Compound targeting c-Met, radionuclide labeled complex based on compound and application of compound and radionuclide labeled complex

Abstract

The invention provides a c-Met targeting compound, a radionuclide labeled complex based on the c-Met targeting compound and application of the c-Met targeting compound and the radionuclide labeled complex. The c-Met targeting compound has a structure as shown in a formula (I) or (II). After being labeled by radionuclide such as 68Ga, the c-Met targeting compound shows relatively high tumor uptake, can be used for specifically detecting tumors with high expression of c-Met receptors, such as brain glioma, colon cancer, liver cancer and gastric cancer, and has a wide clinical application scene.

Description

Technical Field

[0001] This invention belongs to the field of medical diagnostics and treatment, and specifically relates to a compound that targets c-Met, radiolabeled complexes based thereon, and their use in the preparation of medicaments for the diagnosis, prevention and / or treatment of diseases characterized by high c-Met expression. Background Technology

[0002] Mesenchymal-epithelial transition factor (c-Met) is a multifunctional transmembrane tyrosine kinase with autonomous phosphorylation activity, encoded by the MET proto-oncogene and mainly expressed in epithelial and endothelial cells. c-Met is a heterodimer composed of an extracellular α-chain (50 kDa) and a transmembrane β-chain (145 kDa). Under normal circumstances, the c-Met signaling pathway is only fully activated in adults during wound healing and tissue regeneration. Human hepatocyte growth factor (HGF) is currently the only known natural ligand with high affinity for c-Met. When HGF binds to c-Met, it induces c-Met dimerization and activates intracellular signaling pathways, thereby regulating a series of biological effects such as cell growth, survival, movement, and proliferation (Nature Reviews Molecular Cell Biology, 2003, 4(12): 915-925). A growing body of research confirms that c-Met signaling is often abnormally activated in a variety of solid tumors, including glioma, lung cancer, prostate cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, and cervical cancer (Nat Med. 2011; 18: 74-82. Metab Brain Dis. 2013; 28: 355-66. Cancer Res. 2000; 60: 4277-4283. Eur J Nucl Med Mol Imaging 2024; 51, 656-668). Furthermore, high expression of c-Met in tumors often promotes tumor proliferation, metastasis, invasion, growth, and leads to poor patient prognosis (Journal of Clinical Oncology, 2012, 30(26): 3287. Int J Cancer. 1996; 66: 678-685). Based on the role of c-Met in tumors, the development of diagnostic and therapeutic drugs targeting c-Met has become a hot topic of research.

[0003] Currently, major pharmaceutical companies are actively entering the market for small molecule therapies targeting c-Met. To date, eight small molecule drugs have been approved for marketing, including cabozantinib, carmatinib, crizotinib, ensartinib, terpoxtinib, gumetinib, cevotinib, and beritinib. Despite the intense competition in drug development, it is undeniable that the overall response rates of these drugs vary significantly in clinical application. Immunohistochemical staining (IHC) analysis shows that cancer patients with high c-Met expression show significant improvements in progression-free survival and overall survival after treatment; while cancer patients with low c-Met expression show no significant improvement in prognosis (Cancer. 2009; 115: 140-148. Clin Transl Oncol. 2014; 16: 173-177. Cancer Res. 2005; 65: 9355-9362.). Furthermore, the development of resistance to c-Met inhibitors in tumors (Cancer Treat Rev. 2013; 39: 793-801) compels researchers to develop diagnostic tools as early as possible for screening tumor patients with high c-Met expression and for real-time dynamic monitoring of drug resistance.

[0004] Nuclear medicine imaging technology, due to its advantages such as unlimited penetration, high sensitivity, high spatiotemporal resolution, and precise quantification, is widely used in preclinical research and clinical practice. Nuclear medicine imaging probes developed for c-Met mainly focus on three types: antibodies, peptides, and small-molecule radioactive probes. Literature review indicates that the number of small-molecule-based c-Met-targeting radioactive probes is currently extremely limited. 11 C-SU11274 was used to evaluate c-Met expression levels in a mouse subcutaneous tumor model of non-small cell lung cancer (NSCLC) (J. Med. Chem. 2010, 53, 1, 139-146). Imaging results showed that... 11 The uptake SUV of C-SU11274 in c-Met-positive tumors is only about 0.5. Meanwhile, 11 The half-life of C is only 20.38 min, which limits the widespread application of this probe. 18 Imaging results of F-FPC in a c-Met-positive NSCLC mouse model showed that it had extremely high non-specific uptake in the liver and abdomen, while exhibiting slight defluorination (Bioorganic & Medicinal Chemistry, 2020, 28(15): 115577). 18 Although F-AZC showed good tumor uptake in both orthotopic and subcutaneous mouse models of U87MG glioma, its high uptake in the liver, intestine, and stomach resulted in poor imaging contrast (Eur J Nucl Med Mol Imaging 2024; 51, 656-668).

[0005] CN106008339A discloses a radioactive c-Met-targeting affinity small molecule compound, but the patent and related papers report... 18 Although F-AZC shows good radioactive uptake at the tumor site, it also exhibits high radioactive uptake in other normal tissues and organs, such as the liver and abdomen, which limits imaging contrast. Summary of the Invention

[0006] Considering the severe scarcity of existing c-Met-targeting radioactive small molecule compounds, their low uptake in tumors, and poor imaging contrast, this invention provides a compound represented by formulas (I) and (II). This compound can specifically target the c-Met protein highly expressed in tumors, increasing tumor uptake. Furthermore, this invention has discovered that radionuclide-labeled complexes based on this compound can specifically recognize c-Met targets and increase tumor uptake, thereby improving tumor detection rate and / or therapeutic effect.

[0007] Based on this, one object of the present invention is to provide a compound represented by formula (I) or (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof.

[0008] Another object of the present invention is to provide a radionuclide-labeled complex, which is obtained by labeling a radionuclide with a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a transisomer, a polymorph, a solvate, or an isotopically labeled compound.

[0009] Another object of the present invention is to provide a method for preparing the radionuclide-labeled complex.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising one or more of the following: compounds represented by formula (I) and (II), pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates, and isotopically labeled compounds, as well as radionuclide-labeled complexes, and optionally pharmaceutically acceptable excipients.

[0011] Another object of the present invention is to provide the use of the compounds shown in (I) and (II) or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates or isotopically labeled compounds, or the radionuclide-labeled complexes thereof, in the preparation of reagents for inhibiting c-Met activity.

[0012] Another object of the present invention is to provide the use of the compounds of formula (I) and (II) or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates or isotopically labeled compounds, or the radionuclide-labeled complexes thereof, in the preparation of medicaments or reagents for the diagnosis, prevention and / or treatment of diseases characterized by high c-Met expression.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] In a first aspect, a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a transisomer, a polymorph, a solvate, or an isotopically labeled compound thereof, is provided.

[0015]

[0016] R1, R2, R4, and R5 are each independently selected from H, methoxy, and halogen, with H being the preferred choice.

[0017] R3 is selected from -Br, -NH2, -OH, Where R a R b R c Each group is independently selected from H, nitro (-NO2), halogen, C1-C8 alkyl, C1-C8 alkoxy, -OH, -NH2 and aliphatic carboxyl groups, preferably nitro;

[0018] (i) When R3 is selected from -Br, -NH2 or -OH: R6 is absent, or is -(W1)n1-(W1)n2-(W1)n3-(W1)n4-(W1)n5-(W1)n6-; wherein n1 to n6 are each independently 0 or 1, and not all of them are 0; each W1 is independently selected from the following structures: -(CO)(CR a R b )n T NH-, where n7 is an integer between 1 and 4, such as 1, 2, 3, 4, and each R a R b Each is independently selected from H, C1-C4 alkyl (e.g. methyl); each W1 is connected to the others by carbonyl and N phases to form amide bonds, and three or more adjacent W1s are not completely identical;

[0019] (ii) When R3 is selected Time: R6 is -(W1)n1-(W1)n2-(W1)n3-(W1)n4-(W1)n5-(W1)n6-; where n1 to n6 are each independently 0 or 1, and not all of them are 0; each W1 is independently selected from the following structures: -(CO)(CR a R b )n7NH-, where n7 is an integer between 1 and 4, for example, 1, 2, 3, 4, and each R a R b Each is independently selected from H and C. 1- C4 alkyl (e.g., methyl); each W1 is connected by a carbonyl group and an N phase to form an amide bond, and three or more adjacent W1s are not identical, and at least one W1 is selected from the following structures:

[0020] R7 is Where X is -(CH2)n8-, and n8 is an integer from 1 to 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, preferably an integer from 1 to 8; wherein each CH2 is independently selected from -O-, -NH-, -(CO)-, -NH(CO)-, -(CO)-NH- or The substitution condition is that no two adjacent CH2 groups are replaced simultaneously; Y is attached to X by substituting one H in the X group; Y is -NH-, -(CO)-, -NH(CO)-, or -(CO)-NH-; preferably, R7 is More preferably

[0021] L is absent, or L is -(CH2)n9-, where n9 is an integer from 1 to 40, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, preferably an integer from 1 to 30, more preferably an integer from 1 to 18; wherein each CH2 group is independently and optionally replaced by -O-, -NH-, -(CO)-, -NH(CO)-, or -(CO)NH-, provided that no two adjacent CH2 groups are replaced simultaneously; preferably, L is absent, or L is -NH-(CH2)n10(OCH2CH2)n 11 (CO)-, n10, n 11 Independently, L is an integer from 1 to 4; more preferably, L is non-existent, or L is -NH(CH2)2OCH2CH2(CO)-;

[0022] In this case, the substituent positions of L and R6 can be interchanged;

[0023] C is a group derived from bifunctional chelating agents or therapeutic drugs.

[0024] Bifunctional chelating agents are chelating agents capable of simultaneously chelating radionuclides and linking targeted molecular probes, wherein the groups derived from the bifunctional chelating agent are selected from:

[0025] Preferred

[0026] The therapeutic drugs include small molecule inhibitors (such as olaparib, crizotinib, etc.), monoclonal antibody drugs (such as trastuzumab, rituximab, pembrolizumab), biological alkylating agents (such as oxaliplatin), cytotoxic drugs (doxorubicin), hormone drugs (dexamethasone), and biological response modifiers (ubenmethasone), etc.

[0027] In some implementations, R1, R2, R4, and R5 are all H.

[0028] In some embodiments, R3 is Br, NH2, or 3-nitrobenzylamine.

[0029] In some embodiments, when R3 is selected from -Br, -NH2, or -OH, R6 is absent, or is selected from the following structures: Preferably, R6 is absent, or is selected from the following structures:

[0030] In some implementations, when R3 is selected from When R6 is selected from the following structures: Preferred

[0031] In some implementations, R7 is selected from the following structures: Preferred

[0032] In some embodiments, L is absent, or L is -(CH2)n9-, where n9 is an integer from 1 to 30, more preferably an integer from 1 to 18; wherein each -CH2- is independently and optionally replaced by -O-, -NH-, or -(CO)-, provided that no two adjacent -CH2- groups are replaced; preferably, L is absent, or L is -NH-(CH2)n10(OCH2CH2)n 11 (CO)-, n10, n 11 Each is an integer from 1 to 4, for example, 1, 2, 3, 4; more preferably, L is non-existent, or L is -NH(CH2)2OCH2CH2(CO)-.

[0033] In some implementations, C is selected from... Preferred In some embodiments, the compound represented by formula (I) or (II) is selected from the following structures:

[0034]

[0035]

[0036] The definitions of R6, R7, and L are as described above.

[0037] In some embodiments, the compounds of formulas (I) and (II) are selected from the following structures:

[0038]

[0039]

[0040]

[0041] Secondly, the present invention provides a radionuclide-labeled complex, which is obtained by labeling a radionuclide M with a compound of formula (I) or (II) as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof. The radionuclide-labeled complex can be used as a tumor radiodiagnostic probe, that is, as a radionuclide diagnostic probe or a radionuclide therapeutic probe.

[0042] The radionuclide M includes radiodiagnostic radionuclides and radiotherapy radionuclides.

[0043] The radiodiagnostic nuclide may be selected from, for example: 86 Y、 18 F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 Any one of the following, preferably: 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99m Tc, 124 Any one of the following: Grade I;

[0044] The radiotherapy nuclide may be selected from, for example: 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Any one of Th, etc.; preferably 67 Cu、 90 Y、 125 1. 131 I, 177 Lu、 223 Ra、 225 Ac、 211 Any one of At, etc.; more preferably, 68 Ga、 177 Lu or 90 Y.

[0045] In some embodiments, the structure of the radionuclide-labeled complex is shown in formulas (III) and (IV):

[0046]

[0047] in,

[0048] The definitions of L and R1-R7 are as described above;

[0049] M is defined as described above; preferably, M is selected from... 68 Ga、 177 Lu and 90 Any one of Y.

[0050] In some embodiments, the radionuclide-labeled complex has a structure selected from the following:

[0051]

[0052]

[0053]

[0054] Thirdly, the radionuclide-labeled complexes of the present invention can be prepared by using a radionuclide-containing compound and the compounds of formulas (I) and (II) described in the first aspect of the present invention according to various existing labeling methods. Preferred labeling methods of the present invention may be the wet method or the freeze-drying method described below, but are not limited thereto.

[0055] The wet labeling method includes the following steps: dissolving an appropriate amount of the compound of formula (I) or (II) of this invention, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound in a buffer solution or deionized water to obtain a solution; adding a radioactive nuclide solution to the obtained solution, and reacting in a sealed environment for 5-40 minutes to generate a radioactive nuclide-labeled complex;

[0056] The lyophilization labeling method includes the following steps: dissolving an appropriate amount of the compound of formula (I) or (II) of this invention, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, transisomer, polymorph, solvate, or isotopically labeled compound, in a buffer solution or deionized water to obtain a solution; after sterile filtration, the obtained solution is dispensed into containers, lyophilized, and then sealed to obtain a lyophilized drug box; an appropriate amount of acetic acid solution or buffer solution is added to the lyophilized drug box to dissolve it, and then the corresponding radionuclide solution is added, and the reaction is sealed for 5-40 minutes to generate a radionuclide-labeled complex. The dispensing container is preferably a cryovial or a controlled antibiotic vial. Excipients, such as mannitol or ascorbic acid, can be added to the drug box depending on the lyophilized powder forming process, and the optimal drug box forming can be achieved by adjusting the amounts of the compound of formula (I) or (II) of this invention and the excipients.

[0057] The products obtained by the wet labeling scheme and the lyophilized labeling scheme can be further processed into injection solutions by conventional methods (such as chromatographic separation and purification, rotary evaporation to remove solvent, dissolving the residue with PBS, water or physiological saline, sterile filtration, etc.).

[0058] The other chemical substances used in the above synthesis steps are commercially available products.

[0059] The buffer solution contains a substance that stabilizes the pH of the reaction solution, and may be acetate, lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, and phosphate, as well as mixtures thereof.

[0060] Fourthly, the present invention provides a pharmaceutical composition comprising one or more of the compounds selected from those represented by formulas (I) and (II) of the first aspect, pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates, and isotopically labeled compounds, as well as one or more of the radionuclide-labeled complexes of the second aspect, and optionally pharmaceutically acceptable excipients.

[0061] Fifthly, the present invention also provides the use of the compounds of formulas (I) and (II) of the first aspect, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates, or isotopically labeled compounds, the radionuclide-labeled complexes of the second aspect, or the pharmaceutical compositions of the fourth aspect, in the preparation of reagents for inhibiting c-Met activity.

[0062] In a sixth aspect, the present invention also provides the use of the compounds of formulas (I) and (II) of the first aspect, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates, or isotopically labeled compounds thereof, the radionuclide-labeled complexes of the second aspect, or the pharmaceutical compositions of the fourth aspect, in the preparation of medicaments or reagents for the diagnosis, prevention, and / or treatment of diseases characterized by high c-Met expression.

[0063] In some embodiments, the present invention provides the use of the compounds of formulas (I) and (II) of the first aspect or pharmaceutically acceptable salts thereof, the radionuclide-labeled complexes of the second aspect, or the pharmaceutical compositions of the fourth aspect in the preparation of medicaments or reagents for radionuclide therapy or imaging of c-Met-overexpressing tumors.

[0064] In the applications described in this invention, the complex can be prepared as an injection and administered via intravenous injection, but is not limited thereto.

[0065] In a seventh aspect, the present invention provides a method for diagnosing or treating a disease characterized by high c-Met expression, comprising administering to a patient an effective dose of a compound of formula (I) or (II) of the first aspect or a pharmaceutically acceptable salt thereof, a radiolabeled complex of the second aspect, or a pharmaceutical composition of the fourth aspect.

[0066] In this invention, the diseases characterized by high c-Met expression include, but are not limited to: glioma, colorectal cancer, gastric cancer, liver cancer, lung cancer, prostate cancer, breast cancer, esophageal cancer, pancreatic cancer, ovarian cancer, and cervical cancer. Attached Figure Description

[0067] Figure 1The HPLC purity chromatogram for compound 1 in Example 1 is shown.

[0068] Figure 2 The HPLC purity chromatogram for testing non-radioactive Ga-2 in Example 1.

[0069] Figure 3 To test Ga-1 and in Example 2 68 Ga-1 HPLC comparison chart.

[0070] Figure 4 For testing Example 3 68 Stability study of Ga-1 after incubation in PBS for different times.

[0071] Figure 5 For testing Example 4 68 PET / CT images of Ga-2 injected into U87MG tumor-bearing mice at 0.5, 1, and 2 hours. (The white dashed circles represent the tumors.)

[0072] Figure 6 In test embodiment 5, A is... 68 Ga-1 (left) and 18 Two-dimensional PET / CT contrast image of F-AZC (right) 0.5 h after injection into U87MG tumor mice, B is... 68 3D PET / CT image of Ga-1 injected into U87MG tumor mice 0.5 h later. (The white dashed circle represents the tumor.)

[0073] Figure 7 For testing Example 6 68 Ga-1 (left) and 68 PET / CT comparison image of Ga-c-Met-1 (right) 120 min after injection into U87MG tumor mice.

[0074] Figure 8 For testing Example 7 68 Ga-7 and 68 Ga-c-Met-2 in vivo PET / CT contrast imaging of a U87MG human brain glioma in the left axillary region. (The white dashed circle represents the tumor.) Detailed Implementation

[0075] The compounds of the present invention, their preparation methods, and applications will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention. Unless otherwise stated, the raw materials and reagents used in the following embodiments are commercially available products or can be prepared by known methods.

[0076] Experimental instruments and consumables

[0077] Animal model: Female BALB / c nude mice (15-20g) aged 5-7 weeks were purchased from the Shanghai Laboratory Animal Center, Chinese Academy of Sciences. The mice were housed under specific pathogen-free conditions. The housing environment was 25℃, humidity 35-45%, with 12-hour light-dark cycles. All animals had free access to water and food.

[0078] Cell model: U-87MG (human brain astroblastoma cells), from the Molecular Imaging Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0079] Chemical reagents: Acetonitrile, dimethyl sulfoxide (DMSO), N,N-diisopropylethylamine (DIPEA), dichloromethane (DCM), and N,N-dimethylformamide (DMF) were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. Trifluoroacetic acid (TFA) and 2-(1H-benzotriazo-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TBTU) were purchased from Saen Chemical Technology (Shanghai) Co., Ltd. DOTA-NHS Purchased from Shanghai Bailingwei Chemical Technology Co., Ltd. Other chemical reagents were purchased from Sinopharm Group or other chemical companies.

[0080] Biological reagents: DMEM medium, RPMI 1640 medium, fetal bovine serum, trypsin, phosphate-buffered saline (PBS), skim milk powder, 4% paraformaldehyde, and MTT kit were all purchased from Dalian Meilun Biotechnology Co., Ltd.

[0081] Example 1. Preparation of Compound 1:

[0082]

[0083] Step 1. Synthesis of compound b

[0084] Compound a (1.0 g, 6.2 mmol) was dissolved in 10 mL of concentrated sulfuric acid. Potassium nitrate (1.58 g, 15.6 mmol) was slowly added under ice-water bath conditions. After the addition was complete, the mixture was transferred to room temperature and allowed to react overnight. The next day, the reaction was monitored by TLC. After the reaction was complete, the reaction solution was poured into 500 mL of ice-water mixture and stirred continuously. A white solid precipitated continuously. The solution was filtered to obtain the target product b (1.3 g, yield 83%). 1 H NMRδ (400MHz, Chloroform-d) 2.67 (s, 3H) and 8.27 (s, 2H).

[0085] Step 2. Synthesis of compound c

[0086] The synthesis of compound c was carried out according to the literature (Organic & Biomolecular Chemistry, 2011, 9(17): 5930-5933). Compound b (1.0 g, 4.54 mmol) was dissolved in 20 mL of ethanol. 10 mL of ammonium sulfide ethanol solution was slowly added to the above solution and heated to reflux. After reacting for 6 hours, the solid in the reaction was removed by filtration. The filtrate was concentrated under reduced pressure to remove ethanol and then separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain yellow solid c (800 mg, yield 90%). 1 H NMR (400MHz, Chloroform-d) δ7.39 (s, 1H), 7.09 (s, 1H), 4.27 (s, 2H), 2.29 (s, 3H).

[0087] Step 3. Synthesis of compound d

[0088] Compound c (1.0 g, 4.54 mmol) was dissolved in 10 mL of 48% hydrogen bromide aqueous solution and placed in an ice-water bath at 0 °C. Sodium nitrite aqueous solution (344 mg, 4.99 mmol) was slowly added to the reaction solution. After reacting for 30 min, 10 mL of 48% hydrogen bromide solution of cuprous bromide (541.6 mg, 4.54 mmol) was added dropwise. After the addition was complete, the reaction solution was transferred to an oil bath at 100 °C to continue the reaction, and the reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, neutralized with ammonia, and the organic phase was extracted with ethyl acetate. The organic phases were combined and washed with ammonia and saturated brine. Finally, compound d (830 mg, 64%) was separated by silica gel column chromatography. 1 H NMR (400MHz, Chloroform-d) 68.07 (s, 1H), 8.01 (s, 1H), 2.65 (s, 3H).

[0089] Step 4. Synthesis of compound e

[0090] Compound d (1.0 g, 3.5 mmol) was dissolved in 8 mL of DMF, and N,N-dimethylformamide dimethyl acetal (DMF-DMA reagent) (2.1 g, 2.42 mL, 17.5 mmol) was added to the reaction solution. The mixture was heated overnight at 100 °C under nitrogen protection. The next day, the dark red reaction solution was cooled to 0 °C, and a water-DMF mixture of sodium periodate (3.76 g, 17.5 mmol) was slowly added with vigorous stirring. After the addition was complete, the mixture was heated at 0 °C for 4 h, then transferred to room temperature and allowed to react overnight. After the reaction was completed by TLC monitoring, the compound was filtered, extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. Finally, compound e (465 mg, yield 44.7%) was obtained by silica gel column chromatography. 1 H NMR (400MHz, Chloroform-d) δ 10.28 (s, 1H, CHO), 8.32 (s, 1H), 8.22 (s, 1H).

[0091] Step 5. Synthesis of compound f

[0092] Compound e (1.12 g, 3.75 mmol) was dissolved in a mixture of 30 mL ethanol and 12 mL water, and iron powder (1.47 g, 26.3 mmol) and ammonium chloride (2.01 g, 37.5 mmol) were added. The reaction mixture was refluxed for 5 h, filtered, concentrated under reduced pressure, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate to obtain compound f (820 mg, 81%) as a pre-product. This pre-product was not purified and was used in the subsequent reaction. 1 H NMR (400MHz, Chloroform-d) 610.26 (s, 1H, CHO), 8.30 (s, 1H), 8.19 (s, 1H).

[0093] Step 6. Synthesis of compound g

[0094] Compound f (38 mg, 0.14 mmol), 1-piperazine acetaldehyde, and sodium hydroxide were dissolved in an appropriate amount of ethanol and reacted overnight at 80 °C. After filtration, extraction, drying, and separation by silica gel column chromatography, compound g (18 mg, 35% yield) was obtained. 1 H NMR (400MHz, Chloroform-d) δ 8.66 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 3.43 (m, 4H), 3.12 (m, 4H).

[0095] Step 7. Synthesis of compound h

[0096] Compound g (60 mg, 0.16 mmol), 1,1′-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) (10.3 mg, 0.016 mmol), Cs₂CO₃ (62.56 mg, 0.19 mmol), Pd₂(dba)₃ (4.4 mg, 0.0048 mmol), and tert-butyl carbamate (37.5 mg, 0.32 mmol) were dissolved in 5 mL of 1,4-dioxane solution under nitrogen protection. The mixture was reacted overnight in an oil bath at 100 °C. The next day, the reaction solution was cooled to room temperature, filtered, extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography to give compound h (25 mg, 37% yield). 1 H NMR (400MHz, Chloroform-d) δ 8.83 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 3.33 (t, J = 7.0Hz, 4H), 3.02 (t, J = 7.1, 4H), 1.44 (s, 9H).

[0097] Step 8. Synthesis of Compound 1

[0098] Compound h (30 mg, 0.075 mmol) was dissolved in 5 mL of DMF, and DOTA-NHS (190 mg, 0.38 mmol) and DIPEA (97.8 mg, 0.75 mmol) were added. The mixture was stirred at room temperature for 12 hours. After removing the solvent by vacuum concentration, the reaction solution was dissolved in water and filtered through a 0.22 μm filter membrane. The resulting filtrate was purified by preparative HPLC, and compound 1 was obtained as a pale yellow solid (15 mg, yield 29%). 1 H NMR (600MHz, D2O) δ8.38 (dd, J=7.2, 2.5Hz, 1H), 7.26 (dd, J=14.8, 2.0Hz, 1H), 7.16 (d, J=6.1Hz, 1H), 6 .72(s, 1H), 3.77(m, 8H), 3.44(s, 2H), 3.37(m, 18H), 2.56(m, 2H), 2.13(m, 2H). LR-ESI-MS(ESI)+: m / z calcd for C 30 H 41 F3N8O7682.31,found683.64(M+H) + .

[0099] Example 2. Preparation of compound 2:

[0100]

[0101] The preparation method is the same as steps 1 to 6 in Example 1. Then, compound g is directly amide condensed with DOTA-NHS to obtain compound 2.

[0102] Characterization data: 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.41 (s, 1H), 3.22 (m, 32H). 13 C NMR (201MHz, DMSO) 6171.36, 170.11, 169.17, 146.82, 146.22, 140.55, 130.34, 126.51, 126.19, 124.65, 123.29 , 121.14, 112.09, 56.17, 55.27, 53.64, 51.63, 50.95, 49.89, 47.16, 47.02, 44.06, 40.82.LR-ESI-MS(ESI)+: m / z calcd forC 30 H 39 BrF3N7O7745.21, found 784.27(M+K) + .

[0103] Example 3. Preparation of compound 3:

[0104]

[0105] The preparation method followed steps 1-6 of Example 1. Compound g (50 mg, 0.138 mmol), BOC-amino-monoethylene glycol-carboxylic acid (35.6 mg, 0.153 mmol), TBTU (53.48 mg, 0.166 mmol), and DIPEA (114.8 mg, 0.888 mmol) were dissolved in acetonitrile. After reacting for 8 hours, the reaction was monitored by TLC. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layers were combined and separated by silica gel column chromatography to obtain compound i (65.3 mg, yield 82%). 1 H NMR (400MHz, Chloroform-d) δ8.83 (s, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.56 (s, 1H), 5.10 (brs, 1H), 3.89 (s, 2H), 3.79 (m, 4H ), 3.53 (t, J=5.0Hz, 2H), 3.49-3.39 (m, 4H), 3.34-3.26 (m, 2H), 2.67 (t, J=6.1Hz, 2H), 1.41 (s, 9H). LR-ESI-MS (ESI)+: m / z calcd forC 24H 30 BrF3N4O4575.43, found 576.2(M+H) + .

[0106] The synthesis of compound 3 was similar to that of compound 2, except that compound g was replaced by compound i. The characterization data for compound 3 are as follows: 1 H NMR (500MHz, Chloroform-d) 68.48 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.56 (s, 1H), 3.80 (t, J=7.1Hz, 2H), 3.68 (t, J=7.0Hz, 4H), 3.62 -3.56 (m, 2H), 3.45 (s, 5H), 3.47-3.37 (m, 3H), 3.20 (s, 2H), 3.09 (t, J=7.1Hz, 4H), 2.74 (s, 8H), 2.65-2.56 (m, 9H), 2.59-2.54 (m, 2H).

[0107] Example 4. Preparation of compound 4:

[0108]

[0109] The preparation method is the same as in Example 3, except that BOC-amino-monoethylene glycol-carboxylic acid is replaced with Boc-D-glutamic acid to obtain compound j. 1 H NMR (400MHz, Chloroform-d) δ8.88 (t, J=2.8Hz, 2H), 8.26 (s, 2H), 7.94 (d, J=1 .5Hz, 2H), 7.65-7.59(m, 2H), 5.65(d, J=8.1Hz, 1H), 4.85-4.73(m, 1H), 4.18( s, 1H), 4.13 (s, 3H), 3.68 (s, 5H), 3.61-3.42 (m, 8H), 3.15 (q, J=7.1Hz, 1H), 2. 70 (d, J=39.2Hz, 1H), 2.42 (d, J=16.5Hz, 1H), 2.30-2.21 (m, 1H), 1.42 (s, 9H).

[0110] The synthesis of compound 4 was similar to that of compound 3, except that compound i was replaced by compound j. The characterization data for compound 4 are as follows: 1H NMR (500MHz, Chloroform-d) 68.48 (d, J=1.5Hz, 2H), 8.19 (d, J=1.6Hz, 2H), 7.88-7.82 ( m, 2H), 7.74 (d, J=1.5Hz, 2H), 4.41 (dt, J=11.7, 7.0Hz, 1H), 3.72-3.59 (m, 9H), 3.53 (d, J =12.4Hz, 2H), 3.45 (s, 2H), 3.36 (d, J = 12.4Hz, 2H), 3.25 (d, J = 12.3Hz, 1H), 3.19 (d, J = 12.3Hz, 1H), 3.13-3.05 (m, 8H), 2.80-2.68 (m, 9H), 2.65-2.54 (m, 9H), 2.46-2.38 (m, 1H), 2.41-2.34 (m, 1H), 1.92 (m, 1H), 1.78 (m, 1H).

[0111] Example 5. Preparation of compound 5:

[0112]

[0113] The synthesis of compound k was similar to that of compound h, except that tert-butyl carbamate was replaced with 3-nitrobenzylamine. Characterization data are as follows: 1 H NMR (500MHz, Chloroform-d) δ8.41 (s, 1H), 8.20 (s, 1H), 8.14 (dt, J=7.5, 1.6Hz, 1H), 7.88 (d, J=1.4Hz, 1H), 7.65-7.62 (m, 1H), 7.59 (t, J= 7.5Hz, 1H), 7.51-7.45 (m, 1H), 7.38 (d, J=1.6Hz, 1H), 5.89-5.82 (m, 1H), 4.54 (s, 2H), 3.31 (t, J=7.0Hz, 4H), 3.01 (td, J=7.0, 5.0Hz, 4H).

[0114] The synthesis of compound l was similar to that of compound i, except that compound g was replaced with compound k, and BOC-amino-monoethylene glycol-carboxylic acid was replaced with N-[tert-butoxycarbonyl]glycyl-L-proline. Characterization data are as follows: 1H NMR (400MHz, Ch1oroform-d) δ8.79 (d, J=2.4Hz, 1H), 8.31 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.68 (s, 1H), 7.56 (t, J=7.9Hz, 1H ), 7.42(s, 1H), 6.62(s, 1H), 4.89(m, 1H), 4.65(s, 2H), 4.08-3.84(m, 4H ), 3.70-3.29(m, 8H), 3.18-3.09(m, 1H), 2.26-1.89(m, 6H), 1.41(s, 9H).

[0115] The synthesis of compound 5 was performed following that of compound 4, except that compound j was replaced with compound I. The characterization data for compound 5 are as follows: 1 H NMR (600MHz, Chloroform-d) δ8.78 (d, J=2.5Hz, 1H), 8.28 (s, 1H), 8.09-8.02 (m, 2H), 7.82 (d, J=7.7Hz, 1H), 7.53 (s, 1H), 7 .45(t, J=8.0Hz, 1H), 6.36(s, 1H), 4.85(m, 1H), 4.74(s, 2H), 3.98-3.26(m, 16H), 3.09-2.47(m, 12H), 2.20-1.87(m, 12H).

[0116] Example 6. Preparation of compound 6:

[0117]

[0118] The preparation method is the same as in Example 5, except that N-[tert-butoxycarbonyl]glycyl-L-proline is replaced with (S)-1-(3-((tert-butoxycarbonyl)amino)propionyl)-4,4-difluoropyrrolidine-2-carboxylic acid.

[0119] The characterization data are as follows: 1 H NMR (500MHz, Chloroform-d) δ8.41 (d, J=1.5Hz, 1H), 8.19 (d, J=1.2Hz, 1H), 8.15 (dt, J=7.3, 1.6Hz, 1H), 7.89-7.80 (m, 2H), 7.59 ( t, J=7.4Hz, 1H), 7.55 (m, 1H), 7.37 (m, 1H), 5.59 (m, 1H), 4.59 (s, 1H), 4.11-3.69 (m, 10H), 3.57-3.30 (m, 12H), 2.78-2.24 (m, 18H).

[0120] Example 7. Preparation of compound 7:

[0121]

[0122] The preparation method is the same as in Example 6, except that (S)-1-(3-((tert-butoxycarbonyl)amino)propionyl)-4,4-difluoropyrrolidine-2-carboxylic acid is replaced with (S)-1-(3-(2-((tert-butoxycarbonyl)amino)ethoxy)propionyl)-4,4-difluoropyrrolidine-2-carboxylic acid.

[0123] The characterization data are as follows: 1 H NMR (400MHz, Chloroform-d) 68.77 (d, J=2.3Hz, 1H), 8.27 (s, 1H), 8.09-8.03 (m, 1H), 7.93 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7 .55 (s, 1H), 7.46 (t, J=7.9Hz, 2H), 5.14 (m, 1H), 4.71 (s, 2H), 4.11-3.69 (m, 10H), 3.57-3.30 (m, 12H), 2.74-2.30 (m, 22H).

[0124] Example 8. Preparation of compound 8:

[0125]

[0126] The preparation method is the same as in Example 4, except that compound g is replaced with compound h.

[0127] The characterization data are as follows: 1 H NMR (500MHz, Chloroform-d) δ8.35 (d, J=1.5Hz, 2H), 7.80 (d, J=1.4Hz, 2H), 7.59 (d, J=1.4Hz, 2H), 7.40 (d, J=1.6Hz, 2H), 4.41 (dt, J=11.7, 7.0Hz, 1H),

[0128] 3.66-3.25(12H), 3.19(m, 9H), 2.802.45(m, 23H).

[0129] Example 9. Preparation of compound 9:

[0130]

[0131] The preparation method is the same as in Example 6, except that compound k is replaced with compound h.

[0132] The characterization data are as follows: 1H NMR (500MHz, Chloroform-d) δ8.35 (s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 6.72 (s, 1H), 5.43(m, 1H), 4.19-3.65(m, 12H), 3.57-3.30(m, 14H), 2.81-2.20(m, 14H).

[0133] Example 10: 68 Preparation of Ga-labeled radioactive probes

[0134]

[0135]

[0136]

[0137] Radioactivity of compounds 1-9 68 The specific steps for Ga labeling are as follows, taking the labeling of compound 1 as an example:

[0138] Take 0.1M hydrochloric acid from 68 Ge- 68 Elution in Ga generator 68 44 μL of GaCl was mixed with 0.5 μL of a 10 μg / μL aqueous solution of the compound. Then, 400 μL of sodium acetate solution was added to adjust the pH to 4-5. The mixture was then reacted in a metal bath at 95°C for 10 minutes. After the reaction, the reaction solution was diluted with 1 mL of physiological saline and injected into a C18 desalting column using a syringe. The C18 desalting column was then washed multiple times with 10 mL of physiological saline to remove any compounds not bound to compound 1. 68 Ga 3+ Continue eluting until the activity difference between two consecutive washes is less than 10 μCi. Finally, elute the C18 desalting column with 100–200 μL of ethanol to obtain... 68 Ga-1. The radiolabeling of other compounds follows the same method. The radiolabeled compound is characterized by HPLC comparison with the synthesized non-radioactive Ga chelate product. If the peak times and peak shapes are identical, the corresponding radiolabeled compound is considered to have been synthesized.

[0139] Example 11: Preparation of non-radioactive Ga-2

[0140]

[0141] The preparation method is the same as in Example 10, except that radioactive materials are used. 68 Replace GaCl3 with non-radioactive GaCl3.

[0142] Characterization data of Ga-2: LR-ESI-MS (ESI) + m / z calcd for C 30 H 37 BrF3GaN7O7: 812.1, found.813.4(M+H) + .

[0143] Test Example 1: HPLC Purity Determination of Compound 1 and Ga-2

[0144] Compound 1 and non-radioactive Ga-2 were dissolved in water to prepare a solution with a concentration of 1 mg / mL for injection.

[0145] HPLC chromatographic conditions: Thermo Ultimate 3000;

[0146] Chromatographic column: Extend-C18 (Agilent), 5 μm, 4.6 × 100 μm;

[0147] Mobile phase: Phase A: 0.1% trifluoroacetic acid-water solution; Phase B: chromatographic grade methanol. Mobile phase gradient: 10-90% B for 1-8 min, 90% B for 8-15 min;

[0148] Column temperature: 25℃;

[0149] The injection volume was 10 μL;

[0150] Detector: VWD-3400RS fast separation variable wavelength detector; detection wavelength: 254nm.

[0151] The purity determination of other compounds was performed using the same method. The HPLC images of compounds 1 and Ga-2 are shown below. Figure 1 and 2 As shown, the purity of compounds 1 and Ga-2 is both >95%, which meets the test requirements.

[0152] Test Example 2: Non-radioactive standard Ga-1 and 68 HPLC comparison of Ga-1

[0153] Non-radioactive pure Ga-1 was dissolved in water to prepare a solution with a concentration of 1 mg / mL for injection. (Radioactive...) 68 Each Ga-1 injection is 4 μCi / 100 μL;

[0154] HPLC chromatographic conditions: Agilent 35900E Series II;

[0155] Chromatographic column: C18 (Agilent), 5μm, 4.6×250μm;

[0156] Mobile phase: Phase A: 0.1% trifluoroacetic acid-water solution; Phase B: chromatographic grade acetonitrile. Mobile phase gradient: 1-14 min 10-90% B, 14-17 min 95% B, 17-20 min 95-10% B;

[0157] Column temperature: 25℃;

[0158] The injection volume was 10 μL;

[0159] Detection wavelength: 254nm.

[0160] like Figure 3 As shown, radioactivity 68 The peak times of Ga-1 and the non-radioactive standard Ga-1 were consistent. (The difference in HPLC retention time was 0.5 min, which is within the acceptable range.)

[0161] Test Example 3: 68 Stability of Ga-1 after incubation in PBS for different times

[0162] 68 Ga-1 was incubated in PBS for 1 h and 2 h, and then detected by HPLC according to the method in Test Example 2. Figure 4 As shown, its retention time is consistent with that in Example 2, indicating that it is stable in PBS.

[0163] Test Example 4: 68 PET / CT imaging of Ga-2 in rats bearing U87MG human brain gliomas.

[0164] Experimental animals and administration method: U87MG human brain glioma-bearing rats were injected into the right axilla via tail vein.

[0165] Dosage: 150 μCi / 200 μL via tail vein injection 68 Ga-2.

[0166] For injection 68 PET / CT imaging was performed at 0.5, 1, and 2 h after Ga-2 administration to observe the distribution of the probe in mice and its enrichment in tumor areas.

[0167] The results are as follows Figure 5 As shown, the U87MG xenograft model 68 Ga-2 PET imaging revealed high tumor uptake and strong contrast between tumor and background. Tumor accumulation rapidly reached 3.3% ID / g at 0.5 hours post-injection, and the signal remained intact 1 hour after injection. 68After 22 hours of observation, the U87MG tumor in the left anterior axilla of mice was clearly visible, and the tumor uptake reached 2.5% ID / g, indicating that the probe... 68 Ga-2 can remain at the tumor site for a long time.

[0168] Test Example 5: 68 Ga-1 and 18 PET / CT contrastive imaging of F-AZC in rats bearing U87MG human brain gliomas.

[0169] Experimental animals and administration method: U87MG human glioma-bearing mice, administered via tail vein injection.

[0170] Dosage grouping and dosage:

[0171] 68 Ga-1 group: 120 μCi / 200 μl injected via tail vein 68 Ga-1.

[0172] 18 F-AZC group: The images in this group are reported in the literature (Eur J Nucl Med Mol Imaging 2024; 51, 656-668).

[0173]

[0174] For injection 68 PET / CT imaging was performed 0.5 h after Ga-1 to observe the distribution of the probe in mice and its enrichment in the tumor region.

[0175] The results are as follows Figure 6 As shown in Figure A (left), the U87MG xenograft model... 68 Ga-1 PET imaging showed high tumor uptake and strong contrast between tumor and background. Tumor accumulation rapidly reached 3.5% ID / g within 0.5 hours post-injection. Three-dimensional PET / CT imaging ( Figure 6 High uptake of the kidneys in the middle B region indicates 68 Ga-1 is rapidly metabolized by the kidneys. In contrast, 18 F-AZC showed high radioactive uptake throughout the body 0.5 hours after injection. Figure 6 (Figure A, right image) indicates that it is metabolized slowly in vivo, especially showing high uptake in the liver and abdomen, which severely interferes with the application of this type of probe in liver and abdominal tumors. 68 Ga-1's favorable early metabolic properties result in less retention in normal tissues and organs, reducing toxic side effects, and it holds promise for the early diagnosis of liver and abdominal tumors with high c-Met expression.

[0176] Test Example 6:68 Ga-1 and 68 PET / CT contrastive imaging of Ga-c-Met-1 in rats bearing U87MG human brain gliomas.

[0177] compound (CN 106008339A) named 68 Ga-c-Met-1, and compounds 68 Ga-1 for PET / CT contrast imaging.

[0178] Experimental animals and administration method: U87MG human glioma-bearing mice, administered via tail vein injection.

[0179] Dosage grouping and dosage:

[0180] 68 Ga-1 group: 150 μCi / 200 μL injected via tail vein. 68 Ga-1.

[0181] 68 Ga-c-Met-1 group: 100 μCi / 200 μL injected via tail vein. 68 Ga-c-Met-1.

[0182] Two hours after probe injection, PET / CT imaging was performed to observe the distribution of the probe in mice and its enrichment in tumor areas.

[0183] The results are as follows Figure 7 As shown, the U87MG xenograft model 68 Ga-1 PET imaging ( Figure 7 The middle left figure shows high tumor uptake and a strong contrast between the tumor and the background. Two hours after injection, tumor uptake reached 1.3% ID / g, with minimal retention in other normal organs. Its rapid in vivo metabolic properties reduced toxicity to normal organs.

[0184] In comparison, 68 Two hours after injection, Ga-c-Met-1 showed high radioactive uptake throughout the body. Figure 7 The right image shows that it is metabolized slowly in vivo and has extremely low contrast with the surrounding tumor tissue, which seriously interferes with the early diagnosis of this type of probe in tumors with high c-Met expression.

[0185] Test Example 7: 68 Ga-7 and 68 Ga-c-Met-2 in contrasting PET / CT images of rats bearing U87MG human brain gliomas in the left axillary region.

[0186] compound (CN 106008339 A) named 68 Ga-c-Met-2, and compounds 68 Ga-7 for PET / CT contrast imaging.

[0187] Experimental animals and administration method: U87MG human glioma-bearing mice, administered via tail vein injection.

[0188] Dosage grouping and dosage:

[0189] 68 Ga-7 group: 100 μCi / 200 μL injected via tail vein. 68 Ga-7.

[0190] 68 Ga-c-Met-2 group: 100 μCi / 200 μL injected via tail vein. 68 Ga-c-Met-2.

[0191] PET / CT imaging was performed at 0.5, 1, and 2 h after probe injection to observe the distribution of the probe in mice and its enrichment in tumor areas.

[0192] The results are as follows Figure 8 As shown, the U87MG xenograft model 68 Ga-7 PET imaging showed high tumor uptake. Two hours after injection, tumor uptake reached 3.6% ID / g, and the 2-hour tumor radioactive uptake was also significantly higher than in Example 6. 68 Ga-1 (1.3% ID / g).

[0193] In comparison, 68 At 0.5, 1, and 2 hours post-injection, the radiation dose to the tumor was very low, with almost no uptake. These results indicate that the linker between the c-Met targeting molecule and the chelating group in this invention can effectively regulate the radioactive uptake at the tumor site.

Claims

1. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a transisomer, a polymorph, a solvate, or an isotopically labeled compound. in, R1, R2, R4, and R5 are each independently selected from H, methoxy, and halogen; R3 is selected from -Br, -NH2, -OH, Where R a R b R c Each group is independently selected from H, nitro, halogen, C1-C8 alkyl, C1-C8 alkoxy, -OH, -NH2 and aliphatic carboxyl groups; (i) When R3 is selected from -Br, -NH2 or -OH: R6 is absent, or is -(W1)n1-(W1)n2-(W1)n3-(W1)n4-(W1)n5-(W1)n6-; wherein n1 to n6 are each independently 0 or 1, and not all of them are 0; each W1 is independently selected from the following structures: -(CO)(CR a R b )n7NH-, where n7 is an integer between 1 and 4, and each R a R b Each is independently selected from H and C1-C4 alkyl groups; each W1 is connected to the others by carbonyl and N phases to form amide bonds, and three or more adjacent W1s are not completely identical; (ii) When R3 is selected Time: R6 is -(W1)n1-(W1)n2-(W1)n3-(W1)n4-(W1)n5-(W1)n6-; where n1 to n6 are each independently 0 or 1, and not all of them are 0; each W1 is independently selected from the following structures: -(CO)(CR a R b )n7NH-, where n7 is an integer between 1 and 4, and each R a R b Each W1 is independently selected from H and C1-C4 alkyl groups; each W1 is connected by a carbonyl group and an N phase to form an amide bond, and three or more adjacent W1s are not completely identical, and at least one W1 is selected from the following structures: R7 is Wherein, X is -(CH2)n8-, where n8 is an integer from 1 to 10, preferably an integer from 1 to 8; where each CH2 is independently selected from -O-, -NH-, -(CO)-, -NH(CO)-, -(CO)-NH- or The substitution condition is that no two adjacent CH2 groups are replaced simultaneously; Y is connected to X by substituting one H in the X group; Y is -NH-, -(CO)-, -NH(CO)- or -(CO)-NH-; L is absent, or L is -(CH2)n9-, where n9 is an integer from 1 to 40, where each CH2 group is independently and arbitrarily replaced by -O-, -NH-, -(CO)-, -NH(CO)- or -(CO)NH-, provided that no two adjacent CH2 groups are replaced at the same time; In this case, the substituent positions of L and R6 can be interchanged; C is a group derived from bifunctional chelating agents or therapeutic drugs.

2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof, characterized in that, The groups derived from the bifunctional chelating agent are selected from: Preferred More preferably or The therapeutic drugs include small molecule inhibitors, monoclonal antibodies, bioalkylating agents, cytotoxic drugs, hormonal drugs, and biological response modifiers.

3. The compound of formula (I) or (II) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof, characterized in that, R1, R2, R4, and R5 are all H; and / or When R3 is selected from -Br, -NH2, or -OH, R6 is absent, or is selected from the following structures: Preferably, R6 is absent, or is selected from the following structures: When R3 is selected When R6 is selected from the following structures: Preferred and / or R7 is selected from the following structures: Preferred And / or L is absent, or L is -(CH2)n9-, where n9 is an integer from 1 to 30, more preferably an integer from 1 to 18; wherein each -CH2- is independently optionally replaced by -O-, -NH- or -(CO)-, provided that no two adjacent -CH2- groups are replaced; preferably, L is absent, or L is -NH-(CH2)n10(OCH2CH2)n 11 (CO)-, n10, n 11 Each is an integer from 1 to 4; more preferably, L is non-existent, or L is -NH(CH2)2OCH2CH2(CO)-.

4. The compound of formula (I) or (II) according to any one of claims 1-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof, characterized in that, The compounds represented by formula (I) or (II) are selected from the following structures: The definitions of R6, R7, and L are as described in any one of claims 1-3.

5. The compound of formula (I) or (II) according to any one of claims 1-4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound thereof, characterized in that, The compounds of formulas (I) and (II) are selected from the following structures:

6. A radionuclide-labeled complex, which is obtained by labeling radionuclide M with a compound of formula (I) or (II) as claimed in any one of claims 1-5 or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a racemic mixture, a transisomer, a polymorph, a solvate, or an isotopically labeled compound; Specifically, the radionuclide M includes radiodiagnostic radionuclides and radiotherapy radionuclides; Specifically, the radiodiagnostic nuclides are selected from: 86 Y、 18 F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 I, 44 Sc、 47 Any one of Sc, preferred 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99m Tc, 124 Any one of I; Specifically, the radioactive therapeutic nuclide is selected from: 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 203 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Any one of Th; preferred 67 Cu、 90 Y、 125 I, 131 I, 177 Lu、 223 Ra、 225 Ac、 211 Any one of At; more preferably 68 Ga、 177 Lu or 90 Y; Preferably, the structure of the radionuclide-labeled complex is shown in formulas (III) and (IV) below: in, L, R1-R7 are as defined in any one of claims 1-4; M is defined as described above; preferably, M is selected from... 68 Ga、 177 Lu and 90 Any one of Y.

7. The method for preparing the radionuclide-labeled complex according to claim 6, wherein the radionuclide M is labeled using the compound of formula (I) or (II) according to any one of claims 1-5 or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound as a ligand; Specifically, the labeling method is either a wet labeling method or a freeze-drying labeling method; Specifically, the wet labeling method includes the following steps: dissolving an appropriate amount of the compound of formula (I) or (II) according to any one of claims 1-5, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, transisomer, polymorph, solvate, or isotopically labeled compound in a buffer solution or deionized water to obtain a solution; adding a solution of radioactive nuclide M to the obtained solution, and reacting in a sealed environment for 5-40 minutes to generate a radionuclide-labeled complex; Specifically, the lyophilization labeling method includes the following steps: dissolving an appropriate amount of the compound of formula (I) or (II) according to any one of claims 1-5, or its pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, transisomer, polymorph, solvate, or isotopically labeled compound in a buffer solution or deionized water to obtain a solution; after sterile filtration, dispensing the obtained solution into containers, lyophilizing it, and then sealing it to obtain a lyophilized drug box; adding an appropriate amount of acetic acid solution or buffer solution to the lyophilized drug box to dissolve it, then adding the corresponding radioactive nuclide M solution, and reacting in a sealed environment for 5-40 minutes to generate a radioactive nuclide-labeled complex; The radionuclide M is defined as described in claim 6.

8. A pharmaceutical composition comprising one or more selected from the compounds of formula (I) and (II) of any one of claims 1-5, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, transisomers, polymorphs, solvates, isotopically labeled compounds, and radiolabeled complexes of claim 6, and optionally pharmaceutically acceptable excipients.

9. The use of the compound of formula (I) or (II) of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound, or the radionuclide-labeled complex of claim 6, or the pharmaceutical composition of claim 8, in the preparation of a reagent for inhibiting c-Met activity.

10. The use of the compound of formula (I) or (II) of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, transisomer, polymorph, solvate, or isotopically labeled compound, or the radionuclide-labeled complex of claim 6, or the pharmaceutical composition of claim 8, in the preparation of a medicament or reagent for the diagnosis, prevention and / or treatment of diseases characterized by high c-Met expression; Preferred application is in the preparation of drugs or reagents for radionuclide therapy or imaging of tumors with high c-Met expression; Preferably, the tumors with high c-Met expression include glioma, colorectal cancer, gastric cancer, liver cancer, lung cancer, prostate cancer, breast cancer, esophageal cancer, pancreatic cancer, ovarian cancer, and cervical cancer.

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