Azabicyclic compounds as hepatitis B surface antigen inhibitors

Abstract

Provided are azabicyclic compounds as hepatitis B surface antigen inhibitors, specifically compounds of formula I', stereoisomers thereof, pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions containing the compounds, and uses thereof as drugs for treating hepatitis B virus infection.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to azabicyclic compounds as hepatitis B surface antigen inhibitors. The present invention specifically relates to a compound of formula I', its stereoisomers, its pharmaceutically acceptable salts, its preparation method, a pharmaceutical composition containing the compound, and its use as a drug for treating hepatitis B virus infection. Background Art

[0002] Hepatitis B virus (HBV) infection is currently one of the world's health problems, with approximately 400 million chronically infected people worldwide, who have a higher risk of cirrhosis and hepatocellular carcinoma. Currently, chronic hepatitis B cannot be cured but can only be controlled, mainly limited to two types of agents (interferon and nucleoside analogs / inhibitors of viral polymerase).

[0003] Hepatitis B surface antigen (HBsAg) quantification is a significant biomarker for prognosis and treatment response in chronic hepatitis B. Continuous exposure to HBsAg and other viral antigens can lead to HBV-specific T cell loss or progressive functional impairment. In addition, HBsAg has been reported to inhibit the function of immune cells such as monocytes, dendritic cells (DCs) and natural killer (NK) cells through direct interactions. However, HBsAg disappearance and seroconversion are rarely observed in chronically infected patients, which remain the goal of treatment. Current therapies such as nucleoside analogs are molecules that inhibit HBV DNA synthesis but do not reduce HBsAg levels. Existing studies have disclosed inhibitors targeting hepatitis B surface antigen, such as WO2016107832, WO2016177655, WO2018083106, etc.

[0004] This application synthesized a series of new compounds and studied them. Summary of the invention

[0005] The present application provides a compound of formula I', a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0006]

[0007] wherein at least one of X and Y is N, and the other is CH or N;

[0008] A is selected from 5-6 membered heteroaryl, said A optionally substituted by 1, 2 or 3 R 1 replace;

[0009] R 1 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 3-7 Cycloalkyl, 1-3 halogenated C 1-8Alkyl or 1-3 halogenated C 1-8 Alkoxy;

[0010] p is selected from 1, 2, 3 or 4;

[0011] L is selected from a single bond, -CO- or -SO2-;

[0012] R 2 is selected from 6-10 membered aryl, 3-8 membered heteroaryl containing 1-3 selected from N, O or S, or 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S, wherein R 2 Each independently optionally 1-4 R 3 replace;

[0013] The R 3 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 alkyl or a 3-8 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S; 1-8 Alkyl, -C 3-7 Cycloalkyl, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, -S(=O)C 1-6Alkyl or -S(=O)2C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Replace or generate 1-2 oxygen groups;

[0014] The R 4 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, or -SO2C 1-8 alkyl.

[0015] Another aspect of the present application provides a pharmaceutical composition, which includes the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, and optionally further includes a pharmaceutically acceptable excipient.

[0016] On the other hand, the present application provides use of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt in the preparation of a drug for treating hepatitis B virus infection. DETAILED DESCRIPTION

[0017] The present application provides a compound of formula I', a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0018]

[0019] wherein at least one of X and Y is N, and the other is CH or N;

[0020] A is selected from 5-6 membered heteroaryl, said A optionally substituted by 1, 2 or 3 R 1 replace;

[0021] R 1 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, halogen, C 3-7 Cycloalkyl, 1-3 halogenated C1-8 Alkyl or 1-3 halogenated C 1-8 Alkoxy;

[0022] p is selected from 1, 2, 3 or 4;

[0023] L is selected from a single bond, -CO- or -SO2-;

[0024] R 2 is selected from 6-10 membered aryl, 3-8 membered heteroaryl containing 1-3 selected from N, O or S, or 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S, wherein R 2 Each independently optionally 1-4 R 3 replace;

[0025] The R 3 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 alkyl, or a 3-8 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S; 1-8 Alkyl, -C 3-7 Cycloalkyl, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, -S(=O)C1-6 Alkyl or -S(=O)2C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Replace or generate 1-2 oxygen groups;

[0026] The R 4 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 Alkyl, or -SO2C 1-8 alkyl.

[0027] In some embodiments, X is N and Y is CH, X is CH and Y is N, or both X and Y are N. In some embodiments, both X and Y are N.

[0028] In some embodiments, A is selected from a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, and A is optionally substituted by 1, 2 or 3 R 1 In some embodiments, A is selected from in represents a single bond or a double bond, T is selected from C or N, U, V, W and Z are each independently selected from CH, N, O or S, optionally one of U, V and W is selected from a bond, and the A is optionally replaced by 1, 2 or 3 R 1 replace.

[0029] In some embodiments, A is selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazine, pyridazinyl or pyrimidinyl, and A is optionally substituted by 1, 2 or 3 R 1 In some embodiments, A is selected from pyridyl or pyrimidinyl, and A is optionally substituted by 1, 2 or 3 R 1 replace.

[0030] In some embodiments, U, V, W and Z are all CH, or U, V and W are CH and Z is N. In some embodiments, U, V and W are CH and Z is N. In some embodiments, one of U, V and W is selected from a bond, and the others are selected from CH, N, O or S.

[0031] In some embodiments, the R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, F, Cl, Br, C substituted with 1-3 F, Cl or Br 1-6 Alkyl, or 1-3 F, Cl or Br substituted C 1-6 In some embodiments, the R 1 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, F, Cl, Br, C substituted with 1-3 F, Cl or Br 1-4 Alkyl, or 1-3 F, Cl or Br substituted C 1-4 Alkoxy.

[0032] In some embodiments, p is selected from 2 or 3. In some embodiments, p is selected from 2. In some embodiments, p is selected from 3.

[0033] In some embodiments, L is selected from a single bond.

[0034] In some embodiments, the R 2 is selected from 6-8 membered aryl, 4-6 membered heteroaryl containing 1-3 selected from N, O or S, or 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from phenyl, naphthyl, 4-6 membered heteroaryl containing 1-2 selected from N, O or S, or 4-6 membered heterocycloalkyl containing 1-2 selected from N, O or S, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from phenyl, 4-6 membered heteroaryl containing 1-2 selected from N, or 4-6 membered heterocycloalkyl containing 1-2 selected from N or O, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from phenyl, pyridyl, or morpholinyl, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from pyridyl, said R 2 The substituents are as described in the present application.

[0035] In some embodiments, the R 3Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCO-C 1-6 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, or -NHCO-C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0036] In some embodiments, the R 3 Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCO-C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, or -NHCO-C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0037] In some embodiments, the R 3 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, azetidinyl, aziridine, azidine, or 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, wherein -C 1-4Alkyl, -C 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -OC 1-4 Alkyl, or -OC 3-6 The cycloalkyl groups are each independently optionally substituted with 1 to 3 R 4 The azetidinyl, aziridine, azidine, or 4-7 membered heterocycloalkyl containing 2 selected from N, O or S are each optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0038] In some embodiments, the R 3 Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCO-C 1-6 alkyl, or a 4-6 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, or -NHCO-C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4The 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0039] In some embodiments, the R 3 Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCO-C 1-4 alkyl, or a 4-6 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, or -NHCO-C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0040] In some embodiments, the R 3 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, OH, -OC 1-4Alkyl, -OC 3-6 Cycloalkyl, azetidinyl, azetidine, azopentyl, azohexyl, or a 4-6 membered heterocycloalkyl containing 2 selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, or -OC 3-6 The cycloalkyl groups are each independently optionally substituted with 1 to 3 R 4 The azetidinyl, aziridine, azidine, or 4-6 membered heterocycloalkyl containing 2 selected from N, O or S are each optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0041] In some embodiments, the R 3 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, -NHCO-C 1-8 alkyl, or a 3-8 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S; 1-8 Alkyl, -C 3-7 Cycloalkyl, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, or -NHCO-C 1-8 The alkyl groups are each independently optionally substituted with 1 to 3 R4 The 3-8 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0042] In some embodiments, the R 4 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2 or -NHCO-C 1-8 alkyl.

[0043] In some embodiments, the R 4 Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCO-C 1-6 Alkyl, or -S(O)2C 1-6 alkyl.

[0044] In some embodiments, the R 4 Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, -NHCO-C 1-4 Alkyl, or -S(O)2C 1-4 alkyl.

[0045] In some embodiments, the R 4 Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2 or -NHCO-C 1-6 alkyl.

[0046] In some embodiments, the R 4 Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2 or -NHCO-C 1-4 alkyl.

[0047] In some embodiments, the R 4 Selected from F, Cl, Br, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, or -OC 3-6 Cycloalkyl.

[0048] In some embodiments, the R 4 Selected from F, -OCH3, cyclopropyl, or -S(O)2CH3.

[0049] In some embodiments, the R 4 Selected from halogen, -NO2, -CN, -C 1-8 Alkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-8 Alkyl, -OC 3-7 Cycloalkyl, -NH2, -NHC 1-8 Alkyl, -N(C 1-8 Alkyl)2, -SH, -SC 1-8 Alkyl, -SC 3-7 Cycloalkyl, -CO-C 1-8 Alkyl, -COO-C 1-8 Alkyl, -OCO-C 1-8 Alkyl, -CONHC 1-8 Alkyl, -CON(C 1-8 Alkyl)2, or -NHCO-C 1-8 alkyl.

[0050] In some embodiments, the R 4 Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -OCO-C 1-6 Alkyl, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, or -NHCO-C 1-6 alkyl.

[0051] In some embodiments, the R 4Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -CO-C 1-4 Alkyl, -COO-C 1-4 Alkyl, -OCO-C 1-4 Alkyl, -CONHC 1-4 Alkyl, -CON(C 1-4 Alkyl)2, or -NHCO-C 1-4 alkyl.

[0052] In some embodiments, the R 4 Selected from F, Cl, Br, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, or -OC 3-6 In some embodiments, R 4 Selected from F, -OCH3, or cyclopropyl.

[0053] In some embodiments, the R 2 Selected from phenyl, The substituents of the group are as described in the present application. In some embodiments, the R 2 Selected from phenyl or The substituents of the groups are as described herein.

[0054] In some embodiments, the R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3, -SCH2CH3, -S(=O)CH2CH3, -S(=O)2CH2CH3,

[0055] In some embodiments, the R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3,

[0056] In some embodiments, the R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3, -SCH2CH3, -S(=O)CH2CH3, -S(=O)2CH2CH3, or

[0057] In some embodiments, the R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3,

[0058] In some embodiments, the R 2 Selected from

[0059] In some embodiments, the R 2 Selected from

[0060] In some embodiments, the R 2 Selected from

[0061] In some aspects, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0062] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula II', its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0063]

[0064] in, represents a single bond or a double bond;

[0065] T is selected from C or N;

[0066] U, V, W and Z are each independently selected from CH, N, O or S, optionally one of U, V and W is selected from a bond;

[0067] q is selected from 0, 1, 2 or 3;

[0068] p, X, Y, R 1 , L, or R 2 Definitions are as described in this application.

[0069] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula III', its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0070] Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0071] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula IV', its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0072] Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0073] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula V', its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0074] Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0075] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula VI', its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0076] Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0077] In some embodiments, the compound of formula I', its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0078] Among them, A, X, Y, L and R 2 As defined in this application.

[0079] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0080]

[0081] in, represents a single bond or a double bond;

[0082] T is selected from C or N;

[0083] U, V, W and Z are each independently selected from CH, N, O or S, optionally one of U, V and W is selected from a bond;

[0084] q is selected from 0, 1, 2 or 3;

[0085] X, Y, R 1 , L, R 2 , R 3 , R 4 Definitions are as described in this application.

[0086] In some embodiments, U, V, W and Z are all CH, or U, V and W are CH and Z is N. In some embodiments, U, V and W are CH and Z is N.

[0087] In some embodiments, one of U, V and W is selected from a bond, and the others are selected from CH, N, O or S.

[0088] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula III Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0089] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0090] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula V Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0091] In some embodiments, the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula VI Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0092] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VII Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0093] In some embodiments, the structural unit of the compound of formula I, the compound of formula II, the compound of formula III, the compound of formula IV, the compound of formula V, the compound of formula VI, the compound of formula VII, the stereoisomers thereof, or the pharmaceutically acceptable salts thereof The stereoisomers are selected from

[0094] In some embodiments, the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula IB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0095] In some embodiments, the compound of formula II, its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula IIA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula IIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0096] In some embodiments, the compound of formula III, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IIIA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula IIIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0097] In some embodiments, the compound of formula IV, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula IVA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula IVB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0098] In some embodiments, the compound of formula V, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula VB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0099] In some embodiments, the compound of formula VI, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VIA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula VIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0100] In some embodiments, the compound of formula VII, its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from a compound of formula VIIA Its stereoisomers, or pharmaceutically acceptable salts thereof or compounds of formula VIIB Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0101] The present application provides a compound of formula I', a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from a compound of formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0102] Among them, rings A, X, Y, L and R 2 The definition of is the same as before.

[0103] In some embodiments, A is selected from a 6-membered heteroaryl group containing 1-4 atoms selected from N, O or S, and A is optionally substituted by 1, 2 or 3 R 1 In some embodiments, A is selected from a 6-membered heteroaryl group containing 1-2 N, and A is optionally substituted by 1, 2 or 3 R 1 replace.

[0104] In some embodiments, A is selected from Z is selected from CH or N, and A is optionally replaced by 1, 2 or 3 R 1 replace.

[0105] In some embodiments, A is selected from pyridinyl or pyrimidinyl.

[0106] In some embodiments, the R 2 is selected from 6-8 membered aryl or 5-8 membered heteroaryl containing 1-3 selected from N, O or S, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from phenyl or 5-6 membered heteroaryl containing 1-2 selected from N, O or S, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from a 5-6 membered heteroaryl group containing 1-2 N atoms, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from a 6-membered heteroaryl group containing 1-2 N atoms, wherein R 2 The substituents are as described in the present application. In some embodiments, the R 2 is selected from pyridyl, said R 2 The substituents are as described in the present application.

[0107] In some embodiments, the R 3 Selected from F, Cl, Br, -NO2, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, or -S(=O)2C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

[0108] In some embodiments, the R 3 Selected from F, Cl, Br, -NO2, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, -S(=O)C 1-4 Alkyl, or -S(=O)2C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4Substitution or occurrence of 1-2 oxo groups.

[0109] In some embodiments, the R 3 Selected from F, Cl, Br, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, azetidinyl, or a 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, wherein the -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 alkyl, azetidinyl, or 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, each independently optionally substituted by 1-3 R 4 replace.

[0110] In some embodiments, the R 4 Selected from F, Cl, Br, -C 1-4 Alkyl, -OC 1-6 Alkyl, or -S(O)2C 1-4 alkyl.

[0111] In some embodiments, the R 4 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, or -S(O)2C 1-4 alkyl.

[0112] In some embodiments, the R 4 Selected from F, -OCH3, or -S(O)2CH3.

[0113] In some embodiments, the R 2 Selected from The substituents of the groups are as described herein.

[0114] In some embodiments, the R 3 Selected from F, -N(CH3)2, -OCH3, Cl, -CF3, -SCH2CH3, -S(=O)CH2CH3, or -S(=O)2CH2CH3.

[0115] In some embodiments, the R 3 Selected from F, -N(CH3)2, -OCH3,

[0116] In some embodiments, the R2 Selected from

[0117] In some embodiments, the R 2 Selected from

[0118] In some embodiments, the compound of formula (1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (1-2), its stereoisomer, or a pharmaceutically acceptable salt thereof,

[0119]

[0120] in, represents a single bond or a double bond;

[0121] T is selected from C or N;

[0122] U, V, W and Z are each independently selected from CH, N, O or S, optionally one of U, V and W is selected from a bond;

[0123] q is selected from 0, 1, 2 or 3;

[0124] X, Y, R 1 , L, R 2 , R 3 , R 4 Definitions are as described in this application.

[0125] In some embodiments, U, V, W and Z are all CH, or U, V and W are CH and Z is N. In some embodiments, U, V and W are CH and Z is N.

[0126] In some embodiments, one of U, V and W is selected from a bond, and the others are selected from CH, N, O or S.

[0127] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (1-3) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0128] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (1-4) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0129] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (1-5) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0130] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (1-6) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0131] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compounds of formula (1-7) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0132] In some embodiments, the structural unit of the compound of formula (1), the compound of formula (1-2), the compound of formula (1-3), the compound of formula (1-4), the compound of formula (1-5), the compound of formula (1-6), the compound of formula (1-7), their stereoisomers, or their pharmaceutically acceptable salts is The stereoisomers are selected from

[0133] In some embodiments, the compound of formula (1), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0134] In some embodiments, the compound of formula (1-2), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-2A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-2B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0135] In some embodiments, the compound of formula (1-3), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-3A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-3B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0136] In some embodiments, the compound of formula (1-4), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-4A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-4B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0137] In some embodiments, the compound of formula (1-5), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-5A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-5B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0138] In some embodiments, the compound of formula (1-6), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-6A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-6B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0139] In some embodiments, the compound of formula (1-7), its stereoisomer, or its pharmaceutically acceptable salt is selected from the compound of formula (1-7A) Its stereoisomer, or its pharmaceutically acceptable salt or compound of formula (1-7B) Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the groups are defined as described in the present application.

[0140] In some embodiments, the present application provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0141]

[0142]

[0143]

[0144] In some embodiments, the present application provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] Another aspect of the present application provides a pharmaceutical composition, which includes the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, and optionally further includes a pharmaceutically acceptable excipient.

[0151] On the other hand, the present application provides the use of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating hepatitis B virus infection.

[0152] On the other hand, the present application provides use of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment of hepatitis B virus infection.

[0153] Another aspect of the present application provides a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating hepatitis B virus infection.

[0154] On the other hand, the present application provides a method for treating hepatitis B virus infection, comprising administering a therapeutically effective amount of the compound of the present application, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of treatment.

[0155] The compound of the present application has good anti-hepatitis B virus activity.

[0156] definition

[0157] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0158] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0159] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0160] The term oxo (ie, =O) refers to an oxygen atom connected to the substituted atom by a double bond. In non-limiting examples, oxo can occur on a C atom, such as forming -CO-; oxo can also occur on an S atom, such as forming -SO- or -SO2-.

[0161] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0162] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C 1-3 It means that the group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0163] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition in each case is independent. For example, if a group is substituted by 2 Rs, each R has an independent option. Or, for example, if multiple groups are substituted by a certain R, each group substituted by R is independent of each other.

[0164] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0165] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L' in A-L'-Z represents a covalent bond, it means that the structure is actually AZ.

[0166] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene. For example, the structural unit Including but not limited to

[0167] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0168] The term "alkyl" refers to a group of the formula C n H 2n+1The term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0169] The term "alkoxy" refers to an -O-alkyl group.

[0170] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl groups include cyclopropyl and cyclobutyl.

[0171] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 8 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferably, the monocyclic heterocycloalkyl has 5 or 6 ring atoms.

[0172] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0173] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 3 to 8 ring, especially a 5 to 8 ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0174] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by the reorganization of some bonding electrons.

[0175] Certain compounds of the present application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included within the scope of the present application.

[0176] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0177] The compound of the present application can exist in specific geometric isomer or stereoisomer form. The present application envisions all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which belong to the scope of the present application. Other asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0178] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., the formation of a carbamate from an amine).

[0179] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0180] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0181] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.

[0182] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0183] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0184] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0185] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0186] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0187] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0188] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of a disease, i.e., arrests its development; or (b) alleviates the symptoms of a disease, i.e., causes regression of the disease or symptoms.

[0189] The term "effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0190] In the present application, the term "individual" includes humans and animals, for example, mammals (such as primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep and birds, etc.).

[0191] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0192] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0193] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0194] An important consideration in synthetic route planning in the art is to select a suitable protecting group for a reactive functional group (such as the amino group in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein in their entirety.

[0195] In some embodiments, the compounds of the present application, such as compounds of Formula IVA and IVB, can be prepared by a person skilled in the art of organic synthesis by the following method:

[0196]

[0197] Among them, Z or R 2 The definition is the same as in this application.

[0198] This application uses the following abbreviations:

[0199] DMF stands for N,N-dimethylformamide; DCM stands for dichloromethane; MeOH stands for methanol; Pd2(dba)3 stands for tris(benzylideneacetone)dipalladium; EA stands for ethyl acetate; Ru-phos stands for 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl; DMFDMA stands for N-dimethylformamide dimethyl acetal; EtONa stands for sodium ethoxide; TEA is triethylamine.

[0200] Example

[0201] For the sake of clarity, the present invention is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0202] Example 1 (1_A and 1_B)

[0203]

[0204] Step A: Add compound 1-1 (5g), N,N-dimethylformamide dimethyl acetal (3.3g), and DMF (50mL) to the reaction bottle in sequence, heat to 90°C and react for 3 hours, then cool to room temperature. After removing the solvent by rotary evaporation, add 2-pyrimidinecarboxamidine hydrochloride (3.99g), sodium ethoxide (3.43g), and anhydrous ethanol (50mL) to the reaction bottle and reflux for 3 hours. After the reaction solution is dried by rotary evaporation, 100mL of water is added and extracted with ethyl acetate (100mL*3). Combine the organic layers, wash the organic layers with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The crude product is separated by silica gel column chromatography (DCM:MeOH=100:3) to obtain compound 1-2 (3.4g). MS (ESI + ,[M+Na] + )m / z:334.4.

[0205] Step B: Compound 1-2 (3.4 g), potassium hydroxide (4.9 g), methanol (15 mL) and water (15 mL) were added to a microwave tube in sequence and reacted at 100°C for 1 hour. The reaction solution was diluted with 50 mL of water and the pH was adjusted to 6 with dilute hydrochloric acid. After the solvent was removed by rotary evaporation, tetrahydrofuran (80 mL) and triethylamine (10 mL) were added. After stirring at room temperature for 1 hour, the mixture was filtered and the filtrate was dried to obtain compound 1-3 (1.3 g). MS (ESI + ,[M+Na] + )m / z:262.4.

[0206] Step C: Compound 1-3 (500 mg), 2,4,6-trifluoropyridine (278 mg), cesium carbonate (2.042 g), and DMF (20 mL) were added to the reaction bottle in sequence. After heating to 80°C for 8 hours, the reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was separated by C18 column chromatography (acetonitrile: water = 40:60) to obtain Example 1_B compound (100 mg) and Example 1_A compound (80 mg).

[0207] Embodiment 1_A: 1H NMR (500MHz, DMSO-d6) δ8.97(s,1H),8.96(s,1H),8.86(s,1H),7.61(t,J=4.9Hz,1H),6.80(d,J=11.0Hz,1H),6.34(d,J=8.7Hz,1H),5.45(d,J=5. 9Hz,1H),4.97-4.78(m,1H),3.37(dd,J=18.1,4.7Hz,1H),2.87(d,J=18. 3Hz,1H),2.44-2.26(m,2H),2.06-2.01(m,1H),1.96-1.85(m,1H).MS(ESI + ,[M+Na] + )m / z:375.4.

[0208] Embodiment 1_B: 1 H NMR (500MHz, DMSO-d6) δ8.97(s,1H),8.96(s,1H),8.86(s,1H),7.62(t,J=4.9Hz,1H),6.68(s,2H),5.44(d,J=5.9Hz,1H),4.89(t,J =6.0Hz,1H),3.38(dd,J=18.3,4.6Hz,1H),2.88(d,J=18.6Hz,1H),2.45-2.28(m,2H),2.09-2.01(m,1H),1.98-1.89(m,1H).MS(ESI + ,[M+Na] + )m / z:375.4.

[0209] Example 2 (2_A and 2_B)

[0210]

[0211] Compound 1_A (50 mg), 40% dimethylamine aqueous solution (0.8 mL), DMF (1 mL), and cesium carbonate (1.5 g) were added to a microwave tube in sequence. After microwave heating to 90° C. for 1 hour, the reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was separated by high-pressure preparative liquid separation (YMC-TriartPrepC18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 2 (40 mg).

[0212] Embodiment 2: 1H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.8Hz,2H),8.83(s,1H),7.61(t,J=4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J=5.6H z,1H),4.81(t,J=6.3Hz,1H),2.90(s,6H),2.76(d,J=18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI + ,[M+Na] + )m / z:400.5.

[0213] Compound 2 was separated by high pressure preparative liquid separation (CHIRALART Cellulose-SB column; ethanol:n-hexane=20:80) to obtain Example 2_A (15 mg) and Example 2_B (15 mg).

[0214] Embodiment 2_A: 1 H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.8Hz,2H),8.83(s,1H),7.61(t,J=4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J=5.6H z,1H),4.81(t,J=6.3Hz,1H),2.90(s,6H),2.76(d,J=18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI + ,[M+Na] + )m / z:400.5.

[0215] Embodiment 2_B: 1 H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.8Hz,2H),8.83(s,1H),7.61(t,J=4.9Hz,1H),5.84(s,1H),5.62(s,1H),5.36(d,J=5.6H z,1H),4.81(t,J=6.3Hz,1H),2.90(s,6H),2.76(d,J=18.5Hz,1H),2.40–2.24(m,2H),2.01–1.81(m,2H),1.23(s,1H).MS(ESI + ,[M+Na] + )m / z:400.5.

[0216] Example 3

[0217]

[0218] Example 1_B (50 mg), 40% dimethylamine aqueous solution (0.8 mL), DMF (1 mL), cesium carbonate (1.5 g) were added to the microwave tube in sequence, and the reaction solution was slowly poured into 50 mL of water after microwave heating to 90°C for 1 hour, extracted with ethyl acetate (3*20 mL), the organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product was separated by high pressure preparative liquid phase separation (YMC-TriartPrepC18-S column; acetonitrile: water = 30:70) to obtain Example 3 (14 mg). MS (ESI + ,[M+Na] + )m / z:400.5.

[0219] Example 4 (4_A and 4_B)

[0220]

[0221]

[0222] According to Example 2, Example 4 (50 mg) was prepared by substituting 3-methoxyazetidine hydrochloride for the aqueous dimethylamine solution.

[0223] Embodiment 4: 1 H NMR(500MHz,DMSO-d6)δ8.95(d,J=4.8Hz,2H),8.82(s,1H),7.61(t,J=4.9Hz,1H),5.65 (d,J=1.6Hz,1H),5.37(d,J=1.4Hz,1H),5.32(d,J=5.8Hz,1H),4.77(t,J=6.0Hz,1H),4. 31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H), 2.77(d,J=18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI + [M+H] + )m / z:420.2.

[0224] Example 4 was separated by high pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol:n-hexane=20:80) to obtain Example 4_A (20 mg) and Example 4_B (20 mg).

[0225] Embodiment 4_A: 1 H NMR(500MHz,DMSO-d6)δ8.95(d,J=4.8Hz,2H),8.82(s,1H),7.61(t,J=4.9Hz,1H),5.65 (d,J=1.6Hz,1H),5.37(d,J=1.4Hz,1H),5.32(d,J=5.8Hz,1H),4.77(t,J=6.0Hz,1H),4. 31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H), 2.77(d,J=18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI + [M+H] + )m / z:420.2.

[0226] Embodiment 4_B: 1 H NMR(500MHz,DMSO-d6)δ8.95(d,J=4.8Hz,2H),8.82(s,1H),7.61(t,J=4.9Hz,1H),5.65 (d,J=1.6Hz,1H),5.37(d,J=1.4Hz,1H),5.32(d,J=5.8Hz,1H),4.77(t,J=6.0Hz,1H),4. 31-4.25(m,1H),4.08-4.01(m,2H),3.71-3.64(m,2H),3.41-3.37(m,1H),3.21(s,3H), 2.77(d,J=18.6Hz,1H),2.39-2.20(m,2H),2.00-1.92(m,1H),1.84-1.88(m,1H).MS(ESI + [M+H] + )m / z:420.2.

[0227] Example 5 (5_A and 5_B)

[0228]

[0229]

[0230] According to Example 2, Example 5 (50 mg) was prepared by substituting 3-fluoroazetidine hydrochloride for the aqueous dimethylamine solution.

[0231] Embodiment 5: 1H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.76(s,1H),7.41(t,J=4.9Hz,1 H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J=1.5Hz,1H),5.25(d,J=5.8Hz,1H ),4.83(t,J=6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2. 94(d,J=18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI + [M+Na] + )m / z:430.3.

[0232] Compound 5 was separated by high pressure preparative liquid separation (CHIRALART Cellulose-SB column; ethanol:n-hexane=20:80) to obtain Example 5_A (20 mg) and Example 5_B (20 mg).

[0233] Embodiment 5_A: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.76(s,1H),7.41(t,J=4.9Hz,1 H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J=1.5Hz,1H),5.25(d,J=5.8Hz,1H ),4.83(t,J=6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2. 94(d,J=18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI + [M+Na] + )m / z:430.3.

[0234] Embodiment 5_B: 1H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.76(s,1H),7.41(t,J=4.9Hz,1 H),5.47-5.43(m,1H),5.35-5.34(m,1H),5.28(d,J=1.5Hz,1H),5.25(d,J=5.8Hz,1H ),4.83(t,J=6.1Hz,1H),4.23-4.09(m,2H),4.08-3.92(m,2H),3.73-3.60(m,1H),2. 94(d,J=18.6Hz,1H),2.49-2.39(m,2H),2.06-1.99(m,1H),1.93-1.85(m,1H).MS(ESI + [M+Na] + )m / z:430.3.

[0235] Example 6

[0236]

[0237] According to Example 2, 3-methoxyazacyclopentane hydrochloride was used to replace the dimethylamine aqueous solution, and the resulting crude product was separated by high-pressure preparative liquid phase separation (YMC-TriartPrepC18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 6 (11.8 mg).

[0238] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.75(d,J=1.5Hz,1H),7.40(t,J=4.8 Hz,1H),5.48-5.44(m,1H),5.40(d,J=1.5Hz,1H),5.24(t,J=6.1Hz,1H),4.85(s,1H),4.0- 4.03(m,1H),3.72-3.67(m,1H),3.41-3.35(m,2H),3.34(d,J=3.1Hz,3H),3.38-3.24(m,2H ),2.93(d,J=18.6Hz,1H),2.51-2.40(m,2H),2.17-2.04(m,2H),2.00-1.83(m,2H).MS(ESI + [M+Na] + )m / z:456.4.

[0239] Example 7

[0240]

[0241] According to Example 2, isothiazolidine-1,1-dioxide was used to replace the aqueous dimethylamine solution, and the obtained crude product was separated by high pressure preparative liquid phase separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 7 (29 mg).

[0242] 1 H NMR(500MHz,Chloroform-d)δ8.98(d,J=4.8Hz,2H),8.77(s,1H),7.39(t,J=4.8Hz,1H),6.38(s,1H),5.85(d,J=1.6Hz,1H),5.32(d,J=6.0Hz, 1H),4.85(t,J=6.0Hz,1H),3.71(t,J=6.7Hz,3H),3.37(t,J=7.4Hz,2H),2.98(d,J=18.7Hz,1H),2.55-2.38(m,4H),2.10-1.84(m,2H).MS(ESI + [M+H] + )m / z:454.3.

[0243] Example 8

[0244]

[0245] Compound 1-3 (200 mg), 5-bromo-1,2-difluoro-3-methoxybenzene (224 mg), Pd2(dba)3 (38 mg), Ru-phos (20 mg), sodium tert-butoxide (241 mg), 1,4-dioxane (5 mL) were added to the microwave tube in sequence, and the atmosphere was replaced with nitrogen and microwaved at 100°C for 2 hours. 10 mL of water was added to the reaction solution, and EA was extracted (20 mL*2). The organic phases were combined, concentrated, and separated by silica gel column chromatography (DCM:MeOH=100:5) to obtain Example 8 (7 mg).

[0246] 1 H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.9Hz,2H),8.87(s,1H),7.60(t,J=4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J=5.7Hz,1H),4.73(t,J =5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J=18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI + ,[M+Na] +)m / z:404.4.

[0247] Example 9

[0248]

[0249] According to Example 8, 1-bromo-3-methoxy-5-(trifluoromethyl)benzene was used to replace 5-bromo-1,2-difluoro-3-methoxybenzene to prepare Example 9 (3.3 mg). MS (ESI + ,[M+Na] + )m / z:414.5.

[0250] Example 10

[0251]

[0252] According to Example 8, 1-bromo-3-fluoro-5-methoxybenzene was used instead of 5-bromo-1,2-difluoro-3-methoxybenzene to obtain 10 (20 mg). MS (ESI + [M+H] + )m / z:364.5.

[0253] Example 11 (11_A and 11_B)

[0254]

[0255] Example 8 was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol:n-hexane=20:80) to obtain Example 11_A (15 mg) and Example 11_B (15 mg).

[0256] Example 11_A: 1 H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.9Hz,2H),8.87(s,1H),7.60(t,J=4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J=5.7Hz,1H),4.73(t,J =5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J=18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI + ,[M+Na] + )m / z:404.4.

[0257] Embodiment 11_B: 1H NMR (500MHz, DMSO-d6) δ8.95(d,J=4.9Hz,2H),8.87(s,1H),7.60(t,J=4.8Hz,1H),6.60-6.50(m,2H),5.21(d,J=5.7Hz,1H),4.73(t,J =5.8Hz,1H),3.82(s,3H),3.39-3.34(m,1H),2.74(d,J=18.7Hz,1H),2.41-2.26(m,2H),2.03-1.95(m,1H),1.94-1.86(m,1H).MS(ESI + ,[M+Na] + )m / z:404.4.

[0258] Example 12

[0259]

[0260] According to Example 2, cyclopropylmethylamine was used to replace the dimethylamine aqueous solution, and the resulting crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 12 (15 mg).

[0261] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.75(s,1H),7.40(t,J=4.8Hz,1H ),5.54(s,1H),5.44(s,1H),5.20(d,J=5.6Hz,1H),4.82(t,J=5.9Hz,1H),4.31(s,1H) ,3.68(dd,J=18.5,5.0Hz,1H),2.99–2.86(m,3H),2.58–2.27(m,2H),2.14–1.97(m,1H ),1.95–1.83(m,1H),1.08–0.96(m,1H),0.70–0.43(m,2H),0.35–0.09(m,2H).MS(ESI + ,[M+H] + )m / z:404.5.

[0262] Example 13

[0263]

[0264] According to Example 2, 2-methoxyethylamine was used to replace the dimethylamine aqueous solution, and the resulting crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 13 (35 mg).

[0265] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.74(s,1H),7.39(t,J=4.8Hz,1H),5. 58(d,J=1.6Hz,1H),5.46(d,J=1.6Hz,1H),5.21(d,J=5.7Hz,1H),4.81(t,J=6.0Hz,1H),4. 52(t,J=5.5Hz,1H),3.77–3.62(m,1H),3.53(t,J=5.1Hz,2H),3.36(s,3H),3.29–3.18(m,2 H),2.92(d,J=18.6Hz,1H),2.57–2.33(m,2H),2.09–1.96(m,1H),1.94–1.80(m,1H).MS(ESI + ,[M+H] + )m / z:408.4.

[0266] Embodiment 14

[0267]

[0268] According to Example 2, morpholine was used to replace the aqueous dimethylamine solution, and the resulting crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 14 (32 mg).

[0269] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.76(s,1H),7.40(t,J=4.8Hz,1H),5.76(s,1H),5.65(s,1H),5.26(d,J=5.8Hz,1H),5.05–4.73(m,1 H),3.78(t,J=4.9Hz,4H),3.76–3.58(m,1H),3.30–3.10(m,4H),2.94(d,J=1 8.6Hz,1H),2.58–2.38(m,2H),2.16–2.00(m,1H),2.00–1.81(m,1H).MS(ESI + ,[M+Na] + )m / z:442.1.

[0270] Embodiment 15

[0271]

[0272] According to Example 2, 2-methoxyethanol was used to replace the dimethylamine aqueous solution, and the resulting crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 15 (30 mg).

[0273] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.75(s,1H),7.40(t,J=4.8Hz,1H),6.00(s,1H),5.79(d,J=1.7Hz,1H),5.24(d,J=5.8Hz,1H),4.81 (t,J=6.1Hz,1H),4.23–3.95(m,2H),3.75–3.59(m,3H),3.42(s,3H),3.03–2 .92(m,1H),2.57–2.37(m,2H),2.11–1.97(m,1H),1.95–1.84(m,1H).MS(ESI + ,[M+Na] + )m / z:431.1.

[0274] Example 16

[0275]

[0276] According to Example 8, using 1-bromo-3-chloro-5-fluorobenzene instead of 5-bromo-1,2-difluoro-3-methoxybenzene, Example 16 (15 mg) was prepared.

[0277] 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.78(s,1H),7.40(t,J=4.8Hz,1H),6.57(s,1H),6.51–6.34(m,2H),4.88(d,J=5.9Hz ,1H),4.66–4.54(m,1H),3.69–3.51(m,1H),2.93(dd,J=18.7,1.0Hz,1H),2.64–2.37(m,2H),2.12–2.04(m,1H),1.99–1.86(m,1H).MS(ESI + [M+H] + )m / z:368.1.

[0278] Embodiment 17

[0279]

[0280] Step A: According to step A of Example 1, 2-pyridinecarboxamidine hydrochloride was used instead of 2-pyrimidinecarboxamidine hydrochloride to prepare compound 17-2. MS (ESI + ,[M+H] + )m / z:311.4.

[0281] Step B: According to step B of Example 1, compound 17-2 was used to replace compound 1-2 to prepare compound 17-3. MS (ESI + ,[M+Na] + )m / z:262.4.

[0282] Step C: According to step C of Example 1, compound 17-3 was used to replace compound 1-3 to prepare compound 17-4. MS (ESI + [M+H] + )m / z:352.1.

[0283] Step D: Compound 17-4 (200 mg), 3-fluoroazetidine hydrochloride (200 mg), cesium carbonate (700 mg), and DMF (1 mL) were added to a microwave tube in sequence. The mixture was heated to 90°C in a microwave for 1 hour, and then the reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was separated by high-pressure preparative liquid separation (YMC-Triart PrepC18-S column; acetonitrile: water = 30:70) to obtain Example 17 (40 mg).

[0284] 1H NMR(500MHz,Chloroform-d)δ8.80(d,J=5.0Hz,1H),8.64(s,1H),8.42(d,J=8.0Hz,1H),7.82(t, J=7.8,6.5,1.9Hz,1H),7.36(t,J=8.8,4.5,1.9Hz,1H),5.34(s,1H),5.27(s,1H),5.20(d,J=5.9H z,1H),4.84–4.79(m,1H),4.24–4.06(m,2H),4.07–3.93(m,2H),3.66–3.58(m,1H),3.49(d,J=5. 2Hz,1H),2.87(d,J=18.5Hz,1H),2.52–2.35(m,2H),2.06–1.96(m,1H),1.92–1.83(m,1H).MS(ESI + [M+H] + )m / z:407.2.

[0285] Embodiment 18

[0286]

[0287] According to Example 17, in step D, 2-methoxyethanol was used instead of 3-fluoroazetidine hydrochloride, and the obtained crude product was separated by high pressure preparative liquid phase (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 18 (130 mg).

[0288] 1 H NMR(500MHz,Chloroform-d)δ8.80(ddd,J=4.8,1.8,0.9Hz,1H),8.64(s,1H),8.42(d,J=8.0Hz, 1H),7.82(td,J=7.7,1.8Hz,1H),7.39–7.32(m,1H),5.99(s,1H),5.78(d,J=1.7Hz,1H),5.20(d ,J=5.9Hz,1H),4.80(t,J=6.2Hz,1H),4.10–4.03(m,2H),3.73–3.67(m,2H),3.64–3.57(m,1H), 3.42(s,3H),2.91-2.85(m,1H),2.51–2.35(m,2H),2.07–1.97(m,1H),1.92–1.82(m,1H).MS(ESI + [M+H] + )m / z:408.1.

[0289] Embodiment 19

[0290]

[0291] According to Example 17, in step D, 3-fluoroazetidine hydrochloride was replaced with aqueous dimethylamine solution, and the obtained crude product was separated by high pressure preparative liquid phase (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 19 (120 mg).

[0292] 1 H NMR(500MHz,Chloroform-d)δ8.80(ddd,J=4.8,1.8,0.9Hz,1H),8.64(s,1H),8.42(d,J =7.9Hz,1H),7.82(td,J=7.8,1.8Hz,1H),7.36(ddd,J=7.5,4.7,1.2Hz,1H),5.57(s,1H) ,5.50(s,1H),5.21(d,J=5.8Hz,1H),4.84(t,J=6.2Hz,1H),3.70–3.62(m,1H),2.92(s, 6H),2.90–2.81(m,1H),2.51–2.37(m,2H),2.04–1.96(m,1H),1.90–1.83(m,1H).MS(ESI + [M+H] + )m / z:377.1.

[0293] Example 20 (20_A and 20_B)

[0294]

[0295] According to Example 2, Example 20 (80 mg) was prepared by substituting 2-methoxy-N-methylethylamine for the aqueous dimethylamine solution.

[0296] Embodiment 20: 1 H NMR(500MHz,Chloroform-d)δ8.98(d,J=4.8Hz,2H),8.75(s,1H),7.39(t,J=4.8Hz,1H),5.62(s,1H),5.52(s,1H),5.25(d,J=5.9Hz,1H),4.91–4.82(m ,1H),3.70(dd,J=18.6,4.9Hz,1H),3.51–3.37(m,4H),3.31(s,3H),2.98–2 .89(m,4H),2.54–2.38(m,2H),2.08–1.98(m,1H),1.95–1.84(m,1H).MS(ESI +[M+H] + )m / z:422.5.

[0297] Example 20 was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol:n-hexane=20:80) to obtain Example 20_A (35 mg) and Example 20_B (35 mg).

[0298] Example 20_A: 1 H NMR(500MHz,Chloroform-d)δ8.98(d,J=4.8Hz,2H),8.75(s,1H),7.39(t,J=4.8Hz,1H),5.62(s,1H),5.52(s,1H),5.25(d,J=5.8Hz,1H),4.84(t,J=6.1H z,1H),3.70(dd,J=18.6,5.1Hz,1H),3.52–3.39(m,4H),3.31(s,3H),2.98–2 .84(m,4H),2.56–2.38(m,2H),2.09–1.96(m,1H),1.96–1.82(m,1H).MS(ESI + [M+H] + )m / z:422.5.

[0299] Example 20_B: 1 H NMR(500MHz,Chloroform-d)δ8.98(d,J=4.8Hz,2H),8.75(s,1H),7.39(t,J=4.8Hz,1H),5.62(t,J=1.6Hz,1H),5.52(t,J=1.4Hz,1H),5.25(d,J=5.8Hz,1H ),4.84(t,J=6.1Hz,1H),3.83–3.61(m,1H),3.57–3.38(m,4H),3.31(s,3H), 2.94(s,4H),2.54–2.31(m,2H),2.15–1.95(m,1H),1.95–1.84(m,1H).MS(ESI + [M+H] + )m / z:422.5.

[0300] Example 21 (21_A and 21_B)

[0301]

[0302] According to Example 2, ethanethiol was used instead of the aqueous dimethylamine solution to prepare Example 21 (70 mg).

[0303] Embodiment 21: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.77(s,1H),7.40(t,J=4.8H z,1H),6.25(s,1H),6.04(s,1H),5.29(d,J=6.0Hz,1H),4.95–4.76(m,1H),3.65( ddd,J=18.7,5.3,1.7Hz,1H),2.98(d,J=18.6Hz,1H),2.93(q,J=7.4Hz,2H),2.59 –2.35(m,2H),2.12–1.97(m,1H),1.97–1.83(m,1H),1.33(t,J=7.4Hz,3H).MS(ESI + [M+H] + )m / z:395.1.

[0304] Example 21 was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol:n-hexane=20:80) to obtain Example 21_A (30 mg) and Example 21_B (30 mg).

[0305] Example 21_A: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.77(s,1H),7.40(t,J=4 .8Hz,1H),6.25(s,1H),6.05(s,1H),5.29(d,J=6.0Hz,1H),4.83(t,J=6.2Hz,1 H),3.75–3.53(m,1H),2.98(d,J=18.6Hz,1H),2.93(q,J=7.4Hz,2H),2.59–2. 34(m,2H),2.10–1.99(m,1H),1.96–1.83(m,1H),1.33(t,J=7.4Hz,3H).MS(ESI + [M+H] + )m / z:395.1.

[0306] Example 21_B: 1H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.9Hz,2H),8.77(s,1H),7.39(t,J=4.8Hz,1H),6.25(s,1H),6.04(s,1H),5.29(d,J=6.0Hz,1H),4.83 (t,J=6.2Hz,1H),3.70–3.59(m,1H),3.07–2.78(m,3H),2.57–2.37(m,2H),2.19–1.96(m,1H),1.96–1.77(m,1H),1.33(t,J=7.4Hz,3H).MS(ESI + [M+H] + )m / z:395.1.

[0307] Example 22 (22_A and 22_B)

[0308]

[0309] Example 21 (120 mg) and 20 mL of dichloromethane were added to the eggplant-shaped bottle in sequence, and m-chloroperbenzoic acid (68 mg) was added under ice bath. After reacting at 0°C for 1 hour, the reaction solution was slowly poured into 50 mL of saturated NaHCO3 aqueous solution, and extracted with dichloromethane (50 mL*3). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (DCM:MeOH=100:3) to obtain Example 22 compound (127 mg).

[0310] Embodiment 22: 1 H NMR(500MHz,Chloroform-d)δ9.00(d,J=4.8Hz,2H),8.81(s,1H),7.41(t,J=4.8Hz, 1H),6.81(d,J=6.8Hz,1H),6.28–6.14(m,1H),5.44(dd,J=16.0,5.7Hz,1H),4.94(s, 1H),3.71–3.59(m,1H),3.05(d,J=20.6Hz,1H),3.01–2.89(m,1H),2.79–2.62(m,1H) ,2.59–2.37(m,2H),2.18–2.05(m,1H),2.01–1.90(m,1H),1.25–1.16(m,3H).MS(ESI + [M+H] + )m / z:411.4.

[0311] Example 22 was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol:n-hexane=20:80) to obtain Example 22_A (30 mg) and Example 22_B (30 mg).

[0312] Example 22_A: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.80(d,J=1.0Hz,1H),7.40(t,J=4.9Hz, 1H),6.81(d,J=6.7Hz,1H),6.19(ddd,J=4.4,2.9,0.9Hz,1H),5.44(dd,J=16.1,6.2Hz,1H),4. 93(dd,J=14.8,7.4Hz,1H),3.73–3.56(m,1H),3.16–3.01(m,1H),3.01–2.85(m,1H),2.80–2. 64(m,1H),2.59–2.38(m,2H),2.12–2.03(m,1H),2.03–1.84(m,1H),1.26–1.16(m,3H).MS(ESI + [M+H] + )m / z:411.4.

[0313] Example 22_B: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.80(d,J=1.0Hz,1H),7.41(t,J =4.8Hz,1H),6.81(d,J=6.6Hz,1H),6.23–6.14(m,1H),5.51–5.37(m,1H),4.93(d,J=6 .8Hz,1H),3.70–3.59(m,1H),3.09–3.00(m,1H),3.00–2.90(m,1H),2.77–2.65(m,1H ),2.56–2.38(m,2H),2.14–2.02(m,1H),1.99–1.88(m,1H),1.26–1.16(m,3H).MS(ESI + [M+H] + )m / z:411.4.

[0314] Embodiment 23

[0315]

[0316] Example 22 (65 mg) and 20 mL of dichloromethane were added to the eggplant-shaped bottle in sequence, and m-chloroperbenzoic acid (40 mg) was added under ice bath. After reacting at 0°C for 1 hour, the reaction solution was slowly poured into 50 mL of saturated NaHCO3 aqueous solution, and extracted with dichloromethane (50 mL*3). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (DCM:MeOH=100:3) to obtain Example 23 compound (30 mg).

[0317] Embodiment 23: 1 H NMR(500MHz,Chloroform-d)δ8.99(d,J=4.8Hz,2H),8.81(s,1H),7.41(t,J=4.8Hz,1H),6.92(s,1H),6.57(dd,J=3.1,1.1Hz,1H),5.44(s,1H ),4.93(s,1H),3.72–3.54(m,1H),3.14–3.03(m,3H),2.60–2.40(m,2H),2.20–2.07(m,1H),1.98–1.92(m,1H),1.27(t,J=7.4Hz,3H).MS(ESI + [M+H] + )m / z:427.4.

[0318] Example 24 (24_A and 24_B)

[0319]

[0320]

[0321] Step A: Add compound 24-1 (50g) and N,N-dimethylformamide dimethyl acetal (29.9g) to the reaction bottle in sequence, heat to 100°C and react for 7 hours, then cool to room temperature, remove excess DMFDMA by rotary evaporation, and continue to add 2-pyrimidinecarboxamidine hydrochloride (33.9g), sodium tert-butoxide (41.1g), and anhydrous ethanol (500mL) to the reaction bottle, and reflux for 7 hours. The reaction solution was dried by rotary evaporation, and 500mL of water was added, and ethyl acetate was extracted (300mL*3). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM: MeOH = 100: 3) to obtain compound 24-2 (43.0g). MS (ESI + ,[M+H] + )m / z:354.12.

[0322] Step B: Compound 24-2 (43.0 g) and dioxane hydrochloride solution (4.0 M, 50 mL) were added to the reaction bottle in sequence. The reaction was allowed to react at room temperature for 16 h. The reaction solution was adjusted to pH 7 with TEA, filtered, and the filtrate was dried to obtain compound 24-3 (28.0 g). MS (ESI + ,[M+H] + )m / z:253.99.

[0323] Step C: Compound 24-3 (28.0 g), 2,4,6-trifluoropyridine (8.1 g), cesium carbonate (59.4 g), and DMF (100 mL) were added to the reaction bottle in sequence. After heating to 80°C for 14 hours, the reaction solution was slowly poured into 500 mL of ice water and extracted with ethyl acetate (5*200 mL). The organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was separated by C18 column chromatography (acetonitrile: water = 30:70) to obtain Example 24 (4.1 g).

[0324] Embodiment 24: 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=4.8Hz,2H),8.76(s,1H),7.43(t,J=4.8H z,1H),6.25(d,J=11.0,1.6Hz,1H),5.98–5.89(m,1H),5.73(s,1H),4.85(s,1H),3 .62–3.50(m,1H),3.16(d,J=19.1Hz,1H),2.18–2.07(m,1H),2.05–1.93(m,1H),1 .88–1.81(m,1H),1.82–1.72(m,1H),1.71–1.63(m,1H),1.53–1.41(m,1H).MS(ESI + ,[M+H] + )m / z:367.05.

[0325] Example 24 (4.1 g) was separated by supercritical fluid chromatography (CHIRALART Cellulose-SC column, methanol:CO2=30:70). The first peak was Example 24_A (1.25 g), and the last peak was Example 24_B (1.18 g).

[0326] Example 24_A: 11H NMR (500 MHz, Chloroform-d) δ 9.02 (d, J = 4.8 Hz, 2H), 8.76 (s, 1H), 7.43 (t, J = 4.8 Hz, 1H), 6.25 (d, J = 11.0, 1.6 Hz, 1H), 5.98–5.89 (m, 1H), 5.73 (s, 1H), 4.85 (s, 1H), 3.62–3.50 (m, 1H), 3.16 (d, J = 19.1 Hz, 1H), 2.18–2.07 (m, 1H), 2.05–1.93 (m, 1H), 1.88–1.81 (m, 1H), 1.82–1.72 (m, 1H), 1.71–1.63 (m, 1H), 1.53–1.41 (m, 1H). MS (ESI + , [M+H] + ) m / z: 367.05.

[0327] Example 24_B: 1 1H NMR (500 MHz, Chloroform-d) δ 9.02 (d, J = 4.8 Hz, 2H), 8.76 (s, 1H), 7.43 (t, J = 4.8 Hz, 1H), 6.25 (d, J = 11.0, 1.6 Hz, 1H), 5.98–5.89 (m, 1H), 5.73 (s, 1H), 4.85 (s, 1H), 3.62–3.50 (m, 1H), 3.16 (d, J = 19.1 Hz, 1H), 2.18–2.07 (m, 1H), 2.05–1.93 (m, 1H), 1.88–1.81 (m, 1H), 1.82–1.72 (m, 1H), 1.71–1.63 (m, 1H), 1.53–1.41 (m, 1H). MS (ESI + , [M+H] + ) m / z: 367.05.

[0328] Example 25 (25_A and 25_B)

[0329]

[0330] Example 24 (100 mg), 40% dimethylamine aqueous solution (0.615 mL), and DMF (2 mL) were added to the microwave tube in sequence. After heating to 90° C. in the microwave for 1 hour, the reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product Example 25 was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol: n-hexane = 20:80). The first peak was Example 25_A (20 mg), and the later peak was Example 25_B (20 mg).

[0331] Example 25_A: 1 H NMR(500MHz, CDCl3) δ9.01(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H),5. 71(s,1H),5.67(s,1H),5.54(s,1H),4.88(s,1H),3.58(dd,J=19.0,7.7Hz,1H),3. 09(d,J=19.0Hz,1H),2.97(s,6H),2.15(m,1H),2.07–1.98(m,1H),1.85(s,1H),1. 81(dd,J=13.6,1.8Hz,1H),1.73(d,J=11.4Hz,1H),1.62(d,J=14.1Hz,1H).MS(ESI + ,[M+H] + )m / z:392.17.

[0332] Example 25_B: 1 H NMR(500MHz, CDCl3) δ9.01(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H),5. 71(s,1H),5.67(s,1H),5.54(s,1H),4.88(s,1H),3.58(dd,J=19.0,7.7Hz,1H),3. 09(d,J=19.0Hz,1H),2.97(s,6H),2.15(m,1H),2.07–1.98(m,1H),1.85(s,1H),1. 81(dd,J=13.6,1.8Hz,1H),1.73(d,J=11.4Hz,1H),1.62(d,J=14.1Hz,1H).MS(ESI + ,[M+H] + )m / z:392.17.

[0333] Example 26 (26_A and 26_B)

[0334]

[0335] Example 24 (250 mg), 3-fluoroazetidine hydrochloride (230 mg), DMF (4 mL), and cesium carbonate (1.0 g) were added to a microwave tube in sequence. The mixture was heated to 90° C. in a microwave oven and reacted for 1 hour. The reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was separated by high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol: n-hexane = 20:80). The first peak was 26_A (40 mg) and the last peak was 26_B (60 mg).

[0336] Example 26_A: 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H),5.70( s,1H),5.43(d,J=1.6Hz,1H),5.30(s,1H),4.85(s,1H),4.25–4.17(m,2H),4.10–3.96(m,2H),3 .72(q,J=7.0Hz,1H),3.61–3.51(m,1H),3.11(d,J=19.1Hz,1H),2.17–2.08(m,1H),2.07–1.92( m,1H),1.87–1.69(m,2H),1.49–1.38(m,1H),1.67–1.61(m,1H).MS(ESI+,[M+H]+)m / z:422.20.

[0337] Example 26_B: 1H NMR(500MHz,Chloroform-d)δ9.02(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H), 5.70(s,1H),5.43(d,J=1.6Hz,1H),5.30(s,1H),4.85(s,1H),4.26–4.14(m,2H),4.08–3. 98(m,2H),3.72(q,J=7.0Hz,1H),3.61–3.51(m,1H),3.11(d,J=19.1Hz,1H),2.17–2.08(m ,1H),2.05–1.95(m,1H),1.85–1.69(m,2H),1.49–1.38(m,1H),1.67–1.61(m,1H).MS(ESI + ,[M+H] + )m / z:422.19.

[0338] Example 27 (27_A and 27_B)

[0339]

[0340] According to Example 26, N-methyl-2-methoxyethylamine was used to replace 3-fluoroazetidine hydrochloride, and the obtained crude product Example 27 was subjected to high-pressure preparative liquid separation (CHIRALART Cellulose-SB chromatographic column; ethanol: n-hexane = 20:80). The first peak was Example 27_A (25 mg), and the last peak was Example 27_B (25 mg).

[0341] Example 27_A: 1 H NMR(500MHz,Chloroform-d)δ9.01(d,J=4.9Hz,2H),8.75(s,1H),7.41(t,J=4.8Hz,1H),5.7 2(t,J=1.5Hz,1H),5.70(s,1H),5.55(d,J=1.6Hz,1H),4.87(s,1H),3.62–3.54(m,1H),3.54– 3.43(m,4H),3.34(s,3H),3.09(d,J=19.1Hz,1H),2.99(s,3H),2.19–2.10(m,1H),2.06–1.9 6(m,1H),1.84–1.77(m,1H),1.77–1.70(m,1H),1.66–1.58(m,1H),1.49–1.37(m,1H).MS(ESI + ,[M+H] + )m / z:436.18.

[0342] Example 27_B: 1 H NMR(500MHz,Chloroform-d)δ9.01(d,J=4.9Hz,2H),8.75(s,1H),7.41(t,J=4.8Hz,1H),5.7 2(t,J=1.5Hz,1H),5.70(s,1H),5.55(d,J=1.6Hz,1H),4.87(s,1H),3.62–3.54(m,1H),3.54– 3.43(m,4H),3.34(s,3H),3.09(d,J=19.1Hz,1H),2.99(s,3H),2.19–2.10(m,1H),2.06–1.9 6(m,1H),1.84–1.77(m,1H),1.77–1.70(m,1H),1.66–1.58(m,1H),1.49–1.37(m,1H).MS(ESI + ,[M+H] + )m / z:436.15.

[0343] Embodiment 28

[0344]

[0345] Example 24_B (200 mg), methanol (50 uL), DMF (2 mL), and cesium carbonate (0.6 g) were added to a microwave tube in sequence. After heating to 110° C. in a microwave for 2 hours, the reaction solution was slowly poured into 50 mL of water and extracted with ethyl acetate (3*20 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 28 (60 mg).

[0346] Embodiment 28: 1H NMR(500MHz,Chloroform-d)δ9.02(d,J=4.9Hz,2H),8.75(s,1H),7.42(t,J=4.9Hz,1H ),6.03(t,J=1.3Hz,1H),5.79(d,J=1.6Hz,1H),5.71(s,1H),4.87(d,J=6.3Hz,1H),3.8 1(s,3H),3.60–3.52(m,1H),3.12(d,J=19.1Hz,1H),2.18–2.08(m,1H),2.04–1.94(m,1 H),1.87–1.78(m,1H),1.78–1.70(m,1H),1.66–1.63(m,1H),1.52–1.39(m,1H).MS(ESI + ,[M+H] + )m / z:379.12.

[0347] Embodiment 29

[0348]

[0349] According to Example 28, 2-methoxyethanol was used instead of methanol, and the resulting crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 29 (39 mg).

[0350] Embodiment 29: 1 H NMR(500MHz,Chloroform-d)δ9.02(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H), 6.09(s,1H),5.80(s,1H),5.69(s,1H),4.85(s,1H),4.15–4.10(m,2H),3.74–3.71(m,2H) ,3.59–3.51(m,1H),3.44(s,3H),3.11(d,J=19.1Hz,1H),2.12–2.08(m,1H),2.02–1.94(m ,1H),1.85–1.77(m,1H),1.76–1.70(m,1H),1.67–1.60(m,1H),1.47–1.41(m,1H).MS(ESI + ,[M+H] + )m / z:423.18.

[0351] Embodiment 30

[0352]

[0353] According to Example 28, 3-methoxypropanol was used instead of methanol, and the resulting crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 30 (50 mg).

[0354] Embodiment 30: 1 H NMR(500MHz, CDCl3)δ9.01(d,J=4.8Hz,2H),8.75(s,1H),7.42(t,J=4.8Hz,1H),6.04(s,1H), 5.79(s,1H),5.70(s,1H),4.86(s,1H),4.07(t,J=6.3Hz,2H),3.61–3.54(m,1H),3.52(t,J=6. 0Hz,2H),3.35(s,3H),3.11(d,J=19.1Hz,1H),2.16–2.09(m,1H),2.04–2.00(m,2H),2.00–1. 94(m,1H),1.83–1.80(m,1H),1.78–1.71(m,1H),1.66–1.60(m,1H),1.53–1.39(m,1H).MS(ESI + ,[M+H] + )m / z:437.18.

[0355] Embodiment 31

[0356]

[0357] According to Example 28, 2-methoxyethylamine was used to replace methanol, and the resulting crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 31 (57 mg).

[0358] Embodiment 31: 1H NMR(500MHz,Chloroform-d)δ9.01(d,J=4.8Hz,2H),8.74(s,1H),7.41(t,J=4.8Hz,1H),5.68(s,1 H),5.66(s,1H),5.48(s,1H),4.84(s,1H),4.60–4.54(m,1H),3.57(d,J=5.2Hz,2H),3.53(d,J=7.7 Hz,1H),3.38(s,3H),3.29(dd,J=10.4,5.2Hz,2H),3.08(d,J=19.0Hz,1H),2.19–2.09(m,1H),2.0 4–1.95(m,1H),1.82–1.76(m,1H),1.75–1.68(m,1H),1.65–1.59(m,1H),1.49–1.40(m,1H).MS(ESI + ,[M+H] + )m / z:422.19

[0359] Embodiment 32

[0360]

[0361] According to Example 28, 6-oxa-3-aza-bicyclo[3,1,1]heptane hydrochloride was used instead of methanol, and the resulting crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S column; acetonitrile: water = 30:70) to obtain Example 32 (42 mg).

[0362] Embodiment 32: 1 H NMR(500MHz,Methanol-d4)δ9.01(d,J=4.9Hz,2H),8.80(s,1H),7.62(t,J=4.9Hz,1H),5.99(s, 1H),5.73(d,J=18.4Hz,2H),4.97(d,J=6.5Hz,1H),4.73(d,J=6.5Hz,2H),3.65–3.42(m,5H),3.2 8–3.18(m,1H),3.02(d,J=19.3Hz,1H),2.18–2.09(m,1H),2.09–1.97(m,1H),1.93(d,J=8.9Hz,1 H),1.88(d,J=13.6Hz,1H),1.80(d,J=13.4Hz,1H),1.68–1.58(m,1H),1.49–1.36(m,1H).MS(ESI + ,[M+H] + )m / z:446.18.

[0363] Embodiment 33

[0364]

[0365] According to Example 28, 3-fluoroazetidine hydrochloride was used instead of methanol, and the obtained crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 33 (60 mg).

[0366] Embodiment 33: 1 H NMR(500MHz,Chloroform-d)δ9.01(d,J=4.8Hz,2H),8.75(s,1H),7.41(t,J=4.8Hz,1H),5.69(s,1H) ,5.41(d,J=1.7Hz,1H),5.29(d,J=1.3Hz,1H),4.85(s,1H),4.40–4.25(m,1H),4.15–4.04(m,2H),3.8 2–3.76(m,2H),3.61–3.51(m,1H),3.33(s,3H),3.09(d,J=19.0Hz,1H),2.19–2.07(m,1H),2.01–1.9 6(m,1H),1.84–1.76(m,1H),1.75–1.67(m,1H),1.66–1.56(m,1H),1.49–1.37(m,1H).MS(ESI+,[M+H] + )m / z:434.17

[0367] Embodiment 34

[0368]

[0369] According to Example 28, 1-methanesulfonylpiperazine was used to replace methanol, and the resulting crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 34 (30 mg).

[0370] Embodiment 34: 1H NMR(500MHz,Chloroform-d)δ9.01(d,J=4.8Hz,2H),8.76(s,1H),7.42(t,J=4.8Hz,1H),5.87(s ,1H),5.72(s,1H),5.69(s,1H),4.87(d,J=7.0Hz,1H),3.56(dd,J=19.1,7.7Hz,1H),3.47–3.39( m,4H),3.37–3.29(m,4H),3.11(d,J=19.1Hz,1H),2.82(s,3H),2.19–2.06(m,1H),2.05–1.95(m, 1H),1.89–1.80(m,1H),1.79–1.75(m,1H),1.67–1.60(m,1H),1.51–1.39(m,1H).MS(ESI+,[M+H] + )m / z:511.19

[0371] Embodiment 35

[0372]

[0373] Step A: Add 24-1 (20 g) and N,N-dimethylformamide dimethyl acetal (12.0 g) to the reaction bottle in sequence, heat to 100°C and react for 7 hours, then cool to room temperature, remove excess DMFDMA by rotary evaporation, and continue to add 2-pyridinecarboxamidine hydrochloride (10.71 g), sodium tert-butoxide (9.25 g), and anhydrous ethanol (200 mL) to the reaction bottle, and reflux for 7 hours. After the reaction solution is dried by rotary evaporation, 200 mL of water is added, and ethyl acetate is extracted (100 mL*3). The organic layers are combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. The crude product is separated by silica gel column chromatography (DCM: MeOH = 100: 3) to obtain 35-2 (20.0 g). MS (ESI + ,[M+H] + )m / z:353.16.

[0374] Step B: Add 35-2 (20.0 g) and methanol solution of hydrochloric acid (4.0 M, 100 mL) to the reaction bottle in sequence. React at room temperature for 16 h, filter the system directly, wash the filter cake with 20 mL of DCM, add 200 ml of methanol to the filter cake, neutralize with triethylamine to pH = 7-8, and concentrate the system to obtain compound 35-3 (11 g). MS (ESI + ,[M+H] + )m / z:253.04.

[0375] Step C: 35-3 (11.0 g), 2,4,6-trifluoropyridine (7.0 g), cesium carbonate (42.6 g), and DMF (100 mL) were added to the reaction bottle in sequence, and the mixture was heated to 80°C for 14 hours. The reaction solution was slowly poured into 500 mL of ice water and extracted with ethyl acetate (5*200 mL). The organic layers were combined and the solvent was evaporated under reduced pressure. The crude product was separated by C18 column chromatography (acetonitrile: water = 35:65) to obtain Example 35 (2.0 g). MS (ESI + ,[M+H] + )m / z:366.13.

[0376] Step D: Example 35 (2.0 g) was subjected to high pressure preparative liquid separation (CHIRALART Cellulose-SC chromatographic column, methanol:CO2=30:70), the first eluting peak was 35_A (0.9 g), and the last eluting peak was 35_B (0.65 g).

[0377] Embodiment 36

[0378]

[0379] Example 35A (100 mg), 3-fluoroazetidine hydrochloride (183 mg), DMF (1 mL), and cesium carbonate (624 mg) were added to a microwave tube in sequence, and the mixture was heated to 100° C. in a microwave for 2 hours. The reaction solution was slowly poured into 50 mL of water, extracted with ethyl acetate (3*20 mL), and the organic layers were combined. The organic layers were washed with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was separated by high-pressure preparative liquid separation (YMC-Triart Prep C18-S column; acetonitrile: water = 30:70) to obtain Example 36 (40 mg).

[0380] Embodiment 36: 1H NMR(500MHz,Chloroform-d)δ8.83(ddd,J=4.8,1.8,0.8Hz,1H),8.64(s,1H),8.47(dt,J=7.9,1.1Hz,1H),7.8 9–7.83(m,1H),7.38(ddd,J=7.5,4.8,1.2Hz,1H),5.65(s,1H),5.43(t,J=1.6Hz,1H),5.29(d,J=1.4Hz,1H),4. 84(s,1H),4.29–4.13(m,2H),4.10–3.95(m,2H),3.59–3.44(m,1H),3.03(d,J=19.0Hz,1H),2.16–2.07(m,1H), 2.05–1.94(m,2H),1.84–1.77(m,1H),1.72–1.66(m,1H),1.66–1.57(m,1H),1.51–1.42(m,1H).MS(ESI+,[M+H] + )m / z:421.19.

[0381] Embodiment 37

[0382]

[0383] According to Example 36, 3-fluoroazetidine hydrochloride was replaced with an aqueous solution of dimethylamine, and the resulting crude product was subjected to high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 37 (60 mg).

[0384] Embodiment 37: 1 H NMR(500MHz,Chloroform-d)δ8.84–8.80(m,1H),8.64(s,1H),8.50–8.45(m,1H),7. 88–7.82(m,1H),7.41–7.35(m,1H),5.67–5.62(m,2H),5.53(d,J=1.6Hz,1H),4.87(s ,1H),3.58–3.49(m,1H),2.97(s,6H),2.19–2.09(m,1H),2.06–1.95(m,2H),1.84–1 .75(m,1H),1.75–1.67(m,1H),1.65–1.57(m,1H),1.49–1.42(m,1H).MS(ESI+,[M+H] + )m / z:391.13.

[0385] Embodiment 38

[0386]

[0387] According to Example 36, 3-methoxypropanol was used to replace 3-fluoroazetidine hydrochloride, and the resulting crude product was separated by high pressure preparative liquid separation (YMC-Triart Prep C18-S chromatographic column; acetonitrile: water = 30:70) to obtain Example 38 (52 mg).

[0388] Embodiment 38: 1 H NMR(500MHz,Chloroform-d)δ8.86–8.81(m,1H),8.64(s,1H),8.48(dd,J=8.0,1.1Hz,1H),7.84(td,J=7.7, 1.8Hz,1H),7.42–7.35(m,1H),6.04(t,J=1.3Hz,1H),5.78(d,J=1.5Hz,1H),5.65(s,1H),4.85(s,1H),4.07 (t,J=6.3Hz,2H),3.51(dt,J=13.7,6.9Hz,3H),3.35(s,3H),3.04(d,J=19.0Hz,1H),2.15–2.07(m,1H),2.0 4–1.97(m,3H),1.85–1.76(m,1H),1.75–1.69(m,1H),1.64–1.59(m,1H),1.52–1.41(m,1H).MS(ESI+,[M+H] + )m / z:436.16.

[0389] Test Example 1:

[0390] 1) In vitro anti-HBV activity

[0391] Add 5 mL of PBS to the HepG2.2.15 cells in good exponential growth phase to wash them, then add 3 mL of trypsin, and put the resultant into the cell culture incubator for digestion. Observe under a microscope, and when the cells fall off, discard 2 mL of trypsin; digest in a 37°C incubator for 5 minutes, observe the cells under a microscope (whether they are single round and there is no adhesion between cells), add 4 mL of complete culture medium to terminate the digestion reaction and resuspend. After forming a single cell suspension, use a cell counter to count 10 μL of cell suspension. Use complete culture medium to dilute the above 10 μL cell suspension so that the cell density reaches 2*10 5 Use a multichannel pipette to inoculate cells on a 96-well plate (pre-coat the 96-well plate with 50 μg / mL Collagen I solution), 100 μL / well. Place the inoculated plate in a constant temperature CO2 incubator for 24 hours.

[0392] Drug administration

[0393] The DMSO-dissolved test compound was diluted with complete culture medium in a 5-fold gradient, with a total of 8 concentrations. The compound was added to the cells, and the fresh culture medium containing the compound was replaced every 72 hours. The cells were treated with the compound for 6 days.

[0394] HBV DNA testing

[0395] The HBV DNA detection kit of Shengxiang Bio was used for detection. 5 μL of cell supernatant was added to each well of the eight-tube tube, and 5 μL of nucleic acid release agent was added. After standing at room temperature for 10 minutes, PCR mixture was added. The HBV DNA in the supernatant was determined by real-time fluorescence quantitative PCR instrument, and the inhibition rate was calculated according to the Ct value and IU, and the EC50 was calculated by the four-parameter method. The experimental results are shown in Table 1.

[0396] HBsAg testing

[0397] The Beijing Kemei HBsAg detection kit was used for detection. The cell supernatant was diluted 20 times with PBS, 50 μL of the diluted supernatant was added to each well, and then 50 μL of the enzyme reaction solution was added, and incubated at 37°C for 60 minutes. Wash 5 times with washing solution, add the luminescent substrate reaction solution, let it stand for 5 minutes, and perform chemiluminescence detection with the Tecan Spark microplate reader. According to the detection value, the inhibition rate was calculated by the content (ng / ml) calculated by the standard curve, and the EC50 was calculated by the four-parameter method. The experimental results are shown in Table 1.

[0398] 2) Cytotoxicity assay

[0399] Add 5 mL of PBS to the HepG2.2.15 cells in good exponential growth phase to wash them, then add 3 mL of trypsin, and put the resulting mixture into the cell culture incubator for digestion. Observe under a microscope, and when the cells fall off, discard 2 mL of trypsin; digest in a 37°C incubator for 5 minutes, observe the cells under a microscope (whether they are single round and there is no adhesion between cells), add 4 mL of complete culture medium to terminate the digestion reaction and resuspend. Count using a cell counter, and dilute the above cell solution with complete culture medium to make the cell density reach 2*10 5 Use a multichannel pipette to inoculate cells on a 96-well plate (pre-coat the 96-well plate with 50 μg / mL Collagen Ⅰ solution), 100 μL / well. Place the inoculated plate in a constant temperature CO2 incubator for 24 hours.

[0400] Drug administration

[0401] Every 3 days, fresh medium containing the compound was replaced. Medium containing 0.5% DMSO without drugs was added to the control wells, and control wells with ordinary medium were set up. After 6 days of drug treatment, CCK working solution (the ratio of CCK to medium was 1 to 10) was added to the well plate, 110 μL / well. After the well plate was placed at 37°C for 30 minutes, the absorbance was detected at 450nm using a Tecan Spark microplate reader, and the inhibition rate was calculated. The IC was calculated by the four-parameter method. 50 .

[0402] Table 1

[0403] Compound HBV DNA (EC50μM) HBsAg (EC50nM) Example 2 A ++++ Example 3 B +++ Example 4 B +++ Example 5 B +++ Example 6 B +++ Example 7 B +++ Example 10 B Example 11_A B +++ Example 12 B +++ Example 13 A ++++ Embodiment 14 A +++ Embodiment 15 A +++ Embodiment 17 A ++++ Embodiment 18 A ++++ Embodiment 19 A ++++ Example 20_A A ++++ Example 21_A A ++++ Example 22_A B +++ Embodiment 23 A Embodiment 25 A ++++ Example 26_A A ++++ Example 27_A A ++++ Embodiment 28 A ++++ Embodiment 29 A ++++ Embodiment 30 A ++++ Embodiment 31 A ++++ Embodiment 32 A ++++ Embodiment 33 A ++++ Embodiment 34 A ++++

[0404] A means EC50≤0.1μM; B means 0.1μM<EC50≤1μM;

[0405] ++++ means EC50≤0.1μM; +++ means 0.1μM<EC50≤1μM.

[0406] The results showed that the compounds of the present application had good in vitro anti-HBV activity and HepG2.2.15 cell inhibitory activity.

Claims

1. A compound of formula I' or a pharmaceutically acceptable salt thereof, in, X and Y are both N; A is selected from a 6-membered heteroaryl group containing 1-2 N atoms, wherein A is optionally substituted by 1, 2 or 3 R 1 replace; R 1 Selected from C 1-6 Alkyl or halogen; p is selected from 1, 2 or 3; L is selected from a single bond; R 2 is selected from a 6-10 membered aryl group or a 6-membered heteroaryl group containing 1 N, wherein R 2 Each independently optionally 1-4 R 3 replace; The R 3 Selected from halogen, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or 4-7 membered heterocyclic alkyl containing 1-3 selected from N, O or S; said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl, -S(=O)C 1-6 Alkyl or -S(=O)2C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Replace or generate 1-2 oxygen groups; The R 4 Selected from halogen, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl, or -SO2C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound of formula I or a pharmaceutically acceptable salt thereof:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from pyridyl or pyrimidinyl, and A is optionally substituted by 1, 2 or 3 R 1 replace.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, F, Cl or Br.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-4 Alkyl, F, Cl, or Br.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 6-8 membered aryl or 6 membered heteroaryl containing 1 N.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl or pyridyl, said R 2 The substituents are as described in claim 1.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyridyl, said R 2 The substituents are as described in claim 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from phenyl, The R 2 The substituents are as described in claim 1.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from phenyl or The R 2 The substituents are as described in claim 1.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, The R 3 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl, -CO-C 1-6 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or -CO-C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, -CO-C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl or -CO-C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl, OH, -OC 1-4 alkyl, azetidinyl, aziridine, azidine, or a 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 Alkyl or -OC 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The azetidinyl, aziridine, azidine, or 4-7 membered heterocycloalkyl containing 2 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -CO-C 1-6 alkyl, or a 4-6 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, or -CO-C 1-6 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -CO-C 1-4 alkyl, or a 4-6 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, or -CO-C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-6 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, OH, -OC 1-4 alkyl, azetidinyl, aziridine, azidine, or a 4-6 membered heterocycloalkyl containing 2 selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 or -OC 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The azetidinyl, aziridine, azidine, or 4-6 membered heterocycloalkyl containing 2 selected from N, O or S are each optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from halogen, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl or 4-7 membered heterocyclic alkyl containing 1-3 selected from N, O or S; said -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl or -CO-C 1-8 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3, -SCH2CH3, -S(=O)CH2CH3, -S(=O)2CH2CH3, 22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3, -SCH2CH3, -S(=O)CH2CH3, -S(=O)2CH2CH3, or 23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, -N(CH3)2, -OCH3, -CF3, 24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl, or -S(O)2C 1-6 alkyl.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -SC 1-4 Alkyl, -CO-C 1-4 Alkyl, or -S(O)2C 1-4 alkyl.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, or -OC 1-6 alkyl.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, -OCH3, cyclopropyl, or -S(O)2CH3.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogen, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -SC 1-6 Alkyl, or -CO-C 1-8 alkyl.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl-SC 1-6 Alkyl, or -CO-C 1-6 alkyl.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -SC 1-4 Alkyl, or -CO-C 1-4 alkyl.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -OC 1-6 alkyl.

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, -OCH3, or cyclopropyl.

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from a compound of formula (1) or a pharmaceutically acceptable salt thereof, 34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein A is selected from Z is selected from CH or N, and A is optionally replaced by 1, 2 or 3 R 1 replace.

35. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein A is selected from pyridinyl or pyrimidinyl.

36. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein: The R 2 is selected from a 6-8 membered aryl group or a 6 membered heteroaryl group containing 1 N, wherein R 2 Each independently optionally 1-4 R 3 replace.

37. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl, naphthyl, or a 6-membered heteroaryl containing 1 N, wherein R 2 Each independently optionally 1-4 R 3 replace.

38. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl or pyridyl, said R 2 Each independently optionally 1-4 R 3 replace.

39. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a 6-membered heteroaryl group containing 1 N, wherein R 2 Each independently optionally 1-4 R 3 replace.

40. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyridyl, said R 2 Each independently optionally 1-4 R 3 replace.

41. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from phenyl, The R 2 Each independently optionally 1-4 R 3 replace.

42. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from The R 2 Each independently optionally 1-4 R 3 replace.

43. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 44. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 45. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein: The R 3 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SH, -SC 1-6 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -S(=O)C 1-4 Alkyl, or -S(=O)2C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

46. ​​The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SH, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, -S(=O)2C 1-4 alkyl, or a 4-7 membered heterocyclic alkyl containing 1-3 atoms selected from N, O or S, wherein -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -SC 1-4 Alkyl, -S(=O)C 1-4 Alkyl, or -S(=O)2C 1-4 The alkyl groups are each independently optionally substituted with 1 to 3 R 4 The 4-7 membered heterocycloalkyl containing 1-3 selected from N, O or S is optionally substituted by 1-3 R 4 Substitution or occurrence of 1-2 oxo groups.

47. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, Cl, Br, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, azetidinyl, or a 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, wherein the -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, -OC 1-4 alkyl, azetidinyl, or 4-7 membered heterocycloalkyl containing 2 selected from N, O or S, each independently optionally substituted by 1-3 R 4 replace.

48. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, -N(CH3)2, -OCH3、 Cl、-CF3、 -SCH2CH3、-S(=O)CH2CH3、-S(=O)2CH2CH3。 49. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from F, -N(CH3)2, -OCH3、 50. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein: The R 4 Selected from F, Cl, Br, -CN, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -SC 1-6 Alkyl, -CO-C 1-6 Alkyl or -S(O)2C 1-6 alkyl.

51. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -CN, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl, -SC 1-4 Alkyl, -CO-C 1-4 Alkyl or -S(O)2C 1-4 alkyl.

52. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -C 1-4 Alkyl, -C 3-6 Cycloalkyl, -OC 1-4 Alkyl or -S(O)2C 1-4 alkyl.

53. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, -OCH3, cyclopropyl, or -S(O)2CH3.

54. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, Cl, Br, -C 1-4 Alkyl, -OC 1-6 Alkyl, or -S(O)2C 1-4 alkyl.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from F, -OCH3, or -S(O)2CH3.

56. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the compound of formula II' or a pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; T is selected from C or N; U, V, W and Z are each independently selected from CH or N; q is selected from 0, 1, 2 or 3.

57. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the compounds of formula III', formula IV', formula V', formula VI' or a pharmaceutically acceptable salt thereof, in, U, W and Z are each independently selected from CH or N; q is selected from 0, 1, 2 or 3.

58. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from a compound of formula II or formula (1-2) or a pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; T is selected from C or N; U, V, W and Z are each independently selected from CH or N; q is selected from 0, 1, 2 or 3.

59. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from a compound of formula III, formula IV, formula V, formula VI, formula VII, formula (1-3), formula (1-4), formula (1-5), formula (1-6) or formula (1-7) or a pharmaceutically acceptable salt thereof, in, U, W and Z are each independently selected from CH or N; q is selected from 0, 1, 2 or 3.

60. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from a compound of Formula IA, Formula IB, Formula IIA, Formula IIB, Formula IIIA, Formula IIIB, Formula IVA, Formula IVB, Formula VA, Formula VB, Formula VIA, Formula VIB, Formula VIIA, Formula VIIB, Formula (1-A), Formula (1-B), Formula (1-2A), Formula (1-2B), Formula (1-3A), Formula (1-3B), Formula (1-4A), Formula (1-4B), Formula (1-5A), Formula (1-5B), Formula (1-6A), Formula (1-6B), Formula (1-7A) or Formula (1-7B) or a pharmaceutically acceptable salt thereof in, represents a single bond or a double bond; T is selected from C or N; U, V, W and Z are each independently selected from CH or N; q is selected from 0, 1, 2 or 3.

61. The following compound or a pharmaceutically acceptable salt thereof:

62. The following compound or a pharmaceutically acceptable salt thereof:

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof.

64. Use of the compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 63, in the preparation of a medicament for treating hepatitis B virus infection.

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