Endocyclic thiamidinoamide-arylamide compound and its use in the treatment of hepatitis B

Description

FIELD OF INVENTION

[0001] The present invention belongs to the field of medicine, and in particular, the present invention relates to a class of cyclic sulfonimidamide-arylamide compounds and the use as a medicine for treating hepatitis B thereof.BACKGROUND OF THE INVENTION

[0002] Hepatitis B virus (HBV) is an enveloped virus of hepatotropic virus DNA family (Hepadnaviridae) with partially double-stranded DNA (dsDNA). The genome thereof contains 4 overlapped reading frames: precore / core gene, polymerase gene, UM and S genes (which encode three envelope proteins), and X gene. In the early stage of infection, the partially double-stranded DNA genome (open-loop DNA, rcDNA) in the host cell nucleus is transformed into covalently closed circular DNA (cccDNA) and transcribed into virus mRNA. Once encapsulated, the pre-genome RNA (pgRNA) (which encodes the core protein and Pol) serves as a template for reverse transcription, which regenerates this partial dsDNA genome (rcDNA) in the nucleocapsid.

[0003] HBV causes epidemics in certain areas of Asia and Africa, and is endemic in China. HBV has infected about 2 billion people worldwide, of which about 350 million people have developed into chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a highly increased risk of development of cirrhosis and liver cancer.

[0004] The spread of hepatitis B virus is caused by exposure to infectious blood or body fluid, and the virus is detected in the saliva, tears, and urine of chronic carriers with high DNA titers in the serum.

[0005] Although there is currently an effective and well tolerated vaccine, the option of direct treatment is currently limited to interferon and the following antiviral drugs: tenofovir, lamivudine, adefovir, entecavir and telbivudine.

[0006] Additionally, heteroaryldihydropyrimidines (HAPs) are identified as a class of HBV inhibitors in tissue cultivation and animal models (Weber et al., Antiviral Res. 54: 69-78).

[0007] WO2013 / 006394 (published on January 10, 2013) and WO 2013 / 096744 (published on June 27, 2013) also disclosed sulfamoyl-arylamides having anti-HBV activity. Moreover, WO2017 / 001655 (published on January 5, 2017) discloses compounds of formula (Ia) which are used in the treatment of hepatitis B.

[0008] However, problems encountered in these direct HBV antiviral drugs are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.

[0009] Therefore, in order to overcome the above defects, it is necessary to develop HBV inhibitors with advantages such as high potency and lower toxicity.

[0010] An object of the present invention is to provide a class of structurally novel compounds useful as HBV inhibitors.

[0011] In the first aspect of the invention, a compound of the formula L, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided, wherein n is 1; is a substituted or unsubstituted five or six membered ring, wherein the five or six membered ring is pyrrole or pyrazole; the substituted means that the hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of C1-C3 alkyl (especially methyl), C3-C4 cycloalkyl, cyano, or halogen; is a substituted or unsubstituted five- or six-membered aromatic ring, or a substituted or unsubstituted five- or six-membered heteroaromatic ring; X is-CR a< R b< -; Y is unsubstituted C2 alkylene, or substituted or unsubstituted C2 alkenylene, wherein the substituent is selected from the group consisting of C1-C4 alkyl, hydroxyl; Z is a C-C single bond (i.e., Z is none); W is none; R 1< , R 2< , R 3< and R 4< are each independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; wherein the substituted means that hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl; R 5< , R 6< are each independently selected from the group consisting of H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; R a< and R b< are each independently H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O) -substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 1 -C 6 alkoxy-alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; Rc is H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; unless otherwise specified, "substituted" means that the group substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, carboxyl, and unsubstituted or substituted groups selected from the group consisting of C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O; wherein the substituent of the above group is selected from the group consisting of halogen and C1-C6 alkoxy.

[0012] In another preferred embodiment, the Y is selected from the group consisting of C1-C4 alkylene and substituted or unsubstituted C2-C4 alkenylene.

[0013] In another preferred embodiment, the Ra and Rb are each independently substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy; wherein the substituent is selected from the group consisting of halogen, hydroxyl, and cyano.

[0014] In another preferred embodiment, the compound has a structure selected from the group consisting of the following formulas L-1, L-2, L-3, and L-4: In each formula, n is 1; the definitions of ring A, ring B, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described in the first aspect of the present invention.

[0015] In another preferred embodiment, the Ra and Rb are each independently substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy; wherein the substituent is selected from the group consisting of halogen, hydroxyl, and cyano.

[0016] In another preferred embodiment, the formula I compound has the structure shown by the following formula II: wherein X 1 is -CR= or -N=, X 2 is -NR-; and R is H or C1-C4 alkyl.

[0017] In another preferred embodiment, the X 2 is -NCH 3 -.

[0018] In another preferred embodiment, the compound of formula I has the following structure:

[0019] In another preferred embodiment, the compound of formula I has a structure represented by the following formula IV-1 or IV-2:

[0020] In another preferred embodiment, n is 1.

[0021] In another preferred embodiment, Ra is selected from the group consisting of substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, and substituted or unsubstituted C1-C6 alkoxy-alkyl; Rb is H.

[0022] In another preferred embodiment, the Ra is selected from the group consisting of substituted or unsubstituted C 1 -C 8 alkyl; wherein the substituted means that one or more hydrogen atoms on the group are substituted by substituent selected from the group consisting of C1-C4 alkoxy, hydroxyl, C6-C10 aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C1-C6 alkoxy.

[0023] In another preferred embodiment, the B ring is a benzene ring or a pyridine ring.

[0024] In another preferred embodiment, the A ring is a pyrrole ring.

[0025] In another preferred embodiment, said

[0026] In another preferred embodiment, the R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, and cyano.

[0027] In another preferred embodiment, the R 5 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, and substituted or unsubstituted C 3 -C 10 cycloalkyl.

[0028] In another preferred embodiment, the R 6 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, and substituted or unsubstituted C 3 -C 10 cycloalkyl.

[0029] In another preferred embodiment, the compound is the compound 10a1-60y2 as described in Table 1, wherein Peak 1 and Peak 2 refer to the order of the enantiomers' peaks in reversed-phase HPLC, wherein Peak 1 is the first peak in the enantiomer, and Peak 2 is the latter peak of the enantiomer.

[0030] In another preferred embodiment, in the above table, HPLC is reversed-phase HPLC, where peak 1 refers to a compound of greater polarity, and peak 2 refers to a compound of less polarity.

[0031] In the second aspect of the invention, a method for preparing compound of the formula I, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of the first aspect of the present invention is provided, which comprising the following steps: in an inert solvent, reacting formula L1 compound with to provide compound L; wherein, R is a leaving group, and the definitions of the remaining groups are as described in the first aspect of the present invention.

[0032] In another preferred embodiment, the compound of formula L is a compound of formula VII-1, and the method comprises the following steps: wherein Rg is selected from the group consisting of H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; the definition of each group is as set forth above.

[0033] In another preferred embodiment, the compound of formula L is a compound of formula II-2, and the method comprises the following steps:

[0034] In each formula, the definition of each group is as set forth above.

[0035] In another preferred embodiment, the compound of formula L is a compound of formula VII-3, and the method comprises the following steps:

[0036] In each formula, the definition of each group is as set forth above.

[0037] In another preferred embodiment, the compound of formula L is a compound of formula II-4, and the method comprises the following steps:

[0038] In each formula, the definition of each group is as set forth above.

[0039] In the third aspect of the present invention, a compound selected from the following group is provided: in each formula, Rg is selected from the group consisting of H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; while the definitions of R 5< and R 6< are as in the first aspect of the present invention.

[0040] In the fourth aspect of the invention, a pharmaceutical composition is provided, which comprising (1) a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof according to the first aspect of the invention; and (2) pharmaceutically acceptable carriers.

[0041] In the fifth aspect of the invention, a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention for use in prevention and / or treatment of Hepatitis B is provided.

[0042] In the eighth aspect of the invention, an in vitro method for inhibiting replication of hepatitis B virus is provided, which comprises the steps: contacting the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of the first aspect of the invention with hepatitis B virus, thus inhibiting the replication of hepatitis B.

[0043] It should be understood that, in the present invention, each of the technical features specifically described above and below (such as those in the Examples) can be combined with each other, thereby constituting new or preferred technical solutions which are not necessarily specified one by one herein.EMBODIMENTS FOR CARRYING OUT THE INVENTION

[0044] After extensive and intensive research, the inventors have found a novel class of compounds having excellent therapeutic effects on hepatitis B. The inventors have completed the present invention on this basis.DEFINITIONS

[0045] As used herein, the term "alkyl" includes straight or branched alkyl groups. For example, C 1 -C 8 alkyl refers to straight or branched alkyls having from 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0046] As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example, C 2 -C 6 alkenyl refers to straight or branched alkenyls having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and the like.

[0047] As used herein, the term "alkynyl" includes straight or branched alkynyl groups. For example, "C 2 -C 6 alkynyl" refers to straight or branched alkynyl having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, and the like.

[0048] As used herein, the term "C 3 -C 10 cycloalkyl" refers to cycloalkyl groups having 3 to 10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It may also be of bicyclic form, such as bridged or spiro ring form.

[0049] As used herein, the term "C 1 -C 8 alkylamino" refers to amine groups substituted by C 1 -C 8 alkyl, which may be monosubstituted or disubstituted; such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(tert-butyl)amino, and the like.

[0050] As used herein, the term "C 1 -C 8 alkoxy" refers to straight or branched alkoxy groups having 1-8 carbon atoms; such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0051] As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms, wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or bicyclic form, such as bridged or spiro ring form. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, and the like.

[0052] As used herein, the term "C 6 -C 10 aryl" refers to aryl groups having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like.

[0053] As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to cyclic aromatic groups having 5-10 atoms, of which 1-3 is selected from the group consisting of N, S and O. It may be a monocyclic ring or fused ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.

[0054] Unless otherwise specified as "substituted or unsubstituted", all the groups described in the present invention may be substituted with substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, amino, C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 2 -C 6 alkenyl, halogenated C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl-carbonyl, C 3 -C 6 cycloalkyl-carbonyl, C 1 -C 6 alkyl-sulfonyl, etc.

[0055] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl or Br. "Halogenated" means substitution by atom(s) selected from the group consisting of F, Cl, Br, and I.

[0056] Unless otherwise specified, the structural formula described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers)): for example, R, S configuration having asymmetrical centers, (Z), (E) isomers of double bonds, etc. Therefore, the single stereo chemical isomers or enantiomers, diastereomers or geometric isomers (or conformers) of the compounds of the invention, or mixtures thereof all fall within the scope of the invention.

[0057] As used herein, the term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thereby transform between each other. For example, proton tautomers (proton shift) includes interconversion by proton transfer, such as 1H-carbazole and 2H-carbazole. Valence tautomers include interconversion through some bonding electron recombination.

[0058] As used herein, the term "solvate" refers to a complex of specific ratio formed by a compound of the invention coordinating to a solvent molecule.

[0059] As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the invention with water.ACTIVE INGREDIENTS

[0060] As used herein, "compound of the invention" refers to the compound of formula L, as well as various crystal forms of the compound of formula L, or the pharmaceutically acceptable salts, hydrate or solvates thereof.

[0061] As used herein, the "pharmaceutically acceptable salts" refers to salts suitable for use in pharmaceutical which is formed by a compound of the present invention with an acid or base. The pharmaceutically acceptable salts include inorganic and organic salts. Preferred type of salts are salts formed by the compounds of the present invention and acid. Suitable salt-forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydro bromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methane sulfonic acid, toluene sulfonic acid, benzene sulfonic acid and the like; and acidic amino acids such as aspartic acid, glutamic acid.

[0062] In another preferred embodiment, said ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently the corresponding group of each compound in Table 1.

[0063] Preferred compounds of the invention are shown in Table 1: Table 1No.StructureMass Spectrum ESI-MS, (M + H)Remark10a1 395Peak1 (HPLC)10a2 395Peak2 (HPLC)10b1 402Peak1 (HPLC)10b2 402Peak2 (HPLC)10c1 413Peak1 (HPLC)10c2 413Peak2 (HPLC)10d1 360Peak1 (HPLC)10d2 360Peak2 (HPLC)10e1 403Peak1 (HPLC)10e2 403Peak2 (HPLC)10f1 410Peak1 (HPLC)10f2 410Peak2 (HPLC)10g1 395Peak1 (HPLC)10g2 395Peak2 (HPLC)10h1 402Peak1 (HPLC)10h2 402Peak2 (HPLC)10i1 413Peak1 (HPLC)10i2 413Peak2 (HPLC)10j1 360Peak1 (HPLC)10j2 360Peak2 (HPLC)10k1 403Peak1 (HPLC)10k2 403Peak2 (HPLC)10m1 410Peak1 (HPLC)10m2 410Peak2 (HPLC)10n1 409Peak1 (HPLC)10n2 409Peak2 (HPLC)10o1 416Peak1 (HPLC)10o2 416Peak2 (HPLC)10p1 417Peak1 (HPLC)10p2 417Peak2 (HPLC)10q1 424Peak1 (HPLC)10q2 424Peak2 (HPLC)10r1 409Peak1 (HPLC)10r2 409Peak2 (HPLC)10s1 374Peak1 (HPLC)10s2 374Peak2 (HPLC)10t1 417Peak1 (HPLC)10t2 417Peak2 (HPLC)10u1 409Peak1 (HPLC)10u2 409Peak2 (HPLC)10v1 416Peak1 (HPLC)10v2 416Peak2 (HPLC)10w1 417Peak1 (HPLC)10w2 417Peak2 (HPLC)10x1 424Peak1 (HPLC)10x2 424Peak2 (HPLC)10y1 409Peak1 (HPLC)10y2 409Peak2 (HPLC)10z1 374Peak1 (HPLC)10z2 374Peak2 (HPLC)10aa1 417Peak1 (HPLC)10aa2 417Peak2 (HPLC)10bb1 435Peak1 (HPLC)10bb2 435Peak2 (HPLC)10cc1 442Peak1 (HPLC)10cc2 442Peak2 (HPLC)10dd1 443Peak1 (HPLC)10dd2 443Peak2 (HPLC)10ee1 450Peak1 (HPLC)10ee2 450Peak2 (HPLC)10ff1 435Peak1 (HPLC)10ff2 435Peak2 (HPLC)10gg1 400Peak1 (HPLC)10gg2 400Peak2 (HPLC)10hh1 443Peak1 (HPLC)10hh2 443Peak2 (HPLC)10ii1 429Peak1 (HPLC)10ii2 429Peak2 (HPLC)10jj1 436Peak1 (HPLC)10jj2 436Peak2 (HPLC)10kk1 437Peak1 (HPLC)10kk2 437Peak2 (HPLC)10mm1 429Peak1 (HPLC)10mm2 429Peak2 (HPLC)10nn1 436Peak1 (HPLC)10nn2 436Peak2 (HPLC)10oo1 437Peak1 (HPLC)10oo2 437Peak2 (HPLC)10pp1 443Peak1 (HPLC)10pp2 443Peak2 (HPLC)10qq1 450Peak1 (HPLC)10qq2 450Peak2 (HPLC)10rr1 451Peak1 (HPLC)10rr2 451Peak2 (HPLC)10ss1 443Peak1 (HPLC)10ss2 443Peak2 (HPLC)10tt1 450Peak1 (HPLC)10tt2 450Peak2 (HPLC)10uu1 451Peak1 (HPLC)10uu2 451Peak2 (HPLC)10vv1 493Peak1 (HPLC)10vv2 493Peak2 (HPLC)10ww1 500Peak1 (HPLC)10ww2 500Peak2 (HPLC)10xx1 501Peak1 (HPLC)10xx2 501Peak2 (HPLC)10yy1 493Peak1 (HPLC)10yy2 493Peak2 (HPLC)10zz1 500Peak1 (HPLC)10zz2 500Peak2 (HPLC)10aaa1 501Peak1 (HPLC)10aaa2 501Peak2 (HPLC)10bbb1 487Peak1 (HPLC)10bbb2 487Peak2 (HPLC)10ccc1 494Peak1 (HPLC)10ccc2 494Peak2 (HPLC)10ddd1 505Peak1 (HPLC)10ddd2 505Peak2 (HPLC)10eee1 486Peak1 (HPLC)10eee2 486Peak2 (HPLC)10fff1 495Peak1 (HPLC)10fff2 495Peak2 (HPLC)10ggg1 485Peak1 (HPLC)10ggg2 485Peak2 (HPLC)10hhh1 492Peak1 (HPLC)10hhh2 492Peak2 (HPLC)10iii1 503Peak1 (HPLC)10iii2 503Peak2 (HPLC)10jjj1 484Peak1 (HPLC)10jjj2 484Peak2 (HPLC)10kkk1 493Peak1 (HPLC)10kkk2 493Peak2 (HPLC)10mmm1 503Peak1 (HPLC)10mmm2 503Peak2 (HPLC)10nnn1 510Peak1 (HPLC)10nnn2 510Peak2 (HPLC)10ooo1 521Peak1 (HPLC)10ooo2 521Peak2 (HPLC)10ppp1 502Peak1 (HPLC)10ppp2 502Peak2 (HPLC)10qqq1 511Peak1 (HPLC)10qqq2 511Peak2 (HPLC)10rrr1 515Peak1 (HPLC)10rrr2 515Peak2 (HPLC)10sss1 522Peak1 (HPLC)10sss2 522Peak2 (HPLC)10ttt1 533Peak1 (HPLC)10ttt2 533Peak2 (HPLC)10uuu1 514Peak1 (HPLC)10uuu2 514Peak2 (HPLC)10vvv1 523Peak1 (HPLC)10vvv2 523Peak2 (HPLC)10www1 367Peak1 (HPLC)10www2 367Peak2 (HPLC)10xxx1 411Peak1 (HPLC)10xxx2 411Peak2 (HPLC)20a1 397Peak1 (HPLC)20a2 397Peak2 (HPLC)20b1 404Peak1 (HPLC)20b2 404Peak2 (HPLC)20c1 415Peak1 (HPLC)20c2 415Peak2 (HPLC)20d1 362Peak1 (HPLC)20d2 362Peak2 (HPLC)20e1 405Peak1 (HPLC)20e2 405Peak2 (HPLC)20f1 412Peak1 (HPLC)20f2 412Peak2 (HPLC)20g1 397Peak1 (HPLC)20g2 397Peak2 (HPLC)20h1 404Peak1 (HPLC)20h2 404Peak2 (HPLC)20i1 415Peak1 (HPLC)20i2 415Peak2 (HPLC)20j1 362Peak1 (HPLC)20j2 362Peak2 (HPLC)20k1 405Peak1 (HPLC)20k2 405Peak2 (HPLC)20m1 412Peak1 (HPLC)10m2 412Peak2 (HPLC)20n1 411Peak1 (HPLC)20n2 411Peak2 (HPLC)20o1 418Peak1 (HPLC)20o2 418Peak2 (HPLC)20p1 419Peak1 (HPLC)20p2 419Peak2 (HPLC)20q1 426Peak1 (HPLC)20q2 426Peak2 (HPLC)20r1 411Peak1 (HPLC)20r2 411Peak2 (HPLC)20s1 376Peak1 (HPLC)20s2 376Peak2 (HPLC)20t1 419Peak1 (HPLC)20t2 419Peak2 (HPLC)20u1 411Peak1 (HPLC)20u2 411Peak2 (HPLC)20v1 418Peak1 (HPLC)20v2 418Peak2 (HPLC)20w1 419Peak1 (HPLC)20w2 419Peak2 (HPLC)20x1 426Peak1 (HPLC)20x2 426Peak2 (HPLC)20y1 411Peak1 (HPLC)20y2 411Peak2 (HPLC)20z1 376Peak1 (HPLC)20z2 376Peak2 (HPLC)20aa1 419Peak1 (HPLC)20aa2 419Peak2 (HPLC)20bb1 437Peak1 (HPLC)20bb2 437Peak2 (HPLC)20cc1 444Peak1 (HPLC)20cc2 444Peak2 (HPLC)20dd1 445Peak1 (HPLC)20dd2 445Peak2 (HPLC)20ee1 452Peak1 (HPLC)20ee2 452Peak2 (HPLC)20ff1 437Peak1 (HPLC)20ff2 437Peak2 (HPLC)20gg1 402Peak1 (HPLC)20gg2 402Peak2 (HPLC)20hh1 445Peak1 (HPLC)20hh2 445Peak2 (HPLC)20ii1 431Peak1 (HPLC)20ii2 431Peak2 (HPLC)20jj1 438Peak1 (HPLC)20jj2 438Peak2 (HPLC)20kk1 439Peak1 (HPLC)20kk2 439Peak2 (HPLC)20mm1 431Peak1 (HPLC)20mm2 431Peak2 (HPLC)20nn1 438Peak1 (HPLC)20nn2 438Peak2 (HPLC)20oo1 439Peak1 (HPLC)20oo2 439Peak2 (HPLC)20pp1 445Peak1 (HPLC)20pp2 445Peak2 (HPLC)20qq1 452Peak1 (HPLC)20qq2 452Peak2 (HPLC)20rr1 453Peak1 (HPLC)20rr2 453Peak2 (HPLC)20ss1 445Peak1 (HPLC)20ss2 445Peak2 (HPLC)20tt1 452Peak1 (HPLC)20tt2 452Peak2 (HPLC)20uu1 453Peak1 (HPLC)20uu2 453Peak2 (HPLC)20vv1 495Peak1 (HPLC)20vv2 495Peak2 (HPLC)20ww1 502Peak1 (HPLC)20ww2 502Peak2 (HPLC)20xx1 503Peak1 (HPLC)20xx2 503Peak2 (HPLC)20yy1 495Peak1 (HPLC)20yy2 495Peak2 (HPLC)20zz1 502Peak1 (HPLC)20zz2 502Peak2 (HPLC)20aaa1 503Peak1 (HPLC)20aaa2 503Peak2 (HPLC)20bbb1 489Peak1 (HPLC)20bbb2 489Peak2 (HPLC)20ccc1 496Peak1 (HPLC)20ccc2 496Peak2 (HPLC)20ddd1 507Peak1 (HPLC)20ddd2 507Peak2 (HPLC)20eee1 488Peak1 (HPLC)20eee2 488Peak2 (HPLC)20fff1 497Peak1 (HPLC)20fff2 497Peak2 (HPLC)20ggg1 486Peak1 (HPLC)20ggg2 486Peak2 (HPLC)20hhh1 494Peak1 (HPLC)20hhh2 494Peak2 (HPLC)20iii1 505Peak1 (HPLC)20iii2 505Peak2 (HPLC)20jjj1 486Peak1 (HPLC)20jjj2 486Peak2 (HPLC)20kkk1 495Peak1 (HPLC)20kkk2 495Peak2 (HPLC)20mmm1 505Peak1 (HPLC)20mmm2 505Peak2 (HPLC)20nnn1 512Peak1 (HPLC)20nnn2 512Peak2 (HPLC)20ooo1 523Peak1 (HPLC)20ooo2 523Peak2 (HPLC)20ppp1 504Peak1 (HPLC)20ppp2 504Peak2 (HPLC)20qqq1 513Peak1 (HPLC)20qqq2 513Peak2 (HPLC)20rrr1 517Peak1 (HPLC)20rrr2 517Peak2 (HPLC)20sss1 524Peak1 (HPLC)20sss2 524Peak2 (HPLC)20ttt1 535Peak1 (HPLC)20ttt2 535Peak2 (HPLC)20uuu1 516Peak1 (HPLC)20uuu2 516Peak2 (HPLC)20vvv1 525Peak1 (HPLC)20vvv2 525Peak2 (HPLC)20www1 369Peak1 (HPLC)20www2 369Peak2 (HPLC)20xxx1 413Peak1 (HPLC)20xxx2 413Peak2 (HPLC)30a1 397Peak1 (HPLC)30a2 397Peak2 (HPLC)30b1 404Peak1 (HPLC)30b2 404Peak2 (HPLC)30c1 415Peak1 (HPLC)30c2 415Peak2 (HPLC)30d1 362Peak1 (HPLC)30d2 362Peak2 (HPLC)30e1 405Peak1 (HPLC)30e2 405Peak2 (HPLC)30f1 412Peak1 (HPLC)30f2 412Peak2 (HPLC)30g1 383Peak1 (HPLC)30g2 383Peak2 (HPLC)30h1 390Peak1 (HPLC)30h2 390Peak2 (HPLC)30i1 401Peak1 (HPLC)30i2 401Peak2 (HPLC)30j1 348Peak1 (HPLC)30j2 348Peak2 (HPLC)30k1 391Peak1 (HPLC)30k2 391Peak2 (HPLC)30m1 398Peak1 (HPLC)30m2 398Peak2 (HPLC)40a1 399Peak1 (HPLC)40a2 399Peak2 (HPLC)40b1 406Peak1 (HPLC)40b2 406Peak2 (HPLC)40c1 417Peak1 (HPLC)40c2 417Peak2 (HPLC)40d1 364Peak1 (HPLC)40d2 364Peak2 (HPLC)40e1 407Peak1 (HPLC)40e2 407Peak2 (HPLC)40f1 414Peak1 (HPLC)40f2 414Peak2 (HPLC)40g1 385Peak1 (HPLC)40g2 385Peak2 (HPLC)40h1 392Peak1 (HPLC)40h2 392Peak2 (HPLC)40i1 403Peak1 (HPLC)40i2 403Peak2 (HPLC)40j1 350Peak1 (HPLC)40j2 350Peak2 (HPLC)40k1 393Peak1 (HPLC)40k2 393Peak2 (HPLC)40m1 400Peak1 (HPLC)40m2 400Peak2 (HPLC)50a1 409Peak1 (HPLC)50a2 409Peak2 (HPLC)50b1 416Peak1 (HPLC)50b2 416Peak2 (HPLC)50c1 413Peak1 (HPLC)50c2 427Peak2 (HPLC)50d1 374Peak1 (HPLC)50d2 360Peak2 (HPLC)50e1 417Peak1 (HPLC)50e2 417Peak2 (HPLC)50f1 423Peak1 (HPLC)50f2 423Peak2 (HPLC)50g1 430Peak1 (HPLC)50g2 430Peak2 (HPLC)50h1 442Peak1 (HPLC)50h2 442Peak2 (HPLC)50i1 499Peak1 (HPLC)50i2 499Peak2 (HPLC)50j1 506Peak1 (HPLC)50j2 506Peak2 (HPLC)50k1 517Peak1 (HPLC)50k2 427Peak2 (HPLC)50m1 464Peak1 (HPLC)50m2 464Peak2 (HPLC)50n1 507Peak1 (HPLC)50n2 507Peak2 (HPLC)50o1 513Peak1 (HPLC)50o2 513Peak2 (HPLC)50p1 520Peak1 (HPLC)50p2 520Peak2 (HPLC)50q1 525Peak1 (HPLC)50q2 525Peak2 (HPLC)50r1 532Peak1 (HPLC)50r2 532Peak2 (HPLC)50s1 430Peak1 (HPLC)50s2 430Peak2 (HPLC)50t1 444Peak1 (HPLC)50t2 444Peak2 (HPLC)50u1 458Peak1 (HPLC)50u2 458Peak2 (HPLC)50v1 456Peak1 (HPLC)50v2 456Peak2 (HPLC)50w1 381Peak1 (HPLC)50w2 381Peak2 (HPLC)50x1 423Peak1 (HPLC)50x2 423Peak2 (HPLC)60a1 411Peak1 (HPLC)60a2 411Peak2 (HPLC)60b1 418Peak1 (HPLC)60b2 418Peak2 (HPLC)60c1 429Peak1 (HPLC)60c2 429Peak2 (HPLC)60d1 376Peak1 (HPLC)60d2 376Peak2 (HPLC)60e1 419Peak1 (HPLC)60e2 419Peak2 (HPLC)60f1 425Peak1 (HPLC)60f2 425Peak2 (HPLC)60g1 432Peak1 (HPLC)60g2 432Peak2 (HPLC)60h1 446Peak1 (HPLC)60h2 446Peak2 (HPLC)60i1 501Peak1 (HPLC)60i2 501Peak2 (HPLC)60j1 508Peak1 (HPLC)60j2 508Peak2 (HPLC)60k1 519Peak1 (HPLC)60k2 519Peak2 (HPLC)60m1 466Peak1 (HPLC)60m2 466Peak2 (HPLC)60n1 509Peak1 (HPLC)60n2 509Peak2 (HPLC)60o1 515Peak1 (HPLC)60o2 515Peak2 (HPLC)60p1 522Peak1 (HPLC)60p2 522Peak2 (HPLC)60q1 527Peak1 (HPLC)60q2 527Peak2 (HPLC)60r1 534Peak1 (HPLC)60r2 534Peak2 (HPLC)60s1 383Peak1 (HPLC)60s2 383Peak2 (HPLC)60t1 425Peak1 (HPLC)60t2 425Peak2 (HPLC)60u1 451Peak1 (HPLC)60u2 451Peak2 (HPLC)60v1 432Peak1 (HPLC)60v2 432Peak2 (HPLC)60w1 446Peak1 (HPLC)60w2 446Peak2 (HPLC)60x1 460Peak1 (HPLC)60x2 460Peak2 (HPLC)60y1 458Peak1 (HPLC)60y2 458Peak2 (HPLC)70a1 403Peak1 (HPLC)70a2 403Peak2 (HPLC)70b1 417Peak1 (HPLC)70b2 417Peak2 (HPLC)80a1 405Peak1 (HPLC)80a2 405Peak2 (HPLC)80b1 419Peak1 (HPLC)80b2 419Peak2 (HPLC)90a1 419Peak1 (HPLC)90a2 419Peak2 (HPLC)90b1 433Peak1 (HPLC)90b2 433Peak2 (HPLC) PHARMACEUTICAL COMPOSITION AND ADMINISTRATION MODE

[0064] Since the compounds of the present invention have excellent inhibitory activity against hepatitis B virus (HBV), the various compounds of the present invention, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing a compound of the present invention as a main active ingredient can be used for the prevention and / or treatment (stabilization, alleviation or cure) of hepatitis B virus infection or for prevention and / or treatment (stabilization, alleviation or cure) hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation and necrosis which cause cirrhosis, end-stage liver disease, hepatitis B cancer).

[0065] The pharmaceutical composition of the invention comprises the compound of the present invention in a safe and effective dosage range and a pharmaceutically acceptable excipient or carrier. The term "safe and effective dosage" means that the amount of compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg compound of the invention per dose, preferably, 10-200mg compound of the invention per dose. Preferably, the "one dose" is one capsule or one tablet.

[0066] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, or gelatinous materials which are suitable for human use and should be of sufficient purity and sufficiently low toxicity. "Compatibility" means that each component in the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and the derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ®< ), wetting agent (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0067] There is no special limitation on administration mode for the compound or pharmaceutical composition of the present invention, and the representative administration mode includes (but is not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) administration.

[0068] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compounds are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or CaHPO4, or mixed with any of the following components: (a) fillers or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as, glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (e) dissolution-retarding agents, such as paraffin; (f) sorbefacientsabsorption-, such asquaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such askaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or the mixtures thereof. In capsules, tablets and pills, the dosage forms may also contain buffering agents.

[0069] The solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared by using coating and shell materials, such as enteric coatings and any other materials known in the art. They can contain an opaque agent. The release of the active compounds or compounds in the compositions can be released in a delayed mode in a given portion of the digestive tract. Examples of the embedding components include polymers and waxes. If necessary, the active compounds and one or more above excipients can form microcapsules.

[0070] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain any conventional inert diluents known in the art such as water or other solvents, solubilizes and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethyl formamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the combination thereof.

[0071] Besides these inert diluents, the composition may also contain additives such as wetting agents, emulsifiers, and suspending agent, sweetener, flavoring agents and perfume.

[0072] In addition to the active compounds, the suspension may contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.

[0073] The compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be re-dissolved into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable combination thereof.

[0074] The compounds of the present invention can be administrated alone, or in combination with any other pharmaceutically acceptable compounds (such as anti-HBV agents).

[0075] In the case of co-administration, the pharmaceutical composition can also include one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (such as anti-HBV agents). One or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents) may be used simultaneously, separately or sequentially with the compound of the present invention so as to prevent and / or treat HBV infection or HBV related diseases.

[0076] When the pharmaceutical composition is used, a safe and effective amount of compound of the present invention is administered to a mammal (such as human) in need of, wherein the dose of administration is a pharmaceutically effective dose. For a person weighed 60 kg, the daily dose is usually 1-2000 mg, preferably 20-500mg. Of course, the particular dose should also depend on various factors, such as the route of administration, patient healthy status, which are well within the skills of an experienced physician.The main advantages of the present invention include:

[0077] (1) The compounds of the present invention are novel in structure and have an excellent anti-hepatitis B virus infection effect. In this application, the existing endocyclic sulfoxide amide-arylamide compounds are transformed into endocyclic sulfonimid amide-arylamide compounds in order to better interfering with the assembly process of the capsid protein, thus inhibiting the activity or expression of HBV. (2) The compounds of the present invention have very low toxicity to normal cells, and therefore can be applied to a subject in a large dose range. (3) The compounds of the present invention have good drug ability. Compared with the existing compounds, the compounds of the present invention have better solubility and have shown good bioavailability in in vivo experiments. The bioavailability of some compounds has reached 70% or above. Meanwhile, the compounds of the present invention are extremely easy to make into pharmaceutically acceptable salts compared to existing compounds, and thus contribute to the further formation of formulations. (4) The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for prevention and / or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to liver cirrhosis, end-stage liver diseases, hepatitis B liver cancer).

[0078] The present invention will be further illustrated below with reference to the specific examples. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacturer's instructions. Unless indicated otherwise, parts and percentage are calculated by weight. Unless otherwise specified, the raw materials or instruments used in the embodiments of the present invention are commercially available.

[0079] The following are the synthesis of 10 types of compounds:Example 1: Synthesis of compound 10a

[0080] Step 1: Synthesis of Compound 2

[0081]

[0082] Compound 1 (10 g) was dissolved in dichloromethane (40 mL), and ammonia water (30 mL) was added dropwise to the reaction system at room temperature. The reaction was carried out for 5 h at room temperature, then vacuum filtrated, and the filter cake was washed with water (5mL) to provide 5g of light yellow solid, MS (M + 1 = 267).Step 2: Synthesis of Compound 3

[0083]

[0084] The substrate 2 (5 g) was dissolved in DMF (10 mL), sodium hydride (1.5 g) was added into the reaction system at 0 °C, and stirred for 15 min. TBDPSCl was then added to the reaction system, and reacted for 18 h. The reaction system was poured into ice water, and extracted with ethyl acetate (3 * 30 mL), and the organic phase was dried, the solvent was evaporated in vacuum. Crude product was purified via column chromatography (n-heptane: ethyl acetate = 1: 4) to provide the product 3 (3 g). MS (M + 1 = 505).Step 3: Synthesis of Compound 4

[0085]

[0086] The PPh 3 Cl 2 chloroform solution (80 mL) was cooled to 0 °C, and then triethylamine (7 mL) was added, stirred for 10 minutes and then compound 3 was added at 0 °C. After stirred for 20 minutes, 2-isopropyl-3-propenylamine was added to the reaction system and reacted at room temperature for 18h. Water (20 mL) and ethyl acetate (3 * 25mL) were added to the reaction system for extraction. The organic phase was dried and the solvent was evaporated in vacuum. Crude product was purified via column chromatography (n-heptane: ethyl acetate = 1: 5) to provide the product 4 (1.9 g). MS (M + 1 = 586).Step 4: Synthesis of Compound 5

[0087]

[0088] Compound 4 (1.8 g), Tetrakis (triphenylphosphine) palladium (100 mg), pinacol vinylboronate (900 mg), and cesium carbonate (2.7 g) were dissolved in DMF (410 mL), and the mixture was reacted at 100 °C under nitrogen for 15 h. The reaction was quenched with aqueous solution, extracted with ethyl acetate, and the organic phase was dried and the solvent was evaporated in vacuum. The resulting crude product was purified by column chromatography (n-heptane: ethyl acetate = 1: 5) to provide compound 5 (1.0 g). MS (M + 1 = 340).Step 5: Synthesis of Compound 6

[0089]

[0090] Compound 5 (1.0 g) was dissolved in dichloromethane (500 ml), and then the Zhan Catalyst (0.1 g) was added to the reaction system and stirred overnight. The solvent of reaction solution was evaporated in vacuum and crude product was purified via column chromatography (n-heptane: ethyl acetate = 1: 3) to provide compound 6. The lower point indicated by TLC was 6-1 (0.22 g), and the upper point indicated by TLC was 6-2 (0.27 g), MS (M + 1 = 312).Step 6: Synthesis of compound 10a1

[0091]

[0092] Compound 6-1 (30 mg) and 4-fluoro-3-cyanoaniline (20 mg) were dissolved in THF (5 mL), the solution was cooled to 0 °C, and then NaHMDS (0.2 mL) solution was added to the reaction system. The reaction was stirred at room temperature for 16 h, and water was added to the reaction system. The mixture was extracted with ethyl acetate (3 * 15 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuum. The crude product was subjected to column chromatography (n-heptane: ethyl acetate = 1: 3) to provide target product 10a1 (11mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 7.89 - 7.83 (m, 1H), 7.71 (s, 1H), 7.44 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.54 (dd, J = 12.4, 2.7 Hz, 1H), 5.75 (dd, J = 12.4, 2.8 Hz, 1H), 4.0 (dq, J = 7.8, 2.6 Hz, 1H), 3.74 (s, 3H), 1.97-1.89 (m, 1H), 0.98 (dd, J = 12.6, 6.7 Hz, 6H). MS(M+1=395).Example 2: Synthesis of Compound 10a2

[0093]

[0094] The reaction was carried out according to the step 6 of example 1, all the conditions were the same except the compound 6-2 was used instead of 6-1, column chromatography (n-heptane: ethyl acetate = 1: 1) purified to provide target product 10a2 (8mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 7.89 - 7.83 (m, 1H), 7.51 (s, 1H), 7.44 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.53 (dd, J = 12.4, 2.7 Hz, 1H), 5.72 (dd, J = 12.4, 2.8 Hz, 1H), 3.87 (dq, J = 7.8, 2.6 Hz, 1H), 3.72 (s, 3H), 1.91-1.85 ( m, 1H), 0.96 (dd, J = 12.6, 6.7 Hz, 6H). MS(M+1=395).Example 3: Synthesis of Compound 10b1

[0095] Step 1: Synthesis of Compound 7

[0096]

[0097] Compound 2 (2.5 g), vinyl borate (1.5 g), sodium carbonate (3.5 g), palladium acetate (120 mg) and Xphos (500 mg) were dissolved in DMF. Under nitrogen protection, the reaction system was placed in a pre-heated 100°C oil bath to react for 6 hours. Water (50 mL) was added to the reaction system, and extracted with ethyl acetate (3 * 60 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuum. Purified via column chromatography to provide 1.2 g of yellow solid. MS (M + 1 = 259).Step 2: Synthesis of Compound 8

[0098] The reaction system was cooled to 0 °C, sodium hydride (180 mg) was added to DMF, and then stirred for 10 min. TBDPSCl (2.7 g) and 7 (1.1 g) in DMF was added dropwise to the reaction system at 0 °C, and reacted at room temperature for 1.5 h. The reaction liquid was added dropwise to a mixed solution of 1N HCl and saturated ammonium chloride, extracted with ethyl acetate (3 * 50mL), dried over anhydrous sodium sulfate, the organic phase was evaporated in vacuum, and 800 mg of white solid was obtained by column chromatography, MS (M + 1 = 497). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 7.62 - 7.59 (m, 1H), 7.45 - 7.41(m, 1H), 7.33 - 7.29 (m, 3H), 7.13 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.16 (dd, J = 12.4, 2.7 Hz, 1H), 5.58 (dd, J = 12.4, 2.8 Hz, 1H), 5.09 (s, 1H), 4.35-4.40 (m, 2 ), 3.56 (s, 3H), 1.45-1.40 (m,3), 1.04 (s, 9H).Step 3: Synthesis of Compound 11

[0099]

[0100] The PPh 3 Cl 2 mixture was cooled to 0 °C, and then triethylamine (3mL) was added into the reaction system. After the addition, the mixture was reacted at 0 °C for 10 minutes, and then solid 8 (500mg) was added in one batch to the system, and stirred at 0 °C for 20 min. Finally, the chloroform solution of isopropylallylamine (200 mg) was added to the reaction system, and reacted at room temperature for 18 h. The silica gel was directly added to the reaction system, and purified via column chromatography to provide 650 mg of pale yellow oil. MS(M+1=578) 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.81 - 7.73 (m, 4H), 7.38-7.32 (m, 7H), 7.06 - 6.91 (m, 2H), 6.01-5.89 (m, 1 H), 5.48-5.33 (m, 2 H), 4.92-4.70 (m, 2 H), 4.36-4.30 (m, 2 H), 3.79 (s, 1.55H), 3.76 (s, 1.36H), 3.50-3.41(m, 1H ),1.71-1.66 (m, 0. 5H ),1.56-1.51 (m, 0. 5H ), 1.40-1.35 (m, 3 ),1.14 (s, 4.2H), 1.12 (s, 4.5H),0.76-0.73 (m,3H), 0.68-0.64 (m,3H).Step 4: Synthesis of Compound 12

[0101]

[0102] Compound 11 (650mg) was dissolved in 1,2-dichloroethane, and Zhan 1B was added to the reaction system. Under the protection of nitrogen, the system was warmed to 70 °C and stirred for 24h. Silica gel was directly added to the reaction system, and purified by column chromatography, after the solvent was evaporated in vacuum to provide pale yellow oil 12: The lower point of the TLC display was 12-1 (0.22 g), and the upper point of the TLC display was 12-2 (0.27 g), MS (M + 1 = 550). 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.81 - 7.74 (m, 5H), 7.40-7.37 (m, 7H), 7.28-7.21 (m, 1H), 6.01-5.89 (m, 1 H), 6.99 (s, 1H), 5.77-5.73 (m, 1 H), 4.42-4.35 (m, 2 H), 4.15-4.11 (m, 1 H), 3.80 (s, 3H), 1.91-1.86 (m, 1H ), 1.43-1.39 (m, 3 ), 1.14 (s, 9H), 0.87-0.78 (m,6H).Step 5: Synthesis of Compound 13

[0103]

[0104] Compound 12-1 (90 mg) (lower point shown by TLC) and 3,4-difluoroaniline (43 mg) was dissolved in THF (8 mL), then the system was cooled to 0 °C, and 6 eq of NaHMDS was added to the reaction system to react at 0 °C for 1 h. Water (20 mL) was added to the reaction system, and extracted with ethyl acetate (3 * 30 mL), dried over anhydrous sodium sulfate, the solvent was evaporated in vacuum, and purified via column chromatography to provide 80 mg of yellow oil. MS (M + 1 = 640).Step 6: Synthesis of compound 10b1

[0105]

[0106] Compound 13-1 (40 mg) (lower point shown by TLC) was dissolved in THF (3mL), then 120 eq of 3HF.TEA was added dropwise into the reaction system, reacted at room temperature for 3 days, separated by preparation TLC, and freeze-dried to obtain white solid 10b1 (4.5 mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 7.99(ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.78- 7.70 (m, 2H), 7.57 (d, J = 10.3 Hz, 1H), 6.57 (dd, J = 12.4, 2.7 Hz, 1H), 5.77 (dd, J = 12.4, 2.8 Hz, 1H), 4.07 (ddt, J = 10.6, 5.4, 2.7 Hz, 1H), 3.76 (s, 3H), 1.92 (tq, J = 12.1, 6.7, 5.6 Hz, 1H), 0.99 (dd, J = 12.0, 6.7 Hz, 6H). Ms (ESI) m / z = 402(M+1)Example 4: Synthesis of compound 10b2

[0107]

[0108] The reaction was carried out according to the step 6 of example 3, all the conditions were the same except the compound 13-2 (upper point shown by TLC) was used instead of compound 13-1 (lower point shown by TLC), purified by column chromatography (n-heptane: ethyl acetate = 1: 1) to provide target product 10b2 (8mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.97(ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.90- 7.88 (m, 2H), 7.56 (d, J = 10.3 Hz, 1H), 6.65(dd, J = 12.4, 2.7 Hz, 1H), 5.91 (dd, J = 12.4, 2.8 Hz, 1H), 3.80 (s, 3H), 3.69-3.63(m, 1H), 1.95 (tq, J = 12.1, 6.7, 5.6 Hz, 1H), 0.99 (dd, J = 12.0, 6.7 Hz, 6H). Ms (ESI) m / z = 402(M+1)

[0109] The following 10 and 30 series compounds were synthesized according to the method of example 3: No.StructureMass Spectrum ESI-MS, (M + H)Remark10c1 413Peak1 (HPLC)10c2 413Peak2 (HPLC)10d1 360Peak1 (HPLC)10d2 360Peak2 (HPLC)10e1 403Peak1 (HPLC)10e2 403Peak2 (HPLC)10f1 410Peak1 (HPLC)10f2 410Peak2 (HPLC)10g1 395Peak1 (HPLC)10g2 395Peak2 (HPLC)10h1 402Peak1 (HPLC)10h2 402Peak2 (HPLC)10i1 413Peak1 (HPLC)10i2 413Peak2 (HPLC)10j1 360Peak1 (HPLC)10j2 360Peak2 (HPLC)10k1 403Peak1 (HPLC)10k2 403Peak2 (HPLC)10m1 410Peak1 (HPLC)10m2 410Peak2 (HPLC)10n1 409Peak1 (HPLC)10n2 409Peak2 (HPLC)10o1 416Peak1 (HPLC)10o2 416Peak2 (HPLC)10p1 417Peak1 (HPLC)10p2 417Peak2 (HPLC)10q1 424Peak1 (HPLC)10q2 424Peak2 (HPLC)10r1 409Peak1 (HPLC)10r2 409Peak2 (HPLC)10s1 374Peak1 (HPLC)10s2 374Peak2 (HPLC)10t1 417Peak1 (HPLC)10t2 417Peak2 (HPLC)10u1 409Peak1 (HPLC)10u2 409Peak2 (HPLC)10v1 416Peak1 (HPLC)10v2 416Peak2 (HPLC)10w1 417Peak1 (HPLC)10w2 417Peak2 (HPLC)10x1 424Peak1 (HPLC)10x2 424Peak2 (HPLC)10y1 409Peak1 (HPLC)10y2 409Peak2 (HPLC)10z1 374Peak1 (HPLC)10z2 374Peak2 (HPLC)10aa1 417Peak1 (HPLC)10aa2 417Peak2 (HPLC)10bb1 435Peak1 (HPLC)10bb2 435Peak2 (HPLC)10cc1 442Peak1 (HPLC)10cc2 442Peak2 (HPLC)10dd1 443Peak1 (HPLC)10dd2 443Peak2 (HPLC)10ee1 450Peak1 (HPLC)10ee2 450Peak2 (HPLC)10ff1 435Peak1 (HPLC)10ff2 435Peak2 (HPLC)10gg1 400Peak1 (HPLC)10gg2 400Peak2 (HPLC)10hh1 443Peak1 (HPLC)10hh2 443Peak2 (HPLC)10ii1 429Peak1 (HPLC)10ii2 429Peak2 (HPLC)10jj1 436Peak1 (HPLC)10jj2 436Peak2 (HPLC)10kk1 437Peak1 (HPLC)10kk2 437Peak2 (HPLC)10mm1 429Peak1 (HPLC)10mm2 429Peak2 (HPLC)10nn1 436Peak1 (HPLC)10nn2 436Peak2 (HPLC)10oo1 437Peak1 (HPLC)10002 437Peak2 (HPLC)10pp 1< 443Peak1 (HPLC)10pp2 443Peak2 (HPLC)10qq1 450Peak1 (HPLC)10qq2 450Peak2 (HPLC)10rr1 451Peak1 (HPLC)10rr2 451Peak2 (HPLC)10ss1 443Peak1 (HPLC)10ss2 443Peak2 (HPLC)10tt1 450Peak1 (HPLC)10tt2 450Peak2 (HPLC)10uu1 451Peak1 (HPLC)10uu2 451Peak2 (HPLC)10vv1 493Peak1 (HPLC)10vv2 493Peak2 (HPLC)10ww1 500Peak1 (HPLC)10ww2 500Peak2 (HPLC)10xx1 501Peak1 (HPLC)10xx2 501Peak2 (HPLC)10yy1 493Peak1 (HPLC)10yy2 493Peak2 (HPLC)10zz1 500Peak1 (HPLC)10zz2 500Peak2 (HPLC)10aaa1 501Peak1 (HPLC)10aaa2 501Peak2 (HPLC)10bbb1 487Peak1 (HPLC)10bbb2 487Peak2 (HPLC)10ccc1 494Peak1 (HPLC)10ccc2 494Peak2 (HPLC)10ddd1 505Peak1 (HPLC)10ddd2 505Peak2 (HPLC)10eee1 486Peak1 (HPLC)10eee2 486Peak2 (HPLC)10fff1 495Peak1 (HPLC)10fff2 495Peak2 (HPLC)10ggg1 485Peak1 (HPLC)10ggg2 485Peak2 (HPLC)10hhh1 492Peak1 (HPLC)10hhh2 492Peak2 (HPLC)10iii1 503Peak1 (HPLC)10iii2 503Peak2 (HPLC)10jjj1 484Peak1 (HPLC)10jjj2 484Peak2 (HPLC)10kkk1 493Peak1 (HPLC)10kkk2 493Peak2 (HPLC)10mmm1 503Peak1 (HPLC)10mmm2 503Peak2 (HPLC)10nnn1 510Peak1 (HPLC)10nnn2 510Peak2 (HPLC)10ooo1 521Peak1 (HPLC)100002 521Peak2 (HPLC)10ppp1 502Peak1 (HPLC)10ppp2 502Peak2 (HPLC)10qqq1 511Peak1 (HPLC)10qqq2 511Peak2 (HPLC)10rrr1 515Peak1 (HPLC)10rrr2 515Peak2 (HPLC)10sss1 522Peak1 (HPLC)10sss2 522Peak2 (HPLC)10ttt1 533Peak1 (HPLC)10ttt2 533Peak2 (HPLC)10uuu1 514Peak1 (HPLC)10uuu2 514Peak2 (HPLC)10vvv1 523Peak1 (HPLC)10vvv2 523Peak2 (HPLC)10www1 367Peak1 (HPLC)10www2 367Peak2 (HPLC)10xxx1 411Peak1 (HPLC)10xxx2 411Peak2 (HPLC)30a1 397Peak1 (HPLC)30a2 397Peak2 (HPLC)30b1 404Peak1 (HPLC)30b2 404Peak2 (HPLC)30c1 415Peak1 (HPLC)30c2 415Peak2 (HPLC)30d1 362Peak1 (HPLC)30d2 362Peak2 (HPLC)30e1 405Peak1 (HPLC)30e2 405Peak2 (HPLC)30f1 412Peak1 (HPLC)30f2 412Peak2 (HPLC)30g1 383Peak1 (HPLC)30g2 383Peak2 (HPLC)30h1 390Peak1 (HPLC)30h2 390Peak2 (HPLC)30i1 401Peak1 (HPLC)30i2 401Peak2 (HPLC)30j1 348Peak1 (HPLC)30j2 348Peak2 (HPLC)30k1 391Peak1 (HPLC)30k2 391Peak2 (HPLC)30m1 398Peak1 (HPLC)30m2 398Peak2 (HPLC)

[0110] The following are the synthesis of 20 series compounds:Example 72: Synthesis of compound 20a1

[0111] Step 1

[0112]

[0113] Compound 10a1 (20 mg) was dissolved in methanol (5 mL), and then Pd / C (5 mg) was added to the reaction system. The reaction was performed in hydrogen atmophile at room temperature for 6 h. The crude product was column chromatography (n-heptane: ethyl acetate = 1: 3) purified to provide the target product 20a1 (11 mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 7.88- 7.83 (m, 1H), 7.63 (s, 2H), 7.46- 7.42 (m, 1H), 7.21- 6.96 (m, 1H), 3.72 (s, 3H), 3.12 - 3.09 (m, 1H), 3.00 (dd, J = 15.0, 6.7 Hz, 1H), 2.89 - 2.78(m, 1H), 1.89-1.85 (m, 1H), 1.69-1.50 (m, 1H), 1.43 (q, J = 12.0 Hz, 1H), 0.92 (dd, J = 6.8, 3.5 Hz, 6H). MS (M+1=397).Example 73: Synthesis of Compound 20a2

[0114]

[0115] The reaction was carried out according to the step 6 of example 1, all the conditions were the same except the compound 10a2 was used instead of 10a1, purified via column chromatography (n-heptane: ethyl acetate = 1: 1) to provide target product 20a2 (8mg). 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.67 (s, 1H), 8.20- 8.18 (m, 1H), 7.97 (d, J = 3.7 Hz, 1H), 7.68- 7.59 (m, 1H), 7.55 (d, J = 10.3 Hz, 1H), 3.76 (s, 3H), 3.04 - 2.92 (m, 2H), 2.85 (dd, J = 15.0, 6.7 Hz, 1H), 1.90 - 1.83 (m, 1H), 1.73 (dd, J = 14.3, 6.7 Hz, 1H), 1.69-1.50 (m, 1H), 1.45 (q, J = 12.0 Hz, 1H), 0.89 (dd, J = 6.8, 3.5 Hz, 6H). MS (M+1=397).Example 74: Synthesis of compound 20b1

[0116] Step 1

[0117]

[0118] Compound 1 (150 mg) was dissolved in methanol (8 mL), and Pd / C (30 mg) was added to the reaction system, and purged with nitrogen for three times, then purged with hydrogen for three times. The reaction was carried out at room temperature (25 °C) for 18h with a hydrogen balloon, and the raw material was monitored to have been consumed with TLC. The reaction was suction filtrated, and the solvent was evaporated in vacuum, and purified via column chromatography (n-heptane: ethyl acetate = 5: 1) to obtain the target product 130 mg. MS (M + 1 = 552).Step 2

[0119]

[0120] Compound 12-1 (45 mg) (lower point shown by TLC) and 3-cyano-4-fluoroaniline (23 mg) was dissolved in THF (6 mL), then the system was cooled to 0 °C. 8 eq of NaHMDS was added to the reaction system to react at 0 °C for 1 h. Water (20 mL) was added to the reaction system, and extracted with ethyl acetate (3 * 30 mL), dried over anhydrous sodium sulfate, the solvent was evaporated in vacuum, and purified by column chromatography to provide 18 mg of yellow oil. MS (M + 1 = 640).Step 3: Synthesis of compound 20b1

[0121]

[0122] Compound 2 (18 mg) was dissolved in THF (3 mL), and 50 eq of 3HF.TEA was added dropwise to the reaction system. The reaction was performed at room temperature for 3 days. The mixture was purified by preparation TLC and freeze-dried to obtain 4.0 mg of the target product as a white solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 10.77(s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.98 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.90 (s, 1H), 7.51 (t, J = 9.1 Hz, 1H), 3.77 (s, 3H), 3.11 - 3.02 (m, 2H), 2.89 - 2.87 (m, 1H), 1.97-1.92 (m, 1H), 1.78-1.73 (m, 1H), 1.60-1.51 (m, 1H), 0.96 (dd, J = 6.8, 3.4 Hz, 6H).Ms(ESI) m / z = 404(M+1)Example 75: Synthesis of compound 20b2

[0123]

[0124] The reaction was carried out according to the step 3 of example 74, all the conditions were the same except the compound 19b2 was used instead of 19b1, column chromatography (n-heptane: ethyl acetate = 1: 1) purified to provide target product 20b2 (8mg). 1< H NMR (400 MHz, DMSO-d 6 )δ 10.67 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J = 9.1 Hz, 1H), 3.76 (s, 3H), 3.04-2.92(m, 2H), 2.85 - 2.83 (m, 1H), 1.90-1.83 (m, 1H), 1.74-1.69 (m, 1H), 1.67-1.46 (m, 1H), 0.89 (dd, J = 6.8, 3.4 Hz, 6H).Ms(ESI ) m / z = 404(M+1)

[0125] The following 20 and 40 series compounds are synthesized according to the method of example 72 or 74: No.StructureMass Spectrum ESI-MS, (M + H)Remark20c1 415Peak1 (HPLC)20c2 415Peak2 (HPLC)20d1 362Peak1 (HPLC)20d2 362Peak2 (HPLC)20e1 405Peak1 (HPLC)20e2 405Peak2 (HPLC)20f1 412Peak1 (HPLC)20f2 412Peak2 (HPLC)20g1 397Peak1 (HPLC)20g2 397Peak2 (HPLC)20h1 404Peak1 (HPLC)20h2 404Peak2 (HPLC)20i1 415Peak1 (HPLC)20i2 415Peak2 (HPLC)20j1 362Peak1 (HPLC)20j2 362Peak2 (HPLC)20k1 405Peak1 (HPLC)20k2 405Peak2 (HPLC)20m1 412Peak1 (HPLC)10m2 412Peak2 (HPLC)20n1 411Peak1 (HPLC)20n2 411Peak2 (HPLC)20o1 418Peak1 (HPLC)20o2 418Peak2 (HPLC)20p1 419Peak1 (HPLC)20p2 419Peak2 (HPLC)20q1 426Peak1 (HPLC)20q2 426Peak2 (HPLC)20r1 411Peak1 (HPLC)20r2 411Peak2 (HPLC)20s1 376Peak1 (HPLC)20s2 376Peak2 (HPLC)20t1 419Peak1 (HPLC)20t2 419Peak2 (HPLC)20u1 411Peak1 (HPLC)20u2 411Peak2 (HPLC)20v1 418Peak1 (HPLC)20v2 418Peak2 (HPLC)20w1 419Peak1 (HPLC)20w2 419Peak2 (HPLC)20x1 426Peak1 (HPLC)20x2 426Peak2 (HPLC)20y1 411Peak1 (HPLC)20y2 411Peak2 (HPLC)20z1 376Peak1 (HPLC)20z2 376Peak2 (HPLC)20aa1 419Peak1 (HPLC)20aa2 419Peak2 (HPLC)20bb1 437Peak1 (HPLC)20bb2 437Peak2 (HPLC)20cc1 444Peak1 (HPLC)20cc2 444Peak2 (HPLC)20dd1 445Peak1 (HPLC)20dd2 445Peak2 (HPLC)20ee1 452Peak1 (HPLC)20ee2 452Peak2 (HPLC)20ff1 437Peak1 (HPLC)20ff2 437Peak2 (HPLC)20gg1 402Peak1 (HPLC)20gg2 402Peak2 (HPLC)20hh1 445Peak1 (HPLC)20hh2 445Peak2 (HPLC)20ii1 431Peak1 (HPLC)20ii2 431Peak2 (HPLC)20jj1 438Peak1 (HPLC)20jj2 438Peak2 (HPLC)20kk1 439Peak1 (HPLC)20kk2 439Peak2 (HPLC)20mm1 431Peak1 (HPLC)20mm2 431Peak2 (HPLC)20nn1 438Peak1 (HPLC)20nn2 438Peak2 (HPLC)20001 439Peak1 (HPLC)20oo2 439Peak2 (HPLC)20pp1 445Peak1 (HPLC)20pp2 445Peak2 (HPLC)20qq1 452Peak1 (HPLC)20qq2 452Peak2 (HPLC)20rr1 453Peak1 (HPLC)20rr2 453Peak2 (HPLC)20ss1 445Peak1 (HPLC)20ss2 445Peak2 (HPLC)20tt1 452Peak1 (HPLC)20tt2 452Peak2 (HPLC)20uu1 453Peak1 (HPLC)20uu2 453Peak2 (HPLC)20vv1 495Peak1 (HPLC)20vv2 495Peak2 (HPLC)20ww1 502Peak1 (HPLC)20ww2 502Peak2 (HPLC)20xx1 503Peak1 (HPLC)20xx2 503Peak2 (HPLC)20yy1 495Peak1 (HPLC)20yy2 495Peak2 (HPLC)20zz1 502Peak1 (HPLC)20zz2 502Peak2 (HPLC)20aaa1 503Peak1 (HPLC)20aaa2 503Peak2 (HPLC)20bbb1 489Peak1 (HPLC)20bbb2 489Peak2 (HPLC)20ccc1 496Peak1 (HPLC)20ccc2 496Peak2 (HPLC)20ddd1 507Peak1 (HPLC)20ddd2 507Peak2 (HPLC)20eee1 488Peak1 (HPLC)20eee2 488Peak2 (HPLC)20fff1 497Peak1 (HPLC)20fff2 497Peak2 (HPLC)20ggg1 486Peak1 (HPLC)20ggg2 486Peak2 (HPLC)20hhh1 494Peak1 (HPLC)20hhh2 494Peak2 (HPLC)20iii1 505Peak1 (HPLC)20iii2 505Peak2 (HPLC)20jjj1 486Peak1 (HPLC)20jjj2 486Peak2 (HPLC)20kkk1 495Peak1 (HPLC)20kkk2 495Peak2 (HPLC)20mmm1 505Peak1 (HPLC)20mmm2 505Peak2 (HPLC)20nnn1 512Peak1 (HPLC)20nnn2 512Peak2 (HPLC)20ooo1 523Peak1 (HPLC)20ooo2 523Peak2 (HPLC)20ppp1 504Peak1 (HPLC)20ppp2 504Peak2 (HPLC)20qqq1 513Peak1 (HPLC)20qqq2 513Peak2 (HPLC)20rrr1 517Peak1 (HPLC)20rrr2 517Peak2 (HPLC)20sss1 524Peak1 (HPLC)20sss2 524Peak2 (HPLC)20ttt1 535Peak1 (HPLC)20ttt2 535Peak2 (HPLC)20uuu1 516Peak1 (HPLC)20uuu2 516Peak2 (HPLC)20vvv1 525Peak1 (HPLC)20vvv2 525Peak2 (HPLC)20www1 369Peak1 (HPLC)20www2 369Peak2 (HPLC)20xxx1 413Peak1 (HPLC)20xxx2 413Peak2 (HPLC)40a1 399Peak1 (HPLC)40a2 399Peak2 (HPLC)40b1 406Peak1 (HPLC)40b2 406Peak2 (HPLC)40c1 417Peak1 (HPLC)40c2 417Peak2 (HPLC)40d1 364Peak1 (HPLC)40d2 364Peak2 (HPLC)40e1 407Peak1 (HPLC)40e2 407Peak2 (HPLC)40f1 414Peak1 (HPLC)40f2 414Peak2 (HPLC)40g1 385Peak1 (HPLC)40g2 385Peak2 (HPLC)40h1 392Peak1 (HPLC)40h2 392Peak2 (HPLC)40i1 403Peak1 (HPLC)40i2 403Peak2 (HPLC)40j1 350Peak1 (HPLC)40j2 350Peak2 (HPLC)40k1 393Peak1 (HPLC)40k2 393Peak2 (HPLC)40m1 400Peak1 (HPLC)40m2 400Peak2 (HPLC) The following are the synthesis of 50 series compounds:Example 167: Synthesis of compound 50al

[0126] Step 1: Synthesis of Compound 42

[0127]

[0128] Compound 41 (10 g) was dissolved in dichloromethane (40 mL), and methylamine aqueous solution (30 mL) was added dropwise to the reaction system at room temperature. The reaction was carried out for 5 h at room temperature, then suction filtrated, and the filter cake was washed with water (5mL) to provide 5g of light yellow solid 42, MS (M + 1 = 281).Step 2: Synthesis of Compound 43

[0129]

[0130] The PPh 3 Cl 2 chloroform solution (80 mL) was cooled to 0 °C, and then triethylamine (7 mL) was added, stirred for 10 minutes and then compound 42 (5.0g) was added at 0 °C. After stirred for 20 minutes, 2-isopropyl-3-propenylamine (5g) was added to the reaction system and reacted at room temperature for 18h. Water (20 mL) and ethyl acetate (3 * 25mL) were added to the reaction system for extraction. The organic phase was dried and the solvent was evaporated in vacuum. Crude product was purified by column chromatography (n-heptane: ethyl acetate = 1: 5) to provide the product 43 (400 mg). MS (M + 1 = 362).Step 3: Synthesis of Compound 44

[0131]

[0132] Compound 43 (1.8 g), tetrakis (triphenylphosphine) palladium (100 mg), vinyl borate (900 mg), and cesium carbonate (2.7 g) were dissolved in DMF (410 mL), and the mixture was reacted at 100 °C under the protection of nitrogen for 15 h. The reaction was quenched with an aqueous solution, extracted with ethyl acetate, and the organic phase was dried and the solvent was evaporated in vacuum. The resulting crude product was purified by column chromatography (n-heptane: ethyl acetate = 1: 5) to provide compound 44 (0.5 g). MS (M + 1 = 354).Step 4: Synthesis of Compound 45

[0133]

[0134] Compound 44 (1.0 g) was dissolved in dichloromethane (500 ml), and then the Zhan Catalyst (0.1 g) was added to the reaction system and stirred overnight. The reaction solution was evaporated in vacuum and crude product was column chromatography (n-heptane: ethyl acetate = 1: 3) purified to provide compound 45. The lower point of the TLC display was 45-1 (0.22 g), and the upper point of the TLC display was 45-2 (0.27 g), MS (M + 1 = 312).Step 5: Synthesis of compound 50al

[0135]

[0136] Compound 45-1 (30 mg) and 4-fluoro-3-cyanoaniline (20 mg) were dissolved in THF (5 mL), the system was cooled to 0 °C, and then NaHMDS (0.2 mL) was added to the reaction system. The reaction was stirred at room temperature for 16 h, and water was added to the reaction system. The mixture was extracted with ethyl acetate (3 * 15 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuum. The crude product was subjected to column chromatography (n-heptane: ethyl acetate = 1: 3) to provide target product 50a1 (11mg). MS (M + 1 = 409).

[0137] The following 50 series compounds are synthesized according to the method of example 167: No.StructureMass Spectrum ESI-MS, (M + H)Remark50b1 416Peak1 (HPLC)50b2 416Peak2 (HPLC)50c1 413Peak1 (HPLC)50c2 427Peak2 (HPLC)50d1 374Peak1 (HPLC)50d2 360Peak2 (HPLC)50e1 417Peak1 (HPLC)50e2 417Peak2 (HPLC)50f1 423Peak1 (HPLC)50f2 423Peak2 (HPLC)50g1 430Peak1 (HPLC)50g2 430Peak2 (HPLC)50h1 442Peak1 (HPLC)50h2 442Peak2 (HPLC)50i1 499Peak1 (HPLC)50i2 499Peak2 (HPLC)50j1 506Peak1 (HPLC)50j2 506Peak2 (HPLC)50k1 517Peak1 (HPLC)50k2 427Peak2 (HPLC)50m1 464Peak1 (HPLC)50m2 464Peak2 (HPLC)50n1 507Peak1 (HPLC)50n2 507Peak2 (HPLC)50o1 513Peak1 (HPLC)50o2 513Peak2 (HPLC)50p1 520Peak1 (HPLC)50p2 520Peak2 (HPLC)50q1 525Peak1 (HPLC)50q2 525Peak2 (HPLC)50r1 532Peak1 (HPLC)50r2 532Peak2 (HPLC)50s1 430Peak1 (HPLC)50s2 430Peak2 (HPLC)50t1 444Peak1 (HPLC)50t2 444Peak2 (HPLC)50u1 458Peak1 (HPLC)50u2 458Peak2 (HPLC)50v1 456Peak1 (HPLC)50v2 456Peak2 (HPLC)50w1 381Peak1 (HPLC)50w2 381Peak2 (HPLC)50x1 423Peak1 (HPLC)50x2 423Peak2 (HPLC) The following are the synthesis of 60 series compounds:Example 186: Synthesis of compound 60al

[0138] Step 1

[0139]

[0140] Compound 50a1 (20 mg) was dissolved in methanol (5 mL), and then palladium carbon (5 mg) was added to the reaction system. The reaction was performed at room temperature for 6 h under hydrogen. The crude product was purified by column chromatography (n-heptane: ethyl acetate = 1: 3) to provide the target product 60a1 (11 mg). MS (M + 1 = 411)

[0141] The following 60 series compounds are synthesized according to the method of example 186: No.StructureMass Spectrum ESI-MS, (M + H)Remark60a2 411Peak2 (HPLC)60b1 418Peak1 (HPLC)60b2 418Peak2 (HPLC)60c1 429Peak1 (HPLC)60c2 429Peak2 (HPLC)60d1 376Peak1 (HPLC)60d2 376Peak2 (HPLC)60e1 419Peak1 (HPLC)60e2 419Peak2 (HPLC)60f1 425Peak1 (HPLC)60f2 425Peak2 (HPLC)60g1 432Peak1 (HPLC)60g2 432Peak2 (HPLC)60h1 446Peak1 (HPLC)60h2 446Peak2 (HPLC)60i1 501Peak1 (HPLC)60i2 501Peak2 (HPLC)60j1 508Peak1 (HPLC)60j2 508Peak2 (HPLC)60k1 519Peak1 (HPLC)60k2 519Peak2 (HPLC)60m1 466Peak1 (HPLC)60m2 466Peak2 (HPLC)60n1 509Peak1 (HPLC)60n2 509Peak2 (HPLC)60o1 515Peak1 (HPLC)60o2 515Peak2 (HPLC)60p1 522Peak1 (HPLC)60p2 522Peak2 (HPLC)60q1 527Peak1 (HPLC)60q2 527Peak2 (HPLC)60r1 534Peak1 (HPLC)60r2 534Peak2 (HPLC)60s1 383Peak1 (HPLC)60s2 383Peak2 (HPLC)60t1 425Peak1 (HPLC)60t2 425Peak2 (HPLC)60u1 451Peak1 (HPLC)60u2 451Peak2 (HPLC)60v1 432Peak1 (HPLC)60v2 432Peak2 (HPLC)60w1 446Peak1 (HPLC)60w2 446Peak2 (HPLC)60x1 460Peak1 (HPLC)60x2 460Peak2 (HPLC)60y1 458Peak1 (HPLC)60y2 458Peak2 (HPLC)

[0142] The following are the synthesis of 70, 80 and 90 series compounds:Example 234: Synthesis of compound 70a1

[0143] The reaction was carried out according to the example 74 and example 167, while the pyrrole compounds were replaced with pyrazole compounds to obtain the compounds in the following list. 70a1 403Peak1 (HPLC)70a2 403Peak2 (HPLC)70b1 417Peak1 (HPLC)70b2 417Peak2 (HPLC)80a1 405Peak1 (HPLC)80a2 405Peak2 (HPLC)80b1 419Peak1 (HPLC)80b2 419Peak2 (HPLC)90a1 419Peak1 (HPLC)90a2 419Peak2 (HPLC)90b1 433Peak1 (HPLC)90b2 433Peak2 (HPLC) Biological Example-Anti-HBV Activity Experiment Experiment 1: In vitro anti-HBV nucleocapsid assembly activity test Main reagents and raw materials:

[0144] C150 protein was expressed and purified by WuXi Apptec Co., Ltd; BoDIPY ®< FL was purchased from Thermo Fisher Scientific. Protein fluorescent label:

[0145] 150 µL of 2% w / v skimmed milk was added into each well of 96-well plate, and incubated at room temperature for 2 hours. The skimmed milk was aspirated. The plate was washed with deionized water and dried, and stored at room temperature. C150 protein (3 mg per tube) was desalted with 5 ml Hitrap desalting column. The desalted C150 protein of each tube was added with 50 mM BoDIPY ®< FL Fluorescent Dye (20 µl), and incubated under 4 °C overnight in the dark after well mixed. Sephadex G-25 gel was used for filtration to remove fluorescent dyes that were not bounded onto C150. The C150 fluorescent labeling efficiency was calculated according to the following equation: BoDIPY ® FL = A 504 / 78 , 000 M − 1 ; C 150 Bo = A 280 − BoDIPY ® FL × 1300 M − 1 / 60 , 900 M − 1 ; Fluorescent Labeling Efficiency = BoDIPY ® FL / C 150 Bo ; wherein, [BoDIPY ®< FL] represents the concentration of the fluorescent label; [C150Bo] represents the concentration of fluorescently labeled protein; A504 represents the absorbance value at 504nM wavelength; A280 represents the absorbance value at 280nM wavelength; M -1< represents the reciprocal of the molar concentration. Compound dilution:

[0146] The mother liquor of compound was diluted with DMSO to 6 mM, then diluted to 600 µM with 50 mM HEPES, and then further 3-fold diluted with 10 DMSO / 50 mM HEPES to 8 concentrations.

[0147] C150Bo was diluted to 2 µM with 50mM HEPES. 37.5 µL of C150Bo and 2.5 µL of compound at each concentration were added into a 96 well plate and well mixed, then incubated at room temperature for 15 minutes. 10 µl of 750 mM NaCl / 50 mM HEPES were added into the each reaction well, and the final concentration of NaCl was 150 mM.

[0148] Into the control wells in the 0% protein group 10 µL of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.

[0149] Into the control wells in the 100% protein group 10 µL of 5 M / 50 mM HEPES was added, and the final concentration of NaCl was 1 M.

[0150] The final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 µM, and final concentration of C150Bo was 1.5µM. The mixture was incubated at room temperature for 1 hour. Fluorescence signal was measured (excitation light was 485 nm; emission light was 535 nm).Data analysis

[0151]

[0152] IC 50 value was calculated by prism software, and the equation was as follows: Y = Bottom + Top − Bottom / 1 + 10 LogIC 50 − X * HillSlope ; wherein, X represents the logarithm of the concentration, Y represents the effect value, and Y starts from the bottom and fits to the top by S type fitting. Bottom represents the bottom of the curve; Top represents the top of the curve; HillSlope represents the absolute value of the maximum slope of the curve. Experiment 2: Determination of Anti-HBV Activity in HepG2.2.15 Cell Main reagents:

[0153] QIAamp 96 DNA Blood Kit (12) (Qiagen, Item No. 51162); FastStart Universal Probe Master (Roche, Item No. 04914058001); Cell-titer Glo Testing Reagent (Promega, Item No. G7573).

[0154] Compound dilution: all the compounds for in vitro anti-HBV activity assay and cytotoxicity assay were 3-fold diluted into 8 concentrations. The final starting concentration of the tested compound was 30 µM, the final starting concentration of reference compound GLS4 was 1 µM, and the final concentration of DMSO was 0.5%.

[0155] HepG2.2.15 cells (4 × 10 4< cells / well) was inoculated into 96-well plates and cultured overnight at 37 °C, 5% CO 2 . On the second day, fresh culture medium containing different concentrations of compounds was added into the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.

[0156] On the eighth day, the supernatant in the culture well was collected for extraction of HBV DNA, and the content of HBV DNA in the supernatant of HepG2.2.15 was detected by qPCR. After the supernatant was collected, the medium and Cell-titer Glo reagent were added into the culture well, and the chemiluminescence value of each well was measured by microplate reader.

[0157] The activity calculation formula was as follows: Y = Bottom + Top − Bottom / 1 + 10 LogIC 50 − X * HillSlope ; wherein, X represents the logarithm of the concentration, Y represents the effect value, and Y starts from the bottom and fits to the top by S type fitting. Bottom represents the bottom of the curve; Top represents the top of the curve; HillSlope represents the absolute value of the maximum slope of the curve. Experiment 3: Determination of cytotoxicity

[0158] The cytotoxicity of the test compound was tested using HepG2 cells. The cells were incubated for 4 days in the presence of the test compound. Cell activity was assessed using the resazurin assay.

[0159] The results showed that the compound of the present invention had good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and had low cytotoxicity.

[0160] The activity data of experiment 1 to 3 are shown in Table 13: Table 13Compound No.Experiment 1 Protein experiment IC 50 (µM)Experiment 2 Cell experiment EC 50 (nM)Experiment 3 Cytotoxicity CC 50 (nM)10a1++++>3000010a2+++++>3000010b1++++>3000010b2+++++>3000010c1++++>3000010c2+++++>3000010e1++++>3000010e2+++++>3000010f1++++>3000010f2+++++>3000010g1++++>3000010g2+++++>3000010h1+++>3000010h2+++>3000010n1++++>3000010n2+++++>3000010o1++++>3000010o2+++++>3000010w1++++>3000010w2+++++>3000010bb1++++>3000010bb2+++++>3000010cc1++++>3000010cc2+++++>3000010ccc1++++>3000010ccc2+++++>3000010ddd1++++>3000010ddd2+++++>3000010vvv1++++>3000010vvv2+++++>3000020a1++++>3000020a2+++++>3000020b1++++>3000020b2+++++>3000020c1++++>3000020c2+++++>3000020dd1++++>3000020dd2+++++>3000020ee1++++>3000020ee2+++++>3000020ccc1+++++>3000020ccc2+++++>3000020ttt1++++>3000020ttt2+++++>3000030a1++++>3000030a2++++>3000030b1++++>3000030b2++++>3000030c1++++>3000030c2++++>3000030g1++++>3000030g2++++>3000040a1++++>3000040a2++++>3000040b1++++>3000040b2++++>3000040g1++++>3000040g2++++>3000050a1++++>3000050a2+++++>3000050s1++++>3000050s2+++++>3000050t1++++>3000050t2+++++>3000050u1++++>3000050u2+++++>3000050v1++++>3000050v2+++++>3000060a1++++>3000060a2+++++>3000060g1++++>3000060g2+++++>3000060h1++++>3000060h2+++++>3000060v1++++>3000060v2+++++>3000060w1++++>3000060w2+++++>3000060x1++++>3000060x2+++++>3000060y1++++>3000060y2+++++>3000070a1++++>3000070a2+++++>3000070b1++++>3000070b2+++++>3000080a1++++>3000080a2+++++>3000080b1++++>3000080b2+++++>3000090a1++++>3000090a2+++++>3000090b1++++>3000090b2+++++>30000

[0161] In the table: +++ indicates IC 50 <1µM; ++ indicates that IC 50 is 1~100µM; + indicates that IC 50 is >100µM. ++++ indicates EC 50 <0.1nM; +++ indicates that EC 50 is 0.1~100nM; ++ indicates that EC 50 is 100~1000nM; + indicates that EC 50 is >1000nM.

[0162] Therefore, the compounds of the present application have excellent anti-HBV activity.

[0163] Meanwhile, for the compound of the present invention, after being separated by HPLC, the two configuration of compounds based on the chiral sulfur atom center (that is, the S atom in O=S=N-R6) can be effectively separated. The inventors have unexpectedly founded that, between the two configuration compounds based on the chiral sulfur atom center, the enantiomer with less polarity has significantly higher activity against HBV nucleocapsid than the enantiomer with greater polarity, and in some embodiments, and the difference in activity can reach up to several times.Experiment 4 Example of mouse PK experiment:

[0164] 18 male C57 mice (9 intravenously administrated and 9 orally administrated) were randomly grouped according to body weight, and were administered with the test compounds at 2 mg / kg (intravenous) and 50 mg / kg (oral). 3 mice were taken at each time point in each group for a total of 8 time points (5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours). The calculation method of oral bioavailability F was AUC po / Dose po / AUC iv / Dose iv .

[0165] The compound of the present invention was administrated, and the result showed that each compound showed good bioavailability in in vivo experiments, and the bioavailability of some compounds have reached or exceeded 70%.

Claims

1. A compound represented by formula L, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein n is 1; is a substituted or unsubstituted five or six membered ring, wherein the five or six membered ring is pyrrole or pyrazole; the substituted means that the hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of C1-C3 alkyl, C3-C4 cycloalkyl, cyano, or halogen; is a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridinyl; X is-CRaRb-; Y is unsubstituted C2 alkylene or substituted or unsubstituted C2 alkenylene, wherein the substituent is selected from the group consisting of C1-C4 alkyl, hydroxyl; Z is a C-C single bond; W is none; R1, R2, R3 and R4 are each independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; wherein the substituted means that hydrogen atoms on the group are substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl; R5, R6 are each independently selected from the group consisting of H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; Ra and Rb are each independently H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O) -substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C6 alkoxy-alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; Rc is H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; unless otherwise specified, "substituted" means that the group substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, carboxyl, and unsubstituted or substituted groups selected from the group consisting of C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, wherein the substituent of the above group is selected from the group consisting of halogen and C1-C6 alkoxy.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is of a formula selected from the group consisting L-1, L-2, L-3 and L-4: in each formula, n is 1; the definitions of A ring, B ring, X, R1, R2, R3, R4, R5, and R6 are as described in claim 1.

3. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has a structure shown in the following formula II: wherein X1 is -CR= or -N=, X2 is -NR-; and R is H or C1-C4 alkyl.

4. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the X2 is -NCH3-.

5. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has the following structure:

6. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula I has a structure shown by the following formula IV-1 or IV-2:

7. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ra is selected from the group consisting of substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C6 alkoxy-alkyl; Rb is H.

8. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is the compound selected from the group consisting of No.StructureMass Spectrum ESI-MS, (M + H)Remark10a1 395Peak1 (HPLC)10a2 395Peak2 (HPLC)10b1 402Peak1 (HPLC)10b2 402Peak2 (HPLC)10c1 413Peak1 (HPLC)10c2 413Peak2 (HPLC)10d1 360Peak1 (HPLC)10d2 360Peak2 (HPLC)10e1 403Peak1 (HPLC)10e2 403Peak2 (HPLC)10f1 410Peak1 (HPLC)10f2 410Peak2 (HPLC)10g1 395Peak1 (HPLC)10g2 395Peak2 (HPLC)10h1 402Peak1 (HPLC)10h2 402Peak2 (HPLC)10i1 413Peak1 (HPLC)10i2 413Peak2 (HPLC)10j1 360Peak1 (HPLC)10j2 360Peak2 (HPLC)10k1 403Peak1 (HPLC)10k2 403Peak2 (HPLC)10m1 410Peak1 (HPLC)10m2 410Peak2 (HPLC)10n1 409Peak1 (HPLC)10n2 409Peak2 (HPLC)10o1 416Peak1 (HPLC)10o2 416Peak2 (HPLC)10p1 417Peak1 (HPLC)10p2 417Peak2 (HPLC)10q1 424Peak1 (HPLC)10q2 424Peak2 (HPLC)10r1 409Peak1 (HPLC)10r2 409Peak2 (HPLC)10s1 374Peak1 (HPLC)10s2 374Peak2 (HPLC)10t1 417Peak1 (HPLC)10t2 417Peak2 (HPLC)10u1 409Peak1 (HPLC)10u2 409Peak2 (HPLC)10v1 416Peak1 (HPLC)10v2 416Peak2 (HPLC)10w1 417Peak1 (HPLC)10w2 417Peak2 (HPLC)10x1 424Peak1 (HPLC)10x2 424Peak2 (HPLC)10y1 409Peak1 (HPLC)10y2 409Peak2 (HPLC)10z1 374Peak1 (HPLC)10z2 374Peak2 (HPLC)10aa1 417Peak1 (HPLC)10aa2 417Peak2 (HPLC)10bb1 435Peak1 (HPLC)10bb2 435Peak2 (HPLC)10cc1 442Peak1 (HPLC)10cc2 442Peak2 (HPLC)10dd1 443Peak1 (HPLC)10dd2 443Peak2 (HPLC)10ee1 450Peak1 (HPLC)10ee2 450Peak2 (HPLC)10ff1 435Peak1 (HPLC)10ff2 435Peak2 (HPLC)10gg1 400Peak1 (HPLC)10gg2 400Peak2 (HPLC)10hh1 443Peak1 (HPLC)10hh2 443Peak2 (HPLC)10ii1 429Peak1 (HPLC)10ii2 429Peak2 (HPLC)10jj1 436Peak1 (HPLC)10jj2 436Peak2 (HPLC)10kk1 437Peak1 (HPLC)10kk2 437Peak2 (HPLC)10mm1 429Peak1 (HPLC)10mm2 429Peak2 (HPLC)10nn1 436Peak1 (HPLC)10nn2 436Peak2 (HPLC)10oo1 437Peak1 (HPLC)10002 437Peak2 (HPLC)10pp1 443Peak1 (HPLC)10pp2 443Peak2 (HPLC)10qq1 450Peak1 (HPLC)10qq2 450Peak2 (HPLC)10rr1 451Peak1 (HPLC)10rr2 451Peak2 (HPLC)10ss1 443Peak1 (HPLC)10ss2 443Peak2 (HPLC)10tt1 450Peak1 (HPLC)10tt2 450Peak2 (HPLC)10uu1 451Peak1 (HPLC)10uu2 451Peak2 (HPLC)10vv1 493Peak1 (HPLC)10vv2 493Peak2 (HPLC)10ww1 500Peak1 (HPLC)10ww2 500Peak2 (HPLC)10xx1 501Peak1 (HPLC)10xx2 501Peak2 (HPLC)10yy1 493Peak1 (HPLC)10yy2 493Peak2 (HPLC)10zz1 500Peak1 (HPLC)10zz2 500Peak2 (HPLC)10aaa1 501Peak1 (HPLC)10aaa2 501Peak2 (HPLC)10bbb1 487Peak1 (HPLC)10bbb2 487Peak2 (HPLC)10ccc1 494Peak1 (HPLC)10ccc2 494Peak2 (HPLC)10ddd1 505Peak1 (HPLC)10ddd2 505Peak2 (HPLC)10eee1 486Peak1 (HPLC)10eee2 486Peak2 (HPLC)10fff1 495Peak1 (HPLC)10fff2 495Peak2 (HPLC)10ggg1 485Peak1 (HPLC)10ggg2 485Peak2 (HPLC)10hhh1 492Peak1 (HPLC)10hhh2 492Peak2 (HPLC)10iii1 503Peak1 (HPLC)10iii2 503Peak2 (HPLC)10jjj1 484Peak1 (HPLC)10jjj2 484Peak2 (HPLC)10kkk1 493Peak1 (HPLC)10kkk2 493Peak2 (HPLC)10mmm1 503Peak1 (HPLC)10mmm2 503Peak2 (HPLC)10nnn1 510Peak1 (HPLC)10nnn2 510Peak2 (HPLC)10ooo1 521Peak1 (HPLC)100002 521Peak2 (HPLC)10ppp1 502Peak1 (HPLC)10ppp2 502Peak2 (HPLC)10qqq1 511Peak1 (HPLC)10qqq2 511Peak2 (HPLC)10rrr1 515Peak1 (HPLC)10rrr2 515Peak2 (HPLC)10sss1 522Peak1 (HPLC)10sss2 522Peak2 (HPLC)10ttt1 533Peak1 (HPLC)10ttt2 533Peak2 (HPLC)10uuu1 514Peak1 (HPLC)10uuu2 514Peak2 (HPLC)10vvv1 523Peak1 (HPLC)10vvv2 523Peak2 (HPLC)10www1 367Peak1 (HPLC)10www2 367Peak2 (HPLC)10xxx1 411Peak1 (HPLC)10xxx2 411Peak2 (HPLC)20a1 397Peak1 (HPLC)20a2 397Peak2 (HPLC)20b1 404Peak1 (HPLC)20b2 404Peak2 (HPLC)20c1 415Peak1 (HPLC)20c2 415Peak2 (HPLC)20d1 362Peak1 (HPLC)20d2 362Peak2 (HPLC)20e1 405Peak1 (HPLC)20e2 405Peak2 (HPLC)20f1 412Peak1 (HPLC)20f2 412Peak2 (HPLC)20g1 397Peak1 (HPLC)20g2 397Peak2 (HPLC)20h1 404Peak1 (HPLC)20h2 404Peak2 (HPLC)20i1 415Peak1 (HPLC)20i2 415Peak2 (HPLC)20j 1 362Peak1 (HPLC)20j2 362Peak2 (HPLC)20k1 405Peak1 (HPLC)20k2 405Peak2 (HPLC)20m1 412Peak1 (HPLC)10m2 412Peak2 (HPLC)20n1 411Peak1 (HPLC)20n2 411Peak2 (HPLC)20o1 418Peak1 (HPLC)20o2 418Peak2 (HPLC)20p1 419Peak1 (HPLC)20p2 419Peak2 (HPLC)20q1 426Peak1 (HPLC)20q2 426Peak2 (HPLC)20r1 411Peak1 (HPLC)20r2 411Peak2 (HPLC)20s1 376Peak1 (HPLC)20s2 376Peak2 (HPLC)20t1 419Peak1 (HPLC)20t2 419Peak2 (HPLC)20u1 411Peak1 (HPLC)20u2 411Peak2 (HPLC)20v1 418Peak1 (HPLC)20v2 418Peak2 (HPLC)20w1 419Peak1 (HPLC)20w2 419Peak2 (HPLC)20x1 426Peak1 (HPLC)20x2 426Peak2 (HPLC)20y1 411Peak1 (HPLC)20y2 411Peak2 (HPLC)20z1 376Peak1 (HPLC)20z2 376Peak2 (HPLC)20aa1 419Peak1 (HPLC)20aa2 419Peak2 (HPLC)20bb1 437Peak1 (HPLC)20bb2 437Peak2 (HPLC)20cc1 444Peak1 (HPLC)20cc2 444Peak2 (HPLC)20dd1 445Peak1 (HPLC)20dd2 445Peak2 (HPLC)20ee1 452Peak1 (HPLC)20ee2 452Peak2 (HPLC)20ff1 437Peak1 (HPLC)20ff2 437Peak2 (HPLC)20gg1 402Peak1 (HPLC)20gg2 402Peak2 (HPLC)20hh1 445Peak1 (HPLC)20hh2 445Peak2 (HPLC)20ii1 431Peak1 (HPLC)20ii2 431Peak2 (HPLC)20jj1 438Peak1 (HPLC)20jj2 438Peak2 (HPLC)20kk1 439Peak1 (HPLC)20kk2 439Peak2 (HPLC)20mm1 431Peak1 (HPLC)20mm2 431Peak2 (HPLC)20nn1 438Peak1 (HPLC)20nn2 438Peak2 (HPLC)20oo1 439Peak1 (HPLC)20oo2 439Peak2 (HPLC)20pp1 445Peak1 (HPLC)20pp2 445Peak2 (HPLC)20qq1 452Peak1 (HPLC)20qq2 452Peak2 (HPLC)20rr1 453Peak1 (HPLC)20rr2 453Peak2 (HPLC)20ss1 445Peak1 (HPLC)20ss2 445Peak2 (HPLC)20tt1 452Peak1 (HPLC)20tt2 452Peak2 (HPLC)20uu1 453Peak1 (HPLC)20uu2 453Peak2 (HPLC)20vv1 495Peak1 (HPLC)20vv2 495Peak2 (HPLC)20ww1 502Peak1 (HPLC)20ww2 502Peak2 (HPLC)20xx1 503Peak1 (HPLC)20xx2 503Peak2 (HPLC)20yy1 495Peak1 (HPLC)20yy2 495Peak2 (HPLC)20zz1 502Peak1 (HPLC)20zz2 502Peak2 (HPLC)20aaa1 503Peak1 (HPLC)20aaa2 503Peak2 (HPLC)20bbb1 489Peak1 (HPLC)20bbb2 489Peak2 (HPLC)20ccc1 496Peak1 (HPLC)20ccc2 496Peak2 (HPLC)20ddd1 507Peak1 (HPLC)20ddd2 507Peak2 (HPLC)20eee1 488Peak1 (HPLC)20eee2 488Peak2 (HPLC)20fff1 497Peak1 (HPLC)20fff2 497Peak2 (HPLC)20ggg1 486Peak1 (HPLC)20ggg2 486Peak2 (HPLC)20hhh1 494Peak1 (HPLC)20hhh2 494Peak2 (HPLC)20iii1 505Peak1 (HPLC)20iii2 505Peak2 (HPLC)20jjj1 486Peak1 (HPLC)20jjj2 486Peak2 (HPLC)20kkk1 495Peak1 (HPLC)20kkk2 495Peak2 (HPLC)20mmm1 505Peak1 (HPLC)20mmm2 505Peak2 (HPLC)20nnn1 512Peak1 (HPLC)20nnn2 512Peak2 (HPLC)200001 523Peak1 (HPLC)20ooo2 523Peak2 (HPLC)20ppp1 504Peak1 (HPLC)20ppp2 504Peak2 (HPLC)20qqq1 513Peak1 (HPLC)20qqq2 513Peak2 (HPLC)20rrr1 517Peak1 (HPLC)20rrr2 517Peak2 (HPLC)20sss1 524Peak1 (HPLC)20sss2 524Peak2 (HPLC)20ttt1 535Peak1 (HPLC)20ttt2 535Peak2 (HPLC)20uuu1 516Peak1 (HPLC)20uuu2 516Peak2 (HPLC)20vvv1 525Peak1 (HPLC)20vvv2 525Peak2 (HPLC)20www1 369Peak1 (HPLC)20www2 369Peak2 (HPLC)20xxx1 413Peak1 (HPLC)20xxx2 413Peak2 (HPLC)30a1 397Peak1 (HPLC)30a2 397Peak2 (HPLC)30b1 404Peak1 (HPLC)30b2 404Peak2 (HPLC)30c1 415Peak1 (HPLC)30c2 415Peak2 (HPLC)30d1 362Peak1 (HPLC)30d2 362Peak2 (HPLC)30e1 405Peak1 (HPLC)30e2 405Peak2 (HPLC)30f1 412Peak1 (HPLC)30f2 412Peak2 (HPLC)30g1 383Peak1 (HPLC)30g2 383Peak2 (HPLC)30h1 390Peak1 (HPLC)30h2 390Peak2 (HPLC)30i1 401Peak1 (HPLC)30i2 401Peak2 (HPLC)30j 1 348Peak1 (HPLC)30j2 348Peak2 (HPLC)30k1 391Peak1 (HPLC)30k2 391Peak2 (HPLC)30m1 398Peak1 (HPLC)30m2 398Peak2 (HPLC)40a1 399Peak1 (HPLC)40a2 399Peak2 (HPLC)40b1 406Peak1 (HPLC)40b2 406Peak2 (HPLC)40c1 417Peak1 (HPLC)40c2 417Peak2 (HPLC)40d1 364Peak1 (HPLC)40d2 364Peak2 (HPLC)40e1 407Peak1 (HPLC)40e2 407Peak2 (HPLC)40f1 414Peak1 (HPLC)40f2 414Peak2 (HPLC)40g1 385Peak1 (HPLC)40g2 385Peak2 (HPLC)40h1 392Peak1 (HPLC)40h2 392Peak2 (HPLC)40i1 403Peak1 (HPLC)40i2 403Peak2 (HPLC)40j 1 350Peak1 (HPLC)40j2 350Peak2 (HPLC)40k1 393Peak1 (HPLC)40k2 393Peak2 (HPLC)40m1 400Peak1 (HPLC)40m2 400Peak2 (HPLC)50a1 409Peak1 (HPLC)50a2 409Peak2 (HPLC)50b1 416Peak1 (HPLC)50b2 416Peak2 (HPLC)50c1 413Peak1 (HPLC)50c2 427Peak2 (HPLC)50d1 374Peak1 (HPLC)50d2 360Peak2 (HPLC)50e1 417Peak1 (HPLC)50e2 417Peak2 (HPLC)50f1 423Peak1 (HPLC)50f2 423Peak2 (HPLC)50g1 430Peak1 (HPLC)50g2 430Peak2 (HPLC)50h1 442Peak1 (HPLC)50h2 442Peak2 (HPLC)50i1 499Peak1 (HPLC)50i2 499Peak2 (HPLC)50j1 506Peak1 (HPLC)50j2 506Peak2 (HPLC)50k1 517Peak1 (HPLC)50k2 427Peak2 (HPLC)50m1 464Peak1 (HPLC)50m2 464Peak2 (HPLC)50n1 507Peak1 (HPLC)50n2 507Peak2 (HPLC)50o1 513Peak1 (HPLC)50o2 513Peak2 (HPLC)50p1 520Peak1 (HPLC)50p2 520Peak2 (HPLC)50q1 525Peak1 (HPLC)50q2 525Peak2 (HPLC)50r1 532Peak1 (HPLC)50r2 532Peak2 (HPLC)50s1 430Peak1 (HPLC)50s2 430Peak2 (HPLC)50t1 444Peak1 (HPLC)50t2 444Peak2 (HPLC)50u1 458Peak1 (HPLC)50u2 458Peak2 (HPLC)50v1 456Peak1 (HPLC)50v2 456Peak2 (HPLC)50w1 381Peak1 (HPLC)50w2 381Peak2 (HPLC)50x1 423Peak1 (HPLC)50x2 423Peak2 (HPLC)60a1 411Peak1 (HPLC)60a2 411Peak2 (HPLC)60b1 418Peak1 (HPLC)60b2 418Peak2 (HPLC)60c1 429Peak1 (HPLC)60c2 429Peak2 (HPLC)60d1 376Peak1 (HPLC)60d2 376Peak2 (HPLC)60e1 419Peak1 (HPLC)60e2 419Peak2 (HPLC)60f1 425Peak1 (HPLC)60f2 425Peak2 (HPLC)60g1 432Peak1 (HPLC)60g2 432Peak2 (HPLC)60h1 446Peak1 (HPLC)60h2 446Peak2 (HPLC)60i1 501Peak1 (HPLC)60i2 501Peak2 (HPLC)60j 1 508Peak1 (HPLC)60j2 508Peak2 (HPLC)60k1 519Peak1 (HPLC)60k2 519Peak2 (HPLC)60m1 466Peak1 (HPLC)60m2 466Peak2 (HPLC)60n1 509Peak1 (HPLC)60n2 509Peak2 (HPLC)60o1 515Peak1 (HPLC)60o2 515Peak2 (HPLC)60p1 522Peak1 (HPLC)60p2 522Peak2 (HPLC)60q1 527Peak1 (HPLC)60q2 527Peak2 (HPLC)60r1 534Peak1 (HPLC)60r2 534Peak2 (HPLC)60s1 383Peak1 (HPLC)60s2 383Peak2 (HPLC)60t1 425Peak1 (HPLC)60t2 425Peak2 (HPLC)60u1 451Peak1 (HPLC)60u2 451Peak2 (HPLC)60v1 432Peak1 (HPLC)60v2 432Peak2 (HPLC)60w1 446Peak1 (HPLC)60w2 446Peak2 (HPLC)60x1 460Peak1 (HPLC)60x2 460Peak2 (HPLC)60y1 458Peak1 (HPLC)60y2 458Peak2 (HPLC)70a1 403Peak1 (HPLC)70a2 403Peak2 (HPLC)70b1 417Peak1 (HPLC)70b2 417Peak2 (HPLC)80a1 405Peak1 (HPLC)80a2 405Peak2 (HPLC)80b1 419Peak1 (HPLC)80b2 419Peak2 (HPLC)90a1 419Peak1 (HPLC)90a2 419Peak2 (HPLC)90b1 433Peak1 (HPLC)90b2 433Peak2 (HPLC) wherein Peak 1 and Peak 2 refer to the order of the enantiomers' peaks in reversed-phase HPLC, wherein Peak 1 is the first peak in the enantiomer, and Peak 2 is the latter peak of the enantiomer.

9. A method for preparation of compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the formula L compound is a compound represented by formula VII-1, and the method comprises the following steps: in an inert solvent, reacting formula L1 compound with to provide compound L; wherein R is a leaving group, and the definitions of the remaining groups are as described in claim 1.

10. A compound selected from the group consisting of: in each formula, Rg is selected from the group consisting of H, halogen, -CN, hydroxyl, amino, carboxyl, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; the definitions of R5 and R6 are as described in claim 1.

11. A pharmaceutical composition, comprising (1) the compound, or the stereoisomer thereof, tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate of claim 1 and (2) pharmaceutically acceptable carriers.

12. A compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1, or the pharmaceutical composition of claim 11 for use in prevention and / or treatment of hepatitis B virus infection.

13. A method for in vitro inhibiting hepatitis B virus, which comprises the step: contacting the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof of claim 1 with hepatitis B virus so as to inhibit the replication of hepatitis B virus.