Amide pyrrole compound and application thereof in medicine

Abstract

The invention discloses an amide pyrrole compound and application thereof in medicines, and particularly relates to a compound as shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I), and application of the amide pyrrole compound as a medicine. Particularly, the compound can be used as a medicine for treating and / or preventing hepatitis B. The compound has relatively good inhibitory activity on HBV (Hepatitis B Virus) and has small toxicity on cells. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to amide pyrrole compounds and applications thereof in medicines. Background Art

[0002] Hepatitis B virus (HBV) belongs to the family of Hepatoviridae. It can cause acute and / or progressive chronic diseases. HBV can also cause many other clinical manifestations in pathological morphology - especially chronic inflammation of the liver, cirrhosis and carcinogenesis of liver cells. According to the World Health Organization, 2 billion people have been infected with HBV, about 350 million are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma (HCC) caused by HBV infection.

[0003] Currently, the main treatment for chronic hepatitis B (CHB) is antiviral therapy. Interferon α (IFN-α) and pegylated IFN-α and five nucleoside (acid) analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir) have been approved by the US Food and Drug Administration (FDA) for clinical treatment. Interferon is the first anti-HBV drug approved by the FDA. It mainly eliminates the virus through direct antiviral effects and inducing the body's immune response. However, its application is subject to many restrictions due to its low response rate, multiple side effects, high price and limited treatment targets. The common point of nucleoside (acid) drugs against HBV is that they specifically act on viral DNA polymerase and have a strong effect of inhibiting viral replication. Patients have better tolerance to drugs than interferon. However, the widespread and long-term use of nucleoside (acid) drugs can induce DNA polymerase mutations to form drug resistance, leading to the continuous emergence of drug-resistant strains, making the treatment far from achieving the ideal therapeutic effect.

[0004] Therefore, there is still a need for new compounds that can be effectively used as antiviral drugs, especially as drugs for the treatment and / or prevention of hepatitis B. Summary of the invention

[0005] The present invention relates to novel amide pyrrole compounds and their use in preparing drugs for treating and preventing HBV infection. In particular, the present invention relates to novel amide pyrrole compounds and pharmaceutically acceptable compositions thereof, wherein the compounds have good anti-HBV activity and less or substantially no cytotoxicity, and the compounds have good solubility, good stability, substantially no induction effect on liver drug enzymes and very good pharmacokinetic properties. The compounds of the present invention can effectively inhibit HBV infection and have good application prospects in anti-HBV.

[0006] In one aspect, the present invention relates to a compound, which is a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I),

[0007]

[0008] Among them, each R 5a , R 5b , R 5c , R 5d , R 5e , R 2 and R 3 are independently hydrogen, deuterium, F, Cl, Br, I, -CN, SF5, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, trifluoromethoxy, methoxy or ethoxy;

[0009] Ring A is

[0010] Each R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c and R 4d are independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)OC 1-6 Alkyl, amino, C 3-6 Cycloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl or heteroaryl composed of 5-6 ring atoms, wherein the C 3-6 Cycloalkyl, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w2 replaced by;

[0011] Each R 2a , R 2b , R 2c , R 2d and R 6 are independently -CN, -COOH, -C(=O)OR 6a ,-C(=O)NHR6b 、-C(=O)R 7a 、-C(=O)NHCH2R 7b or a heteroaryl group consisting of 5 to 6 ring atoms, wherein the heteroaryl group consisting of 5 to 6 ring atoms is unsubstituted or replaced by 1, 2, 3 or 4 R w3 replaced by;

[0012] Each R 6a and R 6b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or C 1-4 The halogenated alkyl group, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 1-4 Each haloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 R w4 replaced by;

[0013] Each R 7a and R 7b are independently N,N-dimethylamino, a heteroaryl group consisting of 5-6 ring atoms, or a heterocyclic group consisting of 5-6 ring atoms, wherein the heteroaryl group consisting of 5-6 ring atoms and the heterocyclic group consisting of 5-6 ring atoms are unsubstituted or replaced by 1, 2, 3 or 4 R w5 replaced by;

[0014] Each R 1a , R 1b , R 1 , R 4 , R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or C 1-4 The haloalkyl group, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl or C 1-4 Each haloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 R w6 replaced by;

[0015] L1 is a single bond, -CH2NR a -、-NR b -or-CH2CHR 6 NR a -, wherein the -CH2NR a -CH2 and -CH2CHR in 6 NR a-CH2 in each independently is unsubstituted or substituted with 1 or 2 R w7 replaced by;

[0016] Each R w2 , R w3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)OC 1-6 Alkyl, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

[0017] In some embodiments, each R 3a , R 3b , R 3c , R 4a , R 4b and R 4c are independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -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, amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridinyl, 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 R w2 replaced by, where each R w2 Has the meaning described in the present invention.

[0018] In some embodiments, each R 2a , R 2b , R 2c , R 2d and R 6 are independently -CN, -COOH, -C(=O)OR 6a ,-C(=O)NHR6b 、-C(=O)R 7a 、-C(=O)NHCH2R 7b , pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are unsubstituted or substituted with 1, 2, 3 or 4 R w3 replaced by, where each R w3 Has the meaning described in the present invention.

[0019] In some embodiments, each R 7a and R 7b are independently N,N-dimethylamino, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein The pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are unsubstituted or substituted with 1, 2, 3 or 4 R w5 replaced by, where each R w5 Has the meaning described in the present invention.

[0020] In some embodiments, each R w2 , R w3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)OC 1-4 Alkyl, amino, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0021] In some embodiments, each R w2 , Rw3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -C(=O)O tert-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, carboxyl C 1-3 -CHCl, -CF, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy or 2-methyl-l-propoxy.

[0022] In some embodiments, the compounds of the invention comprise one of the following structures:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or a prodrug thereof.

[0038] On the other hand, the present invention also provides a pharmaceutical composition comprising the compound of the present invention. In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.

[0039] In some embodiments, the pharmaceutical composition of the present invention, wherein the other anti-HBV drugs include any one or more of HBV polymerase inhibitors, immunomodulators, and interferons.

[0040] In some embodiments, the pharmaceutical composition described in the present invention, wherein the other anti-HBV drugs include any one or more of lamivudine, telbivudine, tenofovir disoproxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simoleukin, clavudine, emtricitabine, facloprid, interferon, Baoganling CP, Intefen, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mivotilide, nitazoxanide, pegylated interferon α-2a, ribavirin, rointerferon-A, sizoran, Euforavac, Ampligen, Phosphazid, Heplisav, interferon α-2b, levamisole, and propagermanium.

[0041] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0042] On the other hand, the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a drug for preventing, treating, curing or alleviating a viral disease in a patient.

[0043] In some embodiments, the use described in the present invention, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.

[0044] In other embodiments, the use described in the present invention, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

[0045] On the other hand, the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating hepatitis B disease in a patient, comprising administering an effective therapeutic dose of the compound or pharmaceutical composition of the present invention to the patient.

[0046] Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a compound of the present invention.

[0047] Another aspect of the present invention relates to a method for preventing, treating or ameliorating HBV symptoms in a patient, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable effective dose.

[0048] Another aspect of the present invention relates to the use of a compound of the present invention to prepare a medicament for preventing or treating HBV disease in a patient and reducing its severity.

[0049] Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compound of the present invention to prepare a medicament for preventing or treating HBV disease in a patient and reducing its severity.

[0050] Another aspect of the present invention relates to the use of the compound or pharmaceutical composition in the preparation of drugs for inhibiting HBV infection.

[0051] Another aspect of the present invention relates to a method for inhibiting HBV infection, the method comprising contacting cells with a compound or pharmaceutical composition of the present invention at a dose that is effective in inhibiting HBV, and the method does not involve therapeutic purposes. In some other embodiments, the method further comprises contacting cells with other anti-HBV therapeutic agents.

[0052] Another aspect of the present invention relates to a method for treating HBV disease in a patient, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient in need of treatment. In some other embodiments, the method further comprises administering an effective therapeutic dose of other anti-HBV drugs to a patient in need of treatment.

[0053] Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, the method comprising administering an effective therapeutic dose of a compound of the present invention or a pharmaceutical composition thereof to a patient in need of treatment. In some other embodiments, the method further comprises administering an effective therapeutic dose of other anti-HBV drugs to a patient in need of treatment.

[0054] Another aspect of the present invention relates to a method for synthesizing the compound of formula (I), comprising the following step A:

[0055] Compound O or its salt is subjected to a condensation reaction with compound F to obtain a compound represented by formula (I);

[0056]

[0057] Wherein, Y is H, -CH2NHR a 、-NHR b or -CH2CHR 6 NHR a ;

[0058] Ring A, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c , R 5d , R 5e , R a , R b , R 6 and L1 have the meanings as defined in the present invention.

[0059] In some embodiments, the method for synthesizing the compound of formula (I) of the present invention, wherein compound 0 can be obtained by the following step B: compound 0-1 is deprotected under acidic conditions to obtain compound 0 or a salt thereof,

[0060]

[0061] wherein Ring A, Y and L1 have the meanings as described in the present invention, R0 is a protecting group selected from Boc, Cbz, Fmoc, Alloc or Bn, and R0 is connected to the N in the L1 group; when L1 is a single bond, Ring A is In some embodiments, the acid in step B of the present invention is an organic acid or an inorganic acid. In some embodiments, the acid in step B of the present invention is hydrochloric acid or trifluoroacetic acid.

[0062] In some embodiments, the method for synthesizing the compound of formula (I) of the present invention, wherein the compound O-1 is compound (a-4) The synthesis method of the compound of formula (a-4) comprises the following step C: compound (a-3) reacts under DDQ conditions to generate compound (a-4);

[0063] Among them, R 2c , R 3c and R 4c Has the meaning described in the present invention.

[0064] In some embodiments, the synthesis method of the compound of formula (I) described in the present invention, wherein the synthesis method of compound (a-3) comprises the following step D: compound (a-2) is subjected to catalytic hydrogenation reaction, followed by Boc protection, to generate compound (a-3); Among them, R 2c, R 3c and R 4c In some embodiments, the catalytic hydrogenation reaction conditions of step D of the present invention are carried out under H2 and catalyst conditions.

[0065] In some embodiments, the synthesis method of the compound of formula (I) described in the present invention, wherein the synthesis method of compound (a-2) comprises the following step E: compound (a-1) reacts with sodium azide to generate compound (a-2); Among them, R 2c , R 3c and R 4c Has the meaning described in the present invention.

[0066] The present invention has the following beneficial effects: 1) The present invention provides a novel amide pyrrole compound, which, and a pharmaceutically acceptable composition thereof, can effectively inhibit HBV infection, has good inhibitory activity against HBV, and has low toxicity to cells; 2) The synthesis method of the present invention is novel, has a high yield, and the synthesis steps are simple and easy to operate. DETAILED DESCRIPTION

[0067] Definitions and general terms

[0068] The present invention will list the literature corresponding to the determined specific content in detail, and the embodiments are accompanied by diagrams of structural formulas and chemical formulas. The present invention is expected to cover all options, variants and equivalents, which may be included in the existing invention field as defined in the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is by no means limited to the description of methods and materials. There are many documents and similar materials that are different from or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0069] The following definitions shall apply to the present invention unless otherwise indicated. For the purposes of the present invention, the chemical elements are those according to the Periodic Table of the Elements, CAS version and the Handbook of Chemicals, 75, thEd, 1994. In addition, the general principles of organic chemistry are defined 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, and all contents are incorporated by reference.

[0070] In various parts of this specification, substituents of the compounds of the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0071] The term "alkyl" used in the present invention includes 1-20 carbon atoms saturated straight or branched monovalent hydrocarbon groups, wherein the alkyl group can be independently optionally substituted with one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-12 carbon atoms, in other embodiments, the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 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 other embodiments, the alkyl group 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, -CH2CH2CH3), 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)CH 2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3) 2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)C H2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0072] The terms "hydroxyalkyl" and "hydroxyalkoxy" refer to alkyl or alkoxy, as the case may be, substituted with one or more hydroxy groups, wherein "hydroxyalkyl", "hydroxyalkylene" and "hydroxyalkyl" are used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH, -CHOHCH3), hydroxypropyl (e.g., -CH2CH2CH2OH, -CH2CHOHCH3, -CHOHCH2CH3), hydroxymethoxy (-OCH2OH), and the like.

[0073] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position of CC is sp 2 Double bond, wherein the alkenyl group can be independently unsubstituted or substituted with 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=CH2), propenyl (-CH=CHCH3), allyl (-CH2CH=CH2) and the like, wherein the alkenyl group can be independently unsubstituted or substituted with one or more substituents described in the present invention.

[0074] The term "alkynyl" means a straight 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 one position of CC is an sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), propynyl (-C≡C-CH3), 1-ynylbutyl (-CH2CH2C≡CH), 2-ynylbutyl (-CH2C≡CCH3), 3-ynylbutyl (-C≡CCH2CH3) and the like, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.

[0075] The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, wherein alkyl, alkenyl and alkoxy have the meanings described herein. Such examples include, but are not limited to, difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), fluorovinyl (-CH=CHF, -CF=CH2), etc.

[0076] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

[0077] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl- 2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0078] The term "M-M1 ring atoms" or "M-M1 atoms" means that the cyclic group is composed of M-M1 ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "5-6 heteroaryl atoms" means a heteroaryl group consisting of 5 or 6 ring atoms.

[0079] The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system having 3-12 ring carbon atoms and having one or more points of attachment to the rest of the molecule. In some embodiments, the cycloalkyl is a spirobicyclic alkyl of 6-10 atoms; in other embodiments, the cycloalkyl is a fused bicyclic alkyl of 6-10 atoms; in other embodiments, the cycloalkyl is a ring system of 3-10 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system of 3-8 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system of 3-7 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system of 5-8 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system of 3-6 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system of 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

[0080] The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring systems containing 3-12 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 heterocyclyl, bicyclic or polycyclic fused heterocyclyl, spiro or bridged heterocyclyl, and also includes polycyclic ring systems in which the heterocycle may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocycle. Bicyclic heterocyclyl includes bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spiro bicyclic heterocyclyl. Unless otherwise specified, the -CH2- group of the heterocyclyl may be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxide. In some embodiments, the heterocyclyl is a ring system consisting of 3-12 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 4-7 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 5-6 ring atoms; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl consisting of 7-10 ring atoms; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl consisting of 8-10 ring atoms; in some embodiments, the heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms; in other embodiments, the heterocyclyl is a ring system consisting of 3-8 ring atoms; in other embodiments, the heterocyclyl is a ring system consisting of 3-6 ring atoms; in other embodiments, the heterocyclyl is a ring system consisting of 5-7 ring atoms. In some other embodiments, the heterocyclyl is a ring system consisting of 5-8 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 6-8 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 5-6 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 3 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 4 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 5 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 6 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 7 ring atoms; in some other embodiments, the heterocyclyl is a ring system consisting of 8 ring atoms.

[0081] Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3- Pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothiophenyl, pyrazolidinyl, 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-indolylquinolizinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl; examples of ring carbon atoms substituted by oxo (=O) groups include, but are not limited to, pyrimidinedione, 1,2,4-thiadiazole-5(4H)-one, 1,2,4-oxadiazole-5(4H)-one, 1H-1,2,4-triazole-5(4H)-one, etc.; examples of ring carbon atoms substituted 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 heterocyclic group may be optionally substituted by one or more substituents described in the present invention.

[0082] The terms "fused bicyclic ring", "fused ring", "fused bicyclic group" and "fused cyclic group" are used interchangeably herein and refer to a monovalent or polyvalent, saturated or partially unsaturated non-aromatic ring system in which two rings share a bond. Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain aromatic rings or heteroaromatic rings (although aromatic groups may be substituents thereon).

[0083] The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicyclic" are used interchangeably herein and refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic ring system in which one ring originates from a specific ring carbon atom of the other ring and the two rings have only one atom in common.

[0084] For example, as described in the following formula a-1, a saturated ring system (ring C and B') is called a "fused bicyclic ring", while ring A' and ring B share a carbon atom and are called "spiro" or "spiro bicyclic ring". Each ring of the fused bicyclic group and the spiro bicyclic group can be a carbocyclic group or a heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.

[0085]

[0086] The term "bridged bicyclic group" refers to a saturated or partially unsaturated non-aromatic bridged ring system, such as that shown in formula (b), where ring A1 and ring A2 share an alkane chain or a heteroalkane chain, wherein X 3 is C, N, O, P, S; j is 1, 2, 3 or 4. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic rings (but aromatic groups can be substituents thereon). Each of the rings, such as A1 or A2, contains 3-7 atoms, and such examples include, but are not limited to, bicyclo[2.2.1]heptyl, 2-methyl-diazabicyclo[2.2.1]heptyl, etc. The bridged bicyclic group is optionally substituted with one or more substituents described herein.

[0087]

[0088] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one of the ring systems is aromatic, wherein each ring system contains a ring consisting of 3-7 carbon atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring", such as aryl can include phenyl, naphthyl and anthracenyl. The aryl groups can be independently unsubstituted or substituted with one or more substituents described herein.

[0089] The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system containing 5-16 ring atoms, wherein at least one of the ring systems is aromatic and at least one of the ring systems contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms containing 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 containing 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 containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-7 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5-6 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0090] In other embodiments, heteroaryl includes the following monocyclic groups, but is not limited to these monocyclic groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 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-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes The following bicyclic or tricyclic groups, but in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), phenoxathiol, dibenzimidazolyl, dibenzofuranyl or dibenzothienyl, etc. The heteroaryl group is optionally substituted with one or more substituents described in the present invention.

[0091] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used throughout this article, "each... and... are independently", "... and... are each independently", and "... and... are respectively independently" are interchangeable and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0092] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0093] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to 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.

[0094] Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.

[0095] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0096] The definitions and conventions of stereochemistry used in this invention are generally based on the following references: SP 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 centers 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 a part of the present 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 indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to name the sign of rotation of plane polarized light of a compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine isomerization. Valence (chemical valency) tautomers include interconversions that reorganize bonding electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0097] The term "pharmaceutically acceptable" as used in the present invention includes that the substance or composition must be suitable chemically or toxicologically, in relation to the other components of the formulation and the mammals used for treatment. "Pharmaceutically acceptable salts" refer to organic salts 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. If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc. Alternatively, 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; pyranose acids such as glucuronic acid and galacturonic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or combinations thereof can be used.

[0098] If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base, such as ammonia (primary, secondary, tertiary), an alkali metal hydroxide, ammonium, N + (R 14 )4 and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, amines, such as primary, secondary and tertiary amines, N + (R 14 )4 salts, such as R 14 It is H, C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-4 alkyl, etc., and cyclic amines such as piperidine, morpholine and piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. Also included are appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that counteract the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0099] Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts can be obtained by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble 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 appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0100] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0101] The term "protecting group" or "Pg" refers to a substituent that reacts with another functional group, usually used to block or protect a specific functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy 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. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference may be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0102] Pharmaceutical compositions, formulations, administration and uses of the compounds and pharmaceutical compositions of the present invention

[0103] According to another aspect, the pharmaceutical composition of the present invention is characterized by comprising a compound of formula (I), a compound listed in the present invention, or an example compound, and a pharmaceutically acceptable excipient. The compound in the pharmaceutical composition of the present invention can effectively inhibit hepatitis B virus, and is suitable for the treatment of viral diseases, especially acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV may lead to severe morbidity, and chronic hepatitis B virus infection may lead to cirrhosis and / or hepatocellular carcinoma in many cases.

[0104] Areas of disease treatment that may be mentioned for the compounds according to the invention are, for example, the treatment of acute and chronic viral infections which may lead to infectious hepatitis, for example hepatitis B virus infection. The compounds according to the invention are particularly suitable for the treatment of chronic hepatitis B infections and acute and chronic hepatitis B virus infections.

[0105] The present invention includes pharmaceutical preparations which contain, in addition to non-toxic, inert pharmaceutically suitable excipients, one or more compounds of formula (I) of the present invention or their pharmaceutical compositions or contain one or more active ingredients compounds of formula (I) or pharmaceutical compositions of the present invention.

[0106] The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides the compound of formula (I).

[0107] The compounds of the present invention exist in free form, or are 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 adducts or derivatives that can be directly or indirectly administered according to the needs of patients, compounds described in other aspects of the present invention, their metabolites or their residues.

[0108] As described in the present invention, the pharmaceutical composition of the present invention comprises any compound of formula (I) of the present invention, and further comprises pharmaceutically acceptable excipients, such as those used in the present invention, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of the documents herein are summarized, indicating that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional excipients are incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.

[0109] 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 phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; 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 carboxymethyl cellulose; Sodium cellulose, 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; glycol compounds 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 saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0110] The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, 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 medication by means of an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.

[0111] The compound of the present invention or its pharmaceutical composition can be administered in a unit dosage form. The dosage form can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a true solution, a colloid, a microparticle dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, implants, patches, liniments, etc.

[0112] Tablets and capsules for oral administration may contain excipients such as binders, such as syrup, gum arabic, sorbitol, tragacanth, or polyvinyl pyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, aminoacetic acid; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated by methods known in the pharmaceutical industry.

[0113] Oral liquid can be made into suspension, solution, emulsion, syrup or elixir of hydrated oil, or it can be made into dry product, and water or other suitable medium is added before use. Such liquid preparations can contain conventional additives, such as suspending agent, sorbitol, methyl cellulose, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oil, emulsifier, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (which may contain edible oil), such as almond oil, oil such as glycerol, ethylene glycol, or ethanol; preservatives, such as methyl or propyl parahydroxybenzoate, sorbic acid. Flavoring agents or coloring agents can be added as needed.

[0114] Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

[0115] For extragastric administration, liquid dosage forms are usually made of the compound and a sterile excipient. The excipient is preferably water. Depending on the selected excipient and the drug concentration, the compound can be dissolved in the excipient or made into a suspension solution. When making an injection solution, the compound is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.

[0116] When applied topically to the skin, the compounds of the present invention can be made into the form of suitable ointments, lotions, or creams, in which the active ingredient is suspended or dissolved in one or more excipients, wherein the excipients that can be used for ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; the excipients that can be used for lotions and creams include but are not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl esters wax, hexadecene aromatic alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0117] In general, it has proven to be advantageous that the total amount of the active compound of the invention administered per 24 hours is about 0.5-500 mg, preferably 1-100 mg / kg body weight, if appropriate, in a plurality of single doses, in order to achieve the desired effect, both in human medicine and in veterinary medicine. The amount of active compound contained in a single dose is preferably about 1-80 mg, more preferably 1-50 mg / kg body weight, but it may not be in accordance with the above dosage, i.e., it depends on the type and weight of the treated subject, the nature and severity of the disease, the type of preparation and the mode of administration of the drug, as well as the administration cycle or time interval.

[0118] The pharmaceutical composition provided by the present invention also contains anti-HBV drugs, wherein the anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons.

[0119] The anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simu-leukin, clavudine, emtricitabine, facloprid, interferon, Baoganling CP, Intefen, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mivotilide, nitazoxanide, pegylated interferon α-2a, ribavirin, rointerferon-A, sirox, Euforavac, Ampligen, Phosphazid, Heplisav, interferon α-2b, levamisole or propagermanium, etc.

[0120] Another aspect of the present invention relates to the use of a compound or pharmaceutical composition of the present invention to prepare a medicine for preventing, treating or alleviating hepatitis B disease in a patient, comprising administering a pharmaceutically acceptable effective dose to the patient. Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute hepatitis B virus infection can be asymptomatic or manifest as symptoms of acute hepatitis. Chronic viral infection patients suffer from active disease and can develop cirrhosis and liver cancer.

[0121] Anti-HBV drugs can be administered separately from the composition comprising the compounds of the invention as part of a multiple dosing regimen. Alternatively, those drugs can be part of a single dosage form, mixed with the compounds of the 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, so as to obtain the desired agent activity.

[0122] The amount of the compound and pharmaceutical composition (those containing a pharmaceutical composition such as described herein) that can be combined with the excipient materials to produce a single dosage form will vary 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 normally administered in a composition containing the agent as the only active agent. On the other hand, the amount of the pharmaceutical composition disclosed herein ranges from about 50% to 100% of the normal amount of existing pharmaceutical compositions containing the agent as the only active therapeutic agent. In those compositions containing the agent, the composition will act synergistically with the compound of the present invention.

[0123] The compounds of the present invention show strong antiviral effects. Such compounds have unexpected antiviral activity against HBV and are therefore suitable for treating various diseases caused by the virus, especially diseases caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to various complex symptoms of varying severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and / or hepatocellular carcinoma.

[0124] Examples of indications that can be treated with the compounds of the invention are acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Chronic hepatitis B infection and acute hepatitis B virus infection are particularly preferred.

[0125] The present invention also relates to the use of the compound and pharmaceutical composition of the present invention for preparing drugs for treating and preventing viral diseases, especially hepatitis B.

[0126] General Synthesis Methods

[0127] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following synthetic schemes and examples are provided to further illustrate the present invention.

[0128] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0129] In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. 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 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.

[0130] Silica gel column was used as the chromatographic column. Silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. NMR spectra were performed with CDC13, DMSO-d6, CD3OD or acetone-d6 as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appeared, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartets), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet), td (three doublets). Coupling constant J is expressed in Hertz (Hz).

[0131] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0132] Low-resolution mass spectrometry (MS) data were also determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0133] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0134] Table 1: Gradient elution conditions

[0135] Time (min) <![CDATA[A(CH3CN,0.1%HCOOH)]]> <![CDATA[B(H2O,0.1%HCOOH)]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0136] Compound purity was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1×30 mm, 4 μm, 10 min, a flow rate of 0.6 mL / min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.

[0137] The following abbreviations are used throughout this invention:

[0138]

[0139]

[0140] Synthesis method

[0141] The following synthesis scheme lists the experimental steps for preparing the compounds disclosed in the present invention. 2d , R 3d , R 4d , R 5a , R 5b , R 5c , R 5d , R 5e , R 1 , R 2 , R 3 , L1, Y, and Ring A have the meanings as described in the present invention.

[0142] (1) Synthesis of the compound of formula (I)

[0143] The synthesis method of the compound represented by formula (I) comprises the following steps:

[0144]

[0145] Wherein, R0 is a protecting group selected from Boc, Cbz, Fmoc, Alloc or Bn, and R0 is connected to N in the L1 group; when L1 is a single bond, then ring A is

[0146] First, the synthesis method of compound 0 is that compound 0-1 is deprotected under acidic conditions (for example, in trifluoroacetic acid, hydrochloric acid, etc.) to obtain compound 0 or a salt thereof. The specific reaction conditions such as reaction time, acid concentration and temperature can be adjusted according to the technical knowledge in the art; then, compound 0 is subjected to a condensation reaction with compound F to obtain a compound represented by formula (I).

[0147] (2) Synthesis of Compound (b-6)

[0148] Compound (b-6) can be obtained by referring to the synthesis method of compound 42 on page 101 of the specification of WO2017156255, or by referring to the synthesis method of the following intermediate of the present invention.

[0149]

[0150] Among them, R F1 , R F2 Independent as C 1～6 Alkyl, X is halogen Cl, Br, F or I.

[0151] First, in the presence of a methylating agent (such as iodomethane, dimethyl sulfate, methyl p-toluenesulfonate CH3OTs, methyl trifluoromethanesulfonate CH3OTf, etc.), an alkaline substance (such as NaH, etc.) and a suitable solvent (N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, etc.), compound (b-1) reacts with compound (b-2) to obtain compound (b-3); then, compound (b-3) and compound (b-4) undergo Friedel-Crafts acylation in the presence of a Lewis acid (such as anhydrous aluminum chloride, etc.) to obtain compound (b-5); finally, compound (b-5) undergoes a hydrolysis reaction to obtain compound (b-6).

[0152] Preparation Example

[0153] In the following preparation examples, the inventors describe in detail the preparation process of the compounds of the present invention by taking some of the compounds of the present invention as examples.

[0154] Table 2. Example (compound) numbers and their corresponding structures

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] Synthesis of intermediates

[0162] Synthesis of compound F1

[0163] Step 1: Synthesis of compound F1-1

[0164] Add 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (10g, 59.81mmol) and DMF (120mL) to a dry reaction bottle in sequence. After stirring at room temperature and dissolving completely, cool to 0°C, then add NaH (3.11g, 77.75mmol), a large amount of gas escapes, and then add iodomethane (11.04g, 77.75mmol). After the addition is complete, the reaction mixture is transferred to room temperature and stirred for 30min, then NaH (7.18g, 179.43mmol) is added, and after stirring evenly, 3,4-difluoroaniline (11.58g, 89.72mmol) is added. After stirring evenly, the temperature is raised to 30°C and stirred for 12h. Turn off the heating and cool to room temperature. Add water (150mL) to quench the reaction, precipitate a large amount of solid, and stir at room temperature for 20min. Filter and rinse the filter cake with water (200mL) to obtain a gray solid crude product. Add isopropanol (70 mL) to the crude product, stir at room temperature for 23 h, filter, wash the filter cake with isopropanol (70 mL), and then dry in vacuo at 50 ° C for 8 h to obtain the title compound as an off-white solid (14.37 g, 90.91%). MS (ESI, pos.ion) m / z: 265.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H), 7.88–7.81 (m, 1H), 7.44–7.33 (m, 2H), 5.74 (s, 1H), 3.56 (s, 3H), 2.17 (d, J = 4.0Hz, 6H).

[0165] Step 2: Synthesis of Compound F1-2

[0166] Compound F1-1 (45 g, 170.28 mmol) and DCM (450 mL) were added to a dry reaction bottle in sequence. The mixture was stirred at room temperature until completely dissolved. The mixture was cooled to 0°C and methyl oxalyl chloride (96.78 g, 766.26 mmol) was slowly added dropwise. The addition time was controlled within 15-20 min. After the addition was completed, the mixture was stirred for 5 min. Anhydrous aluminum chloride (68.80 g, 510.84 mmol) was then added in batches. After the addition was completed, the mixture was stirred at room temperature for 12 h. Methyl oxalyl chloride (26.6 g, 217 mmol) was added. The mixture was stirred at room temperature for 6 h. Methyl oxalyl chloride (26.6 g, 217 mmol) was added. The mixture was stirred at room temperature for 19 h. The mixture was cooled in an ice bath and ice water (500 g) was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for complete dissolution. The layers were separated. The aqueous layer was extracted with DCM (200 mL) and the organic phases were combined. The organic phase was washed with saturated aqueous sodium bicarbonate solution (400 mL), saturated aqueous ammonium chloride solution (400 mL) and saturated aqueous sodium chloride solution (400 mL) in sequence and dried over anhydrous sodium sulfate. Filtered, the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. Isopropanol (200 mL) was added to the crude product to dilute it, and stirred at room temperature for 12 hours, filtered, and the filter cake was washed with isopropanol (100 mL) and dried in vacuo at 50°C for 8 hours to obtain the title compound as a white solid (44.7 g, 74.9%). MS (ESI, pos.ion) m / z: 351.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm): 7.77–7.70 (m, 1H), 7.64 (s, 1H), 7.20–7.16 (m, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 2.37 (s, 3H).

[0167] Step 3: Synthesis of Compound F1

[0168] Compound F1-2 (40 g, 114.18 mmol), methanol (300 mL) and THF (100 mL) were added to a dry reaction bottle in sequence and stirred evenly. Sodium hydroxide (23.79 g, 570.90 mmol) was dissolved in water (200 mL) and then added dropwise to the reaction system. After the addition was complete, the mixture was reacted at room temperature for 1.5 h. Part of the solvent (about 200 mL) was evaporated under reduced pressure. The residue was stirred and adjusted to pH 1-2 with concentrated hydrochloric acid. A large amount of solid was precipitated. The mixture was stirred at room temperature for 30 min and filtered. The filter cake was dried under vacuum at 60 ° C for 8 h to obtain a light pink solid (38.4 g, 100%). MS (ESI, pos.ion) m / z: 337.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 7.91–7.83 (m, 1H), 7.47–7.40 (m, 2H), 3.60 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H).

[0169] Synthesis of compound F2

[0170]

[0171] Step 1: Synthesis of compound F2-1

[0172] Add Boc-L-aspartic acid 1-benzyl ester (100g, 309.27mmol) and dichloromethane (200mL) in a dry reaction bottle, stir and dissolve completely, add DMAP (56.68g, 463.90mmol), stir at room temperature for 10min, then add cycloisopropyl malonate (51.26g, 355.65mmol), cool to 0℃, dilute EDCI (88.93g, 463.90mmol) with DCM (300mL) and slowly drop into the above reaction system, keep warm and stir for 16h. The reaction solution is washed with 1N hydrochloric acid (100mL×3) and saturated sodium chloride aqueous solution (100mL×3) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure to remove the solvent to obtain the title compound as a yellow oil (140g, 100%). MS(ESI,pos.ion)m / z:472.2[M+Na] + .

[0173] Step 2: Synthesis of Compound F2

[0174] Compound F2-1 (140 g, 311.49 mmol), methanol (140 mL) and toluene (420 mL) were added to a dry reaction bottle, and the mixture was stirred at 70°C for 18 h. The solvent was evaporated under reduced pressure, and ethanol (120 mL) and petroleum ether (200 mL) were added to the residue. The mixture was cooled to 10°C with stirring, and solids gradually precipitated. The mixture was stirred for 6 h, filtered, and the solids were collected. The filtrate was further cooled to -10°C, stirred for 2.5 h, filtered, and the solids were collected. The solids were combined and dried under vacuum at 50°C for 1 h to obtain the title compound as a white solid (105.2 g, 89.02%). MS (ESI, pos.ion) m / z: 280.2 [M+H-100] + ; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.41–7.30 (m, 5H), 5.50 (d, J = 8.2 Hz, 1H), 5.18 (s, 2H), 4.64–4.51 (m, 1H), 3.73 (s, 3H), 3.46 (s, 2H), 3.33–3.25 (m, 1H), 3.17–3.09 (m, 1H), 1.44 (s, 9H). Synthesis of compound F3

[0175]

[0176] 4-Trifluoromethoxyaniline was substituted for 3,4-difluoroaniline, and the rest of the operations were performed according to the synthesis method of compound F1 to obtain compound F3 as a pink solid (0.82 g, 69.9%). MS (ESI, pos.ion) m / z: 385.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.43 (s, 1H), 7.81 (d, J = 9.0Hz, 2H), 7.36 (d, J = 8.7Hz, 2H), 3.60 (s, 3H), 2.46 (s, 3H), 2.26 (s, 3H).

[0177] Synthesis of compound F4

[0178]

[0179] 3-Trifluoromethoxyaniline was substituted for 3,4-difluoroaniline, and the rest of the operations were performed according to the synthesis method of compound F1 to obtain compound F4 as a slightly brown solid (1.58 g, 57.9%). MS (ESI, pos.ion) m / z: 385.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.43 (s, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.1Hz, 1H), 7 .46(t,J=8.2Hz,1H),7.07(d,J=7.6Hz,1H),3.58(s,3H),2.43(s,3H),2.28(s,3H).

[0180] Synthesis of compound F5

[0181]

[0182] Boc-D-aspartic acid 1-benzyl ester was used to replace Boc-L-aspartic acid 1-benzyl ester, and the remaining operations were referred to the synthesis method of compound F2. 1H NMR(400MHz, CDCl3)δ7.44–7.30(m,5H),5.49(d,J=8.1Hz,1H),5.17(s,2H),4.66–4.48(m,1H),3 .72(s,3H),3.45(s,2H),3.29(dd,J=18.3,4.2Hz,1H),3.12(dd,J=18.3,4.3Hz,1H),1.44(s,9H).

[0183] Synthesis of compound F6

[0184]

[0185] The synthesis method of compound F6 was obtained by referring to the synthesis method of compound 82-8 in WO2015 / 180631.

[0186] Example 1

[0187] Synthesis of compound 1

[0188]

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

[0190] Add 2-thiazolecarboximidamide hydrochloride (1.0kg, 4990mmol), 2-bromo-4-fluorobenzaldehyde (1.01kg, 4980mmol), ethyl acetoacetate (780g, 5993.5mmol), anhydrous sodium acetate (532g, 6485mmol) and anhydrous ethanol (8.2L) to a dry reaction bottle, and heat to 78°C for 12h. Turn off the heating and cool to room temperature. Continue stirring at room temperature for 12h, filter, wash the filter cake with anhydrous ethanol (2.4L) and water (9.0L) in turn, and then vacuum dry at 60°C for 18h to obtain the title compound as a yellow solid (1.28kg, 60.4%). MS (ESI, pos.ion) m / z: 424.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.91 (s, 1H), 7.96 (d, J = 3.1Hz, 1H), 7.89 (d, J = 3.1Hz, 1H), 7.54 (dd, J = 8.6, 2.6Hz, 1H), 7.35 (dd,J=8.6,6.3Hz,1H),7.23(td,J=8.5,2.5Hz,1H),5.96(s,1H),3.93(q,J=7.1Hz,2H),2.46(s,3H),1.02(t,J=7.1Hz,3H).

[0191] Step 2: Synthesis of compound 1-2:

[0192] Compound 1-1 (40 g, 94.28 mmol) and DCM (450 mL) were added to a dry reaction bottle in sequence, and the temperature was raised to 40°C. The solid was completely dissolved. NBS (18.46 g, 103.71 mmol) was added in 4 batches. The addition was completed in batches of about 5 minutes each. The mixture was stirred for 5 minutes at a temperature of 100 °C. The heating was turned off and the solvent was evaporated under reduced pressure. Ethanol (100 mL) was added to the residue. The mixture was stirred at room temperature for about 2.5 hours. The mixture was filtered and the filter cake was washed with ethanol (100 mL). The filter cake was then dried under vacuum at 50°C for 8 hours to obtain the title compound as a yellow solid (40.8 g, 86%). MS (ESI, pos.ion) m / z: 502.2 [M+H] + ; 1 HNMR (400MHz, CD3OD) δ (ppm): 7.93 (d, J=3.1Hz, 1H), 7.78 (s, 1H), 7.55–7.36 (m, 2H), 7.13 (t,J=7.8Hz,1H),6.11(s,1H),4.62(s,2H),4.10(q,J=7.0Hz,2H),1.17(t,J=7.1Hz,3H).

[0193] Step 3: Synthesis of Compound 1-3

[0194] Compound 1-2 (9.05 g, 17.99 mmol) and DMF (80 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, sodium azide (2.34 g, 35.98 mmol) was added and stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate (150 mL), washed with saturated sodium chloride aqueous solution (100 mL × 4), and dried over anhydrous sodium sulfate. Filtered, the filtrate was evaporated to remove the solvent under reduced pressure to obtain the title compound as a brown oil (8.37 g, 100%). MS (ESI, pos.ion) m / z: 465.2 [M+H] + .

[0195] Step 4: Synthesis of Compound 1-4

[0196] Compound 1-3 (8.37 g, 17.99 mmol) and THF (100 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, di-tert-butyl dicarbonate (4.71 g, 21.59 mmol) and palladium carbon (0.82 g, 10%) were added and stirred evenly. The mixture was stirred at room temperature for 23 h under a hydrogen atmosphere, filtered through celite, and the solvent was evaporated from the filtrate under reduced pressure. The crude product was separated and purified by column chromatography (PE / EtOAc (V / V=5 / 1)) to obtain the title compound as a yellow oil (3.62 g, 37.3%). MS (ESI, pos.ion) m / z: 539.0 [M+H]+ ; 1 H NMR(400MHz, CDCl3)δ(ppm):8.93(s,1H),7.87–7.81(m,1H),7.45–7.40(m,1H),7.38–7.31(m,2H),7.05–6.95(m,1 H),6.17–6.07(m,1H),5.40(s,1H),4.59–4.32(m,2H),4.18–3.94(m,2H),1.52–1.45(m,9H),1.15(t,J=7.1Hz,3H).

[0197] Step 5: Synthesis of Compound 1-5

[0198] Compound 1-4 (0.86 g, 1.59 mmol) and toluene (12 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, DDQ (0.43 g, 1.89 mmol) was added, and the temperature was raised to 110°C. The reaction was kept warm for 1.5 h, and the heating was turned off and the temperature was lowered to room temperature. The reaction solution was diluted with toluene (40 mL), and the organic layer was washed with 2% sodium hydroxide aqueous solution (40 mL × 3). The organic layer was evaporated under reduced pressure to remove the solvent. The crude product was separated and purified by column chromatography (PE / EtOAc (V / V=3 / 1)) to obtain the title compound as an off-white solid (0.48 g, 56.18%). MS (ESI, pos.ion) m / z: 537.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ (ppm): 8.11 (d, J = 3.1Hz, 1H), 7.63 (d, J = 3.1Hz, 1H), 7.44-7.34 (m, 2H), 7.16 (td, J = 8.3, 2.4 Hz,1H),5.77(s,1H),4.78(d,J=4.5Hz,2H),4.18(q,J=7.0Hz,2H),1.48(d,J=23.2Hz,9H),1.06(t,J=7.2Hz,3H).

[0199] Step 6: Synthesis of Compound 1-6

[0200] Compound 1-5 (3.1 g, 5.77 mmol) and ethyl acetate solution of hydrogen chloride (30 mL, 4 mol / L) were added to a dry reaction bottle in sequence, and the mixture was stirred at room temperature until it was completely dissolved. Then, a solid gradually precipitated. The mixture was stirred at room temperature for 5.5 h, filtered, and the filter cake was washed with ethyl acetate (15 mL), and then dried under vacuum at room temperature for 2 h to obtain the title compound as a white solid (2.7 g, 98.76%). MS (ESI, pos.ion) m / z: 437.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.76 (s, 2H), 8.20 (s, 2H), 7.82 (dd, J = 8.6, 2.4Hz, 1H), 7.56 (dd, J = 8.5, 6. 0Hz, 1H), 7.48 (td, J = 8.5, 2.4Hz, 1H), 4.60 (d, J = 4.7Hz, 2H), 4.10 (q, J = 7.1Hz, 2H), 0.91 (t, J = 7.1Hz, 3H).

[0201] Step 7: Synthesis of compound 1:

[0202] Compound F1 (0.3 g, 0.89 mmol), compound 1-6 (0.42 g, 0.89 mmol), HATU (0.41 g, 1.08 mmol) and DMF (8 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, DIPEA (0.39 g, 3.02 mmol) was added and stirred at room temperature for 12 h under nitrogen protection. EtOAc (100 mL) and water (100 mL) were added to the reaction solution. The pH was adjusted to 3-4 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated sodium chloride water (50 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (PE / EtOAc (V / V=3 / 1)) to obtain the title compound as a light yellow solid (0.48 g, 71.38%). MS (ESI, pos.ion) m / z: 755.4 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ(ppm):10.39(s,1H),9.35(t,J=5.6Hz,1H),8.13(d,J=3.1Hz,1H),8.09(d,J=3.1Hz,1H),7.90–7.79(m,2H),7.52(dd,J =8.5,6.0Hz,1H),7.49–7.39(m,3H),4.81(d,J=5.6Hz,2H),4.11(q,J=7 .1Hz,2H),3.58(s,3H),2.37(s,3H),2.21(s,3H),0.93(t,J=7.1Hz,3H).

[0203] Example 2

[0204] Synthesis of compound 2

[0205]

[0206] Compound 1 (i.e., Example 1, 260 mg, 0.34 mmol), methanol (3 mL) and THF (3 mL) were added to a dry reaction bottle in sequence. The mixture was stirred at room temperature until completely dissolved. Sodium hydroxide (41 mg, 1.02 mmol) was dissolved in water (0.5 mL) and then added to the above reaction system. The color became darker after addition. The mixture was stirred at room temperature for 10 min. EtOAc (30 mL) and water (20 mL) were added to the system. The pH was adjusted to 3-4 with concentrated hydrochloric acid under stirring. The mixture was allowed to stand for stratification. The organic layer was washed with saturated sodium chloride water (50 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The crude product was separated and purified by column chromatography (DCM / CH3OH (V / V=15 / 1)) to obtain a gray solid (67 mg, 26.7%). MS (ESI, pos.ion) m / z: 727.1 [M+H] + ; 1 H NMR (400MHz, CD3OD) δ (ppm): 8.11 (d, J = 3.1Hz, 1H), 7.93 (d, J = 3.1Hz, 1H), 7.82-7.75 (m, 1H), 7.57 (dd, J = 8.5, 2 .4Hz,1H),7.53(dd,J=8.6,5.9Hz,1H),7.37–7.19(m,3H),5.05(s,2H),3.66(s,3H),2.47(s,3H),2.35(s,3H).

[0207] Example 3

[0208] Synthesis of compound 3

[0209]

[0210] Step 1: Synthesis of compound 3-1

[0211] Compound F2 (1.20 g, 3.15 mmol), 2-chloro-4-fluorobenzaldehyde (0.50 g, 3.15 mmol), 2-thiazolecarboxamidine hydrochloride (0.43 g, 3.15 mmol) and THF (25 mL) were added to a dry reaction bottle in sequence. After stirring at room temperature, 4-methylmorpholine (0.80 g, 7.91 mmol) was added, and the temperature was raised to 80°C and stirred for 15 h. Turn off the heating and cool to room temperature. Filter, evaporate the filtrate under reduced pressure to remove the solvent, add EtOAc (80 mL) and water (80 mL) to the residue, adjust the pH to 4-5 with 37.5% concentrated hydrochloric acid while stirring, let stand to separate, and wash the organic layer with saturated sodium chloride aqueous solution (80 mL). The organic layer was extracted with a sodium hydroxide aqueous solution at pH about 10 (80 mL × 3), the aqueous layers were combined, EtOAc (150 mL) was added, and the pH was adjusted to 4-5 with concentrated hydrochloric acid under stirring, and the organic layer was washed with a saturated sodium chloride aqueous solution (100 mL × 3), and dried over anhydrous sodium sulfate. Filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and a yellow foamy solid (0.51 g, 30.04%) was obtained. MS (ESI, pos.ion) m / z: 539.4 [M+H] + .

[0212] Step 2: Synthesis of compound 3-2

[0213] Compound 3-1 (0.47 g, 0.87 mmol), acetonitrile (8 mL), iodomethane (0.15 g, 1.04 mmol) and anhydrous potassium carbonate (0.24 g, 1.74 mmol) were added to a dry reaction bottle in sequence. After stirring at room temperature, the temperature was raised to 80°C and stirred for 2 hours. The heating was turned off, the temperature was lowered to room temperature, and the filtrate was filtered. The solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (PE / EtOAc (V / V=5 / 1)) to obtain the title compound as a yellow foamy solid (0.31 g, 64.29%). MS (ESI, pos.ion) m / z: 553.4 [M+H] + .

[0214] Step 3: Synthesis of compound 3-3

[0215] Compound 3-2 (0.18 g, 0.33 mmol) and toluene (10 mL) were added to a dry reaction bottle in sequence, stirred at room temperature until completely dissolved, DDQ (0.082 g, 0.36 mmol) was added, the temperature was raised to 110°C, and the reaction was kept warm for 2.5 h. The heating was turned off and the temperature was lowered to room temperature. The filter cake was washed with toluene (30 mL), the filtrate was washed with 10% sodium hydroxide aqueous solution (35 mL × 3), the organic layer was washed with saturated sodium chloride water (35 mL × 3), and the solvent was evaporated under reduced pressure to obtain the title compound as a light yellow oil (0.18 g, 99.00%). MS (ESI, pos.ion) m / z: 551.1 [M+H] + .

[0216] Step 4: Synthesis of compound 3-4

[0217] Compound 3-3 (0.18 g, 0.33 mmol) and DCM (3 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, TFA (3 mL) was added and stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, and the residue was azeotropically evaporated with DCM (10 mL × 3) to obtain the title compound as a yellow oil (0.19 g, 100%). MS (ESI, pos.ion) m / z: 451.1 [M+H] + .

[0218] Step 5: Synthesis of compound 3

[0219] Compound 3-4 (0.19 g, 0.34 mmol), compound F1 (0.11 g, 0.34 mmol), HATU (0.16 g, 0.41 mmol), and DMF (8 mL) were added to a dry reaction bottle in sequence. After stirring at room temperature, DIPEA (0.44 g, 3.40 mmol) was added and stirred at room temperature for 12 h under nitrogen protection. EtOAc (60 mL) and water (50 mL) were added to the reaction solution. The pH was adjusted to 3-4 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated sodium chloride aqueous solution (50 mL × 2), 1.5% sodium hydroxide aqueous solution (30 mL × 3) and saturated sodium chloride water (50 mL × 3) in sequence and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (DCM / CH3OH (V / V=150 / 1)) to obtain the title compound as a white solid (0.12 g, 46.39%). MS (ESI, pos.ion) m / z: 769.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 9.26 (d, J = 8.0Hz, 1H), 8.12 (d, J = 3.1H z,1H),8.09(d,J=3.1Hz,1H),7.88-7.81(m,1H),7.65(dd,J=8.8,2.4Hz,1H),7.53( dd,J=8.6,6.1Hz,1H),7.45-7.37(m,3H),4.39(t,J=5.2Hz,1H),3.70(s,3H),3.63( s,3H),3.61–3.57(m,1H),3.56(s,3H),3.32–3.25(m,1H),2.32(s,3H),2.09(s,3H).

[0220] Example 4

[0221] Synthesis of compound 4

[0222] 2-Chloro-4-fluorobenzaldehyde was substituted for 2-bromo-4-fluorobenzaldehyde, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain an off-white solid (123 mg, 42.2%). MS (ESI, pos.ion) m / z: 711.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 9.35 (t, J=5.6Hz, 1H), 8.13 (d, J= 3.1Hz,1H),8.10(d,J=3.1Hz,1H),7.90–7.82(m,1H),7.69(dd,J=8.9,2.4Hz,1 H),7.57(dd,J=8.6,6.1Hz,1H),7.49–7.36(m,3H),4.81(d,J=5.6Hz,2H),4.12 (q,J=7.1Hz,2H),3.58(s,3H),2.37(s,3H),2.21(s,3H),0.94(t,J=7.1Hz,3H).

[0223] Example 5

[0224] Synthesis of compound 5

[0225] Cyclopropanecarboxaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate, respectively, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (400 mg, 51.1%). MS (ESI, pos.ion) m / z: 609.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.38 (s, 1H), 9.26 (t, J = 5.5Hz, 1H), 8.08 (d, J = 3.1Hz, 1H), 8.01 (d, J = 3.1Hz, 1H), 7.88–7.82 (m, 1H), 7.45–7.39(m,2H),4.59(d,J=5.5Hz,2H),3.99(s,3H),3.57(s,3H),2.35(s,3H),2.31-2.25(m,1H),2.20(s,3H),1.25–1.20(m,4H).

[0226] Example 6

[0227] Synthesis of compound 6

[0228] 2-Chlorobenzaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate respectively, and the rest of the operations were carried out according to the synthesis method of Example 1 to obtain a white solid (350 mg, 69.9%). MS (ESI, pos.ion) m / z: 679.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 9.35 (t, J = 5.6 Hz, 1H), 8.13 (d, J =3.1Hz,1H),8.09(d,J=3.1Hz,1H),7.90–7.83(m,1H),7.66-7.62(m,1H),7.57 (td,J=7.6,1.8Hz,1H),7.54–7.49(m,1H),7.49–7.45(m,1H),7.44–7.38(m,2 H), 4.80 (d, J = 5.6Hz, 2H), 3.63 (s, 3H), 3.57 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H).

[0229] Example 7

[0230] Synthesis of compound 7

[0231] 2,3,4-trifluorobenzaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate respectively, and the rest of the operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (90 mg, 20.6%). MS (ESI, pos.ion) m / z: 699.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.38 (s, 1H), 9.35 (t, J = 5.6Hz, 1H), 8.15 (d, J = 3.1Hz, 1H), 8.11 (d, J = 3.1Hz, 1H), 7.89–7.8 2(m,1H),7.62–7.52(m,2H),7.46–7.36(m,2H),4.81(d,J=5.6Hz,2H),3.77(s,3H),3.57(s,3H),2.36(s,3H),2.21(s,3H).

[0232] Example 8

[0233] Synthesis of compound 8

[0234] Benzaldehyde and methyl acetoacetate were substituted for 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate, respectively, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (360 mg, 74.5%). MS (ESI, pos.ion) m / z: 645.2 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.37 (s, 1H), 9.33 (t, J = 5.5Hz, 1H), 8.13 (d, J = 3.1Hz, 1H), 8.07 (d, J = 3.1Hz, 1H), 7.85 (dd, J = 12.4, 7.0Hz ,1H),7.72–7.65(m,2H),7.63–7.55(m,3H),7.44–7.38(m,2H),4.69(d,J=5.6Hz,2H),3.74(s,3H),3.56(s,3H),2.36(s,3H),2.21(s,3H).

[0235] Example 9

[0236] Synthesis of compound 9

[0237] 4-methoxybenzaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate, respectively, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (250 mg, 41.5%). MS (ESI, pos.ion) m / z: 675.5 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.38 (s, 1H), 9.32 (t, J = 5.6Hz, 1H), 8.13 (d, J = 3.1Hz, 1H), 8.07 (d, J = 3.1Hz, 1H), 7.90–7.82 (m, 1H), 7.70 (d, J = 8.8Hz,2H),7.47–7.36(m,2H),7.16(d,J=8.8Hz,2H),4.66(d,J=5.6Hz, 2H),3.86(s,3H),3.80(s,3H),3.57(s,3H),2.37(s,3H),2.22(s,3H).

[0238] Example 10

[0239] Synthesis of compound 10

[0240] 2,4-dichlorobenzaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate, respectively, and the remaining operations were carried out in accordance with the method of Example 1 to obtain an off-white solid (220 mg, 62.9%). MS (ESI, pos.ion) m / z: 713.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 9.35 (t, J = 5.6Hz, 1H), 8.13 (d, J = 3.0Hz, 1H), 8.10 (d, J = 3.0Hz, 1H), 7.89-7.82 (m, 2H), 7.63 ( dd,J=8.2,1.8Hz,1H),7.53(d,J=8.3Hz,1H),7.47–7.37(m,2H),4.81(d,J=5.5Hz,2H),3.68(s,3H),3.57(s,3H),2.36(s,3H),2.21(s,3H).

[0241] Embodiment 11

[0242] Synthesis of compound 11

[0243] Thiophene-3-carboxaldehyde was substituted for 2-chloro-4-fluorobenzaldehyde, and the remaining operations were carried out in accordance with the synthesis method of Example 3 to obtain a yellow solid (450 mg, 68.4%). MS (ESI, pos.ion) m / z: 723.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 3.1 Hz,1H),8.12–8.09(m,1H),8.07(d,J=3.1Hz,1H),7.89–7.81(m,1H),7.76(dd,J=5. 1,2.9Hz,1H),7.48(dd,J=5.1,1.1Hz,1H),7.45–7.39(m,2H),5.26–5.19(m,1H),3 .87(s,3H),3.69(s,3H),3.55(s,3H),3.47–3.37(m,2H),2.31(s,3H),2.12(s,3H).

[0244] Example 12

[0245] Synthesis of compound 12

[0246] Compound F3 was substituted for compound F1, and the rest of the operations were performed in accordance with the synthesis method of step 7 of Example 1 to obtain a light yellow solid (0.38 g, 74.7%). MS (ESI, pos.ion) m / z: 803.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.37 (s, 1H), 9.34 (t, J = 5.6 Hz, 1H), 8.13 (d, J =3.0Hz,1H),8.09(d,J=3.1Hz,1H),7.83–7.78(m,3H),7.55–7.50(m,1H),7.4 5(td,J=8.4,2.2Hz,1H),7.36(d,J=8.6Hz,2H),4.81(d,J=5.6Hz,2H),4.11(q ,J=7.1Hz,2H),3.58(s,3H),2.37(s,3H),2.23(s,3H),0.93(t,J=7.1Hz,3H).

[0247] Embodiment 13

[0248] Synthesis of compound 13

[0249] Compound F4 was substituted for compound F1, and the rest of the operations were performed in accordance with the synthesis method of step 7 of Example 1 to obtain a yellow solid (0.23 g, 44.4%). MS (ESI, pos.ion) m / z: 803.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 9.35 (t, J = 5.6 Hz, 1H), 8.13 (d, J = 3. 1Hz,1H),8.09(d,J=3.1Hz,1H),7.87(s,1H),7.81(dd,J=8.6,2.4Hz,1H),7.63(d, J=8.3Hz,1H),7.56–7.42(m,3H),7.09(d,J=8.4Hz,1H),4.81(d,J=5.6Hz,2H),4. 11(q,J=7.1Hz,2H),3.59(s,3H),2.37(s,3H),2.23(s,3H),0.93(t,J=7.1Hz,3H).

[0250] Embodiment 14

[0251] Synthesis of compound 14

[0252]

[0253] Compound 11 (ie, Example 11, 0.147 g, 0.20 mmol), methanol (1 mL) and THF (1 mL) were added to a dry reaction bottle in sequence, stirred at room temperature, and the solid was completely dissolved. Sodium hydroxide (0.024 g, 0.60 mmol) was dissolved in water (0.5 mL) and added to the reaction system. After the addition was completed, it was stirred at room temperature for 15 min. Ethyl acetate (30 mL) and water (30 mL) were added to the system, and the pH was adjusted to 5-6 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated sodium chloride water (30 mL × 2) and dried over anhydrous sodium sulfate. Filter, evaporate the filtrate to remove the solvent under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (DCM / CH3OH (V / V=10 / 1)) to obtain a light yellow solid (82 mg, 56.89%). MS (ESI, pos.ion) m / z: 707.2 [MH] - ; 1 H NMR(400MHz, DMSO-d6)δ(ppm):10.29(s,1H),8.29(s,1H),8.10(d,J=3.1Hz,1H),8.07–8.02(m,2H),7.86–7.79(m,1H),7.73(dd,J=5.0,2.9H z,1H),7.50–7.34(m,3H),4.75(s,1H),3.85(s,3H),3.49(s,3H),3.47-3.43(m,1H),3.14(dd,J=14.5,9.2Hz,1H),2.16(s,3H),2.02(s,3H).

[0254] Embodiment 15

[0255] Synthesis of compound 15

[0256]

[0257] Step 1: Synthesis of compound 15-1

[0258] 1-5 (7 g, 13.03 mmol) and ethanol (56 mL) were added to a dry reaction bottle in sequence, and the mixture was completely dissolved by stirring at room temperature. Sodium hydroxide (1.04 g, 26.06 mmol) was dissolved in water (5 mL) and added to the system. The mixture was stirred at room temperature for 20 min, and then the solvent was evaporated under reduced pressure. Water (100 mL) and EOtAc (100 mL) were added to the residue, and the layers were separated by extraction. The aqueous layer was extracted with EOtAc (100 mL) and the organic layer was discarded. Finally, EOtAc (150 mL) was added to the aqueous layer, and the pH was adjusted to 4-5 with concentrated hydrochloric acid under stirring. The mixture was allowed to stand for separation, and the aqueous layer was discarded. The organic layer was washed with saturated sodium chloride water (100 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was evaporated from the filtrate under reduced pressure to obtain a yellow-white foamy solid (5.6 g, 84.41%). MS (ESI, pos.ion) m / z: 509.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm): 13.81 (s, 1H), 8.11 (d, J = 3.0Hz, 1H), 8.08 (d, J = 2.9Hz, 1H), 7.78 (dd, J = 8.6, 2.1H z,1H),7.55–7.48(m,1H),7.43(td,J=8.5,2.4Hz,1H),7.31(t,J=5.7Hz,1H),4.50(d,J=5.8Hz,2H),1.43(s,9H).

[0259] Step 2: Synthesis of compound 15-2

[0260] Compound 15-1 (0.3 g, 0.59 mmol), ethylamine hydrochloride (0.058 g, 0.71 mmol), HATU (0.27 g, 0.71 mmol), and DMF (5 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, DIPEA (0.38 g, 2.95 mmol) was added and stirred at room temperature for 23 h under nitrogen protection. EOtAc (50 mL) and water (40 mL) were added to the reaction solution. The pH was adjusted to 4-5 with concentrated hydrochloric acid under stirring. The mixture was allowed to stand for stratification. The aqueous layer was discarded and the organic layer was washed with saturated sodium chloride aqueous solution (50 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (PE / EOtAc (V / V=1 / 1)) to obtain a white solid (0.28 g, 88.62%). MS (ESI, pos.ion) m / z: 536.1 [M+H] + ; 1 HNMR(400MHz, DMSO-d6)δ(ppm):8.50(t,J=5.5Hz,1H),8.09(d,J=3.1Hz,1H),8.04(d,J=3.0Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.62–7.5 2(m,1H),7.42(td,J=8.5,2.4Hz,1H),7.31(t,J=5.8Hz,1H),4.39(d,J=5.9Hz,2H),3.15–3.01(m,2H),1.45(s,9H),0.87(t,J=7.1Hz,3H).

[0261] Step 3: Synthesis of compound 15-3

[0262] Compound 15-2 (0.28 g, 0.52 mmol) and DCM (2 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, TFA (2.96 g, 26 mmol) was added and stirred at room temperature for 6 h. The solvent was evaporated under reduced pressure to obtain a light yellow oil (0.29 g, 100%). MS (ESI, pos.ion) m / z: 436.2 [M+H] + .

[0263] Step 4: Synthesis of compound 15

[0264] Compound 15-3 (0.29 g, 0.66 mmol), compound F1 (0.22 g, 0.66 mmol), HATU (0.30 g, 0.79 mmol), and DMF (8 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, DIPEA (0.43 g, 3.30 mmol) was added and stirred at room temperature for 10 h under nitrogen protection. EOtAc (60 mL) and water (40 mL) were added to the reaction solution. The pH was adjusted to 4-5 with concentrated hydrochloric acid under stirring. The mixture was allowed to stand for stratification, the aqueous layer was discarded, and the organic layer was washed with saturated sodium chloride aqueous solution (50 mL × 2) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (PE / EOtAc (V / V=2 / 3)) to obtain a white solid (0.2 g, 39.9%). MS (ESI, pos.ion) m / z: 754.10 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 9.32 (t, J = 5.5 Hz, 1H), 8.58 (t, J = 5 .5Hz,1H),8.09(d,J=2.9Hz,1H),8.03(d,J=2.9Hz,1H),7.87(dd,J=12.4,7.4Hz,1 H),7.80–7.72(m,1H),7.64–7.55(m,1H),7.47–7.38(m,3H),4.67(d,J=5.6Hz,2H) ,3.59(s,3H),3.17–3.06(m,2H),2.41(s,3H),2.25(s,3H),0.89(t,J=7.2Hz,3H).

[0265] Example 16

[0266] Synthesis of compound 16

[0267] Ethylamine hydrochloride was replaced with isopropylamine, and the remaining operations were carried out according to the method of Example 15 to obtain a white solid (0.2 g, 47.4%). MS (ESI, pos.ion) m / z: 768.40 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 9.34 (t, J = 5.5Hz, 1H), 8.47 (d, J = 7.8H z,1H),8.09(d,J=2.9Hz,1H),8.03(d,J=2.9Hz,1H),7.87(dd,J=12.5,7.2Hz,1H),7. 77(dd,J=8.6,2.0Hz,1H),7.66–7.56(m,1H),7.49–7.35(m,3H),4.67(d,J=5.5Hz,2 H),3.93-3.82(m,1H),3.59(s,3H),2.41(s,3H),2.25(s,3H),0.98(d,J=6.5Hz,6H).

[0268] Embodiment 17

[0269] Synthesis of compound 17

[0270] Ethylamine hydrochloride was replaced with methylamine hydrochloride, and the remaining operations were carried out according to the method of Example 15 to obtain a white solid (0.23 g, 42.3%). MS (ESI, pos.ion) m / z: 740.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.32(t,J=5.7Hz,1H),8.56(d,J=4.6Hz,1 H),8.09(d,J=3.1Hz,1H),8.03(d,J=3.1Hz,1H),7.87(dd,J=12.7,7.2Hz,1H),7 .77(dd,J=8.6,2.4Hz,1H),7.57(dd,J=8.5,6.1Hz,1H),7.48–7.36(m,3H),4.66 (d,J=5.6Hz,2H),3.59(s,3H),2.64(d,J=4.6Hz,3H),2.41(s,3H),2.25(s,3H).

[0271] Embodiment 18

[0272] Synthesis of compound 18

[0273] Ethylamine hydrochloride was replaced by ammonium chloride, and the rest of the operation was carried out according to the synthesis method of Example 15 to obtain a white solid (0.16 g, 50.0%). MS (ESI, pos.ion) m / z: 726.1 [M+H] +; 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.33(t,J=5.6Hz,1H),8.13–8.06(m,2H),8.03(d,J=3.0Hz,1H),7.95–7.82(m,2H),7.78(dd ,J=8.6,2.2Hz,1H),7.62(dd,J=8.4,6.1Hz,1H),7.49–7.37(m,3H),4.72(d,J=5.6Hz,2H),3.59(s,3H),2.41(s,3H),2.26(s,3H).

[0274] Embodiment 19

[0275] Synthesis of compound 19

[0276] Isopropyl acetoacetate was substituted for ethyl acetoacetate, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (230 mg, 60.3%). MS (ESI, pos.ion) m / z: 769.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.34(t,J=5.7Hz,1H),8.13(d,J=3.1Hz,1H),8.09(d,J=3.1Hz,1H),7.91–7.78(m,2H),7.54-7. 49(m,1H),7.48–7.38(m,3H),5.00–4.91(m,1H),4.80(d,J=5.7Hz,2H),3.58(s,3H),2.37(s,3H),2.21(s,3H),0.97(d,J=5.7Hz,6H).

[0277] Embodiment 20

[0278] Synthesis of compound 20

[0279] Methyl acetoacetate was substituted for ethyl acetoacetate, and the remaining operations were carried out in accordance with the synthesis method of Example 1 to obtain a white solid (140 mg, 59.7%). MS (ESI, pos.ion) m / z: 741.8 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.35(t,J=5.6Hz,1H),8.12(d,J=3.1Hz,1H),8.08(d,J=3.1Hz,1H),7.90–7.81(m ,1H),7.79(dd,J=8.6,2.3Hz,1H),7.51(dd,J=8.5,6.1Hz,1H),7.47–7.36(m,3 H), 4.80 (d, J = 5.6Hz, 2H), 3.65 (s, 3H), 3.57 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H).

[0280] Embodiment 21

[0281] Synthesis of compound 21

[0282] 3-Furfurylaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate respectively, and the rest of the operations were carried out according to the synthesis method of Example 1 to obtain a white solid (420 mg, 55.6%). MS (ESI, pos.ion) m / z: 635.5 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ10.38(s,1H),9.33(t,J=5.6Hz,1H),8.32(s,1H),8.13(d,J=3.1Hz,1H),8.07(d,J=3.1Hz,1H),7.92(t,J=1.5Hz,1 H),7.88–7.83(m,1H),7.44–7.40(m,2H),6.85(d,J=1.0Hz,1H),4.61(d,J=5.6Hz,2H),3.98(s,3H),3.57(s,3H),2.37(s,3H),2.22(s,3H).

[0283] Embodiment 22

[0284] Synthesis of compound 22

[0285] 2-Chloro-4-fluorobenzaldehyde and methyl acetoacetate were used to replace 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate respectively, and the rest of the operations were carried out according to the synthesis method of Example 1 to obtain a white solid (454 mg, 56.6%). MS (ESI, pos.ion) m / z: 697.1 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ10.39(s,1H),9.35(t,J=5.2Hz,1H),8.13(d,J=2.2Hz,1H),8.10(d,J=2.3Hz,1H),7.86(dd,J=12.5,7.2Hz,1H), 7.67(d,J=7.6Hz,1H),7.58–7.55(m,1H),7.45–7.41(m,3H),4.81(d,J=5.3Hz,2H),3.67(s,3H),3.58(s,3H),2.37(s,3H),2.21(s,3H).

[0286] Embodiment 23

[0287] Synthesis of compound 23

[0288] 4-methoxybenzaldehyde was substituted for 2-bromo-4-fluorobenzaldehyde, and the rest of the synthesis method was the same as that in Example 1 to obtain a white solid (63 mg, 39.6%). MS (ESI, pos.ion) m / z: 689.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.31(t,J=5.4Hz,1H),8.12(d,J=3.0Hz,1 H),8.06(d,J=3.0Hz,1H),7.86(dd,J=12.7,7.0Hz,1H),7.70(d,J=8.7Hz,2H),7 .46–7.40(m,2H),7.15(d,J=8.7Hz,2H),4.68(d,J=5.5Hz,2H),4.29(q,J=7.1Hz ,2H),3.86(s,3H),3.58(s,3H),2.37(s,3H),2.22(s,3H),1.13(t,J=7.1Hz,3H).

[0289] Embodiment 24

[0290] Synthesis of compound 24

[0291] 1-Methyl-1H-1,2,4-triazole-3-carboximidamide hydrochloride was substituted for 2-thiazolecarboximidamide hydrochloride, and the synthesis method thereof was referred to the synthesis method of Example 1 to obtain a white solid (63 mg, 39.6%). MS (ESI, pos.ion) m / z: 753.6 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.33(s,1H),8.65(s,1H),7.92–7.81(m,1H),7.78(d,J=7.6Hz,1H),7.58–7.33( m,4H),4.79(s,2H),4.10(q,J=6.6Hz,2H),3.97(s,3H),3.57(s,3H),2.36(s,3H),2.20(s,3H),0.93(t,J=6.2Hz,3H).

[0292] Embodiment 25

[0293] Synthesis of compound 25

[0294]

[0295] Step 1: Synthesis of compound 25-1

[0296] Compound 25-0 (3.05 g, 7.24 mmol), DMF (10 mL) and DMAP (890 mg, 7.28 mmol) were added to a dry reaction bottle in sequence, stirred evenly, and di-tert-butyl dicarbonate (2.00 mL, 8.69 mmol) was added dropwise. The system quickly dissolved and reacted at room temperature for 20 min. Water (60 mL) was added and stirred for 15 min, filtered, and the filter cake was rinsed with water (30 mL). The filter cake was evaporated to dryness to obtain a yellow solid (3.60 g, 95.37%).

[0297] Step 2: Synthesis of compound 25-2

[0298] Compound 25-1 (4.75 g, 9.11 mmol) and DCM (50 mL) were added to a dry reaction bottle in sequence, stirred to dissolve, heated to 38°C, and NBS (2.41 g, 13.56 mmol) was added in 4 portions, each time interval was about 3-5 min, and stirring was continued for 10 min after addition. The solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (PE / EtOAc (V / V) = 4 / 1) to obtain a yellow solid (1.34 g, 24.5%). MS (ESI, pos.ion) m / z: 599.4 [M+H] + .

[0299] Step 3: Synthesis of compound 25-3

[0300] Compound 25-2 (1.34 g, 2.23 mmol), DCM (15 mL) and TFA (3.0 mL) were added sequentially to a dry reaction bottle. The reaction mixture was reacted at room temperature for about 1 h. The solvent was evaporated under reduced pressure to obtain a yellow foamy solid (1.05 g, 94.04%).

[0301] Step 4: Synthesis of compound 25-4

[0302] Compound 25-3 (1.05 g, 2.10 mmol) and DMF (12 mL) were added to a dry reaction bottle in sequence, stirred to dissolve, sodium azide (0.38 g, 5.85 mmol) was added under ice bath, the reaction mixture was reacted at room temperature for 2 h, water (30 mL) and ethyl acetate (30 mL) were added, the layers were separated by extraction, the organic layer was washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a reddish brown viscous substance (0.97 g, 100%). MS (ESI, pos.ion) m / z: 462.1 [M+H] + .

[0303] Step 5: Synthesis of compound 25-5

[0304] Compound 25-4 (0.97 g, 2.10 mmol), THF (20 mL), 10% palladium on carbon (0.10 g) and di-tert-butyl dicarbonate (0.57 g, 2.61 mmol) were added to a dry reaction bottle in sequence, and the mixture was reacted at room temperature for 5 h under a hydrogen atmosphere. The filtrate was filtered and evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EtOAc (V / V) = 3 / 1) to obtain an off-white solid (0.48 g, 42.65%). MS (ESI, pos.ion) m / z: 536.5 [M+H] + .

[0305] Step 6: Synthesis of 25-6

[0306] Compound 25-5 (100 mg, 0.15 mmol), DCM (4 mL) and manganese dioxide (308 mg, 3.01 mmol) were added to a dry reaction bottle in sequence, and the reaction mixture was reacted at 40°C for 10 h. The filtrate was filtered and dried to obtain a gray solid (90 mg, 90.3%). MS (ESI, pos.ion) m / z: 534.5 [M+H] + .

[0307] Step 7: Synthesis of compound 25-7

[0308] Compound 25-6 (90 mg, 0.17 mmol), DCM (5 mL) and TFA (0.3 mL) were added to a dry reaction bottle in sequence, and the reaction mixture was reacted at room temperature for 2 h. The solvent was evaporated under reduced pressure to obtain a brown viscous product (92 mg, 99.6%). MS (ESI, pos.ion) m / z: 434.3 [M+H] + .

[0309] Step 8: Synthesis of compound 25

[0310] Compound 25-7 (90 mg, 0.17 mmol), DMF (5 mL), compound F1 (57 mg, 0.17 mmol), DIPEA (0.3 mL, 1.81 mmol) and HATU (78 mg, 0.20 mmol) were added to a dry reaction bottle in sequence, and the reaction mixture was reacted at room temperature for 6 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution for extraction, and the organic layer was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was slurried with a mixture of (DCM / PE (V / V) = 2 / 3) (3 mL) to obtain an off-white solid (28 mg, 22.17%). MS (ESI, pos.ion) m / z: 752.5 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),9.34(t,J=5.9Hz,1H),7.92–7.83(m,1H),7.78(dd,J=8.6,2.5Hz,1H),7.55–7.37(m ,5H),7.12(s,1H),4.82(d,J=5.8Hz,2H),4.17–4.01(m,5H),3.58(s,3H),2.35(s,3H),2.21(s,3H),0.92(t,J=7.1Hz,3H).

[0311] Embodiment 26

[0312] Synthesis of compound 26

[0313] Ethylamine hydrochloride was replaced with 2-thiophenemethylamine, and the synthesis method was referred to the synthesis method of Example 15 to obtain a white solid (0.35 g, 79.7%). MS (ESI, pos.ion) m / z: 822.6 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.32(t,J=5.7Hz,1H),9.21(t,J=5.9Hz,1H),8.09(d,J=3. 1Hz,1H),8.03(d,J=3.1Hz,1H),7.92–7.82(m,1H),7.71(dd,J=8.6,2.5Hz,1H),7.52(dd,J=8.6,6 .0Hz,1H),7.46–7.36(m,3H),7.27(td,J=8.5,2.5Hz,1H),6.92(dd,J=5.0,3.5Hz,1H),6.84(d,J =2.7Hz,1H),4.67(d,J=5.7Hz,2H),4.50(d,J=5.8Hz,2H),3.59(s,3H),2.41(s,3H),2.25(s,3H).

[0314] Embodiment 27

[0315] Synthesis of compound 27

[0316] Ethylamine hydrochloride was replaced by propargylamine, and the synthesis method was referred to the synthesis method of Example 15 to obtain a white solid (0.20 g, 69.5%). MS (ESI, pos.ion) m / z: 764.0 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ10.40(s,1H),9.33(t,J=5.7Hz,1H),9.10(t,J=5.5Hz,1H), 8.09(d,J=3.1Hz,1H),8.04(d,J=3.1Hz,1H),7.90–7.83(m,1H),7.76(dd,J=8.6,2.5 Hz,1H),7.57(dd,J=8.6,6.0Hz,1H),7.46–7.36(m,3H),4.67(d,J=5.7Hz,2H),3.94( dd,J=5.4,2.2Hz,2H),3.59(s,3H),3.12(t,J=2.4Hz,1H),2.41(s,3H),2.25(s,3H).

[0317] Embodiment 28

[0318] Synthesis of compound 28

[0319] Cyclopropylamine was used to replace ethylamine hydrochloride, and the synthesis method was referred to the synthesis method of Example 15 to obtain a white solid (0.1 g, 62.7%). MS (ESI, pos.ion) m / z: 766.1 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ10.40 (s, 1H), 9.33 (t, J = 5.7Hz, 1H), 8.66 (d, J = 3.3Hz, 1H), 8.09(d,J=3.0Hz,1H),8.03(d,J=3.1Hz,1H),7.90–7.83(m,1H),7.78(dd,J=8.5,2. 3Hz,1H),7.59–7.52(m,1H),7.49–7.37(m,3H),4.66(d,J=5.6Hz,2H),3.59(s,3H), 2.67–2.58(m,1H),2.41(s,3H),2.25(s,3H),0.65–0.58(m,2H),0.26–0.22(m,2H).

[0320] Embodiment 29

[0321] Synthesis of compound 29

[0322] Morpholine was used to replace ethylamine hydrochloride, and the synthesis method was referred to the synthesis method of Example 15 to obtain a white solid (0.26 g, 62.4%). MS (ESI, pos.ion) m / z: 796.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.42(t,J=5.3Hz,1H),8.11(d,J=3.0Hz,1H),8.04(d,J= 3.0Hz,1H),7.92–7.82(m,2H),7.57–7.46(m,2H),7.45–7.37(m,2H),4.66(dd,J=16.1,5.6Hz, 1H),4.51(dd,J=16.2,5.4Hz,1H),3.67–3.61(m,1H),3.58(s,3H),3.55–3.39(m,3H),3.34–3. 22(m,1H),3.12–3.05(m,1H),3.04–2.96(m,1H),2.95–2.85(m,1H),2.38(s,3H),2.22(s,3H).

[0323] Embodiment 30

[0324] Synthesis of compound 30

[0325]

[0326] Step 1: Synthesis of compound 30-1:

[0327] Add 2-bromo-4-fluorobenzaldehyde (2.0g, 9.85mmol), 2-thiazolecarboxamidine hydrochloride (1.73g, 9.85mmol), compound F2 (4.48g, 11.82mmol) and tetrahydrofuran (40mL) to a dry reaction bottle in sequence, stir evenly at room temperature, add 4-methylmorpholine (2.49g, 24.63mmol), heat to 65 degrees, and stir for 12h. Turn off the heating, cool to room temperature, filter, and evaporate the solvent from the filtrate under reduced pressure to obtain a yellow oil. Add ethyl acetate (80mL) and water (80mL) to the oil, and adjust the pH to 9-10 with 2.5% sodium hydroxide aqueous solution while stirring. Let stand and separate, discard the organic layer, add ethyl acetate (100mL) to the aqueous layer, adjust the pH to 5-6 with concentrated hydrochloric acid while stirring, let stand and separate, wash the organic layer with saturated sodium chloride water (100mL×2), and dry over anhydrous sodium sulfate. Filter, evaporate the filtrate to remove the solvent under reduced pressure to obtain a yellow foamy solid (4.3 g, 74.8%). MS (ESI, pos.ion) m / z 583.10 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.61–7.49(m,1H),7.48–7.29(m,3H),7.03(t,J=7.6Hz,1H),6.13 –5.91(m,2H),4.71(s,1H),3.80–3.67(m,1H),3.64(s,3H),3.44–3.15(m,1H),1.44(d,J=2.8Hz,9H).

[0328] Step 2: Synthesis of compound 30-2:

[0329] Compound 30-1 (0.5 g, 0.86 mmol), HATU (0.39 g, 1.03 mmol) and DMF (8 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, isopropylamine (0.51 g, 8.6 mmol) and DIPEA (0.56 g, 4.3 mmol) were added and stirred at room temperature for 12 h under nitrogen protection. EA (60 mL) and water (50 mL) were added to the reaction solution. The pH was adjusted to 5-6 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated brine (60 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE / EA (V / V) = 1 / 2) to obtain a yellow solid (0.46 g, 85.95%). MS (ESI, pos.ion ) m / z:624.15[M+H] + ; 1H NMR(400MHz, DMSO-d6)δ9.61(d,J=51.6Hz,1H),7.99(d,J=2.9Hz,1H),7.94–7.87(m,1H),7.62–7.52(m,2H),7. 47 –7.35(m,1H),7.18–7.04(m,1H),6.75(d,J=9.0Hz,1H),5.96(d,J=9.0Hz,1H),4.40–4.30(m,1H),3.90–3.8 0(m,1H),3.53(d,J=2.8Hz,3H),3.32–3.25(m,1H),3.09–2.91(m,1H),1.35–1.23(m,9H),1.11–1.04(m,6H).

[0330] Step 3: Synthesis of compound 30-3:

[0331] Compound 30-2 (0.39 g, 0.62 mmol) and toluene (11 mL) were added to a dry reaction bottle in sequence. After stirring at room temperature, DDQ (0.20 g, 0.87 mmol) was added and the temperature was raised to 110°C for 4 h. The heating was turned off and the temperature was lowered to room temperature. The filter cake was washed with toluene (40 mL), and the filtrate was washed with 5% aqueous sodium hydroxide solution (50 mL × 3), and then washed with saturated sodium chloride water (50 mL × 3), and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure to obtain an off-white solid (0.375 g, 96.46%). MS (ESI, pos.ion) m / z: 622.20 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.10(d,J=3.1Hz,1H),7.63(d,J=3.1Hz,1H),7.49–7.35( m,2H),7.20–7.17(m,1H),6.94(br,1H),6.09(d,J=7.2Hz,1H),4.85(d,J=5.9H z,1H),4.11–4.00(m,1H),3.68(s,3H),3.57(dd,J=16.1,6.7Hz,1H),3.49(dd, J=16.1,6.0Hz,1H),1.41(s,9H),1.15(d,J=6.5Hz,3H),1.10(d,J=6.5Hz,3H).

[0332] Step 4: Synthesis of compound 30-4:

[0333] Compound 30-3 (0.31 g, 0.50 mmol) and DCM (2 mL) were added to a dry reaction bottle in sequence, stirred at room temperature, and after complete dissolution, TFA (2 mL) was added and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to obtain a slightly brown oil (0.32 g, 100%). MS (ESI, pos.ion) m / z: 522.10 [M+H] + .

[0334] Step 5: Synthesis of compound 30:

[0335] Compound 30-4 (0.32 g, 0.50 mmol), compound F1 (0.18 g, 0.55 mmol), HATU (0.23 g, 0.60 mmol) and DMF (8 mL) were added to a dry reaction bottle in sequence. After the reaction mixture was stirred at room temperature and dissolved completely, DIPEA (0.39 g, 3 mmol) was added, and then stirred at room temperature for 12 h under nitrogen protection. After the reaction was completed, EA (50 mL) and water (40 mL) were added to the reaction solution for dilution, and the pH was adjusted to 4-6 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated sodium chloride water (50 mL × 4) and dried over anhydrous sodium sulfate. Filter, evaporate the filtrate under reduced pressure to remove the solvent, and obtain a crude product. EA (6 mL) was added to the crude product for dilution, and stirred at room temperature for 12 h, and a solid was gradually precipitated. Filter, wash the solid with EA (6 mL), and dry the solid at room temperature overnight in vacuum to obtain a white solid (0.27 g, 63.87%). MS(ESI,pos.ion)m / z:840.20[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.96(d,J=8.0Hz,1H),8.13(d,J=2.9Hz,1H),8.10( d,J=2.9Hz,1H),7.91(d,J=7.6Hz,1H),7.88–7.81(m,1H),7.78(dd,J=8.5,1.7Hz,1H),7.5 1–7.38(m,4H),5.09(dd,J=14.6,7.4Hz,1H),3.90–3.78(m,1H),3.61(s,3H),3.56(s,3H), 3.51–3.46(m,2H),2.31(s,3H),2.10(s,3H),1.07(d,J=6.5Hz,3H),0.98(d,J=6.5Hz,3H).

[0336] Embodiment 31

[0337] Synthesis of compound 31

[0338] Cyclopropylamine was used to replace isopropylamine. The synthesis method was similar to that of Example 30 to obtain an off-white solid (0.17 g, 81.8%). MS (ESI, pos.ion) m / z: 838.10 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.96(d,J=7.9Hz,1H),8.20(d,J=4.0Hz,1H),8.13(d,J=3.0Hz,1H),8.10(d,J=3. 0 Hz,1H),7.88–7.82(m,1H),7.79(dd,J=8.6,2.2Hz,1H),7.50–7.37(m,4H),5.05(q,J=7.4Hz,1H),3.61(s,3H),3.56(s ,3H),3.46(dd,J=12.3,7.2Hz,2H),2.68–2.61(m,1H),2.31(s,3H),2.10(s,3H),0.67–0.50(m,2H),0.49–0.32(m,2H).

[0339] Embodiment 32

[0340] Synthesis of compound 32

[0341] Dimethylamine hydrochloride was used to replace isopropylamine. The synthesis method was similar to that of Example 30 to obtain an off-white solid (0.17 g, 81.8%). MS (ESI, pos.ion) m / z: 826.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.07(d,J=3.1Hz,1H),7.85(d,J=8.9Hz,1H),7.77(s,1H),7.71–7.63(m,1H),7.60(d,J=3.1Hz,1H),7.43–7.33(m,2H),7. 19–7.04(m,3H),5.71(dd,J=15.4,7.3Hz,1H),3.66(s,3H),3.64(s,3H) ,3.60–3.49(m,2H),3.32(s,3H),3.01(s,3H),2.28(s,3H),2.20(s,3H).

[0342] Embodiment 33

[0343] Synthesis of compound 33

[0344]

[0345] The compound F5 was used to replace the compound F2 in step 1 of Example 30, and dimethylamine hydrochloride was used to replace the isopropylamine in step 2 of Example 30. The synthesis method was the same as that of Example 30 to obtain a white solid (0.18 g, 79.7%). MS (ESI, pos.ion) m / z: 826.10 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.95(s,1H),7.83(d,J=8.1Hz,1H),7.71–7.62(m,1H),7.59(s,1H),7.37(d,J=6.3Hz,2H),7.19 –7.02(m,3H),5.73–5.63(m,1H),3.64(s,3H),3.61(s,3H),3.57–3.47(m,2H),3.30(s,3H),2.99(s,3H),2.25(s,3H),2.18(s,3H).

[0346] Embodiment 34

[0347] Synthesis of compound 34

[0348]

[0349] Compound F6 (0.33 g, 0.71 mmol), compound F1 (0.26 g, 0.78 mmol), HATU (0.32 g, 0.85 mmol) and DMF (8 mL) were added to a dry reaction bottle in sequence. After complete dissolution by stirring at room temperature, DIPEA (0.46 g, 3.55 mmol) was added. The reaction mixture was stirred at room temperature for 12 h under nitrogen protection. EA (80 mL) and water (50 mL) were added to the reaction solution. The pH was adjusted to 5-7 with concentrated hydrochloric acid under stirring. The organic layer was washed with saturated sodium chloride water (60 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and the solvent was evaporated under reduced pressure. The crude product was separated and purified by column chromatography (DCM / CH3OH (V / V=75 / 1)) to obtain a yellow solid (0.43 g, 77.4%). MS (ESI, pos.ion) m / z: 783.6 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ10.44(d,J=25.0Hz,1H),8.03–7.80(m,3H),7.60(td,J=8.5,2.6H z,1H),7.50–7.36(m,3H),7.27–7.17(m,1H),6.00(d,J=22.4Hz,1H),5.52–5.25(m,1H),5. 13–5.02(m,1H),4.83–4.50(m,1H),4.25–3.95(m,3H),3.91–3.73(m,2H),3.70–3.62(m,1H ),3.58(d,J=3.9Hz,3H),2.40(d,J=7.6Hz,3H),2.23(d,J=12.6Hz,3H),1.12–0.94(m,3H).

[0350] Embodiment 35

[0351] Synthesis of compound 35

[0352] Compound F3 was used to replace compound F1, and its synthesis method was referred to the synthesis method of Example 34 to obtain a yellow solid (0.1 g, 62.2%). MS (ESI, pos.ion) m / z: 831.60 [M+H] + .

[0353] Performance Testing

[0354] Biological tests

[0355] 1. Evaluation of compound cytotoxicity and inhibition of HBV DNA replication activity using HepAD38 cells (qPCR method)

[0356] HBV cell lines and culture conditions

[0357] HepAD38: Ladner et al. (Ladner, Otto et al. 1997) connected the tetracycline-sensitive cytomegalovirus CMV promoter to the PBR322 plasmid and connected it to the ayw subtype HBV DNA to form a ptetHBV plasmid, and transfected HepG2 cells to obtain the HepAD38 cell line. Due to the damage of the pre-C region gene, the HBV DNA production was about 11 times higher than that of HepG2.2.15 cells. Tetracycline can be used to regulate HBV replication, and the culture time required is only half of that of HepG2.2.15 cells. It is suitable for studying the HBV replication process and replication intermediates and anti-HBV drug screening. HepAD38 was cultured in DMEM / F-12K medium containing 10% FBS and 1% double antibody (also containing Tetracycline at a final concentration of 300ng / mL and G418 at a final concentration of 400μg / ml).

[0358] The viral DNA secreted by HepAD38 cells can be quantified by qPCR, and the effect of the compound on viral replication can be detected.

[0359] In vitro cytotoxicity assay

[0360] HepAD38 cells were revived and digested and counted after they were well grown. The cells were diluted to a concentration of 1×10 5 / mL cell suspension, inoculate 100 μL per well in a 96-well plate (cover the entire plate), and incubate in a 37°C, 5% CO2 constant temperature incubator for 24 hours. After 24 hours, discard the old culture medium and add 200 μL of fresh DMEM / F-12K culture medium containing 2% FBS and 1% double antibody.

[0361] Compound preparation and cell treatment in in vitro cytotoxicity assay: Dissolve the compound to 20 mM in DMSO, then perform 8 dilutions of 4-fold dilutions, with the highest concentration being 20 mM. Add 1 μL of the serially diluted compound to each well of the above cell plate, with the highest final concentration of the experiment being 100 μM (200-fold dilution). Staurosporine (Selleck, CAS No. 62996-74-1) was used as a positive control compound, with a maximum concentration of 1 μM. Add 1 μL of DMSO to the negative control wells, with a final concentration of 0.5%.

[0362] After 72 h, the old culture medium was discarded and a culture medium containing 10% CCK8 solution was added. The cells were incubated for 20-40 min and detected in a microplate reader to obtain the OD value. The data were exported to calculate the inhibition rate. The nonlinear regression model of Graphpad Prism 5 software was used to process and draw the curve to calculate the CC value of the compound. 50 The experimental results are shown in Table 3.

[0363] In vitro anti-HBV activity assay

[0364] After HepAD38 cells were revived and in good condition, Tetracycline (final concentration of 300 ng / ml) and G418 (final concentration of 400 μg / ml) were added to the culture medium. The virus was not expressed in the presence of Tetracycline. After the cells were fully grown, they were digested and counted. The cells were diluted to a concentration of 2×10 with DMEM / F-12K culture 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). 5 / mL cell suspension, inoculate 100 μL per well in a 96-well plate (cover the entire plate), and incubate in a 37°C, 5% CO2 constant temperature incubator for 24 hours. After 24 hours, discard the old culture medium and add 200 μL of fresh DMEM / F-12K culture medium containing 2% FBS and 1% double antibody.

[0365] Compound preparation and cell treatment in antiviral experiments: Dissolve the compound to 20mM with DMSO, further dilute the compound to 800μM with DMSO, and then perform 8 dilutions of 4-fold dilutions, with the highest concentration being 800μM. Add 1μL of the serially diluted compound to each well of the above cell plate, and the highest final concentration of the experiment is 4μM (200-fold dilution). TDF (tenofovir disoproxil fumarate, Selleck, Cat S1400) is used as a positive control compound, with a maximum concentration of 4μM. 1μLDMSO is added to the negative control well, with a final concentration of 0.5%.

[0366] HBV DNA Q-PCR

[0367] Q-PCR was performed using the Shengxiang Bio 48-person (PCR-fluorescent probe method) one-step hepatitis B virus nucleic acid quantitative determination kit. 2.5 μL of supernatant was aspirated for Q-PCR. Before use, the reagents in the kit were vortexed and mixed. After centrifugation, the enzyme mixture was placed on ice for use, and subsequent steps were completed on ice. 2.5 μL of sample release agent and 2.5 μL of test sample supernatant were added to each well of the Q-PCR plate (experimental group, control group, standard curve group). The number of viral DNA copies in each well was obtained after the QPCR reaction. The concentration-viral copy number was processed using Graphpad Prism 5 software, and the EC value of the compound on viral replication was calculated using a four-parameter nonlinear regression model. 50 The experimental results are shown in Table 3.

[0368] Table 3: In vitro anti-HBV activity and cytotoxicity test results of the compounds of the present invention

[0369] Example No. <![CDATA[EC 50 (nM)]]> <![CDATA[CC 50 (μM)]]> 1 80 >100 2 >4000 >100 3 276 >100 4 48 >100 6 151.6 >100 7 98 >100 8 129 N / A 9 254 N / A 10 217.4 >100 11 267 >100 12 >4000 60 13 >4000 63 14 >4000 >100 15 18 N / A 16 6 N / A 17 67 50 18 380 >100 19 49 >100 20 94 >100 22 187 >100 23 28 >100 24 380 >100 25 46 >100 26 204 56 27 13 >100 28 7 60 29 288 N / A 30 156 >100 31 194 >100 32 26 68 33 44 >100 34 604 63

[0370] Note: N / A means not tested

[0371] Conclusion: The experimental results show that the compounds of the present invention have good inhibitory activity against HBV and have low toxicity to cells.

[0372] 2. Stability of test compounds in liver microsomes of different species

[0373] Experimental methods:

[0374] The metabolic stability of the test compound was evaluated using liver microsome systems of different species. After the test compound and microsome were pre-incubated at 37°C for 10 minutes, 15 μL of NADPH solution (6 mM) was added at different time points. The final concentration of the test compound was 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentration of NADPH was 2 mM. Incubate for 0, 15, 30, and 60 minutes respectively. After the incubation, 150 μL of acetonitrile (containing internal standard) was added to the mixed system to terminate the reaction. The sample diluted with acetonitrile was centrifuged at 4000 rpm for 5 minutes, and the supernatant was taken for LC-MS / MS analysis. The concentration of the test compound in the solution at each time point was detected, and the half-life (T 1 / 2 ) and metabolic rate (μL / min / mg). The experimental results are shown in 4.

[0375] Table 4: Stability results of compounds in liver microsomes of different species

[0376]

[0377] The experimental results show that the compounds of the present invention have good stability in various liver microsomes.

[0378] 3. PK (Pharmacokinetic) Experiment of Test Compounds in Beagle Dogs

[0379] Experimental methods:

[0380] Beagles were given 2.5 mg / kg or 5 mg / kg of the test compound by oral gavage and 1 mg / kg or 2 mg / kg by intravenous injection. Whole blood was collected intravenously at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration, collected in anticoagulant tubes with EDTA-K2, and centrifuged to prepare plasma. After pretreatment, the plasma samples were quantitatively analyzed by a triple quadrupole tandem mass spectrometer in a multiple reaction ion monitoring (MRM) mode to detect the concentration of the test compound in plasma, and the pharmacokinetic parameters of the test compound were calculated using the WinNonlin 6.3 software non-compartmental model method. The experimental results show that the compound of the present invention has good pharmacokinetic properties in beagles.

[0381] 4. PK (Pharmacokinetic) experiment of test compounds in SD rats

[0382] Experimental methods:

[0383] Rats were given 2.5 mg / kg or 5 mg / kg of the test compound by oral gavage and 1 mg / kg by intravenous injection.

[0384] After administration, venous blood was collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours), collected in anticoagulant tubes with EDTA-K2, and centrifuged to prepare plasma. After pretreatment, plasma samples were quantitatively analyzed by triple quadrupole tandem mass spectrometry in multiple reaction ion monitoring (MRM) mode to detect the concentration of test compounds in plasma. WinNonlin 6.3 software was used to calculate pharmacokinetic parameters using the non-compartmental model method.

[0385] The experimental results show that the compound of the present invention has good pharmacokinetic properties in SD rats.

[0386] 5. PK (Pharmacokinetic) experiments of test compounds in mice

[0387] Experimental methods:

[0388] ICR mice were given 10 mg / kg of the test compound by oral gavage and 2 mg / kg or 10 mg / kg by tail vein injection. Blood was collected from the orbital vein at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration, collected in anticoagulant tubes with EDTA-K2, and centrifuged to prepare plasma. After pretreatment, the plasma samples were quantitatively analyzed by a triple quadrupole tandem mass spectrometer in a multiple reaction ion monitoring (MRM) mode to detect the concentration of the test compound in plasma. Pharmacokinetic parameters were calculated using WinNonlin 6.1 software using the non-compartmental model method.

[0389] The experimental results show that the compound of the present invention has good pharmacokinetic properties in mice.

[0390] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention will be described as examples, but are not limited to the contents described in the present invention. It is understood that the above embodiments are exemplary and cannot be understood as limitations of the present invention. Those of ordinary skill in the art can change, modify, replace and modify the above embodiments within the scope of the present invention. It may also be modifications made within the scope of the present invention or equivalent contents added in the claims. All publications or patents cited in the present invention will serve as references for the present invention.

Claims

1. A compound, which is a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I), It is characterized in that Each R 5a , R 5b , R 5c , R 5d , R 5e , R 2 and R 3 are independently hydrogen, deuterium, F, Cl, Br, I, -CN, SF5, amino, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl, trifluoromethoxy, methoxy or ethoxy; Ring A is Each R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c and R 4d are independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)OC 1-6 Alkyl, amino, C 3-6 Cycloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl or heteroaryl composed of 5-6 ring atoms, wherein the C 3-6 Cycloalkyl, C 6-10 The aryl group and the heteroaryl group consisting of 5-6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w2 replaced by; Each R 2a , R 2b , R 2c , R 2d and R 6 are independently -CN, -COOH, -C(=O)OR 6a ,-C(=O)NHR 6b 、-C(=O)R 7a 、-C(=O)NHCH2R 7b or a heteroaryl group consisting of 5 to 6 ring atoms, wherein the heteroaryl group consisting of 5 to 6 ring atoms is unsubstituted or replaced by 1, 2, 3 or 4 R w3 replaced by; Each R 6a and R 6b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or C 1-4 The halogenated alkyl group, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and C 1-4 Each haloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 R w4 replaced by; Each R 7a and R 7b are independently N,N-dimethylamino, a heteroaryl group consisting of 5-6 ring atoms, or a heterocyclic group consisting of 5-6 ring atoms, wherein the heteroaryl group consisting of 5-6 ring atoms and the heterocyclic group consisting of 5-6 ring atoms are unsubstituted or replaced by 1, 2, 3 or 4 R w5 replaced by; Each R 1a , R 1b , R 1 , R 4 , R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or C 1-4 The methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-n-butyl or C 1-4 Each haloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 R w6 replaced by; L1 is a single bond, -CH2NR a -、-NR b -or-CH2CHR 6 NR a -, wherein the -CH2NR a -CH2 and -CH2CHR in 6 NR a -CH2 in each independently is unsubstituted or substituted with 1 or 2 R w7 replaced by; Each R w2 , R w3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -C(=O)OC 1-6 Alkyl, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, carboxyl C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

2. The compound according to claim 1, characterized in that Each R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c and R 4d are independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -COOH, nitro, -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, amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridinyl, 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 R w2 replaced.

3. The compound according to claim 1, characterized in that Each R 2a , R 2b , R 2c , R 2d and R 6 are independently -CN, -COOH, -C(=O)OR 6a ,-C(=O)NHR 6b 、-C(=O)R 7a 、-C(=O)NHCH2R 7b , pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are unsubstituted or substituted with 1, 2, 3 or 4 R w3 replaced.

4. The compound according to claim 1, characterized in that Each R 7a and R 7b are independently N,N-dimethylamino, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein The pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are unsubstituted or substituted with 1, 2, 3 or 4 R w5 replaced.

5. The compound according to claim 1, characterized in that Each R w2 , R w3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)OC 1-4 Alkyl, amino, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, carboxyl C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

6. The compound according to claim 5, characterized in that Each R w2 , R w3 , R w4 , R w5 , R w6 and R w7 are independently deuterium, F, Cl, Br, CN, -OH, -COOH, nitro, -C(=O)O methyl, -C(=O)O ethyl, -C(=O)O n-propyl, -C(=O)O isopropyl, -C(=O)O tert-butyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, carboxyl C 1-3 -CHCl, -CF, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy or 2-methyl-l-propoxy.

7. The compound according to claim 1, characterized in that The compound includes one of the following structures: or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or a prodrug thereof.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 7.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating, curing or alleviating a viral disease in a patient, wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection, wherein the disease caused by hepatitis B virus infection refers to cirrhosis or hepatocellular carcinoma.

10. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a drug for inhibiting HBV infection.

11. A method for synthesizing a compound according to any one of claims 1 to 7, characterized in that: The method includes the following steps A: Compound O or its salt is subjected to a condensation reaction with compound F to obtain a compound represented by formula (I); Wherein, Y is H, -CH2NHR a 、-NHR b or -CH2CHR 6 NHR a .

Images