Boron compound for targeting ASCT2, and preparation method therefor and use thereof

Abstract

The present invention relates to the field of boron neutron capture therapies, and particularly provides a boron compound for targeting ASCT2, and a preparation method therefor and a use thereof. The compound is composed of a 10B compound and a scaffold structure targeting ASCT2. In addition to having the advantages of high targetability in ASCT2-directed therapies and spatial positioning provided by neutron beams, more importantly, the compound can form a high boron enrichment concentration in tumor, so that good therapeutic effects can be achieved after high-intensity neutron irradiation.

Description

Boron compound for targeting ASCT2 and preparation method and use thereof

[0001] This application claims priority to a Chinese patent application filed with the Patent Office of China on February 1, 2024, with application number 202410143779.6 and invention name “Boron compounds for targeting ASCT2, preparation methods and uses thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of boron neutron capture therapy (BNCT), and in particular, the present invention relates to a method for boron neutron capture therapy containing 10 A compound comprising a B compound and a scaffold structure targeting ASCT2, a preparation method thereof, and a cancer therapy using the same. Background Art

[0003] Globally, cancer is the second leading cause of death after coronary heart disease. Millions of people die from cancer each year. In 2018, approximately 17.1 million new cancer cases were reported worldwide, of which approximately 3.8 million were in China, the highest incidence rate worldwide. This disease poses a serious threat to people's lives and health. Currently, cancer treatment options are primarily categorized into surgery, chemotherapy, targeted therapy, and radiotherapy, depending on the type and stage of cancer. For patients with early- and mid-stage cancer, surgical resection combined with adjuvant chemotherapy generally offers a high five-year survival rate. However, for advanced cancer, surgery is often not feasible due to large tumor size, metastasis, or the patient's physical condition. Therefore, systemic chemotherapy or radiotherapy is recommended. However, most chemotherapy drugs and radiotherapy lack tumor tissue specificity. While inhibiting tumor cell growth, they can also damage healthy tissue, resulting in severe toxic side effects. Therefore, there is an urgent need to develop novel cancer treatments to improve the quality of life and prolong survival for patients with advanced cancer.

[0004] In recent years, boron neutron capture therapy (BNCT) has become an attractive treatment option for cancer, particularly malignant tumors, as it can selectively kill tumor cells using boron-containing agents while sparing normal cells. Specifically, BNCT is a novel radiotherapy method based on neutron capture and boron fission reactions. This treatment consists of two separate steps: delivery of a boron-containing agent and neutron irradiation. First, the boron-containing agent is injected externally and accumulates in tumor cells. Then, during neutron irradiation, the boron captures neutrons and undergoes nuclear fission, producing high-energy alpha ions and high-energy lithium-7. These neutrons then release gamma rays that kill tumor cells within a range of 5-9 μm. Compared to traditional chemotherapy and radiotherapy, BNCT offers several advantages: 1) the gamma ray range is narrow (5-9 μm), specifically targeting boron-containing cells without damaging surrounding tissues; 2) there is no radioresistance to hypoxic cells; and 3) it avoids the multidrug resistance often associated with chemotherapy and targeted drugs.

[0005] Although the concept of BNCT is well known, the technical limitations associated with this type of treatment have slowed the development of this treatment method. The main barrier is the lack of ideal boron-containing reagents. Ideal boron-containing reagents should have the following characteristics: high intratumoral enrichment concentration, high selectivity (in vivo biodistribution tumor tissue / blood (T / B) concentration ratio ≥3 and tumor tissue / normal tissue (T / N) concentration ratio ≥3) and low systemic toxicity, etc. From the current research and development history of boron-containing reagents, there are mainly three generations of boron reagents. The first generation of boron-containing reagents is boric acid and its derivatives, which were first used in clinical trials in the 1950s and 1960s. They are basic compounds, but they have no discriminatory properties for tumors and low specificity. Subsequently, the second generation of boron-containing reagents was developed, mainly including the low molecular weight boron-containing compounds disodium undecahydrothiododecaboride (BSH) and boron parahydroxyphenylalanine (BPA). Although the performance has been greatly improved compared with the first generation of boron-containing reagents, and BPA has been approved for marketing and BSH has also been approved for clinical trials, they still cannot meet the requirements of BNCT. Their retention time in tumor cells is short and their selectivity is low (T / B and T / N concentration ratios can only reach >1), so the effect of treating tumors is not very ideal.

[0006] In recent years, research on the third-generation boron-containing reagents has also developed rapidly, which mainly involves connecting boron-containing compounds with tumor-targeting components to form novel boron-containing reagents.

[0007] Patent applications such as US4959356A, CN1988848A, US5149801A, and CN101605459A disclose various boronated porphyrin compounds. Porphyrins are naturally occurring tetrapyrrole compounds that can remain in tumors for days to weeks and have an affinity for various types of cancer. Therefore, boronated porphyrins can enhance their selectivity for tumor cells, further improving the targeted nature of cancer treatment. However, studies have shown that injection of these drugs can result in high mortality in mice.

[0008] Patent applications such as CN1124921A, US5328678A, and US20150238622A1 disclose different liposomes containing boron compounds. Liposomes can embed boron-containing compounds in their double-layer structure to increase their transport efficiency. 10 The amount of boron and / or the tumor specificity of liposomes can be increased, thereby increasing the concentration of boron in tumor tissue and reducing its concentration in the blood. However, for liposomes containing hydrophilic boron-containing compounds, when the boron-containing compound is encapsulated at high concentrations, the ion osmotic pressure of the hydrophilic layer causes bilayer instability and electroplating collapse, leading to leakage of the boron-containing compound. This results in boron accumulation in normal tissues, thereby reducing the therapeutic effect. In addition, technologies have been developed that combine liposomes with hydrophobic boron-containing compounds to encapsulate boron compounds within the phospholipid bilayer membrane. However, due to the multi-stage and complex synthesis required, there are many issues with efficiency and cost.

[0009] In addition, there are many other novel boron-containing reagents, such as boronated folate receptor, boronated epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), boron-containing nanoparticles, etc. Although these boron-containing reagents have achieved certain therapeutic effects and increased the concentration and selectivity of boron in tumor cells, the tumor cell killing efficiency is low. Therefore, in order to achieve sufficient therapeutic effects in BNCT, new boron-containing reagents still need to be developed.

[0010] Breast cancer accounts for 31% of all cancer diagnoses in women and is the second leading cause of cancer-related death in women. Although a large proportion of breast cancer cases are treatable, the 5-year survival rate for patients with metastatic breast cancer is only 22%, with distant organ metastasis causing the majority of breast cancer deaths.

[0011] ASCT2 is a sodium-dependent amino acid transporter with broad substrate specificity, preferring zwitterionic amino acids. It accepts all neutral amino acids as substrates, including glutamine, asparagine, branched-chain amino acids, and aromatic amino acids, but excludes methylated, anionic, and cationic amino acids. Through binding to the fusion protein syncytin-1 / ERWW-1, it mediates trophoblast syncytia, the spontaneous fusion of its plasma membranes, a crucial process in placental development.

[0012] The lack of effective and selective inhibitors has hampered the development of therapeutic strategies targeting ASCT2 for the treatment of cancer. Second, the development of such therapeutic strategies is hampered by the fact that different membrane transporters can carry the same amino acid (in the specific case of glutamine, it is transported not only by ASCT2 but also by other transporters such as LAT1 and ASCT1). Furthermore, ablation of ASCT2 leads to increased expression of other glutamine transporters, namely SNAT1 and SNAT2, in certain cancers. These transporters are also capable of mediating glutamine cellular uptake, and this can be sufficient to meet tumor demand, compensating for ASCT2 silencing. Therefore, cancer cells with increased expression of other glutamine transporters are less susceptible to ASCT2 inhibition. Third, in addition to its role in cancer, ASCT2 is also expressed in non-malignant tissues throughout the body: brain, lung, intestine, kidney, and skeletal muscle. Therefore, inhibiting ASCT2 may have adverse effects on non-cancerous cells. Fourth, the effects attributed to glutamine, and therefore to ASCT2, appear to differ depending on the tumor type. This may be due not only to the different tissue origins of the malignant tumor but also to the tumor microenvironment. Therefore, although ASCT2 is a target of great interest to scientists, it is undeniable that there are many uncertainties and difficulties in developing anti-cancer drugs targeting ASCT2. Developing a combination of other anti-tumor therapies and ASCT2 inhibitors may be a very effective strategy for treating certain cancers and improving the response of cancer cells to treatment, which deserves further study. Summary of the Invention

[0013] The purpose of the present invention is to overcome the deficiencies in the prior art. The inventors of the present invention have repeatedly studied new boron-containing compounds suitable for BNCT from the perspective of improving the targeting and enrichment concentration of boron in tumor cells, which can accurately inhibit the growth of tumor cells while not causing damage to normal healthy tissues. The inventors of the present invention have attempted to develop a boron 10 compound ( 10 B compound), provides a new boron-containing compound targeting ASCT2. The inventors surprisingly found that the boron-containing compound can further improve the targeting and enrichment concentration of boron in tumor tissue, thereby enhancing the therapeutic effect of BNCT.

[0014] To achieve the purpose of the present invention, the following technical solutions are provided:

[0015] A targeted ASCT2-containing protein for BNCT therapy 10 Compound B has a structure shown in general formula I:

[0016] in:

[0017] R1 is

[0018] R2, R3 and R4 are each independently lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, aldehyde, lower acyloxy, lower alkylcarboxylic acid, lower alkylcarbonyl, lower carboxylic acid ester, lower carboxamide R2 substituents may be linked together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring containing zero to three heteroatoms, such as methylenedioxy or ethylenedioxy.

[0019] m and n are each independently 0-4, and m+n<5.

[0020] W is -NHCO-, -CONH- or -CH2-.

[0021] p is 1-10, preferably 1-5, and most preferably 1-3.

[0022] R5 and R6 are each independently lower alkyl, lower haloalkyl, lower cycloalkyl, lower alkoxy, lower haloalkoxy, hydrogen, lower alkanoyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, methylcarbonyl, ethylcarbonyl, trifluoroacetyl, phthaloyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, 2-trimethylsilylethylsulfonyl, allyl, benzyl, ethyl dimethylbenzoate, p-methoxybenzyl or trityl. Selective R5 and R6 can be linked together to form a fused five-, six- or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms. Further preferably, R5 and R6 are each independently hydrogen or tert-butyloxycarbonyl.

[0023] Y is an alkyl group, an alkylcarboxylic acid group, an alkylcarbonyl group, an alkylcarboxylate group, an alkylamide group, a cyano group, an amino group, an alkylamino group, an arylamino group, an amide group, a carboxyl group, an aromatic amide group, an alkoxycarbonyl group, an aminoacyl group, a hydrazineacyl group or -COOR7. Preferably, Y is an alkyl group, an alkoxycarbonyl group, an aromatic amide group, an aminoacyl group, a hydrazineacyl group or -COOR7, wherein R7 is a hydrophobic group.

[0024] Preferably, Y is -COOR7, alkyl, or hydrazinoyl, wherein the hydrogen on the amine in the hydrazinoyl may be substituted, for example, as in the compound of formula O29.

[0025] A, B, D, E and G are each independently C and N and at least three of A, B, D, E and G are C. Preferably, A, B, D, E and G are all C.

[0026] Preferably, the targeting ASCT2 contains 10 Compound B has a structure shown in Formula Ia:

[0027] Wherein R1, R2, R3, R4, R5, R6, W, m, n, p, A, B, D, E and G are defined as above, and R7 is a hydrophobic group.

[0028] Preferably, the hydrophobic group is selected from an alkyl group, an unsaturated chain hydrocarbon group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aryl-substituted alkyl group, a cycloalkyl-substituted alkyl group, or an arylamide group. Preferably, the aryl group may have 1-2 heteroatoms bound to the aryl ring, and the heteroatoms are preferably nitrogen.

[0029] Preferably, the hydrophobic group is an alkyl group substituted with an aromatic group, and the aromatic group may be substituted with one or more groups. Preferably, the substituent is a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkenyl group, a C1-C6 cycloalkenyl group, a C1-C6 cycloalkyl group, a dihydroxyboron group, an amino group, a trifluoromethoxy group, an aromatic group, a heteroaromatic group, an aldehyde, an amino group, a carboxylic acid, an ester, an ether, a halogen, a hydroxyl group, a ketone, a nitro group, a silyl group or a thiol group.

[0030] Preferably, the targeting ASCT2 contains 10 Compound B has the structure shown in general formula Ib:

[0031] wherein R1, R2, R3, R4, R7, W, m and p are defined the same as above.

[0032] Preferably, the targeting ASCT2 contains 10 Compound B has a structure shown in general formula Ic:

[0033] wherein R1, R3, R4, R7, W, m and p are defined the same as above.

[0034] Preferably, the targeting ASCT2 contains 10 Compound B has the structure shown in formula Id:

[0035] The definitions of R1, R7, W, m and p are the same as above.

[0036] In a preferred technical solution, R7 is tert-butyl, aryl, or aralkyl.

[0037] In a preferred embodiment, R7 is not methyl or hydrogen.

[0038] In another embodiment, the compound of the present disclosure is a compound of any one of Formula I or a pharmaceutically acceptable salt or solvate thereof.

[0039] In another embodiment, the compound of the present disclosure is a compound selected from any one or more of the following, or a pharmaceutically acceptable salt or solvate thereof.

[0040] The salts, hydrates and solvates of the compounds of the present disclosure may also be used in the methods disclosed herein. The disclosure also includes all possible stereoisomers and geometric isomers of the compounds of the present disclosure, to include racemic compounds and optical isomers. When the compounds of the present disclosure are needed as single enantiomers, they can be obtained by splitting the final product or by stereospecific synthesis from isomerically pure starting materials or using chiral auxiliary reagents, for example, referring to Z.Ma et al., Tetrahedron:Asymmetry, 8 (6), pp. 883-888 (1997). The splitting of the final product, intermediate or starting material can be achieved by any suitable method known in the art. In addition, in the case where the tautomers of the compounds of the present disclosure are possible, the disclosure is intended to include all tautomeric forms of the compounds.

[0041] The present disclosure encompasses the preparation and use of salts (including pharmaceutically acceptable salts) of compounds of the present disclosure. As used herein, pharmaceutically "pharmaceutically acceptable salts" refer to salts or zwitterionic forms of compounds of the present disclosure. Salts of compounds of the present disclosure can be prepared during the final separation and purification process of the compound, or prepared separately by reacting the compound with an acid having a suitable cation. Pharmaceutically acceptable salts of compounds of the present disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Non-limiting examples of salts of the compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate (n- 1 ... The compounds of the present invention may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In accordance with the foregoing, any reference to a compound of the present invention appearing herein is intended to encompass the compound of the present invention as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0042] The present disclosure encompasses the use of solvates of compounds of the present disclosure. Solvates generally do not significantly change the physiological activity or toxicity of the compound, and therefore can function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical combination and / or solvation of a compound of the present disclosure and a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of the solvent molecule to the compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical combination involves varying degrees of ionic and covalent bonds, including hydrogen bonds. In some cases, solvates can be separated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Therefore, "solvate" encompasses solution phases and separable solvates. Compounds of the present disclosure can exist in solvated forms with pharmaceutically acceptable solvents (such as water, methanol, ethanol, etc.), and the present disclosure is intended to include solvated and non-solvated forms of the compounds of the present disclosure. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally be used as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93 (3): 601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5 (1): Article 12 (2004) and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting method for preparing solvates includes dissolving a compound of the present disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in solvate crystals.

[0043] The compounds of the present invention may also contain a radionuclide, such as fluorine-18, for use in radiomedical imaging applications in patients (e.g., humans) to diagnose or track the progression of diseases, disorders, conditions, or symptoms associated with ASCT2 dysfunction, including but not limited to cancer, microbial infection, and central nervous system symptoms associated with ischemia.

[0044] Another object of the present invention is to provide a method for preparing the ASCT2-targeting 10Compound B, the intermediate compound of formula II and the intermediate compound of formula III are condensed to obtain a compound of formula I,

[0045] wherein R1, R2, R3, R4, R5, R6, W, m, n, p, A, B, D, E and G are the same as those defined above, W1 and W2 are each independently -NH2 or -COOH and are different, and when R5 and R6 are both hydrogen, the compound of formula III needs to be protected by a protecting group selected from benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloromethanesulfonyl (Cbz), methylthiophene (McCl ... Ethoxycarbonyl (Troc), methylcarbonyl (Meoc), ethylcarbonyl (Etoc), trifluoroacetyl (Tfa), o-phthaloyl (Pht), p-toluenesulfonyl (Tos), o-nitrobenzenesulfonyl (oNbs), p-nitrobenzenesulfonyl (pNbs), 2-trimethylsilylethylsulfonyl (SES), allyl (Al), benzyl (Bn), ethyl dimethylbenzoate (Dmb), p-methoxybenzyl (Pmb), trityl (Trt), the specific structures are as follows:

[0046] Another object of the present invention is to provide the above-mentioned ASCT2-targeting 10 Use of compound B in BNCT therapy.

[0047] In one embodiment, the present disclosure provides methods, uses, and compositions for treating cancer. These methods, uses, and compositions comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure.

[0048] In another embodiment, the compounds of the present disclosure are administered to an individual suffering from cancer as the sole chemotherapeutic agent.

[0049] In another embodiment, the compounds of the present disclosure are administered to an individual with cancer in combination with one or more optional therapeutic agents. The compounds of the present disclosure and the optional therapeutic agents may be administered in combination under one or more of the following conditions: in different cycles, different durations, different concentrations, by different routes of administration, etc. In some embodiments, the compounds of the present disclosure are administered to a patient according to an intermittent dosing schedule.

[0050] The therapeutic methods provided herein include administering to cancer patients a compound of the present disclosure in an amount that effectively achieves its intended purpose. Although individual needs are different, determining the optimal range of each component effective dose is within the technical scope of the art. Typically, a compound of the present disclosure is administered in an amount of about 0.05 mg / kg to about 500 mg / kg, about 0.05 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, or about 0.05 mg / kg to about 10 mg / kg. These dosages are exemplary, but there may be individual circumstances where higher or lower dosages are needed, and these are all within the scope of the present disclosure. In fact, the doctor determines the actual dosing regimen that best suits the individual patient, which may vary with the age, weight, and response of the particular patient.

[0051] The unit oral dose of compound of the present disclosure can include about 0.01 to about 1000mg, for example, about 0.01 to about 100mg of compound of the present disclosure. In one embodiment, the unit oral dose of compound of the present disclosure is 0.05mg, 1mg, 3mg, 5mg, 7mg, 9mg, 10mg, 12mg, 14mg, 15mg, 17mg, 20mg, 22mg, 25mg, 27mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg or 100mg. The unit dose can be applied once or multiple times per day, for example, in the form of one or more tablets or capsules. The unit dose can also be applied to an individual by IV or subcutaneous administration. In fact, the doctor determines the actual dosage regimen that is most suitable for an individual patient, which can change with the age, weight and reaction of a particular patient.

[0052] In addition to administering the compounds of the present disclosure as chemical raw materials, they can also be administered as part of a pharmaceutical preparation or composition. In some embodiments, the pharmaceutical preparation or composition may comprise one or more pharmaceutically acceptable carriers, excipients and / or adjuvants. In some embodiments, one or more carriers, excipients and adjuvants facilitate the processing of the compounds of the present disclosure into pharmaceutically usable preparations or compositions. The preparations, especially those that can be administered orally, subcutaneously or topically and can be used for a type of administration, such as tablets, capsules, and rectal administration preparations such as suppositories, as well as suitable solutions for intravenous infusion, subcutaneous injection, topical or oral administration, contain about 0.01% to 99%, in one embodiment about 0.25% to 75% of the active compound and one or more carriers, excipients and / or adjuvants.

[0053] The compounds and pharmaceutical compositions provided herein can be applied to any individual who may experience the beneficial effects of the compounds of the present disclosure. The most important of such individuals are mammals (e.g., humans), but the methods and compositions provided herein are not intended to be so limited. Other individuals include animals (cattle, sheep, pigs, horses, dogs, cats, etc.) treated by veterinary medicine. In one embodiment, the individual is a human cancer patient.

[0054] The pharmaceutical preparations provided herein are prepared by conventional mixing, granulation, dragee preparation, dissolution or lyophilization processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules after adding suitable auxiliaries (if desired or necessary) to obtain tablets or dragee cores.

[0055] Suitable excipients are fillers in particular, such as sugars, such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, such as tricalcium phosphate or calcium hydrogen phosphate, and binding agents, such as starch paste, use such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone. If desired, disintegrants can be added, such as above-mentioned starch, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or its salt, such as sodium alginate. Auxiliary agents can be suitable flow regulators and lubricants. Suitable auxiliary agents include, for example, silicon dioxide, talc, stearic acid or its salt, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, a suitable coating for resisting gastric juice is provided to the dragee core. For this reason, concentrated sugar solutions can be used, which optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce a coating that resists gastric juice, solutions of suitable cellulose preparations are used, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to tablets or dragee coatings, for example, for identification or in order to characterize the combination of active compound dosage.

[0056] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules can contain the active compound in the form of granules mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, in one embodiment, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil or liquid paraffin. In addition, stabilizers can be added.

[0057] Possible pharmaceutical preparations for rectal administration include, for example, suppositories consisting of a combination of one or more active compounds and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. In addition, gelatin rectal capsules consisting of a combination of an active compound and a base may also be used. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

[0058] Suitable dosage forms for parenteral administration include aqueous solutions of water-soluble forms of the active compound (e.g., water-soluble salts and alkaline solutions). In addition, suspensions of the active compound can be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils (e.g., sesame oil), or synthetic fatty acid esters (e.g., ethyl oleate or triglycerides or polyethylene glycol-400). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspension may also include a stabilizer.

[0059] A therapeutically effective amount of a compound of the present disclosure and an optional therapeutic agent can be formulated according to standard pharmaceutical practice and administered to a human subject in need thereof. Whether such treatment is necessary depends on the individual case and is subject to a medical evaluation (diagnosis) that takes into account the presence of signs, symptoms, and / or disorders, the risk of developing specific signs, symptoms, and / or disorders, and other factors.

[0060] The compounds of the present disclosure and optional therapeutic agents can be administered by any suitable route, for example, orally, buccal, inhaled, sublingually, rectally, vaginally, intracisternal or intrathecally by lumbar puncture, transurethral, ​​nasal, transdermal (i.e., transdermal) or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation of a specific site). Parenteral administration can be accomplished using a needle and syringe or using high-pressure techniques.

[0061] The toxicity and therapeutic effect of the compounds of the present disclosure and optional therapeutic agents can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, for determining the maximum tolerated dose (MTD) of the compound, which is defined as the highest dose that does not cause toxicity in patients. The dose ratio between the maximum tolerated dose and the therapeutic effect (such as inhibition of tumor growth) is the therapeutic index. The dosage can vary within this range, depending on the dosage form used and the route of administration used. The determination of a therapeutically effective amount is fully within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein.

[0062] The therapeutically effective amount of the compounds of the present invention and the optional therapeutic agent used for treatment varies with the nature of the condition being treated, the desired duration of activity, and the age and condition of the individual, and is ultimately determined by the attending physician. For example, dosage and interval can be adjusted individually to provide plasma levels of the compounds of the present invention and / or the optional therapeutic agent sufficient to maintain the desired therapeutic effect.

[0063] In one embodiment, the present disclosure provides a method of treating cancer in a subject, wherein the cancer is a solid tumor. In another embodiment, the cancer is a hematological cancer.

[0064] In another embodiment, the cancer is selected from the group consisting of adrenal cancer, acinar cell carcinoma, acoustic neuroma, acral lentiginous nevus in situ melanoma, apical spiral leukemia, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenoid tumor, adenosquamous carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia, adult T-cell lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, Tumor, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell promyelocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, brown tumor, breast cancer, brain cancer, malignant tumor, carcinoma in situ, cartilage tumor, cementum tumor, myeloid sarcoma, chondroma, choriocarcinoma, Cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, diffuse large B-cell lymphoma, endocrine gland tumors, esophageal cancer, fibroma, fibrosarcoma, gastrointestinal cancer, germ cell tumor, giant cell tumor of bone, glioma, glioma, glucagonoma, gallbladder cancer, gastric cancer, head and neck cancer, hematological cancer, intestinal cancer, kidney cancer, laryngeal cancer, liposarcoma, lung cancer, lymphangioma, lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malignant fibrous histiocytoma, mast cell leukemia Blood cancer, melanoma, meningioma, multiple myeloma, muscle tissue tumors, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, nodular melanoma, eye cancer, oncocytoma, oral cancer, osteosarcoma, ovarian cancer, plasma cell tumor, prostate cancer, pancreatic cancer, renal cell carcinoma, rhabdoid tumor, rhabdomyosarcoma, rectal cancer, sarcoma, skin cancer, small cell carcinoma, soft tissue sarcoma, squamous cell carcinoma, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary tract cancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' cell carcinoma.

[0065] Exemplary hematologic cancers include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), Hodgkin lymphoma (HL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, splenic marginal zone lymphoma, follicular lymphoma (FL), Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), marginal zone B-cell lymphoma (MDCL), and splenic marginal zone lymphoma. Lymphoma (MZL), hairy cell leukemia (HCL), Burkitt lymphoma (BL), acute eosinophilic leukemia, acute erythroleukemia, acute lymphocytic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, B-cell promyelocytic leukemia, B-cell lymphoma, MALT lymphoma, precursor T-lymphocytic lymphoma, T-cell lymphoma, mast cell leukemia, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, angioimmunoblastic T-cell lymphoma. In another embodiment, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia) or acute myeloid leukemia.

[0066] In another embodiment, the cancer is selected from the group consisting of head and neck squamous cell carcinoma, adenocarcinoma, esophageal squamous cell carcinoma, gastric adenocarcinoma, colon adenocarcinoma, hepatocellular carcinoma, biliary tract bile duct carcinoma, gallbladder adenocarcinoma, pancreatic adenocarcinoma, breast ductal carcinoma in situ, breast adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, bladder transitional cell carcinoma, bladder squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, endometrial carcinoma, penile squamous cell carcinoma, and skin squamous cell carcinoma.

[0067] In another embodiment, the precancerous tumor is selected from the group consisting of leukoplakia of the head and neck, Barrett's esophagus, gastric metaplasia, colon adenoma, chronic hepatitis, bile duct hyperplasia, pancreatic intraepithelial neoplasia, atypical adenomatous hyperplasia of the lung, bladder dysplasia, cervical intraepithelial neoplasia, penile intraepithelial neoplasia, and actinic keratosis of the skin.

[0068] In another embodiment, the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, lung cancer, breast cancer, head and neck cancer, prostate cancer, melanoma, and colorectal cancer.

[0069] In another embodiment, the cancer is selected from colorectal cancer, breast cancer, lymphoma, melanoma, renal cancer, and lung cancer.

[0070] In another embodiment, the cancer has become resistant to conventional cancer treatments. As used herein, the term "conventional cancer treatment" refers to any cancer drug, biologic, or radiation therapy, or combination of cancer drugs and / or biologics and / or radiation therapy, that has been tested and / or approved for therapeutic use in humans by the U.S. Food and Drug Administration, the European Medicines Agency, or similar regulatory agencies.

[0071] Preferably, the targeting ASCT2 contains 10 The use of compound B for treating tumors with boron neutron capture therapy further includes malignant tumors or metastatic tumors.

[0072] Preferably, the tumor is breast cancer or other solid tumors.

[0073] Further preferably, a method for treating tumors comprises the following two steps:

[0074] (1) The ASCT2-targeting 10 Compound B is administered to the patient externally;

[0075] (2) The compound of step (1) is enriched in tumor cells, and when irradiated with thermal neutrons, the compound has a tumor-treating effect.

[0076] Beneficial effects of the present invention:

[0077] The present invention provides a new boron-containing compound, which is composed of 10 Compound B and a scaffold portion targeting ASCT2 are combined. Compared to boron-containing compounds disclosed in the prior art, the boron-containing compound obtained by the technical solution of the present invention not only has the advantages of high targeting for ASCT2-directed therapy and spatial localization provided by neutron beams, but also has a very high boron enrichment concentration in tumors, achieving a good therapeutic effect without the need for high-intensity neutron irradiation. This significantly enhances the pharmaceutical effect of the boron-containing compound and reduces the damage caused by neutron irradiation to normal healthy tissue, which is of great significance in the medical field for tumor treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG1 is a histogram showing the tissue distribution of O02 in the MDA-MB-231 cell transplant tumor model.

[0079] FIG2 is a histogram showing the tissue distribution of O01-A in the MDA-MB-231 cell transplant tumor model.

[0080] FIG3 is a histogram showing the tissue distribution of O07 in the MDA-MB-231 cell transplant tumor model.

[0081] FIG4 is a histogram showing the tissue distribution of BPA in the MDA-MB-231 cell transplant tumor model. DETAILED DESCRIPTION

[0082] It should be noted that the boron (B) in the present invention is boron 10 ( 10 B).

[0083] the term

[0084] ASCT2: Glutamine import is carried out by amino acid transporters belonging to the SLC family. ASCT2 (alanine-serine-cysteine ​​transporter 2, SLC1A5) is a sodium-dependent neutral amino acid transporter encoded by the SLC1A5 gene and is primarily localized to the cell membrane. ASCT2 is considered an essential exchanger of neutral amino acids and is involved in both glutamine uptake and glutamine efflux. It mediates the exchange of amino acid substrates, which is crucial for glutamine uptake in rapidly growing tumor cells (Kekuda, R., Prasad, P.D., Fei, Y.J., Torres-Zamorano, V., Sinha, S., Yang-Feng, T.L., Leibach, F.H., Ganapathy, V., 1996. Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line.).

[0085] As used herein, the term "alkyl" or "alk" refers to a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups, including but not limited to optionally substituted alkyl, cycloalkyl, aryl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, thioether, sulfo-oxo or thiol. A "lower alkyl group" is an alkyl group containing one to six carbon atoms, for example, one to four alkyl groups.

[0086] Throughout the specification, "alkyl" or "alk*" is generally used to refer to both unsubstituted and substituted alkyl groups.

[0087] As used herein, the term "cycloalkyl" is a non-aromatic carbonyl ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" is a cycloalkyl group as defined above, and included within the meaning of the term "cycloalkyl," in which at least one of the ring carbon atoms is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups may be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups may be substituted with one or more groups, including, but not limited to, optionally substituted alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol groups, as described herein.

[0088] As used herein, the term "aryl" or "aryl*" refers to a group comprising any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term "aryl" also includes "heteroaryl," which is defined as a group comprising an aryl group having at least one heteroatom incorporated within the aryl ring. Examples of heteroatoms include but are not limited to nitrogen, oxygen, sulfur, and phosphorus, with 1-2 nitrogen atoms being preferred. Similarly, the term "non-heteroaryl," also encompassed within the term "aryl," defines a group comprising an aryl group that does not contain heteroatoms. Aryl groups may be substituted or unsubstituted. Aryl groups may be substituted with one or more groups, including but not limited to optionally substituted alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxy, ketone, azide, nitro, silyl, boronyl, amino, trifluoromethoxy, sulfo-oxo, or thiol.

[0089] As used herein, the term "heterocycle" refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Heterocycles include pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, oxadiazole, including, for example, 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3 , 4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, imidazolethiadiazole, imidazoleoxadiazole, imidazolethiazole, thiazoletriazole, etc.

[0090] In this specification, "halogen" means fluorine, chlorine, bromine or iodine.

[0091] The boron-containing compounds of the present invention are intended to include all stereoisomers, geometric isomers, and tautomers conforming to the general structural formula I, wherein each atom (excluding the boron atom) includes all isotopes. When one or more chiral centers are present in the molecule, the compound of the general structural formula I may be in the form of a pharmaceutically acceptable racemic mixture or a single stereoisomer.

[0092] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0093] Example 1: Preparation of Compound O07

[0094] Process Description: 8g O00, 23.9g 1-benzyl-N-benzyloxycarbonyl-L-glutamic acid, 13.4g EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), 7.9g DMAP (4-dimethylaminopyridine), and 100mL DMF were accurately weighed into a 250mL three-necked flask and reacted at 20-25°C for 12 hours. After monitoring with a plate, the reaction was complete, and water was added. The solution was extracted with EA. The aqueous layer was then added with EA and the extraction was repeated twice. The organic phases were combined and concentrated to dryness. The eluate was purified by column chromatography and concentrated to dryness. Acetic acid and hydrogen bromide were added. The reaction was continued at 20-25°C for 3 hours, concentrated to dryness, and lyophilized to yield 3.41g O07.

[0095] The compounds in Table 1 below were prepared according to the method provided in Example 1.

[0096] Table 1

[0097] Example 2 Cytotoxicity and cellular uptake assay

[0098] This study used MDA-MB-231 (human breast cancer cell line) and MDA-KB2 (human breast cell line). Cells in the logarithmic growth phase were collected, counted, and resuspended in complete culture medium to adjust the cell concentration to 2×10 5 Cells were seeded at 100 μl / mL in a 96-well plate, and 100 μl of cell suspension was added to each well. The cells were incubated in a 37°C, 100% relative humidity, 5% CO2 incubator for 24 hours.

[0099] The stock solution of the compound of the present invention was diluted to 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.062 mM using complete culture medium. A total of 8 concentration gradients were set up, with 6 replicates for each gradient. The culture medium in the wells was aspirated, and 100 μl of the prepared drug-containing culture medium was added thereto in sequence. The control group was added with complete culture medium, and the blank control group was a complete culture medium without cells and compounds. Each experimental group had 6 replicates. The 96-well plate was incubated in an incubator at 37°C, 100% relative humidity, and 5% CO2 for 24 hours. The cell activity was determined by the CCK8 kit, and the concentration / inhibition rate curve was drawn with the drug concentration as the horizontal axis and the inhibition rate as the vertical axis. The IC value of the compound was calculated based on the curve. 50 value.

[0100] Cells were transferred to 10 cm culture dishes and grown to a cell density of 60-70%. The dishes were washed twice with PBS and then incubated in a 37°C, 5% CO2 incubator for 24 hours. Cells were harvested and counted, and digested in a 120°C metal bath with 0.1 mL of concentrated nitric acid for 40 minutes. After dilution with ultrapure water, the B content was determined by ICP-MS. B uptake was calculated based on the cell population.

[0101] The results are shown in Table 2 below.

[0102] Table 2

[0103] As can be seen from the data in Table 2 above, the IC50 values ​​of compounds with different structures for MDA-MB-231 (human breast cancer cell line) and MDA-KB2 (human mammary gland cell line) cells are similar, while the differences in B cell uptake are more pronounced. Among them, compounds such as O01-A, O07, L-O02-A, L-O03, O16, O18, O21, O25, O26, O27, O28, O30, O33, O34, O39, and O23-IMP0 exhibit higher cellular uptake, meet the requirements of BNCT therapy, and have great development potential.

[0104] Example 3 Tissue distribution test

[0105] This study used female Balb / c mice bearing tumors, and the tumor cell line was MDA-MB-231 (breast cancer). The tumor volume reached 150-200 mm. 3After that, drug administration began. Animals were given a single intravenous injection of 10 mg / kg of the corresponding drug. Whole blood and tissue samples were collected at five time points: 0, 0.5, 1, 2, and 4 hours after administration. After collecting the complete blood sample, samples were collected from whole blood, heart, liver, spleen, lung, kidney, pancreas, brain, tumor, muscle, fat, stomach, large intestine, small intestine, ovary, and breast. The total B concentration in whole blood and tissues was analyzed by ICP-MS, and the boron concentration in tumor, tissues, and whole blood was finally calculated.

[0106] Each group included 15 female mice, with three female mice at each time point. The average boron concentrations in tumors, various tissues, and whole blood were calculated at each time point. For example, the average boron concentrations for compounds O02, O01-A, O07, and BPA are shown in Tables 3-6 below, and the corresponding tissue distribution patterns are shown in Figures 1-4.

[0107] Table 3

[0108] Table 4

[0109] Table 5

[0110] Table 6

[0111] The data presented in Tables 3-6 and the corresponding tissue distribution Figures 1-4 indicate that, following a single intravenous injection of compounds O02, O01-A, O07, and BPA into unfed female tumor-bearing mice, boron was primarily distributed in the kidneys and tumors, with virtually no detectable concentration in fat. Peak concentrations in tumor tissue (15081.38 ng / g, 11019.87, 10259.83, and 9755.78 ng / g, respectively) were reached at 0.5, 1, 0.5, and 2 hours after administration for O02, O01-A, O07, and BPA, respectively. Calculated T / B ratios reached 1.7, 3.1, 3.1, and 2.0, respectively. Boron distribution and clearance from tissues is rapid over time, preventing tissue accumulation.

[0112] The B element concentrations of the remaining compounds in animal whole blood, tumor tissue, and normal breast tissue were detected by ICP-MS, and the T / N and T / B ratios were calculated to evaluate the targeting and BNCT therapeutic effects of the compounds. The experimental results are statistically shown in Table 7.

[0113] Table 7

Claims

1. [Corrected 11.02.2025 according to Rule 26] A targeted ASCT2-containing 10 Compound B or a pharmaceutically acceptable salt thereof has a structure shown in Formula I: in: R1 is R2, R3 and R4 are each independently lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, aldehyde, lower acyloxy, lower alkylcarboxylic acid, lower alkylcarbonyl, lower carboxylic acid ester, lower carboxamide R2 substituents may be linked together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring containing zero to three heteroatoms, such as methylenedioxy or ethylenedioxy. m and n are each independently 0-4, and m+n<5; W is -NHCO-, -CONH- or -CH2-; p is 1-10, preferably 1-5, most preferably 1-3; R5 and R6 are each independently lower alkyl, lower haloalkyl, lower cycloalkyl, lower alkoxy, lower haloalkoxy, hydrogen, lower alkanoyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, trichloroethoxycarbonyl, methylcarbonyl, ethylcarbonyl, trifluoroacetyl, phthaloyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, 2-trimethylsilylethylsulfonyl, allyl, benzyl, ethyl dimethylbenzoate, p-methoxybenzyl, or trityl. Optionally, R5 and R6 may be linked together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring containing zero to three heteroatoms. Y is an alkyl group, an alkylcarboxylic acid group, an alkylcarbonyl group, an alkylcarboxylate group, an alkylamide group, a cyano group, an amino group, an alkylamino group, an arylamino group, an amide group, a carboxyl group, an arylamide group, an alkoxycarbonyl group, an aminoacyl group, a hydrazineacyl group or -COOR7, wherein R7 is a hydrophobic group; A, B, D, E and G are each independently C and N and at least three of A, B, D, E and G are C.

2. The compound according to claim 1, wherein the compound of formula I has a structure shown in general formula Ia: wherein R1, R2, R3, R4, R5, R6, W, m, n, p, A, B, D, E and G are defined as those in claim 1, and R7 is a hydrophobic group.

3. The compound according to claim 2, wherein R7 is tert-butyl, aryl or aralkyl.

4. The compound according to claim 2, wherein R7 is not methyl or hydrogen.

5. The compound according to claim 2, wherein the hydrophobic group is selected from the group consisting of an alkyl group, an unsaturated chain hydrocarbon group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aryl-substituted alkyl group, a cycloalkyl-substituted alkyl group, and an aromatic amide group.

6. The compound according to claim 1, wherein the compound of formula I has a structure shown in general formula Ib: wherein R1, R2, R3, R4, R7, W, m, p, A, B, D, E and G are defined as in claim 2.

7. The compound according to claim 1, wherein the compound of formula I has a structure shown in general formula Ic: wherein R1, R3, R4, R7, W, m, p, A, B, D, E and G are defined the same as in claim 2.

8. The compound according to claim 1, wherein the compound of formula I has a structure shown in general formula Id: wherein R1, R7, W, m, p, A, B, D, E and G are defined as those in claim 2.

9. The compound of claim 1 , wherein the pharmaceutically acceptable salt comprises hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-isothionate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthenate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, edisylate, benzenesulfonate, and p-toluenesulfonate.

10. The compound according to claim 1, selected from the following structures:

11. A method for preparing a compound of formula I, comprising condensing an intermediate compound of formula II with an intermediate compound of formula III to obtain a compound of formula I, Wherein R1, R2, R3, R4, R5, R6, W, m, n, p, A, B, D, E and G are defined as in claim 1, and W1 and W2 are each independently -NH2 or -COOH and are different.

12. The preparation method according to claim 11, when R5 and R6 are both hydrogen, the compound of formula III needs to be protected by a protecting group, and the protecting group is selected from benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), methylcarbonyl (Meoc), ethylcarbonyl (Etoc), trifluoroacetyl (Tfa), phthaloyl (Pht), p-toluenesulfonyl (Tos), o-nitrobenzenesulfonyl (oNbs), p-nitrobenzenesulfonyl (pNbs), 2-trimethylsilylethylsulfonyl (SES), allyl (Al), benzyl (Bn), ethyl dimethylbenzoate (Dmb), p-methoxybenzyl (Pmb), and trityl (Trt).

13. Use of the compound according to any one of claims 1 to 10 in the preparation of a cancer drug for BNCT therapy. The use according to claim 13 , wherein the cancer comprises a malignant tumor or a metastatic tumor.

15. The use according to claim 13, wherein the cancer is selected from the group consisting of adrenal carcinoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous nevus, melanoma in situ, apical spiral leukemia, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenoid tumor, adenosquamous carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia, adult T-cell lymphoma, aggressive NK-cell leukemia, AID S-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell promyelocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, brown tumor, breast cancer, brain cancer, malignant tumor, carcinoma in situ, cartilage tumor, cementum tumor, myeloid sarcoma, enchondroma, villous tumor Meningeal cancer, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, diffuse large B-cell lymphoma, endocrine gland tumors, esophageal cancer, fibroma, fibrosarcoma, gastrointestinal cancer, germ cell tumor, giant cell tumor of bone, glioma, glioma, glucagonoma, gallbladder cancer, gastric cancer, head and neck cancer, hematological cancer, intestinal cancer, kidney cancer, laryngeal cancer, liposarcoma, lung cancer, lymphangioma, lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malignant fibrous histiocytoma, mast cell carcinoma These include: leukemia, melanoma, meningioma, multiple myeloma, muscle tissue tumors, nasopharyngeal carcinoma, neuroblastoma, neurofibroma, nodular melanoma, eye cancer, oncocytoma, oral cancer, osteosarcoma, ovarian cancer, plasma cell tumor, prostate cancer, pancreatic cancer, renal cell carcinoma, rhabdoid tumor, rhabdomyosarcoma, rectal cancer, sarcoma, skin cancer, small cell carcinoma, soft tissue sarcoma, squamous cell carcinoma, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, laryngeal cancer, genitourinary tract cancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' cell carcinoma. The use according to claim 14 , wherein the cancer is breast cancer.

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