Aminothiophene compounds, methods of making and uses thereof

Abstract

The present application relates to a kind of amino thiophene compounds, its preparation method and purposes.The structure of the compound is as shown in formula (I).The compound shown is a kind of new anti-HBV compound.The present application further relates to the pharmaceutical composition comprising the compound as active ingredient, which can be used for treating and / or preventing HBV infection, and has important application value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to an amino thiophene compound for treating HBV infection, a preparation method and use thereof. BACKGROUND

[0002] Hepatitis B virus (HBV) can cause viral hepatitis B, and is still one of the most concerning viruses in the world. At present, more than 2.5 billion people in the world carry hepatitis B virus, and such patients have an increased risk of suffering from major liver diseases including liver cirrhosis, permanent liver scarring, and liver failure and cancer. The World Health Organization estimates that more than 780,000 people die from hepatitis B disease every year. According to the data of Hepatitis B Foundation, hepatitis B virus accounts for 80% of the factors inducing liver cancer, and the five-year survival rate of liver cancer patients is usually only 15%.

[0003] Although there is an effective vaccine, the coverage of the vaccine is still unsatisfactory in the HBV epidemic area [1] . At present, there are mainly two types of drugs approved for the treatment of chronic hepatitis B. One is interferon (IFN-alpha) and its pegylated form (Peg-IFN-alpha), and IFN-alpha is an immunomodulator that can induce interferon-stimulated gene (ISG) expression in a non-specific manner. The 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 injection of IFN-alpha, the effective rate of HBV patients is only 25% [3]IFN-α has low response rate and other deficiencies such as injection administration, adverse reactions such as severe flu-like symptoms, contraindications for patients with compensated cirrhosis, severe hepatitis, and combined autoimmune and psychological diseases. Another approved drug is nucleoside analogs (NAs), of which there are currently five approved NAs, including Lamivudine (LMV), Telbivudine (Ldt), Adefovir dipivoxil (ADV), Tenofovir (TFV), and Entecavir (ETV). NAs directly inhibit HBV polymerase activity to reduce viral particles, thereby interrupting the cycle of nucleocapsid to the nucleus of infected cells, which theoretically reduces the expression of cccDNA. However, NAs cannot inhibit the de novo synthesis of cccDNA in newly infected cells after treatment, which indicates that residual viral particles during antiviral therapy can cause infection of new cells and reconstruction of the cccDNA library, and patients may experience virological rebound once they stop taking the drug. Therefore, chronic hepatitis B virus infection rarely achieves functional cure, and most patients need to take the drug for life, but long-term use of NAs drugs can easily cause viral variation and drug resistance.

[0004] Based on the deficiencies of current therapies, some drugs targeting the HBV replication cycle or enhancing the body's immune response are being developed and have entered the clinical research stage. The core protein in the HBV replication process is crucial for the packaging of HBV pgRNA and reverse transcription, and the molecules developed against 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 heteroaryl dihydro pyrimidine (HAP), which enhances the kinetics of nucleocapsid formation, leading to the incorrect assembly of nucleocapsid; Class II CpAMs represented by phenylpropenamide (PPAs) and sulfonamide benzamide (SBAs) structural types, which accelerate the assembly of nucleocapsid and form nucleocapsid that is morphologically normal but lacks the packaging of viral pgRNA and HBV polymerase [4] .

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

[0006] Most of the current anti-HBV drugs show good in vitro anti-HBV activity, but after entering the clinic, due to the low efficacy and some adverse reactions such as ALT elevation, recurrence after drug withdrawal, etc., some drugs have failed in clinical trials. Therefore, although there are currently more drugs and methods for treating HBV, molecules with new structure types and new mechanisms of action for achieving hepatitis B cure are still urgently needed in the field of HBV treatment. SUMMARY

[0007] The present application provides a compound represented by formula (I), or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0008]

[0009] wherein R1 is selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 deuteroalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 deuteroalkoxy, halogen, cyano, amino;

[0010] R2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkylacyl, C 1-3 haloalkylacyl, 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 aryl and 5-10 membered heteroaryl are independently selected from halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 haloalkoxy, amino, cyano;

[0012] R4is 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,

[0013] the C 1-10 substituents of the C alkyl 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; -CH2- in the 5-6 membered heterocycloalkyl ring is optionally replaced with -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 cycloalkyl 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 heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S; the C 3-10 heteroalkyl are selected from halogen, C 1-8 alkyl, C 1-8 haloalkyl, -NR a R b , cyano, hydroxyl.

[0015] said C 3-14 -CH2- on the cycloalkyl ring is optionally replaced with -C(=O)-, -C(=S)-, -S(=O)2-; said C 3-14 substituents of the cycloalkyl are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 alkyl, C 1-8 alkyl, C 1-8 haloalkyl, 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 , -NR a R a , -COOR b , substituted or unsubstituted 5-6 membered heteroaryl; said 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; substituents of said 5-6 membered heteroaryl are selected from C 1-8 haloalkyl, C 1-8 alkyl; said C 3-10 heteroalkyl contains 1 to 4 heteroatoms selected from N, O and S;

[0016] -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced with -C(=O)-, -C(=S)-, -S(=O)2-; said 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; substituents of said 4-14 membered heterocycloalkyl are selected from hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, 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, halogen substituted phenyl; said 4-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; said 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S;

[0017] said 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; substituents of said 5-10 membered heteroaryl are selected from halogen, C 1-8 alkyl, C 1-8 haloalkyl, -NR aR b , -COOR a , -C(O)NR a R b ;

[0018] The C 6-10 substituents of the aryl group are selected from the group consisting of 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 the group consisting of hydrogen, C 1-4 alkyl;

[0020] R5is selected from the group consisting of hydrogen, deuterium, hydroxyl; R6is selected from the group consisting of hydrogen, deuterium, C 1-8 alkyl, amino; m is selected from 0 or 1 ;

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

[0022] In one embodiment, in the above-mentioned compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R1is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkoxy, halogen, cyano, amino.

[0023] In one preferred embodiment, R1is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, halogen, cyano, amino.

[0024] In one more preferred embodiment, R1is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuteroalkyl, halogen, cyano, amino.

[0025] In one still more preferred embodiment, R1is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, -CF3, -CH2F, -CHF2, -CD3, haloethyl, halopropyl, deuteroethyl, deuteropropyl, fluorine, chlorine, bromine, cyano, amino.

[0026] In a preferred embodiment, R1is selected from methyl, -CF3, -CD3, fluoro, chloro, bromo, cyano, amino.

[0027] In a preferred embodiment, R1is selected from methyl, chloro.

[0028] In a most preferred embodiment, R1is selected from methyl.

[0029] In an embodiment, the above compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R2is selected from hydrogen, methyl, ethyl, propyl, isopropyl, methylacyl, ethylacyl, propylacyl, isopropylacyl, halomethylacyl, haloethylacyl, halopropylacyl, haloisopropylacyl, ethenyl, propenyl, ethynyl, propynyl.

[0030] In a preferred embodiment, R2is selected from methyl, ethyl, propyl, methylacyl, ethylacyl, propylacyl.

[0031] In a more preferred embodiment, R2is selected from hydrogen, methyl, ethyl, methylacyl, ethylacyl.

[0032] In a preferred embodiment, R2is selected from hydrogen, methyl, methylacyl.

[0033] In a most preferred embodiment, R2is selected from hydrogen.

[0034] In an embodiment, the above compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R3is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, the substituents of said phenyl and pyridyl are independently selected from halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, cyano.

[0035] In a preferred embodiment, R3is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, the substituents of said phenyl and pyridyl are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano.

[0036] In a more preferred embodiment, R3is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituents of said phenyl are selected from the group consisting of fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano; substituents of said pyridyl are selected from the group consisting of fluorine, chlorine, bromine, C 1-4 alkyl.

[0037] In a further preferred embodiment, R3is selected from the group consisting of

[0038] In a further preferred embodiment, R3is selected from the group consisting of

[0039] In a further preferred embodiment, R3is selected from the group consisting of

[0040] In a preferred embodiment, R3is selected from the group consisting of

[0041] In a most preferred embodiment, R3is selected from the group consisting of

[0042] In an embodiment, R3is selected from the group consisting of

[0043] In an embodiment, R3is selected from the group consisting of substituted or unsubstituted phenyl; substituents of said phenyl are selected from the group consisting of fluorine, chlorine, bromine, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, cyano.

[0044] In an embodiment, R3is selected from the group consisting of

[0045] In an embodiment, the above compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R4is selected from the group consisting of 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] said C 1-10 substituents of the alkyl group are selected from the group consisting of 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)-, -S(=O)2-; substituents of the 5-6 membered heterocycloalkyl are selected from the group consisting of hydroxyl, C 1-8 alkyl; substituents of the C 3-8 cycloalkyl group are selected from the group consisting of C 1-8 hydroxyalkyl;

[0047] said C 3-10 heteroalkyl contains 1 to 4 heteroatoms selected from the group consisting of N, O and S;

[0048] said C 3-14 -CH2- on the cycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; substituents of the C 3-14 cycloalkyl group are selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-8 alkynyl, C 1-8 alkyl, C 3-10 heteroalkyl, C 1-8 haloalkyl, 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 the group consisting of N, O and S; substituents of the 5-6 membered heteroaryl are selected from the group consisting of C 1-8 haloalkyl, C 1-8 alkyl; substituents of the C 3-10 heteroalkyl contains 1 to 4 heteroatoms selected from the group consisting of N, O and S;

[0049] -CH2- on the 4-14 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; the 4-14 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S; substituents of the 4-14 membered heterocycloalkyl are selected from the group consisting of hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -C(O)Ra -S(O)2CH3;

[0050] said 5-10 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; a substituent of said 5-10 membered heteroaryl is selected from halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl;

[0051] said C 6-10 aryl is selected from halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl;

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

[0053] R5is selected from hydrogen, deuterium, hydroxyl; R6is selected from hydrogen, deuterium, C 1-8 alkyl, amino; m is selected from 0 or 1 ;

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

[0055] In a preferred embodiment, R4is 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] said C 1-8 alkyl is 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- in the 5-6 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; a substituent of said 5-6 membered heterocycloalkyl is selected from hydroxyl, C 1-6 alkyl; a substituent of said C 3-8 cycloalkyl is selected from C 1-6 hydroxyalkyl;

[0057] said C 3-8the heteroalkyl group 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)-, -S(=O)2-; the C 3-10 substituents of the cycloalkyl group are selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 2-6 alkyl, C 1-6 alkyl, C 3-8 heteroalkyl, C 1-6 haloalkyl, 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 haloalkyl, C 1-6 alkyl; the C 3-8 heteroalkyl group contains 1 to 3 heteroatoms selected from N, O and S;

[0059] -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -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 haloalkyl, C 1-6 hydroxyalkyl, -C(O)R a , -S(O)2CH3;

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

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

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

[0063] R5is selected from hydrogen, deuterium, hydroxyl; R6is selected from hydrogen, deuterium, C 1-6 alkyl, amino; m is selected from 0 or 1 ;

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

[0065] In a more preferred embodiment, R4is 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] said C 1-6 substituents of said 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- in said 5-6 membered heterocycloalkyl ring is optionally replaced with -C(=0)-, -C(=S)-, -S(=0)2-; substituents of said 5-6 membered heterocycloalkyl are selected from hydroxyl, C 1-4 alkyl; said C 3-5 substituents of said C 1-3 hydroxylalkyl;

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

[0068] said C 3-8 -CH2- in said cycloalkyl ring is optionally replaced with -C(=0)-, -C(=S)-, -S(=0)2-; substituents of said C 3-8 substituents of said C 2-4 alkynyl, C 1-4 alkyl, C 3-6 heteroalkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, -C(O)NR a R b , -C(O)R a , -COOR a , -NR a R bsubstituted or unsubstituted 5-6 membered heteroaryl; said 5-6 membered heteroaryl contains 1 to 4 heteroatoms selected from N, O and S; substituents of said 5-6 membered heteroaryl are selected from the group consisting of halogen, cyano, C 1-4 haloalkyl, C 1-4 alkyl; substituents of said C 3-6 heteroalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0069] -CH2- on said 4-12 membered heterocycloalkyl ring is optionally replaced by -C(=O)-, -C(=S)-, -S(=O)2-; said 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; substituents of said 4-12 membered heterocycloalkyl are selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, -C(O)R a , -S(O)2CH3;

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

[0071] substituents of said phenyl are selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl;

[0072] R a , R b are each independently selected from the group consisting of hydrogen, C 1-3 alkyl;

[0073] R5is selected from the group consisting of hydrogen, deuterium, hydroxyl; R6is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, amino; m is selected from 0 or 1 ;

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

[0075] In a still more preferred embodiment, R4is 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] said C 1-6Alkyl includes straight chain or branched alkyl; the C 1-6 Substituents of alkyl are selected from the group consisting of 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 with -C(=0)-, -C(=S)-, -S(=0)2-; substituents of the 5-6 membered heterocycloalkyl are selected from the group consisting of hydroxyl, methyl, ethyl, propyl; the C 3-5 Substituents of cycloalkyl are selected from the group consisting of methylhydroxyl, ethylhydroxyl, propylhydroxyl;

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

[0078] The C 3-8 Cycloalkyl includes spiro, bridged and fused rings; the C 3-8 -CH2- on the cycloalkyl ring is optionally replaced with -C(=0)-, -C(=S)-, -S(=0)2-; substituents of the C 3-8 Substituents of cycloalkyl are selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, hydroxyl, 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 the group consisting of N, O and S; substituents of the 5-6 membered heteroaryl are selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl; the heteropropyl, heterobutyl, heteropentyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S;

[0079] The 4-12 membered heterocycloalkyl includes spiro, bridged and fused rings; -CH2- on the 4-12 membered heterocycloalkyl ring is optionally replaced with -C(=0)-, -C(=S)-, -S(=0)2-; the 4-12 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S; substituents of the 4-12 membered heterocycloalkyl are selected from the group consisting of hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, fluoromethyl, fluoroethyl, fluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C(O)R a , -S(O)2CH3;

[0080] said 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S; substituents of said 5-6 membered heteroaryl are selected from fluoro, chloro, bromo, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl;

[0081] substituents of said phenyl are selected from fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, fluoromethyl, fluoroethyl, fluoropropyl;

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

[0083] R5is selected from hydrogen, deuterium, hydroxyl; R6is selected from hydrogen, deuterium, methyl, ethyl, propyl, amino; m is selected from 0 or 1 ;

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

[0085] In a preferred embodiment, R4is 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] said C 1-6 alkyl includes linear or branched alkyl; said C 1-6 substituents of said C substituents of said cyclopropyl, cyclobutyl are each independently selected from hydroxymethyl, hydroxyethyl, hydroxypropyl;

[0087] said C 3-8 cycloalkyl includes spiro, bridged or fused ring; said C 3-8 substituents of said C -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 spiro, bridged or fused rings; 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 the group consisting of hydroxy, fluoro, chloro, bromo, 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 the group consisting of pyridyl, thiazolyl, isoxazolyl, pyrazolyl; the substituents of the pyridyl group are selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl; the substituents of the thiazolyl, isoxazolyl, pyrazolyl groups are each independently selected from the group consisting of methyl, ethyl, propyl;

[0090] The substituents of the phenyl group are selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl.

[0091] In a preferred embodiment, R4 is selected from the group consisting of 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 alkyl includes straight chain or branched alkyl; the C 1-6 substituents of the C

[0093] The C 1-3 alkyl includes straight chain or branched alkyl; the C 1-3 substituents of the C hydroxymethyl-substituted cyclopropyl;

[0094] The C 3-8 cycloalkyl includes spiro, bridged or fused rings; the C 3-8 substituents of the C -CF3, hydroxymethyl, methoxy, amino, -C(O)NH2, -C(O)NHCH3, -C(O)OCH3, -COOH, -C(O)CH3,

[0095] said 4-11 membered heterocycloalkyl comprises a spiro, bridged or fused ring; said 4-11 membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O and S; said 4-11 membered heterocycloalkyl is substituted with a substituent selected from the group consisting of hydroxy, methyl, ethyl, isopropyl, -CF3, ethynyl, hydroxymethyl, -C(O)CH3, -S(O)2CH3;

[0096] said 5-6 membered heteroaryl is selected from the group consisting of pyridyl, thiazolyl, isoxazolyl, pyrazolyl; said pyridyl is substituted with a substituent selected from the group consisting of fluoro, -CF3; said thiazolyl, isoxazolyl, pyrazolyl are each independently substituted with a substituent selected from the group consisting of methyl;

[0097] said phenyl is substituted with a substituent selected from the group consisting of fluoro, chloro, bromo, cyano, methyl, -CF3.

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

[0099] In one embodiment, R4 is selected from the group consisting of

[0100] In one embodiment, R4 is selected from the group consisting of

[0101] In one embodiment, R4 is selected from the group consisting of

[0102] In one embodiment, R4 is selected from the group consisting of

[0103] In one embodiment, R4 is selected from the group consisting of

[0104] In one most preferred embodiment, R4 is selected from the group consisting of

[0105] In one embodiment, the above compound, or a prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof, said compound of formula (I) has the structure according to formula (II):

[0106]

[0107] wherein R3 and R4 are defined with reference to the foregoing definitions.

[0108] In one embodiment, the above compound, or a prodrug, solvate, crystal, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, the compound of Formula (I) has the structure according to Formula (II):

[0109]

[0110] wherein R3is selected from the group consisting of unsubstituted or substituted C m aryl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C n aryl, unsubstituted or substituted C m , R n are each independently selected from the same or different halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 haloalkoxy, amino, cyano, hydroxyl;

[0111] R4is selected from the group consisting of adamantyl, unsubstituted or substituted C c alkyl, unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C d alkyl, unsubstituted or substituted C 3-8 cycloalkyl, R8, R9, in combination with the carbon to which they are attached, form unsubstituted or substituted C e alkyl, unsubstituted or substituted C 3-8 cycloalkyl, or unsubstituted or substituted C f heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O, and S; R7is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 2-4 alkynyl, -C(O)NR i R j , unsubstituted or substituted C g heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S; each R c , R d , R e , R f , R g are each independently selected from the same or different halogen, hydroxyl, C 2-4 alkyl, C 1-8 alkyl, C 1-8 alkoxy; R i , R j are each independently selected from H, C 1-4 alkyl.

[0112] In one embodiment, the above compound, or a prodrug, solvate, crystal, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, R3is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n , R m , R n each independently selected from the same or different halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 haloalkoxy, amino, cyano, hydroxyl.

[0113] In one embodiment, R3is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n , R m , R n each independently selected from the same or different halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, cyano, hydroxyl.

[0114] In one embodiment, R3is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n , R m , R n each independently selected from the same or different halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, cyano, hydroxyl.

[0115] In one embodiment, R3is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n , R m , R n each independently selected from the same or different F, Cl, Br, methyl, ethyl, isopropyl, t-butyl, fluoromethyl, fluoroethyl, amino, cyano, hydroxyl.

[0116] In one embodiment, R3is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n , R m , R nEach is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl groups.

[0117] In one implementation, R3 is selected from unsubstituted or substituted R3s. m Substituted phenyl, unsubstituted, or substituted with one, two, or three R... n Substituted pyridinyl groups; each R m R n Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl groups.

[0118] In one implementation, R3 is unsubstituted or replaced by one, two, or three Rs. m Substituted phenyl; each R m Each is independently selected from the same or different F, Cl, Br, methyl, -CF3, amino, cyano, and hydroxyl groups.

[0119] In one implementation, R3 is selected from...

[0120] In one implementation, R3 is selected from...

[0121] 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 group, with one or more R c Replacement C 1-6 Alkyl, unsubstituted, or with one or more R d Replacement C 3-6 cycloalkyl, R8, R9, and the carbon atoms attached to them form unsubstituted or compounded groups with one or more R atoms. e Replacement C 3-6 Cycloalkyl or unsubstituted or with one or more R f The substituted 4-8 membered heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; R7 is selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-4 alkynyl group, -C(O)NR i R j Unreplaced or replaced by one or more R g The substituted 5-membered heteroaryl group contains 1-3 heteroatoms selected from N, O, and S; each R c R d R e R f Rg Each is independently selected from the same or different halogens, hydroxyl groups, and C. 2-4 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy; R i R j Each is independently selected from H and C. 1-4 alkyl.

[0122] In one embodiment, R4 is selected from adamantyl, C 1-8 Alkyl group, with one or more R c Replacement C 1-4 Alkyl, unsubstituted, or with one or more R d Replacement C 3-6 cycloalkyl, R8, R9, and the carbon atoms attached to them form unsubstituted or compounded groups with one or more R atoms. e Replacement C 3-6 Cycloalkyl or unsubstituted or with one or more R f The substituted 4-8 membered heterocyclic alkyl group contains 1-2 heteroatoms selected from N, O, and S; R7 is selected from C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group, -C(O)NR i R j Unreplaced or replaced by one or more R g The substituted 5-membered heteroaryl group contains 1-3 heteroatoms selected from N; each R c R d R e R f R g Each is independently selected from the same or different halogens, hydroxyl groups, and C. 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy; R i R j Each is independently selected from H and C. 1-4 alkyl.

[0123] In one implementation, R4 is selected from... C 1-2 Alkyl, C 3-8 Alkyl group, with one or more halogen or ethynyl groups or C 1-2 alkoxy-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, with one or more hydroxyl groups or C 1-2 alkoxy-substituted C 3-6 cycloalkyl, R8, R9, and the carbon atoms they are attached to form unsubstituted or substituted carbon atoms (C3-C4) with one or more halogens. 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 triazole groups or those substituted with one or more methyl, ethyl, or isopropyl groups; R i R j Each is independently selected from H, methyl, and ethyl.

[0124] In one implementation, R4 is selected from... C 1-2 Alkyl, C 3-6 Alkyl groups, C atoms substituted with 1, 2, or 3 F atoms 1-4 Alkyl group, C substituted with one ethynyl group 1-4 Alkyl groups, C atoms substituted with one methoxy or ethoxy group 1-4 Alkyl, C 3-6 Cycloalkyl groups, C substituted with one hydroxyl, methoxy, or ethoxy group 4-6 cycloalkyl, R8 and R9, together with the carbon atoms attached to them, form cyclopropyl, cyclobutyl, cyclobutyl substituted with one or two F atoms, or 4-6 membered heterocyclic alkyl groups containing one O atom; R7 is selected from methyl, ethyl, -CF3, ethynyl, -C(O)NH2, -C(O)NH(CH3), unsubstituted or triazolyl substituted with one methyl, ethyl, or isopropyl atom.

[0125] In one implementation, R4 is selected from...

[0126] In one implementation, R4 is selected from...

[0127] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, wherein the compound of formula (I) has the structure of formula (III-1), (III-2), or (III-3):

[0128]

[0129] The definition of R4 references the aforementioned definition.

[0130] In one embodiment, the above-mentioned compound, or its prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer, or tautomer, wherein the compound of formula (I) has the structure shown in formula (III-1):

[0131]

[0132] wherein R4is as defined above.

[0133] In one embodiment, the above compound, or a prodrug, solvate, crystal, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (III-2):

[0134]

[0135] wherein R4is as defined above.

[0136] In one embodiment, the above compound, or a prodrug, solvate, crystal, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound of Formula (III-3):

[0137]

[0138] wherein R4is as defined above.

[0139] In one embodiment, the above compound, or a prodrug, solvate, crystal, pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, is a compound selected from the following:

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] 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 set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by 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 performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. For the purposes of the present application, suitable conditions for the reactions are understood to include the reaction of a compound of the present application with a reagent or in the presence of reacting conditions, under appropriate reaction conditions, including, but not limited to, temperature, pressure, time, and the like, to provide the compounds of the present application.

[0152] One important consideration in the synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups, such as amino groups in the present application, for example, see Chem. Commun., 2019, 55, 7331-7334. All references cited in the present application are incorporated herein in their entirety, or used in combination with synthetic methods known in the art and methods described in the present application. The products of each step are isolated using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemical reagents required for the synthesis can be obtained according to conventional synthesis (such as provided by Scifinder) or purchased.

[0153] In some embodiments, the compounds of general formula (I) of the present application can be prepared by the following route by those skilled in the art of organic synthesis using standard methods in the art:

[0154] Method I:

[0155]

[0156] Step 1: reacting the compound of formula 1-a with TFAA to give the compound of formula 1-b;

[0157] Step 2: reacting the compound of formula 1-b with the compound of formula 1-c under basic conditions (such as LiHMDS) to give the compound of formula 1-d;

[0158] Step 3: reacting the compound of formula 1-d with the compound of formula 1-e under Lewis acidic conditions (such as AlCl3) to give the compound of formula 1-f;

[0159] Step 4: reacting the compound of formula 1-f with the compound of formula 1-g to give the compound of formula 1-h;

[0160] Step 5: deprotecting the compound of formula 1-h under acidic conditions (such as HCl) to give the compound of formula 1;

[0161] Method two:

[0162]

[0163] Step 1: coupling reaction of the compound shown as formula 1-h with the compound shown as formula 2-a to obtain the compound shown as formula 2-b;

[0164] Step 2: deprotection of the compound shown as formula 2-b under acidic conditions to obtain the compound shown as formula 2-c;

[0165] Step 3: deprotection of the compound shown as formula 2-c under basic conditions to obtain the compound shown as formula 2;

[0166] wherein, the definitions of R1, R3 and R4 are as described in the application.

[0167] The application also provides a pharmaceutical composition comprising the compound shown as formula (I), (II), (III-1), (III-2) or (III-3), the prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof and pharmaceutically acceptable auxiliary ingredients.

[0168] The application also provides the use of the compound shown as formula (I), (II), (III-1), (III-2) or (III-3), the prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for resisting HBV infection.

[0169] The application also provides the use of the compound shown as formula (I), (II), (III-1), (III-2) or (III-3), the prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for treating, preventing and / or reducing HBV infection.

[0170] The application also provides a method for resisting HBV infection, administering a therapeutically effective amount of the compound shown as formula (I), (II), (III-1), (III-2) or (III-3), the prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or the above-mentioned pharmaceutical composition to a patient in need.

[0171] The application also provides a method for treating, preventing and / or reducing HBV infection, administering a therapeutically effective amount of the compound shown as formula (I), (II), (III-1), (III-2) or (III-3), the prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer thereof or the above-mentioned pharmaceutical composition to a patient in need.

[0172] The present application also provides the compound, prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer of formula (I), (II), (III-1), (III-2) or (III-3) or the pharmaceutical composition thereof for use in the treatment, prevention and / or reduction of HBV infection.

[0173] The present application also provides the compound, prodrug, solvate, crystal form, pharmaceutically acceptable salt, stereoisomer or tautomer of formula (I), (II), (III-1), (III-2) or (III-3) or the pharmaceutical composition thereof for use in the treatment, prevention and / or reduction of HBV infection.

[0174] Technical terms of the present application:

[0175] In the following description, certain specific details are set forth in order to provide a thorough understanding of different implementations. However, one skilled in the relevant arts will recognize that the application can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures or functions have not been described in detail in order to avoid obscuring aspects of the implementations. Unless otherwise noted, the use of the word "or" in the context of describing technical features in the application's description or claims for this application should not be understood as having an exclusive nature. In addition, the headings provided herein are merely for convenience and should have no interpretive affect on the scope or meaning of the application.

[0176] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the content clearly dictates otherwise.

[0177] According to the conventions of the art, In the structural formulae herein, bonds are used to describe the point of attachment of the moiety or substituent to the parent or main structure.

[0178] In the present invention, the term "substituted" means that an atom or atom group is formally replacing a hydrogen as a "substituent" attached to another group. Unless otherwise indicated, the term "substituted" refers to any degree of substitution, e.g. mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is possible. The substituents are selected independently, and substitution can be at any chemically accessible position. It will be appreciated that substitution on a specified atom is limited by the valency of the atom. It will be appreciated that substitution on a specified atom results in a chemically stable molecule.

[0179] In the present invention, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon radical which can be straight-chain or branched. The term "C 1-10 In the present invention, the term "alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon radical which can be straight-chain or branched. The term "C

[0180] In the present invention, the term "heteroalkyl", used alone or in combination with other terms, refers to an alkyl group in which a CH2is replaced by a different heteroatom selected from N, O, S, wherein the term "alkyl" is defined above. For example 3-10 Heteroalkyl refers to an alkyl group containing 3-10 carbon atoms, and wherein a CH2is replaced by 1-4 heteroatoms selected from N, O, S. In some embodiments, heteroalkyl refers to an alkyl group containing 3 carbon atoms, and wherein one CH2is replaced by 1 heteroatom selected from N, O, S.

[0181] In the present invention, the term "halo" or "halogen", used alone or in combination with other terms, refers to F, CI, Br, and I. In some embodiments, the term "halo" refers to a halogen atom selected from F, CI, or Br.

[0182] In the present invention, the term "haloalkyl", used alone or in combination with other terms, refers to an alkyl group substituted with one or more halogens, wherein the terms "halogen", "alkyl" are defined above.

[0183] In the present invention, the term "hydroxyalkyl", used alone or in combination with other terms, refers to an alkyl group substituted with one or more hydroxyl groups, wherein the term "alkyl" is defined above.

[0184] In the present invention, the term "heteroatom" used alone or in combination with other terminology, includes S, O, and N.

[0185] In the present invention, the term "alkenyl" used alone or in combination with other terminology, means an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in the cis- or trans- configuration about the double bond, and it is to be understood that both isomers are included. Examples include, but are not limited to, ethenyl ( -CH=CH2), 1-propenyl ( -CH2CH=CH2), isopropenyl [ -C(CH3)=CH2], butenyl, 1,3-buten- dienyl, and the like. Whenever it appears herein, a numerical range such as "C2-C10 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the terms "alkenyl" that appear without a specified number of carbon atoms. Unless specifically indicated otherwise, an alkenyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen. 2‐6 Whenever it appears herein, a numerical range such as "C2-C10 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the terms "alkenyl" that appear without a specified number of carbon atoms. Unless specifically indicated otherwise, an alkenyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0186] In the present invention, the term "alkynyl" used alone or in combination with other terminology, means an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having from 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, and the like. Whenever it appears herein, a numerical range such as "C2-C10 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the terms "alkynyl" that appear without a specified number of carbon atoms. Unless specifically indicated otherwise, an alkynyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. 2-6 Whenever it appears herein, a numerical range such as "C2-C10 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but also encompasses the terms "alkenyl" that appear without a specified number of carbon atoms. Unless specifically indicated otherwise, an alkenyl group can be optionally substituted as described below, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0187] In the present application, 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 otherwise specifically noted in the specification, an alkoxy group can optionally be substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy group is optionally substituted with halogen, -CN, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy group is optionally substituted with halogen.

[0188] In the present application, the term "haloalkoxy," used alone or in combination with other terms, refers to an alkoxy group that is substituted with one or more halogen, wherein the term "halogen," "alkoxy" is as defined above.

[0189] In the present application, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C 6-10 In the present application, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C

[0190] 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 ring member heteroatom selected from S, O, and N, which can be in any ring thereof, or in multiple (e.g., two or three) rings thereof. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 ring member heteroatoms 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 ring member heteroatoms 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 ring member heteroatoms independently selected from S, O, and N. In some embodiments, the heteroaryl group has 5 to 6 ring atoms, and 1 or 2 ring member heteroatoms independently selected from S, O, and N. In some embodiments, the heteroaryl group is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl group is an eight-, nine-, 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, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthridinyl (including 1,2-naphthridine, 1,3-naphthridine, 1,4-naphthridine, 1,5-naphthridine, 1,6-naphthridine, 1,7-naphthridine, 1,8-naphthridine, 2,3-naphthridine, and 2,6-naphthridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0191] 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), including cyclized alkyl groups, including fused rings, spirocyclic rings, bridged rings, and the like. The term "C 3-8 cycloalkyl" or "C 3-14 cycloalkyl" refers to cycloalkyl groups 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 spirocyclic rings. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14 ). In some embodiments, cycloalkyl groups have 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, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyl groups are monocyclic or bicyclic. In some embodiments, cycloalkyl groups are C 3-8Monocyclic cycloalkyl. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form an oxo or thio 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.

[0192] In the present application, the term "heterocycloalkyl" used alone or in combination with other terminology means a saturated ring system (monocyclic, bicyclic, or polycyclic), polycyclic (e.g., bicyclic or tricyclic) including fused, spiro, bridged, having at least one ring member that is a heteroatom independently selected from N, S, and O, and having 4-14 ring members, 4-12 ring members, 4-10 ring members, or 4-8 ring members, the heteroatom(s) can be on any ring thereof, or on multiple (e.g., two or three) rings simultaneously. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from N, S, and O. In some embodiments, the heterocycloalkyl group is a spiro ring having 1, 2, or 3 heteroatoms independently selected from N, S, and O. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can optionally be oxidized to form an oxo or thio group or other oxidized bond (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or a nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.

[0193] In the present application, the term "optionally" means that the selection can or can not be made. For example, "the -CH2- on the ring is optionally replaced with -C(=O)-, -C(=S)-, -S(=O)2-," means that the -CH2- can or can not be replaced with -C(=O)-, -C(=S)-, and / or -S(=O)2-.

[0194] In the present application, the term "therapeutically effective amount" used alone or in combination with other terminology means an amount of a compound, administered to a mammal and / or subject, either as a single dose or as part of a series of doses, that is effective to produce a desired therapeutic effect.

[0195] Advantages of the Invention:

[0196] The compounds and pharmaceutical compositions provided herein exhibit good anti-HBV infection activity, and can be used as drugs for the prevention and / or improvement and / or treatment of diseases related to the action. Specific Embodiments

[0197] Unless otherwise defined, all technical and scientific terms used in the application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials similar or equivalent to those described herein can be used in the practice of the application. The following description is presented to enable any person skilled in the art to make and use the application.

[0198] The application is described in detail below with reference to Examples, but is not meant to be limited by any of the specific embodiments listed herein. The compounds of the application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by a combination of the specific embodiments listed below with other chemical synthetic methods known to those skilled in the art, and equivalents thereof, preferred embodiments including but not limited to the Examples of the application. Various modifications and improvements to the embodiments of the application as described below will be apparent to those skilled in the art from the description contained herein, and it is intended to use all such modifications and improvements in the scope of the application.

[0199] Example 1 Preparation of compound 1

[0200]

[0201] Step 1: Synthesis of compound 1-b

[0202] 1-a (10 g, 54.00 mmol) was added to a single-neck flask, dissolved in dichloromethane (100 mL), then acetyl chloride (19.27 mL, 269.98 mmol) was added under ice water bath, stirred at room temperature overnight under nitrogen protection. The reaction solution was slowly poured into ice water (200 mL) for quenching, stirred for 5 minutes, then the aqueous phase was extracted with dichloromethane (100 mL), the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (100 mL), then washed with saturated brine (100 mL), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain brown solid compound 1-b (11 g, 48.39 mmol). MS m / z (ESI): 228.15 [M+H] + .

[0203] Step 2: Synthesis of compound 1-d

[0204] Into a three-necked flask, 1-b (11 g, 48.39 mmol) and 1-c (9.9 g, 72.59 mmol) were added, dissolved in tetrahydrofuran (200 mL), stirred for five minutes under ice water bath protection, lithium bis(trimethylsilyl)amide (435.51 mL, 435.51 mmol) was slowly dropped into it under ice water bath, after dropping, the reaction was carried out at 25 °C for 1 hour, the reaction liquid was quenched with ice water (200 mL), saturated brine (200 mL) was added, the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, a small amount of ethyl acetate was added to the obtained solid to make a slurry, suction filtered, and washed with a small amount of ethyl acetate, and the filter cake was evaporated to dryness to obtain white solid compound 1-d (10 g, 65.1 mmol). MS m / z (ESI): 318.08 [M+H] + .

[0205] Step 3: Synthesis of compound 1-e

[0206] Into a single-necked flask, 1-d (4 g, 12.61 mmol) was added, 2M hydrochloric acid ethanol solution (30 mL) was added, heated to 80 °C under nitrogen protection, and stirred for 1 hour. The reaction liquid was concentrated, a small amount of ethyl acetate was added to the obtained solid to make a slurry, suction filtered, and washed with a small amount of ethyl acetate, and the filter cake was evaporated to dryness to obtain white solid compound 1-e (2 g, 3.63 mmol). MS m / z (ESI): 276.10 [M+H] + .

[0207] Step 4: Synthesis of compound 1-f

[0208] Into a single-necked flask, 1-e (2 g, 2.63 mmol) was added, trifluoroacetic anhydride (20 mL) was added, heated to 50 °C under nitrogen protection, and stirred for 3 hours. The reaction liquid was concentrated, purified by C18 column, eluent ratio: 55% (acetonitrile): 45% (0.05% formic acid aqueous solution), the purified product was collected, concentrated under reduced pressure, and gray-white solid compound 1-f (530 mg, 1.43 mmol) was obtained. MS m / z (ESI): 372.07 [M+H] + .

[0209] Step 5: Synthesis of compound 1-h

[0210] To a reaction flask was added 1-f (0.53 g, 1.43 mmol), dichloromethane (20 mL), 1-g (5.59 mL, 49.96 mmol) was added slowly under ice water bath, then aluminum trichloride (6.7 g, 49.96 mmol) was added portion wise, the reaction mixture was stirred at room temperature overnight under nitrogen protection. The reaction mixture was diluted with ethyl acetate (40 mL), then the reaction mixture was slowly poured into ice water (100 mL) to quench, extracted with ethyl acetate (40 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, the organic phase was concentrated under reduced pressure to give compound 1-h (0.6 g, 1.35 mmol) as a white solid. MS m / z (ESI): 442.0 [M-H] - .

[0211] Step 6: Synthesis of compound 1-j

[0212] To a reaction flask was added 1-h (150 mg, 0.34 mmol) and 1-i (61 mg, 0.41 mmol), dissolved in N,N-dimethylformamide (5 mL), then N,N-diisopropylethylamine (0.23 mL, 1.36 mmol) was added, stirred for 1 min under ice water bath, then HATU (154 mg, 0.41 mmol) was added, stirred for 20 min under ice water bath. The reaction mixture was directly purified by C18 column, eluent ratio: 55% (acetonitrile): 45% (0.05% formic acid in water), the purified product was collected, concentrated under reduced pressure to give compound 1-j (100 mg, 0.19 mmol) as a yellow solid. MS m / z (ESI): 537.11 [M-H] - .

[0213] Step 7: Synthesis of compound 1

[0214] To a sealed tube was added 1-j (50 mg, 0.09 mmol), 2M hydrochloric acid in ethanol (5 mL), sealed, heated to 80 °C under nitrogen protection, stirred for 1 h. The reaction mixture was concentrated, prepared by high performance liquid chromatography to give compound 1 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 443.04 [M+H] + .

[0215] 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.33 (d, J = 9.2 Hz, 1H), 8.22 (dd, J = 6.0, 2.8 Hz, 1H), 7.97-7.93 (m, 1H), 7.80 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 4.68-4.61 (m, 1H), 2.55 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0216] Preparation of compound 2 in Example 2

[0217]

[0218] Step 1: synthesis of compound 2-b

[0219] The operation steps are the same as the synthesis of compound 1-j, except that 1-i is replaced by 2-a (50 mg, 0.41 mmol), and finally 90 mg of yellow solid product, compound 2-b, is obtained. MS m / z (ESI): 513.08 [M+H] + .

[0220] Step 2: synthesis of compound 2

[0221] 2-b (50 mg, 0.10 mmol) was added to a single-neck flask, dissolved in methanol (5 mL), followed by the addition of potassium phosphate (207 mg, 0.98 mmol), and heated to 80°C under nitrogen protection, and stirred at reflux for 1.5 hours. The reaction solution was concentrated, and compound 2 (5 mg, 0.01 mmol) was obtained as a yellow solid by high performance liquid chromatography preparation. MS m / z (ESI): 417.10 [M+H] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.31 (s, 1H), 8.23 (dd, J = 5.8, 2.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.74 (s, 2H), 7.56 (t, J = 9.2 Hz, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.35 (d, J = 6.4 Hz, 2H), 2.57 (s, 3H), 1.57 (s, 3H).

[0223] Preparation of intermediate 1-h in Example 3

[0224]

[0225] Step 1: synthesis of compound 3-a

[0226] Into a single-neck flask was placed 1-a (10 g, 54 mmol), trifluoroacetic anhydride (50 mL), heated to 50 °C, stirred for 3 h. The reaction solution was concentrated, washed with water (100 mL), saturated aqueous Na2CO3(50 mL), brine (50 mL), separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 3-a (14 g, 49.79 mmol) as a white solid. MS m / z (ESI): 282.15 [M+H] + .

[0227] Step 2: Synthesis of compound 1-f

[0228] Into a three-neck flask was placed 3-a (3 g, 10.67 mmol) and 1-c (1.7 g, 12.80 mmol), dissolved in tetrahydrofuran (40 mL), stirred for 5 min under ice water bath, lithium bis(trimethylsilyl)amide (53.35 mL, 53.35 mmol) was slowly added dropwise under ice water bath, after the addition was completed, the reaction was allowed to react at room temperature for 1 h. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, separated, the organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, swelled with a mixed solvent of PE / EA = 1 / 2, suction filtered, washed, and the filter cake was evaporated to dryness to give compound 1-f (3.9 g, 10.50 mmol) as a black brown solid. MS m / z (ESI): 372.05 [M+H] + .

[0229] Step 3: Synthesis of compound 1-h

[0230] Into a reaction flask was placed 1-f (3.9 g, 10.50 mmol), dichloromethane (100 mL), 1-g (41.13 mL, 367.63 mmol) was slowly added under ice water bath, then aluminum chloride (49.0 g, 367.63 mmol) was added portionwise, stirred at room temperature under nitrogen protection overnight. The reaction solution was diluted with ethyl acetate (150 mL), then the reaction solution was slowly poured into ice water (100 mL) for quenching, extracted with ethyl acetate (50 mL), the organic phase was washed with saturated brine (80 mL), dried over anhydrous Na2SO4, filtered, and the organic phase was concentrated under reduced pressure to give compound 1-h (4.5 g, 10.15 mmol) as a dark yellow solid. MS m / z (ESI): 442.0 [M-H] - .

[0231] Preparation of compound 4 of Example 4

[0232]

[0233] Step 1: Synthesis of compound 4-b

[0234] The operation step is the same as the synthesis of compound 1-j, 1-i is replaced by 4-a (60.1 mg, 0.41 mmol) to obtain compound 4-b (60 mg, 0.09 mmol) in yellow solid. MS m / z (ESI): 537.11 [M-H] - .

[0235] Step 2: Synthesis of compound 4

[0236] The operation step is the same as the synthesis of compound 1, 1-j is replaced by 4-b (50 mg, 0.09 mmol) to obtain compound 4 (8 mg, 0.02 mmol) in yellow solid. MS m / z (ESI): 443.23 [M+H] + .

[0237] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.34 (d, J = 9.2 Hz, 1H), 8.22 (dd, J = 5.8, 2.6 Hz, 1H), 7.97-7.93 (m, 1H), 7.80 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 4.70-4.60 (m, 1H), 2.55 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H).

[0238] Example 5 Preparation of compound 5

[0239]

[0240] Step 1: Synthesis of compound 5-b

[0241] 3-a (4 g, 14.22 mmol) and 5-a (2.2 g, 17.07 mmol) were added to a three-necked flask, dissolved in tetrahydrofuran (40 mL), stirred in an ice water bath for five minutes, and then lithium bis(trimethylsilyl)amide (42.66 mL, 42.66 mmol) was slowly added dropwise under nitrogen protection. After the dropwise addition was completed, the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, and the organic phase was separated and washed with saturated brine (50 mL). After drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and slurry washing with a mixed solvent of PE / EA = 1 / 2, filtration, and drying of the filter cake, compound 5-b (5 g, 17.32 mmol) was obtained in white solid. MS m / z (ESI): 365.21 [M+H] + .

[0242] Step 2: Synthesis of compound 5-c

[0243] The operating steps are the same as the synthesis of compound 1-h, 1-f (3.9 g, 10.50 mmol) is replaced by 5-b (1 g, 2.74 mmol) to obtain compound 5-c (1.1 g, 2.52 mmol) as a dark yellow solid. MS m / z (ESI): 435.00 [M-H] - .

[0244] Step 3: Synthesis of compound 5-d

[0245] The operating steps are the same as the synthesis of compound 1-j, 1-h (61 mg, 0.41 mmol) is replaced by 5-c (150 mg, 0.34 mmol) to obtain compound 5-d (100 mg, 0.19 mmol) as a yellow solid. MS m / z (ESI): 532.07 [M+H] + .

[0246] Step 4: Synthesis of compound 5

[0247] The operating steps are the same as the synthesis of compound 2, 2-b (50 mg, 0.10 mmol) is replaced by 5-d (50 mg, 0.09 mmol) to obtain compound 5 (15 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 436.18 [M+H] + .

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.33 (d, J = 8.8 Hz, 1H), 7.91-7.86 (m, 1H), 7.77 (s, 2H), 7.47-7.41 (m, 2H), 4.68-4.60 (m, 1H), 2.54 (s, 1H), 1.35 (d, J = 6.8 Hz, 3H).

[0249] Example 6: Preparation of compound 6

[0250]

[0251] Step 1: Synthesis of compound 6-a

[0252] The operating steps are the same as the synthesis of compound 5-d, 1-i is replaced by 2-a (68 mg, 1.2 mmol) to obtain compound 6-a (115 mg, 0.23 mmol) as a yellow solid. MS m / z (ESI): 506.08 [M+H] + .

[0253] Step 2: Synthesis of compound 6

[0254] Compound 6 was prepared according to the procedures for the synthesis of compound 5-d, using 6-a (115 mg, 0.23 mmol) instead of 5-a (120 mg, 0.24 mmol). MS m / z (ESI): 410.07 [M+H] + .

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.27 (s, 1H), 7.89-7.83 (m, 1H), 7.67 (s, 2H), 7.44-7.38 (m, 2H), 4.67 (d, J = 6.4 Hz, 2H), 4.33 (d, J = 6.4 Hz, 2H), 2.54 (s, 3H), 1.54 (s, 3H).

[0256] Preparation of compound 7

[0257]

[0258] Step 1: Synthesis of compound 7-b

[0259] The operating steps were the same as the synthesis of compound 5-d, using 7-a (45.7 mg, 0.55 mmol) instead of 1-i (120 mg, 0.24 mmol), to give compound 7-b (140 mg, 0.28 mmol) as a yellow solid. MS m / z (ESI): 502.10 [M+H] + .

[0260] Step 2: Synthesis of compound 7

[0261] The operating steps were the same as the synthesis of compound 6, using 7-b (120 mg, 0.24 mmol) instead of 6-a (115 mg, 0.23 mmol), to give compound 7 (13 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 406.11 [M+H] + .

[0262] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (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).

[0263] Preparation of compound 8

[0264]

[0265] Step 1: Synthesis of compound 8-b

[0266] The operation steps are the same as the synthesis of compound 5-d, 1-i is replaced by 8-a (37.9 mg, 0.69 mmol) to obtain compound 8-b (100 mg, 0.21 mmol) as a yellow solid. MS m / z (ESI): 474.06 [M+H] + .

[0267] Step 2: Synthesis of compound 8

[0268] The operation steps are the same as the synthesis of compound 6, 6-a is replaced by 8-b (100 mg, 0.21 mmol) to obtain compound 8 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 378.08 [M+H] + .

[0269] 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.18 (t, J = 6.0 Hz, 1H), 7.89-7.83 (m, 1H), 7.70 (s, 2H), 7.44-7.38 (m, 2H), 3.93 (dd, J = 6.4, 2.8 Hz, 2H), 3.13 (t, J = 2.8 Hz, 1H), 2.52 (s, 3H).

[0270] Example 9 Preparation of compound 9

[0271]

[0272] Step 1: Synthesis of compound 9-a

[0273] The operation steps are the same as the synthesis of compound 5-d, 1-i is replaced by 4-a (37.9 mg, 81.2 mmol) to obtain compound 9-a (120 mg, 0.23 mmol) as a yellow solid. MS m / z (ESI): 532.03 [M+H] + .

[0274] Step 2: Synthesis of compound 9

[0275] The operation steps are the same as the synthesis of compound 6, 6-a is replaced by 9-a (120 mg, 0.23 mmol) to obtain compound 9 (15 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 436.05 [M+H] + .

[0276] 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.31 (d, J = 9.2 Hz, 1H), 7.90-7.82 (m, 1H), 7.75 (s, 2H), 7.46-7.34 (m, 2H), 4.66-4.60 (m, 1H), 2.52 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H).

[0277] Preparation of compound 10 of Example 10

[0278]

[0279] Step 1: Synthesis of compound 10-b

[0280] The operating procedure was the same as the synthesis of compound 5-d, 1-i was replaced by 10-a (64.7 mg, 0.55 mmol) to give compound 10-b (130 mg, 0.26 mmol) as a yellow solid. MS m / z (ESI): 500.02 [M+H] + .

[0281] Step 2: Synthesis of compound 10

[0282] The operating procedure was the same as the synthesis of compound 6, 6-a was replaced by 10-b (80 mg, 0.16 mmol) to give compound 10 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 404.10 [M+H] + .

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.31 (d, J = 9.2 Hz, 1H), 7.90-7.82 (m, 1H), 7.75 (s, 2H), 7.46-7.34 (m, 2H), 4.66-4.60 (m, 1H), 2.52 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H).

[0284] Preparation of compound 11

[0285]

[0286] Step 1: Synthesis of compound 11-b

[0287] The operating procedure was the same as the synthesis of compound 5-d, 1-i was replaced by 11-a (110.4 mg, 0.55 mmol) to give compound 11-b (140 mg, 0.24 mmol) as a yellow solid. MS m / z (ESI): 583.08 [M+H] + .

[0288] Step 2: Synthesis of compound 11

[0289] Into a single-neck flask, 11-b (100 mg, 0.17 mmol) was dissolved in methanol (20 mL), followed by the addition of potassium phosphate (729.1 mg, 3.43 mmol), heated to 70 °C, stirred at reflux for 1.5 h. Cooled to room temperature, ethyl acetate (20 mL), water (2 mL), saturated brine (20 mL) were added, the organic phase was concentrated, and compound 11 (5 mg, 0.01 mmol) was obtained as a yellow solid by preparative high performance liquid chromatography. MS m / z (ESI): 487.11 [M+H] + .

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (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).

[0291] Example 12 Preparation of compound 12

[0292]

[0293] Step 1: Synthesis of compound 12-b

[0294] The operating steps were the same as the synthesis of compound 5-d, except that 1-i was replaced by 12-a (52.3 mg, 0.55 mmol), to give compound 12-b (100 mg, 0.19 mmol) as a yellow solid. MS m / z (ESI): 514.09 [M+H] + .

[0295] Step 2: Synthesis of compound 12

[0296] The operating steps were the same as the synthesis of compound 11, except that 11-b was replaced by 12-b (80 mg, 0.16 mmol), to give compound 12 (10 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 418.28 [M+H] + .

[0297] 1H NMR (400 MHz, DMSO-d6) δ 10.18 (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).

[0298] Preparation of compound 13 of Example 13

[0299]

[0300] Step 1: synthesis of compound 13-b

[0301] The operating steps are the same as the synthesis of compound 5-b, except that 5-a (2.2 g, 17.07 mmol) is replaced by 13-a (2.5 g, 17.06 mmol) to obtain compound 13-b (4.6 g, 12.03 mmol) in the form of a white solid. MS m / z (ESI): 383.01 [M+H] + .

[0302] Step 2: synthesis of compound 13-c

[0303] The operating steps are the same as the synthesis of compound 1-h, except that 1-f (3.9 g, 10.50 mmol) is replaced by 13-b (1 g, 2.62 mmol) to obtain compound 13-c (1.0 g, 2.2 mmol) in the form of a dark yellow solid. MS m / z (ESI): 453.0 [M-H] - .

[0304] Step 3: synthesis of compound 13-d

[0305] The operating steps are the same as the synthesis of compound 1-j, except that 1-h (61 mg, 0.41 mmol) is replaced by 13-c (150 mg, 0.33 mmol) to obtain compound 13-d (120 mg, 0.22 mmol) in the form of a yellow solid. MS m / z (ESI): 550.00 [M+H] + .

[0306] Step 4: synthesis of compound 13

[0307] The operating steps are the same as the synthesis of compound 2, except that 2-b is replaced by 13-d (120 mg, 0.22 mmol) to obtain compound 13 (20 mg, 0.04 mmol) in the form of a yellow solid. MS m / z (ESI): 454.05 [M+H] + .

[0308] 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.32 (d, J = 9.2 Hz, 1H), 7.78 (s, 2H), 7.59 (dd, J = 10.4, 6.4 Hz, 2H), 4.66 - 4.58 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H).

[0309] Preparation of compound 14

[0310]

[0311] Step 1: Synthesis of compound 14-a

[0312] The operating steps are the same as the synthesis of compound 13-d, 1-i is replaced by 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] + .

[0313] Step 2: Synthesis of compound 14

[0314] The operating steps are the same as the synthesis of compound 2, 2-b is replaced by 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] + .

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.32 (d, J = 9.2 Hz, 1H), 7.78 (s, 2H), 7.59 (dd, J = 10.4, 6.4 Hz, 2H), 4.66 - 4.58 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H).

[0316] Preparation of compound 15

[0317]

[0318] Step 1: Synthesis of compound 15-b

[0319] 15-a (1.2 g, 7.5 mmol) was dissolved in methanol (20 mL), Pd / C (220 mg, 5% wet) was added, stirred at room temperature under hydrogen atmosphere overnight. Filtration was performed, and the filtrate was concentrated to obtain orange solid compound 15-b (955 mg, 7.34 mmol), which was directly used in the next step. MS m / z (ESI): 131.00 [M+H]+ .

[0320] Step 2: Synthesis of compound 15-c

[0321] The operating steps were the same as the synthesis of compound 5-b, 5-a (2.2 g, 17.07 mmol) was replaced by 15-b (950 mg, 7.30 mmol) to obtain compound 15-c (1.7 g, 4.65 mmol) as a yellow solid. MS m / z (ESI): 366.04 [M+H] + .

[0322] Step 3: Synthesis of compound 15-d

[0323] The operating steps were the same as the synthesis of compound 1-h, 1-f (3.9 g, 10.50 mmol) was replaced by 15-c (500 mg, 1.37 mmol) to obtain compound 15-d (300 mg, 0.69 mmol) as a yellow solid. MS m / z (ESI): 436.0 [M-H] - .

[0324] Step 4: Synthesis of compound 15-e

[0325] The operating steps were the same as the synthesis of compound 1-j, 1-h (61 mg, 0.41 mmol) was replaced by 15-d (300 mg, 0.69 mmol) to obtain compound 15-e (280 mg, 0.53 mmol) as a yellow solid. MS m / z (ESI): 533.13 [M+H] + .

[0326] Step 5: Synthesis of compound 15

[0327] 15-e (80 mg, 0.15 mmol) was added to a single-neck flask, dissolved in methanol (20 mL), followed by the addition of potassium phosphate (638 mg, 3.01 mmol), heated to 70°C, and stirred to reflux for half an hour. Cooled to room temperature, added ethyl acetate (20 mL), water (2 mL), saturated brine (20 mL), separated, the organic phase was concentrated, and prepared 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] + .

[0328] 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.30 (d, J = 9.2 Hz, 1H), 8.34-8.28 (m, 1H), 8.26-8.25 (m, 1H), 7.80 (s, 2H), 4.66-4.60 (m, 1H), 2.54 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H).

[0329] Example 16 Preparation of compound 17

[0330]

[0331] Step 1: Synthesis of compound 17-b

[0332] The operating steps are the same as the synthesis of compound 1-j, 1-i (61 mg, 0.41 mmol) is replaced by 17-a (55 mg, 0.54 mmol) to obtain compound 17-b (89 mg, 0.17 mmol) as a yellow solid. MS m / z (ESI): 527.13 [M+H] + .

[0333] Step 2: Synthesis of compound 17

[0334] The operating steps are the same as the synthesis of compound 11, 11-b is replaced by 17-b (89 mg, 0.17 mmol) to obtain compound 17 (8 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 431.15 [M+H] + .

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.30 (d, J = 9.2 Hz, 1H), 8.34-8.28 (m, 1H), 8.26-8.25 (m, 1H), 7.80 (s, 2H), 4.66-4.60 (m, 1H), 2.54 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H).

[0336] Example 17 Preparation of compound 20

[0337]

[0338] Step 1: Synthesis of compound 20-b

[0339] The operating procedure was the same as the synthesis of compound 1-j, 1-i (61 mg, 0.41 mmol) was replaced by 20-a (47 mg, 0.54 mmol) to give compound 20-b (153 mg, 0.28 mmol) as a yellow solid. MS m / z (ESI): 541.24 [M+H] + .

[0340] Step 2: Synthesis of compound 20

[0341] The operating procedure was the same as the synthesis of compound 11, 11-b was replaced by 20-b (153 mg, 0.28 mmol) to give compound 20 (27 mg, 0.06 mmol) as a yellow solid. MS m / z (ESI): 445.10 [M+H] + .

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.21 (dd, J = 5.6, 2.4 Hz, 1H), 8.12 (s, 1H), 7.97-7.92 (m, 1H), 7.69 (s, 2H), 7.54 (t, J = 9.2 Hz, 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).

[0343] Example 18 Preparation of compound 23

[0344]

[0345] Step 1: Synthesis of compound 23-a

[0346] The operating procedure was the same as the synthesis of compound 1-j, 1-i (61 mg, 0.41 mmol) was replaced by 7-a (45 mg, 0.54 mmol) to give compound 23-a (80 mg, 0.16 mmol) as a yellow solid. MS m / z (ESI): 507.14 [M-H] - .

[0347] Step 2: Synthesis of compound 23

[0348] The operating procedure was the same as the synthesis of compound 11, 11-b was replaced by 23-a (80 mg, 0.16 mmol) to give compound 23 (13 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 413.09 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (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 = 9.2 Hz, 1H), 3.22 (s, 1H), 2.54 (s, 3H), 1.59 (s, 6H).

[0350] Preparation of compound 24 of Example 19

[0351]

[0352] Step 1: Synthesis of compound 24-b

[0353] The operating steps are the same as the synthesis of compound 1-j, 1-i (61 mg, 0.41 mmol) is replaced by 24-a (37 mg, 0.54 mmol) to obtain compound 24-b (140 mg, 0.28 mmol) as a yellow solid. MS m / z (ESI): 493.32 [M-H] - .

[0354] Step 2: Synthesis of compound 24

[0355] The operating steps are the same as the synthesis of compound 11, 11-b is replaced by 24-b (140 mg, 0.28 mmol) to obtain compound 24 (5 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 399.09 [M+H] + .

[0356] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.14 (d, J = 8.2 Hz, 1H), 8.25-8.19 (m, 1H), 7.99-7.91 (m, 1H), 7.74 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 4.73-4.61 (m, 1H), 3.22 (d, J = 2.4 Hz, 1H), 2.54 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H).

[0357] Preparation of compound 25 of Example 20

[0358]

[0359] Step 1: Synthesis of compound 25-a

[0360] The operating procedure was the same as the synthesis of compound 1-j, 1-i (61 mg, 0.41 mmol) was replaced by 10-a (43.8 mg, 0.54 mmol) to give compound 25-a (130 mg, 0.26 mmol) as a yellow solid. MS m / z (ESI): 505.09 [M-H] - .

[0361] Step 2: Synthesis of compound 25

[0362] The operating procedure was the same as the synthesis of compound 11, 11-b was replaced by 25-a (130 mg, 0.26 mmol) to give compound 25 (6 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 411.06 [M+H] + .

[0363] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (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 = 9.2 Hz, 1H), 3.04 (s, 1H), 2.54 (s, 3H), 1.18-1.12 (m, 2H), 1.11-1.05 (m, 2H).

[0364] Example 21 Preparation of compound 26

[0365]

[0366] Step 1: Synthesis of compound 26-b

[0367] The operating procedure was the same as the synthesis of compound 1-j, 1-i was replaced by 26-a (30 mg, 0.41 mmol) to give 90 mg of compound 26-b as a yellow solid. MS m / z (ESI): 499.10 [M+H] + .

[0368] Step 2: Synthesis of compound 26

[0369] 26-b (90 mg, 0.13 mmol) was added to a single-neck flask, dissolved in methanol (5 mL), followed by the addition of potassium phosphate (274 mg, 1.3 mmol), and heated to 80 °C under nitrogen protection, and stirred for 1.5 hours. The reaction solution was concentrated, and compound 26 (8 mg, 0.01 mmol) was obtained as a yellow solid by high performance liquid chromatography preparation. MS m / z (ESI): 403.10 [M+H] + .

[0370] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.20 (dd, J = 5.8, 2.6 Hz, 1H), 8.00 (s, 1H), 7.94 (ddd, J = 9.0, 4.8, 2.6 Hz, 1H), 7.68 (s, 2H), 7.52 (t, J = 9.2 Hz, 1H), 2.52 (s, 3H), 1.34 (s, 9H).

[0371] Preparation of compound 27 of Example 22

[0372]

[0373] Step 1: synthesis of compound 27-b

[0374] The operation steps are the same as the synthesis of compound 1-j, 1-i is replaced by 27-a (80 mg, 0.30 mmol), finally 115 mg of yellow solid product compound 27-b is obtained. MS m / z (ESI): 553.07 [M+H] + .

[0375] Step 2: synthesis of compound 27

[0376] 27-b (115 mg, 0.21 mmol) is added to a single-neck flask, dissolved in methanol (5 mL), followed by the addition of potassium phosphate (445 mg, 2.1 mmol), and heated to 80°C under nitrogen protection, stirred for 1.5 hours. The reaction solution is concentrated, and compound 27 (15 mg, 0.03 mmol) is obtained by high performance liquid chromatography preparation. MS m / z (ESI): 457.09 [M+H] + .

[0377] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.50 (s, 1H), 8.19 (dd, J = 5.8, 2.8 Hz, 1H), 7.93 (ddd, J = 9.0, 5.0, 2.8 Hz, 1H), 7.76 (s, 2H), 7.52 (t, J = 9.2 Hz, 1H), 2.55 (s, 3H), 1.58 (s, 6H).

[0378] Preparation of compound 29 of Example 23

[0379]

[0380] Step 1: synthesis of compound 29-a

[0381] Into a reaction vial was placed 1-h (63 g, 133.64 mmol) and DMF (200 mL), followed by 10% aqueous sodium hydroxide solution (200 mL, 500.12 mmol), and the reaction was stirred at room temperature for 3 h. The reaction was quenched with water (500 mL), extracted with EA (500 mL), and the aqueous layer was collected and adjusted to pH 2-3, extracted with EA / MeOH = 2:1 (500 mL), and the organic layer was collected and concentrated under reduced pressure to give crude product 11g. The crude product was dissolved in EA (200 mL), filtered, and the solid was collected to give yellow solid compound 29-a (9.0 g, 25.53 mmol). MS m / z (ESI): 348.08 [M+H] + .

[0382] Step 2: Synthesis of compound 29-c

[0383] Compound 29-b (10 mg, 0.04 mmol) was dissolved in methanol (5 mL), followed by 10% Pd / C (10 mg, 0.09 mmol), and the reaction was stirred at room temperature for 1 h under a hydrogen atmosphere. 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) + .

[0384] Step 3: Synthesis of compound 29

[0385] Into a reaction vial was placed 29-c (5.00 mg, 0.04 mmol) and 29-a (16.7 mg, 0.05 mmol), followed by N,N-dimethylformamide (1.0 mL), and the mixture was dissolved, followed by the addition of N,N-diisopropylethylamine (0.02 mL, 0.11 mmol) and HATU (21.1 mg, 0.06 mmol), and the reaction was stirred at room temperature for 20 min. The reaction was purified by preparative purification to give yellow solid compound 29 (8.3 mg, 0.02 mmol). MS m / z (ESI): 465.18 [M+H] + .

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.07 (s, 1H), 8.19 (dd, J = 5.6, 2.8 Hz, 1H), 7.98-7.89 (m, 1H), 7.69 (s, 2H), 7.52 (t, J = 9.2 Hz, 1H), 2.98-2.87 (m, 2H), 2.72-2.64 (m, 2H), 2.54 (s, 3H), 1.83 (q, J = 7.2 Hz, 2H), 0.79 (t, J = 7.2 Hz, 3H).

[0387] Preparation of compound 30 of Example 24

[0388]

[0389] Step 1: Synthesis of compound 30

[0390] The operation steps are the same as the synthesis of compound 29, except that 29-c is replaced by 30-a (10.2 mg, 0.06 mmol) to obtain 4.2 mg of yellow product compound 30. MS m / z (ESI): 471.07 [M+H] + .

[0391] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.94 (s, 1H), 8.22 (dd, J = 6.0, 2.8 Hz, 1H), 7.99-7.91 (m, 1H), 7.81 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 4.87 (d, J = 8.4 Hz, 2H), 4.74 (d, J = 8.4 Hz, 2H), 2.58 (s, 3H).

[0392] Preparation of compound 31 of Example 25

[0393]

[0394] Step 1: Synthesis of compound 31-b

[0395] The operation steps are the same as the synthesis of compound 1-f, except that 1-c is replaced by 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 [M-H] - .

[0396] Step 2: Synthesis of compound 31-c

[0397] The operation steps are the same as the synthesis of compound 1-h, except that 1-f is replaced by 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 [M-H] - .

[0398] Step 3: Synthesis of compound 31-d

[0399] The operating procedure was the same as the synthesis of compound 1-j, 1-h was replaced by 31-c (400 mg, 0.88 mmol) to give compound 31-d (480 mg, 0.88 mmol) as a yellow solid. MS m / z (ESI): 546.05 [M-H] - .

[0400] Step 4: Synthesis of compound 31

[0401] The operating procedure was the same as the synthesis of compound 11, 11-b was replaced by 31-d (480 mg, 0.88 mmol) to give compound 31 (20 mg, 0.04 mmol) as a yellow solid. MS m / z (ESI): 452.02 [M+H] + .

[0402] 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.31 (d, J = 9.2 Hz, 1H), 8.06-8.01 (m, 1H), 7.77 (s, 2H), 7.63-7.55 (m, 1H), 7.42 (t, J = 9.2 Hz, 1H), 4.75-4.59 (m, 1H), 2.55 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H).

[0403] Example 26 Preparation of compound 32

[0404]

[0405] Step 1: Synthesis of compound 32-b

[0406] The operating procedure was the same as the synthesis of compound 1-j, 1-i was replaced by 32-a (69 mg, 0.30 mmol) to give 109 mg of compound 32-b as a yellow solid. MS m / z (ESI): 517.09 [M+H] + .

[0407] Step 2: Synthesis of compound 32

[0408] 32-b (109 mg, 0.22 mmol) was added to a single-neck flask, dissolved in methanol (5 mL), followed by the addition of potassium phosphate (446 mg, 2.2 mmol), and heated to 80 °C under nitrogen protection, and stirred for 1.5 hours. The reaction solution was concentrated, and compound 32 (13 mg, 0.03 mmol) was obtained as a yellow solid by high performance liquid chromatography preparation. MS m / z (ESI): 421.11 [M+H] + .

[0409] 1H NMR (400 MHz, DMSO-d6) δ 10.31 (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 = 9.2 Hz, 1H), 4.57 (s, 1H), 4.45 (s, 1H), 2.53 (s, 3H), 1.32 (s, 6H).

[0410] Preparation of compound 33 in example 27

[0411]

[0412] Step 1: synthesis of compound 33

[0413] The operating procedure was the same as the synthesis of compound 1-j, 1-h was replaced by 29-a (52 mg, 0.15 mmol) and 1-i was replaced by 33-a (47 mg, 0.18 mmol), the starting material was consumed up in 30 min. Preparation by high performance liquid chromatography, finally 24 mg of yellow solid product compound 33 was obtained. MS m / z (ESI): 455.07 [M+H] + .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.50 (s, 1H), 8.19 (dd, J = 5.8, 2.6 Hz, 1H), 7.93 (ddd, J = 9.0, 4.8, 2.6 Hz, 1H), 7.76 (s, 2H), 7.52 (t, J = 9.2 Hz, 1H), 1.31-1.27 (m, 2H), 2.52 (s, 3H), 1.13-1.08 (m, 2H).

[0415] Preparation of compound 34 in example 28

[0416]

[0417] Step 1: synthesis of compound 34-b

[0418] Into a three-necked flask, 3-a (2 g, 7.11 mmol) and 34-a (1.1 g, 9.24 mmol) were dissolved in THF (30 mL), stirred for 5 min in an ice-water bath under nitrogen protection, lithium bis(trimethylsilyl)amide (21.33 mL, 21.33 mmol) was slowly added dropwise into it under ice-water bath, after dropwise addition, it was reacted at room temperature for 1 h. The reaction solution was quenched with ice water (50 mL), saturated brine (50 mL) was added, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, swelled with a mixed solvent of PE / EA = 1 / 2, suction filtered, washed, and the filter cake was evaporated to dryness to obtain compound 34-b (2.5 g, 6.94 mmol) as a white solid. MS m / z (ESI): 361.06 [M+H] + .

[0419] Step 2: Synthesis of compound 34-c

[0420] The operating steps were the same as the synthesis of compound 1-h, and 1-f (3.9 g, 10.50 mmol) was replaced by 34-b (2.5 g, 6.94 mmol) to obtain compound 34-c (2.6 g, 6.01 mmol) as a dark yellow solid. MS m / z (ESI): 433.04 [M-H] - .

[0421] Step 3: Synthesis of compound 34-d

[0422] The operating steps were the same as the synthesis of compound 1-j, and 1-h (61 mg, 0.41 mmol) was replaced by 34-c (150 mg, 0.34 mmol) to obtain compound 34-d (100 mg, 0.19 mmol) as a yellow solid. MS m / z (ESI): 528.07 [M+H] + .

[0423] Step 4: Synthesis of compound 34

[0424] The operating steps were the same as the synthesis of compound 2, and 2-b (50 mg, 0.10 mmol) was replaced by 34-d (100 mg, 0.19 mmol) to obtain compound 34 (15 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 432.09 [M+H] + .

[0425] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.27 (d, J = 9.0 Hz, 1H), 7.69 (s, 2H), 7.61 (dd, J = 7.0, 2.2 Hz, 1H), 7.55 - 7.34 (m, 1H), 7.09 (t, J = 9.2 Hz, 1H), 4.73 - 4.54 (m, 1H), 2.54 (s, 3H), 2.22 (d, J = 1.2 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H).

[0426] Preparation of compound 37 in example 29

[0427]

[0428] Step 1: synthesis of compound 37

[0429] The operation steps are the same as the synthesis of compound 29, 29-c is replaced by 37-a (7 mg, 0.07 mmol) to obtain compound 37 (15 mg, 0.03 mmol) as a yellow solid. MS m / z (ESI): 427.07 [M+H] + .

[0430] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.84 (s, 1H), 8.23 (dd, J = 5.8, 2.6 Hz, 1H), 8.02 - 7.89 (m, 1H), 7.79 (s, 2H), 7.56 (t, J = 9.2 Hz, 1H), 4.78 (d, J = 6.6 Hz, 2H), 4.72 (d, J = 6.6 Hz, 2H), 3.61 (s, 1H), 2.58 (s, 3H).

[0431] Preparation of compound 38 in example 30

[0432]

[0433] Step 1: synthesis of compound 38

[0434] The operation steps are the same as the synthesis of compound 29, 29-c is replaced by 38-a (27.4 mg, 0.23 mmol) to obtain compound 38 (9 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 413.15 [M+H] + .

[0435] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.25 (s, 1H), 8.22 (dd, J = 5.8, 2.6 Hz, 1H), 7.95 (ddd, J = 9.2, 4.8, 2.6 Hz, 1H), 7.70 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 2.54 (s, 3H), 2.47 (s, 1H), 2.07 (s, 6H).

[0436] Preparation of compound 39 in example 31

[0437]

[0438] Step 1: synthesis of compound 39

[0439] The operation steps are the same as the synthesis of compound 29, 29-c is replaced by 39-a (23.7 mg, 0.23 mmol) to obtain compound 39 (6 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 433.10 [M+H] + .

[0440] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.25 (s, 1H), 8.22 (dd, J = 5.8, 2.6 Hz, 1H), 7.95 (ddd, J = 9.2, 4.8, 2.6 Hz, 1H), 7.70 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 2.54 (s, 3H), 2.47 (s, 1H), 2.07 (s, 6H).

[0441] Preparation of compound 40 in example 32

[0442]

[0443] Step 1: synthesis of compound 40

[0444] The operation steps are the same as the synthesis of compound 29, 29-c is replaced by 40-a (15 mg, 0.09 mmol) to obtain compound 40 (4 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 461.07 [M+H] + .

[0445] 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.68 (s, 1H), 8.21 (dd, J = 5.9, 2.7 Hz, 1H), 7.95 (ddd, J = 9.2, 4.8, 2.6 Hz, 1H), 7.77 (s, 2H), 7.55 (t, J = 9.2 Hz, 1H), 3.46 (s, 1H), 3.23 - 3.06 (m, 4H), 2.55 (s, 3H).

[0446] Example 33 Preparation of compound 41

[0447]

[0448] Step 1: Synthesis of compound 41-b

[0449] The operation steps are the same as the synthesis of compound 5-b, 5-a (2.2 g, 17.07 mmol) is replaced by 41-a (1.6 g, 8.53 mmol) to obtain compound 41-b (2.95 g, 6.54 mmol) as a white solid. MS m / z (ESI): 427.00 [M+H] + .

[0450] Step 2: Synthesis of compound 41-c

[0451] The operation steps are the same as the synthesis of compound 1-h, 1-f (3.9 g, 10.50 mmol) is replaced by 41-b (1 g, 2.35 mmol) to obtain compound 41-c (1.0 g, 2.01 mmol) as a dark yellow solid. MS m / z (ESI): 496.93 [M+H] + .

[0452] Step 3: Synthesis of compound 41-d

[0453] The operation steps are the same as the synthesis of compound 1-j, 1-h (61 mg, 0.41 mmol) is replaced by 41-c (900 mg, 1.81 mmol) to obtain compound 41-d (600 mg, 1.01 mmol) as a yellow solid. MS m / z (ESI): 594.12 [M+H] + .

[0454] Step 4: Synthesis of compound 41

[0455] The operation steps are the same as the synthesis of compound 6, 6-a is replaced by 41-d (200 mg, 0.34 mmol) to obtain compound 41 (38 mg, 0.08 mmol) as a yellow solid. MS m / z (ESI): 498.00 [M+H] + .

[0456] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.31 (d, J = 9.2 Hz, 1H), 8.16 (dd, J = 6.6, 2.6 Hz, 1H), 7.76 (s, 2H), 7.65 - 7.61 (m, 1H), 7.38 (t, J = 8.8 Hz, 1H), 4.73 - 4.57 (m, 1H), 2.55 (s, 3H), 1.36 (d, J = 7.2 Hz, 3H).

[0457] Preparation of compound 42 of example 34

[0458]

[0459] Step 1: synthesis of compound 42-a

[0460] Into a sealed tube was placed 41-d (413 mg, 0.7 mmol), 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, nitrogen was replaced, sealed tube, heated to 100 °C, stirred overnight. Concentration, silica gel column purification (PE / EA = 3 / 1), to get yellow solid compound 42-a (200 mg, 0.32 mmol). MS m / z (ESI): 573.00 [M-56+H] + .

[0461] Step 2: synthesis of compound 42-b

[0462] Compound 42-a (200 mg, 0.32 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, stirred at room temperature for 1 hour. The reaction solution was concentrated, purified by C18 column, eluent ratio: 55% (acetonitrile): 45% (0.05% formic acid aqueous solution), the purified product was collected and concentrated under reduced pressure to get yellow solid compound 42-b (150 mg, 0.28 mmol). MS m / z (ESI): 529.06 [M+H] + .

[0463] Step 3: synthesis of compound 42

[0464] The operation steps were the same as the synthesis of compound 6, 6-a was replaced by 42-b (200 mg, 0.34 mmol) to get yellow solid compound 42 (17 mg, 0.04 mmol). MS m / z (ESI): 433.06 [M+H] + .

[0465] 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.27 (d, J = 9.2 Hz, 1H), 7.66 (s, 2H), 7.22 (dd, J = 8.4, 2.6 Hz, 1H), 6.92 (dd, J = 11.2, 8.6 Hz, 1H), 6.80 (dq, J = 8.6, 2.8 Hz, 1H), 5.14 (s, 2H), 4.71 - 4.58 (m, 1H), 2.54 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H).

[0466] Preparation of compounds 43 and 44 of Examples 35 and 36

[0467]

[0468] Step 1: Synthesis of intermediate 43-b

[0469] The operating procedure was the same as the synthesis of compound 29, 29-c was replaced by 43-a (60.2 mg, 0.35 mmol) to give compound 43-b (100 mg, 0.02 mmol) as a yellow solid. MS m / z (ESI): 504.09 [M+H] + .

[0470] Step 2: Synthesis of compounds 43, 44

[0471] 43-b (20 mg, 0.04 mmol) was dissolved in 2 mL DMF, potassium carbonate (11 mg, 0.08 mmol), methyl iodide (6.8 mg, 0.05 mmol) were added, stirred at room temperature for 1 hour, the reaction was completed, 50 mL water was added to the reaction solution, extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated brine, anhydrous sodium sulfate was added to dry the organic phase, concentrated, 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] + .

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.74 (s, 1H), 8.21 (dd, J = 5.8, 2.8 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.72 (s, 2H), 7.54 (t, J = 9.2 Hz, 1H), 4.03 (s, 3H), 3.30 - 3.17 (m, 4H), 2.55 (s, 3H).

[0473] 44 (2 mg, 0.01 mmol); MS m / z (ESI): 517.85 [M+H] +

[0474] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.78 (s, 1H), 8.22 (dd, J = 5.7, 2.6 Hz, 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).

[0475] Preparation of compound 45 of Example 37

[0476]

[0477] Step 1: Synthesis of compound 45

[0478] The operating procedure was the same as the synthesis of compound 43, except that methyl iodide was replaced by ethyl iodide (7.8 mg, 0.05 mmol) to give compound 45 (2 mg, 0.01 mmol) as a yellow solid. MS m / z (ESI): 532.09 [M+H] + .

[0479] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.78 (s, 1H), 8.22 (dd, J = 5.7, 2.6 Hz, 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).

[0480] Example 38: Anti-HBV activity test in vitro of HepG2.2.15 cells

[0481] 1. Compound dilution: Dilution method 1, 20 μM compound stock solution was diluted 10 times with DMSO to get 2 μM compound solution, then 20 μM and 2 μM compound solution was diluted 200 times with culture medium to get 100 nM and 10 nM final concentration of compound solution. Dilution method 2, 20 μM compound stock solution was diluted 10 times and 100 times with DMSO to get 2 μM and 0.2 μM compound solution, then 2 μM and 0.2 μM compound solution was diluted 200 times with culture medium to get 10 nM and 1 nM final concentration of compound solution. Dilution method 3, 400 μM compound stock solution was diluted 4 times gradient to get 8 concentration points, 400 μM, 100 μM, 25.0 μM, 6.25 μM, 1.56 μM, 0.391 μM, 0.0977 μM and 0.0244 μM, then the gradient diluted compound solution was diluted 200 times with culture medium to get 2000 nM, 500 nM, 125 nM, 31.3 nM, 7.81 nM, 1.95 nM, 0.488 nM and 0.122 nM final concentration of compound solution.

[0482] 2. Experimental operation: On the first day, HepG2.2.15 cells (Wuhan Institute of Virology, CAS) (1 x 10 5 cells / well) were plated into 96-well cell culture plates and incubated at 37 °C, 5% CO2 overnight. The wells without cells containing only culture medium were set as culture medium control. On the second day, the culture medium containing different final concentration of compound in step 1 was added into the cell culture plates, 3 replicates for each concentration. The final concentration of DMSO in cell culture medium was 0.5%, and the final volume in culture wells was 200 μl. The wells without compound containing 0.5% DMSO were set as DMSO control. The incubation was continued to the fifth day, and the same fresh culture medium as before was replaced into the compound treated wells and control wells. On the eighth day, the cell supernatant in culture wells was collected, and part of the sample was detected for the content of HBV DNA. The plasmid containing D type HBV DNA full-length sequence was used as the standard for qPCR, and the standard range was 10 7 -10 1 copies / μl. The content of HBV DNA in all samples was determined by qPCR. After the supernatant was collected, Cell Titer-Glo reagent was added into the cell culture wells, and incubated at room temperature for 10 minutes. Then the chemiluminescence value in all wells was read by microplate reader, and the cell proliferation activity was calculated.

[0483] 3. Data analysis: The inhibition percentage was calculated by the following formula:

[0484] HBV DNA inhibition rate % = (1 - DNA copy number in compound sample / DNA copy number in DMSO control) x 100%.

[0485] Cell Viability % = (luminescence value in compound sample - luminescence value of medium control) / (luminescence value of DMSO control - luminescence value of medium control) x 100%.

[0486] The compounds detected according to the dilution methods ① and ② are obtained according to the HBV DNA inhibition rate (%) to obtain the EC 50 range; the compounds detected according to the dilution method ③ are obtained according to the HBV DNA inhibition rate (%) and the compound concentration by four-parameter fitting [log (agonist) vs. response - Variable slope] using GraphPad Prism software to obtain the EC 50 accurate value.

[0487] Using the above experimental method, the anti-HBV activity of some compounds of the present application is as follows in Table 1.

[0488] Table 1. HepG2.2.15 cell HBV DNA inhibition

[0489]

[0490]

[0491] Among them, the dilution method of compound 1 in Table 1 adopts method ③, and the EC 50 range is obtained by the accurate value; the dilution method of compounds 10, 12-14, 17, 20, 23-27, 29-34, 37-45 adopts method ②, and the dilution method of the rest of the compounds adopts method ①. According to Table 1, the compounds of the present application have excellent anti-HBV activity.

[0492] Example 39: Liver microsomal stability study (MMS)

[0493] Experimental materials, methods and result analysis:

[0494] The human liver microsomes (BIOIVT) used in the experiment are used;

[0495] Preparation of reagents:

[0496] PBS: 0.1M KH2PO4 and K2HPO4 buffer, pH 7.4.

[0497] MgCl2: A certain amount of MgCl2 is weighed and prepared into a 16mM MgCl2 solution with PBS.

[0498] 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.

[0499] Compound: Prepare the test compound to 4 mM with PBS, and the final incubation concentration is 1 mM.

[0500] Liver microsomes: Dilute the liver microsomes to 1 mg / ml with PBS, and the final incubation concentration is 0.5 mg / ml.

[0501] Experimental steps:

[0502] Add the test compound in the test tube, then add the prepared NADPH, and mix well. Pre-incubate in a 37℃, 220 rpm incubator for 5 min, then add the liver microsomes to start the reaction, and operate in duplicate.

[0503] After a certain time of reaction, add a certain volume of ice acetonitrile solution containing an internal standard to precipitate the protein, shake and vortex for 5 min, then centrifuge at 4000 rpm for 10 min, and take the supernatant to a 96-well plate. Put it into LC-MS / MS (Shimadzu LC-30A, AB API4500) for analysis.

[0504] Determine the concentration (peak area ratio) of the example compound by LC-MS / MS, plot "Ln (compound residual amount %)" against "incubation time" in Excel to obtain the rate constant, and calculate the half-life and intrinsic clearance of the drug, which provides a basis for predicting the in vivo clearance.

[0505] Data analysis:

[0506] CL int = (0.693 / t 1 / 2 , microsomes) x [incubation liquid volume (ml) / microsomal protein mass (mg)] x [microsomal protein mass (mg) / liver mass (g)] x [liver mass (g) / body weight (kg)]

[0507] CL [8]

[0508] CL H = CL int x f u x Q h / (CL int x f u + Q h )

[0509] In the formula

[0510] CL int --intrinsic clearance (ml / min / kg)

[0511] CL H --Liver clearance (ml / min / kg)

[0512] f u --Plasma unbound fraction is 1

[0513] Q h --Liver blood flow

[0514] Table 2

[0515]

[0516] As can be seen from Table 2, the compound of the application has a long half-life.

[0517] Example 40: PK experiment in rats and mice

[0518] Experimental materials and methods:

[0519] The experimental animals were healthy adult SD male rats and BALB / c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[0520] Rat administration and sample collection:

[0521] SD male rats were administered a single intravenous dose (1 mg / kg, 5% DMSO + 5% Solutol + 90% saline) (DMSO: AR500ml, Cologne; Solutol: 42966-1KG, BASF; saline: 100ml / bag, Sichuan Meida Kangjia Pharmaceutical Co., Ltd.) or a single oral dose (10 mg / kg, 0.5% CMC-Na) (CMC-Na, 419273-100G, sigma). The rats were collected at different time points after administration, i.e. 0.083 (only intravenous), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and 200 μL of whole blood was collected from the rat retinal plexus, and the plasma was obtained by centrifugation at 4000 rpm for 6 min.

[0522] Mouse administration and sample collection:

[0523] BALB / c female mice were administered a single intravenous (1 mg / kg, 5% DMSO + 5% Solutol + 90% saline) (DMSO: AR 500ml, Cologne; Solutol: 42966-1KG, BASF; saline: 100ml / bag, Sichuan Meidagangjiale Pharmaceutical Co., Ltd.) or gavage (10 mg / kg, 0.5% CMC-Na) (CMC-Na, 419273-100G, sigma) at different time points, and 60 μL of whole blood was collected from the fundus plexus at 0.083 (only intravenous), 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration. The plasma was obtained by centrifugation at 4000 rpm for 6 min.

[0524] Sample analysis:

[0525] 10 μL of mouse plasma samples were taken, and a certain volume of acetonitrile solution containing an internal standard was added to precipitate the protein, vortexed for 10 min, then centrifuged at 4000 rpm for 10 min, and the supernatant was taken into a 96-well plate. The sample was analyzed by LC-MS / MS (Shimadzu LC-30A, ABAPI 4500).

[0526] LC-MS / MS method was used to determine the drug concentration in the plasma of rats and mice at different time points after a single intravenous and gavage administration of the compound of the present application, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in rats and mice and evaluate the pharmacokinetic characteristics thereof.

[0527] The pharmacokinetic data of compound 1 are shown in Tables 3 and 4 below.

[0528] Table 3 Rat full-PK data

[0529]

[0530] Table 4 Mouse full-PK data

[0531]

[0532] From the above Tables 3 and 4, it can be seen that the compound of the present application has good pharmacokinetic properties.

[0533] Example 41: Tissue distribution study in rats and mice

[0534] Experimental materials, methods and results analysis:

[0535] The experimental animals were healthy adult SD male rats and BALB / c female mice (provided by Beijing Huafukang Biotechnology Co., Ltd.);

[0536] Administration method and sample collection of rats:

[0537] SD male rats were given gavage (15 mg / kg, 0.2% Tween 80 + 99.8% 0.5% CMC-Na) (CMC-Na, 419273-100G, sigma), and plasma, brain, liver, heart and kidney samples were collected at different time points after administration. 200 μL of whole blood was collected from the ophthalmic plexus, centrifuged at 4000 rpm for 6 min to obtain plasma; the abdominal cavity was opened and the heart was perfused with physiological saline, and then brain, liver, heart and kidney tissues were taken, wiped with filter paper to remove water, weighed and added with a certain amount of physiological saline for homogenization, and then placed in an EP tube.

[0538] Administration method and sample collection of mice:

[0539] BALB / c female mice were given gavage (30 mg / kg, 0.5% CMC-Na) (CMC-Na, 419273-100G, sigma), and plasma, brain, liver, heart and kidney samples were collected at different time points after administration. 60 μL of whole blood was collected from the ophthalmic plexus, centrifuged at 4000 rpm for 6 min to obtain plasma; the abdominal cavity was opened and the heart was perfused with physiological saline, and then brain, liver, heart and kidney tissues were taken, wiped with filter paper to remove water, weighed and added with a certain amount of physiological saline, homogenized and then placed in an EP tube.

[0540] Sample analysis:

[0541] 10 μL of plasma and tissue samples from rats and mice were taken, and a certain volume of acetonitrile solution containing an internal standard was added to precipitate the protein, vortexed for 10 min, then centrifuged at 4000 rpm for 10 min, and the supernatant was taken to a 96-well plate. LC-MS / MS (Shimadzu LC-30A, AB API 4500) was used for analysis.

[0542] LC-MS / MS method was used to determine the drug concentration in plasma and tissues of rats and mice at different time points after gavage administration of the compound of the example, and the relevant pharmacokinetic parameters were calculated to study the pharmacokinetic behavior of the compound in rats and mice and evaluate its pharmacokinetic characteristics.

[0543] Table 5 Distribution data of compound 1 in rat tissues

[0544]

[0545] Table 6 Distribution data of compound 1 in mouse tissues

[0546]

[0547] From the above Table 5 and Table 6, it can be seen that the exposure amount of the compound of the present application in the target organ liver is maintained at a high and stable level, which shows that the compound of the present application can better exert an effect in the target organ.

[0548] Example 42: hERG inhibition study

[0549] 1.1 hERG inhibition study

[0550] Using Predictor TM hERG Fluorescence Polarization Assay Kit (ThermoFisher Scientific PV5365) was used for hERG inhibition detection. 4xPredictor TM hERG Tracer Red and 4x E-4031 positive control were prepared in advance. In a 384-well plate, 5 μL Predictor TM hERG FP Assay Buffer and 5 μL Predictor TM hERG Membrane. 2.5 μL Predictor was added to the negative control, positive control and test compound wells, respectively TM hERG FP Assay Buffer, 2.5 μL 4x E-4031 Positive Control, 2.5 μL 4x Test Compound, and then 5 μL Predictor were added in turn TM hERG Membrane and 2.5 μL 4xPredictor TM hERG Tracer Red. Incubate at room temperature (25°C) for 3.5 h in the dark. After the reaction is completed, detect the fluorescence polarization value on the microplate reader, and the GFactor is 2.14.

[0551] 1.2 Inhibition rate calculation

[0552] The inhibition rate of the compound or positive control was calculated using the following formula.

[0553] Inhibition rate % = (mP negative control - mP compound) / (mP negative control - mP positive control) * 100%

[0554] Using the above experimental method, the hERG inhibition test results of some compounds of the present application are as follows in Table 7.

[0555] Table 7 hERG inhibition test results

[0556]

[0557] Industrial applicability

[0558] The compounds of the present application have excellent anti-HBV activity and can be used as drugs for treating or preventing diseases related to the action.

[0559] The above is only the preferred embodiment of the present application, it should be pointed out that for the ordinary skilled in the art, without departing from the principles of the present application, can also make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

[0560] References:

[0561] [1] Villain P, Gonzalez P, Almonte M, et al. European Code against Cancer 4th Edition: Infections and Cancer [J]. Cancer Epidemiology, 2015.

[0562] [2] Samuel, E C. Antiviral actions of interferons [Table of Contents] [J]. Clinical Microbiology Reviews, 2001, 14(4): 778-809.

[0563] [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.

[0564] [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.

[0565] [5] Berke, Martin J, Dehertogh, et al. Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus.

[0566] [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.

[0567] [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.

[0568] [8] Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993; 10: 1093-5.

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R1is selected from methyl; R2is selected from hydrogen; R3is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; the substituents of the phenyl are selected from the group consisting of fluorine, chlorine, bromine, C 1-4 alkyl, cyano; the substituents of the pyridyl are selected from the group consisting of fluorine, chlorine, bromine; R4is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocycloalkyl; The C 1-6 Alkyl includes straight chain or branched chain alkyl; the C 1-6 Substituents of alkyl are selected from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, ethynyl, propynyl; The C 3-8 Cycloalkyl groups include spiro, bridged or fused rings; the C 3-8 Substituents of cycloalkyl groups are selected from the group consisting of fluoro, chloro, bromo, ethynyl, propynyl, methyl, ethyl, propyl, -CF3, fluoroethyl, fluoropropyl, -C(O)NH2, -C(O)NHCH3, the 4-12 membered heterocycloalkyl is selected from a monocyclic or polycyclic saturated ring system, the polycyclic ring being selected from a spiro, bridged or fused ring; the 4-12 membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O and S; the substituents of the 4-12 membered heterocycloalkyl are selected from methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, -CF3, fluoroethyl, fluoropropyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R3is selected from 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from 4. The compound of claim 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from 5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R3is selected from 6. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from 7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R4is 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; The C 1-6 Alkyl includes straight chain or branched chain alkyl; the C 1-6 Substituents for alkyl are selected from fluoro, methoxy; The C 1-3 Alkyl includes straight-chain or branched-chain alkyl groups; the C 1-3 Substituents for alkyl are selected from ethynyl; The C 3-6 Cycloalkyl groups include spiro, bridged or fused rings; the C 3-8 Cycloalkyl groups include spiro, bridged or fused rings; the C 3-8 Substituents of cycloalkyl groups are selected from fluoro, ethynyl, methyl, ethyl, -CF3, -C(O)NH2, -C(O)NHCH3, the 4-11 membered heterocycloalkyl is selected from a monocyclic or polycyclic saturated ring system, the polycyclic ring being selected from a spiro, bridged or fused ring; the 4-11 membered heterocycloalkyl contains 1 to 2 heteroatoms selected from N, O and S; the substituents of the 4-11 membered heterocycloalkyl are selected from methyl, ethyl, isopropyl, -CF3, ethynyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from methyl, ethyl, propyl, isopropyl, 9. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R4is selected from 10. The compound of claim 9, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 11. The compound of claim 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R4is selected from 12. The compound of claim 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 13. The compound of claim 12, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 14. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 15. The compound of any one of claims 1, 8-14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: having the structure of Formula (III-1): wherein R4 is as defined in any one of claims 1, 8-14.

16. The compound of any one of claims 1, 8-14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: having the structure of Formula (III-2): wherein R4 is as defined in any one of claims 1, 8-14.

17. The compound of any one of claims 1, 8-14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: having the structure of Formula (III-3): wherein R4 is as defined in any one of claims 1, 8-14.

18. A compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: wherein R3is selected from unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n substituted pyridyl; each R m , R n each independently selected from the same or different halogen, C 1-4 alkyl, amino, cyano; R4is selected from C 1-8 alkyl, substituted by one or more R c substituted C 1-4 alkyl, unsubstituted or substituted by one or more R d substituted C 3-6 cycloalkyl, R8, R9, in combination with the carbon to which they are attached, form an unsubstituted or substituted C e substituted C 3-6 cycloalkyl or unsubstituted or substituted by one or more R f substituted 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, said 4-8 membered heterocycloalkyl being selected from a monocyclic or polycyclic saturated ring system, said polycyclic being selected from a spiro, bridged or fused ring; R7is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, -C(O)NR i R j , 5-membered heteroaryl containing 1-3 N heteroatoms, unsubstituted or substituted by one or more Rg; each R c , R d , R e , R f , R g are each independently selected from the same or different halogen, C 2-4 alkynyl, C 1-4 alkyl, C 1-4 alkoxy; R i , R j are each independently selected from H, C 1-4 alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n substituted phenyl, unsubstituted or substituted pyridyl; each R m , R n each independently selected from the same or different F, CI, Br, methyl, ethyl, isopropyl, tert-butyl, amino, cyano.

20. The compound of claim 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n substituted phenyl, unsubstituted or substituted pyridyl; each R m , R n each independently selected from the same or different F, Cl, Br, methyl, amino, cyano.

21. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl; each R m substituted phenyl, unsubstituted or substituted pyridyl; each R n substituted phenyl, unsubstituted or substituted pyridyl; each R m , R n each independently selected from the same or different F, Cl, Br, methyl, amino, cyano.

22. The compound of claim 21, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is unsubstituted or substituted by 1, 2 or 3 R m substituted phenyl; each R m each independently selected from the same or different F, Cl, Br, methyl, amino, cyano.

23. The compound of claim 21, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R3is selected from 24. The compound of claim 23, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R3is selected from 25. The compound of claim 18 or 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R4is selected from C 1-2 alkyl, C 3-8 alkyl, C 1-2 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, R8, R9, in combination with the carbon to which they are attached, form a C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N and O, said 4-6 membered heterocycloalkyl being selected from monocyclic or polycyclic saturated ring systems, said polycyclic being selected from spiro, bridged or fused rings; R7is selected from methyl, ethyl, fluoromethyl, fluoroethyl, ethynyl, propynyl, -C(O)NR i R j , triazolyl unsubstituted or substituted by 1 or more methyl or ethyl or isopropyl; R i , R j are each independently selected from H, methyl, ethyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from C 1-2 alkyl, C 3-6 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, R8, R9in combination with the carbon to which they are attached form a cyclopropyl, cyclobutyl, cyclobutyl substituted with 1 or 2 F, or a 4-6 membered heterocycloalkyl containing 1 O, said 4-6 membered heterocycloalkyl is selected from a monocyclic or polycyclic saturated ring system, said polycyclic is selected from a spiro, bridged or fused ring; R7is selected from methyl, ethyl, -CF3, ethynyl, -C(O)NH2, -C(O)NH(CH3), triazolyl unsubstituted or substituted with 1 methyl or ethyl or isopropyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 28. The compound of claim 27, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R4is selected from 29. A compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized by: the compound is selected from the following compounds:

30. A pharmaceutical composition comprising a compound of any one of claims 1-29, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable auxiliary ingredient.

31. Use of a compound of any one of claims 1-29, a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 30 for the manufacture of a medicament for the treatment and / or amelioration and / or prevention of HBV infection.

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