WO2022156758A1

WO2022156758A1 - Novel amide pyrrole compound and use thereof in drugs

Info

Publication number: WO2022156758A1
Application number: PCT/CN2022/073101
Authority: WO
Inventors: 任青云; 刘辛昌; 张英俊; 王猛; 冀石龙; 余国森; 颜光华; 雷斗兴
Original assignee: 广东东阳光药业有限公司
Priority date: 2021-01-22
Filing date: 2022-01-21
Publication date: 2022-07-28
Also published as: CN114805362A

Abstract

A novel amide pyrrole compound and a use thereof in drugs, in particular, a use thereof as drugs for treating and/or preventing hepatitis B virus infections or diseases caused by the hepatitis B virus infections. Specifically, the present invention relates to a compound represented by general formula (I) or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrug thereof, and a use thereof in the preparation of drugs, in particular, a use thereof as drugs for treating and/or preventing hepatitis B virus infections or diseases caused by the hepatitis B virus infections, wherein variables are as defined in the description.

Description

Novel amide pyrroles and their use in medicine

technical field

The present invention belongs to the field of medicine. Specifically, it relates to a novel amide pyrrole compound and its use as a medicine, especially as a medicine for the treatment and/or prevention of hepatitis B virus infection or diseases caused by hepatitis B virus infection. The present invention also relates to a composition comprising the novel amide pyrrole compound and/or other antiviral agents, and its use in the treatment and/or prevention of hepatitis B virus (HBV) infection or HBV infection. disease use.

Background technique

Hepatitis B virus belongs to the Hepatoviridae family. It can cause acute and/or progressive chronic disease. Hepatitis B virus can also cause many other clinical manifestations of pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of hepatocytes. According to World Health Organization estimates, 2 billion people worldwide have been infected with HBV, about 350 million people are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma caused by HBV infection ( hepatocellular carcinoma, HCC).

The current treatment for chronic hepatitis B (CHB) is mainly antiviral therapy. Interferon alpha (IFN-alpha) and pegylated IFN-alpha and 5 nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir dipivoxil) ) is approved by the U.S. Food and Drug Administration (FDA) for clinical use. Interferon is the earliest anti-HBV drug approved by the FDA. It mainly achieves the effect of clearing the virus through direct antiviral effect and inducing the body's immune response. However, due to its low response rate, it has various side effects, high price and limited treatment targets. For many reasons, its application is subject to many restrictions. The common point of nucleoside (acid) drugs against HBV is that they specifically act on the viral DNA polymerase, which has a strong effect of inhibiting viral replication, and patients have better tolerance to drugs than interferon. However, the extensive and long-term use of nucleoside (acid) drugs can induce the mutation of DNA polymerase to form drug resistance, resulting in the continuous emergence of drug-resistant strains, so that the treatment is far from reaching the ideal curative effect.

Therefore, there is still a need for new drugs that can be effectively used for the treatment and/or prevention of hepatitis B.

SUMMARY OF THE INVENTION

The present invention relates to novel amide pyrrole compounds and their use in preparing medicines for treating and/or preventing HBV infection or diseases caused by HBV infection. In particular, the present invention relates to a novel amide pyrrole compound and a pharmaceutically acceptable composition thereof. The compound has the advantages of good solubility, good stability, basically no induction effect on liver drug enzymes and less toxicity. , especially with very good pharmacokinetic properties. The compound of the present invention can effectively inhibit HBV infection, and has a good application prospect in anti-HBV.

In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmacy of a compound of formula (I) on an acceptable salt or prodrug,

Wherein, R ¹ is a C _1-6 alkyl group, a C _2-6 alkynyl group, a C _2-6 alkenyl group, a C _3-6 cycloalkyl group, a C _5-10 aryl group or a hetero group consisting of 5-10 ring atoms Aryl, wherein said C _1-6 alkyl group, C _2-6 alkynyl group, C _2-6 alkenyl group, C _3-6 cycloalkyl group, C _5-10 aryl group and 5-10 ring atoms The heteroaryl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w1 ;

Each R2 and ^R3 is independently ^hydrogen , deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C _1-4 haloalkyl, methoxy or ethoxy;

Each R4, ^Ra , ^Rb and ^Rc is independently hydrogen, deuterium, methyl, ethyl, n ^- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C _1-4 haloalkyl;

Ring A is

Wherein, X is N or CR ¹⁰ ; Y is O or S;

Each R ¹¹ and R ^11a is independently hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl base, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C _2-4 alkenyl, C _2-4 alkynyl, carboxyl C _1-4 alkyl, C _1-4 haloalkyl or C _1-4 alkoxy;

each of n1 and n2 is independently 1, 2, 3 or 4;

Each of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is independently H, deuterium, CN, -C(=O)OR ^1a , -C(=O)NR ^1b R ^1c , -C( =O)R, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl or 5- Heteroaryl group consisting of 6 ring atoms, wherein the C _1-6 alkyl group, C _1-6 haloalkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group , C _6-10 aryl group and heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R ^w2 ;

Each R ^1a is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C _1-4 haloalkyl, wherein the The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C _1-4 haloalkyl groups are each independently unsubstituted or replaced by 1, 2, 3 or 4 R ^w1 substitutions;

Each R ^1b and R ^1c is independently hydrogen, deuterium, -S(=O) ₂ C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _{3 -6} cycloalkyl groups or heterocyclic groups consisting of 4-6 ring atoms, or R ^1b and R ^1c together with the nitrogen atoms to which they are attached form a heterocyclic group consisting of 3-7 ring atoms, wherein said -S(=O) ₂ C _1-6 alkyl, C _1-6 alkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _3-6 cycloalkyl, 4-6 ring atoms The heterocyclyl group and the heterocyclyl group consisting of 3-7 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R ^w3 ;

Each R is independently a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a heterocyclic group consisting of 3-7 ring atoms, wherein the C _1-6 alkyl group, C _3-6 cycloalkyl group and the heterocyclyl groups consisting of 3-7 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w4 ;

Each R ^w1 is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, _-SF6 , -C(=O)O-methyl, -C(=O)O-ethyl , -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert-butyl, C _2-4 alkenyl, C _2-4 alkynyl, carboxy C _1-4 alkyl, -CH ₂ F, -CH ₂ Cl, -CF ₃ , -CHF ₂ , -CHCl ₂ , _-CH2CH2F , _-CH2CH2Cl , _-CH2CHF2 , _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl _, _-CH2CF3 _, _-CH ₍ _CF3 ₎ ₂ , -CF ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , phenyl, -OCF ₃ , C _2-4 haloalkoxy or C _1-4 alkoxy, wherein the phenyl group is optionally selected by 1, 2, 3 or 4 independently selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy and ethoxy substituents;

Each R ^w2 , R ^w3 and R ^w4 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC _1-6 alkyl, C _{1 -6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, carboxy C _1-6 alkyl, C _6-12 aryl group or heteroaryl group composed of 5-6 ring atoms, wherein the amino group, -C(=O)OC _1-6 alkyl group, C _1-6 alkyl group, C _1-6 alkyl group Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, carboxy C _1-6 alkyl, C _6-12 aryl and 5- Heteroaryl groups of 6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w1 .

In some embodiments, R ¹ is C _1-4 alkyl, C _2-4 alkynyl, C _2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalene group, a heteroaryl group consisting of 5-6 ring atoms or a heteroaryl group consisting of 7-10 atoms, wherein the C _1-4 alkyl group, C _2-4 alkynyl group, C _2-4 alkenyl group, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5-6 ring atoms and heteroaryl of 7-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R ^w1 ;

Here, each R ^w1 has the meaning described in the present invention. In some embodiments, R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl , 1-alkynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, Pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl , pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl or isoquinolinyl, wherein the methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzene imidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w1 ;

Here, each R ^w1 has the meaning described in the present invention.

In some embodiments, each of R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is independently H, deuterium, CN, -C(=O)OR ^1a , -C(=O)NR ^1b R ^1c , -C(=O)R, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F, -CH ₂ _Cl , _-CHF2 , _-CF3 , _-CHCl2 , _-CH2CH2F , _-CH2CH2Cl , _-CH2CHF2 _, _-CH2CHCl2 _, _-CHFCH2F _, _-CHClCH2Cl , _-CH2CF3 , _-CH ₍ _CF3 ₎ ₂ _, _-CF2CH2CH3 _, _-CH2CH2CH2F _, _-CH2CH2CHF2 _, _-CH2CH2CF3 _, _vinyl , propenyl, allyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazine group, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert _- _Butyl , _-CH2F , _-CH2Cl , _-CHF2 , _-CHCl2 , _-CH2CH2F , _-CH2CH2Cl , _-CH2CHF2 _, _-CH2CHCl2 , _-CHFCH _2F _, _-CHClCH2Cl , _-CH2CF3 _, _-CH ₍ _CF3 ₎ ₂ , _-CF2CH2CH3 , _-CH2CH2CH2F _, _-CH2CH2CHF2 _, _-CH2 CH ₂ CF ₃ , vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclobutane base, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 ^Rw2 ;

Wherein, each of R ^1a , R ^1b , R ^1c , R and R ^w2 has the meaning described in the present invention.

In some embodiments, each R ^1b and R ^1c is independently hydrogen, deuterium, -S(=O) ₂ C _1-4 alkyl, C _1-4 alkyl, C _2-4 alkynyl, C _{2 -4} alkenyl, C _3-6 cycloalkyl or heterocyclic group consisting of 4-6 ring atoms, or R ^1b and R ^1c together with the nitrogen atom to which they are attached form a heterocyclic ring consisting of 3-6 ring atoms group, wherein the -S(=O) ₂ C _1-4 alkyl group, C _1-4 alkyl group, C _2-4 alkynyl group, C _2-4 alkenyl group, C _3-6 cycloalkyl group, The heterocyclic group consisting of 4-6 ring atoms and the heterocyclic group consisting of 3-6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w3 ;

Wherein, each R ^w3 has the meaning described in the present invention.

In some embodiments, each R ^1b and R ^1c is independently hydrogen, deuterium, -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) _2- n-propyl, -S(=O) ₂ -isopropyl, -S(=O) ₂ -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propenyl, allyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidine, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl , tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the -S(=O) ₂ -methyl, -S( =O) ₂ -ethyl, -S(=O) ₂ -n-propyl, -S(=O) ₂ -isopropyl, -S(=O) ₂ -n-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynyl Butyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, Pyrazolidine, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl are each independently substituted or substituted by 1, 2, 3 or 4 R ^w3 ; or R ^1b and R ^1c together with the nitrogen atom to which they are attached form azetidinyl, azetidinyl, pyrrolidinyl, pyrazolidine group, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 ^Rw3 ;

Wherein, each R ^w3 has the meaning described in the present invention.

In some embodiments, each R is independently C _1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or heterocyclyl of 3-6 ring atoms, wherein said C _1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and heterocyclyl consisting of 3-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R ^w4 replace;

Here, each R ^w4 has the meaning described in the present invention.

In some embodiments, each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, Cyclohexyl, Azacyclopropyl, Azacyclobutyl, Oxetanyl, Thietanyl, Pyrrolidine, Pyrazolidinyl, Imidazolidinyl, Tetrahydrofuranyl, Tetrahydrothiophene base, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclopropyl, azetidine, oxetanyl, sulfur Heterocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine and piperazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R ^w4 ;

Here, each R ^w4 has the meaning described in the present invention.

In some embodiments, each ^Rw2 , ^Rw3 , and ^Rw4 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C( ₌ O)OC1 _-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F, -CH ₂ Cl, -CHF ₂ , - _CHCl2 , _-CH2CH2F , _-CH2CH2Cl _, _-CH2CHF2 , _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl _, _-CH2CF3 _, _-CH ₍ _CF3 ) ₂ , -CF ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , C _1-4 alkoxy, C _1-4 haloalkoxy base, C _2-4 alkenyl, C _2-4 alkynyl, carboxy C _1-4 alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl , oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the amino, - C(=O)OC _1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F, -CH ₂ _Cl , _-CHF2 , _-CHCl2 , _-CH2CH2F _, _-CH2CH2Cl _, _-CH2CHF2 _, _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl , _-CH2CF ₃ , -CH(CF ₃ ) ₂ , -CF ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , C _1-4 alkoxy , C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, carboxy C _1-4 alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently ground is unsubstituted or substituted with 1, 2, 3 or 4 R ^w1 ;

Here, each R ^w1 has the meaning described in the present invention.

On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable adjuvant.

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

In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator, or an interferon.

In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drug is lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simoleukin, Clavudine, Emtricitabine, Faciclovir, Interferon, Baoganling CP, Interferon, Interferon alpha-1b, Interferon alpha, Interferon alpha-2a, Interferon beta -1a, interferon alfa-2, interleukin-2, mivotiate, nitazoxanide, peginterferon alfa-2a, ribavirin, rasteron-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon alfa-2b, levamisole, or propagium.

In another aspect, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a viral disease of a patient.

In some embodiments, the use of the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

In other embodiments, the use of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.

In another aspect, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating hepatitis B disease in a patient, comprising administering an effective therapeutic dose of the compound or the present invention The pharmaceutical composition is administered to a patient.

Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.

Another aspect of the present invention pertains to a method of preventing, treating or alleviating an HBV disorder in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition comprising a compound of the present invention.

Another aspect of the present invention pertains to the use of a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.

Another aspect of the present invention pertains to the use of a pharmaceutical composition comprising a compound of the present invention for the manufacture of a medicament for the prevention or treatment of HBV disorders in a patient, and to lessen the severity thereof.

Another aspect of the present invention pertains to a method of inhibiting HBV infection, the method comprising contacting a cell with a compound or pharmaceutical composition of the present invention in an amount effective to inhibit HBV. In other embodiments, the method further comprises contacting the cells with other anti-HBV therapeutics.

Another aspect of the present invention pertains to a method of treating HBV disease in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.

Another aspect of the present invention pertains to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV drug.

Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or formula (II).

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.

Detailed Description of the Invention

Definitions and General Terms

The present invention will list the documents corresponding to the determined concrete contents in detail, and the embodiments are accompanied by diagrams of structural formula and chemical formula. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the prior art as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the description of the methods and materials. There are numerous documents and similar materials that differ from or contradict this application, including but not limited to definitions of terms, usage of terms, techniques described, or the scope as controlled by this application.

The present invention shall apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Version and Handbook of Chemicals, 75, ^th Ed, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The contents of are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula above, or as in the Examples, subclasses, and encompassed by the present invention. a class of compounds.

In various sections of this specification, substituents of the compounds of the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl groups _.

The term "alkyl" as used herein includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-12 carbon atoms, in other embodiments, the alkyl group contains 1-10 carbon atoms, and in still other embodiments, the alkyl group contains 1-8 carbon atoms. carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, and in still other embodiments, the alkyl group contains Contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), n _- _propyl (n _- Pr, -CH2CH2 ₎ _CH3 ), isopropyl (i-Pr, -CH( _CH3 ) ₂ ), n-butyl (n _- Bu, _{-CH2CH2CH2CH3} ), ₂ _- methylpropyl or isobutyl (i-Bu, -CH2CH( _CH3 ) ₂ ), ₁ -methylpropyl or sec-butyl (s-Bu, -CH( _CH3 ) _CH2CH3 ₎ , tert-butyl (t-Bu , -C( _CH3 ) ₃ ), n-pentyl ( _{-CH2CH2CH2CH2CH3} ), ₂ _- pentyl (-CH( _CH3 ₎ _CH2CH2CH3 ₎ , ₃ _- pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH _{3 )} )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ ) CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH( _CH3 )CH( _CH3 ) _CH2CH3 ), 4-methyl- _{2-pentyl (-CH(CH3)CH2CH(CH3)2} ₎ _, ₃ _- methyl-3 -Pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-di Methyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, etc.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least There is a position CC for sp ² double bond, wherein the alkenyl group can be independently unsubstituted or substituted by one or more substituents described in the present invention, including "cis", "trans" or "Z","E" isomers, specific examples of which include, but are not limited to, vinyl (-CH=CH ₂ ), propenyl (-CH=CHCH ₃ ), allyl (-CH ₂ CH= _CH2 ) and the like, wherein the alkenyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least CC in one position is an sp triple bond, and specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), propynyl (-C≡C- CH ₃ ), 1-alkynylbutyl (-CH ₂ CH ₂ C≡CH), 2-alkynylbutyl (-CH ₂ C≡CCH ₃ ), 3-alkynylbutyl (-C≡CCH ₂ CH ₃ ), etc. etc., wherein the alkynyl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

The term "haloalkyl" or "haloalkoxy" refers to an alkyl group, wherein alkyl and alkoxy have the meanings described herein. Such examples include, but are not limited to, difluoroethyl ₍ _-CH2CHF2 , _-CF2CH3 , _-CHFCH2F ₎ , trifluoroethyl ₍ _-CH2CF3 , _-CF2CH2F ₎ , -CFHCHF ₂ ), trifluoromethyl (-CF ₃ ), trifluoromethoxy (-OCF ₃ ), fluorovinyl (-CH=CHF, -CF=CH ₂ ) and the like.

The term "carboxyalkyl" means that an alkyl group is substituted with one or two carboxyl substituents, wherein "carboxyl" is -COOH, and the alkyl group has the meaning described in the present invention. Such examples include, but are not _limited to, _-CH2COOH , _-CH2CH2COOH _, _{-CH2CH2CH2COOH} , _{-CH2CH2CH2CH2COOH} _, _and _the _like .

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, alkoxy groups contain 1-8 carbon atoms; in other embodiments, alkoxy groups contain 1-6 carbon atoms; in other embodiments, alkoxy groups groups contain 1-4 carbon atoms; in yet other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), ₁ -pentyloxy (n _- pentyloxy, -OCH2CH2CH2CH2CH3), ₂ _- pentyloxy (-OCH ₍ _CH3 ₎ _CH2CH2CH3 ₎ , 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "consisting of MM ₁ ring atoms" or "consisting of MM ₁ atoms" means that the cyclic group consists of MM ₁ ring atoms including carbon atoms and/or O, N, S, P and other heteroatoms. For example, "heteroaryl of 6-10 atoms" means that it includes a heteroaryl group of 6, 7, 8, 9 or 10 ring atoms.

The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein and all refer to a saturated or non-aromatic non-aromatic containing one or more units of unsaturation containing 3-14 ring carbon atoms carbocyclic system. In some embodiments, the number of carbon atoms is 3-12; in other embodiments, the number of carbon atoms is 3-10; in other embodiments, the number of carbon atoms is 3-8; In other embodiments, the number of carbon atoms is 3-6; in other embodiments, the number of carbon atoms is 5-6; in other embodiments, the number of carbon atoms is 5-8 . In other embodiments, the number of carbon atoms is 6-8. This "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes those wherein the carbocyclic ring may be combined with one or more non-aromatic carbocyclic or heterocyclic rings or one or more A polycyclic ring system in which one aromatic ring or a combination thereof is fused, in which the atomic group or point of attachment is on a carbocyclic ring. Bicyclic carbocyclyls include bridged bicyclic carbocyclyls, fused bicyclic carbocyclyls, and spirobicyclic carbocyclyls, "fused" bicyclic ring systems comprising two rings that share 2 adjacent ring atoms. Bridged bicyclic groups include two rings that share 3 or 4 adjacent ring atoms. Spirocyclic ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclyl groups include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl base, wait.

The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system having one or more points of attachment to the remainder of the molecule, containing from 3 to 12 ring carbon atoms, including monocyclic, bicyclic or polycyclic rings Ring fused, spiro or bridged ring systems. In some embodiments, the cycloalkyl group is a spirobicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkyl group is a fused bicycloalkyl group composed of 6-10 atoms; in other embodiments, the cycloalkane group In other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-7 ring carbon atoms carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms; For example, cycloalkyl is a ring system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, And the cycloalkyl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein At least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic heterocyclyls, bicyclic or polycyclic fused heterocyclyls, spiro or bridged heterocyclic heterocyclyls, and also wherein heterocycles may be combined with one or more non-aromatic carbocyclic rings or a heterocyclic ring or a polycyclic ring system in which one or more aromatic rings or combinations thereof are fused, wherein the atomic group or point of attachment is on the heterocyclic ring. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. Unless otherwise specified, the _-CH2- group of a heterocyclyl group can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. In some embodiments, heterocyclyl is a ring system of 3-12 ring atoms; in some embodiments, heterocyclyl is a monocyclic heterocyclyl of 4-7 ring atoms; in some embodiments , the heterocyclyl group is a monocyclic heterocyclyl group composed of 3-7 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group composed of 4-6 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group composed of 4-6 ring atoms The cyclyl group is a monocyclic heterocyclyl group consisting of 3-6 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group consisting of 5-6 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl consisting of 7-10 ring atoms; in some embodiments, a heterocyclyl is a fused bicyclic heterocyclyl consisting of 8-10 ring atoms; in some embodiments, a heterocyclyl Bridged bicyclic heterocyclyl of 6-10 ring atoms In other embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is 3-6 ring system consisting of ring atoms; in other embodiments, heterocyclyl is a ring system consisting of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring consisting of 5-8 ring atoms system; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; heterocyclyl is a ring system of 3 ring atoms; in other embodiments, heterocyclyl is 4 ring systems of ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments In embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl Propyl, Azacycloheptyl, Oxepeptyl, Thiepanyl, Oxazepinyl, Diazepanyl, Thiazepinyl, 2-Pyrrololinyl, 3-Pyrrololinyl , Indoline, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithianyl, dithianyl, Dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl and N-pyridylurea. Examples of heterocyclic groups also include, 1,1-dioxothiomorpholinyl; examples in which the carbon atoms on the ring are replaced by oxo (=O) groups include, but are not limited to, pyrimidinedione, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H )-keto, etc.; examples in which the carbon atoms on the ring are replaced by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thione, 1,3,4- Oxadiazole-2(3H)-thione, etc. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicycle" are used interchangeably herein to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system, One of the rings originates from a specific ring carbon atom on the other, and the two rings share only one atom.

For example, as depicted in formula a-1 below, a saturated ring system (rings B and B') is referred to as a "fused bicyclic", while rings A' and B share a carbon atom, referred to as a "spiro ring" or "spirobicyclic". Each ring of the fused bicyclyl and spirobicyclyl groups can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

The term "fused bicyclic heterocyclyl" refers to a monovalent saturated or partially unsaturated non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic heterocycles (although aromatics may be used as substituents thereon). Each ring in the ring system contains 3-7 atoms, and at least one ring contains one or more heteroatoms, i.e. 1-6 carbon atoms and 1-3 selected from N, O, P, S heteroatoms, where S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, _PO2 , and in some embodiments, the fused bicyclic heterocyclyl is ₇ - A fused bicyclic heterocyclyl of 10 ring atoms; in some embodiments, a fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; such examples include, but do not Limited to, 3-aza-fused[3.1.0]hexane, 3-azabicyclo[3.3.0]octane, hexahydro-furan[3,4-c]pyrrolyl, hexahydro-thiophene[3, 4-c]pyrrolyl, 3,4,5,6-tetrahydro-cyclopentane[c]thienyl and the like. The fused heterobicyclyl group is optionally substituted with one or more substituents described herein.

The term "bridged bicyclic group" refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula b, that is, ring A1 and ring A2 share an alkane chain or a heteroalkane chain, wherein j is 1, 2, 3 or 4. Such systems may contain independent or conjugated unsaturation, but whose core structure does not contain aromatic or aromatic rings (although aromatics may be substituents thereon). wherein each ring, such as A1 or A2, contains 3-7 atoms, such examples include, but are not limited to, bicyclo[2.2.1]heptyl, 2-methyl-diazabicyclo[2.2. 1] Heptyl, etc. The bridged bicyclyl is optionally substituted with one or more substituents described herein.

The term "bridged carbobicyclyl" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 carbon atoms, examples of which include, but are not limited to, bicyclic [2.2.1] Heptyl, etc. The bridged bicyclyl is optionally substituted with one or more substituents described herein.

The term "bridged bicyclic heterocyclyl" denotes a saturated or partially unsaturated non-aromatic bridged bicyclic ring system wherein each ring contains 3-7 atoms and at least one ring contains one or more heteroatoms, i.e., contains 1- 6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO, SO ₂ , PO, PO ₂ The group, in some embodiments, bridged bicyclic heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms, such examples include, but are not limited to 2-oxo-5-azabicyclo[2.2 .1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-di Azabicyclo[2.2.1]heptyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptyl. The bridged bicyclic heterocyclyl is optionally substituted with one or more substituents described herein.

The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one ring system are aromatic in which each ring system contains a ring of 3-7 carbon atoms with one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", eg aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

The term "heteroaryl" may be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy" to denote a monocyclic, bicyclic or tricyclic ring system containing 5-16 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5-7 ring atoms with one or more points of attachment to The rest of the molecule is connected. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". In some embodiments, a heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-12 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 7-10 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

In other embodiments, heteroaryl groups include, but are not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazole base, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazine base), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl azolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazole radicals (eg, 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiooxadiazolyl, 1,3,4-thiooxadiazolyl, 1,2,5-thiooxadiazolyl , pyrazinyl, 1,3,5-triazinyl; also include the following bi- or tricyclic groups, but are by no means limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indium dolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl) , 3-isoquinolinyl or 4-isoquinolinyl), phenoxthiyl, dibenzimidazolyl, dibenzofuranyl or dibenzothienyl, etc. The heteroaryl group is optionally substituted with one or more substituents described herein.

In addition, it should be noted that, unless expressly stated otherwise, the descriptions used throughout this document "each ... and ... are independently", "... and ... are each independently" and "... and ... are each independently "" can be interchanged and should be understood in a broad sense. It can either mean that in different groups, the specific options expressed by the same symbol do not affect each other, or it can mean that in the same group, the same symbol is the same. The specific options expressed between them do not affect each other.

It should also be noted in the present invention that the present invention

R ¹¹ and R ^11a are respectively substituted on the pyrrole ring, that is, R ¹¹ can be substituted on the * position of the formula (I-1), and R ^11a can be substituted on the * position of the formula (I-2). replace:

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (eg, enantiomers, diastereomers, and geometrical isomers (or conformations): for example, R containing an asymmetric center , S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Thus, individual stereochemical isomers (eg, enantiomeric isomers of compounds of the present invention) isomers, diastereomers), or mixtures of geometric isomers (or conformational isomers) are within the scope of the present invention.

As used in the present invention, the term "prodrug" refers to the conversion of a compound into a compound of formula (I) or formula (II) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 , 51, 2328-2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

Use of definitions and conventions of stereochemistry in the present invention is generally referred to by S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. part of the invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their steric structures are not the same. A particular stereoisomer may be an enantiomer, and a mixture of enantiomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions by migration of protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include interconversions that recombine bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange methods described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate , borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate acid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoic acid Salts, valerates, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality when it reacts with another functional group. For example, "protecting group for amino" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

Description of Compounds of the Invention

The compounds involved in the present invention, and their pharmaceutically acceptable compositions, can effectively inhibit HBV infection.

Ring A is

Wherein, X is N or CR ¹⁰ ; Y is O or S;

each of n1 and n2 is independently 1, 2, 3 or 4;

In some embodiments, the present invention relates to a compound of formula (II) or a stereoisomer, tautomer, nitroxide, solvate, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, each of R ^a , R ^b , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹¹ and n1 has the meaning described in the present invention.

Here, each R ^w1 has the meaning described in the present invention.

Wherein, each R ^w3 has the meaning described in the present invention.

Here, each R ^w4 has the meaning described in the present invention.

Here, each R ^w1 has the meaning described in the present invention.

In some embodiments, each ^Rw2 , ^Rw3 , and ^Rw4 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)O- Methyl, -C(=O)O-ethyl, -C(=O)O-n-propyl, -C(=O)O-isopropyl, -C(=O)O-n-butyl, -C(=O)O-isobutyl, -C(=O)O-sec-butyl, -C(=O)O-tert-butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec _- butyl, tert _- butyl, _-CF3 , _-CH2F , _-CH2Cl , _-CHF2 , _-CHCl2 , _-CH2CH2F , _-CH2CH2 _Cl , _-CH2CHF2 , _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl , _-CH2CF3 , _-CH ₍ _CF3 ₎ ₂ , _-CF2CH2CH3 _, _-CH2CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl Base-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH ₂ F, -OCF ₃ , -OCH ₂ Cl, -OCHF ₂ , -OCHCl ₂ , -OCH ₂ _CH2F , _-OCH2CH2Cl , _-OCH2CHF2 , _-OCH2CHCl2 , _-OCHFCH2F , _-OCHClCH2Cl , _-OCH2CF3 , _-OCH ₍ _CF3 ₎ ₂ _, _-OCF2 CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ F, -OCH ₂ CH ₂ CHF ₂ , -OCH ₂ CH ₂ CF ₃ , C _2-4 alkenyl, C _2-4 alkynyl, carboxy C _1-4 alkane base, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazolyl azinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the amino, -C(=O)OC _1-4 alkyl, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec _- butyl, tert _- butyl, _-CH2F , _-CH2Cl , _-CHF2 , _-CHCl2 , _-CH2CH2F , _-CH2CH2 _Cl , _-CH2CHF2 , _-CH2CHCl2 , _-CHFCH2F , _-CHClCH2Cl , _-CH2CF3 , _-CH ₍ _CF3 ₎ ₂ , _-CF2CH2CH3 _, _-CH2 CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2- Methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, -OCH ₂ F, -OCF ₃ , -OCH ₂ Cl, -OCHF ₂ , -OCHCl ₂ , -OCH _2CH2F , _-OCH2CH2Cl , _-OCH2CHF2 , _-OCH2CHCl2 , _-OCHFCH2F , _-OCHClCH2Cl , _-OCH2CF3 , _-OCH ₍ _CF3 ₎ ₂ _, _-OCF ₂ CH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₂ F, -OCH ₂ CH ₂ CHF ₂ , -OCH ₂ CH ₂ CF ₃ , C _2-4 alkenyl, C _2-4 alkynyl, carboxyl C _1-4 Alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5- Triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 ^Rw1 ;

Here, each R ^w1 has the meaning described in the present invention.

In another aspect, the present invention comprises a structure of one of the following, or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

In another aspect, the compound or the pharmaceutical composition of the present invention is used for the preparation of a medicament for preventing, treating or alleviating a viral disease in a patient.

In some embodiments, the use of the compound or the pharmaceutical composition of the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

In other embodiments, the use of the compound or the pharmaceutical composition of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.

In some embodiments, the method of the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

In other embodiments, the method of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.

In another aspect, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicine for preventing, treating or alleviating hepatitis B disease in a patient.

In some embodiments, the patient is a mammal, and in other embodiments, the patient is a human. In other embodiments, the use further comprises contacting the cells with an anti-HBV therapeutic.

Another aspect of the present invention pertains to a method of treating HBV disease in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV therapeutic agent.

Another aspect of the present invention pertains to a method of inhibiting HBV infection in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In other embodiments, the method further comprises administering to a patient in need thereof a therapeutically effective amount of another anti-HBV therapeutic agent.

The present invention also relates to the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of medicinal products to effectively inhibit HBV infection, and the application of the compounds of the present invention to the production of drugs for effectively inhibiting HBV infection. The compounds of the present invention are also useful in the manufacture of a pharmaceutical product for alleviating, preventing, controlling or treating the condition of hepatitis B in a patient.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are belong to the scope of the present invention.

Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.

Salts of compounds of the present invention also include salts of intermediates used in the preparation or purification of compounds of formula (I) or (II) or salts of separated enantiomers of compounds of formula (I) or (II) , but not necessarily a pharmaceutically acceptable salt.

If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid ; Pyranonic acids, such as glucuronic and galacturonic acids; Alpha-hydroxy acids, such as citric and tartaric acids; Amino acids, such as aspartic and glutamic acids; Aromatic acids, such as benzoic and cinnamic acids; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like, or combinations thereof.

If the compounds of the present invention are acidic, the desired salts can be prepared by suitable methods, eg, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N ⁺ (R ¹⁴ ) ₄ salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary ammonia, salts of N ⁺ (R ¹⁴ ) ₄ , such as R ¹⁴ is H, C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium give inorganic salts. Also included are suitable, nontoxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and Aromatic sulfonates.

Pharmaceutical Compositions, Formulations, Administration of Compounds of the Invention and Use of Compounds and Pharmaceutical Compositions

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I) or formula (II), the compounds listed in the present invention, or the example compounds, and pharmaceutically acceptable excipients. The compounds in the pharmaceutical composition of the present invention can effectively inhibit hepatitis B virus, and are suitable for the treatment of diseases caused by viruses, especially acute and chronic persistent HBV infection. Hepatitis virus infection can lead to cirrhosis and/or hepatocellular carcinoma in many cases.

An area of disease treatment that may be mentioned for the compounds of the present invention is, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, eg, hepatitis B virus infection. The compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, also contain one or more compounds of formula (I) of the present invention or their pharmaceutical compositions.

The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients than the compounds represented by formula (I) or formula (II).

The compounds of the present invention exist in free form, or as suitable, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.

As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the compounds represented by formula (I) or formula (II) of the present invention, and further comprises pharmaceutically acceptable adjuvants, such as those described in the present invention. Applied, including any solvents, solid excipients, diluents, binders, disintegrating agents, other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents , emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999 , Marcel Dekker, New York, synthesizing the contents of the documents herein, shows that different excipients can be applied to the formulation of pharmaceutically acceptable compositions and their well-known preparation methods. Except to the extent that any conventional excipients are incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, their Use is also contemplated by the present invention.

Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil , olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents ; Coatings; Sweeteners; Flavourings; Perfumes; Preservatives and Antioxidants.

Pharmaceutical compositions of compounds of the present invention may be administered in any of the following ways: oral administration, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous , intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.

The compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage form. The dosage form for administration can be a liquid dosage form, a solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticles, and suspensions. Other dosage forms such as tablets, capsules, dropping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, patches, wipes agent, etc.

Oral tablets and capsules may contain excipients such as binders, such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, cornstarch, calcium phosphate, sorbitol, amino acids acetic acid; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as potato starch; or acceptable emollients such as sodium lauryl sulfate. Tablets can be coated by methods known in pharmacy.

Oral solutions can be prepared as suspensions, solutions, emulsions, syrups or elixirs in hydrated oils, or they can be prepared as dry products for replenishment with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible Fats, emulsifiers such as lecithin, sorbitan monooleate, acacia; or non-aqueous excipients (may contain edible oils) such as almond oil, oils such as glycerol, glycol, or ethanol; preservatives, Such as methyl or propyl paraben, sorbic acid. Flavoring or coloring agents may be added if desired.

Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, liquid dosage forms are usually prepared from the compound and a sterile excipient. The first choice for excipients is water. According to the different excipients and drug concentrations selected, the compound can be dissolved in the excipient or made into a suspension solution. When preparing a solution for injection, the compound is first dissolved in water, filtered and sterilized, and then put into a sealed bottle or ampule.

When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more excipients which may be used in the ointment formulation including but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water; excipients that can be used in lotions and creams include but are not limited to: mineral oil, sorbitan monohydrate Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

In general, it has proven to be advantageous, whether in human medicine or in veterinary medicine, to administer the active compound of the invention in a total amount of about 0.5-500 mg/kg body weight per 24 hours, preferably 1-100 mg/kg body weight, if appropriate If so, administer in multiple single doses to achieve the desired effect. The amount of active compound contained in a single dose is preferably about 1-80 mg/kg body weight, more preferably 1-50 mg/kg body weight, but may not be in accordance with the above-mentioned doses, that is, depending on the type and body weight of the subject, the nature of the disease and severity, type of preparation and mode of administration of the drug, and the period or interval of administration.

The pharmaceutical composition provided by the present invention also includes an anti-HBV drug. The anti-HBV drug is HBV polymerase inhibitor, immunomodulator or interferon.

The anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simoleukin, clavudine, emtricitabine, faprol Wei, interferon, Baoganling CP, interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta-1a, interferon alpha-2, interleukin-2, mivo Tietate, Nitazoxanide, Pegylated Interferon alfa-2a, Ribavirin, Rosferon-A, Sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alfa-2b, Levamisole Or propagium and so on.

Another aspect of the present invention relates to the use of a compound or pharmaceutical composition of the present invention to prepare a medicament for preventing, treating or alleviating hepatitis B disease in a patient, including administering to the patient a pharmaceutically acceptable effective dose. . Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Acute HBV infection can be asymptomatic or present with acute hepatitis symptoms. Patients with chronic viral infection have active disease that can develop cirrhosis and liver cancer.

The anti-HBV drug may be administered separately from the composition comprising the compound of the present invention as part of a multiple dosing regimen. Alternatively, those drugs may be part of a single dosage form that is mixed with the compounds of the present invention to form a single composition. If administered as part of a multiple-dosing regimen, the two active agents can be delivered to each other simultaneously, continuously or over a period of time, to achieve the desired agent activity.

The amount of compounds and pharmaceutical compositions that can be combined with excipient substances to produce a single dosage form (those comprising a pharmaceutical composition as described herein) varies depending on the indication and the particular mode of administration. Normally, the amount of the pharmaceutical composition of the present invention will not exceed the amount in which the composition contains as the only active agent normally administered. On the other hand, the amounts of the presently disclosed pharmaceutical compositions range from about 50% to 100% of the normal amount of existing pharmaceutical compositions, containing the agent as the only active therapeutic agent. In those included compositions, the compositions will act synergistically with the compounds of the present invention.

The compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for the treatment of various diseases caused by viruses, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to syndromes of varying severity, and chronic HBV infection is known to lead to cirrhosis and/or hepatocellular carcinoma.

Examples of indications that can be treated with the compounds of the present invention are acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.

The present invention also relates to the use of the compounds and pharmaceutical compositions of the present invention in the preparation of medicaments for the treatment and prevention of viral diseases, especially hepatitis B.

General synthetic methods

In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I) or formula (II). The following synthetic schemes and examples serve to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (°C). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

The chromatographic column used silica gel column, and silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Factory. The NMR spectra were performed with CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvents (in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), q (quartets, four doublet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet), br.s (broadened singlet, broad singlet). The coupling constant, J, is expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector were used for analysis, ESI sources are used in LC-MS spectrometers.

Low-resolution mass spectrometry (MS) data were also determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector for analysis , ESI source applied to LC-MS spectrometer.

Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were read by recording UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:

Table 1: Gradient elution conditions

时间(min)time (min)	A(CH ₃CN，0.1％HCOOH) A( _CH3CN , 0.1% HCOOH)	B(H ₂O，0.1％HCOOH) B( _H2O , 0.1% HCOOH)
0-30-3	5-1005-100	95-095-0
3-63-6	100100	00
6-6.16-6.1	100-5100-5	0-950-95
6.1-86.1-8	55	9595

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

The following abbreviations are used throughout this disclosure:

MeOH methanol Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium

MeOH-d ₄ /CD ₃ OD Deuterated methanol DMAP 4-dimethylaminopyridine

DCM, CH ₂ Cl ₂ dichloromethane HATU O-(7-azabenzotriazole-1-

CDC1 ₃ deuterochloroformyl)-N,N,N',N'-tetramethylurea hexafluorophosphate

TFA Trifluoroacetic acid

(Boc) ₂ O Di-tert-butyl dicarbonate DIPEA N,N-diisopropylethylamine

NBS N-bromosuccinimide DMF DMF N,N-dimethylformamide

DDQ 2,3-dichloro-5,6-dicyanobenzoquine THF THF

PE , petroleum ether , DMSO , dimethyl sulfoxide

EtOAc, EA ethyl acetate DMSO-d ₄ -deuterated dimethyl sulfoxide

EtOH ethanol t _1/2 half-life

Et ₃ N,TEA triethylamine AUC area under the curve

mL,ml

RT,rt CL,clearance

Rt Retention time F,absolute bioavailability

LDA Dose Dose Dose

Time to peak CDI N,N'-carbonyldiimidazole T _max

1atm 101.325kPa C _max maximum concentration

hr ^* ng/mL plasma concentration * time

resolve resolution

The following synthetic schemes list experimental procedures for the preparation of compounds disclosed in this invention. Wherein, each ring A, R ^b , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X has the meaning as described in the present invention.

Synthesis Scheme 1

The compound represented by formula (A-4) can be prepared by the method described in Synthesis Scheme 1. First, compound (A-1) is removed under suitable conditions (for example, in the presence of trifluoroacetic acid or hydrochloric acid, etc.) to remove the Boc protecting group to generate compound (A-2) or a salt thereof; then, compound (A-2) The compound (A-4) is obtained by condensation reaction of the salt thereof and the compound (A-3).

Synthesis Scheme 2

The compound represented by formula (b-4) can be prepared by the method described in Synthesis Scheme 2. First, compound (b-1) undergoes a ring closure reaction in the presence of isobutyl chloroformate to generate compound (b- ₂ ); Under the action, compound (b-3) is generated; finally compound (b-3) is closed under suitable conditions (such as adding triethylamine and methanesulfonyl chloride, or DMAP and methanesulfonyl chloride, etc.) to obtain compound (b- 4).

Synthesis Scheme 3

The compound represented by formula (C-1) can be prepared by the method described in Synthesis Scheme 3. First, compound (b-4) removes the Boc protecting group under suitable conditions (eg, in the presence of trifluoroacetic acid or hydrochloric acid, etc.) to generate compound (b-5) or a salt thereof; then, compound (b-5) The compound (C-1) is obtained by condensation reaction of the salt thereof and the compound (A-3).

Detailed ways

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

Preparation Examples

In the following preparation examples, the inventors take some compounds of the present invention as examples to describe the preparation process of the compounds of the present invention in detail.

Synthesis of Example 1

Step 1: Synthesis of Compound 1-1

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

Step 2: Synthesis of Compound 1

Compound F2 (500 mg, 1.49 mmol, which was prepared with reference to the synthesis method of compound 42 in WO2017156255A1) and HATU (893 mg, 2.23 mmol) were dissolved in DMF (5 mL), and DIPEA (578 mg, 4.46 mmol) and compound were added thereto, respectively. 1-1 (666 mg, 1.64 mmol) was stirred at room temperature for 15 h, then added water (50 mL) to quench the reaction, and then extracted with dichloromethane (50 mL), the organic phase was concentrated under reduced pressure, and the obtained residue was filtered through a silica gel column Analytical purification (PE/EA(V/V)=1/1) gave the title compound as an off-white solid (420 mg, 39%). MS (ESI, pos.ion) m/z: 725.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.41 (s, 1H), 9.22 (d, J=6.4 Hz ,1H),7.95(d,J＝3.2Hz,1H),7.91–7.86(m,1H),7.84(d,J＝3.2Hz,1H),7.50(dd,J＝8.6,6.3Hz,1H) ,7.46–7.37(m,3H),7.17(td,J=8.4,2.5Hz,1H),6.04(s,1H),4.63–4.55(m,1H),4.46(d,J=5.2Hz,2H) ), 3.59(s, 3H), 3.52(s, 3H), 3.50–3.42(m, 1H), 3.31–3.25(m, 1H), 2.39(s, 3H), 2.20(s, 3H).

Synthesis of Example 2

Step 1: Synthesis of Compound 2-1

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

Step 2: Synthesis of Compound 2-2

In a dry reaction flask, F3 (5.30 g, 14.0 mmol, prepared with reference to the synthesis method of compound 4 in Example 1 of WO2017076286), compound 2-1 (3.36 g, 16.8 mmol), 2-thiazolecarboxamidine hydrochloride were added in sequence Salt (3.14 g, 18.2 mmol), 4-methylmorpholine (3.53 g, 34.9 mmol) and THF (60 mL) were reacted at 60° C. for 24 h. Turn off heat and let cool to room temperature. The solvent was evaporated under reduced pressure, ethyl acetate (70 mL) and water (50 mL) were added to the residue, the layers were extracted, and the organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (DCM/CH ₃ OH (V/V)=30/1) and purified to obtain a yellow solid (3.32 g, 40.9%). MS (ESI, pos.ion) m/z: 581.2 [M+H] ⁺ .

Step 3: Synthesis of Compounds 2-3

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

Step 4: Synthesis of Compounds 2-4

Compound 2-3 (160 mg, 0.28 mmol) and THF (6 mL) were sequentially added to a dry reaction flask, and then NaBH ₄ (34 mg, 0.86 mmol) was added under ice bath. After the addition, the reaction system was moved to room temperature for 6h. Ethyl acetate (30 mL) was added, the organic layer was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a yellow foamy solid (158 mg, 98.05%). MS (ESI, pos.ion) m/z: 567.2 [M+H] ⁺ .

Step 5: Synthesis of Compounds 2-5

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

Step 6: Synthesis of Compounds 2-6

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

Step 7: Synthesis of Compound 2

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

Synthesis of Example 3

Step 1: Synthesis of Compound 3-1

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

Step 2: Synthesis of Compound 3-2

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

Step 3: Synthesis of Compound 3-3

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

Step 4: Synthesis of Compound 3

Compound F2 (100 mg, 0.30 mmol) and HATU (140 mg, 0.35 mmol) were dissolved in DMF (5 mL), and compound 3-3 (180 mg, 0.33 mmol) and DIPEA (116 mg, 0.90 mmol) were added thereto, respectively, at room temperature. Stir for 19h. Water (20 mL) was added to it, extracted with dichloromethane (20 mL), and the organic phase was washed with dilute hydrochloric acid (1 M, 10 mL), saturated sodium bicarbonate solution (10 mL), water (10 mL) and saturated brine (10 mL), respectively. , dried over anhydrous sodium sulfate, spin-dried, and the obtained residue was purified by silica gel column chromatography (EA) to obtain the title compound as a white solid (120 mg, 54%). MS (ESI, pos.ion): m/z 748.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.39 (s, 1H), 9.20 (d, J=5.9 Hz , 1H), 7.98–7.73 (m, 4H), 7.50–7.30 (m, 4H), 7.16 (td, J=8.4, 1.7Hz, 1H), 6.05 (s, 1H), 4.55–4.37 (m, 2H) ),4.32(dd,J＝11.4,5.8Hz,1H),3.85(dd,J＝17.9,3.7Hz,1H),3.72(dd,J＝16.8,2.6Hz,1H),3.57(s,3H) ,3.42(dd,J=17.1,6.9Hz,1H),3.06–2.96(m,2H),2.35(s,3H),2.17(s,3H).

Synthesis of Example 4

Step 1: Synthesis of Compound 4-1

Compound F4 (refer to the synthesis method of WO2017156255A1 Example 1 Fragment 4, 500 mg, 1.97 mmol), DIPEA (0.7 mL, 4 mmol) and HATU (1.027 g, 2.57 mmol) were dissolved in DCM (10 mL) and stirred for ten minutes Then compound 1-1 (1.03 g, 1.98 mmol) was added to the reaction system. The reaction mixture was stirred at room temperature for 17 h, then washed with dilute hydrochloric acid (1 M, 10 mL) and sodium hydroxide solution (1 M, 10 mL), respectively, the organic layer was spin-dried, and the obtained residue was separated by silica gel column chromatography (DCM/CH _{3 )} . OH (V/V)=50/1) was purified to give a brown solid (400 mg, 31.6%). MS(ESI, pos.ion) m/z: 642.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 4-2

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

Step 3: Synthesis of Compound 4

Compound 4-2 (225 mg, 0.38 mmol), DIPEA (0.1 mL, 0.60 mmol) and HATU (450 mg, 1.12 mmol) were dissolved in DCM (6 mL), and after stirring for 10 min, propargylamine (61 mg, 1.11 mmol) was dissolved The system was added, and the reaction was stirred at room temperature for 16 h. The reaction system was washed with dilute hydrochloric acid (1M, 10mL), sodium hydroxide solution (1M, 10mL) and saturated brine (10mL), respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove the solvent, and the obtained residue was filtered through a silica gel column. Purification by analytical separation (DCM/CH3OH (V/V) ₌ 50/1 ) gave a yellow solid (12 mg, 5%). MS (ESI, pos.ion) m/z: 651.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 9.19 (d, J=6.5 Hz, 1 H), 8.58 (t ,J=5.7Hz,1H),7.95(d,J=3.2Hz,1H),7.86(d,J=3.2Hz,1H),7.49(dd,J=8.7,6.3Hz,1H),7.40(dd , J=8.9, 2.6Hz, 1H), 7.17 (td, J=8.5, 2.6Hz, 1H), 6.02 (s, 1H), 4.61–4.53 (m, 1H), 4.44 (d, J=5.1Hz, 2H), 4.01(dd, J=5.6, 2.4Hz, 2H), 3.52(s, 3H), 3.45(s, 3H), 3.40–3.35(m, 1H), 3.30–3.25(m, 1H), 3.13 (t, J=2.4Hz, 1H), 2.33(s, 3H), 2.15(s, 3H).

Synthesis of Example 5

Step 1: Synthesis of Compound 5-1

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

Step 2: Synthesis of Compound 5-2

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

Step 3: Synthesis of Compound 5-3

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

Step 4: Synthesis of Compounds 5-4

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

Step 5: Synthesis of Compounds 5-5

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

Step 6: Synthesis of Compound 5

Compound 5-5 (0.29 g, 0.56 mmol) was dissolved in DMF (10 mL), and then DIPEA (0.20 g, 1.6 mmol), compound F2 (0.22 g, 0.65 mmol) and HATU (0.25 g, 0.66 mmol) were added thereto. was stirred at room temperature for 6 h, then ethyl acetate (20 mL) and water (50 mL) were added to the system, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined, and the organic phase was washed with saturated brine (50 mL), no Dry over aqueous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (PE/EA(V/V)=1/2) to obtain the title compound as a white solid (160 mg, 40%). MS (ESI, pos.ion) m/z: 725.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.83 (d, J=3.2 Hz, 1 H), 7.76-7.69 (m ,1H),7.44(s,1H),7.41(d,J=3.2Hz,1H),7.34(dd,J=8.6,6.1Hz,1H),7.22–7.12(s,4H),7.03(td, J=8.3, 2.6Hz, 1H), 6.21 (s, 1H), 4.78–4.72 (m, 1H), 4.62–4.53 (m, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 3.63 –3.58(m,1H),3.38(dd,J=18.2,6.6Hz,1H),2.44(s,3H),2.41(s,3H).

Synthesis of Example 6

Step 1: Synthesis of Compound 6-1

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

Step 2: Synthesis of Compound 6-2

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

Step 3: Synthesis of Compound 6-3

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

Step 4: Synthesis of Compounds 6-4

Compound 6-3 (550 mg, 1.34 mmol) and triethylamine (406 mg, 4.01 mmol) were dissolved in dichloromethane (10 mL), to which was added methanesulfonyl chloride (308 mg, 2.69 mmol) under an ice-water bath, and then the temperature was raised. The reaction was carried out at 35°C for 2 h, cooled and concentrated under reduced pressure to obtain the title compound as a yellow solid (410 mg, 78%). MS (ESI, pos.ion) m/z: 393.2 [M+H] ⁺ .

Step 5: Synthesis of Compounds 6-5

Compound 6-4 (200 mg, 0.51 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added thereto, stirred at room temperature for 2 h, and spin-dried to obtain the title compound as a brown oil (200 mg, 97%) .

Step 6: Synthesis of Compound 6

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

Synthesis of Example 7

Step 1: Synthesis of Compound 7-1

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

Step 2: Synthesis of Compound 7-2

Compound 7-1 (160 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.1 mL) was added, stirred at room temperature for 12 h, spin-dried to remove the solvent, and the residue was used in the next reaction.

Step 3: Synthesis of Compound 7

Compound 7-2 (160 mg, 0.29 mmol) was dissolved in DMF (5 mL), compound F2 (120 mg, 0.36 mmol), HATU (130 mg, 0.34 mmol) and DIPEA (110 mg, 0.85 mmol) were added, stirred at room temperature for 26 h, and acetic acid was added Ethyl ester (25 mL) and water (50 mL) were separated and extracted, the aqueous phase was back-extracted with ethyl acetate (20 mL×2), the organic phases were combined, the combined organic phases were washed with saturated brine (50 mL), and anhydrous sodium sulfate It was dried, filtered, and the filter cake was purified by thin layer chromatography (PE/EA(V/V)=1/6) to give a white solid (30 mg, 13%). MS (ESI, pos.ion) m/z: 764.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.67 (s, 1H), 7.87 (d, J=3.2 Hz, 1H ), 7.82–7.72 (m, 1H), 7.63 (d, J=7.6Hz, 1H), 7.43 (d, J=3.1Hz, 1H), 7.37 (d, J=8.8Hz, 1H), 7.32–7.29 (m, 1H), 7.15–7.07 (m, 2H), 6.98 (td, J=8.4, 2.4Hz, 1H), 6.10 (s, 1H), 4.76–4.69 (m, 1H), 4.61–4.53 (m ,1H),4.48–4.41(m,1H),3.65(s,3H),3.30(s,3H),3.05–2.91(m,2H),2.35(s,3H),2.31(s,3H), 1.89–1.69(m,5H).

Synthesis of Example 8

Example 8 can be prepared by referring to the synthetic method of Example 7, and it is an off-white solid (70 mg, 33.50%). MS (ESI, pos.ion) m/z: 724.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.20 (d, J=5.9 Hz ,1H),7.92(d,J＝3.2Hz,1H),7.91-7.83(m,1H),7.80(d,J＝3.2Hz,1H),7.47-7.39(m,4H),7.18(td, J=8.5, 2.5Hz, 1H), 6.06 (s, 1H), 4.52–4.39 (m, 2H), 4.37–4.27 (m, 1H), 3.58 (s, 3H), 3.50–3.42 (m, 2H) ,3.08–2.95(m,1H),2.52(s,3H),2.37(s,3H),2.17(s,3H).

Synthesis of Example 9

Example 9 can be prepared by referring to the synthetic method of Example 7, and it is a yellow solid (110 mg, 96.48%). MS (ESI, pos.ion) m/z: 780.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.28 (s, 1H), 7.87 (d, J=3.2 Hz, 1H ), 7.78–7.66 (m, 1H), 7.58 (d, J=7.5Hz, 1H), 7.44 (d, J=3.2Hz, 1H), 7.34–7.29 (m, 2H), 7.20–7.09 (m, 2H), 6.99(td, J=8.3, 2.5Hz, 1H), 6.09(s, 1H), 4.77-4.69(m, 1H), 4.63-4.53(m, 1H), 4.53-4.45(m, 1H) ,3.66(s,3H),3.55-3.40(m,4H),3.39-3.14(m,4H),2.91(dd,J=16.4,6.8Hz,1H),2.75(dd,J=16.3,5.1Hz ,1H),2.36(s,3H),2.32(s,3H).

Synthesis of Example 10

Step 1: Synthesis of Compound 10-1

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

Step 2: Synthesis of Compound 10-2

To the reaction flask was added compound 10-1 (6.00g, 12.9mmol), 2-chloro-4-fluorobenzaldehyde (2.15g, 13.6mmol), thiazolecarboxamidine hydrochloride (2.53g, 14.8mmol), 4- Methylmorpholine (3.6 mL, 32 mmol) and tetrahydrofuran (50 mL) were reacted at 60° C. for 23 h, cooled to room temperature and used for the next reaction. MS (ESI, pos.ion) m/z: 625.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 10-3

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

Step 4: Synthesis of Compound 10-4

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

Step 5: Synthesis of Compound 10-5

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

Step 6: Synthesis of Compound 10-6

Compound 10-5 (250 mg, 0.42 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added thereto, stirred at room temperature for 1 h, and concentrated under reduced pressure to give the title compound as a brown oil (250 mg, 98 %).

Step 7: Synthesis of Compound 10

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

Synthesis of Example 11

Step 1: Synthesis of Compound 11-1

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

Step 2: Synthesis of Compound 11-2

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

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

Step 3: Synthesis of Compound 11-3

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

Step 4: Synthesis of Compound 11-4

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

Step 5: Synthesis of Compound 11-5

Compound 11-4 (200 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added thereto, stirred at room temperature for 0.5 h, and concentrated under reduced pressure to give the title compound as a brown oil (200 mg, 97%).

Step 6: Synthesis of Compound 11

Compound F2 (152 mg, 0.45 mmol) and HATU (199 mg, 0.50 mmol) were dissolved in DMF (5 mL), DIPEA (160 mg, 1.23 mmol) and compound 11-5 (150 mg, 0.41 mmol) were added thereto, and the mixture was stirred at room temperature for 11 h . Add water (20 mL) to dilute, extract with dichloromethane (20 mL), wash the organic phase with 1M hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and saturated brine (20 mL) successively, dry over anhydrous sodium sulfate, reduce It was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA(V/V)=1/1) to obtain the title compound as a yellow solid (110 mg, 39%). MS (ESI, pos.ion) m/z: 682.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.59 (s, 1H), 8.09–7.98 (m, 1H), 7.77 –7.68(m,1H),7.25(d,J=8.8Hz,1H),7.17–7.09(m,2H),7.06(dd,J=8.5,2.3Hz,1H),6.88(td,J=8.4 ,2.2Hz,1H),5.81(s,1H),4.89–4.75(m,1H),4.33–4.21(m,1H),3.96–3.86(m,1H),3.66(s,3H),3.64– 3.58(m, 1H), 3.55(s, 3H), 3.23(dd, J=18.2, 6.9Hz, 1H), 2.38(s, 3H), 2.32(s, 3H), 1.59–1.50(m, 1H) ,1.16–1.08(m,1H),0.86–0.79(m,1H),0.78–0.71(m,1H),0.60–0.51(m,1H).

Synthesis of Example 12

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

Synthesis of Example 13

Example 13 can be prepared by referring to the synthesis method of Example 6, and it is a yellow solid (150 mg, 55.7%). MS (ESI, pos.ion) m/z: 719.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.63 (s, 2H), 8.05-7.96 (m, 1H), 7.76 –7.65(m,2H),7.53(d,J=6.3Hz,1H),7.37–7.30(m,2H),7.19–7.09(m,3H),6.98(td,J=8.3,2.5Hz,1H) ), 6.12(s, 1H), 4.72–4.67(m, 1H), 3.98–3.90(m, 1H), 3.68(s, 3H), 3.62(s, 3H), 3.60–3.50(m, 2H), 3.41(dd,J=18.4,4.8Hz,1H),2.37(s,3H),2.30(s,3H).

Synthesis of Example 14

Example 14 can be prepared by referring to the synthesis method of Example 11, and it is a yellow solid (181 mg, 80.4%). MS (ESI, pos.ion) m/z: 682.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.06 (d, J=7.9 Hz, 1 H), 7.77-7.67 (m ,1H),7.52(d,J＝4.8Hz,1H),7.33-7.26(m,1H),7.21(d,J＝8.7Hz,1H),7.17-7.11(m,1H),7.08(dd, J=8.6, 2.4Hz, 1H), 6.96–6.89 (m, 1H), 5.92 (s, 1H), 4.70 (d, J=4.7Hz, 1H), 4.19–4.12 (m, 1H), 4.09 (d , J＝10.6Hz, 1H), 3.69(s, 3H), 3.59(s, 3H), 3.49(d, J＝18.2Hz, 1H), 3.39(dd, J＝18.5, 6.7Hz, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 1.60–1.51 (m, 1H), 1.19–1.10 (m, 1H), 0.88–0.79 (m, 2H), 0.78–0.67 (m, 1H).

Synthesis of Example 15

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

Synthesis of Example 16

Example 16 can be prepared by referring to the synthetic method of Example 7, and it is a white solid (35 mg, 14.46%). MS (ESI, pos.ion) m/z: 764.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.17 (d, J=5.5 Hz ,1H),7.93(d,J＝3.1Hz,1H),7.91-7.83(m,1H),7.81(d,J＝3.0Hz,1H),7.65(s,1H),7.48-7.40(m, 2H), 7.38 (dd, J=8.8, 2.4Hz, 1H), 7.23–7.14 (m, 1H), 6.03 (s, 1H), 4.44 (d, J=9.1Hz, 1H), 4.35–4.25 (m ,1H),3.58(s,3H),3.28(d,J=7.6Hz,1H),2.92(d,J=15.6Hz,1H),2.38(s,3H),2.17(s,3H),1.11 (s,3H),0.41(s,3H).

Synthesis of Example 17

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

Synthesis of Example 18

Example 18 can be prepared by referring to the synthesis method of Example 7, and it is a pale yellow solid (90 mg, 22%). MS (ESI, pos.ion) m/z: 806.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.43 (s, 1H), 9.18 (d, J=5.7 Hz ,1H),7.97–7.92(m,1H),7.88–7.79(m,2H),7.51–7.46(m,1H),7.46–7.42(m,1H),7.38(dd,J=8.9,2.4Hz ,1H),7.23–7.14(m,2H),6.08(s,1H),4.44(d,J=10.6Hz,2H),4.37–4.27(m,1H),3.58(s,3H),3.45– 3.41 (m, 1H), 3.32–3.26 (m, 1H), 3.04–2.93 (m, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 1.66–1.51 (m, 3H), 1.46 ( d, J=12.8Hz, 1H), 1.20–1.15 (m, 1H), 1.14–1.02 (m, 2H), 0.90–0.83 (m, 1H), 0.79 (d, J=6.5Hz, 3H).

Synthesis of Example 19

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

Synthesis of Example 20

Example 20 can be prepared by referring to the synthetic method of Example 7, and it is a white solid (70 mg, 20%). MS (ESI, pos.ion) m/z: 856.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.26 (s, 1H), 7.85 (d, J=3.1 Hz, 1H ), 7.80–7.71 (m, 1H), 7.43 (d, J=3.2Hz, 1H), 7.39–7.32 (m, 3H), 7.31–7.27 (m, 4H), 7.20–7.08 (m, 2H), 7.00(t, J＝6.8Hz, 1H), 6.18(s, 1H), 5.62(br, 1H), 4.71–4.61(m, 1H), 4.60–4.53(m, 1H), 4.47–4.35(m, 2H), 3.72–3.55 (m, 5H), 3.45–3.35 (m, 1H), 3.27–3.17 (m, 2H), 2.75–2.55 (m 3H), 2.36 (s, 3H), 2.34 (s, 3H) ).

Synthesis of Example 21

Example 21 can be prepared by referring to the synthesis method of Example 7, and it is a white solid (0.16 g, 48%). MS (ESI, pos.ion) m/z: 750.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.41 (s, 1H), 9.18 (d, J=5.5 Hz ,1H),7.93(d,J＝3.1Hz,1H),7.91–7.83(m,1H),7.81(d,J＝3.1Hz,1H),7.55(d,J＝3.5Hz,1H),7.48 –7.41(m,2H),7.39(dd,J=8.8,2.3Hz,1H),7.19(td,J=8.4,2.3Hz,1H),6.06(s,1H),4.45(d,J=9.2 Hz, 2H), 4.37–4.20(m, 1H), 3.58(s, 3H), 2.95(d, J=14.8Hz, 1H), 2.53(d, J=8.8Hz, 2H), 2.38(s, 3H) ), 2.17(s, 3H), 0.52(d, J=6.9Hz, 2H), 0.42–0.28(m, 1H), 0.29–0.19(m, 1H).

Synthesis of Example 22

Example 22 can be prepared by referring to the synthesis method of Example 6, and it is a yellow solid (210 mg, 75.2%). MS (ESI, pos.ion) m/z: 719.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.41 (s, 1H), 9.33 (d, J=4.6 Hz ,1H),8.82(d,J＝4.0Hz,1H),8.77(s,1H),8.10(d,J＝7.7Hz,1H),7.90–7.81(m,1H),7.77–7.68(m, 1H), 7.63(dd, J=7.8, 4.9Hz, 1H), 7.50–7.36(m, 3H), 7.13(td, J=8.4, 2.4Hz, 1H), 6.16(s, 1H), 4.49(d , J=1.5Hz, 1H), 4.15–4.08(m, 1H), 3.79(d, J=11.2Hz, 2H), 3.59(s, 3H), 3.57(s, 3H), 3.35(dd, J= 18.1, 6.3Hz, 1H), 2.34(s, 3H), 2.18(s, 3H).

Synthesis of Example 23

Example 23 can be prepared by referring to the synthesis method of Example 6, and it is a white solid (180 mg, 59.9%). MS (ESI, pos.ion) m/z: 611.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.41 (s, 1H), 9.21 (d, J=5.6 Hz ,1H),7.98(d,J＝3.2Hz,1H),7.88(d,J＝3.2Hz,1H),7.87–7.82(m,1H),7.49–7.36(m,2H),4.55(q, J=6.3Hz, 1H), 4.50–4.43(m, 1H), 4.40(d, J=11.7Hz, 1H), 4.34(dd, J=11.8, 5.2Hz, 1H), 3.65(s, 3H), 3.58(s, 3H), 3.28(d, J=17.9Hz, 1H), 3.14(dd, J=18.0, 6.7Hz, 1H), 2.38(s, 3H), 2.20(s, 3H), 1.16(d ,J=6.4Hz,3H).

Synthesis of Example 24

Example 24 can be prepared by referring to the synthetic method of Example 6, and it is a white solid (150 mg, 52.2%). MS (ESI, pos.ion) m/z: 673.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.22 (d, J=6.2 Hz ,1H),7.96(d,J＝3.2Hz,1H),7.92-7.81(m,2H),7.48-7.40(m,2H),7.37-7.29(m,4H),7.27-7.20(m,1H ), 5.62 (s, 1H), 4.57–4.41 (m, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 3.34–3.31 (m, 1H), 3.23 (dd, J=18.0, 4.9 Hz,1H),2.38(s,3H),2.19(s,3H).

Synthesis of Example 25

Example 25 can be prepared by referring to the synthetic method of Example 6, and it is a white solid (530 mg, 73.8%). MS (ESI, pos.ion) m/z: 673.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.38 (s, 1H), 9.24 (d, J=4.5 Hz ,1H),8.12(d,J＝5.2Hz,2H),7.92-7.81(m,1H),7.49-7.37(m,4H),7.31-7.22(m,3H),5.65(s,1H), 4.52(d,J＝10.6Hz,2H),4.42(dd,J＝11.8,5.2Hz,2H),3.60(s,3H),3.53(s,3H),3.26(dd,J＝17.9,6.3Hz ,1H),2.28(s,3H),2.18(s,3H).

Synthesis of Example 26

Example 26 can be prepared by referring to the synthesis method of Example 6, and it is a yellow solid (120 mg, 39.5%). MS (ESI, pos.ion) m/z: 597.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.46 (s, 1H), 9.20 (d, J=6.1 Hz ,1H),7.97(d,J＝3.2Hz,1H),7.92-7.83(m,2H),7.48-7.37(m,2H),4.50-4.40(m,2H),4.38-4.27(m,3H) ), 3.64(s, 3H), 3.58(s, 3H), 3.20–3.14(m, 2H), 2.38(s, 3H), 2.20(s, 3H).

Synthesis of Example 27

Example 27 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (112 mg, 53.80%). MS (ESI, pos.ion) m/z: 663.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.45 (s, 1H), 9.21 (d, J=6.4 Hz ,1H),7.97(d,J＝3.2Hz,1H),7.92–7.81(m,2H),7.52(d,J＝15.6Hz,2H),7.44(d,J＝5.5Hz,2H),6.42 (s, 1H), 5.56 (s, 1H), 4.59–4.38 (m, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 3.44–3.39 (m, 1H), 3.15 (dd, J =17.6,5.8Hz,1H),2.38(s,3H),2.19(s,3H).

Synthesis of Example 28

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

Synthesis of Example 29

Example 29 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (153 mg, 76.1%). MS (ESI, pos.ion) m/z: 663.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.40 (s, 1H), 9.21 (d, J=4.6 Hz ,1H),7.98(d,J=3.2Hz,1H),7.92-7.80(m,2H),7.47(s,1H),7.45-7.37(m,2H),6.31(d,J=2.8Hz, 1H), 6.24(d, J＝3.0Hz, 1H), 5.67(s, 1H), 4.54(d, J＝11.6Hz, 1H), 4.45(d, J＝5.0Hz, 1H), 4.37(dd, J=11.6, 5.3Hz, 1H), 3.61(s, 3H), 3.56(s, 3H), 3.45(d, J=18.0Hz, 1H), 3.28–3.13(m, 1H), 2.34(s, 3H) ),2.20(s,3H).

Synthesis of Example 30

Example 30 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (53 mg, 60.1%). MS (ESI, pos.ion) m/z: 663.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.22 (d, J=6.1 Hz ,1H),7.97(d,J＝3.2Hz,1H),7.91-7.83(m,2H),7.54(s,1H),7.47-7.39(m,2H),6.39-6.33(m,1H), 6.23(d, J=3.1Hz, 1H), 5.70(s, 1H), 4.60–4.38(m, 3H), 3.60(s, 3H), 3.58(s, 3H), 3.41(dd, J=16.9, 5.8Hz, 1H), 3.22(dd, J=17.9, 4.8Hz, 1H), 2.37(s, 3H), 2.18(s, 3H).

Synthesis of Example 31

Example 31 can be prepared by referring to the synthesis method of Example 3, and it is a white solid (70 mg, 25%) (wherein compound 31-5 can be prepared by referring to the synthesis method of compound 3-1). MS (ESI, pos.ion) m/z: 650.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.39 (s, 1H), 9.15 (d, J=6.0 Hz, 1H ), 7.94 (d, J=3.2Hz, 1H), 7.90–7.82 (m, 2H), 7.46–7.40 (m, 2H), 5.76 (s, 1H), 4.52 (q, J=6.3Hz, 1H) ,4.42–4.36(m,2H),4.33–4.25(m,2H),3.57(s,3H),3.42(d,J=2.4Hz,2H),2.91(dd,J=16.2,6.4Hz,1H ), 2.59–2.55(m, 1H), 2.36(s, 3H), 2.16(s, 3H), 1.92–1.69(m, 4H), 1.16(d, J=6.5Hz, 3H).

Synthesis of Example 32

Example 32 can be prepared by referring to the synthetic method of Example 3, and it is a white solid (85 mg, 21%). MS (ESI, pos.ion) m/z: 650.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.41 (s, 1H), 9.19 (d, J=5.8 Hz, 1H ), 7.95(d, J=3.1Hz, 1H), 7.91–7.82 (m, 2H), 7.48–7.37 (m, 2H), 4.50–4.32 (m, 3H), 4.22 (d, J=9.3Hz, 1H), 3.59(s, 3H), 3.38(s, 4H), 2.81(dd, J=16.1, 6.3Hz, 1H), 2.72–2.65(m, 1H), 2.40(s, 3H), 2.23(s ,3H),1.80(d,J＝6.6Hz,4H),1.19(d,J＝6.4Hz,3H).

Synthesis of Example 33

Example 33 can be prepared by referring to the synthetic method of Example 7, and it is a white solid (74 mg, 26%). MS (ESI, pos.ion) m/z: 666.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.40 (s, 1H), 9.17 (d, J=6.2 Hz ,1H),7.94(d,J＝3.2Hz,1H),7.90-7.85(m,1H),7.83(d,J＝3.2Hz,1H),7.46-7.41(m,2H),4.47(q, J=6.3Hz, 1H), 4.44–4.37 (m, 1H), 4.36–4.25 (m, 2H), 3.60 (s, 2H), 3.58 (d, J=5.8Hz, 6H), 3.48–3.41 (m ,2H),2.86(dd,J＝16.1,6.5Hz,1H),2.54(d,J＝3.3Hz,1H),2.35(s,3H),2.16(s,3H),1.18(d,J＝ 6.5Hz, 3H).

Synthesis of Example 34

Example 34 can be prepared by referring to the synthetic method of Example 7, and it is a white solid (90 mg, 22%). MS (ESI, pos.ion) m/z: 666.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.21 (d, J=5.7 Hz ,1H),7.95(d,J=3.0Hz,1H),7.91-7.81(m,2H),7.47-7.39(m,2H),4.48-4.31(m,3H),4.22(d,J=10.6 Hz, 1H), 3.59 (s, 3H), 3.57 (s, 4H), 3.55–3.51 (m, 2H), 3.50–3.44 (m, 2H), 2.80 (dd, J=16.1, 6.2Hz, 1H) ,2.65(d,J＝15.5Hz,1H),2.40(s,3H),2.23(s,3H),1.21(d,J＝6.4Hz,3H).

Synthesis of Example 35

Step 1: Synthesis of Compound 35-1

Compound 3-1 (150 mg, 0.86 mmol) was dissolved in DMF (5 mL), DIPEA (445 mg, 3.44 mmol) and HATU (491 mg, 1.29 mmol) were added, and ammonium chloride (68 mg, 1.32 mmol) was added after stirring for 20 min. Stir at room temperature for 23 h, add dichloromethane (20 mL), then wash with water (10 mL×5), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is subjected to silica gel column chromatography (petroleum ether/ethyl acetate) Ester (V/V)=1/2) was purified to give the title compound as a yellow solid (371 mg, 88%). MS (ESI, pos.ion) m/z: 492.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 35-2

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

Step 3: Synthesis of Compound 35-3

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

Step 4: Synthesis of Compound 35

Compound F2 (153 mg, 0.46 mmol) and HATU (213 mg, 0.56 mmol) were dissolved in DMF (10 mL), then DIPEA (179 mg, 1.38 mmol) was added, and compound 35-3 (190 mg, 0.46 mmol) was added after stirring at room temperature for 10 min. , the reaction mixture was stirred at room temperature for 21 h, diluted with ethyl acetate (20 mL), and then washed with water (10 mL×5). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography ( Purification with petroleum ether/ethyl acetate (V/V)=1/1) gave the title compound as an off-white solid (131 mg, 41%). MS (ESI, pos.ion) m/z: 692.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.31 (d, J=5.8 Hz ,1H),8.01(d,J＝3.2Hz,1H),7.92(d,J＝3.2Hz,1H),7.91-7.83(m,1H),7.67-7.58(m,1H),7.51(dd, J=8.7, 2.7Hz, 1H), 7.48–7.38 (m, 2H), 7.32 (td, J=8.5, 2.6Hz, 1H), 5.92 (s, 1H), 4.55 (d, J=10.3Hz, 2H) ), 4.52–4.45(m, 1H), 3.60(s, 3H), 3.23(dd, J=16.9, 6.6Hz, 1H), 2.90(dd, J=17.0, 2.9Hz, 1H), 2.41(s, 3H), 2.22(s, 3H).

Synthesis of Example 36

Step 1: Synthesis of Compound 36-1

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

Step 2: Synthesis of Compound 36-2

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

Step 3: Synthesis of Compound 36-3

Compound 36-2 (2.35g, 6.19mmol), 2-chloro-4-fluoro-benzaldehyde (1.05g, 6.49mmol), 2-thiazolecarboxamidine hydrochloride (1.23g, 7.11mmol, 94.6g) were added to the reaction flask %), THF (20 mL) and NMM (1.7 mL, 15 mmol), the reaction was stirred at 60° C. for 5 h, cooled to room temperature, and used directly for the next reaction.

Step 4: Synthesis of Compound 36-4

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

Step 5: Synthesis of Compound 36-5

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

Step 6: Synthesis of Compound 36-6

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

Step 7: Synthesis of Compound 36-7

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

Step 8: Synthesis of Compound 36

Compound 36-7 (0.21 g, 0.40 mmol) was dissolved in DMF (5 mL), DIPEA (0.10 g, 0.77 mmol), compound F2 (0.16 g, 0.48 mmol) and HATU (0.18 g, 0.47 mmol) were added at room temperature. under stirring for 24h. Dichloromethane (20 mL) and water (50 mL) were added to dilute, the aqueous phase was back-extracted with dichloromethane (20 mL), the organic phases were combined, and the organic phases were sequentially washed with 1M hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL), saturated Washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=1/1) to obtain a white solid (90 mg, 30%). MS (ESI, pos.ion) m/z: 724.90 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.19 (t, J=30.4 Hz ,1H),7.97(d,J=3.2Hz,1H),7.91-7.83(m,2H),7.56-7.47(m,1H),7.47-7.37(m,3H),7.18(td,J=8.5 ,2.6Hz,1H),6.02(s,1H),4.65–4.53(m,1H),4.46(d,J=5.2Hz,2H),3.57(s,3H),3.52(s,3H),3.49 –3.41(m,1H),3.28(dd,J=17.8,4.7Hz,1H),2.39(s,3H),2.20(s,3H).

Synthesis of Example 37

Example 37 can be prepared by referring to the synthetic method of Example 36, and it is a white solid product (0.28 g, 94%). MS (ESI, pos.ion) m/z: 724.90 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.39 (s, 1H), 9.31 (d, J=5.0 Hz ,1H),7.97(d,J＝3.2Hz,1H),7.91-7.83(m,2H),7.53(dd,J＝8.6,6.4Hz,1H),7.46-7.38(m,3H),6.98( td, J=8.4, 2.5Hz, 1H), 6.01 (s, 1H), 4.56 (d, J=11.7Hz, 1H), 4.53–4.45 (m, 1H), 4.34 (dd, J=11.7, 5.2Hz) ,1H),3.62–3.46(m,7H),3.28(dd,J=18.0,6.6Hz,1H),2.36(s,3H),2.22(s,3H).

Synthesis of Example 38

Example 38 can be prepared by referring to the synthetic method of Example 6, and it is a beige solid (206 mg, 62.39%). MS (ESI, pos.ion) m/z: 715.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.84 (d, J=18.0 Hz, 2H), 7.77-7.66 (m ,1H),7.59–7.38(m,2H),7.26–7.08(m,2H),4.71(s,2H),4.60–4.38(m,2H),3.73(s,3H),3.62(s,3H) ), 3.22–3.06 (m, 1H), 2.35 (s, 3H), 2.28 (s, 3H), 2.17–2.04 (m, 2H), 1.87 (d, J=13.1Hz, 1H), 1.77–1.56 ( m,5H),1.46–1.30(m,2H).

Synthesis of Example 39

Example 39 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (134 mg, 35.14%). MS (ESI, pos.ion) m/z: 637.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.17 (d, J=6.3 Hz ,1H),7.96(d,J=3.2Hz,1H),7.91-7.82(m,2H),7.48-7.38(m,2H),4.45-4.33(m,3H),4.27(d,J=6.7 Hz, 1H), 3.66(s, 3H), 3.58(s, 3H), 3.40–3.35(m, 1H), 3.11(dd, J=17.7, 5.5Hz, 1H), 2.38(s, 3H), 2.18 (s, 3H), 1.09–0.94 (m, 1H), 0.45–0.19 (m, 4H).

Synthesis of Example 40

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

Synthesis of Example 41

Example 41 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (168 mg, 57.02%). MS (ESI, pos.ion) m/z: 679.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.42 (s, 1H), 9.21 (d, J=6.2 Hz ,1H),7.97(d,J＝3.2Hz,1H),7.91-7.82(m,2H),7.48-7.39(m,3H),7.28(d,J＝2.2Hz,1H),7.09(d, J=5.0Hz, 1H), 5.71(s, 1H), 4.59-4.39(m, 3H), 3.62(s, 3H), 3.58(d, J=10.0Hz, 3H), 3.45-3.37(m, 1H) ), 3.18(dd, J=17.7, 5.4Hz, 1H), 2.39(s, 3H), 2.20(s, 3H).

Synthesis of Example 42

Example 42 can be prepared by referring to the synthetic method of Example 6, and it is an off-white solid (157 mg, 53.28%). MS (ESI, pos.ion) m/z: 679.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.38 (s, 1H), 9.18 (d, J=4.6 Hz ,1H),7.99(d,J＝3.2Hz,1H),7.92-7.82(m,2H),7.47-7.39(m,2H),7.37-7.34(m,1H),7.32(s,1H), 7.12(d,J＝4.9Hz,1H),5.69(s,1H),4.54(d,J＝11.6Hz,1H),4.49–4.42(m,1H),4.38(dd,J＝11.7,5.2Hz ,1H),3.62(s,3H),3.55(s,3H),3.45(d,J＝17.9Hz,1H),3.22(dd,J＝18.0,6.6Hz,1H),2.29(s,3H) ,2.18(s,3H).

Synthesis of Example 43

Example 43 can be prepared by referring to the synthetic method of Example 6, and it is a beige solid (69 mg, 8.3%). MS (ESI, pos.ion) m/z: 715.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.86 (s, 1H), 7.78–7.64 (m, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.21–7.05 (m, 3H), 4.87–4.75 (m, 1H), 4.75–4.64 (m, 1H), 4.61–4.40 (m, 2H), 3.76 (s, 3H), 3.71 (s, 3H), 3.46 (d, J=18.1Hz, 1H), 3.34–3.18 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.22– 2.08 (m, 2H), 1.90 (d, J=12.0Hz, 1H), 1.81–1.68 (m, 5H), 1.46–1.41 (m, 1H).

Synthesis of Example 44

Example 44 can be prepared by referring to the synthetic method of Example 6, and it is a pale yellow solid (93 mg, 57.45%). MS (ESI, pos.ion) m/z: 677.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.05 (d, J=6.2 Hz, 1 H), 8.80 (s, 1 H ), 7.90(d, J=3.2Hz, 1H), 7.71-7.62(m, 1H), 7.49(d, J=3.2Hz, 1H), 7.32-7.27(m, 1H), 7.14-7.05(m, 2H), 6.14(s, 1H), 4.84–4.76(m, 1H), 4.65(d, J=12.6Hz, 1H), 4.55(dd, J=12.6, 4.7Hz, 1H), 4.13(s, 3H) ), 3.86(d, J＝13.3Hz, 1H), 3.73(s, 3H), 3.59(s, 3H), 3.23–3.15(m, 2H), 2.37(s, 3H), 2.31(s, 3H) .

Synthesis of Example 45

A solution of compound 1 (that is, the compound of Example 1) (500 mg, 0.69 mmol), methanol (4 mL), tetrahydrofuran (4 mL), and sodium hydroxide (82.8 mg, 2.07 mmol) in water (2 mL) was added to the reaction flask, and the temperature was raised to 80 ℃ reaction 16h. The reaction solution was spin-dried, diluted with dichloromethane (50 mL) and 1M (50 mL) hydrochloric acid, the layers were separated, the aqueous phase was back-extracted with dichloromethane (20 mL×2), the organic phases were combined, and the organic phase was washed with saturated brine (50 mL). ), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=2/3) to obtain a white solid (75 mg, 15.1%) . MS (ESI, pos.ion) m/z: 711.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.97 (s, 2H), 7.81 (s, 1H), 7.70 (s ,1H),7.40(s,1H),7.28(s,2H),7.24–7.18(m,1H),7.13(d,J＝7.5Hz,1H),6.93(t,J＝10.0Hz,1H) ,6.05(s,1H),4.82(s,1H),4.62(d,J＝5.5Hz,1H),3.68(d,J＝19.2Hz,2H),3.61(s,2H),2.35(s, 3H), 2.28(s, 3H).

Synthesis of Example 46

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

Synthesis of Example 47

Step 1: Synthesis of Compound 47-1

Compound F5 (240mg, 0.49mmol, which can be prepared with reference to the synthesis method of compound 3-1), ammonium chloride (27.52mg, 0.51mmol), HATU (224mg, 0.59mmol), DIPEA (127mg, 0.98 mmol) and DMF (6 mL), and the reaction was stirred at room temperature for 5 h. Add water (50 mL) to dilute, then extract with dichloromethane (25 mL), extract the aqueous phase with dichloromethane (10 mL), combine the organic phases, wash the organic phases with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter , the filtrate was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=2/3) to obtain a yellow solid product (220 mg, 91.3%). MS (ESI, pos.ion) m/z: 492.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 47-2

Compound 47-1 was dissolved in 1,4-dioxane (4 mL), HCl in 1.4-dioxane solution (4 mL, 4.01 M/L) was added, stirred at room temperature for 17 h, the reaction solution was spin-dried, and used directly in the next step. MS (ESI, pos.ion) m/z: 392.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 47

Compound 47-2 (0.19 g, 0.44 mmol), compound F2 (0.15 g, 0.44 mmol), HATU (0.20 g, 0.53 mmol), DIPEA (0.11 g, 0.88 mmol) and DMF (10 mL) were added to the reaction flask, and the room temperature under stirring for 7h. 1M hydrochloric acid (50 mL) was added to dilute, then extracted with ethyl acetate (20 mL), the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, After filtration, the filtrate was spin-dried, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=1/2) to obtain a pale yellow solid (44 mg, 13.2%). MS (ESI, pos.ion) m/z: 710.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.41 (s, 1H), 9.21 (d, J=5.9 Hz ,1H),7.92(d,J＝3.1Hz,1H),7.86(dd,J＝13.1,7.7Hz,1H),7.80(d,J＝3.1Hz,1H),7.49–7.36(m,4H) ,7.26–7.16(m,1H),6.86(s,2H),6.06(s,1H),4.53–4.38(m,2H),4.33(dd,J=11.8,5.9Hz,1H),3.58(s ,3H),3.49–3.44(m,1H),3.05(dd,J=17.1,3.0Hz,1H),2.37(s,3H),2.18(s,3H).

Synthesis of Example 48

Compound 48-6 (0.37 g, 0.51 mmol, which can be prepared by reference to the synthetic method of Example 6) was dissolved in methanol (9 mL) and THF (6 mL), and sodium hydroxide (0.10 g, 2.55 mmol) in water was added (3mL) solution, stirred at room temperature for 6h, spin-dried the reaction solution, added (50mL) water to dilute, then extracted with dichloromethane (50mL), the aqueous phase was then extracted with dichloromethane (20mL), the organic phases were combined, the organic phase Washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, the residue was added with ethyl acetate (10 mL), slurried for 19 h, filtered, and the filter cake was washed with ethyl acetate (5 mL), at 50° C. Dry by rotary evaporation to obtain a yellow solid (37 mg, 9.47%). MS (ESI, pos.ion) m/z: 717.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.48 (s, 1H), 9.30 (d, J=6.4 Hz ,1H),8.11–8.05(m,2H),7.92(d,J=8.1Hz,2H),7.90–7.85(m,1H),7.55(d,J=8.1Hz,2H),7.48–7.39( m, 2H), 5.76 (s, 1H), 4.65–4.58 (m, 1H), 4.52–4.42 (m, 2H), 3.59 (s, 6H), 3.50–3.44 (m, 1H), 3.26 (dd, J=17.8, 5.2Hz, 1H), 2.39(s, 3H), 2.20(s, 3H).

Synthesis of Example 49

Example 49 can be prepared by referring to the synthesis method of Example 48, and it is a pale yellow solid (67 mg, 16.07%). MS (ESI, pos.ion) m/z: 717.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.37 (s, 1H), 9.24 (d, J=4.6 Hz ,1H),7.99(d,J＝3.0Hz,1H),7.89(d,J＝2.9Hz,1H),7.83(d,J＝8.0Hz,2H),7.51(d,J＝8.1Hz,2H) ), 7.45–7.37 (m, 2H), 5.69 (s, 1H), 4.56 (d, J=11.7Hz, 1H), 4.51–3.43 (m, 1H), 4.38 (dd, J=11.6, 5.1Hz, 1H), 3.58(s, 3H), 3.55(s, 3H), 3.46–3.43(m, 1H), 3.29–3.25(m, 1H), 2.31(s, 3H), 2.21(s, 3H).

Synthesis of Example 50

Step 1: Synthesis of Compound 50-1

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

Step 2: Synthesis of Compound 50-2

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

Step 3: Synthesis of Compound 50

Compound 50-2 (192 mg, 0.57 mmol), HATU (260 mg, 0.68 mmol), DMF (10 mL) and DIPEA (223 mg, 1.73 mmol) were added to the reaction flask, and compound F2 (310 mg, 0.57 mmol) was added after the reaction was stirred at room temperature for 10 min. , the reaction mixture was reacted at room temperature for 16h. EA (20 mL) was added to dilute, then washed with saturated NaCl solution (20 mL×5), the organic phase was concentrated, and the residue was purified by thin layer chromatography (DCM/MeOH (V/V)=10/1) to obtain a light khaki solid (57 mg, 12.7%). MS (ESI, pos.ion) m/z: 788.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.17 (s, 1H), 10.46 (s, 1H), 9.25 (d, J=6.2Hz, 1H), 8.00–7.76 (m, 3H), 7.56–7.32 (m, 4H), 7.20 (t, J=8.7Hz, 1H), 6.14 (s, 1H), 4.59– 4.33(m, 3H), 3.59(s, 3H), 3.54–3.47(m, 1H), 3.36(s, 3H), 3.16(dd, J=17.4, 4.3Hz, 1H), 2.38(s, 3H) ,2.19(s,3H).

Synthesis of Example 51

Step 1: Synthesis of Compound 51-1

Formic acid (23 mL, 609.60 mmol) was added to the reaction flask, triethylamine (42 mL, 303 mmol) was slowly added under an ice-water bath, and 4-formyl benzonitrile (10.00 g, 76.26 mmol) and Mylbauer’s acid (10.99 mmol) were added after stirring evenly. g, 76.26 mmol), the temperature was raised to about 100 °C and the reaction was carried out for about 16.5 h. Turn off heating. The reaction system was cooled to about 5°C, water (120 mL) was slowly added, a white solid was precipitated, acidified with hydrochloric acid (6M, 45 mL) to pH=1～2, and stirring was continued at about 5°C for 4 h. After suction filtration, the filter cake was washed with water (20 mL), and rotary evaporated at 50°C for 1 h to obtain the title compound as a white solid (11.21 g, 83.91%). MS (ESI, pos.ion) m/z: 176.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 51-2

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

Step 3: Synthesis of Compound 51-3

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

Step 4: Synthesis of Compound 51-4

Compound 51-3 (3.36g, 17.48mmol), compound F3 (6.73g, 17.13mmol), 2-thiazolecarboxamidine hydrochloride (3.95g, 19.21mmol, content 79.6%), isopropanol ( 15 mL) and 4-methylmorpholine (4.42 g, 43.66 mmol), and the temperature was raised to 80 °C with stirring for 5.5 h. The heating was turned off, cooled to room temperature, concentrated to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (V/V)=20/1) to obtain a yellow solid (7.06 g, 70.5%). MS(ESI,pos.ion)m/z:573.2[M+H]

Step 5: Synthesis of Compounds 51-5

Compound 51-4 (7.06 g, 12.33 mmol), THF (30 mL) and 4-methylmorpholine (2.49 g, 24.66 mmol) were added to the reaction flask, the temperature was lowered to about 5 °C, and isobutyl chloroformate (2.02 mmol) was added dropwise. g, 14.80 mmol) in THF (10 mL) solution, dripping was completed, the reaction was continued for 0.5 h, concentrated, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V)=1/1) to obtain Yellow solid (1.77 g, 25.9%). MS (ESI, pos.ion) m/z: 555.5 [M+H] ⁺ .

Step 6: Synthesis of Compounds 51-6

NaBH ₄ (0.24 g, 6.38 mmol) and water (5 mL) were added to the reaction flask, a solution of compound 51-5 (1.77 g, 3.19 mmol) in THF (10 mL) was added under stirring in an ice bath, and the reaction was continued in an ice bath for about For 30 min, ethyl acetate (20 mL) and water (10 mL) were added, the aqueous phase was discarded, the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, and the filter cake was washed with ethyl acetate (10 mL) was washed, and the filtrate was concentrated to give a yellow solid (1.59 g, 89.2%). MS (ESI, pos.ion) m/z: 559.1 [M+H] ⁺ .

Step 7: Synthesis of Compounds 51-7

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

Step 8: Synthesis of Compounds 51-8

Compound 51-7 (518 mg, 0.96 mmol) and hydrochloric acid in 1,4-dioxane (6 mL, 4 M) were added to the reaction flask, and the reaction was stirred at room temperature for 2 h. Suction filtration, the filter cake was washed with dioxane (5 mL), and rotary evaporated at 50° C. for 1 h to obtain a light brown solid (437 mg, 95.4%). MS (ESI, pos.ion) m/z: 441.3 [M+H] ⁺ .

Step 9: Synthesis of Compounds 51-9

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

Step 10: Synthesis of Compound 51

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

Synthesis of Example 52

Example 52 can be prepared by referring to the synthesis method of Example 51, and it is an off-white solid (113 mg, 58.36%). MS (ESI, pos.ion) m/z: 745.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.36 (s, 1H), 9.23 (d, J=4.9 Hz ,1H),7.98(d,J＝3.3Hz,1H),7.91-7.80(m,2H),7.47-7.36(m,2H),7.28(d,J＝7.7Hz,2H),7.08(d, J=7.8Hz, 2H), 5.57(s, 1H), 4.56(d, J=11.7Hz, 1H), 4.50-4.42(m, 1H), 4.41-4.32(m, 1H), 3.57(s, 3H) ),3.56(s,3H),3.46(d,J＝18.0Hz,1H),3.24(dd,J＝18.2,6.9Hz,1H),2.77(t,J＝7.6Hz,2H),2.48(t , J=7.9Hz, 2H), 2.34(s, 3H), 2.22(s, 3H).

Synthesis of Example 53

Example 53 can be prepared by referring to the synthetic method of Example 3, and it is an off-white solid (43 mg, 36.41%) MS (ESI, pos.ion) m/z: 622.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm) 10.42(s, 1H), 9.11(d, J=5.6Hz, 1H), 7.99-7.73(m, 3H), 7.50-7.33(m, 2H), 6.90(s, 2H), 4.47–4.24 (m, 4H), 3.57 (s, 3H), 3.43–3.39 (m, 1H), 2.94 (dd, J=17.3, 5.1Hz, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 1.07–0.89 (m, 1H), 0.45–0.19 (m, 4H).

Synthesis of Example 54

Example 54 can be prepared by referring to the synthetic method of Example 35, and it is a brown solid (88 mg, 49.92%). MS (ESI, pos.ion) m/z: 630.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.39 (s, 1H), 9.26 (d, J=5.0 Hz ,1H),7.99(d,J＝3.0Hz,1H),7.90(d,J＝3.0Hz,1H),7.86(dd,J＝12.5,7.4Hz,1H),7.65(s,1H),7.46 –7.36(m,2H),6.44(d,J=7.0Hz,2H),5.66(s,1H),4.60–4.42(m,3H),3.58(s,3H),3.26(dd,J=16.5 ,5.4Hz,1H),2.91(d,J=16.8Hz,1H),2.39(s,3H),2.20(s,3H).

Synthesis of Example 55

Example 55 can be prepared by referring to the synthetic method of Example 45, and it is an off-white solid (91 mg, 15.8%). MS (ESI, pos.ion) m/z: 623.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.55 (s, 1H), 9.66 (s, 1H), 8.39 (s, 1H), 7.95 (d, J=3.1Hz, 1H), 7.90–7.80 (m, 2H), 7.48–7.29 (m, 2H), 5.73 (s, 1H), 4.43–4.31 (m, 3H) ), 4.23(d, J＝6.9Hz, 2H), 3.48(s, 3H), 2.18(s, 3H), 2.04(s, 3H), 1.00-0.86(m, 1H), 0.36-0.16(m, 4H).

Synthesis of Example 56

Example 56 can be prepared by referring to the synthesis method of Example 51, and it is a light brown solid (527 mg, 74.68%). MS (ESI, pos.ion) m/z: 759.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.40 (s, 1H), 9.20 (d, J=6.3 Hz ,1H),7.96(d,J＝3.2Hz,1H),7.92-7.81(m,2H),7.51-7.37(m,2H),7.25(d,J＝7.7Hz,2H),7.17(d, J=7.8Hz, 2H), 5.60(s, 1H), 4.61–4.39(m, 3H), 3.60(s, 3H), 3.58(s, 6H), 3.42(dd, J=17.7, 6.5Hz, 1H ),3.22(dd,J＝18.0,3.6Hz,1H),2.82(t,J＝7.7Hz,2H),2.61(t,J＝7.7Hz,2H),2.39(s,3H),2.21(s , 3H).

Synthesis of Example 57

Example 57 can be prepared by referring to the synthesis method of Example 51, and it is a light brown solid (379 mg, 66.60%). MS (ESI, pos.ion) m/z: 759.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.36 (s, 1H), 9.21 (d, J=4.8 Hz ,1H),8.07–7.94(m,1H),7.93–7.77(m,2H),7.42(d,J=6.2Hz,2H),7.28(d,J=7.6Hz,2H),7.07(d, J=7.7Hz, 2H), 5.57(s, 1H), 4.56(d, J=11.6Hz, 1H), 4.51-4.42(m, 1H), 4.41-4.31(m, 1H), 3.56(s, 9H) ), 3.47(d, J＝18.3Hz, 1H), 3.28–3.18(m, 1H), 2.80(t, J＝7.6Hz, 2H), 2.58(t, J＝7.9Hz, 2H), 2.33(s ,3H),2.22(s,3H).

Synthesis of Example 58

Example 58 can be prepared by referring to the synthesis method of Example 48, and it is a pale yellow solid (97 mg, 40.22%). MS (ESI, pos.ion) m/z: 731.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.39 (s, 1H), 9.20 (d, J=6.3 Hz ,1H),8.02–7.81(m,5H),7.50(d,J=8.0Hz,2H),7.47–7.37(m,2H),5.73(s,1H),4.64–4.40(m,3H), 3.84(s,3H),3.59(s,3H),3.57(s,3H),3.43(dd,J=17.8,7.0Hz,1H),3.24(dd,J=18.1,5.0Hz,1H),2.39 (s,3H),2.21(s,3H).

Synthesis of Example 59

Example 59 can be prepared by referring to the synthetic method of Example 49, and it is a pale yellow solid (193 mg, 53.90%). MS (ESI, pos.ion) m/z: 731.5 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.32 (s, 1H), 9.19 (d, J=4.9 Hz ,1H),7.99(d,J＝3.2Hz,1H),7.92-7.78(m,4H),7.54(d,J＝7.9Hz,2H),7.46-7.34(m,2H),5.69(s, 1H), 4.56(d, J=11.8Hz, 1H), 4.47(d, J=6.7Hz, 1H), 4.43–4.35(m, 1H), 3.82(s, 3H), 3.57(s, 3H), 3.55(s, 3H), 3.48(d, J=18.6Hz, 1H), 3.29–3.21(m, 1H), 2.31(s, 3H), 2.19(s, 3H).

Synthesis of Example 60

Example 60 can be prepared by referring to the synthetic method of Example 6, and it is a yellow solid (180.9 mg, 81.31%). MS (ESI, pos.ion) m/z: 727.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93-7.91 (m, 1H), 7.75-7.71 (m, 1H), 7.62 (s, 1H), 7.57–7.54 (m, 1H), 7.37–7.35 (m, 1H), 7.18–7.15 (m, 1H), 6.99–6.96 (m, 1H), 6.06 (s, 1H), 4.82 –4.75(m, 1H), 4.73 – 4.68(m, 1H), 4.62 – 4.55(m, 1H), 3.70(s, 3H), 3.68(s, 3H), 3.64 – 3.60(m, 1H), 3.39 –3.33(m, 1H), 3.34(s, 1H), 2.40(s, 3H), 2.36(s, 3H).

Synthesis of Example 61

Example 61 can be prepared by referring to the synthetic method of Example 6, and it is a yellowish solid (265.7 mg, 85.74%). MS (ESI, pos.ion) m/z: 727.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, J=3.2 Hz, 1 H), 7.76-7.68 (m, 1 H ), 7.46(s, 1H), 7.44(d, J=3.2Hz, 1H), 7.21-7.17(m, 1H), 7.16-7.10(m, 2H), 6.98(dd, J=16.7, 8.1Hz, 1H), 6.02(s, 1H), 4.80-4.72(m, 1H), 4.65-4.54(m, 2H), 3.73(s, 3H), 3.68(s, 3H), 3.51(d, J=18.3Hz ,1H),3.34(dd,J=18.3,6.6Hz,1H),2.43(s,3H),2.40(s,3H).

Synthesis of Example 62

Example 62 can be prepared by referring to the synthetic method of Example 6, and it is a pale yellow solid (267.1 mg, 90.42%). MS: (ESI, pos.ion) m/z: 773.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J=3.1 Hz, 1 H), 7.64 (d, J= 8.9Hz, 2H), 7.55(s, 1H), 7.40(d, J=3.1Hz, 1H), 7.27–7.22(m, 2H), 7.16(dd, J=8.6, 2.4Hz, 1H), 6.96( t, J=8.2Hz, 1H), 6.19 (s, 1H), 4.82–4.75 (m, 1H), 4.64–4.54 (m, 2H), 3.73 (s, 3H), 3.68 (d, J=7.4Hz ,1H),3.63(s,3H),3.33–3.27(m,1H),2.42(s,3H),2.39(s,3H).

Synthesis of Example 63

Example 63 can be prepared by referring to the synthetic method of Example 6, and it is a pale yellow solid (116.6 mg, 76.32%). MS (ESI, pos.ion) m/z: 773.50 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J=3.2 Hz, 1 H), 7.69 (s, 1 H), 7.52(s, 1H), 7.40(d, J=3.5Hz, 2H), 7.19-7.14(m, 2H), 7.07-7.02(m, 1H), 6.99-6.93(m, 1H), 6.20(s, 1H), 4.80–4.75 (m, 1H), 4.63–4.56 (m, 2H), 3.74 (s, 3H), 3.68 (d, J=7.8Hz, 1H), 3.63 (s, 3H), 3.31 (dd , J=18.0, 6.3Hz, 1H), 2.43(s, 3H), 2.41(s, 3H).

Synthesis of Example 64

Example 64 can be prepared by referring to the synthetic method of Example 6, and it is a khaki solid (95.4 mg, 83.88%). MS (ESI, pos.ion) m/z: 732.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (d, J=6.7 Hz, 1 H), 8.55 (d, J = 8.4Hz, 1H), 8.24–8.20 (m, 1H), 7.95 (d, J=3.4Hz, 2H), 7.85 (d, J=3.2Hz, 1H), 7.58–7.46 (m, 2H), 7.43 –7.39(m, 1H), 7.21 – 7.15(m, 1H), 6.03(s, 1H), 4.61 – 4.57(m, 1H), 4.48 – 4.44(m, 2H), 3.60(s, 3H), 3.52 (s, 3H), 3.44(d, J=7.3Hz, 1H), 2.40(s, 3H), 2.21(s, 3H).

Synthesis of Example 65

Example 65 can be prepared by referring to the synthesis method of Example 6, and it is a khaki solid (152.3 mg, 51.90%). MS (ESI, pos.ion) m/z: 815.00 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 9.29 (d, J=6.5 Hz, 1H ),8.44(s,1H),7.96-7.92(m,2H),7.84(d,J=3.2Hz,1H),7.63-7.59(m,2H),7.50(dd,J=8.6,6.3Hz, 1H), 7.40(dd, J=8.9, 2.6Hz, 1H), 7.17(td, J=8.5, 2.6Hz, 1H), 6.03(s, 1H), 4.63–4.58(m, 1H), 4.46(d , J=5.4Hz, 2H), 3.61(s, 3H), 3.51(s, 3H), 3.49-3.44(m, 1H), 3.32-3.26(m, 1H), 2.40(s, 3H), 2.23( s, 3H).

Synthesis of Example 66

Example 66 can be prepared by referring to the synthetic method of Example 6, and it is a khaki solid (211.8 mg, 75.19%). MS (ESI, pos.ion) m/z: 741.45 [M+H] ⁺ ; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H), 9.24 (d, J=5.9 Hz, 1H ),8.02(d,J=4.7Hz,1H),7.95(d,J=2.0Hz,1H),7.84(s,1H),7.61(br,1H),7.53–7.47(m,1H),7.44 –7.38(m, 2H), 7.18(t, J=7.0Hz, 1H), 6.04(s, 1H), 4.59(d, J=4.5Hz, 1H), 4.47(s, 2H), 3.59(s, 3H), 3.52(s, 3H), 3.47(dd, J=17.8, 7.0Hz, 1H), 2.40(s, 3H), 2.20(s, 3H).

Synthesis of Example 67

Example 67 can be prepared by referring to the synthesis method of Example 6, and it is a pale yellow solid (184.3 mg, 65.48%). MS (ESI, pos.ion) m/z: 689.3 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 9.22 (d, J=6.5 Hz, 1H) ,7.95(d,J＝3.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.70(d,J＝7.9Hz,2H),7.49(dd,J＝8.6,6.3Hz,1H) ,7.40(dd,J＝8.9,2.5Hz,1H),7.34(t,J＝7.9Hz,2H),7.18(td,J＝8.4,2.5Hz,1H),7.10(t,J＝7.4Hz, 1H), 6.03(s, 1H), 4.62–4.55(m, 1H), 4.46(d, J=5.1Hz, 2H), 3.59(s, 3H), 3.51(s, 3H), 3.49–3.40(m ,1H),3.32–3.25(m,1H),2.39(s,3H),2.20(s,3H).

biological test

HepAD38 cells to evaluate the compound of the present invention inhibiting HBV DNA replication activity (qPCR method) and compound cytotoxicity

HBV cell lines and culture conditions

HepAD38: Ladner et al. (Ladner, Otto et al. 1997) linked the tetracycline-sensitive cytomegalovirus CMV promoter to the PBR322 plasmid and linked the ayw subtype HBV DNA to the ptetHBV plasmid, and transfected HepG2 cells to obtain the HepAD38 cell line. The HBV DNA yield was about 11-fold higher than that of HepG2.2.15 cells due to the disruption of the pre-C region gene. Tetracycline can be used to regulate HBV replication, and the time required for culturing is only half of that of HepG2.2.15 cells, which is suitable for the study of HBV replication process and replication intermediates and the screening of anti-HBV drugs. HepAD38 was cultured in DMEM/F-12K medium containing 10% FBS and 1% double antibody (also containing Tetracycline at a final concentration of 300 ng/mL and G418 at a final concentration of 400 μg/ml).

In vitro cytotoxicity assay

HepAD38 was revived, digested and counted after the cells were in good condition, and diluted with DMEM/F-12K medium containing 10% FBS and 1% double antibody to a concentration of 1×10 ⁵ /mL cell suspension. The amount of 100 μL was inoculated in a 96-well plate (the whole plate was covered), and incubated in a 37° C., 5% CO ₂ constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 μL of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.

Compound formulation and cell treatment in in vitro cytotoxicity assays: Compounds were solubilized to 20 mM in DMSO, followed by 8 dilutions of 4-fold dilution, with a maximum concentration of 20 mM. Add 1 μL of serially diluted compounds to each well of the above cell plate, and the highest final concentration in the experiment is 100 μM (200-fold dilution). Staurosporine (staurosporine, Selleck, CAS No. 62996-74-1) was used as a positive control compound at a maximum concentration of 1 μM. Negative control wells were added with 1 μL DMSO at a final concentration of 0.5%.

After 72h, discard the old medium, add medium containing 10% CCK8 solution, incubate for 20-40min, detect in the microplate reader, get the OD value, export the data to calculate the inhibition rate, use Graphpad Prism 5 software nonlinear regression model Process and plot a curve to calculate the _CC50 of the compound. The experimental results are shown in Table 2.

In vitro anti-HBV activity assay

After recovering HepAD38 and waiting for the cells to be in good condition, add Tetracycline (final concentration of 300ng/mL) and G418 (final concentration of 400 μg/mL) to the culture medium. The virus does not express in the presence of Tetracycline, digested and counted after it has grown to full size. DMEM/F-12K medium containing 10% FBS (containing Tetracycline at a final concentration of 300 ng/mL and G418 at a final concentration of 400 μg/mL, 1% double antibody) was diluted to a concentration of 2×10 ⁵ /mL cell suspension , inoculate 100 μL per well in a 96-well plate (the whole plate is covered), and incubate in a 37° C., 5% CO ₂ constant temperature incubator for 24 h. After 24 hours, the old medium was discarded, and 200 μL of fresh DMEM/F-12K medium containing 2% FBS and 1% double antibody was added.

Compound formulation and cell treatment in antiviral experiments: Compounds were dissolved in DMSO to 20 mM, further diluted in DMSO to 800 μM, and then 4-fold dilution was performed in 8 dilutions, with a maximum concentration of 800 μM. Add 1 μL of serially diluted compounds to each well of the above cell plate, and the highest final concentration in the experiment is 4 μM (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) was used as a positive control compound at a maximum concentration of 4 μM. Negative control wells were added with 1 μL DMSO at a final concentration of 0.5%.

HBV DNA QPCR

qPCR was performed using Shengxiang Bio's 48-part (PCR-fluorescent probe method) one-step hepatitis B virus nucleic acid quantitative assay kit, 2.5uL of supernatant was aspirated for qPCR, and the kit reagents were thawed and vortexed before use. , after centrifugation, place the enzyme mixture on ice for later use, and ensure that the subsequent steps are completed on ice. 2.5uL of sample release agent and 2.5uL of test sample supernatant (experimental group, control group, standard curve group) were added to each well of the qPCR plate. The number of viral DNA copies in each well was obtained after qPCR reaction. Concentration-viral copy number was processed with Graphpad Prism 5 software, and the _EC50 of compounds for viral replication was calculated by a four-parameter nonlinear regression model. The experimental results are shown in Table 2.

Table 2: In vitro anti-HBV activity and cytotoxicity test results of the compounds of the present invention

实施例Example	EC ₅₀(nM) _EC50 (nM)	CC ₅₀(μM) CC ₅₀ (μM)
实施例1Example 1	88	>100>100
实施例2Example 2	4141	>100>100
实施例3Example 3	4040	N/AN/A
实施例4Example 4	4242	>100>100
实施例5Example 5	1010	>100>100
实施例6Example 6	66	>100>100
实施例7Example 7	22twenty two	>100>100
实施例8Example 8	4646	N/AN/A
实施例9Example 9	23twenty three	8282
实施例10Example 10	107107	>100>100
实施例11Example 11	4848	7373
实施例12Example 12	111111	>100>100
实施例13Example 13	3030	>100>100
实施例14Example 14	3030	N/AN/A
实施例15Example 15	4141	>100>100
实施例16Example 16	3030	>100>100
实施例17Example 17	104104	>100>100
实施例18Example 18	N/AN/A	>100>100
实施例19Example 19	7474	>100>100
实施例20Example 20	4848	>100>100
实施例21Example 21	1919	>100>100
实施例22Example 22	3333	N/AN/A
实施例23Example 23	22	>100>100
实施例24Example 24	44	>100>100
实施例25Example 25	99	8282
实施例26Example 26	22	>100>100
实施例27Example 27	44	>100>100
实施例28Example 28	1515	>100>100
实施例29Example 29	77	>100>100
实施例30Example 30	55	>100>100
实施例31Example 31	4747	>100>100
实施例32Example 32	1111	>100>100
实施例33Example 33	5656	>100>100
实施例34Example 34	2020	>100>100
实施例35Example 35	2525	>100>100
实施例36Example 36	1010	>100>100
实施例37Example 37	1212	>100>100
实施例38Example 38	44	>100>100
实施例39Example 39	55	9292
实施例40Example 40	44	>100>100

实施例41Example 41	44	>100>100
实施例42Example 42	1010	>100>100
实施例43Example 43	1717	>100>100
实施例44Example 44	1313	>100>100
实施例45Example 45	1717	N/AN/A
实施例46Example 46	2929	N/AN/A
实施例47Example 47	66	>100>100
实施例48Example 48	153153	>100>100
实施例49Example 49	141141	>100>100
实施例50Example 50	N/AN/A	>100>100
实施例51Example 51	6161	>100>100
实施例52Example 52	N/AN/A	>100>100
实施例53Example 53	77	>100>100
实施例54Example 54	44	>100>100
实施例55Example 55	55	>100>100
实施例56Example 56	6262	>100>100
实施例57Example 57	5757	>100>100
实施例58Example 58	2929	>100>100
实施例59Example 59	99	>100>100
实施例60Example 60	1212	N/AN/A
实施例61Example 61	88	>100>100
实施例62Example 62	4040	>100>100
实施例63Example 63	2929	>100>100
实施例64Example 64	22twenty two	>100>100

Note: N/A means not tested

Conclusion: The experimental results show that the compounds of the present invention have good inhibitory activity against HBV, and the compounds of the present invention are less toxic to cells.

Claims

A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable compound of the compound represented by formula (I) accepted salt or prodrug,

Wherein, R 1 is a C 1-6 alkyl group, a C 2-6 alkynyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, a C 5-10 aryl group or a hetero group consisting of 5-10 ring atoms Aryl, wherein said C 1-6 alkyl group, C 2-6 alkynyl group, C 2-6 alkenyl group, C 3-6 cycloalkyl group, C 5-10 aryl group and 5-10 ring atoms The heteroaryl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 ;

Each R2 and R3 is independently hydrogen , deuterium, F, Cl, Br, I, CN, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, methoxy or ethoxy;

Each R4, Ra , Rb and Rc is independently hydrogen, deuterium, methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 haloalkyl;

Ring A is

Wherein, X is N or CR 10 ; Y is O or S;

Each R 11 and R 11a is independently hydrogen, deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O-methyl, -C(=O)O-ethyl base, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, carboxyl C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy;

each of n1 and n2 is independently 1, 2, 3 or 4;

Each of R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently H, deuterium, CN, -C(=O)OR 1a , -C(=O)NR 1b R 1c , -C( =O)R, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl or 5- Heteroaryl group consisting of 6 ring atoms, wherein the C 1-6 alkyl group, C 1-6 haloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group , C 6-10 aryl group and heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w2 ;

Each R 1a is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 haloalkyl, wherein the The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C 1-4 haloalkyl groups are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w1 substitutions;

Each R 1b and R 1c is independently hydrogen, deuterium, -S(=O) 2 C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 3 -6 cycloalkyl groups or heterocyclic groups consisting of 4-6 ring atoms, or R 1b and R 1c together with the nitrogen atoms to which they are attached form a heterocyclic group consisting of 3-7 ring atoms, wherein said -S(=O) 2 C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 4-6 ring atoms The heterocyclyl group and the heterocyclyl group consisting of 3-7 ring atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w3 ;

Each R is independently a C 1-6 alkyl group, a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3-7 ring atoms, wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and the heterocyclyl groups consisting of 3-7 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w4 ;

Each R w1 is independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -SF6 , -C(=O)O-methyl, -C(=O)O-ethyl , -C(=O)O-n-propyl, -C(=O)O-isopropyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, -CH 2 F, -CH 2 Cl, -CF 3 , -CHF 2 , -CHCl 2 , -CH2CH2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , phenyl, -OCF 3 , C 2-4 haloalkoxy or C 1-4 alkoxy, wherein the phenyl group is optionally selected by 1, 2, 3 or 4 independently selected from F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy and ethoxy substituents;

Each R w2 , R w3 and R w4 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, -C(=O)OC 1-6 alkyl, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl, C 6-12 aryl group or heteroaryl group composed of 5-6 ring atoms, wherein the amino group, -C(=O)OC 1-6 alkyl group, C 1-6 alkyl group, C 1-6 alkyl group Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, carboxy C 1-6 alkyl, C 6-12 aryl and 5- Heteroaryl groups of 6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 .
The compound of claim 1, wherein R 1 is C 1-4 alkyl, C 2-4 alkynyl, C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, naphthyl, heteroaryl consisting of 5-6 ring atoms or heteroaryl consisting of 7-10 atoms, wherein the C 1-4 alkyl, C 2-4 alkynyl, C 2- 4Alkenyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, heteroaryl of 5-6 ring atoms and heteroaryl of 7-10 atoms each independently Unsubstituted or substituted with 1, 2, 3 or 4 R w1 .
The compound according to claim 1 or 2, wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, alkyne Propyl, propynyl, 1-alkynyl, 2-alkynyl, 3-alkynyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl , thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl or isoquinolinyl, wherein The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-alkynyl, 2-alkynyl, 3-alkynyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyridine azolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazine , pyrimidinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w1 substitutions.
The compound of any one of claims 1-3, wherein each R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently H, deuterium, CN, -C(=O)OR 1a , -C(=O)NR 1b R 1c , -C(=O)R, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , -CH2F , -CH2Cl , -CHF2 , -CF3 , -CHCl2 , -CH2CH2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , - CHFCH 2 F, -CHClCH 2 Cl, -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl , 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec - butyl, tert - butyl , -CH2F , -CH2Cl , -CHF2 , -CHCl2 , -CH2CH2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynyl Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, iso oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 R w2 substitutions.
The compound of any one of claims 1-4, wherein each R 1b and R 1c is independently hydrogen, deuterium, -S(=O) 2 C 1-4 alkyl, C 1-4 alkyl, C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl or heterocyclyl consisting of 4-6 ring atoms, or R 1b and R 1c together with the nitrogen atoms to which they are attached form 3 -Heterocyclic group consisting of 6 ring atoms, wherein -S(=O) 2 C 1-4 alkyl group, C 1-4 alkyl group, C 2-4 alkynyl group, C 2-4 alkenyl group , C 3-6 cycloalkyl, heterocyclyl consisting of 4-6 ring atoms and heterocyclyl consisting of 3-6 ring atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w3 replace.
The compound of any one of claims 1-5, wherein each R 1b and R 1c is independently hydrogen, deuterium, -S(=O) 2 -methyl, -S(=O) 2 -ethyl , -S(=O) 2 -n-propyl, -S(=O) 2 -isopropyl, -S(=O) 2 -n-butyl, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-ynylbutyl, 3-ynylbutyl, vinyl, propylene radical, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidine, imidazolidine base, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the -S(=O ) 2 -methyl, -S(=O) 2 -ethyl, -S(=O) 2 -n-propyl, -S(=O) 2 -isopropyl, -S(=O) 2 -n-propyl Butyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, 1-ynylbutyl, 2-alkynylbutyl, 3-alkynylbutyl, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, sulfur Heterocyclobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine and piperazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w3 ; or R 1b and R 1c together with the nitrogen atom to which they are attached form azetidinyl, azetidine group, pyrrolidinyl, pyrazolidine, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the azetidinyl, azetidinyl, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 Rw3 .
The compound according to any one of claims 1-6, wherein each R is independently C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or consists of 3-6 ring atoms The heterocyclyl group, wherein the C 1-4 alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the heterocyclyl group composed of 3-6 ring atoms are each independently unsubstituted or by 1, 2, 3 or 4 R w4 substitutions.
The compound of any one of claims 1-7, wherein each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetidine, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidine, imidazole Alkyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein said methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetidine base, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl , morpholinyl, thiomorpholinyl and piperazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w4 .
The compound of any one of claims 1-8, wherein each R w2 , R w3 and R w4 is independently deuterium, F, Cl, Br, I, CN, -OH, -COOH, nitro, amino, - C(=O)OC 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CF 3 , -CH 2 F , -CH2Cl , -CHF2 , -CHCl2 , -CH2CH2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , -CHFCH2F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH2CF3 , C1- 4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl , imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or Pyrimidyl, wherein said amino, -C(=O)OC 1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary Butyl , -CH2F , -CH2Cl , -CHF2 , -CHCl2 , -CH2CH2F , -CH2CH2Cl , -CH2CHF2 , -CH2CHCl2 , -CHFCH2 F , -CHClCH2Cl , -CH2CF3 , -CH ( CF3 ) 2 , -CF2CH2CH3 , -CH2CH2CH2F , -CH2CH2CHF2 , -CH2CH 2 CF 3 , C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, carboxy C 1-4 alkyl, phenyl, naphthyl, pyrrolyl , pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyridine Azinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w1 .
A compound comprising the structure of one of the following:

or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.
A pharmaceutical composition, comprising the compound of any one of claims 1-10, and pharmaceutically acceptable excipients thereof.
The pharmaceutical composition according to claim 11, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons.
The pharmaceutical composition according to claim 11, further comprising other anti-HBV drugs, wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir Wei Dipivoxil, Alfaferone, Alloferon, Simoleukin, Clavudine, Emtricitabine, Faciclovir, Progenin CP, Interferon, Interferon alfa-1b, Interferon alfa, Interferon alfa-2a, Interferon beta-1a, interferon alpha-2, interleukin-2, mivotelate, nitazoxanide, peginterferon alfa-2a, ribavirin, rointerferon-A, sizoran , Euforavac, Ampligen, Phosphazid, Heplisav, interferon alpha-2b, levamisole, or propagium.
Use of the compound of any one of claims 1-10 or the pharmaceutical composition of any one of claims 11-13 in the preparation of a medicament for preventing, treating, treating or alleviating a viral disease in a patient.
The use according to claim 14, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
The use according to claim 15, wherein the disease caused by hepatitis B virus infection is liver cirrhosis or hepatocellular carcinoma.