of the alkyl group are selected from cyano, ethynyl, N,N-dimethylamino, cyclopropyl substituted with hydroxymethyl; The C 3-6 Cycloalkyl includes spiro ring, bridge ring or fused ring; said C 3-8 Cycloalkyl includes spiro ring, bridge ring or fused ring; said C 3-8 The substituents of the cycloalkyl group are selected from fluorine, cyano, hydroxy, ethynyl, methyl, ethyl, -CF3, hydroxymethyl, methoxy, amino, -C(O)NH2, -C(O)NHCH3, -C(O)OCH3, -COOH, -C(O)CH3, The 4-11 membered heterocycloalkyl group includes a spiro ring, a bridged ring or a condensed ring; the 4-11 membered heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, O and S; the substituent of the 4-11 membered heterocycloalkyl group is selected from hydroxyl, methyl, ethyl, isopropyl, -CF3, ethynyl, hydroxymethyl, -C(O)CH3, -S(O)2CH3; The 5-6 membered heteroaryl group is selected from pyridyl, thiazolyl, isoxazolyl, pyrazolyl; the substituent of the pyridyl group is selected from fluorine and -CF3; the substituents of the thiazolyl, isoxazolyl, pyrazolyl are each independently selected from methyl; The substituent of the phenyl group is selected from fluorine, chlorine, bromine, cyano, methyl, -CF3; Further, R4 is selected from methyl, ethyl, propyl, isopropyl, Further, R4 is selected from Further, R4 is selected from Further, R4 is selected from Further, R4 is selected from Preferably, R4 is selected from Most preferably, R4 is selected from 6. The compound according to any one of claims 1, 4 or 5, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound has the structure described by formula (II): wherein R3 and R4 are as defined in claim 1, 4 or 5.

7. The compound of formula (II) according to claim 6, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, characterized in that: R3 is selected from unsubstituted or substituted by one or more R m Substituted C 6-10 Aryl, unsubstituted or substituted with one or more R n Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; each R m 、R n are independently selected from the same or different halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano, hydroxy; R4 is selected from adamantyl, unsubstituted or substituted by one or more R c Substituted C 1-8 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-8 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-8 Cycloalkyl or unsubstituted or substituted by one or more R f Pick substituted 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S; R7 is selected from C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; each R c 、R d 、R e 、R f 、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-8 Alkyl, C 1-8 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl.

8. The compound according to claim 7, or its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, characterized in that: R3 is selected from unsubstituted or substituted by one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Haloalkoxy, amino, cyano, hydroxy; Preferably, R3 is selected from unsubstituted or substituted by one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, amino, cyano, hydroxy; Preferably, R3 is selected from unsubstituted or substituted by one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n are independently selected from the same or different halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, amino, cyano, hydroxy; Preferably, R3 is selected from unsubstituted or substituted by one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n Each is independently selected from the same or different F, Cl, Br, methyl, ethyl, isopropyl, tert-butyl, fluoromethyl, fluoroethyl, amino, cyano, hydroxyl; Preferably, R3 is selected from unsubstituted or substituted by one or more R m Substituted phenyl, unsubstituted or replaced by one or more R n Substituted pyridyl; each R m 、R n Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, hydroxyl; Preferably, R3 is selected from unsubstituted or substituted by 1, 2 or 3 R m Substituted phenyl, unsubstituted or substituted by 1, 2 or 3 R n Substituted pyridyl; each R m 、R n Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, hydroxyl; Preferably, R3 is unsubstituted or replaced by 1, 2 or 3 R m Substituted phenyl; each R m Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, hydroxyl; Preferably, R3 is selected from Most preferably, R3 is selected from 9. The compound according to claim 7 or 8, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: R4 is selected from adamantyl, C 1-8 Alkyl, 1 or more R c Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-6 Cycloalkyl or unsubstituted or substituted by one or more R f Substituted 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl contains 1-3 heteroatoms selected from N, O and S; R7 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-membered heteroaryl, the 5-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S; each R c 、R d 、R e 、R f 、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl; Preferably, R4 is selected from adamantyl, C 1-8 Alkyl, 1 or more R c Substituted C 1-4 Alkyl, unsubstituted or substituted with one or more R d Substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form an unsubstituted or substituted group. e Substituted C 3-6 Cycloalkyl or unsubstituted or substituted by one or more R f Substituted 4-8 membered heterocycloalkyl, wherein the 4-8 membered heterocycloalkyl contains 1-2 heteroatoms selected from N, O and S; R7 is selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, -C(O)NR i R j , unsubstituted or replaced by one or more R g substituted 5-membered heteroaryl, wherein the 5-membered heteroaryl contains 1-3 heteroatoms selected from N; each R c 、R d 、R e 、R f 、R g Each independently selected from the same or different halogen, hydroxyl, C 2-4 Alkynyl, C 1-4 Alkyl, C 1-4 Alkoxy; R i 、R j Each independently selected from H, C 1-4 alkyl; Preferably, R4 is selected from C 1-2 Alkyl, C 3-8 Alkyl, substituted by one or more halogen or ethynyl or C 1-2 Alkoxy-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 1 or more hydroxyl groups or C 1-2 Alkoxy-substituted C 3-6 Cycloalkyl, R8, R9 and the carbon to which they are attached form a C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains 1-2 heteroatoms selected from N and O; R7 is selected from methyl, ethyl, fluoromethyl, fluoroethyl, ethynyl, propynyl, -C(O)NR i R j , unsubstituted or triazolyl substituted by one or more methyl, ethyl or isopropyl groups; R i 、R j Each independently selected from H, methyl, ethyl; Preferably, R4 is selected from C 1-2 Alkyl, C 3-6 Alkyl, C substituted with 1, 2 or 3 F 1-4 Alkyl, C substituted with 1 ethynyl 1-4 Alkyl, C substituted with 1 methoxy or ethoxy 1-4 Alkyl, C 3-6 Cycloalkyl, C substituted by 1 hydroxyl or methoxy or ethoxy 4-6 Cycloalkyl, R8, R9 and the carbon to which they are attached are combined to form a cyclopropyl, cyclobutyl, cyclobutyl substituted with 1 or 2 Fs, or a 4-6 membered heterocycloalkyl containing 1 O; R7 is selected from methyl, ethyl, -CF3, ethynyl, -C(O)NH2, -C(O)NH(CH3), unsubstituted or triazolyl substituted with 1 methyl, ethyl or isopropyl; Preferably, R4 is selected from Most preferably, R4 is selected from 10. The compound according to any one of claims 1 to 9, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound has the structure of formula (III-1), (III-2) or (III-3): wherein R4 is as defined in any one of claims 1, 5, 7 or 9.

11. The compound according to any one of claims 1 to 10, or a prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, characterized in that: The compound is selected from the following compounds:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer and a pharmaceutically acceptable auxiliary ingredient.

13. Use of the compound according to any one of claims 1 to 11, its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating and / or ameliorating and / or preventing HBV infection.

14. A method for treating and / or improving and / or preventing HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 11, its prodrug, solvate, crystalline form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the pharmaceutical composition according to claim 12.

15. The compound according to any one of claims 1 to 11, its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer, or the pharmaceutical composition according to claim 12, for use in treating and / or improving and / or preventing HBV infection.

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