Bipyrimidine heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a bipyrimidine heterocyclic compound and a preparation method and application thereof, the bipyrimidine heterocyclic compound has a structure as shown in a formula (I), and the invention also provides a pharmaceutical composition containing the compound or a stereoisomer, a medicinal salt, a hydrate, a solvate or a crystal thereof. The invention also discloses application of the compounds in preparation of drugs for treating hepatitis B virus infection, and particularly the compounds can be used as PAPD5 / 7 enzyme inhibitors and hepatitis B RNA non-stabilizers for treating hepatitis B viruses. The compound provided by the invention has the characteristics that the concentration of hepatitis B surface antigen and hepatitis B DNA and RNA can be remarkably reduced, and the probability of functional healing of hepatitis B can be remarkably improved by clinically combining with nucleoside drugs, oligonucleotide drugs / PD-L1 compounds and the like.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and specifically to a class of bipyrimidine heterocyclic compounds, racemic compounds or stereoisomers thereof, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the bipyrimidine heterocyclic compounds, racemic compounds or stereoisomers thereof, and pharmaceutically acceptable salts thereof, and their use as antiviral drugs, in particular, their use as drugs for preparing HBV RNA destabilizing agents for treating hepatitis B virus, and their use in combination with nucleoside drugs, oligonucleotides and immune agonists for functionally curing hepatitis B virus. Background Art

[0002] Hepatitis B remains one of the most prevalent diseases worldwide. Despite the availability of a safe and effective hepatitis B vaccine, 240 million people worldwide still suffer from chronic hepatitis B. Liver cancer, cirrhosis, and related complications caused by chronic hepatitis B result in 500,000 to 1 million deaths annually. Currently approved treatments for hepatitis B are primarily nucleos(t)ide drugs and interferon α. ​​Peg-INF-2α can achieve optimal serological milestones in one-third of treated patients, but is associated with significant side effects. Entecavir and TDF / TAF are first-line hepatitis B treatments that effectively suppress HBV DNA (HBV DNA). However, their drawbacks are the need for long-term or lifelong medication, and the emergence of drug-resistant strains can negate the efficacy of these first-line drugs. Clinical patients urgently need a novel therapy with a novel mechanism of action, distinct from nucleos(t)ide drugs, that can avoid the emergence of drug-resistant strains in clinical practice and serve as a future combination therapy option. Furthermore, patients need a drug with a completely new mechanism to achieve the goal of functional cure, so as to avoid long-term or lifelong medication. A more likely way to achieve this is to stimulate and restore the patient's immune function by reducing the concentration of the patient's surface antigen. It is very likely that an effective functional cure for hepatitis B can be developed.

[0003] Hepatitis B virus (HBV) is an enveloped hepatitis virus containing a double-stranded DNA genome. The RNA transcribed from HBV DNA and the viral proteins translated from RNA can both serve as potential targets for antiviral drugs. Hepatitis B surface antigen (HBsAg) is one of the criteria for HBV infection and the most important indicator of functional cure. Long-term exposure to HBsAg can lead to the loss or functional damage of HBV-specific T cells, and high concentrations of HBsAg can also suppress the function of immune cells. On the other hand, the key to clearing HBV from the body lies in restoring the innate immune environment suppressed by HBsAg. The antibodies or immune cells produced can kill infected liver cells, potentially curing hepatitis B patients.

[0004] We hope to develop an antiviral drug with a novel mechanism of action that, by inhibiting the activity of the PAPD5 / 7 enzyme, destabilizes RNA and causes its degradation, thereby reducing corresponding protein concentrations, particularly HBsAg. Such an antiviral drug with a novel mechanism of action could effectively and persistently reduce HBsAg levels, restore the patient's immune function, and achieve a functional cure. Summary of the Invention

[0005] The object of the present invention is to overcome one or more deficiencies in the prior art and to provide a novel bipyrimidine heterocyclic compound that inhibits the activity of the PAPD5 / 7 enzyme, thereby promoting RNA instability and degradation, thereby reducing the corresponding protein concentration, especially the concentration of HBsAg. The bipyrimidine heterocyclic compound is superior to existing RNA destabilizing agents in at least one of activity, pharmacokinetic properties such as bioavailability, and cytotoxicity.

[0006] The present invention also provides a pharmaceutical composition comprising the novel bipyrimidine heterocyclic compound.

[0007] The present invention also provides a use of the novel bipyrimidine heterocyclic compound and / or the pharmaceutical composition in the preparation of a drug for preventing and / or treating a viral infectious disease, wherein the viral infectious disease is preferably an infectious disease caused by hepatitis B virus.

[0008] In order to achieve the above object, a technical solution adopted by the present invention is:

[0009] A bipyrimidine heterocyclic compound having a structure represented by formula (I), a racemic compound or stereoisomer, or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in:

[0012] (1) R1 is selected from the following groups: unsubstituted or substituted: C 6-12 Aromatic carbon ring, C 6-12 Aromatic carbon ring C 1-3 Alkyl, C 2-12 Heterocyclic, C 2-12 Heterocycle C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl or benzyloxy C 1-3 Alkyl; wherein the substituents used are selected from F, Cl, Br, I, unsubstituted or substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, unsubstituted or substituted C 3-6Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups;

[0013] (2) A is selected from CH or N;

[0014] (3)R2, R5, R6, R7, R8, R9, R 10 independently selected from H, F, Cl, Br, I, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0015] (4) R3 and R4 are independently selected from H, F, Cl, Br, I, and the following groups which are unsubstituted or substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heterocycle; wherein the substituents used are selected from F, Cl, Br, I, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups;

[0016] Alternatively, R3, R4 and the carbon atoms on the benzene ring to which they are attached together form a 4-8 membered heterocyclic ring;

[0017] (5) When R3 and R4 are independently selected from H, F, Cl, Br, I, and the following groups which are unsubstituted or substituted: 1-6 Alkyl, C 1-6 When alkoxy and A is selected from CH, R1 is selected from the following groups which are unsubstituted or substituted: C 2-12 Heterocycle C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl or benzyloxy C 1-3 Alkyl, n is 0, 1, 2 or 3, R 11 For O, R 12 For CH2 or Among them, the substituents used in R1, R3, and R4 are independently selected from F, Cl, Br, I, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups;

[0018] (6) C 3-12 Heteroaryl, C 2-12 Heterocyclic, C 2-6 The heteroatoms in the heterocyclic ring or the 4- to 8-membered heterocyclic ring are independently selected from one or more of N, O and S.

[0019] In the present invention, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. 1-3 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0020] In the present invention, the halogenated C 1-6 The alkyl group can be obtained by replacing the hydrogen in methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. with one or more of F, Cl, Br, and I.

[0021] In the present invention, C 1-6 Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, and the like.

[0022] In the present invention, the halogenated C 1-6 Alkoxy groups include, but are not limited to, those obtained by replacing the hydrogen in methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, etc. by one or more of F, Cl, Br, and I.

[0023] In the present invention, C 3-6 Cycloalkanes include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclohexenyl, etc. 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0024] In the present invention, C 6-12 Aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.

[0025] In the present invention, heteroaryl includes but is not limited to furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromenone, fluorenone, quinoxaline, 3,4-dihydronaphthalenone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc., C 3-12 Heteroaryl means that the number of carbon atoms in the heteroaryl is 3-12, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0026] In the present invention, the aromatic carbon ring may be a benzene ring, a naphthyl ring, or the like.

[0027] In the present invention, the heterocycle can be an aromatic heterocycle or a non-aromatic heterocycle, which is a cyclic group containing at least one heteroatom, wherein the heteroatom is nitrogen, oxygen, sulfur, etc., and can be a monocyclic heterocycle or a polycyclic heterocycle. 2-12 Heterocyclic or C 2-6 The number of carbon atoms in each heterocyclic ring is limited. 2-12 That is, the number of carbon atoms is 2-12, C 2-6 That is, the number of carbon atoms is 2-6.

[0028] According to some preferred aspects of the present invention, R1 is selected from the following groups which are unsubstituted or substituted: phenyl, naphthyl, phenyl C 1-3 Alkyl, naphthyl C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered oxygen heterocycle C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, benzyloxy C 1-3 alkyl, The substituents used are selected from one or more of F, Cl, Br, I, methyl, ethyl, n-propyl and isopropyl.

[0029] Furthermore, in some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl, phenyl, naphthyl, phenyl C 1-3 Alkyl, naphthyl C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered oxygen heterocycle C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, benzyloxy C 1-3 alkyl,

[0030] Furthermore, in some embodiments of the present invention, R1 is selected from the following groups:

[0031]

[0032] According to some preferred aspects of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, I, and the following unsubstituted or substituted groups: methoxy, ethoxy, propoxy, R 13 、R 17 Independently selected from C 1-6 Alkyl, R 14 、R 15 、R 16 Independently selected from H, C 1-6 Alkyl, X is N or CH; wherein the substituent used is selected from one or more of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, phenyl, pyrazole, pyrimidine, thiazole, thiophene, furan, and pyrrole.

[0033] In some embodiments, R3 and R4 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, phenyl, pyrazole, pyrimidine, thiazole, thiophene, furan, pyrrole, R 13 、R 17 Independently selected from C 1-6 Alkyl, R 14 、R 15 、R 16 Independently selected from H, C 1-6 Alkyl, X is N or CH.

[0034] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, methoxy, ethoxy,

[0035] In some embodiments of the present invention, R2, R5, R6, R7, R8, R9, R 10 are independently H, F, Cl, or methyl. Further, R2, R5, R6, R7, R8, R9, R 10 Both are H.

[0036] According to a specific aspect of the present invention, the bipyrimidine heterocyclic compound is represented by the following formula (II):

[0037]

[0038] In formula (II), m is 1, 2 or 3, t and s are independently 0, 1, 2 or 3, and t and s are not 0 at the same time, and Y1 is H, F, Cl, Br, C 1-6 Alkyl or halogenated C 1-6 Alkyl, Y2 is CH2, CF2, SO2, S or O, and A, R2, R3, R4, R5, R6 and R7 are as defined above.

[0039] Furthermore, in some embodiments, Y1 is H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, halogenated methyl, halogenated ethyl, halogenated n-propyl, or halogenated isopropyl; wherein the halogen atom used for the halogenation can be selected from one or more of F, Cl, and Br.

[0040] According to some preferred and specific aspects of the present invention, R3, R4 and the carbon atoms on the benzene ring to which they are connected together form a 5-membered oxygen heterocycle or a 6-membered oxygen heterocycle.

[0041] According to a specific aspect of the present invention, the bipyrimidine heterocyclic compound is represented by the following formula (III) or formula (IV):

[0042]

[0043] In formula (III), p is 0, 1, 2 or 3, and Y3 is C 1-6 Alkyl or halogenated C 1-6 Alkyl, A, R1, R2, R5, R6, R7 are as defined above;

[0044]

[0045] In formula (IV), among Y4 and Y5, one is selected from H, C 1-6 Alkyl or halogenated C 1-6 Alkyl, the other p is 0, 1, 2 or 3, and A, R1, R2, R5, R6 and R7 are as defined above.

[0046] In some embodiments of the present invention, the bipyrimidine heterocyclic compound is selected from the following compounds:

[0047]

[0048]

[0049] According to the present invention, all hydrogen atoms except active hydrogen can be independently replaced by deuterium.

[0050] Another technical solution provided by the present invention is a pharmaceutical composition comprising the above-mentioned bipyrimidine heterocyclic compound having a structure represented by formula (I), its racemic compound or stereoisomer, and pharmaceutically acceptable salt.

[0051] Furthermore, the pharmaceutical composition is a pharmaceutical preparation, and the pharmaceutical preparation is selected from tablets, powders, capsules, granules, oral liquids, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions, and nano preparations.

[0052] In some embodiments of the present invention, the medicine prepared with the compound of the present invention as the active ingredient can be in various forms such as tablets, powders, capsules, granules, oral solutions and injections. The dosage form of the pharmaceutical composition is preferably tablets, capsules or injections.

[0053] In some embodiments of the present invention, the pharmaceutical composition includes a pharmaceutically acceptable carrier, for example, selected from pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavoring agents, sweeteners, etc.

[0054] According to some preferred aspects of the present invention, the pharmaceutical composition is an antiviral pharmaceutical composition, which optionally further includes one or more therapeutic agents selected from the following group: nucleoside drugs, capsid inhibitors, PD-L1 agonists, TLR-7 or TLR-8 or TLR-9 agonists, oligonucleotides or other antiviral drugs.

[0055] Specifically, the mechanism of the antiviral drug is to inhibit the activity of PAPD5 / 7 enzyme, causing HBV RNA to lose stability, further reducing the secretion of hepatitis B surface antigen, thereby achieving a functional cure for HBV.

[0056] The pharmaceutical composition according to the present invention, wherein the compound of the present invention is preferably present in a therapeutically effective amount.

[0057] According to some preferred and specific aspects of the present invention, the pharmaceutical composition is composed of the following mass ratios:

[0058] The bipyrimidine heterocyclic compound having the structure shown in formula (I), its racemic compound or stereoisomer, and pharmaceutically acceptable salt thereof are 5-95%

[0059]

[0060] In some embodiments of the present invention, the various dosage forms of the drugs mentioned above can be prepared according to conventional methods in the pharmaceutical field.

[0061] The present invention also provides the use of the compound of the present invention in the preparation of a composition for preventing and / or treating viral infections, preferably for treating viral infections caused by hepatitis B virus infection, and more preferably for the functional cure of HBV in combination with a nucleoside anti-hepatitis B drug, an oligonucleotide, and an immune agonist such as TLR7 / 8 / 9 or PD-L1.

[0062] Furthermore, the present invention provides another technical solution: the use of a combination of the bipyrimidine heterocyclic compound having a structure represented by formula (I) as described above, its racemic compound or stereoisomer, and pharmaceutically acceptable salt, and one or more of the above-mentioned pharmaceutical compositions in the preparation of a drug for preventing and / or treating viral infectious diseases, wherein the viral infectious disease is preferably an infectious disease caused by hepatitis B virus.

[0063] Another technical solution provided by the present invention is a method for preparing the above-mentioned bipyrimidine heterocyclic compound having a structure represented by formula (I), its racemic compound or stereoisomer, and pharmaceutically acceptable salt, wherein the preparation method comprises synthesizing the bipyrimidine heterocyclic compound by the following route:

[0064] In the above formula, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 The definitions of are the same as before.

[0065] Furthermore, in the above preparation route, the intermediate Schiff base (I-A) can be conveniently prepared from the corresponding aldehyde and S-tert-butylsulfenamide in a nonpolar solvent, using copper sulfate as a water absorbent. Alternatively, tetraisopropoxytitanium can be used as a Lewis acid. The prepared Schiff base reacts with an alkyl (aryl) Grignard reagent or a lithium reagent at room temperature for 3 hours to overnight, resulting in nucleophilic addition to the intermediate (I-B). The solvent can be other inert solvents such as dichloromethane, chloroform, 1,2-dichloroethane, THF, and diethyl ether. The resulting amide compound (I-B) can be reacted with an aromatic chloride (I-C) in two options. The first is to use cesium carbonate as a base, catalyzed by copper iodide and N,N-dimethylethylenediamine, in a high-temperature DMSO solvent to allow the bipyrimidine chloride and amide to react to yield the bipyrimidine heterocyclic compound represented by Formula (I). The second reaction is carried out in the presence of a Pd reagent, a phosphine reagent, and a base such as cesium carbonate, using 1,4-dioxane as a solvent, under a protective atmosphere such as nitrogen, at 90-110°C, and post-processing to obtain a bipyrimidine heterocyclic compound represented by formula (I). The base includes organic bases and inorganic bases. The organic base is selected from triethylamine, DIPEA, DBU, pyridine, etc.; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium bicarbonate, etc. The Pd reagent includes, but is not limited to, Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)2Cl2, PdG3, etc.; the phosphine reagent includes, but is not limited to, Xphos, Sphos, Xantphos, etc.

[0066] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0067] The present invention provides a new generation of bipyrimidine heterocyclic compounds, which, compared with the first generation of compounds with the same target, have high activity in inhibiting HBsAg, avoid the ketoacid structural characteristics of binding to metal ions, reduce the toxicity to CNS nerve cells, and have a large therapeutic window in clinical practice.

[0068] Furthermore, the compounds of the present invention have the activity of highly efficient inhibition of HBsAg concentration, effectively relieving the pressure on the immune system, and combined with other anti-hepatitis B drugs such as nucleoside drugs, oligonucleotide drugs, TLR7 / 8 / 9 and PD-L1 agonists, etc., may significantly increase the proportion of functionally cured patients in clinical practice. DETAILED DESCRIPTION

[0069] Definition of terms

[0070] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of the definition at every other occurrence. Similarly, combinations of substituents and variables are permitted as long as such combinations result in a stable compound. Lines drawn from substituents into the ring system indicate that the indicated bond may be attached to any substitutable ring atom. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic carbon and heteroatom substituents of organic compounds. It is understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stable.

[0071] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0072] The term "stereoisomer" refers to isomers resulting from differences in the spatial arrangement of atoms in a molecule. This includes cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present invention. The compounds of the present invention may be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.

[0073] The term "salt" refers to a pharmaceutically acceptable salt formed between the compound of the present invention and an acid, wherein the acid can be an organic acid or an inorganic acid, and can be specifically selected from phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.

[0074] The term "solvate" refers to a form of the compound of the present invention which forms a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.

[0075] The term "crystalline" refers to various solid forms of the compounds of the present invention, including crystalline forms and amorphous forms.

[0076] The term "hydrocarbyl" refers to saturated alkyl, alkenylalkyl and alkynylalkyl groups.

[0077] The term "saturated alkyl" refers to a linear, branched or cyclic saturated or unsaturated substituent mainly composed of carbon and hydrogen. Preferably 1-20 carbon atoms, more preferably 1-12 carbon atoms. The term "alkyl" refers to a linear, branched or cyclic saturated hydrocarbon group. Alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2-methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C 1-20 "Alkyl" refers to a straight chain, branched or cyclic saturated hydrocarbon group containing 1 to 20 carbon atoms. Alkyl includes substituted and unsubstituted alkyl groups. When the alkyl group is substituted, the substituent may be substituted at any available connection point, and the substituent may be monosubstituted or polysubstituted. The substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, and the substituents are usually placed before the alkyl group when naming, for example, C 1-3 Alkoxy C 3-8 Cycloalkyl C 1-6 Alkyl refers to C 1-6 Alkyl, which is C 3-8 Cycloalkyl substituted, and the C 3-8 Cycloalkyl is C 1-3 Alkoxy substitution, for example: the structural formula of methoxycyclobutylmethyl is:

[0078]

[0079] The terms "alkenyl" and "alkynyl" refer to straight, branched or cyclic unsaturated hydrocarbon groups containing double bonds and triple bonds, preferably 2-20 carbon atoms, more preferably 2-12 carbon atoms. Alkenyl and alkynyl include substituted and unsubstituted alkenyl and alkynyl. When substituted, the substituent can be substituted at any available point of attachment, and the substituent can be monosubstituted or polysubstituted. The substituent is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester group, cyano group, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkoxy, cycloalkylthio, oxo, and the substituent is usually placed before the alkenyl and alkynyl groups when naming.

[0080] The term "ring" refers to both carbocyclic and heterocyclic rings. "Carbocyclyl" or "carbocycle" refers to a carbocyclic ring having 3 to 20 carbon atoms, preferably 3 to 16 carbon atoms, and more preferably 4 to 12 carbon atoms, and includes cycloalkyl, cycloalkenyl, aryl, bicyclic carbocyclic, and polycyclic carbocyclic rings. "Heterocyclyl" or "heterocycle" includes heteroaryl, non-aromatic heterocyclic, bicyclic heterocyclic, and polycyclic heterocyclic rings having one or more heteroatoms selected from O, S, and N, which may be the same or different, in the ring. The term "ring" includes monocyclic, bridged, spirocyclic, fused, and polycyclic rings.

[0081] The term "cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon radical. The monocyclic ring may contain 3-10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, etc. Polycyclic cycloalkyl radicals include cycloalkyl radicals of spirocyclic, fused, and bridged rings. Cycloalkyl radicals include those without substituents and those containing substituents. Substituents may be selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester group, amino, amide, hydroxyl, cyano, nitro, aryl, and heteroaryl.

[0082] The term "aryl" refers to both carbocyclic aromatic and heteroaryl groups.

[0083] The term "carbocyclic aryl" refers to a 6-10 membered, all-carbon monocyclic or polycyclic aromatic group, including phenyl, naphthyl, biphenyl, and the like. The aryl group may be substituted or unsubstituted. Substituents are independently selected from alkyl, cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, and the like.

[0084] The term "heteroaryl" refers to a group containing a heteroaromatic system of 1-10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Monocyclic heterocyclic groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, and isoxazoline. Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromenone, fluorenone, quinoxaline, 3,4-dihydronaphthalenone, dibenzofuran, hydrodibenzofuran, and benzoxazolyl. Heteroaryl groups may be substituted or unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropyl, cyclobutyl and cyclopentyl, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine.

[0086] The term "deuterium" refers to an isotope of hydrogen that has twice the atomic mass and bonds more strongly to carbon. "Deuterated" and "deuterium" indicate that hydrogen has been replaced with deuterium at the specified position. A "deuterated substituent" is a substituent in which at least one hydrogen has been replaced with deuterium enriched at a specified percentage.

[0087] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.

[0088] The term "heterocyclic group" refers to a cyclic group containing at least one heteroatom, wherein the heteroatom is nitrogen, oxygen, sulfur, sulfur, etc. The heterocyclic group includes a monocyclic group and a polycyclic group.

[0089] The above scheme is further described below in conjunction with specific examples; it should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples; the implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are generally the conditions in routine experiments.

[0090] Unless otherwise specified in the following examples, all raw materials were purchased from commercial sources or prepared by conventional methods in the art.

[0091] The structures of all compounds were 1 confirmed by H NMR or MS.

[0092] The abbreviations of the compound names used in the examples are as follows:

[0093] DCM: dichloromethane

[0094] EtOAc: ethyl acetate

[0095] THF:Tetrahydrofuran

[0096] DME: Ethylene glycol dimethyl ether

[0097] 1,4-Dioxane:1,4-dioxane

[0098] TEA: triethylamine

[0099] T3P: 1-propylphosphoric anhydride

[0100] PPA: Polyphosphoric acid

[0101] TBAF: Tetrabutylammonium fluoride

[0102] NBS: N-bromosuccinimide

[0103] AIBN: Azobisisobutyronitrile

[0104] HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0105] TFA: trifluoroacetic acid

[0106] DIPEA: N,N-diisopropylethylamine

[0107] DMF: N,N-dimethylformamide

[0108] Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0109] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0110] The present invention will be further described below with reference to specific embodiments:

[0111] Embodiment 1:

[0112] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-cyclobutyl-5-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one (Compound I-17)

[0113]

[0114] Step 1: Synthesis of methyl 4-bromo-2-formylbenzoate (Compound 1-1)

[0115] Dissolve 4-bromo-2-formylbenzoic acid (0.90 g, 3.93 mol) in acetone (5 mL) under nitrogen atmosphere. Add iodomethane (0.83 g, 5.89 mol) dropwise at room temperature over approximately 10 minutes. Maintain stirring at this temperature for 3 hours. TLC confirms complete conversion. Pour the reaction mixture into ice water (50 mL) and extract with ethyl acetate (30 mL). Wash the organic layer with sodium bicarbonate solution (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 1.03 g of crude product.

[0116] Step 2: Synthesis of methyl (E)-4-bromo-2-(((tert-butylsulfinyl)imino)methyl)benzoate (Compound 1-2)

[0117] Compound 1-1 (1.00 g, 4.12 mmol) was dissolved in 1,2-dichloroethane (5 mL) under nitrogen atmosphere. Copper sulfate (1.50 g, 12.36 mmol) was added and the mixture was heated to 80°C and stirred for 8 h. TLC confirmed complete conversion of the starting material. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 10:1 → 5:1) to obtain the target compound 1-2 as a white solid (1.20 g). 1 HNMR (400MHz, CDCl3): δ9.21 (s, 1H), 8.16 (d, J = 2Hz, 1H), 7.86–7.84 (d, J = 8Hz, 1H), 7.69–7.66 (dd, J1 = 8Hz, J2 = 8Hz, 1H), 3.94 (s, 3H), 1.29 (s, 9H).

[0118] Step 3: Synthesis of 5-bromo-3-cyclobutylisoindolin-1-one (Compound 1-3)

[0119] Compound 1-2 (600 mg, 1.73 mmol) was dissolved in dichloroethane (5 mL) under nitrogen protection. The mixture was cooled to 0°C and cyclobutylmagnesium bromide (0.83 g, 5.89 mol) was slowly added dropwise over a period of approximately 30 min. The mixture was heated to 25°C and stirred for 3 h. TLC indicated a small amount of residual starting material. The reaction mixture was poured into ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 1-3 as a yellow solid (130 mg). LCMS: M+H + =266.3 / 268.3. 1HNMR (400MHz, CDCl3): δ7.75-7.72(d,J=8Hz,1H),7.65–7.62(d,J=8Hz,1H),7.59(s, 1H), 4.55 (d, J = 7.2Hz, 1H), 2.69-2.61 (m, 1H), 2.30-2.20 (m, 1H), 2.10-1.80 (m, 6H).

[0120] Step 4: Synthesis of 3-cyclobutyl-5-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one (Compound 1-4)

[0121] Compound 1-3 (40 mg, 0.15 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (34 mg, 0.165 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), and cesium carbonate (59 mg, 0.18 mmol) were dissolved in 1,4-dioxane:water (3 mL:0.4 mL), replaced with nitrogen, and heated to 100°C with stirring for 6 h. TLC analysis showed that the raw material conversion was complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 1-4 as a yellow solid (48 mg). LCMS: M+H + =268.5. 1 H NMR (400MHz, CDCl3): δ7.87-7.83(d,J=7.6Hz,2H),7.72(s,1H),7.61–7.58(d,J=8Hz,1H),7.51–7.47(d,J=8Hz,1H ),6.31(s,1H),4.62–4.58(d,J=6.8Hz,1H),4.02(s,3H),2.78-2.67(m,1H),2.32-2.22(m,1H),2.15-1.80(m,5H).

[0122] Step 5: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-cyclobutyl-5-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one (Compound I-17)

[0123] Compound 1-4 (45 mg, 0.18 mmol), 4-chloro-2,2'-bipyrimidine (38 mg, 0.20 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xphos (4 mg, 0.01 mmol), and cesium carbonate (118 mg, 0.36 mmol) were dissolved in 1,4-dioxane (4 mL), replaced with nitrogen, and heated to 100°C with stirring for 4 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH = 10:1) to obtain 55 mg of the target compound as a light yellow solid. LCMS: M+H + =424.5. 1 HNMR (400MHz, CDCl3): δ9.06 (s, 2H), 8.96 (s, 1H), 8.62 (s, 1H), 7.94–7.91 (d, J = 8Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.64–7.60 (d,J=8Hz,2H),7.48(s,1H),6.06–6.02(d,J=6.4Hz,1H),4.00(s,3H),3.10-3.00(m,1H),2.30-2.20(m,1H),1.74-1.52(m,5H).

[0124] Example 2:

[0125] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-cyclobutyl-5-(3,5-dimethylisoxazol-4-yl)isoindolin-1-one) (Compound I-22)

[0126]

[0127] Step 1: Synthesis of 3-cyclobutyl-5-(3,5-dimethylisoxazol-4-yl)isoindolin-1-one (Compound 2-2):

[0128] 5-Bromo-3-cyclobutylisoindolin-1-one (compound 2-1, 40 mg, 0.15 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (37 mg, 0.165 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), and cesium carbonate (59 mg, 0.18 mmol) were dissolved in 1,4-dioxane:water (3 mL:0.4 mL), replaced with nitrogen, and heated to 100°C with stirring for 6 h. TLC analysis confirmed complete conversion of the starting material. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 2-2 as a yellow solid (50 mg). LCMS: M+H + =283.4.

[0129] Step 2: Synthesis of 2-([2,2'-bipyrimidine]-4-yl)-3-cyclobutyl 1-5-(3,5-dimethylisoxazol-4-yl)isoindolin-1-one (Compound I-22)

[0130] Compound 2-2 (50 mg, 0.18 mmol), 4-chloro-2,2'-bipyrimidine (38 mg, 0.20 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xphos (4 mg, 0.01 mmol), and cesium carbonate (115 mg, 0.36 mmol) were dissolved in 1,4-dioxane (3 mL), replaced with nitrogen, and heated to 100°C with stirring for 6 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH = 10:1) to obtain 43 mg of the target compound as a light yellow solid. LCMS: M+H + =439.5. 1 HNMR (400MHz, CDCl3): δ9.05 (s, 2H), 8.95 (s, 1H), 8.61–8.56 (d, J = 6Hz, 1H), 8.03–8.00 (d, J = 8.4Hz, 1H), 7.49–7.45 (t, J = 4.8Hz, 1H), 7.45–7.40 (d ,J=7.2Hz,2H),6.11–6.07(d,J=6.8Hz,1H),3.06-2.94(m,1H),2.48(s,3 H),2.34(s,3H),2.31-2.24(m,1H),1.84-1.72(m,4H),1.63-1.55(m,1H).

[0131] Example 3:

[0132] Synthesis of 6-([2,2'-bipyrimidinyl]-4-yl)-7-cyclobutyl-2-cyclopropyl-2-methyl-6,7-dihydro-5H-[1,3]dioxo[4,5-isoindolin-5-one (Compound I-27)

[0133]

[0134] Step 1: Synthesis of methyl 2-formyl-4,5-dimethoxybenzoate (Compound 3-1)

[0135] Methyl 3,4-dimethoxybenzoate (50 g, 255 mmol) and dichloro(methoxy)methane (58.6 g, 510 mmol) were dissolved in dichloromethane (300 mL) and cooled in an ice bath. Tin tetrachloride (132.8 g, 510 mmol) was added dropwise under nitrogen protection, and the temperature was raised to 40°C and stirred for 6 h. The reaction solution was slowly poured into water (2000 mL), and ethyl acetate (2000 mL) was added to separate the layers. Solid sodium bicarbonate was added to adjust the pH of the aqueous phase to 7-8. The suspension was filtered through celite, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with 100 mL of (PE:EA=5:1) and filtered to obtain compound 3-1 as a gray solid (50.1 g).

[0136] Step 2: Synthesis of methyl (E)-2-(((tert-butylsulfinyl)imino)methyl)-4,5-dimethoxybenzoate (Compound 3-2)

[0137] Compound 3-1 (20 g, 89.2 mmol), (S)-2-methylpropane-2-sulfamide (13 g, 107 mmol), and copper sulfate (71.2 g, 446 mmol) were dissolved in 1,2-dichloroethane (200 mL), heated to 80°C, and stirred for 3 h. The reaction solution was cooled, poured into water (1000 mL), and extracted with ethyl acetate (1000 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried through 60 mL of (PE:EA = 5:1) and filtered to obtain compound 3-2 as a brown solid (26.5 g).

[0138] Step 3: Synthesis of 3-cyclobutyl-5,6-dimethoxyisoindolin-1-one (Compound 3-3)

[0139] Compound 3-2 (1 g, 3.05 mmol) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, and cooled in an ice bath. Cyclobutylmagnesium bromide (0.5 M, 14 mL, 7.10 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 2 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with 10 mL of (PE:EA = 5:1) and filtered to obtain compound 3-3 as a gray solid (550 mg).

[0140] Step 4: Synthesis of 3-cyclobutyl-5,6-dihydroxyisoindolin-1-one (Compound 3-4):

[0141] Compound 3-3 (200 mg, 0.81 mol) was dissolved in DCM (2 mL, dry) under nitrogen protection. Boron tribromide (4 mL, 20 v) was added dropwise at room temperature (about 20°C) over a period of about 10 min; the above temperature was maintained and stirred overnight. TLC analysis showed that the conversion of the raw material was complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and sodium chloride solution (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 3-4 as a brown solid (160 mg). LCMS: M+H + =220.4.

[0142] Step 5: Synthesis of 7-cyclobutyl-2-cyclopropyl-2-methyl-6,7-dihydro-5H-[1,3]dioxacyclo[4,5-and]isoindolin-5-one (Compound 3-5)

[0143] Compound 3-4 (160 mg, 0.73 mmol), cyclopropylacetylene (73 mg, 1.10 mmol), triphenylphosphine (18 mg, 0.07 mmol), Ru3(CO) 12 (128 mg, 0.20 mmol) was dissolved in toluene (4 mL), replaced with nitrogen, and heated to 100 ° C. and stirred for 6 h. TLC detection showed that the raw material was basically converted. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and sodium chloride solution (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography preparative plate (PE: EA = 2: 1) to obtain the target compound 3-5 as a brown solid 40 mg, LCMS: M+H + =286.4.

[0144] Step 6:

[0145] Synthesis of 6-([2,2'-bipyrimidinyl]-4-yl)-7-cyclobutyl-2-cyclopropyl-2-methyl-6,7-dihydro-5H-[1,3]dioxolane[4,5-and]isoindolin-5-one (Compound I-27)

[0146] Compound 3-5 (50 mg, 0.18 mmol), 4-chloro-2,2'-bipyrimidine (37 mg, 0.19 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xphos (4 mg, 0.01 mmol) and cesium carbonate (114 mg, 0.35 mmol) were dissolved in 1,4-dioxane (3 mL), replaced with nitrogen, and heated to 90°C with stirring for 6 h. TLC analysis showed that the conversion of the starting materials was essentially complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and sodium chloride solution (50 mL) in sequence, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH=10:1) to obtain 27 mg of the target compound as a light yellow solid. LCMS: M+H + =442.5. 1 HNMR (400MHz, DMSO-d6): δ9.03(d,J=4.8Hz,2H),8.90(d,J=6Hz,1H),8.40(d,J=5.6Hz,1H),7.66(t,J=4.8Hz,1H),7.19(d,J=3.2Hz,2H),5.69(dd, J1=6.4Hz, J2=3.2Hz,1H),3.01-2.95(m,1H),2.11-2.00(m,1H),1.72(s,2 H),1.67(s,2H),1.63-1.60(m,3H),1.55-1.46(m,2H),0.55-0.48(m,4H).

[0147] Embodiment 4:

[0148] Synthesis of 6-([2,2'-bipyrimidinyl]-4-yl)-2,7-dicyclobutyl-2-methyl-6,7-dihydro-5H-[1,3]dioxo[4,5-isoindolin-5-one (Compound I-28)

[0149]

[0150] Step 1: Synthesis of 2,7-dicyclobutyl-2-methyl-6,7-dihydro-5H-[1,3]dioxo[4,5-and]isoindolin-5-one (Compound 4-2):

[0151] 3-Cyclobutyl-5,6-dihydroxyisoindolin-1-one (100 mg, 0.46 mmol), cyclobutaneacetylene (55 mg, 0.69 mmol), triphenylphosphine (12 mg, 0.046 mmol), Ru3(CO) 12 (73 mg, 0.11 mmol) was dissolved in toluene (2 mL), replaced with nitrogen, and heated to 70°C with stirring for 6 h. TLC analysis showed that the starting material was essentially converted. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and sodium chloride solution (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (PE:EA = 10:1 → 3:1) to obtain the target compound 4-2 as a brown solid (108 mg). 1 H NMR (400MHz, DMSO-d6): δ7.10(s,1H),6.69(s,1H),6.25(s,1H),4.39(d,J=6.8Hz,1H),2.90-2.78(m,1H),2.60-2. 50(m,1H),2.25-2.12(m,1H),2.10-1.95(m,5H),1.92-1.84(m,2H),1.83-1.77(m,3H),1.55(s,2H),1.521(s,2H).

[0152] Step 2:

[0153] Synthesis of 6-([2,2'-bicyclo]-4-yl)-2,7-dicyclobutyl-2-methyl-6,7-dihydro-5H-[1,3]dioxolane[4,5-and]isoindolin-5-one (Compound I-28)

[0154] Compound 4-2 (100 mg, 0.33 mmol), 4-chloro-2,2'-bipyrimidine (71 mg, 0.37 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), Xphos (8 mg, 0.02 mmol) and cesium carbonate (218 mg, 0.67 mmol) were dissolved in 1,4-dioxane (3 mL), replaced with nitrogen, and heated to 90°C with stirring for 10 h. TLC analysis showed that the conversion of the starting materials was essentially complete. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and sodium chloride solution (50 mL) in sequence, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH=10:1) to obtain 12 mg of the target compound as a light yellow solid. LCMS: M+H + =456.5. 1HNMR (400MHz, DMSO-d6): δ9.06(d,J=4.4Hz,2H),8.93(d,J=5.2Hz,1H),8.44(d,J=5.6Hz,1H),7.69(t,J=4.8Hz,1H),7.25(d,J=2Hz,2 H), 5.72 (t, J = 6.4Hz, 1H), 3.06-2.92 (m, 2H), 2.15-1.93 (m, 6H), 1.80-1.70 (m, 2H), 1.68-1.64 (m, 3H), 1.67 (s, 2H), 1.55-1.45 (m, 2H).

[0155] Example 5:

[0156] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-1-cyclobutyl-5,6-dimethoxy-1,2-dihydro-3H-indazol-3-one (Compound I-35)

[0157]

[0158] Step 1: Synthesis of 2-bromo-N'-cyclobutyl-4,5-dimethoxybenzohydrazide (Compound 5-1)

[0159] 2-Bromo-4,5-dimethoxybenzoic acid (387 mg, 1.49 mmol), cyclobutylhydrazine hydrochloride (220 mg, 1.79 mmol), HATU (680 mg, 1.79 mmol), and diisopropylethylamine (579 mg, 4.48 mmol) were dissolved in N,N-dimethylformamide (4 mL) and stirred at room temperature for 2 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography on a preparative plate (DCM:MeOH = 20:1) to obtain the target compound 5-1 as a light yellow solid (70 mg). 1 HNMR (400MHz, DMSO-d6): δ9.66(d,J=6.4Hz,1H),7.16(s,1H),6.93(s,1H),5.14(t,J=6.6Hz,1H ),3.80(s,3H),3.77(s,3H),3.55(dt,J=14.2,7.9Hz,1H),2.05–1.89(m,4H),1.70–1.49(m,2H).

[0160] Step 2: Synthesis of 1-cyclobutyl-5,6-dimethoxy-1,2-dihydro-3H-indazol-3-one (Compound 5-2)

[0161] Compound 5-1 (70 mg, 0.21 mmol), cuprous iodide (0.4 mg, 0.5% mmol), L-proline (14 mg, 20% mmol), and potassium carbonate (58 mg, 0.42 mmol) were dissolved in dimethyl sulfoxide (1 mL), replaced with nitrogen, and heated to 50°C with stirring for 1 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative column chromatography (DCM:MeOH = 20:1) to obtain the target compound 5-2 as a light yellow solid (32 mg).

[0162] Step 3: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-1-cyclobutyl-5,6-dimethoxy-1,2-dihydro-3H-indazol-3-one (Compound I-35)

[0163] Compound 5-2 (60 mg, 0.24 mmol), 4-chloro-2,2'-bipyrimidine (50 mg, 0.26 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and cesium carbonate (156 mg, 0.48 mmol) were dissolved in 1,4-dioxane (2 mL), replaced with nitrogen, and heated to 100°C with stirring for 2 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH = 20:1) to obtain 55 mg of the target compound as a light yellow solid. 1 HNMR (400MHz, DMSO-d6): δ8.94(d,J=4.8Hz,3H),7.61(t,J=12.0Hz,1H),7.30(d,J=5.8Hz,1H),7.22(s,1H),6.86 (s,1H),5.24(t,J=8.2Hz,1H),3.87(s,3H),3.68(s,3H),2.58–2.52(m,2H),2.45–2.41(m,2H),1.86–1.76(m,2H).

[0164] Example 6:

[0165] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(cyclobutylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-4)

[0166]

[0167] Step 1: Synthesis of 3-(cyclobutylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound 6-2)

[0168] Methyl (E)-2-(((tert-butylsulfinyl)imino)methyl)-4,5-dimethoxybenzoate (1.5 g, 4.41 mmol) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, and cooled in an ice bath. Cyclobutylmethylmagnesium bromide (1 M, 13.5 mL, 13.5 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 2 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried through 10 ml of (PE:EA=5:1) and filtered to obtain compound 6-2 as a gray solid (550 mg).

[0169] Step 2: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(cyclobutylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-4)

[0170] Compound 6-2 (460 mg, 2.4 mmol), 4-chloro-2,2'-bipyrimidine (440 mg, 2.4 mmol), Pd2(dba)3 (659 mg, 0.72 mmol), Xantphos (416 mg, 0.72 mmol) and cesium carbonate (2.3 g, 7.2 mmol) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen, and heated to 100°C with stirring for 5 h. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (EA:MeOH=1:1) and further purified on a silica gel preparative plate (DCM:MeOH=10:1) to obtain 65 mg of the target compound as an off-white solid. M+H + =418.6. 1 HNMR (400MHz, CDCl3): δ9.04 (s, 2H), 8.62 (t, J = 6.0Hz, 1H), 7.44 (s, 1H), 7.3 5(d,J=2.0Hz,1H),6.91(s,1H),5.87-5.82(m,1H),5.60-5.51(m,0.5H),4.84 -4.78(m,1H),4.00(s,3H),3.97(s,3H),2.66–2.57(m,1H),2.21–2.05(m,1H) ,1.98–1.91(m,1H),1.77–1.71(m,2H),1.57–1.51(m,2H),1.15–0.93(m,1H).

[0171] Example 7:

[0172] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(cyclopropylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-1)

[0173]

[0174]

[0175] Step 1: Synthesis of 3-(cyclopropylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound 7-2)

[0176] Methyl (E)-2-(((tert-butylsulfinyl)imino)methyl)-4,5-dimethoxybenzoate (Compound 7-1, 1.2 g, 3.67 mmol) was dissolved in dichloromethane (10 mL), replaced with nitrogen, and cooled in an ice bath. (Cyclopropylmethyl)magnesium bromide (0.5 M, 15.0 mL, 7.33 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 16 h. The reaction solution was poured into a saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain 350 mg of a brown solid.

[0177] Step 2: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(cyclopropylmethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-1)

[0178] Compound 7-2 (100 mg, 0.41 mmol), 4-chloro-2,2'-bipyrimidine (86 mg, 0.45 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (9 mg, 0.016 mmol) and cesium carbonate (263 mg, 0.81 mmol) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen, and heated to 90 ° C. and stirred for 5 h. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a preparative plate (DCM:MeOH=10:1) to obtain 71 mg of the target compound as an off-white solid. M+H + =404.5. 1HNMR (400MHz, CDCl3): δ9.03(d,J=4.8Hz,2H),8.91(d,J=5.6Hz,1H),8.63(d,J=5.6Hz,1H),7.45(t,J=4.8Hz,1H),7.35(s,1H),6.94(s,1H), 5.90-5.88(m,1H),5.66-5.55(m,1H),4.87-4.80(m,2H),4.01(s,3H), 3.96(s,3H),2.75–2.66(m,1H),2.24–2.16(m,1H),1.84–1.74(m,2H).

[0179] Example 8:

[0180] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-5,6-dimethoxy-3-(1-methyl-2-oxopyrrolidin-3-yl)isoindolin-1-one (Compound I-11)

[0181]

[0182]

[0183] Step 1: Synthesis of methyl 2-(((tert-butylsulfinyl)amino)(1-methyl-2-oxopyrrolidin-3-yl)methyl)-4,5-dimethoxybenzoate (Compound 8-2)

[0184] Dissolve 1-methylpyrrolidin-2-one (0.91 g, 9.15 mol) in THF (5 mL, dry) under nitrogen atmosphere and cool to -70-78°C. Add nBuLi (1.6 M, 5.8 mL, 9.15 mol) dropwise over approximately 10 minutes and maintain the same temperature with stirring for 1 hour. Dissolve (E)-methyl 2-(((tert-butylsulfinyl)imino)methyl)-4,5-dimethoxybenzoate (Compound 8-1, 1.00 g, 3.25 mmol) in tetrahydrofuran (10 mL, dry) under nitrogen atmosphere and cool to -70-78°C. Add the solution dropwise to the previously prepared lithium reagent solution and maintain the same temperature with stirring for approximately 10 minutes. Maintain the same temperature with stirring for 2 hours and then check by TLC to confirm complete conversion of the Schiff base compound 8-1. The reaction solution was poured into saturated ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH=10:1) to obtain the target compound 8-2 as a light yellow oil (600 mg). LCMS: M+H + =427.6.

[0185] Step 2: Synthesis of 5,6-dimethoxy-3-(1-methyl-2-oxopyrrolidin-3-yl)isoindolin-1-one (Compound 8-3)

[0186] Compound 8-2 (400 mg, 0.94 mmol) was dissolved in methanol (5 mL), and methanolic hydrochloric acid (5 M, 5 mL) was added, and the mixture was stirred at room temperature for 0.5 h. After TLC analysis, the reaction mixture was poured into saturated sodium bicarbonate to quench the reaction, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH=10:1) to obtain the target compound 8-3 as a brown oil (50 mg). LCMS: M+H + =291.5.

[0187] Step 3: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-5,6-dimethoxy-3-(1-methyl-2-oxopyrrolidin-3-yl)isoindolin-1-one (Compound I-11)

[0188] Compound 8-3 (50 mg, 0.17 mmol), 4-chloro-2,2'-bipyrimidine (36 mg, 0.19 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xphos (4 mg, 0.01 mmol) and cesium carbonate (115 mg, 0.34 mmol) were dissolved in 1,4-dioxane (3 mL), replaced with nitrogen, and heated to 100°C with stirring for 6 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography on a preparative plate (DCM:MeOH=10:1) to obtain 55 mg of the target compound as a light yellow solid. LCMS: M+H + =447.5. 1 H NMR (400MHz, DMSO-d6): δ9.07 (s, 2H), 8.95 (s, 1H), 8.65 (d, J = 5.2Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.08 (s, 1H), 6.29 (s, 1H), 4.0 2(s,3H),4.01(s,3H),3.35-3.34(m,1H),3.19-3.17(m,1H),3.08-3.06(m,1H),2.38(s,3H),2.21–2.19(m,1H),1.88–1.76(m,1H).

[0189] Example 9:

[0190] Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(2-(benzyloxy)ethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-8)

[0191]

[0192] Step 1: Synthesis of (Z)-N-(3-(benzyloxy)propylidene)-2-methylpropane-2-sulfamide (Compound 9-1)

[0193] 3-(Benzyloxy)propanal (1.00 g, 6.09 mol), (S)-2-methylpropane-2-sulfamide (0.89 g, 7.31 mol), and anhydrous magnesium sulfate (3.67 g, 30.45 mol) were added to dichloromethane (30 mL) under nitrogen and stirred at room temperature for 16 hours. The concentrated sample was separated by silica gel column chromatography (PE:EA = 10:1) to obtain the target compound 9-1 as a colorless oil (1.30 g).

[0194] Step 2: Synthesis of tert-butyl 2-bromo-4,5-dimethoxybenzoate (Compound 9-2)

[0195] 2-Bromo-4,5-dimethoxybenzoic acid (3.00 g, 1.49 mmol), 2-bromo-2-methylpropane (15.75 g, 114.90 mmol), potassium carbonate (10.32 g, 74.69 mmol), and triethylbenzyl ammonium chloride (2.62 g, 11.49 mmol) were added sequentially to N,N-dimethylformamide (60 mL) and stirred at 40-50°C for 16 h. TLC confirmed complete conversion of the starting materials. The reaction mixture was quenched by pouring into water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, compound 9-2. The crude product was separated by column chromatography (PE:EA = 20:1) to obtain 300 mg of the target compound as a colorless oil.

[0196] Step 3: Synthesis of 3-(2-(benzyloxy)ethyl)-5,6-dimethoxyisoindolin-1-one (Compound 9-3)

[0197] Compound 9-2 (200 mg, 0.63 mmol) and compound 9-1 (185 mg, 0.69 mmol) were added to a reaction flask and the atmosphere was fully replaced with nitrogen. Tetrahydrofuran (3 mL, dry) was added and the mixture was cooled to -70 to -78 °C. Bulk lithium (1.6 M, 0.7 mL, 0.69 mmol) was added dropwise while maintaining the above temperature. The mixture was stirred for 3 h after the addition, and then naturally warmed to rt and stirred overnight. The reaction solution was poured into saturated ammonium chloride for quenching and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was separated on a silica gel preparative plate to obtain compound 9-3 as a brown waxy solid (70 mg). LCMS: M+H+ =328.4.

[0198] Step 4: Synthesis of 2-([2,2'-bipyrimidinyl]-4-yl)-3-(2-(benzyloxy)ethyl)-5,6-dimethoxyisoindolin-1-one (Compound I-8)

[0199] Compound 9-3 (70 mg, 0.21 mmol), 4-chloro-2,2'-bipyrimidine (45 mg, 0.24 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xphos (5 mg, 0.011 mmol) and cesium carbonate (139 mg, 0.43 mmol) were dissolved in 1,4-dioxane (3 mL), replaced with nitrogen, and heated to 90°C with stirring for 6 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated on a secondary preparative plate (DCM:MeOH=10:1) to obtain 29 mg of the target compound as a light yellow solid. LCMS: M+H + =484.5. 1 HNMR (400MHz, DMSO-d6): δ9.07 (s, 2H), 8.95 (s, 1H), 8.65 (d, J = 5.2Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.08 (s, 1H), 6.29 (s, 1H), 4.0 2(s,3H),4.01(s,3H),3.35-3.34(m,1H),3.19-3.17(m,1H),3.08-3.06(m,1H),2.38(s,3H),2.21–2.19(m,1H),1.88–1.76(m,1H).

[0200] Example 10. In vitro biological activity studies

[0201] Test compounds: Compound Examples 1-9 of the present invention (compound I-17, compound I-22, compound I-27, compound I-28, compound I-35, compound I-4, compound I-1, compound I-11, compound I-8), and control racemic compounds:

[0202]

[0203] In vitro biological activity study method: HepG2.2.15 cells were plated in 96-well plates at a rate of 1.5×10 4Cells were plated at 100 cells / well. On the second day, the cells were treated with the compound, diluted 3-fold, at 8 concentrations, and assayed in duplicate. The final DMSO concentration in the culture medium was 0.5%. On the fifth day, the culture medium containing the compound was replaced with fresh medium. On the eighth day, the supernatant was collected and assayed for HBsAg in the cell supernatant by ELISA. Percent inhibition was calculated relative to the blank control. Results are shown in Table 1.

[0204] Table 1. Inhibitory activity of compounds against HBsAg:

[0205] Example ID (racemic compound) <![CDATA[EC 50 (nM)]]> Example 1 13.8 Example 3 3.0 Example 6 1.9 Example 7 3.3 Control compound 6.9

[0206] Conclusion: The second-generation HBV RNA destabilizing agents prepared in Examples 1, 3, 6, and 7 have excellent HBsAg inhibitory activity, with some compounds having an activity at the single-digit nanomolar level, and have good clinical application prospects.

[0207] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

[0208] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

Claims

1. A bipyrimidine heterocyclic compound having a structure represented by formula (I), a racemic compound or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: (1) R1 is selected from the following groups: unsubstituted or substituted: C 6-12 Aromatic carbon ring, C 6-12 Aromatic carbon ring C 1-3 Alkyl, C 2-12 Heterocyclic, C 2-12 Heterocycle C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl or benzyloxy C 1-3 Alkyl; wherein the substituents used are selected from F, Cl, Br, I, unsubstituted or substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, unsubstituted or substituted C 3-6 Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups; (2) A is selected from CH or N; (3)R2, R5, R6, R7, R8, R9, R 10 independently selected from H, F, Cl, Br, I, C 1-6 Alkyl or halogenated C 1-6 alkyl; (4) R3 and R4 are independently selected from H, F, Cl, Br, I, and the following groups which are unsubstituted or substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heterocycle; wherein the substituents used are selected from F, Cl, Br, I, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups; Alternatively, R3, R4 and the carbon atoms on the benzene ring to which they are attached together form a 4-8 membered heterocyclic ring; (5) When R3 and R4 are independently selected from H, F, Cl, Br, I, and the following groups which are unsubstituted or substituted: 1-6 Alkyl, C 1-6 When alkoxy and A is selected from CH, R1 is selected from the following groups which are unsubstituted or substituted: C 2-12 Heterocycle C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl or benzyloxy C 1-3 Alkyl, n is 0, 1, 2 or 3, R 11 For O, R 12 For CH2 or Among them, the substituents used in R1, R3, and R4 are independently selected from F, Cl, Br, I, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkanes, unsubstituted or substituted C 6-12 Aryl, unsubstituted or substituted C 3-12 one or more of heteroaryl groups; (6) C 3-12 Heteroaryl, C 2-12 Heterocyclic, C 2-6 The heteroatoms in the heterocyclic ring or the 4- to 8-membered heterocyclic ring are independently selected from one or more of N, O and S.

2. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following groups: unsubstituted or substituted: phenyl, naphthyl, phenyl C 1-3 Alkyl, naphthyl C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered oxygen heterocycle C 1-3 Alkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, benzyloxy C 1-3 alkyl, The substituents used are selected from one or more of F, Cl, Br, I, methyl, ethyl, n-propyl and isopropyl.

3. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R1 is selected from the following groups:

4. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R2, R5, R6, R7, R8, R9, R 10 are independently H, F, Cl, or methyl; further, R2, R5, R6, R7, R8, R9, R 10 Both are H.

5. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R3 and R4 are independently selected from H, F, Cl, Br, I, and the following groups which are unsubstituted or substituted: methoxy, ethoxy, propoxy, R 13 、R 17 Independently selected from C 1-6 Alkyl, R 14 、R 15 、R 16 Independently selected from H, C 1-6 Alkyl, X is N or CH; wherein the substituent used is selected from one or more of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, phenyl, pyrazole, pyrimidine, thiazole, thiophene, furan, and pyrrole.

6. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 5, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R3, R4 are independently selected from H, F, Cl, Br, methoxy, ethoxy, 7. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: The bipyrimidine heterocyclic compound is shown in the following formula (II): In formula (II), m is 1, 2 or 3, t and s are independently 0, 1, 2 or 3, and t and s are not 0 at the same time, and Y1 is H, F, Cl, Br, C 1-6 Alkyl or halogenated C 1-6 Alkyl, Y2 is CH2, CF2, SO2, S or O, and A, R2, R3, R4, R5, R6 and R7 are as defined in the preceding claims.

8. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: R3, R4 and the carbon atoms on the benzene ring to which they are connected together form a 5-membered oxygen heterocycle or a 6-membered oxygen heterocycle.

9. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 8, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: The bipyrimidine heterocyclic compound is represented by the following formula (III) or formula (IV): In formula (III), p is 0, 1, 2 or 3, and Y3 is C 1-6 Alkyl or halogenated C 1-6 Alkyl, A, R1, R2, R5, R6, R7 are as defined in the preceding claims; In formula (IV), among Y4 and Y5, one is selected from H, C 1-6 Alkyl or halogenated C 1-6 Alkyl, the other p is 0, 1, 2 or 3, and A, R1, R2, R5, R6, and R7 are defined as in the preceding claims.

10. The bipyrimidine heterocyclic compound having the structure represented by formula (I) according to claim 1, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: The bipyrimidine heterocyclic compound is selected from the following compounds:

11. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the bipyrimidine heterocyclic compound having a structure represented by formula (I) according to any one of claims 1 to 10, its racemic compound or stereoisomer, and pharmaceutically acceptable salt; Preferably, the pharmaceutical composition is a pharmaceutical preparation, and the pharmaceutical preparation is selected from tablets, powders, capsules, granules, oral liquids, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions, and nano preparations.

12. The pharmaceutical composition according to claim 11, characterized in that: The pharmaceutical composition is an antiviral pharmaceutical composition, which optionally further includes one or more therapeutic agents, wherein the therapeutic agents are selected from the following group: nucleoside drugs, capsid inhibitors, PD-L1 agonists, TLR-7 or TLR-8 or TLR-9 agonists, oligonucleotides or other antiviral drugs.

13. The pharmaceutical composition according to claim 11, characterized in that: The pharmaceutical composition is composed of the following mass ratios: The bipyrimidine heterocyclic compound having the structure shown in formula (I), its racemic compound or stereoisomer, and pharmaceutically acceptable salt thereof are 5-95% 14. Use of a combination of one or more of the bipyrimidine heterocyclic compound having a structure represented by formula (I) according to any one of claims 1 to 10, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, and the pharmaceutical composition according to any one of claims 11 to 13 in the preparation of a medicament for preventing and / or treating a viral infectious disease, wherein the viral infectious disease is preferably an infectious disease caused by hepatitis B virus.

15. A method for preparing the bipyrimidine heterocyclic compound having the structure represented by formula (I) according to any one of claims 1 to 10, its racemic compound or stereoisomer, or pharmaceutically acceptable salt, characterized in that: The preparation method comprises synthesizing the bipyrimidine heterocyclic compound by the following route: In the above formula, A, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 The definitions are the same as those in the preceding claims.

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