Hnrnpa2b1 agonist and tumor prevention and treatment application of co-administration of same and immune checkpoint inhibitor

Abstract

Provided are a heterogeneous nuclear ribosomal protein A2B1(hnRNPA2B1)hnRNPA2B1 agonist compound and an anti-tumor application of the co-administration of same and an immune checkpoint inhibitor. Specifically, a condensed cyclic compound as represented by formula (I), a cis-trans isomer thereof, an enantiomer thereof, a diastereoisomer thereof, a racemate thereof, a solvate thereof, a hydrate or a pharmaceutically acceptable salt thereof or a prodrug thereof, a composition and product comprising any one of the foregoing, and a use of the described substances as an hnRNPA2B1 agonist in the preparation of a product for tumor prevention and / or treatment. The product can further comprise an immune checkpoint inhibitor or can be co-administered with an immune checkpoint inhibitor. The product an be used for broad-spectrum tumor prevention and treatment, and has a wide application prospect.

Description

hnRNPA2B1 Agonists and Their Application in the Prevention and Treatment of Tumors in Combination with Immune Checkpoint Inhibitors Technical Field The present disclosure relates to the fields of medicine and biotechnology. Specifically, the present disclosure relates to a class of compounds that act as agonists of the nuclear protein hnRNPA2B1 (i.e., heterogeneous nuclear ribonucleoprotein A2B1), products containing the compounds, and their effects, mechanisms of action, implementation methods, and uses in combination with immune checkpoint inhibitors in the prevention or treatment of diseases or symptoms related to tumors and injuries caused by tumors. Background Art Type I interferons are crucial for the functional regulation and activation of various immune cells and are key cytokines for regulating tumor immunity. Interferons can directly inhibit the proliferation of human tumor cells and can act synergistically with a variety of anti-tumor drugs. Type I interferons can significantly enhance the anti-tumor immune response by inducing the activation of adaptive and innate immune cells, especially by enhancing the uptake, processing, presentation, and cross-presentation of antigens by dendritic cells and macrophages to T cells to enhance the activation of T cells. At the same time, interferons can also inhibit tumor invasion by regulating the expression of proteins related to tissue remodeling. Therefore, interferons and compounds that can induce the production of interferons have great uses in tumor treatment. Programmed cell death 1 (PD1) and programmed cell death ligand 1 (PD-L1) are immune checkpoint proteins, and their interaction plays an important role in restricting T cell activity. They provide the main immune resistance mechanism by which tumor cells evade immune surveillance. A variety of reagents targeting the PD-1 / PD-L1 pathway have been developed and have been shown to be effective in treating various cancer types. In recent years, a large number of clinical trials involving combinations of PD-1 / PD-L1 checkpoint inhibitors with a wide range of other reagents have been conducted. Most of these are combinations of PD1 with CTLA4, angiogenesis inhibitors, or chemotherapeutic agents. The results of these trials have shown a variety of outcomes (Schmidt, E.V., Semin Immunopathol; 41(1), 21-30

[2019] ). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNP-A2B1) is a newly identified DNA recognition receptor in the cell nucleus in recent years and belongs to the hnRNP family. On the one hand, hnRNP-A2B1 can sense and recognize the nucleic acid components of DNA viruses (such as HSV-1, etc.), and It forms a homodimer through self-activation, undergoes demethylation mediated by the demethylase JMJD6, translocates from the nucleus to the cytoplasm, and then activates the TBK1-IRF3 signaling pathway to initiate the expression of type I interferon and exert an antiviral effect. On the other hand, as an RNA-binding protein, hnRNPA2B1 can also promote m6A modification, nucleocytoplasmic transport, and translation of cGAS, IFI16, and STING mRNAs, thus ensuring the sufficient induction and expression of type I interferon. hnRNPA2B1 is overexpressed in a variety of tumors, including lung cancer, liver cancer, breast cancer, pancreatic cancer, and glioblastoma, etc., and is generally considered an important factor promoting tumorigenesis and development. In recent decades, numerous studies have shown that hnRNPA2B1 is involved in regulating a variety of basic biological functions, such as regulating cell metabolism, migration and invasion, proliferation, and response to mitochondrial stress, etc. For example, the activation of the invasive phenotype mediated by hnRNPA2 involves different mechanisms, including alternative splicing of TP53INP2, activation of the CXCL12 / CXCR4 axis, and activation of invasive behavior after mitochondrial DNA depletion, where hnRNPA2, as a novel transcriptional co-activator, mediates this process through interactions with NF-κB, NFAT, CREB, and C / EBPδ. Generally speaking, hnRNPA2B1 is widely involved in the regulation of cancer cell phenotypes such as metabolism, proliferation, apoptosis, migration, and invasion through different molecular mechanisms. In addition, hnRNPA2B1 has been reported to induce epithelial-mesenchymal transition (EMT) in a variety of cancer cell lines. Moreover, hnRNPA2B1 is also involved in regulating basic cancer processes such as aerobic glycolysis. It has been reported that hnRNPA2 can regulate the alternative splicing of pyruvate kinase isoenzyme M2 (PKM2) and activate the metabolic switch of cancer cells to aerobic glycolysis. hnRNPA2B1 also plays an important role in the regulation of hypoxia. Generally speaking, hnRNPA2B1 is widely involved in the occurrence and development of a variety of tumors. Developing small molecules targeting hnRNPA2B1 will hopefully block the pro-tumor effect of hnRNPAB1 and provide effective assistance for tumor treatment. In clinical practice, the means of tumor treatment are becoming increasingly diverse, such as surgical treatment, radiotherapy, chemotherapy, endocrine therapy, targeted therapy, etc. However, due to the heterogeneity of tumors and the patient's tolerance to different therapies, it is difficult to achieve good results by relying solely on a single treatment method. At the same time, problems such as drug resistance will occur during the treatment process. Therefore, the combined treatment of tumors using two or more methods has become an important strategy. The immune system can recognize and kill tumor cells, while tumor cells can adopt different strategies to inhibit the human immune system and achieve immune escape. Immunotherapy has become a great hope for curing tumors, and the combined treatment including immunotherapy has become an important direction in this field. It is necessary to invent effective drugs to activate the immune system and cooperate with other therapies to more effectively kill and eliminate tumors. In summary, the development of specific agonists targeting hnRNPA2B1 and their combination with other anti-tumor therapies or drugs have great potential in the treatment of tumors. There is an urgent need in this field to develop an immunologically active substance that can initiate or promote the production of interferon, enhance the anti-tumor effect, and effectively prevent tumor metastasis, as well as its combination products and methods. Summary of the Invention The present disclosure provides fused-ring compounds having the structure shown in formula (I), their related derivatives (such as their cis-trans isomers, their enantiomers, their diastereoisomers, their racemates, their solvates, their hydrates, or their pharmaceutically acceptable salts or their prodrugs), and products containing the compounds or their related derivatives. The present disclosure also provides the uses of the compounds, derivatives, and products in the prevention and treatment of tumors, and further provides their uses in the treatment or prevention of tumors and related diseases or symptoms. The compounds, drugs, pharmaceutical compositions, or kits of the present disclosure can be used to effectively anti-tumor and control the occurrence and / or development of tumors. In some aspects of the present disclosure, there are provided fused-ring compounds shown in formula (I), their cis-trans isomers, their enantiomers, their diastereoisomers, their racemates, their solvates, their hydrates, or their pharmaceutically acceptable salts or their prodrugs, wherein L is -(CH2)n-, and n is an integer from 0 to 6; X is a halogen; R 1 is -NR 4 R 5 wherein R 4 and R 5 are each independently H or C 1-6 alkyl; R 2 and R 3 are each independently H or C 1-6 alkyl; or R2 and R 3 together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; The said C 1-6 alkyl group and the said 5- to 8-membered heterocycloalkyl group are unsubstituted or substituted by one or more substituent groups selected from the group consisting of: hydroxy, amino, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 alkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl C 1-6 alkyl, 6- to 10-membered aryl, 6- to 10-membered aryl C 1-6 alkyl or 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl C 1-6 alkyl. In some aspects of the present disclosure, there is provided the use of the compounds of the present invention in the preparation of a product for preventing and / or treating tumors, and the said product may further comprise an immune checkpoint inhibitor in combination with the said compound. In some aspects of the present disclosure, there is further provided a method for preventing and / or treating tumors, the said method comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of the compound or product of the present disclosure, which includes further comprising or administering an immune checkpoint inhibitor in combination with the said compound. In some aspects of the present disclosure, there is further provided the compound, composition or product of the present disclosure for preventing and / or treating tumors. In some aspects of the present disclosure, there is provided the use of the compound or product of the present disclosure in increasing the level of interferon (such as type I interferon, for example IFN-α and / or IFN-β). Those skilled in the art can make any combination of the foregoing technical solutions and technical features without departing from the inventive concept and protection scope of the present disclosure. Other aspects of the present disclosure will be apparent to those skilled in the art in view of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure will be further described below in conjunction with the accompanying drawings, wherein these illustrations are only for illustrating the embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Figure 1: Activation effect of the test compound on the nuclear export of hnRNPA2B1 in A549 lung cancer cells. Figure 2: Activation of TBK1 and IRF3 downstream of hnRNPA2B1 nuclear export by the test compound in A549 lung cancer cells. Figure 3: Detection of the activation of type I interferon (IFN-β) in tumor cells by the compound using ELISA method. Figure 4: Combined inhibition of LLC tumor growth by the test compound and the immune checkpoint inhibitor anti-PD-1 antibody growth. Figure 5: Reversal of the unresponsiveness of B16F10 melanoma to the immune checkpoint inhibitor anti-PD-1 antibody by the test compound. Detailed implementation manners In this application, through a large number of research and development and experiments, a novel class of polycyclic compounds was discovered, which can specifically bind to the hnRNPA2B1 protein with high affinity and can further widely induce a higher level of IFN-β, and is thus defined as an hnRNPA2B1 agonist. In the anti-tumor tests of different types of tumor cells, the hnRNPA2B1 agonist compounds disclosed in this disclosure can significantly activate type I interferon in tumor cells, inhibit the proliferation of LLC tumors, and promote the survival of tumor-bearing mice. Moreover, since the hnRNPA2B1 agonist compounds disclosed in this disclosure can widely induce a higher level of IFN-β, it is expected that these compounds can play an anti-tumor role through the action of type I interferon. And when the compounds of this application are used in combination with immune checkpoint inhibitors, more type I interferon can be induced, and can significantly kill tumors and inhibit their growth. Therefore, this disclosure provides methods and strategies for jointly applying novel anti-tumor hnRNPA2B1 agonist compounds and immune checkpoint inhibitors to the prevention and treatment of inhibiting tumors. All numerical ranges provided herein are intended to clearly include all numerical values falling between the range endpoints and the numerical ranges therebetween. The features mentioned in this disclosure or the features mentioned in the embodiments can be combined. All features disclosed in this specification can be used in combination with any composition form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features. As used herein, "comprising", "having" or "including" includes "containing", "consisting essentially of...", "consisting substantially of...", and "consisting of..."; "consisting essentially of...", "consisting substantially of..." and "consisting of..." are subordinate concepts of "comprising", "having" or "including". hnRNPA2B1 agonist compound As used herein, the terms "hnRNPA2B1 protein (polypeptide)" and "hnRNPA2B1" are used interchangeably and refer to heterogeneous nuclear ribonucleoprotein A2B1. The hnRNPA2B1 protein involved in the present disclosure may be a protein encoded by the hnRNPA2B1 gene, its cDNA or CDS in an animal body (such as a human or a mouse, etc.), or a homologous sequence (such as a homologous sequence of hnRNPA2B1 can be obtained through databases or alignment software known in the art) of these proteins that has the effect of promoting interferon expression, a variant or a modified form. in an animal body (such as a human or a mouse, etc.), a protein encoded by the hnRNPA2B1 gene, its cDNA or CDS, or a homologous sequence (such as a homologous sequence of hnRNPA2B1 can be obtained through databases or alignment software known in the art) of these proteins that has the effect of promoting interferon expression, a variant or a modified form. As used herein, the terms "hnRNPA2B1 gene", "hnRNPA2B1 coding gene", "hnRNPA2B1 protein coding gene" or "nucleic acid molecule encoding hnRNPA2B1" are used interchangeably, and all refer to a nucleotide sequence encoding the hnRNPA2B1 protein or polypeptide described in the present disclosure, which may be, for example, the human hnRNPA2B1 gene of Gene ID: 3181, the mouse hnRNPA2B1 gene of Gene ID: 53379. This term also includes a molecule that hybridizes with the signed nucleic acid molecule under stringent conditions, or a family gene molecule that is highly homologous to the above molecule, and it is believed that the expression of the said gene has a certain promoting effect on the production and influence of interferon. The present disclosure provides a class of novel compounds as "agonists" (or "promoters") of hnRNPA2B1. The terms "agonist" or "hnRNPA2B1 agonist compound" are used interchangeably, and refer to a class of novel fused-ring compounds that can increase the level or activity of hnRNPA2B1, which can specifically bind to the hnRNPA2B1 protein with high affinity, and can further widely induce the production of a higher level of IFN-β, exerting the agonist effect of hnRNPA2B1. The hnRNPA2B1 agonist compound of the present disclosure can inhibit tumors, and thus can be further used for preventing or treating diseases related to tumors and / or related symptoms caused by tumors. The present application provides a fused-ring compound represented by formula (I), its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, wherein, L is -(CH2)n-, and n is an integer from 0 to 6; X is a halogen; R 1 is -NR 4 R 5 wherein R 4 and R 5 are each independently H or C 1-6 alkyl; R2 and R 3 are each independently H or C 1-6 alkyl; or R 2 and R 3 together with the N atom to which they are attached form a 5- to 8-membered heteroalkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; the C 1-6 alkyl and the 5- to 8-membered heteroalkyl group are unsubstituted or substituted by one or more substituent groups selected from the group consisting of: hydroxy, amino, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6-alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 alkyl, 3- to 6-membered heteroalkyl, 3- to 6-membered heteroalkyl C 1-6 alkyl, 6- to 10-membered aryl, 6- to 10-membered aryl C 1-6 alkyl or 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl C 1-6 alkyl. Preferably, X is F or Cl, more preferably, X is F. Preferably, L is -(CH2)n-, where n is 1, 2 or 3, more preferably, n is 2. Preferably, R 4 , R 5 are each independently H, methyl or ethyl. Preferably, R 2 and R 3 are each independently C 1-3 alkyl, preferably methyl, ethyl or isopropyl, the C 1-3 alkyl is unsubstituted or substituted by a 3- to 8-membered heteroalkyl group containing 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, more preferably, R 2 and R 3 are each independently C 1-3 alkyl, preferably methyl, ethyl or isopropyl, the C 1-3 alkyl is unsubstituted or substituted by a 4- to 6-membered heteroalkyl group containing 1 nitrogen heteroatom, most preferably, R 2 and R 3 are each independently C 1-3 alkyl, preferably methyl, ethyl or isopropyl, the C1-3 alkyl is unsubstituted or substituted by pyrrolidinyl. Preferably, R 2 and R 3Together with the N atoms to which they are attached, form a 5-8-membered heterocycloalkyl group containing 2 nitrogen atoms, said 5-8-membered heterocycloalkyl group being substituted by a 3-8-membered heterocycloalkyl C 1-6 alkyl or hydroxy C 1-6 alkyl; more preferably, R 2 and R 3 Together with the N atoms to which they are attached, form a 6-membered heterocycloalkyl group containing 2 nitrogen atoms, said 6-membered heterocycloalkyl group being substituted by a 4-6-membered heterocycloalkyl C 1-6 alkyl or hydroxy C 1-6 alkyl; further preferably, R 2 and R 3 Together with the N atoms to which they are attached, form a piperazinyl group, said piperazinyl group being substituted by a 4-6-membered heterocycloalkyl C 1-6 alkyl or hydroxy C 1-6 alkyl; most preferably, R 2 and R 3 Together with the N atoms to which they are attached, form a piperazinyl group, said piperazinyl group being substituted by a 5-6-membered heterocycloalkyl C 1-6 alkyl containing one N atom or by hydroxy C 1-6 alkyl; preferably, said piperazinyl group is substituted by pyrrolidinyl C 1-6 alkyl or by hydroxy C 1-6 alkyl; more preferably, said piperazinyl group is substituted by pyrrolidinylethyl substituted or by hydroxyethyl substituted. Preferably, the compound has the following formula (II): Wherein, R a , R b are each independently H or C 1-6 alkyl, preferably, R a , R b are each independently H, methyl or ethyl; M is -(CH2)n-, where n is 1, 2 or 3, more preferably, n is 2; X is F or Cl, more preferably, X is F; R c is hydroxy, amino, a 3-8-membered heterocycloalkyl group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, more preferably, R c is hydroxy or a 4-6-membered heterocycloalkyl group containing 1 nitrogen heteroatom, even more preferably, R c is hydroxy or pyrrolidinyl, most preferably, R c is hydroxy or 1-pyrrolidinyl. Preferably, the compound is selected from the group consisting of the following compounds or salts thereof (such as hydrochloride): Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following definitions. A particular term or phrase should not be considered indefinite or unclear merely because it is not specifically defined, but should be construed according to its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding article or active ingredient. The term "pharmaceutically acceptable" as used herein pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc., and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, etc.; salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compounds containing acid or base groups. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both. The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention. Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other. Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" are caused by the inability of double bonds or single bonds of ring-forming carbon atoms to rotate freely. Unless otherwise specified, the term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other. The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of tautomers may be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding units. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-en-2-one. The term "prodrug" generally refers to a functional group derivative of a compound of formula (I), and its derivative can be easily converted into a compound of formula (I) in vivo. Generally, the selection and preparation of suitable prodrugs can be referred to, for example, as described in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. The isotopes have the same number of atoms, but their atomic masses or mass numbers are different from the atomic masses or mass numbers that predominantly exist in nature. For example, a compound can be labeled with a radioactive isotope, such as deuterium ( 2 H), tritium ( 3H), iodine-125( 125 I), or C-14( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. Isotope variants may offer certain therapeutic advantages. For example, deuterium can replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than that formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic and side effects, increased drug stability, enhanced efficacy, and extended drug biological half-life, or they can provide standard compounds that can be used for the characterization of biological samples. Through conventional techniques well-known to those skilled in the art, or through methods similar to those described in the routes and examples of the present invention, using appropriate isotopically enriched reagents and / or intermediates, isotopically enriched compounds within the general formula (I) can be prepared without excessive experimentation. The term "optionally" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and this description includes the cases where the described event or condition occurs and the cases where the described event or condition does not occur. The nomenclature rules used in the present invention are based on the IUPAC system nomenclature generated by ChemDraw software. Any open valence bond appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures given in the present invention indicates the presence of a hydrogen atom. The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, which may include deuterium and variants of hydrogen, as long as the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxygen substitution does not occur on the re-aromatic group. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on what is chemically achievable. When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 0 - 2 Rs, the group may optionally be substituted by at most two Rs, and each R has independent options in each case. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in stable compounds. When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z. ​When the listed linking groups do not specify their linking directions, the linking directions are arbitrary. For example, the linking group L in at this time can link the benzene ring and the cyclopentyl group in the same direction as the reading order from left to right to form or can link the phenyl group and the cyclopentyl group in the opposite direction to the reading order from left to right to form The combination of the said linking group, substituent and / or its variant is only permitted if such a combination results in a stable compound. Permitted. Unless otherwise specified, the number of atoms in a ring is usually defined as the ring size. For example, "3-7 membered ring" refers to a "ring" composed of 3-7 atoms arranged in a ring. Unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine and iodine. Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C6 and C5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 2-4 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc. 1-6 Unless otherwise specified, the term "C alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-3 and C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-3 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc. Unless otherwise specified, the term "C 2-6"Alkenyl" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position in the group. The C 2-6 alkenyl includes C 2-4 、C 2-3 、C4, C3, C2 alkenyl, etc.; it can be monovalent, divalent or polyvalent. C 2-6 Examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, etc. Unless otherwise specified, the term "C 1-6 alkoxy" denotes those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-6 alkyl includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4 and C3 alkoxy, etc.; C 1-6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc. Unless otherwise specified, the term "C 1-6 alkylamino" denotes those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. The C 1-6 alkyl includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4, C3 and C2 alkylamino, etc.; C 1-6 Examples of alkylamino include, but are not limited to -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, -NHCH2CH2CH3, -NHCH(CH3)2, -NHCH2CH2CH2CH3, etc. Unless otherwise specified, the term "C 3-6 cycloalkyl" denotes a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system. The C 3-6 cycloalkyl includes C 3-5 、C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. C 3-6Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Unless otherwise specified, the term "3-8 membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated monocyclic group composed of 3 to 8 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). In addition, with respect to the "3-8 membered heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 7-8 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuryl (including tetrahydrofuran-2-yl), piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, etc. Unless otherwise specified, the terms "6-10 membered aromatic ring" and "6-10 membered aryl" can be used interchangeably, and the term "6-10 aryl" represents a monovalent aromatic carbocyclic ring system containing 6-10 carbon atoms and having at least one aromatic ring or at least one of the rings therein being an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, biphenyl or indanyl, etc. Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" of the present invention can be used interchangeably, and the term "5-10 membered heteroaryl" represents a cyclic group having a conjugated π electron system composed of 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic and fused bicyclic system, wherein at least one of the rings in the system is aromatic. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). The 5-10 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-10 membered heteroaryl includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, etc. Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 2-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indazolyl (including 5-indazolyl, etc.), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl, 6-quinolinyl, etc.), and so on. Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl group" in the present invention can be used interchangeably. The term "5-6 membered heteroaryl group" refers to a cyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Among them, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) z , z is 1 or 2). The 5-6 membered heteroaryl group can be connected to the rest of the molecule through a heteroatom or a carbon atom, and the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups, etc. Examples of the 5-6 membered heteroaryl group include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), etc. Unless otherwise specified, C n-n+m or C n-Cn+m in any specific case including from n to n + m carbons, such as C including C1, C2, C3, C4, C5, C6, and C7, and also including any range from n to n + m, such as C 1-7 including C 1-7 including C 1-3 , C 1-6 , C 3-6 , C 4-7 , and C 5-7 etc.; similarly, n - to n + m - membered rings mean rings having from n to n + m atoms in the ring, such as 3 - to 7 - membered rings including 3 - membered, 4 - membered, 5 - membered, 6 - membered, and 7 - membered rings, and also including any range from n to n + m, such as 3 - to 7 - membered rings including 3 - to 6 - membered rings, 4 - to 7 - membered rings, 5 - to 7 - membered rings, and 6 - to 7 - membered rings, etc. Preparation method The present invention also relates to a method for producing a compound of general formula (I) as defined above. In some embodiments, the synthesis method of the compounds of the present application is as shown in the figure: When X is selected from halogens other than Br, such as F, Cl, I, etc., the method comprises the following steps: a) Brominating a compound of formula I - a with a brominating reagent to form a compound of formula I - b. Preferably, the brominating reagent includes but is not limited to N - bromosuccinimide (NBS) or 1,3 - dibromo - 5,5 - dimethylhydantoin. Preferably, the reaction temperature is 0 - 30°C; b) Substituting one Br atom in the compound of formula I - b with another halogen atom to obtain a compound of formula I - c. Preferably, step b) is carried out using and a strong base of metal - organic salt at low temperature, where X is a halogen other than Br, such as F, Cl, I. More preferably, the strong base of metal - organic salt is n - butyllithium. Preferably, the reaction temperature is - 78°C; c) Oxidizing the compound of formula I - c with an oxidizing agent to form a compound of formula I - d. Preferably, the oxidizing agent includes but is not limited to K2Cr2O7. Preferably, the reaction temperature is 60 - 150°C; d) Reacting the compound of formula I - d with H2N - L - R 1 to obtain a compound of formula I - e. Preferably, the reaction temperature is 50 - 150°C; e) Reacting the compound of formula I - e with R 2 R 3 NH to obtain a compound of formula I. Preferably, the reaction is carried out in the presence of the catalyst bis(triphenylphosphine)palladium(II) chloride. Preferably, the reaction temperature is 20 - 150°C. When X is selected from Br, the method comprises: a) brominating a compound of formula I-a with a brominating reagent to form a compound of formula I-b, preferably, the brominating reagent includes but is not limited to N-bromosuccinimide (NBS), preferably, the reaction temperature is 0-30 °C; c) oxidizing the compound of formula I-b with an oxidizing agent to form a compound of formula I-d, preferably, the oxidizing agent includes but is not limited to K2Cr2O7, preferably, the reaction temperature is 60-150 °C; d) reacting the compound of formula I-d with H2N-L-R1 to obtain a compound of formula I-e, preferably, the reaction temperature is 50-150 °C; e) reacting the compound of formula I-e with R 2 R 3 NH to obtain a compound of formula I, preferably, the reaction is carried out in the presence of the catalyst bis(triphenylphosphine)palladium(II) chloride, preferably, the reaction temperature is 20-150 °C. Alternatively, when X is selected from halogens other than Br, such as F, Cl, I, etc., the method comprises the following steps: f) brominating a compound of formula I-a with a brominating reagent to form a compound of formula I-b, preferably, the brominating reagent includes but is not limited to N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin, preferably, the reaction temperature is 0-30 °C; g) completely replacing the 2 Br atoms in the compound of formula I-b with other halogen atoms to obtain a compound of formula I-c, preferably, step b) is carried out using and a strong base of metal-organic salt at low temperature, where X is a halogen other than Br, such as F, Cl or I, more preferably, the strong base of metal-organic salt is n-butyllithium, preferably, the reaction temperature is -78 °C; h) oxidizing the compound of formula I-c’ with an oxidizing agent to form a compound of formula I-d’, preferably, the oxidizing agent includes but is not limited to K2Cr2O7, preferably, the reaction temperature is 60-150 °C; i) reacting the compound of formula I-d’ with H2N-L-R 1 to obtain a compound of formula I-e’, preferably, the reaction temperature is 50-150 °C; j) reacting the compound of formula I-e’ with R 2 R 3 NH to obtain a compound of formula I, preferably, the reaction is carried out in the presence of the catalyst bis(triphenylphosphine)palladium(II) chloride, preferably, the reaction temperature is 20-150 °C. As is known to those skilled in the art, certain active groups (such as -NH2, -OH, etc.) need to be routinely protected and deprotected when necessary, which is familiar to those skilled in the art. Immune checkpoint inhibitor According to the content disclosed in the present application and experimental verification, the compounds of the present application can be used in combination with immune checkpoint inhibitors to enhance their anti-tumor effects, preferably to produce a synergistic effect. Immune checkpoint inhibitors that can be used in combination with the hnRNPA2B1 agonist of the present application include, but are not limited to, one or more selected from the following group: PD1 / PD-L1 inhibitors, such as nivolumab (MDX-1106, Opdivo; Bristol-Myers Squibb), pembrolizumab (MK-3475, Keytruda, lambrolizumab, BMS-936558; Merck), dostarlimab (TSR-042 Tesaro, Inc.), cemiplimab (REGN-2810, Libtayo, Regeneron), EH12.2H7 (Bailerjin Company, catalog number 329902), batrilizumab (Agenus Inc), avelumab (Bavencio; Merck Serono, Pfizer), durvalumab (Imfinzi, AstraZeneca), BMS-936559, atezolizumab (Tecentriq, Genentech) or their equivalents. It should be understood that those of ordinary skill in the art can select immune checkpoint inhibitor active substances as needed based on the content disclosed in the present application and use them in combination with the hnRNPA2B1 agonist compounds of the present application. Product and its application The present disclosure also provides a product, which can be, for example, a drug, a pharmaceutical composition or a kit / cartridge, containing an effective amount of the hnRNPA2B1 agonist compound of the present disclosure, and a pharmaceutically or immunologically acceptable carrier. As used herein, the terms "active substance" or "active substance of the present disclosure" can be used interchangeably and refer to the hnRNPA2B1 agonist compound having the structural formula of formula (I) or its derivatives or products. The product of the present disclosure may further comprise an immune checkpoint inhibitor used in combination with the hnRNPA2B1 agonist compound. As used herein, the term "pharmaceutically acceptable" ingredient is a substance that is suitable for humans and / or animals without excessive adverse reactions (such as toxicity, irritation and allergic reactions), that is, a substance with a reasonable benefit / risk ratio. As used herein, the term "effective amount" refers to an amount that can produce a function or activity in humans and / or animals and can be accepted by humans and / or animals. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier for administering a therapeutic agent, including various excipients and diluents. This term refers to those pharmaceutical carriers which are not necessarily the active ingredient per se and which are not unduly toxic when administered. Suitable carriers are well known to those of ordinary skill in the art, and a full discussion of pharmaceutically acceptable excipients can be found in Remington’s Pharmaceutical Sciences, Mack Pub. Co., N.J. 1991. The pharmaceutically acceptable carrier in the composition may contain liquids such as water, saline, glycerol, and ethanol. Additionally, auxiliary substances may also be present in these carriers, such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting agents or emulsifiers, flavoring agents, pH buffering substances, etc. Generally, these substances can be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium, where the pH is usually about 5 - 8, and preferably, the pH is about 6 - 8. The active substance in the product of the present disclosure accounts for 0.001 - 99.9 wt% of the total weight of the composition; preferably 1 - 95 wt% of the total weight of the composition, more preferably 5 - 90 wt%, and even more preferably 10 - 80 wt%. The balance is pharmaceutically acceptable carriers and other additive substances. The hnRNPA2B1 agonist compound and the immune checkpoint inhibitor can be combined and applied in a ratio of 1:100 - 100:1. As used herein, the term "unit dosage form" refers to a dosage form prepared for convenient administration of the product of the present disclosure for single administration, including but not limited to various solid forms (such as tablets), liquid forms, capsules, sustained-release forms. In another preferred embodiment of the present disclosure, the product is in unit dosage form or multiple dosage forms, and the content of the active substance is 0.01 - 2000 mg / dose, preferably 0.1 - 1500 mg / dose, more preferably 1 - 1000 mg / dose. In another preferred example of the present disclosure, 1 - 6 doses of the composition of the present disclosure are administered per day, preferably 1 - 3 doses; most preferably, the daily dose is 1 dose. And, when used in combination, the composition may further contain a therapeutically effective amount of an immune checkpoint inhibitor, or the product containing the compound of the present application may be used in combination with the product containing an immune checkpoint inhibitor. It should be understood that the effective doses of the active substances such as the hnRNPA2B1 agonist compound and the immune checkpoint inhibitor used may vary depending on the severity of the subject to be administered or treated. The specific situation is determined according to the individual conditions of the subject (such as the subject's body weight, age, physical condition, the effect to be achieved), which is within the scope that can be judged by a skilled physician. The products of the present disclosure can be in solid state (such as granules, tablets, lyophilized powder, suppositories, capsules, sublingual tablets) or liquid state (such as oral liquid) or other suitable forms. The administration routes may include but are not limited to: (1) traditional administration methods, such as gastrointestinal administration (such as oral administration), parenteral administration (such as solution injection, intravenous infusion), such as mucosal administration, transdermal administration, respiratory atomization inhalation, nasal drops, spraying, oral administration, intramuscular injection and / or intravenous administration, etc.; (2) connecting hnRNPA2B1 agonist and / or immune checkpoint inhibitor with transferrin / poly-L-lysine complex to enhance its biological effect; (3) mediating the entry of the drug into cells after encapsulating it with liposomes, which is beneficial for the smooth entry of compound molecules and protects them from hydrolysis by various extracellular enzymes; (4) transporting active substances with liposomes to specifically transport them to target tissues and target cells. In addition, the products of the present disclosure may also contain other active substances for improving and treating tumors or can be combined with other tumor prevention and treatment means. In some embodiments, before simultaneously with or after administering the products of the present disclosure, other active substances for regulating anti-tumor are administered. In some embodiments, the immune system is further regulated to prevent and treat tumors by activating hnRNPA2B1 and immune checkpoint inhibitors with the compounds or products of the present application. The term "subject" can refer to an animal, including but not limited to primates (such as humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" can be used interchangeably herein, for example, referring to a mammalian subject, such as a human subject. In the context of treating a disease, disorder or condition, the terms "treatment", "treatment" and "therapy" are intended to include alleviating or eliminating the disease, disorder or condition or one or more symptoms associated with the disease, disease or condition; or slowing the progression, spread or worsening of the disease, disorder or condition or one or more of its symptoms. "Cancer treatment" refers to one or more of the following effects: (1) inhibiting tumor growth to a certain extent, including (i) slowing down and (ii) completely halting growth; (2) reducing the number of tumor cells; (3) maintaining the tumor size; (4) reducing the tumor size; (5) inhibiting, including (i) reducing, (ii) slowing down or (iii) completely preventing the infiltration of tumor cells into surrounding organs; (6) inhibiting, including (i) reducing, (ii) slowing down or (iii) completely preventing cancer metastasis; (7) enhancing the anti-tumor immune response, which can (i) maintain the tumor size, (ii) reduce the tumor size, (iii) slow down tumor growth, (iv) reduce, slow down or prevent invasion and / or (8) alleviating the severity or number of one or more symptoms associated with the disorder to a certain extent. In a specific embodiment, the disease or disorder to be treated is a cell proliferative disease. In certain embodiments, the cell proliferative disease is cancer. In a specific embodiment, the cancer is selected from: brain and spinal cancer, head and neck cancer, leukemia and blood cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, liver and bile duct cancer, pancreatic cancer, kidney cancer, prostate cancer and bladder cancer, bone cancer, lung cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancer, and cancer of unknown primary (i.e., cancer with metastatic cancer found but the original cancer site is unknown). In a specific embodiment, the cancer is present in an adult patient. In additional embodiments, the cancer is present in a pediatric patient. In a specific embodiment, the cancer is associated with AIDS. In a specific embodiment, the cancer is selected from brain and spinal cancer. In a specific embodiment, the cancer is selected from: anaplastic astrocytoma, glioblastoma, astrocytoma, and esthesioneuroblastoma (also known as olfactory neuroblastoma). In a specific embodiment, the brain cancer is selected from: astrocytoma (e.g., cellular astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, pleomorphic xantho astrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), maxillary neuroma (e.g., oligodendroglioma and anaplastic oligodendroglioma), oligoastrocytoma (such as oligoastrocytoma and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brainstem glioma, cerebellar astrocytoma, cerebral aneurysm / malignant glioma, visual pathway and hypothalamic glioma, and primary central nervous system lymphoma. In specific examples of these embodiments, the brain cancer is selected from: glioma, glioblastoma multiforme, paraganglioma, and supratentorial primitive neuroectodermal tumor (sPNET). In a specific embodiment, the cancer is selected from: head and neck cancer, including nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, hypopharyngeal cancer, oral cancer (e.g., squamous cell carcinoma, lymphoma, and sarcoma), lip cancer, oropharyngeal cancer, salivary gland tumors, laryngeal cancer (e.g., laryngeal squamous cell carcinoma, rhabdomyosarcoma), and ocular cancer or eye cancer. In a specific embodiment, the eye cancer is selected from intraocular melanoma and retinoblastoma. In specific embodiments, the cancer is selected from leukemia and blood cancers. In specific embodiments, the cancer is selected from: myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), AML following MPN, AML following MDS, high-risk MDS or AML associated with del(5q), blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasmacytoma (including plasmacytoma and multiple myeloma). The leukemia mentioned herein can be acute or chronic. In specific embodiments, the cancer is selected from skin cancers. In specific embodiments, the skin cancer is selected from melanoma, squamous cell carcinoma, and basal cell carcinoma. In specific embodiments, the cancer is selected from cancers of the reproductive system. In specific embodiments, the cancer is selected from: breast cancer, cervical cancer, vaginal cancer, ovarian cancer, prostate cancer, penile cancer, and testicular cancer. In specific examples of these embodiments, the cancer is breast cancer, which is selected from ductal carcinoma and phyllodes tumors. In specific examples of these embodiments, the breast cancer can be male breast cancer or female breast cancer. In specific examples of these embodiments, the cancer is cervical cancer, which is selected from squamous cell carcinoma and adenocarcinoma. In specific examples of these embodiments, the cancer is ovarian cancer, which is selected from epithelial carcinoma. In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In specific embodiments, the cancer is selected from: esophageal cancer, gastric cancer (also known as stomach cancer), gastrointestinal carcinoid tumors, pancreatic cancer, gallbladder cancer, colorectal cancer, and anal cancer. In examples of these embodiments, the cancer is selected from: esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphoma, gastrointestinal lymphoma, solid pseudopapillary pancreatic tumors, pancreatoblastoma, islet cell tumors, pancreatic cancer (including acinar cell carcinoma and ductal adenocarcinoma), gallbladder adenocarcinoma, colorectal adenocarcinoma, and anal squamous cell carcinoma. In specific embodiments, the cancer is selected from liver cancer and cholangiocarcinoma. In specific embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma). In specific embodiments, the cancer is cholangiocarcinoma (also known as cholangiocellular carcinoma). In examples of these embodiments, the cholangiocarcinoma is selected from intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. In specific embodiments, the cancer is selected from renal cancer and bladder cancer. In specific embodiments, the cancer is renal cancer, which is selected from: renal cell carcinoma, Wilms tumor, and transitional cell carcinoma. In specific embodiments, the cancer is bladder cancer, which is selected from: ureteral cancer (transitional cell carcinoma), squamous cell carcinoma, and adenocarcinoma. In specific embodiments, the cancer is selected from bone cancer. In specific embodiments, bone cancer is selected from: osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, chordoma (bone cancer along the spine). In specific embodiments, the cancer is selected from lung cancer. In specific embodiments, lung cancer is selected from: non-small cell lung cancer, small cell lung cancer, bronchial tumor, and pleuropulmonary blastoma. In specific embodiments, the cancer is selected from malignant mesothelioma. In specific embodiments, the cancer is selected from epitheloid mesothelioma and sarcomatoid mesothelioma. In specific embodiments, the cancer is selected from sarcoma. In specific embodiments, sarcoma is selected from: central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheath, and Kaposi sarcoma. In specific embodiments, the cancer is selected from lymphoma. In specific embodiments, the cancer is selected from: Hodgkin lymphoma (e.g., Reed-Stemberg cells), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphoma, primary central nervous system lymphoma. In specific embodiments, the cancer is selected from adenocarcinoma. In specific embodiments, the cancer is selected from: adrenocortical carcinoma (also known as adrenocortical carcinoma or adrenal cortical carcinoma), pheochromocytoma, paraganglioma, pituitary tumor, thymoma, and thymic carcinoma. In specific embodiments, the cancer is selected from thyroid cancer. In specific embodiments, thyroid cancer is selected from: medullary thyroid carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma. In specific embodiments, the cancer is selected from germ cell tumors. In specific embodiments, the cancer is selected from: malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific examples of these embodiments, malignant extragonadal germ cell tumors are selected from non-seminoma and seminoma. In specific embodiments, the cancer is selected from cardiac tumors. In specific embodiments, cardiac tumors are selected from: malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma. In specific embodiments, the cancer is selected from cardiac tumors. In specific embodiments, cardiac tumors are selected from: malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma. In specific embodiments, the cell proliferative disease is selected from: benign papillomatosis, benign neoplastic diseases, and gestational trophoblastic diseases. In specific embodiments, the benign neoplastic diseases are selected from: cutaneous papilloma (wart) and genital papilloma. In specific embodiments, the gestational trophoblastic diseases are selected from: hydatidiform mole and gestational trophoblastic neoplasia (such as invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor). In some embodiments, the compounds or products of the present application are administered prophylactically as prophylactic drugs before tumorigenesis to prevent tumorigenesis or reduce the severity of subsequent tumors. In some embodiments, the compounds or products of the present application are administered as therapeutic drugs after tumorigenesis to reduce the severity of tumor diseases including their metastasis. In some embodiments, the compounds or products of the present application are used both as prophylactic drugs and as therapeutic drugs, and are administered continuously or intermittently before and after tumorigenesis. Those skilled in the art can make any combination of the foregoing technical solutions and technical features without departing from the inventive concept and protection scope of the present invention. Other aspects of the present invention will be apparent to those skilled in the art from the disclosure herein. Examples The following specific examples are used to further illustrate the present disclosure. It should be understood that these examples are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. Those skilled in the art can make appropriate modifications and changes to the present disclosure, and these modifications and changes are within the scope of the present disclosure. For the experimental methods without specific conditions noted in the following examples, conventional methods in the art can be used, such as referring to "Molecular Cloning: A Laboratory Manual" (Third Edition, New York, Cold Spring Harbor Laboratory Press, New York: Cold Spring Harbor Laboratory Press, 1989) or according to the conditions recommended by the supplier. The DNA sequencing method is a conventional method in the art and can also be tested by commercial companies. Unless otherwise specified, percentages and parts are by weight. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present disclosure. The preferred implementation methods and materials described herein are for illustrative purposes only. I. Examples of the Synthesis and Characterization of Compounds Example I.1: Synthesis of Compound A (FPC-1): *eq equivalent 1-1. Preparation of Compound 2 NBS (57.5 g, 320 mmol) was added to DMF (120 mL) and cooled to 0°C, compound 1 (20 g, 130 mmol) was added, the resulting suspension was stirred to allow it to naturally warm to room temperature and stirred overnight. The reaction solution was filtered, the filter cake was washed three times with ethanol, the dried filter cake was collected, and recrystallized with EA to obtain a pure product (10.1 g, off-white crystals). 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.79 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 3.30 (s, 4H). 1-2. Preparation of Compound 3 Compound 2 (6 g, 19.2 mol) was dissolved in 300 mL of anhydrous THF and cooled to -80 ° C. Then n-butyl lithium (9.2 mL, 2.5 M) was added dropwise, and the reaction mixture was stirred at the same temperature for at least one hour. After N-fluorobisbenzenesulfonamide (NFSI) (9 g, 28.8 mmol) in 100 mL of anhydrous THF was slowly added, the mixture was stirred for another 60 minutes at -80 ° C. The reaction mixture was then heated to room temperature overnight and then poured into NH4Cl solution. The aqueous phase was then extracted with DCM (3 × 50 mL), the organic phases were combined, and dried with MgSO4. The solvent was removed under low pressure. The product was purified by column chromatography using n-hexane as eluent. Compound 3 (4.1 g, white solid) was obtained. 1 H NMR (300 MHz, chloroform-d) δ 7.66 (d, J=7.4 Hz, 1H), 7.21-7.09 (m, 3H), 3.35 (s, 4H). 1-3. Preparation of Compound 4 Compound 3 (4.5 g, 17.9 mmol) was added to a solution of potassium dichromate (24 g, 82.4 mmol) in glacial acetic acid. The product was stirred for 2 hours at 4 ℃ for 10 minutes at 4 ℃ for 5 minutes.Then add 1% 4-(2-nitropropene)-2-nitropropene (50mL).The solution was heated to reflux for 16 hours, then poured into ice water.The resulting precipitate was collected by filtration and washed with water.The filter cake was air-dried, added to DCM and refluxed for 30 minutes, filtered, washed with DCM, the filter cake was added to DCM and refluxed for 15 minutes, filtered and washed with DCM.Merge all filtrates and vacuum concentrate to obtain compound 4 (4.1g, crude product, yellow solid). 1-4. Preparation of INT-1 N-Boc-ethylenediamine (3.3 g, 20.8 mmol) was added to a solution of compound 4 (4.1 g, 13.9 mmol) in EtOH (100 mL), and the mixture was heated under reflux for 1 h. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (PE / EA = 5 / 1). A off-white solid (2.8 g) was obtained. 1 H NMR (300 MHz, chloroform-d) δ 8.65 (dd, J = 8.2, 4.6 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 12.1, 8.1 Hz, 1H), 4.89 (s, 1H), 4.39 - 4.28 (m, 2H), 3.58 - 3.44 (m, 2H), 1.26 (s, 9H). Preparation of 1-5. FPC-1-1 Cesium carbonate (5.55 g, 17 mmol) and 1-(2-pyridoneethyl)piperazine (1.05 g, 5.7 mmol) were added to a toluene solution (175 mL) of INT-1 (2.5 g, 5.7 mol), and bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.57 mmol) was added to the mixture under argon protection. The reaction was carried out at 80 °C for 16 h. The reaction solution was cooled to room temperature, water was added to the reaction solution and stirred, and the organic phase was separated. The aqueous phase was extracted once with DCM The combined organic phases were dried over anhydrous magnesium sulfate. The crude product was purified by vacuum concentration and column purification, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1 + NH3·H2O) to obtain 240 mg of a pure yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.56 (dd, J = 7.7, 4.3 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.99 (s, 1H), 4.31 (s, 2H), 3.79 - 2.45 (m, 18H), 2.18 (s, 4H), 1.28 (s, 9H). Preparation of 1-6. FPC-1 Compound FPC-1-1 (240 mg, 0.44 mmol) was dissolved in 11 mL of DCM / MeOH (10 / 1). 5M HCl / 1,4-dioxane (5 mL) was added to the mixture and stirred at room temperature for 2 hours. Vacuum concentration was carried out, and the residue was dissolved in a small amount of methanol, precipitated with ether, centrifuged, the precipitate was washed with ether, centrifuged and dried in vacuo to obtain 240 mg of pure product (yellow solid). 1 H NMR (300 MHz, methanol-d4) δ 8.67 - 8.58 (m, 2H), 7.56 (dd, J = 13.2, 8.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 4.49 - 4.42 (m, 2H), 4.02 - 3.69 (m, 10H), 3.69 - 3.38 (m, 8H), 2.18 (s, 4H). MS (ESI) m / z [M+H] + = 440.3. Example I.2: Synthesis of Compound B (FPC-2) 2-1. Preparation of FPC-2-1 10 mL of ethylene glycol monomethyl ether was added to a single-necked flask, then INT-1 (110 mg, 0.25 mmol) and 3-(piperazin-1-yl)propan-1-ol (44 mg, 0.3 mmol) were added, and the reaction mixture was stirred at 100 °C. After 2 hours, the solvent was removed in vacuo, and the residue was purified by TLC to obtain 20 mg of yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.63 - 8.49 (m, 2H), 7.31 (dd, J = 12.8, 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.97 (s, 1H), 4.42 - 4.23 (m, 2H), 3.87 (t, J = 5.0 Hz, 2H), 3.60 - 3.28 (m, 8H), 2.92 (s, 4H), 1.89 (s, 2H), 1.29 (s, 9H). 2-2. Preparation of FPC-2 Compound FPC-2-1 (20 mg, mmol) was dissolved in 2 mL of DCM / MeOH (1 / 1). 5M HCl / 1,4-dioxane (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. Vacuum concentration was carried out, the residue was dissolved in a small amount of methanol, precipitated with ether, centrifuged, the precipitate was washed with ether, centrifuged and dried in vacuo to obtain 5 mg of pure product (yellow solid). 1 1H NMR (400 MHz, methanol-d4) δ 8.72 - 8.46 (m, 2H), 7.50 (ddd, J = 26.1, 12.4, 8.3 Hz, 2H), 4.45 (t, J = 5.6 Hz, 2H), 3.93 - 3.69 (m, 6H), 3.45 (dt, J = 15.0, 9.8 Hz, 5H), 3.34 (s, 3H), 2.07 (dt, J = 12.2, 6.1 Hz, 2H). MS (ESI) m / z [M + H] + = 401.47. Example I.3: Synthesis of Compound C (FPC-3) 3-1. Preparation of FPC-3-1 Cesium carbonate (1.78 g, 5.48 mmol) and N-ethyl-2-(pyrrolidin-1-yl)ethan-1-amine (286 mg, 2.01 mmol) were added to a toluene solution (70 mL) of INT-1 (800 mg, 1.82 mmol). Under argon protection, bis(triphenylphosphine)palladium(II) chloride (128 mg, 0.18 mmol) was added to the mixture. The reaction was carried out at 80 °C for 16 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution and stirred. The organic phase was separated, and the aqueous phase was extracted once with DCM. The obtained organic phases were combined and dried over anhydrous magnesium sulfate. The crude product was purified by vacuum concentration and column purification, and the crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1 + NH3·H2O) to obtain 30 mg of a pure yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.63 - 8.52 (m, 2H), 7.37 - 7.28 (m, 2H), 4.96 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.99 (s, 2H), 3.93 - 3.75 (m, 2H), 3.49 (s, 2H), 3.44 (d, J = 6.8 Hz, 2H), 3.36 - 3.16 (m, 2H), 2.87 - 2.62 (m, 2H), 2.29 - 2.12 (m, 2H), 2.12 - 1.91 (m, 2H), 1.28 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H). 3-2. Preparation of FPC-3 Compound FPC-3-1 (30 mg, 0.06 mmol) was dissolved in 4.4 mL of DCM / MeOH (10 / 1). 5M HCl / 1,4-dioxane (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. Vacuum concentration was carried out, and the residue was dissolved in a small amount of methanol, precipitated with ether, centrifuged, the precipitate was washed with ether, centrifuged and dried in vacuo to obtain 25 mg of the pure product (yellow solid). 1 1H NMR (300 MHz, methanol-d4) δ 8.67 - 8.54 (m, 2H), 7.58 - 7.46 (m, 2H), 4.51 - 4.41 (m, 2H), 3.87 - 3.77 (m, 2H), 3.77 - 3.65 (m, 2H), 3.51 (q, J = 6.6 Hz, 4H), 3.34 (d, J = 1.8 Hz, 1H), 3.20 - 3.05 (m, 2H), 2.20 - 1.92 (m, 5H), 1.10 (t, J = 7.0 Hz, 3H). MS (ESI) m / z [M+H] + = 399.47. Example I.4: Synthesis of Compound D (FPC-5) 4-1. Preparation of FPC-5-1 Cesium carbonate (460 mg, 1.41 mmol) and N,2-dimethylpropan-1-amine (49 mg, 0.56 mmol) were added to a toluene solution (20 mL) of INT-1 (205 mg, 0.47 mmol). Under argon protection, bis(triphenylphosphine)palladium(II) chloride (32 mg, 0.0.045 mmol) was added to the mixture, and the reaction was carried out at 80 °C for 16 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution and stirred, the organic phase was separated, the aqueous phase was extracted once with DCM, the combined organic phases were dried over anhydrous magnesium sulfate. By vacuum concentration and column purification, the crude product was purified by TLC (DCM / MeOH = 10 / 1 + NH3·H2O) to obtain 10 mg of a pure yellow solid. 11H NMR (300 MHz, chloroform-d) δ 8.56 (dd, J = 8.2, 4.9 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.05 (s, 1H), 4.39 - 4.26 (m, 2H), 3.51 (dd, J = 11.9, 5.2 Hz, 2H), 3.20 - 3.13 (m, 1H), 3.05 (d, J = 4.0 Hz, 3H), 2.17 - 2.05 (m, 2H), 1.31 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H). 4 - 2. Preparation of FPC-5 Dissolve compound FPC-5-1 (10 mg, 0.022 mmol) in 1.1 mL of DCM / MeOH (10 / 1). Add 5 M HCl / 1,4-dioxane (0.5 mL), and stir the mixture at room temperature for 2 hours. Perform vacuum concentration, dissolve the residue in a small amount of methanol, precipitate with ether, centrifuge, wash the precipitate with ether, centrifuge again, and dry under vacuum to obtain 9 mg of pure product (yellow solid). 1 1H NMR (400 MHz, methanol-d4) δ 8.61 - 8.52 (m, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 12.5, 8.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.44 (t, J = 5.1 Hz, 2H), 3.22 (dd, J = 19.7, 7.1 Hz, 4H), 3.10 (d, J = 3.1 Hz, 3H), 2.16 (dp, J = 13.3, 7.2 Hz, 1H), 1.31 (d, J = 7.7 Hz, 1H), 0.87 (d, J = 6.4 Hz, 6H). MS (ESI) m / z [M + H] + = 344.42. Example I.5: Synthesis of Compound E (AIR-2) 5 - 1. Preparation of Compound 5 Compound 3 (31.90 g, 127.04 mmol) was dissolved in anhydrous THF (800 mL). The reaction system was purged with argon three times and then cooled to -78 °C. Then, n-BuLi (60.98 mL, 2.5 M / L, 152.45 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for at least 10 minutes. N-Fluorobenzenesulfonimide (NFSI) (60.09 g, 190.57 mmol) in 200 mL of anhydrous THF was added dropwise. After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm to room temperature naturally and stirred overnight. The reaction mixture was quenched with NH4Cl solution and then extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated to obtain a crude product, which was added to DCM and stirred. The resulting precipitate was filtered, and the filter cake was washed twice with DCM. All the filtrates were combined and concentrated in vacuo to obtain a crude product, which was then purified by column chromatography (PE) to give compound 5 as a white solid (15.42 g, 63.82%). 1 1H NMR (300 MHz, Chloroform-d) δ 7.16 (d, J = 7.6 Hz, 2H), 7.12 - 7.04 (m, 2H), 3.37 (s, 4H). Preparation of 5-2.INT-2 Compound 5 (15.42 g, 81.08 mmol) was added to an ice acetic acid solution (220 mL) of potassium dichromate (109.72 g, 372.96 mmol). The solution was stirred at 80 °C for 12 hours. The reaction mixture was quenched with EA and water and extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated to obtain a crude product, and PE and an ultrasonic dispersion were added. The resulting precipitate was filtered and dried to obtain crude INT-2 as a brown-yellow solid (10.55 g), which could be used without further purification. Preparation of 5-3.AIR-2-1 INT-2 (5 g, 21.35 mmol) was dissolved in EtOH (120 mL). The reaction system was purged with argon three times and then heated to 50 °C. N 1 ,N 1 -Dimethylethane-1,2-diamine (2.79 mL, 25.62 mmol) was added, and the mixture was heated to 80 °C (reflux) for 4 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated, and the residue obtained was purified by column chromatography (DCM∶MeOH = 30∶1 to 10∶1) to give AIR-2-1 as a brown-yellow solid (1.81 g, 27.86%). MS (ESI), m / z: 305.4 [M+H]+ 。 1 H NMR (300 MHz, Chloroform-d) δ 8.65 (t, J = 2.5 Hz, 1H), 8.62 (t, J = 2.5 Hz, 1H), 7.47 - 7.39 (m, 2H), 4.38 (t, J = 6.7 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.49 (s, 6H). Preparation of 5 - 4. AIR - 2 Dissolve AIR - 2 - 1 (1.81 g, 5.95 mmol) in 1,4 - dioxane (150 mL), and displace the reaction system with argon three times. Add 1-(2 - pyridone - ethyl)piperazine (Compound A) (1.20 g, 6.54 mmol), and stir the mixture at room temperature overnight. Concentrate the reaction mixture, and purify the resulting residue by column chromatography (DCM∶MeOH = 15∶1 to 5∶1) to obtain the pure product dissolved in DCM. Then add 5M HCl / 1,4 - dioxane (1.5 mL) and continue stirring, and precipitate with diethyl ether. Filter the resulting precipitate, wash it with diethyl ether, and dry it to obtain yellow solid AIR - 2 (1.21 g). MS (ESI), m / z: 468.47 [M + H] + 。 1 H NMR (300 MHz, D2O) δ 8.36 (dd, J = 8.3, 4.7 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 13.1, 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.42 (t, J = 6.0 Hz, 2H), 3.90 - 3.54 (m, 12H), 3.47 (t, J = 6.0 Hz, 2H), 3.38 - 3.12 (m, 4H), 2.99 (s, 6H), 2.21 - 2.02 (m, 4H). Example I.6: Synthesis of Compound F (AIR - 3) 6 - 1. Preparation of Compound 2 NBS (499.72 g, 2.81 mol) was added to DMF (1000 mL) and stirred until most of the solid dissolved. The reaction system was purged with argon twice and then cooled to 9 °C. Compound 1 (176 g, 1.14 mol) was added. After stirring at 9 °C for 2 h, the reaction mixture was allowed to warm to room temperature naturally and stirred over the weekend. The reaction solution was filtered, and the filter cake was washed twice with PE / EA = 1 / 1. The dried filter cake was collected, recrystallized from EA, and the pure compound 2 as off-white crystals was obtained (102.57 g, 28.80%). 1 1H NMR (300 MHz, Chloroform-d) δ 7.79 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 3.30 (s, 4H). 6-2. Preparation of Compound 3 Compound 2 (50 g, 160.26 mmol) was dissolved in anhydrous THF (950 mL). The reaction system was purged with argon three times and then cooled to -78 °C. Then n-BuLi (76.92 mL, 2.5 M / L, 192.31 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for at least 20 min. N-Fluorobenzenesulfonimide (NFSI) (75.8 g, 240.38 mmol) in 250 mL of anhydrous THF was added dropwise. After stirring at -78 °C for 1.5 h, the reaction mixture was allowed to warm to room temperature naturally and stirred overnight. The reaction mixture was quenched with NH4Cl solution and then extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated to give a crude product, which was added to DCM and stirred. The resulting precipitate was filtered, and the filter cake was washed twice with DCM. All the filtrates were combined and concentrated in vacuo to give a crude product, which was then purified by column chromatography (PE∶EA = 50∶1) to give compound 3 as a white solid (31.90 g, 79.27%). 1 1H NMR (300 MHz, Chloroform-d) δ 7.66 (d, J = 7.4 Hz, 1H), 7.21 - 7.09 (m, 3H), 3.35 (s, 4H). 6-3. Preparation of Compound 4 Compound 3 (9.29 g, 37.00 mmol) was added to an acetic acid solution (100 ml) of potassium dichromate (50.07 g, 170.19 mmol). The solution was heated under reflux for 16 hours and then poured into ice water. The resulting precipitate was collected by filtration and washed with water. The filter cake was air-dried, added to DCM and refluxed for 30 minutes, filtered, washed with DCM, the filter cake was added to DCM and refluxed for 15 minutes, filtered and washed with DCM. All the filtrates were concentrated to obtain crude compound 3 (6.72 g), which could be used without further purification. Preparation of 6-4.AIR-3-1 DIPEA (358.48 uL, 2.17 mmol) and (2-aminoethyl)(methyl)carbamic acid tert-butyl ester hydrochloride (428.46 mg, 2.03 mmol) were added to an EtOH solution (20 mL) of compound 4 (400 mg, 1.36 mmol). The reaction system was purged with argon 5 times and then stirred (refluxed) at 80 °C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated, and the obtained residue was purified by column chromatography (PE∶EA = 10∶1 to 4∶1) to obtain yellow solid AIR-3-1 (244 mg, 39.88%). Preparation of 6-5.AIR-3-2 NaOt-Bu (103.92 mg, 1.08 mmol), 1-(2-pyridone-ethyl)piperazine (118.92 mg, 648.81 mmol) and BINAP (101.00 mg, 162.20 mmol) were added to a toluene solution (15 mL) of AIR-3-1 (244 mg, 540.68 mmol). The reaction system was purged with argon 5 times and then Pd(OAc)2 (24.28 mg, 108.14 mmol) was added. The reaction system was purged with argon three times, and the reaction mixture was stirred at 90 °C for 12 hours under argon protection. The reaction mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated to obtain a crude product, which was purified by column chromatography (DCM∶MeOH = 100∶1 to 10∶1, adding NH3·H2O) and Prep-TLC (DCM∶MeOH = 10∶1, adding NH3·H2O) to obtain AIR-3-2 (40 mg, 13.36%). 11H NMR (300 MHz, Chloroform-d) δ 8.56 (dd, J = 8.2, 4.7 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 7.7, 5.1 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 4.36 - 4.29 (m, 2H), 3.62 - 3.55 (m, 2H), 3.45 - 3.11 (m, 6H), 2.95 (s, 3H), 2.82 - 2.62 (m, 10H), 1.82 - 1.89 (m, 4H), 1.14 (s, 9H). 6 - 6. Preparation of AIR-3 The DCM / MeOH = 10 / 1 solution (3 mL) of AIR-3-2 (40 mg, 72.24 mmol) was purged with argon three times and then 5 M HCl / 1,4-dioxane (1.5 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. TLC showed the reaction was complete. The reaction mixture was precipitated with ether, centrifuged, the precipitate was washed with ether, centrifuged, and dried to obtain 33 mg of the crude product. The crude product was further purified by Prep-TLC (DCM∶MeOH = 20∶1, adding NH3·H2O) to obtain yellow solid AIR-3 (10 mg). MS (ESI), m / z: 454.58 [M + H] + . HPLC 92.439% (220 nm), HPLC 96.712% (254 nm). 1 1H NMR (300 MHz, D2O) δ 8.35 (dd, J = 8.4, 4.7 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 13.2, 8.5 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.39 - 4.31 (m, 2H), 3.86 - 3.62 (m, 14H), 3.37 - 3.31 (m, 2H), 3.25 - 3.15 (m, 2H), 2.70 (s, 3H), 2.24 - 2.13 (m, 2H), 2.08 - 1.98 (m, 2H). Example II. Activity Test Example II.1: Testing the activation of hnRNPA2B1 and TBK1-IRF3 pathways in tumor cells by the test compound After stimulating A549 lung cancer cells (cell density: 1x10^5 cells per well) with the test compound E at a concentration of 20 μM (prepared as in Example I.5 and dissolved in normal saline) for 30 minutes, the subcellular localization of hnRNPA2B1 was detected by immunofluorescence, and the activation of TBK1 and IRF3 was detected by SDS-PAGE electrophoresis and immunoblotting. The activation status of hnRNPA2B1, TBK1, and IRF3 is shown in Figures 1 and 2. The results showed that the test compound E could significantly activate the nuclear export of hnRNPA2B1 in tumor cells and the activation of downstream TBK1 and IRF3. In addition, similar results were obtained when the same experiment was carried out using other compounds prepared in Example I. The above results demonstrated that the test compound had an activating effect on the hnRNPA2B1 pathway and was a hnRNPA2B1 agonist. Example II.2: Broad induction of type I interferon production by the test compound in various types of tumors A549 (non-small cell lung cancer), HepG2 (liver cancer), LLC (Lewis lung cancer), and B16F10 (melanoma) tumor cells (cell density: 1x10^4 cells per well) were stimulated with the test compound E at a concentration of 20 μM; after 18 hours of stimulation, the cell culture supernatant was collected, and the IFN-β protein level was detected by ELISA. The activation of type I interferon by the test compound is shown in Figure 3. The results showed that the test compound E could significantly activate the expression of type I interferon in various cells. In addition, similar results were obtained when the same experiment was carried out using other compounds prepared in Example I. The above results demonstrated that the test compound could induce the production of type I interferon by activating the hnRNPA2B1 pathway and was a bioactive hnRNPA2B1 agonist. Therefore, in the present disclosure, such novel compounds were defined as hnRNPA2B1 agonists. Example II.3: hnRNPA2B1 agonist combined with immune checkpoint inhibitor synergistically inhibits tumor growth Male C57BL / 6J mice, 6 - 8 weeks old, were subcutaneously inoculated with 5x10^5 LLC tumor cells. From the 10th day after inoculation, the mice were randomly divided into groups: control group (only received tail vein injection and intraperitoneal injection, without drug administration), compound E single administration group, anti-PD-1 antibody administration group, and combined administration group. Compound E was administered by tail vein injection at a dose of 15 mg / kg mouse body weight, once every four days, for a total of four times. Anti-PD-1 antibody (Cat. No.: BE0273-100MG, purchased from BioXCell) was administered by intraperitoneal injection at a dose of 30 mg / kg of mouse body weight once a day for 7 consecutive days. The tumor growth of the mice was continuously observed, and the tumor size = length x width 2 / 2, and the survival period of the mice was observed. The results are shown in Figure 4. The results showed that: the hnRNPA2B1 agonist compound E could cooperate with the immune checkpoint inhibitor anti-PD-1 antibody to exert a stronger tumor growth inhibitory effect. In addition, similar results were obtained when the same experiment was carried out with other compounds prepared in Example I. Example II.5: hnRNPA2B1 agonist reverses the non-responsiveness of melanoma to immune checkpoint inhibitors Male C57BL / 6J mice (6-8 weeks old) were subcutaneously inoculated with 5x10^5 B16-F10 melanoma cells. From the 10th day after inoculation, the mice were randomly divided into groups: control group (only tail vein injection and intraperitoneal injection, without drug administration), compound E single administration group, anti-PD-1 antibody administration group, and combined administration group. Compound E was administered by tail vein injection at a dose of 15 mg / kg of mouse body weight once every four days for a total of four times. Anti-PD-1 antibody (Cat. No.: BE0273-100MG, purchased from BioXCell), was administered by intraperitoneal injection at 10 mg / kg, intraperitoneally once every 4 days for a total of 4 times. The tumor growth of the mice was continuously observed, and the tumor size = length x width 2 / 2. The results are shown in Figure 5. The results showed that: the hnRNPA2B1 agonist could inhibit the proliferation of B16F10 tumors, reverse its non-responsiveness to anti-PD-1 antibody, and showed a stronger therapeutic effect in the combined administration group. In addition, similar results were obtained when the same experiment was carried out with other compounds prepared in Example I. Biological evaluation The compounds of the present disclosure are defined as hnRNPA2B1 agonists by the following: (i) binding to the hnRNPA2B1 protein, which is demonstrated by the high affinity of the compound for the hnRNPA2B1 protein as low as 20 μM by Biacore assay; (ii) the compound was demonstrated to widely induce higher levels of IFN-β at a concentration as low as 20 μM by cell analysis. (i) Detection of the binding between the compound and hnRNPA2B1 by Biacore T200 Using S series CM5 chips; amino coupling reagents (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDC and N-hydroxysuccinimide NHS); Coupling buffer: 10 mM sodium acetate, pH 4.0, pH 4.5; Running buffer: 10×PBS-P+; Analytical grade DMSO, deionized water (filtered through a 0.22 μm membrane); hnRNPA2B1 recombinant protein (concentration should be greater than 0.5 mg / mL, total protein amount should be at least 20 μg or more); Compound: The concentration of the stock solution is greater than 20 mM, the volume is greater than 30 μL, the purity is greater than 90%, and it is dissolved in 100% DMSO; Other consumables: 96-well plates and sealing films, 1.5 mL centrifuge tubes without lids, type 2 rubber bottle caps. Experimental procedures: 1. Place 1×PBS of the running buffer and the waste liquid bottle at the designated positions, and place the chip. 2. Protein coupling. Select the immobilization program in Wizard template, check flow cell 2 or 4, select amine for the method, select specify contact time and flow rate to achieve high coupling, input contact time 900 s, and flow rate 10 μL / min. 3. Prepare the required protein solution according to the prompts. Dilute the protein with sodium acetate at pH 4.0 to the required volume, and the final concentration is 20 μg / mL. Place 100 μL of EDC, 100 μL of NHS, and 140 μL of ethanolamine at the corresponding positions. 4. The system will automatically coat the surface of the chip with the target coupling amount of hnRNPA2B1 protein and automatically generate a coupling report. 5. Prepare the running buffer for interaction. The running buffer for small molecule samples is 1×PBS-P+ containing 5% DMSO: Dilute 105 mL of 10×PBS-P+ with deionized water to 1 L to prepare 1.05×PBS-P+. Solvent calibration stock solution containing 4.5% DMSO: 9.5 mL of 1.05×PBS-P+ + 0.45 mL of DMSO Solvent calibration stock solution containing 5.8% DMSO: 9.5 mL of 1.05×PBS-P+ + 0.58 mL of DMSO Running buffer containing 5% DMSO: 950 mL of 1.05×PBS-P+ + 50 mL of DMSO Dilute the 10 mM small molecule mother liquor with 1.05×PBS-P+ buffer without DMSO: 0.7 μL of small molecule mother liquor + 6.3 μL of DMSO + 133 μL of 1.05×PBS-P+ buffer, with a total volume of 140 μL and a final concentration of 50 μM. Add it to a 96-well plate and stick on the sealing film. After the detection, use the Kinetics or Affinity mode to perform the binding affinity assay. (ii) Total cellular RNA can be extracted using TRIzol or an RNA rapid extraction kit. RNA rapid extraction from 24-well plate cells (about 2 - 3×10 5 cells / well): Discard the medium, add 500 μL of RA2 lysis solution to each well, pipette several times to lyse, transfer to the inner sleeve of a dedicated adsorption tube, and centrifuge at 12,000 rpm for 1 min at room temperature. Discard the filtrate, add 500 μL of washing buffer, and centrifuge at 12,000 rpm for 1 min at room temperature. Repeat the washing operation once. Discard the filtrate, put the inner sleeve back, without adding Wash Buffer, and centrifuge at 12,000 rpm for 2 min at room temperature. Transfer the inner sleeve to a new 1.5 mL centrifuge tube, add 25 μL of Elution Buffer to the center of the membrane, let it stand at room temperature for 5 min, and centrifuge at 12,000 rpm for 1 min at room temperature. The obtained filtrate is RNA, and the RNA concentration is measured using Nanodrop One. qRT-PCR: After measuring the concentration of each sample, take 1 μg of total RNA and use ReverTra Reverse transcribe the RNA into cDNA using qRT-PCR RT Master Mix. The reverse transcription system and reaction conditions are as follows: Reverse transcription reaction system (20 μL system) Reverse transcription reaction conditions (20 μL system) Add 60 μL of deionized water to dilute the cDNA sample obtained by reverse transcription, mix well and centrifuge briefly. The primer sequence information for qRT-PCR is shown in the table. Use SYBR Green Realtime PCR Master Mix to perform relative quantitative detection of the mRNA level of the gene. qRT-PCR reaction system (20 μL system) qRT-PCR reaction conditions qRT-PCR primers All documents mentioned in this disclosure are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of this disclosure, those skilled in the art can make various changes or modifications to this disclosure, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A fused ring compound represented by formula (I), its cis-trans isomers, its enantiomers, its diastereomers, its racemates, its solvates, its hydrates, or its pharmaceutically acceptable salts or its prodrugs, Among them, L is -(CH2)n-, where n is an integer from 0 to 6; X is a halogen; R 1 is -NR 4 R 5 , where R 4 and R 5 are each independently H or C 1-6 alkyl; R 2 and R 3 each independently is H or C 1-6 alkyl; or R 2 and R 3 together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur; The said C 1-6 alkyl group and the said 5- to 8-membered heteroalkyl group are unsubstituted or substituted by one or more substituent groups selected from the group consisting of: hydroxyl, amino, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 alkyl, 3- to 6-membered heteroalkyl, 3- to 6-membered heteroalkyl C 1-6 alkyl, 6- to 10-membered aryl, 6- to 10-membered aryl C 1-6 alkyl or 5- to 10-membered heteroaryl and 5- to 10-membered heteroaryl C 1-6 alkyl.

2. The compound according to claim 1, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, Among them, X is F or Cl; L is -(CH2)n-, where n is 1, 2 or 3; R 4 、R 5 Each independently is H, methyl or ethyl; R 2 and R 3 each independently is C 1-3 alkyl, and the C 1-3 alkyl is unsubstituted or substituted by a 3- to 8-membered heterocyclic alkyl containing 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur; or R 2 and R 3 together with the N atom to which they are attached form a 5- to 8-membered heterocycloalkyl group containing 2 nitrogen atoms, said 5- to 8-membered heterocycloalkyl group being substituted by a 3- to 8-membered heterocycloalkyl C 1-6 alkyl or hydroxy C 1-6 alkyl substituted.

3. The compound according to claim 1, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, Among them, X is F; L is -(CH2)n-, where n is 2; R 4 、R 5 each independently is H, methyl or ethyl; R 2 and R 3 each independently is C 1-3 alkyl, and the C 1-3 alkyl is unsubstituted or substituted by a 4- to 6-membered heteroalkyl containing 1 nitrogen heteroatom; or R 2 and R 3 together with the N atom to which they are attached form a piperazinyl group, said piperazinyl group being substituted with a 4- to 6-membered heterocycloalkyl C 1-6 alkyl or hydroxy C 1-6 alkyl substituted.

4. The compound according to claim 1, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, Among them, X is F; L is -(CH2)n-, where n is 2; R 4 、R 5 are each independently H, methyl or ethyl; R 2 and R 3 each independently represents methyl, ethyl or isopropyl, and the C 1-3 alkyl group is unsubstituted or is substituted with pyrrolidinyl; or R 2 and R 3 together with the N atom to which they are attached form a piperazinyl group, which is substituted by pyrrolidinoethyl or by hydroxyethyl.

5. The compound according to claim 1, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, said compound having the following formula (II): Among them, R a 、R b Each independently is H or C 1-6 alkyl; M is -(CH2)n-, where n is 1, 2 or 3; X is F or Cl; R c is hydroxy, amino, a 3- to 8-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from nitrogen, oxygen or sulfur, more preferably R c is hydroxy or a 4- to 6-membered heterocycloalkyl group containing 1 nitrogen heteroatom, more preferably, R c is hydroxy or pyrrolidinyl, most preferably, R c is hydroxy or 1-pyrrolidinyl.

6. The compound according to claim 1, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates or its pharmaceutically acceptable salts or its prodrugs, wherein the compound is selected from the group consisting of: or its hydrochloride.

7. A product comprising the compound according to any one of claims 1 to 6, and a pharmaceutically or immunologically acceptable carrier or excipient.

8. The product according to claim 7, wherein: The product is selected from: pharmaceutical compositions, medicaments, kits or cartridges; and / or wherein, the product further comprises an immune checkpoint inhibitor or is used in combination with an immune checkpoint inhibitor, for example, the immune checkpoint inhibitor is selected from: PD1 / PD-L1 inhibitors, such as nivolumab, pembrolizumab, dostarlimab, cemiplimab, EH12.2H7, batrilimab, avelumab, durvalumab, BMS-936559, atezolizumab or their equivalents; wherein, the product is for inducing the production of type I interferon in a subject and / or for preventing and / or treating tumors of a subject.

9. Use of the compound according to any one of claims 1 to 6 in the preparation of a product for use in combination with an immune checkpoint inhibitor to induce the production of type I interferon in a subject or for use in combination with an immune checkpoint inhibitor to prevent and / or treat tumors of a subject.

10. The application according to claim 9, wherein, The subject is a human or non-human mammal, such as non-human primates (gorillas, chimpanzees), pets (such as pet cats, dogs, guinea pigs, rabbits), livestock animals (such as cows, horses, donkeys, mules, camels, pigs, sheep, chickens, ducks, geese, rabbits, deer, minks, otters, musks, etc.); and / or wherein, the production of the type I interferon is mediated by hnRNPA2B1; and / or wherein, the prevention and / or treatment of tumors of the subject can benefit from the production or increased level of type I interferon in vivo; and / or wherein, the tumor is one or more tumors selected from the following group: solid tumors, such as liver cancer, lung cancer, melanoma, breast cancer, ovarian cancer, prostate cancer, kidney cancer, intestinal cancer, head and neck cancer, skin cancer, bladder cancer, pancreatic cancer; non-solid tumors, such as hematological tumors (such as leukemia), nervous system tumors (such as glioma); preferably, non-small cell lung cancer, liver cancer, Lewis lung cancer, melanoma, breast cancer, colon cancer; and / or Wherein, the product is selected from: pharmaceutical composition, medicine, kit or medicine box; and / or Wherein, the immune checkpoint inhibitor is selected from: PD1 / PD-L1 inhibitors, such as nivolumab, pembrolizumab, dostarlimab, cemiplimab, EH12.2H7, batrilimab, avelumab, durvalumab, BMS-936559, atezolizumab or equivalents thereof; and / or The product is for inducing the production of type I interferon in a subject and / or for preventing and / or treating tumors in a subject.

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