Multivalency long-acting radiopharmaceuticals and uses thereof

Abstract

The application discloses a multivalent long-acting radiopharmaceutical and application thereof. The multivalent long-acting radiopharmaceutical is a compound shown in formula I, a pharmaceutically acceptable salt, a tautomer, a racemate, a hydrate, a solvate or an isotopically labeled compound thereof: wherein AT represents a fibroblast activation protein specific binding ligand structure; (AT) n represents a targeting moiety and two (AT) n do not appear simultaneously, n is 1, 2 or 3; wherein when n is 3, BT is hydrogen; wherein when n is 1 or 2, BT is a functionally active group; CL is a chelating ligand moiety which chelates a radionuclide; La and Lb are linear, branched or three to seven-membered ring linkers, each independently a bond, a monovalent linker, a divalent linker or a trivalent linker. The multivalent long-acting radiopharmaceutical has excellent pharmacokinetic characteristics, novel and diverse structural design and strong radionuclide adaptability.

Description

Technical Field

[0001] This invention relates to a multivalent long-acting radiopharmaceutical and its application, belonging to the field of radiopharmaceuticals. Background Technology

[0002] Fibroblast activation protein (FAP) is a type II transmembrane serine protease highly expressed in the tumor microenvironment (TME), primarily found in cancer-associated fibroblasts (CAFs). FAP not only participates in the formation and remodeling of the tumor stroma but is also closely related to tumor cell proliferation, invasion, and metastasis, making it an important target for novel tracers. FAP shows significant enrichment in the CAFs of various solid tumors and is overexpressed in over 90% of epithelial tumors, particularly prominent in the TMEs of ovarian, gastric, lung, pancreatic, and breast cancers. This characteristic makes it an important molecular target for tumor diagnosis and treatment.

[0003] Currently, research on radiopharmaceuticals targeting FAP (fibrillated acute excitatory phosphatase) primarily relies on in vivo imaging techniques, among which positron emission tomography / computed tomography (PET / CT) and single-photon emission computed tomography (SPECT / CT) are two advanced medical imaging methods. These two technologies, by fusing functional imaging and anatomical structural information, provide crucial support for clinical diagnosis and treatment decisions.

[0004] Significant progress has been made in the development of small molecule FAP inhibitors. For example, research conducted by the University of Heidelberg in Germany... 68 Ga-FAPI-04 began clinical trials in 2018, and studies have shown that it exhibits high tumor uptake in various cancers. Additionally... 68 Ga-FAPI-46 68 Ga-OncoFAP-DOTAGA, 68 Ga-FAP-2286, 177 Lu-FAP-2286, [ 18 F]FAPI-74 and 177 Lu-PNT6555 has entered clinical trials. The development of small molecule FAP inhibitors is of great significance for improving the specificity of tumor imaging and reducing non-specific uptake by non-target organs.

[0005] While radioligands targeting fibroblast activation proteins have shown great potential in the field of therapeutic applications, their clinical translation is significantly hampered by two inherent limitations: first, their rapid in vivo clearance results in an extremely narrow effective action window; second, their insufficient retention at the tumor site makes it difficult for radiopharmaceuticals to reach effective therapeutic concentrations in target tissues. These pharmacokinetic shortcomings not only severely weaken therapeutic efficacy but also increase the risk of radiation exposure to normal tissues due to non-specific distribution. Therefore, systematically optimizing their pharmacokinetic behavior to effectively enhance tumor-specific uptake and significantly prolong intratumoral retention time has become a key direction for overcoming efficacy bottlenecks and reducing the incidence of adverse reactions.

[0006] To address the limitations in therapeutic efficacy caused by the rapid in vivo clearance and insufficient tumor retention of traditional FAP radioligands, this invention employs a strategy combining polymerization modification and the introduction of retention-extending functional fragments to construct a novel class of FAP-targeting multimeric compounds. This design aims to prolong tumor radiation exposure time while maintaining rapid clearance from non-target organs, thereby improving therapeutic efficacy and reducing the risk of adverse reactions. Summary of the Invention

[0007] Purpose of the invention: The purpose of this invention is to provide a multivalent long-acting radiopharmaceutical and its application.

[0008] Technical solution: This invention provides a multivalent long-acting radiopharmaceutical, wherein the multivalent long-acting radiopharmaceutical is a compound of formula I, its pharmaceutically acceptable salt, tautomer, racemate, hydrate, solvate, or isotope-labeled form: ; Wherein, AT represents the ligand-specific binding structure of fibroblast activation protein; (AT) n Indicates the target portion and two (AT) n They do not appear simultaneously, and n is 1, 2, or 3; when n is 3, BT is hydrogen; when n is 1 or 2, BT is a functional active group. CL is the chelating ligand portion, which chelates radionuclides; La and Lb are connectors that are straight chains, branches, or ternary to 7-membered rings, and each can be a bond, monovalent connector, divalent connector, or trivalent connector independently. AT is a compound represented by formula II, wherein the general formula of II is: ; R1 and R2 are independently selected from hydrogen, halogen or methyl; R3 is selected from hydrogen, methyl, isopropyl or isobutyl; Ar is selected from the following structures: ; The end is connected to the L1 group. The end is connected to a carbonyl group; R4 is selected from hydrogen, methyl, ethyl, or cyclopropyl; R5 is selected from hydrogen, halogen, or methyl; L1 is selected from the following structures or combinations thereof: Or based on -(CH2) n - substitution structures, where n is an integer from 0 to 20, wherein each -CH2- is individually replaced with or without -O-, -NH-, -(CO)-, -NH-(CO)-, -(CO)-NH-, -Gly- or -Arg-, provided that no two adjacent -CH2- groups are replaced; The general formula of BT is IIIa, IIIb, IIIc or IIId, and the general formula of IIIa is: ; R6 is selected from -H, -OH, halogen, or C. 1-5 alkyl; L2 is selected from the following structures: Where X is -NH-, -(CO)-, or -(CO)-NH-; The general formula for IIIb is: ; Among them, R7 is selected from H and C. 1-6 Alkyl or C 3-6 cycloalkyl; R8 is selected from H, halogens, and C. 1-6 Alkyl or C 3-6 cycloalkyl; R9 is selected from the following structure: ; X1 is a single bond, -NH- or -(CO)-; L3 is selected from the following structures or combinations thereof: , where p is an integer from 1 to 5; The general formula of IIIc is: ; Among them, R 1 R 2 and R 3 Independently selected from -H, -OH, halogens, or C 1-5 alkyl; L4 is selected from Where X is -CH2-, -NH-, or -(CO)-; The general formula for IIId is: ; Among them, R 4 R 5 and R 6 Independently selected from -H, -OH, halogens, or C 1-5 alkyl; R 7 Selected from H or C 1-5 alkyl; L5 is selected from or , where X is -CH2-, -C≡C-, -NH- or -(CO)-; Wherein, CL is selected from: .

[0009] Wherein, La and Lb are each independently selected from the following structures or combinations thereof: .

[0010] Compared to traditional FAPI monomers, polymerization modification or the introduction of functional fragments that prolong tumor retention are two effective strategies to enhance tumor radiation dose. After radionuclide labeling, this series of compounds exhibits ideal in vivo distribution characteristics, enabling efficient uptake and prolonged retention at the tumor site, while being rapidly cleared from non-target organs such as the blood and liver. This significantly improves the signal-to-noise ratio of diagnostic imaging and enhances the efficacy and safety of radionuclide therapy.

[0011] The compounds are designed to improve the sensitivity of diagnostic imaging and the efficacy and safety of treatment by polymerizing FAP-targeting molecules or introducing functional fragments that prolong tumor retention.

[0012] It has the following structure: .

[0013] The present invention also provides a radioactive preparation comprising the aforementioned multivalent long-acting radiopharmaceutical.

[0014] It also contains radioactive nuclides.

[0015] The radionuclides include diagnostically active nuclides or therapeutically active nuclides.

[0016] The diagnostically active nuclide is 64 Cu、 68 Ga、 203 Pb, 111 In、 44 Sc、 177 Lu or 188 Re, therapeutic active nuclide 90 Y、 177 Lu、 188 Re、 225 Ac、 161 Tb, 212 Pb, 47 Sc、 67 Cu.

[0017] The present invention also provides the use of the multivalent long-acting radiopharmaceutical or the radioactive agent in the preparation of a medicament or pharmaceutical composition for the diagnosis and / or treatment of diseases characterized by overexpression of fibroblast-activating proteins.

[0018] The diseases characterized by overexpression of fibroblast activation protein include liver cancer, lung cancer, colorectal cancer, bile duct cancer, pancreatic cancer, esophageal cancer, gastric cancer, thyroid cancer, head and neck cancer, breast cancer, or cervical cancer.

[0019] Beneficial Effects: Compared with existing technologies, this invention has the following significant advantages: 1. Excellent pharmacokinetic characteristics: High uptake and long retention time at the tumor site, which is beneficial for enhancing the cumulative radiation dose; at the same time, rapid clearance from non-target organs such as blood, liver, and kidneys, and less tissue enrichment, significantly improving the contrast between tumor and normal tissues, balancing high signal-to-noise ratio in diagnostic imaging with the safety and efficacy of treatment. 2. Novel and diverse structural designs: Not only has the polymerization modification of FAP inhibitors been achieved, but also heteropolymers between different ligands have been innovatively constructed, enriching the types of compound structures; at the same time, the use of multiple ligands and diverse linking chains provides ample space for structural optimization. 3. Strong radionuclide compatibility: The chelating agent used can efficiently chelate multiple radionuclides, possessing both diagnostic and therapeutic isotope chelating capabilities, and is suitable for most commonly used radionuclides in scientific research and clinical practice, exhibiting good versatility. Attached Figure Description

[0020] Figure 1 This is the mass spectrum of compound 1 in Example 1 of the present invention; Figure 2 This is the mass spectrum of compound 2 in Example 2 of the present invention; Figure 3 This is the mass spectrum of compound 3 in Example 3 of the present invention; Figure 4 This is the mass spectrum of compound 7 in Example 7 of the present invention; Figure 5 This is the mass spectrum of compound 8 in Example 8 of the present invention; Figure 6 This is the mass spectrum of compound 14 in Example 14 of the present invention; Figure 7 This is the mass spectrum of compound 15 in Example 15 of the present invention; Figure 8 for 177 Imaging results of Lu-labeled compounds 1-3 in U87MG tumor-bearing mice; Figure 9 for 177 Imaging results of Lu-labeled compounds 4-6 in U87MG tumor-bearing mice; Figure 10 for 177 Imaging results of Lu-labeled compounds 7-9 in U87MG tumor-bearing mice; Figure 11 for 177 Imaging results of Lu-labeled compounds 10-12 in U87MG tumor-bearing mice; Figure 12 for 177 Imaging results of Lu-labeled compounds 15, 17, and 19 in U87MG tumor-bearing mice; Figure 13 for 177 Imaging results of Lu-labeled compounds 22, 24, and 25 in HCT116 and U87MG tumor-bearing mice; Figure 14 for 177 Imaging results of Lu-labeled compounds 26, 28 and 30 in HCT116 and U87MG tumor-bearing mice; Figure 15 for 177 Imaging results of Lu-labeled compounds 32-34 in U87MG tumor-bearing mice; Figure 16 for 177 Imaging results of Lu-labeled compounds 35 and 36 in U87MG tumor-bearing mice; Figure 17 for 177 Imaging results of Lu-labeled compounds 37 and 38 in U87MG tumor-bearing mice; Figure 18 for 177 Imaging results of Lu-labeled compound 15 in FAP-HCT116, Aspc-1 and A549 tumor-bearing mice; Figure 19 for 177 Imaging results of Lu-labeled compound 15 in 4T1 and MKN-45 tumor-bearing mice; Figure 20 As described in the embodiments of the present invention 177 In vitro distribution statistics of Lu-labeled compounds 2, 8 and 15 in vital organs at 6, 12 and 24 hours after injection in ICR mice; Figure 21 for 177 The changes in tumor volume and mouse weight during treatment of U87MG tumor-bearing mice by Lu-labeled compounds 2, 8 and 15; Figure 22 for 225 Statistical distribution of Ac-labeled compound 8 in vital organs at 12 and 24 hours after injection in ICR mice. Detailed Implementation

[0021] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0022] Example 1: Synthesis of Compound 1 Synthesis route:

[0023] 1. Synthesis of compound A3: 4-Pentynic acid (A2, 0.50 g, 5.10 mmol) and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU, 1.69 g, 5.61 mmol) were dissolved in 10 mL of DMF, followed by the addition of N,N-diisopropylethylamine (DIPEA, 2.63 g, 20.40 mmol) and stirring at room temperature. After 6 h, norfloxacin (A1, 1.63 g, 5.10 mmol) was added, and the reaction was continued at room temperature for another 4 h. TLC monitoring showed that the reaction was complete. Upon adding the reaction solution to 100 mL of ice water, a large amount of solid precipitated. The mixture was filtered, the filter cake was washed with 50 mL of water, dried at 50 °C, and the crude product was slurried with 10 mL of isopropanol at room temperature for 2 h. The mixture was then filtered and dried to obtain the target product, 1-ethyl-6-fluoro-4-oxo-7-(4-(pentan-4-ynyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (A3, 1.59 g, yield 78%). MS (ESI): 400.43 [M+H] + .

[0024] 2. Synthesis of compound A5: Dissolve A3 (0.50 g, 1.25 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 0.62 g, 1.63 mmol) in 10 mL of DMF, then add DIPEA (0.65 g, 20.40 mmol) and stir at room temperature. After 0.5 h, add (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carboxynitrile hydrochloride (A4, 0.31 g, 1.37 mmol) and react at room temperature for 4 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 100 mL of ice water, and a large amount of solid precipitated. The mixture was filtered, washed with 50 mL of water, and dried at 50 °C. The crude product was slurried with 10 mL of isopropanol at room temperature for 4 h, filtered, and dried to obtain the target product (S)-N-(2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)-1-ethyl-6-fluoro-4-oxo-7-(4-(pentan-4-ynyl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (A5, 0.57 g, yield 80%). MS (ESI): 571.58 [M+H] + .

[0025] 3. Synthesis of compound A7: Dissolve A5 (10.00 mg, 0.018 mmol) and 15-azido-4,7,10,13-tetraoxapentadecanoic acid (A6, 5.10 mg, 0.018 mmol) in 400 μL of DMSO. Add a solution prepared by dissolving sodium ascorbate (1.73 mg, 0.0088 mmol) and copper sulfate pentahydrate (1.10 mg, 0.0044 mmol) in 80 μL of water. The mixture was then reacted with shaking in a metal bath at 50 °C for 4 h. After the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product (S)-1-[4-(3-{4-[3-({[2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl]carbamoyl}-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-yl]-3-oxopropyl}-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-acid (A7, 6.50 mg, yield 43%). MS (ESI): 862.90 [M+H] + .

[0026] 4. Synthesis of compound A10: 3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)glutaric acid (A8, 0.50 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.04 g, 5.41 mmol), and 1-hydroxybenzotriazole (HOBT, 1.83 g, 13.54 mmol) were dissolved in 20 mL of acetonitrile and stirred at room temperature. After 2 h, amino-pentaethylene glycol-azide (A9, CAS: 951671-92-4, 0.78 g, 2.98 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated, 50 mL of ice water was added, and the pH was adjusted to 10-11 with saturated Na2CO3 aqueous solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, the filter cake was washed with 50 mL of water, and dried at 50 °C. The crude product was homogenized in a mixture of 7 mL isopropanol and 14 mL n-hexane for 4 hours at room temperature, filtered again, and dried to obtain the target product (9H-fluorene-9-yl)methyl (1,35-diazido-16,20-dioxo-3,6,9,12,24,27,30,33-octaoxa-15,21-diazapentadecane-18-yl)carbamate (A10, 0.88 g, yield 76%). MS (ESI): 858.99 [M+H] + .

[0027] 5. Synthesis of compound A11: Dissolve A10 (200.00 mg, 0.23 mmol) and A5 (319.21 mg, 0.56 mmol) in 4 mL of DMSO. Add a solution prepared by dissolving sodium ascorbate (46.18 mg, 0.23 mmol) and copper sulfate pentahydrate (29.10 mg, 0.12 mmol) in 800 μL of water. Heat in an oil bath at 50 °C for 8 h. After TLC monitoring showed that the reaction was complete, add the reaction solution to 50 mL of ice water, and a large amount of solid precipitated. Filter the mixture, wash the filter cake with 10 mL of water, and dry at 50 °C. The crude product was purified by column chromatography to obtain the target product (9H-fluorene-9-yl)methyl(1,35-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-16,20-dioxo-3,6,9,12,24,27,30,33-octaoxa-15,21-diazapentadecane-18-yl)carbamate (A11, 302.91 mg, yield 65%). MS (ESI): 1000.10 [M+2H) 2+ .

[0028] 6. Synthesis of compound A12: A11 (200 mg, 0.10 mmol) was dissolved in a mixed solvent of 5 mL acetonitrile and 1 mL morpholine and stirred at room temperature for 2 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated. A mixed solvent of 5 mL isopropanol and 5 mL n-hexane was added and stirred for 2 h. The mixture was filtered, and the filter cake was dried to give the target product 3-amino-N1,N5-bis(14-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A12, 156.43 mg, yield 88%). MS (ESI): 889.02 [M+2H] 2+ .

[0029] 7. Synthesis of compound A14: N2-(((9H-fluorene-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysine (A13, 26.37 mg, 0.056 mmol) and HATU (27.82 mg, 0.073 mmol) were dissolved in 800 μL of DMSO, followed by the addition of DIPEA (29.09 mg, 0.23 mmol), and the mixture was stirred at room temperature. After 0.5 h, A12 (100 mg, 0.056 mmol) was added, and the reaction was continued at room temperature for another 4 h. TLC monitoring showed that the reaction was complete. When the reaction solution was added to 7 mL of ice water, a large amount of solid precipitated. The mixture was centrifuged to obtain a crude product. The crude product was stirred for 2 hours at room temperature with a mixed solvent of 3 mL isopropanol and 3 mL n-hexane. After filtration and drying of the filter cake, the target product (9H-fluorene-9-yl)methyl tert-butyl((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-( 4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-21,25-diyl)dicarbamate (A14, 104.04 mg, 83% yield). MS (ESI): 1114.20 [M+2H] 2+ .

[0030] 8. Synthesis of compound A15: A14 (100 mg, 0.045 mmol) was dissolved in a mixed solvent of 5 mL acetonitrile and 1 mL morpholine and stirred at room temperature for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. A mixed solvent of 2 mL isopropanol and 2 mL n-hexane was added and stirred for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product tert-butyl((S)-21-amino-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-(2-(S)-2-amino-1 ...2-(S)-2-amino-1-(4-(4-(2-(S)-2-amino-1-(4-(4-(2-(S)-2-amino-1-( -((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-25-yl)carbamate (A15, 76.52 mg, 85% yield). MS (ESI): 1003.08 [M+2H] 2+ .

[0031] 9. Synthesis of compound A16: A7 (4.00 mg, 0.0046 mmol) and HATU (2.65 mg, 0.0070 mmol) were dissolved in 300 μL of DMSO, followed by the addition of DIPEA (6.00 mg, 0.046 mmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (9.30 mg, 0.0046 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl((S)-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3 -Oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4- Dihydroquinolino-7-yl)piperazino-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amido)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-25-yl)carbamate (A16, 6.61 mg, 50% yield). MS (ESI): 953.69 [M+3H] 3+ .

[0032] 10. Synthesis of Compound 1: Dissolve A16 (5.00 mg, 1.75 μmol) in 1 mL of a mixed solution (V TFA V DCM=200μL:800μL) The reaction system was shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. Then the residue was dissolved in 300μL DMSO, and DIPEA (2.27mg, 17.55μmol) and DOTA-NHS ester (1.14mg, 2.28μmol, CAS No.: 170908-81-3) were added sequentially, and the reaction was shaken in a metal bath at 40℃. After TLC monitoring showed that the reaction was complete, the reaction solution was separated and purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product 2,2',2''-(10-((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7 -yl)piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)-3-oxopropyl)-1 H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3 (-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amido)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctacosane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (1, 3.30 mg, yield 60%). MS (ESI): 1046.18 [M+3H] 3+ The mass spectrum of compound 1 is as follows: Figure 1 As shown.

[0033] Example 2: Synthesis of Compound 2 The synthesis route is as follows:

[0034] 1. Synthesis of compound A17: Dissolve A5 (10.00 mg, 17.53 μmol) and A9 (4.60 mg, 17.53 μmol) in 400 μL of DMSO, add a solution containing 80 μL of water with sodium ascorbate (1.39 mg, 7.01 μmol) and copper sulfate pentahydrate (0.88 mg, 3.51 μmol), and react in a metal bath at 50 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product (S)-7-(4-(3-(1-(14-amino-3,6,9,12-tetraoxatetradecyl)-1H-1,2,3-triazol-4-yl)propionyl)piperazin-1-yl)-N-(2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide (A17, 11.53 mg, yield 79%). MS (ESI): 833.91 [M+H] + .

[0035] 2. Synthesis of compound A19: 3,3'-((2-((tert-Butoxycarbonyl)amino)-2-((2-carboxyethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionic acid (A18, 2.00 mg, 4.57 μmol) and HATU (6.95 mg, 18.29 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (9.45 mg, 73.15 μmol), and the mixture was stirred at room temperature. After 0.5 h, A17 (12.57 mg, 15.09 μmol) was added, and the reaction was continued at room temperature for 6 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl(1,41-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-21-(20- ...-7-yl)-yl)-21-(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoro-7-yl)-yl)-yl)-21-(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoro-7-yl)-yl)-yl)-21-(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoro-7-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) -Difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5-oxo-2,9,12,15,18-pentaoxa-6-azaeicosyl)-16,26-dioxo-3,6,9,12,19,23,30,33,36,39-decaoxa-15,27-diazattracarbamate-21-yl)carbamate (A19, 3.95 mg, 30% yield). MS (ESI): 961.03 [M+3H] 3+ .

[0036] 3. Synthesis of compound A20: Dissolve A19 (6.00 mg, 2.08 μmol) in 1 mL of a mixed solution (V TFA V DCMIn a mixture of 200 μL and 800 μL, the reaction system was shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. Subsequently, the residue was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 1,41-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-21-(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoro) Pyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5-oxo-2,9,12,15,18-pentaoxa-6-azaeicosyl)-16,26-dioxo-3,6,9,12,19,23,30,33,36,39-decaoxa-15,27-diazattramocarbamo-21-amine (A20, 4.69 mg, yield 81%). MS (ESI): 927.70 [M+3H] 3+ .

[0037] 4. Synthesis of Compound 2: A20 (2.00 mg, 0.72 μmol) and DOTA-NHS ester (0.43 mg, 0.86 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (0.93 mg, 7.19 μmol), and the mixture was reacted with shaking in a metal bath at 40 °C. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-21,21-bis(20-(4-(3-(4-(3-((2-((S)-2-cyano-4- 4-Difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5-oxo-2,9,12,15,18-pentaoxa-6-azaeicosyl)-16,23-dioxo-3,6,9,12,19-pentaoxa-15,22-diazatetracosane-24-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (2, 1.59 mg, 70% yield). MS (ESI): 1057.19 [M+3H] 3+ The mass spectrum of compound 2 is as follows: Figure 2 As shown.

[0038] Example 3: Synthesis of Compound 3 The synthesis route is as follows:

[0039] 1. Synthesis of compound A22: 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecano-1-yl)valeric acid (A21, 1.00 mg, 1.43 μmol) and HATU (0.81 mg, 2.1 μmol) were dissolved in 200 μL LMF, followed by the addition of DIPEA (1.11 mg, 8.57 μmol), and the mixture was stirred at room temperature. After 0.5 h, A20 (3.97 mg, 1.43 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tritert-butyl-2,2',2''-(10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-21,21-bis(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine)) -1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5-oxo-2,9,12,15,18-pentaoxa-6-azaeicosyl)-29,29-dimethyl-16,23,27-trioxo-3,6,9,12,19,28-hexoxa-15,22-diazatriacontane-26-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (A22, 2.97 mg, 60% yield). MS (ESI): 1155.28 [M+3H] 3+ .

[0040] 2. Synthesis of compound 3: A22 (2 mg, 0.58 μmol) was dissolved in 1 mL of trifluoroacetic acid (TFA), and the reaction system was shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(26-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-21,21-bis(20-(4-(3-(4-(3-((2-((S)-2-cyano-4,4- -Difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-5-oxo-2,9,12,15,18-pentaoxa-6-azaeicosyl)-16,23-dioxo-3,6,9,12,19-pentaoxa-15,22-diazahexacosane-26-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3, 1.23 mg, yield 66%). MS (ESI): 1081.24 [M+3H] 3+ The mass spectrum of compound 3 is as follows: Figure 3 As shown.

[0041] Example 4: Synthesis of Compound 4 The synthesis route is as follows:

[0042] 1. Synthesis of compound A25: Methyl 7-bromoquinoline-4-carboxylate (A23, 500.00 mg, 1.88 mmol), potassium N-aminomethyltrifluoroborate (A24, 579.11 mg, 2.44 mmol), Pd(OAc)2 (84.37 mg, 0.38 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos, 434.91 mg, 0.75 mmol), and Cs2CO3 (1.27 g, 5.64 mmol) were added to a mixed solvent of 10 mL THF and 2.5 mL H2O. The reaction system was carried out at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated, and purified by column chromatography to obtain the target product methyl 7-(((tert-butyloxycarbonyl)amino)methyl)quinoline-4-carboxylate (A25, 356.68 mg, yield 60%). MS (ESI): 317.37 [M+H] + .

[0043] 2. Synthesis of compound A26: A25 (200.00 mg, 0.63 mmol) was dissolved in 6 mL of MeOH, followed by the addition of 2 mL of H2O containing LiOH (45.42 mg, 1.90 mmol). The reaction was stirred at 40 °C for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated, the pH was adjusted to 6-7 with 2 M acetic acid aqueous solution, and the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to give the target product 7-(((tert-Butoxycarbonyl)amino)methyl)quinoline-4-carboxylic acid (A26, 172.02 mg, 90% yield). MS (ESI): 303.34 [M+H] + .

[0044] 3. Synthesis of compound A27: A26 (200.00 mg, 0.66 mmol) and HATU (326.99 mg, 0.86 mmol) were dissolved in 2 mL of DMF, followed by the addition of DIPEA (341.98 mg, 2.65 mmol), and the mixture was stirred at room temperature. After 0.5 h, A4 (164.18 mg, 0.73 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed complete reaction, the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography to obtain the target product tert-butyl(S)-((4-((2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)carbamate (A27, 238.05 mg, yield 76%). MS (ESI): 474.48 [M+H]+ .

[0045] 4. Synthesis of compound A28: Dissolve A27 (200.00 mg, 0.42 mmol) in 5 mL of solution (V TFA V DCM The reaction mixture was prepared in a ratio of 1 mL to 4 mL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated to obtain the target product (S)-7-(aminomethyl)-N-(2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A28). This crude product was used directly in the next step without further purification.

[0046] 5. Synthesis of compound A30: 2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecane-14-acid (A29, 10.00 mg, 36.06 μmol) and HATU (17.82 mg, 46.88 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (18.64 mg, 144.24 μmol), and the mixture was stirred at room temperature. After 0.5 h, A28 (13.61 mg, 36.06 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl(S)-(2-(2-(3-(((4-(((2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate (A30, 18.02 mg, yield 79%). MS (ESI): 633.69 [M+H) + .

[0047] 6. Synthesis of compound A31: Dissolve A30 (20 mg, 0.032 mmol) in 2 mL of a mixed solution (V TFA V DCM The reaction system was mixed in a ratio of 400 μL to 1600 μL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product (S)-7-((3-(2-(2-aminoethoxy)ethoxy)propamido)methyl)-N-(2-(2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A31, 16.84 mg, yield 88%). MS (ESI): 533.66 [M+H] + .

[0048] 7. Synthesis of compound A32: A18 (2.00 mg, 4.60 μmol) and HATU (7.00 mg, 18.41 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (9.52 mg, 73.66 μmol), and the mixture was stirred at room temperature. After 0.5 h, A31 (8.83 mg, 16.57 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed complete reaction, the product was purified by C18 reversed-phase preparative liquid chromatography, freeze-dried, and the target product tert-butyl(1,35-bis(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-18-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)- 2-Oxoethyl)carbamoyl)quinoline-7-yl)-3,13-dioxo-6,9,16-trioxa-2,12-diazaheptadecane-17-yl)-3,13,23,33-tetraoxo-6,9,16,20,27,30-hexaoxa-2,12,24,34-tetraazapentadecane-18-yl)carbamate (A30, 3.65 mg, 40% yield). MS (ESI): 991.03 [M+2H] 2+ .

[0049] 8. Synthesis of compound A33: Dissolve A32 (5.00 mg, 1.01 μmol) in 1 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 7,7'-(18-amino-18-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-3,13-dioxo-6,9,16-trioxa-2,12-diazaheptadecane-17-yl)-3,13,23,33-tetraoxo-6,9,16,20,27,30-hexaoxa-2,12,24,34-tetraazapentadecane-1,35-diyl)bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (A33, 4.08 mg, yield 86%). MS (ESI): 940.98 [M+2H] 2+ .

[0050] 9. Synthesis of Compound 4: A33 (2.00 mg, 1.06 μmol) and DOTA-NHS ester (0.64 mg, 1.28 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (1.37 mg, 10.63 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-18,18-bis(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl) (2-O-ethyl)carbamoyl)quinoline-7-yl)-3,13-dioxo-6,9,16-trioxa-2,12-diazaheptadecane-17-yl)-3,13,20-trioxo-6,9,16-trioxa-2,12,19-triazatetracosane-21-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (4, 1.62 mg, yield 67%). MS (ESI): 1134.78 [M+3H] 3+ .

[0051] Example 5: Synthesis of Compound 5 The synthesis route is as follows:

[0052] 1. Synthesis of compound A38: Compound 7,7'-(24-amino-24-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-3,19-dioxo-6,9,12,15,22-pentaoxa-2,18-diazatocetane-23-yl)-3,19,29,45-tetraoxo-6,9,12,15,22,26,33,3 The synthesis of 6,39,42-decaoxa-2,18,30,46-tetraazaheptadecane-1,47-diyl)bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A38) is similar to that of compound A33, except that A29 is replaced with tert-butoxycarbonyl tetraethylene glycol propionate (A34). MS (ESI): 1073.10 [M+2H] 2+ .

[0053] 2. Synthesis of Compound 5: A38 (2.00 mg, 0.93 μmol) and DOTA-NHS ester (0.61 mg, 1.21 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (1.20 mg, 9.32 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-24,24-bis(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-24,24-bis(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) Ethyl)carbamoyl)quinoline-7-yl)-3,19-dioxo-6,9,12,15,22-pentaoxa-2,18-diazatocetane-23-yl)-3,19,26-trioxo-6,9,12,15,22-pentaoxa-2,18,25-triazaheptadecane-27-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (5, 1.56 mg, yield 66%). MS (ESI): 845.21 [M+3H] 3+ .

[0054] Example 6: Synthesis of Compound 6 The synthesis route is as follows:

[0055] 1. Synthesis of compound A39: A21 (1.00 mg, 1.43 μmol) and HATU (0.81 mg, 2.1 μmol) were dissolved in 200 μL of DMF, followed by the addition of DIPEA (1.11 mg, 8.57 μmol), and the mixture was stirred at room temperature. After 0.5 h, A33 (2.69 mg, 1.43 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product tri-tert-butyl-2,2',2''-(10-(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-18,18-bis(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) Carbamoyl)quinoline-7-yl)-3,13-dioxo-6,9,16-trioxa-2,12-diazaheptadecane-17-yl)-26,26-dimethyl-3,13,20,24-tetraoxo-6,9,16,25-tetraoxa-2,12,19-trizaheptadecane-23-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (A39, 2.35 mg, yield 64%). MS (ESI): 854.95 [M+3H] 3+ .

[0056] 2. Synthesis of Compound 6: A39 (2.00 mg, 0.78 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(23-carboxy-1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)-18,18-bis(1-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)- 2-O-ethyl)carbamoyl)quinoline-7-yl)-3,13-dioxo-6,9,16-trioxa-2,12-diazaheptadecane-17-yl)-3,13,20-trioxo-6,9,16-trioxa-2,12,19-triazatocetane-23-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (6, 1.24 mg, 68% yield). MS (ESI): 1170.88 [M+2H] 2+ .

[0057] Example 7: Synthesis of Compound 7 The synthesis route is as follows:

[0058] 1. Synthesis of compound A41: A23 (500.00 mg, 1.88 mmol), potassium (4-tert-butyloxycarbonylpiperazin-1-yl)methyltrifluoroborate (A40, 747.08 mg, 2.44 mmol), Pd(OAc)2 (84.37 mg, 0.38 mmol), Xantphos (434.91 mg, 0.75 mmol), and Cs2CO3 (1.27 g, 5.64 mmol) were added to a mixed solvent of 10 mL THF and 2.5 mL H2O. The reaction system was reacted at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction solution was filtered with diatomaceous earth, the filtrate was concentrated, and purified by column chromatography to obtain the target product methyl 7-((4-(tert-butyloxycarbonyl)piperazin-1-yl)methyl)quinoline-4-carboxylate (A41, 427.71 mg, yield 59%). MS (ESI): 386.50 [M+H] + .

[0059] 2. Synthesis of compound A42: A41 (240.00 mg, 0.63 mmol) was dissolved in 6 mL of MeOH, followed by the addition of a 2 mL H2O solution of LiOH (45.42 mg, 1.90 mmol). The reaction was stirred at 40 °C for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated, the pH was adjusted to 6-7 with 2 M acetic acid aqueous solution, and the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to give the target product 7-((4-(tert-butyloxycarbonyl)piperazin-1-yl)methyl)quinoline-4-carboxylic acid (A42, 211.87 mg, yield 91%). MS (ESI): 372.42 [M+H] + .

[0060] 3. Synthesis of compound A43: A42 (245.15 mg, 0.66 mmol) and HATU (326.99 mg, 0.86 mmol) were dissolved in 2 mL of DMF, followed by the addition of DIPEA (341.98 mg, 2.65 mmol), and the mixture was stirred at room temperature. After 0.5 h, A4 (164.18 mg, 0.73 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography to obtain the target product tert-butyl(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazine-1-carboxylic acid ester (A43, 282.91 mg, yield 76%). MS (ESI): 543.63 [M+H] + .

[0061] 4. Synthesis of compound A44: Dissolve A43 (250.00 mg, 0.46 mmol) in 5 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 1 mL to 4 mL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated to obtain the target product (S)-N-(2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)-7-(piperazin-1-ylmethyl)quinoline-4-carboxamide (A44). This crude product was used directly in the next step without further purification. MS (ESI): 443.58 [M+H] + .

[0062] 5. Synthesis of compound A45: Fmoc-Pbf-arginine (Fmoc-Arg(Pbf)-OH, 293.53 mg, 0.45 mmol) and HATU (223.66 mg, 0.59 mmol) were dissolved in 2 mL of DMF, followed by the addition of DIPEA (233.90 mg, 1.81 mmol), and the mixture was stirred at room temperature. After 0.5 h, A44 (200 mg, 0.45 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the mixture was extracted three times with 20 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography to obtain the target product (9H-fluorene-9-yl)methyl(1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-1-oxo-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinyl)pentan-2-yl)carbamate (A45, 309.09 mg, yield 64%). MS (ESI): 1074.44 [M+H] + .

[0063] 6. Synthesis of compound A46: A45 (200.00 mg, 0.19 mmol) was dissolved in a mixed solvent of 5 mL acetonitrile and 1 mL morpholine, and stirred at room temperature for 2 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated, and the residue was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product N-(2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)-7-((4-(Nw-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)arginyl)piperazin-1-yl)methyl)quinoline-4-carboxamide (A46, 126.87 mg, yield 80%). MS (ESI): 851.96 [M+H] + .

[0064] 7. Synthesis of compound A47: 1-tert-butyl 5,8,11,14-tetraoxa-2-azaheptadecanoic acid (A34, 42.94 mg, 0.12 mmol) and HATU (58.09 mg, 0.15 mmol) were dissolved in 2 mL of DMF, followed by the addition of DIPEA (60.75 mg, 0.47 mmol), and the mixture was stirred at room temperature. After 0.5 h, A46 (100.00 mg, 0.12 mmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the target product, tert-butyl-(6-(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazine-1-carbonyl)-1-imino-8-oxo-1-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran)-5-sulfonamido)-11,14,17,20-tetraoxa-2,7-diazadocosahexaenoic-22-yl)carbamate (A47). This crude product was used directly in the next step without further purification.

[0065] 8. Synthesis of compound A48: Dissolve the above A47 in 5 mL of a mixed solution (V TFA V DCM The reaction system was mixed at 1 mL:4 mL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated and purified by C18 reversed-phase preparative liquid chromatography. The purified solution was then freeze-dried to obtain the target product 7-((4-((1-amino-3,6,9,12-tetraoxapentadecano-15-acyl)argininoyl)piperazin-1-yl)methyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A48, 49.48 mg, yield 50%). MS (ESI): 847.07 [M+H] + .

[0066] 9. Synthesis of compound A49: A48 (2.00 mg, 4.60 μmol) and HATU (7.00 mg, 18.41 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (9.52 mg, 73.66 μmol), and the mixture was stirred at room temperature. After 0.5 h, A18 (14.02 mg, 16.57 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl(1,57-diamino-29-(28-amino-23-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazine-1-carbonyl)-28-imino-5,21-dioxo-2,9,12,15,18-pentaoxa-6,22,27-triazaoctadecyl)- 6,52-Bis(4-((4-(((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-carbonyl)-1,57-diimino-8,24,34,50-tetraoxo-11,14,17,20,27,31,38,41,44,47-decaoxa-2,7,23,35,51,56-hexaazaheptadecane-29-yl)carbamate (A49, 5.48 mg, yield 41%). MS (ESI): 974.10 [M+3H] 3+ .

[0067] 10. Synthesis of compound A50: Dissolve A49 (5.00 mg, 1.71 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction system was mixed in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 7,7',7''-(((25-amino-25-(28-amino-23-formyl-28-imino-5,21-dioxo-2,9,12,15,18-pentaoxa-6,22,27-triazaoctadecyl)-2,48-bis(3-guanidinopropyl)-4,20,30,46-tetraoxo-7,10,1 3,16,23,27,34,37,40,43-Decaoxa-3,19,31,47-tetraaza-tetranonadecanoyl)tris(piperazin-4,1-diyl)tris(methylene)tris(N-(2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A50, 4.10 mg, yield 86%). MS (ESI): 940.76 [M+3H] 3+ .

[0068] 11. Synthesis of Compound 7: A50 (2.00 mg, 0.71 μmol) and DOTA-NHS ester (0.46 mg, 0.92 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (0.92 mg, 7.09 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(1-amino-30,30-bis(28-amino-23-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazine-1-carbonyl)-28-imino-5,21-dioxo-2,9,12,15,18-pentaoxa-6,22,27 -triazaoctadecyl)-6-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-carbonyl)-1-imino-9,25,32-trioxo-12,15,18,21,28-pentaoxa-2,7,24,31-tetraazatritriacontria-33-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (7, 1.51 mg, yield 66%). MS (ESI): 1070.38 [M+3H] 3+ The mass spectrum of compound 7 is as follows: Figure 4 As shown.

[0069] Example 8: Synthesis of Compound 8 The synthesis route is as follows:

[0070] 1. Synthesis of compound A54: 4-(4-iodophenyl)butyric acid (A51, 10 mg, 34.47 μmol) and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (A52, 11.42 mg, 37.91 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (26.73 mg, 206.83 μmol) and stirring at room temperature. After 6 h, 3-(2-(2-aminoethoxy)ethoxy)propionic acid (A53, 6.11 mg, 34.47 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product 3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propionic acid (A54, 11.93 mg, yield 77%). MS (ESI): 450.32 [M+H] + .

[0071] 2. Synthesis of compound A55: A54 (4.00 mg, 8.90 μmol) and HATU (4.40 mg, 11.57 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (4.60 mg, 35.61 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (17.85 mg, 8.90 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product tert-butyl((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)) -2-Oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propamido)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-25-yl)carbamate (A55, 14.07 mg, 65% yield). MS (ESI): 1218.79 [M+2H] 2+ .

[0072] 3. Synthesis of compound A56: Dissolve A55 (10.00 mg, 4.10 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 3-((S)-2-(4-aminobutyl)-17-(4-iodophenyl)-4,14-dioxo-7,10-dioxa-3,13-diazaheptadecanoamide)-N1,N5-bis(14-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A56, 9.59 mg, yield 80%). MS (ESI): 1168.77 [M+2H] 2+ .

[0073] 4. Synthesis of Compound 8: A56 (4.00 mg, 1.71 μmol) and DOTA-NHS ester (0.94 mg, 1.89 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (2.21 mg, 17.12 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) (carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propamido)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (8, 4.75 mg, 65% yield). MS (ESI): 908.66 [M+3H] 3+The mass spectrum of compound 8 is as follows: Figure 5 As shown.

[0074] Example 9: Synthesis of Compound 9 The synthesis route is as follows:

[0075] Compound 2,2',2''-(10-((S)-8-((1,35-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-16,20-dioxo-3,6,9,12,24,27,30, The synthesis of 33-octaoxa-15,21-diazapentadecane-18-yl)carbamoyl)-29-(4-iodophenyl)-2,10,26-trioxo-13,16,19,22-tetraoxa-3,9,25-triazanonadecanyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (9) is similar to that of compound 8, except that A53 is replaced with 1-amino-3,6,9,12-tetraoxapentadecane-15-acid (A57). MS (ESI): 937.81 [M+3H] 3+ .

[0076] Example 10: Synthesis of Compound 10 The synthesis route is as follows:

[0077] 1. Synthesis of compound A61: A21 (1.00 mg, 1.43 μmol) and HATU (0.81 mg, 2.10 μmol) were dissolved in 200 μL of DMF, followed by the addition of DIPEA (1.11 mg, 8.57 μmol), and the mixture was stirred at room temperature. After 0.5 h, A56 (3.34 mg, 1.43 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tri-tert-butyl-2,2',2''-(10-((21S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)- 1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propamido)-33,33-dimethyl-16,20,27,31-tetraoxa-3,6,9,12,32-pentaoxa-15,19,26-triazatritetratetradecane-30-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (A61, 2.61 mg, 60% yield). MS (ESI): 1168.77 [M+3H] 3+ .

[0078] 2. Synthesis of Compound 10: A61 (2.00 mg, 0.66 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(((21S)-30-carboxy-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl) Carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propamido)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazatriacontane-30-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (10, 1.23 mg, 67% yield). MS (ESI): 932.79 [M+3H] 3+ .

[0079] Example 11: Synthesis of Compound 11 The synthesis route is as follows:

[0080] Compound 2,2',2''-(10-((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl) The synthesis of (11) piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-21-(3-(2-(2-(4-(p-tolyl)butamido)ethoxy)ethoxy)propamido)-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid is similar to that of compound 8, except that A51 is replaced with 4-(p-tolyl)butyric acid (A62). MS (ESI): 871.62 [M+3H] 3+ .

[0081] Example 12: Synthesis of Compound 12 The synthesis route is as follows:

[0082] 1. Synthesis of compound A73: The compound tert-butyl((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine The synthesis of (A73) is similar to that of compound 16, except that A1 is replaced with 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (A66). MS (ESI): 1230.92 [M+2H] 2+ .

[0083] 2. Synthesis of compound A74: Dissolve A73 (10.00 mg, 4.06 μmol) in 1 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 3-((S)-2-(4-aminobutyl)-17-(4-iodophenyl)-4,14-dioxo-7,10-dioxa-3,13-diazaheptadecanoamide)-N1,N5-bis(14-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A74, 7.77 mg, yield 81%). MS (ESI): 1180.67 [M+2H] 2+ .

[0084] 3. Synthesis of Compound 12: A74 (4.00 mg, 1.70 μmol) and DOTA-NHS ester (0.94 mg, 1.89 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (2.21 mg, 17.12 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) Carbamoyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(4-(4-iodophenyl)butamido)ethoxy)ethoxy)propamido)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (12, 3.16 mg, 67% yield). MS (ESI): 9116.81 [M+3H] 3+ .

[0085] Example 13: Synthesis of Compound 13 The synthesis route is as follows:

[0086] 1. Synthesis of compound A77: 4-(5-(2,6-dimethoxyphenyl)-3-(methoxycarbonyl)-1H-pyrazol-1-yl)-3-isopropylbenzoic acid (A75, 0.30 g, 0.71 mmol) and HATU (0.35 g, 0.92 mmol) were dissolved in 4 mL of DMF, and then DIPEA (0.36 g, 2.82 mmol) was added and stirred at room temperature. After 0.5 h, tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylic acid ester (A76, 0.21 g, 0.78 mmol) was added, and the reaction was carried out at room temperature for 4 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 40 mL of ice water, and a large amount of solid precipitated. The mixture was filtered, washed with 10 mL of water, and dried at 50 °C. The crude product was slurried with 10 mL of isopropanol at room temperature for 2 h, filtered, and dried to obtain the target product tert-butyl 4-(4-(4-(5-(2,6-dimethoxyphenyl)-3-(methoxycarbonyl)-1H-pyrazole-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidine-1-carboxylic acid ester (A77, 0.38 g, yield 79%). MS (ESI): 676.93 [M+H] + .

[0087] 2. Synthesis of compound A78: A77 (300.00 mg, 0.44 mmol) was dissolved in 6 mL of MeOH, followed by the addition of 2 mL of H2O containing LiOH (106.53 mg, 4.44 mmol). The reaction was stirred at 40 °C for 2 h. After TLC monitoring showed complete reaction, the reaction solution was concentrated, and the pH was adjusted to 6-7 with 2 M acetic acid aqueous solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, washed with 50 mL of water, and dried at 50 °C to obtain the target product 1-(4-(4-(1-(tert-butyloxycarbonyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid (A78, 264.39 mg, yield 91%). MS (ESI): 662.60 [M+H] + .

[0088] 3. Synthesis of compound A80: A78 (200.00 mg, 0.30 mmol) and HATU (0.15 g, 0.39 mmol) were dissolved in 4 mL of DMF, and then DIPEA (156.23 mg, 1.21 mmol) was added and stirred at room temperature. After 0.5 h, 2-aminoadamantane-2-carboxylic acid tert-butyl ester (A79, 83.56 mg, 0.33 mmol) was added, and the reaction was carried out at room temperature for 4 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 40 mL of ice water, and a large amount of solid precipitated. The mixture was filtered, washed with 10 mL of water, and dried at 50 °C. The crude product was slurried with 10 mL of isopropanol at room temperature for 2 h, filtered, and dried to obtain the target product tert-butyl 4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidine-1-carboxylic acid ester (A80, 202.89 g, yield 75%). MS (ESI): 896.52 [M+H] + .

[0089] 4. Synthesis of compound A81: A80 (200.00 mg, 0.22 mmol) was dissolved in a mixed solvent of 4 mL THF and 1 mL MeOH. A mixed solution of 0.2 mL trimethylbromosilane (TMBS) and 1 mL THF was slowly added under an ice bath at 0 °C. The reaction was allowed to warm naturally to room temperature and stirred for 4 h. After TLC monitoring showed complete reaction, the reaction solution was quenched in 10 mL of ice water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain the target product, tert-butyl-2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(4-(piperidin-4-yl)piperazin-1-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A81, 70.05 mg, yield 40%). MS (ESI): 796.13 [M+H] + .

[0090] 5. Synthesis of compound A82: A81 (20.000 mg, 25.16 μmol) and diethylene glycol anhydride (5.83 mg, 50.03 μmol) were dissolved in 4 mL of THF, and then DIPEA (19.5 mg, 150.09 μmol) was added and stirred at 50 °C for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then separated and purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product 2-(2-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-2-oxoethoxy)acetic acid (A82, 17.88 mg, yield 78%). MS (ESI): 912.22 [M+H] + .

[0091] 6. Synthesis of compound A83: A82 (4.00 mg, 4.39 μmol) and HATU (2.17 mg, 5.71 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (2.27 mg, 17.56 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (8.80 mg, 4.39 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl-2-(1-(4-(4-(1-((S)-21-(4-((tert-butoxycarbonyl)amino)butyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine))-1 ... -1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,25-pentaoxa-15,19,22-triazaheptadecane-27-acyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A83, 8.40 mg, yield 66%). MS (ESI): 963.81 [M+3H] 3+ .

[0092] 7. Synthesis of compound A84: Dissolve A83 (8.00 mg, 2.76 μmol) in 1 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-((S)-21-(4-aminobutyl)-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) (Ethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,25-pentaoxa-15,19,22-triazaheptadecane-27-acyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A84, 6.06 mg, 80% yield). MS (ESI): 914.43 [M+3H] 3+ .

[0093] 8. Synthesis of Compound 13: A84 (4.00 mg, 1.46 μmol) and DOTA-NHS ester (0.94 mg, 1.89 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (1.89 mg, 14.6 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(2-(2-(4-(4-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-2-oxoethoxy)acetamyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl) )-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3- Triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (13, 3.10 mg, yield 68%). MS (ESI): 1043.99 [M+3H] 3+ .

[0094] Example 14: Synthesis of Compound 14 The synthesis route is as follows:

[0095] 1. Synthesis of compound A87: N1,N3-dimethyl-N1-(3-(methylamino)propyl)propane-1,3-diamine (A85, CAS No. 33329-35-0, 300.00 mg, 1.73 mmol) and di-tert-butyl carbonate anhydride ((Boc)₂O, 415.59 mg, 1.90 mmol) were dissolved in 5 mL of DCM, and DIPEA (335.57 mg, 2.60 mmol) was added. The reaction was carried out at room temperature for 8 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated to obtain intermediate A86 for later use. A75 (300.00 mg, 0.71 mmol) and HATU (349.37 mg, 0.82 mmol) were dissolved in 3 mL of DMF, and DIPEA (365.36 mg, 2.83 mmol) was added. The mixture was stirred at room temperature. After 0.5 h, A8 was added, and the reaction was carried out at room temperature for 4 h. After TLC monitoring showed the reaction was complete, the reaction solution was added to 10 mL of ice water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain the target product methyl 1-(4-((3-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid ester (A87, 360.39 mg, yield 75%). MS (ESI): 680.81 [M+H] + .

[0096] 2. Synthesis of compound A88: A87 (299.14 mg, 0.44 mmol) was dissolved in 6 mL of MeOH, followed by the addition of a 2 mL H₂O solution of LiOH (106.53 mg, 4.44 mmol). The reaction was stirred at 40 °C for 2 h. After TLC monitoring showed complete reaction, the reaction solution was concentrated, and the pH was adjusted to 6-7 with 2 M acetic acid aqueous solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, washed with 50 mL of water, and dried at 50 °C to obtain the target product 1-(4-((3-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylic acid (A88, 263.67 mg, 90% yield). MS (ESI): 666.78 [M+H] + .

[0097] 3. Synthesis of compound A89: A88 (200.00 mg, 0.30 mmol) and HATU (0.15 g, 0.39 mmol) were dissolved in 4 mL of DMF, and then DIPEA (156.23 mg, 1.21 mmol) was added and stirred at room temperature. After 0.5 h, A79 (83.56 mg, 0.33 mmol) was added, and the reaction was allowed to proceed for 4 h at room temperature. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 40 mL of ice water, and a large amount of solid precipitated out. The mixture was filtered, washed with 10 mL of water, and dried at 50 °C. The crude product was slurried with 10 mL of isopropanol at room temperature for 2 h, filtered, and dried to obtain the target product tert-butyl 2-(1-(4-((3-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A89, 205.02 g, yield 74%). MS (ESI): 899.91 [M+H] + .

[0098] 4. Synthesis of compound A90: A89 (200.00 mg, 0.22 mmol) was dissolved in a mixed solvent of 4 mL THF and 1 mL MeOH. A mixed solution of 0.2 mL TMBS and 1 mL THF was slowly added under an ice bath at 0 °C. The reaction was allowed to naturally warm to room temperature and stirred for 4 h. After TLC monitoring showed complete reaction, the reaction solution was quenched in 10 mL of ice water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain the target product, tert-butyl-2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(methyl(3-(methyl(3-(methylamino)propyl)amino)propyl)carbamoyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A90, 66.80 mg, yield 38%). MS (ESI): 799.97 [M+H] + .

[0099] 5. Synthesis of compound A91: A90 (20.00 mg, 25.03 μmol) and diethylene glycol anhydride (5.83 mg, 50.03 μmol) were dissolved in 4 mL of THF, and then DIPEA (19.5 mg, 150.09 μmol) was added and stirred at 50 °C for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then separated and purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product 1-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10-trimethyl-1,11-dioxo-13-oxa-2,6,10-triazapentadecan-15-acid (A91, 17.41 mg, yield 76%). MS (ESI): 916.24 [M+H] + .

[0100] 6. Synthesis of compound A92: A91 (4.00 mg, 4.37 μmol) and HATU (2.17 mg, 5.71 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (2.27 mg, 17.56 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (8.80 mg, 4.39 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl2-(1-(4-(((S)-21-(4-((tert-butyloxycarbonyl)amino)butyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) (Ethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-28,32-dimethyl-16,20,23,27-tetraoxa-3,6,9,12,25-pentaoxa-15,19,22,28,32-pentazapentadecane-35-yl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A92, 8.12 mg, yield 64%). MS (ESI): 967.79 [M+3H]3+ .

[0101] 7. Synthesis of compound A93: Dissolve A92 (8.00 mg, 2.76 μmol) in 1 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(((S)-21-(4-aminobutyl)-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl) 1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-28,32-dimethyl-16,20,23,27-tetraoxo-3,6,9,12,25-pentaoxa-15,19,22,28,32-pentazapentadecane-35-yl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-carboxamido)adamantane-2-carboxylic acid (A93, 6.05 mg, 80% yield). MS (ESI): 915.75 [M+3H] 3+ .

[0102] 8. Synthesis of compound 14: A93 (4.00 mg, 1.46 μmol) and DOTA-NHS ester (0.94 mg, 1.89 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (1.89 mg, 14.6 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(1-(4-(3-((2-carboxymethylphosphono-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10-trimethyl-1,11-dioxo-13-oxa-2,6,10-triazapentadecan-15-amido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3 -Oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolid-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2 3-Triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (14, 3.10 mg, yield 68%). MS (ESI): 1045.45 [M+3H] 3+ The mass spectrum of compound 14 is shown below. Figure 6 As shown.

[0103] Example 15: Synthesis of Compound 15 The synthesis route is as follows:

[0104] 1. Synthesis of compound A94: Bis-PEG3-COOH (4.09 mg, 16.35 μmol) and HATU (7.17 mg, 18.86 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (9.75 mg, 75.55 μmol), and the mixture was stirred at room temperature. After 0.5 h, A81 (10 mg, 12.58 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product 3-(2-(2-(3-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)propionic acid (A94, 6.45 mg, yield 50%). MS (ESI): 1028.38 [M+H] + .

[0105] 2. Synthesis of compound A95: A94 (4.00 mg, 3.89 μmol) and HATU (1.92 mg, 5.06 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (2.01 mg, 15.58 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (7.80 mg, 3.89 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl2-(1-(4-(4-(1-((S)-21-(4-((tert-butoxycarbonyl)amino)butyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl) (2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,26,29,32-heptaoxa-15,19,22-triazapentadecane-35-acyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A95, 7.74 mg, yield 66%). MS (ESI): 1005.18 [M+3H] 3+ .

[0106] 3. Synthesis of compound A96: Dissolve A95 (8.00 mg, 2.65 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-((S)-21-(4-aminobutyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) (carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,26,29,32-heptaoxa-15,19,22-triazapentadecane-35-acyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A96, 6.15 mg, yield 81%). MS (ESI): 953.28 [M+3H] 3+ .

[0107] 4. Synthesis of Compound 15: A96 (4.00 mg, 1.40 μmol) and DOTA-NHS ester (0.90 mg, 1.82 μmol) were dissolved in 300 μL DMSO, followed by DIPEA (1.89 mg, 14.6 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(3-(2-(2-(3-(4-(4-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3 -Isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)propamido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolid-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl) -3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolid-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1, 2,3-Triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (15, 3.14 mg, 68% yield). MS (ESI): 1082.70 [M+3H] 3+ The mass spectrum of compound 15 is shown below. Figure 7 As shown.

[0108] Example 16: Synthesis of Compound 16 The synthesis route is as follows:

[0109] 1. Synthesis of compound A97: A2 (1.23 mg, 12.58 μmol) and HATU (6.22 mg, 16.35 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (9.75 mg, 75.55 μmol), and the mixture was stirred at room temperature. After 0.5 h, A81 (10.00 mg, 12.58 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(4-(1-(pent-4-ethynyl)piperidin-4-yl)piperazin-1-carbonyl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A97, 9.02 mg, yield 82%). MS (ESI): 876.13 [M+H] + .

[0110] 2. Synthesis of compound A98: Dissolve A97 (10.00 mg, 11.43 μmol) and A6 (3.33 mg, 11.43 μmol) in 400 μL of DMSO. Add a solution prepared by dissolving VcNa (0.91 mg, 4.57 μmol) and copper sulfate pentahydrate (0.57 mg, 2.28 μmol) in 80 μL of water. The mixture is then reacted with shaking in a metal bath at 50 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography, and freeze-dried to obtain the target product 1-(4-(3-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-acid (A98, 10.66 mg, yield 80%). MS (ESI): 1167.34 [M+H] + .

[0111] 3. Synthesis of compound A100: Compound 2-(1-(4-(4-(1-(3-(1-((S)-21-(4-aminobutyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline- The synthesis of 7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,26,29,32,35-octaoxa-15,19,22-triazaheptadecane-37-yl)-1H-1,2,3-triazol-4-yl)propionyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A100) is similar to that of compound A96, except that A94 is replaced with A98. MS (ESI): 999.18 [M+3H] 3+ .

[0112] 4. Synthesis of Compound 16: A100 (4.00 mg, 1.27 μmol) and DOTA-NHS ester (0.83 mg, 1.65 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (1.63 mg, 12.69 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(1-(4-(3-(4-(4-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-1-yl)-3-isopropylbenzoyl) Piperazin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline -7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl) -1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (16, 4.29 mg, yield 68%). MS (ESI): 1029.10 [M+3H] 3+ .

[0113] Example 17: Synthesis of Compound 17 The synthesis route is as follows:

[0114] 1. Synthesis of compound A102: 2-Isopropylaniline (A101, 8.00 g, 59.22 mmol) was dissolved in a mixture of 187.5 mL methanol and 1.5 mL water. NaOH (4.70 g, 118.44 mmol) and N-iodosuccinimide (NIS, 13.99 g, 62.18 mmol) were added sequentially at -40 °C, and the mixture was stirred for 20 min. The reaction mixture was then transferred to room temperature and allowed to react overnight. The reaction was monitored by TLC until complete. The reaction solution was concentrated, diluted with 100 mL of water, and extracted three times with 50 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated. The product 4-iodo-2-isopropylaniline (A102, 12.36 g, 80% yield) was purified by column chromatography. MS (ESI): 262.13 [M+H] + .

[0115] 2. Synthesis of compound A103: A102 (8.00 g, 30.65 mmol) was dissolved in 100 mL of 6 M HCl, and a solution of NaNO2 (4.24 g, 61.30 mmol) dissolved in 15 mL of water was added at 0 °C. After stirring for 1 h, a solution of SnCl2-2H2O (22.81 g, 101.12 mmol) dissolved in 15 mL of 6 M HCl was slowly added at 0 °C, and the reaction mixture was allowed to react at room temperature for 6 h. After TLC monitoring showed that the reaction was complete, the mixture was filtered, the filter cake was washed with a small amount of diethyl ether (2 mL), and dried to obtain the target product (4-iodo-2-isopropylphenyl)hydrazine (A103, 4.23 g, yield 50%). MS (ESI): 277.24 [M+H] + .

[0116] 3. Synthesis of compound A105: 1-(2,6-dimethoxyphenyl)ethyl-1-one (A104, 10.00 g, 55.5 mmol) was dissolved in 50 mL of dioxane. Dimethyl oxalate (8.19 g, 69.4 mmol) and sodium methoxide solution (3.30 g, 61.05 mmol) dissolved in 10 mL of water were added at room temperature. The reaction mixture was stirred overnight at 70 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, the pH was adjusted to 5 with 3 M HCl at 0 °C, and the mixture was extracted three times with 50 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated. The product was purified by column chromatography to obtain methyl 4-(2,6-dimethoxyphenyl)-2,4-dioxobutyrate (A105, 13.30 g, 90% yield). MS (ESI): 267.26 [M+H] + .

[0117] 4. Synthesis of compound A106: A103 (3.74 g, 13.53 mmol) and A105 (3 g, 11.28 mmol) were dissolved in 100 mL of AcOH solution, and the reaction mixture was stirred overnight at 60 °C. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The pH was adjusted to 7-8 with Na2CO3 aqueous solution at 0 °C. The mixture was extracted three times with ethyl acetate (EA), 30 mL each time. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by column chromatography to obtain the target product methyl 5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid ester (A106, 4.57 g, yield 80%). MS (ESI): 507.54 [M+H] + .

[0118] 5. Synthesis of compound A107: A106 (2.00 g, 3.95 mmol) was dissolved in 15 mL of MeOH, followed by the addition of a 5 mL H2O solution of LiOH (0.95 g, 39.49 mmol). The reaction was stirred at 40 °C for 2 h. After TLC monitoring showed complete reaction, the reaction solution was concentrated, and the pH was adjusted to 6-7 with 2 M acetic acid aqueous solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, washed with 50 mL of water, and dried at 50 °C to obtain the target product 5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid (A107, 1.75 g, 90% yield). MS (ESI): 493.34 [M+H] + .

[0119] 6. Synthesis of compound 108: A107 (1.00 g, 2.03 mmol) and HATU (1.00 g, 2.64 mmol) were dissolved in 8 mL of DMF, and then DIPEA (1.05 g, 8.12 mmol) was added and stirred at room temperature. After 0.5 h, A79 (0.51 g, 2.03 mmol) was added, and the reaction was continued at room temperature for 4 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 80 mL of ice water, and a large amount of solid precipitated. The mixture was filtered, washed with 30 mL of water, dried at 50 °C, and the crude product was slurried with 10 mL of isopropanol at room temperature for 2 h. After filtration and drying, the target product tert-butyl 2-(5-(2,6-dimethoxyphenyl)-1-(4-iodo-2-isopropylphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A108, 1.16 g, yield 79%) was obtained. MS (ESI): 726.78 [M+H] + .

[0120] 7. Synthesis of compound A109: A108 (200.00 mg, 0.28 mmol) and A76 (96.38 mg, 0.36 mmol) were dissolved in 10 mL of toluene, followed by the addition of compound Cs2CO3 (269.40 mg, 0.83 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (XantPhos, 15.95 mg, 0.028 mmol), and Pd2(dba)3 (6.18 mg, 0.028 mmol). The reaction system was subjected to a nitrogen atmosphere at 110 °C for 12 h. After the reaction was complete as monitored by TLC, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by column chromatography to obtain the target product, tert-butyl 4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)piperazin-1-yl)piperidine-1-carboxylic acid ester (A109, 95.59 mg, yield 40%). MS (ESI): 868.54 [M+H] + .

[0121] 8. Synthesis of compound A110: A109 (100.00 mg, 0.12 mmol) was dissolved in a mixed solvent of 4 mL THF and 1 mL MeOH. A mixed solution of 0.2 mL TMBS and 1 mL THF was slowly added under an ice bath at 0 °C. The reaction was allowed to naturally warm to room temperature and stirred for 4 h. After TLC monitoring showed complete reaction, the reaction solution was quenched in 10 mL of ice water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain the target product, tert-butyl-2-(5-(2,6-dimethoxyphenyl)-1-(2-isopropyl-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A110, 33.63 mg, yield 38%). MS (ESI): 768.20 [M+H] + .

[0122] 9. Synthesis of compound A111: Bis-PEG5-COOH (4.00 mg, 11.82 μmol) and HATU (5.84 mg, 15.37 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (6.11 mg, 47.29 μmol), and the mixture was stirred at room temperature. After 0.5 h, A110 (8.16 mg, 10.64 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 19-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)piperazin-1-yl)piperidin-1-yl)-19-oxo-4,7,10,13,16-pentaenoic acid (A111, 5.78 mg, yield 50%). MS (ESI): 1088.27 [M+H] + .

[0123] 10. Synthesis of compound A112: A111 (4.00 mg, 3.68 μmol) and HATU (1.82 mg, 4.78 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (1.90 mg, 14.71 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (7.37 mg, 3.68 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl2-(1-(4-(4-(1-((S)-21-(4-((tert-butoxycarbonyl)amino)butyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)- 2-Oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,26,29,32,35,38-nonoxa-15,19,22-triazatetrazo-41-acyl)piperidin-4-yl)piperazin-1-yl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A112, 7.80 mg, yield 69%). MS (ESI): 1025.18 [M+3H] 3+ .

[0124] 11. Synthesis of compound A113: Dissolve A112 (5.00 mg, 1.63 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction mixture was prepared in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-((S)-21-(4-aminobutyl)-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)amino) (Formyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,23-trioxo-3,6,9,12,26,29,32,35,38-nonoxa-15,19,22-triazatetradecane-41-acyl)piperidin-4-yl)piperazin-1-yl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A113, 3.98 mg, yield 84%). MS (ESI): 973.13 [M+3H] 3+ .

[0125] 12. Synthesis of Compound 17: A113 (4.00 mg, 1.37 μmol) and DOTA-NHS ester (0.89 mg, 1.79 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (1.77 mg, 13.71 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(19-(4-(4-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)piperazine (azin-1-yl)piperidin-1-yl)-19-oxo-4,7,10,13,16-pentaenocarbamate)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)- 3-Oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2 3-Triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (17, 3.08 mg, yield 68%). MS (ESI): 1102.73 [M+3H] 3+ .

[0126] Example 18: Synthesis of Compound 18 The synthesis route is as follows:

[0127] 1. Synthesis of compound A115: 8-Aminoquinoline-4-carboxylic acid (A114, 300.00 mg, 1.59 mmol) and HATU (789.98 mg, 2.07 mmol) were added to 3 mL of DMF, followed by DIPEA (822.57 mg, 6.37 mmol), and the mixture was stirred at room temperature. After 0.5 h, A4 (395.64 mg, 1.75 mmol) was added, and the reaction was continued at room temperature for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was added to 10 mL of water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain the target product (S)-8-amino-N-(2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A115, 446.81 mg, yield 78%). MS (ESI): 360.44 [M+H] + .

[0128] 2. Synthesis of compound A116: A115 (400.00 mg, 1.11 mmol), succinic anhydride (222.63 mg, 2.22 mmol), and 4-dimethylaminopyridine (DMAP, 13.59 mg, 0.11 mmol) were dissolved in 15 mL of THF and stirred at 60 °C for 5 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated and purified by column chromatography to obtain the target product (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutyric acid (A116, 391.20 mg, yield 77%). MS (ESI): 460.41 [M+H] + .

[0129] 3. Synthesis of compound A119: (S)-2,6-di-tert-butoxycarbonylaminohexanoic acid (A117, 200.00 mg, 0.57 mmol) and HATU (285.35 mg, 0.75 mmol) were added to 3 mL of DMF, followed by DIPEA (298.37 mg, 2.31 mmol), and the mixture was stirred at room temperature. After 0.5 h, N-fluorenylmethoxycarbonyl-1,2-diaminoethane hydrochloride (A118, 202.46 mg, 0.64 mmol) was added, and the mixture was reacted at room temperature for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was added to 10 mL of water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain the target product, di-tert-butyl(6-((2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)amino)-6-oxohexane-1,5-diyl)(S)-dicarbamate (A119, 282.08 mg, yield 80%). MS (ESI): 611.71 [M+H] + .

[0130] 4. Synthesis of compound A120: Dissolve A119 (250.00 mg, 0.41 mmol) in 5 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a 100 μL:400 μL solution and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then slurried with a mixture of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product (9H-fluorene-9-yl)methyl(S)-(2-(2,6-diaminohexamido)ethyl)carbamate (A120, 136.11 mg, yield 81%). MS (ESI): 411.51 [M+H] + .

[0131] 5. Synthesis of compound A121: A116 (123.10 mg, 0.27 mmol) and HATU (132.37 mg, 0.35 mmol) were dissolved in 3 mL of DMF, and then DIPEA (138.48 mg, 1.07 mmol) was added and stirred at room temperature. After 0.5 h, A120 (50.00 mg, 0.12 mmol) was added, and the reaction was carried out at room temperature for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was added to 10 mL of water and extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and then slurried with a mixture of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product (9H-fluorene-9-yl)methyl(2-((S)-2,6-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)carbamate (A121, 114.99 mg, yield 73%). MS (ESI): 646.99 [M+2H] 2+ .

[0132] 6. Synthesis of compound A122: A121 (100.00 mg, 77.32 μmol) was dissolved in a mixed solvent of 4 mL DCM and 1 mL morpholine, and the reaction system was shaken at room temperature for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The mixture was stirred with a mixed solvent of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to give the target product N1,N1'-((S)-6-((2-aminoethyl)amino)-6-oxohexane-1,5-diyl)bis(N4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)succinamide)(A122, 61.28 mg, yield 74%). MS (ESI): 1071.96 [M+H] + .

[0133] 7. Synthesis of compound A123: A13 (43.75 mg, 93.37 μmol) and HATU (37.41 mg, 121.38 μmol) were dissolved in 800 μL of DMF, followed by the addition of DIPEA (48.25 mg, 373.48 μmol), and the mixture was stirred at room temperature. After 0.5 h, A122 (100 mg, 93.37 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with 15 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and then slurried with a mixture of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product (9H-fluorene-9-yl)methyl tert-butyl((S)-6-((2-((S)-2,6-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)amino)-6-oxohexane-1,5-diyl)dicarbamate (A123, 99.43 mg, yield 70%). MS (ESI): 761.30 [M+2H] 2+ .

[0134] 8. Synthesis of compound A124: A123 (100.00 mg, 65.73 μmol) was dissolved in a mixed solvent of 4 mL DCM and 1 mL morpholine, and the reaction system was shaken at room temperature for 2 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated. The mixture was then stirred with a mixed solvent of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product tert-butyl((S)-5-amino-6-((2-((S)-2,6-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)amino)-6-oxohexyl)carbamate (A124, 61.49 mg, yield 72%). MS (ESI): 650.18 [M+2H] 2+ .

[0135] 9. Synthesis of compound A125: A97 (8.00 mg, 6.86 μmol) and HATU (3.38 mg, 8.92 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (3.54 mg, 27.44 μmol), and the mixture was stirred at room temperature. After 0.5 h, A124 (8.91 mg, 6.86 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was separated and purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product tert-butyl2-(1-(4-(4-(1-(3-(1-((17S,24S)-17-(4-((tert-butyloxycarbonyl)amino)butyl)-33-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-24-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-24-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl) -yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)-15,18,23,30,33-pentoxo-3,6,9,12-tetraoxa-16,19,22,29-tetraazatritane)-1H-1,2,3-triazol-4-yl)propionyl)piperidin-4-yl)piperazine-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A125, 13.26 mg, yield 79%). MS (ESI): 1224.44 [M+2H] 2+ .

[0136] 10. Synthesis of compound A126: Dissolve A125 (5.00 mg, 2.04 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction system was mixed in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-(3-(1-((17S,24S)-17-(4-aminobutyl)-33-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-24-(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl) Carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)-15,18,23,30,33-pentoxo-3,6,9,12-tetraoxa-16,19,22,29-tetraazatritane)-1H-1,2,3-triazol-4-yl)propionyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A126, 4.68 mg, 80% yield). MS (ESI): 1146.33 [M+2H] 2+ .

[0137] 11. Synthesis of Compound 18: A126 (4.00 mg, 1.75 μmol) and DOTA-NHS ester (1.14 mg, 2.27 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.25 mg, 17.45 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-17-((2-((S)-2,6-bis(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)carbamoyl)-1-(4-(3-(4-(4-(4-(3-(( 2-Carboxymethylbenzyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-15,23-dioxo-3,6,9,12-tetraoxa-16,22-diazacotetracosane-24-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (18, 3.09 mg, yield 66%). MS (ESI): 893.91 [M+3H]3+ .

[0138] Example 19: Synthesis of Compound 19 The synthesis route is as follows:

[0139] 1. Synthesis of compound A128: A108 (200.00 mg, 0.28 mmol) and N,N-bis(3-aminopropyl)methylamine (A127, 52.29 mg, 0.36 mmol) were dissolved in 10 mL of toluene, followed by the addition of Cs₂CO₃ (269.40 mg, 0.83 mmol), XantPhos (15.95 mg, 0.028 mmol), and Pd₂(dba)₃ (6.18 mg, 0.028 mmol). The reaction system was carried out at 110 °C for 12 h under a nitrogen atmosphere. After the reaction was monitored to be complete by TLC, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and purified by column chromatography to obtain the target product tert-butyl 2-(1-(4-((3-(((3-aminopropyl)(methyl)amino)propyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A128, 41.61 mg, yield 20%). MS (ESI): 743.97 [M+H] + .

[0140] 2. Synthesis of compound A129: Bis-PEG3-COOH (4.00 mg, 16.35 μmol) and HATU (7.17 mg, 18.86 μmol) were dissolved in 300 μL LMF, followed by the addition of DIPEA (9.75 mg, 75.55 μmol), and the mixture was stirred at room temperature. After 0.5 h, A128 (10.93 mg, 14.71 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 21-((4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)-18-methyl-13-oxo-4,7,10-trioxa-14,18-diazaeicosanoic acid (A129, 7.18 mg, yield 50%). MS (ESI): 976.42 [M+H] + .

[0141] 3. Synthesis of compound A130: A129 (4.00 mg, 4.10 μmol) and HATU (2.03 mg, 5.33 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (2.12 mg, 16.40 μmol), and the mixture was stirred at room temperature. After 0.5 h, A124 (5.33 mg, 4.10 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was separated and purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl2-(1-(4-(((23S,30S)-23-(4-((tert-butyloxycarbonyl)amino)butyl)-39-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-30-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine) -1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)-4-methyl-9,21,24,29,36,39-hexaoxo-12,15,18-trioxa-4,8,22,25,28,35-hexaazanonadecanyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbamoyl)adamantane-2-carboxylic acid ester (A130, 6.38 mg, yield 69%). MS (ESI): 1142.85 [M+2H] 2+ .

[0142] 4. Synthesis of compound A131: Dissolve A130 (5.00 mg, 2.22 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction system was mixed in a ratio of 200 μL to 800 μL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(((23S,30S)-23-(4-aminobutyl)-39-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-30-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl) (Ethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)-4-methyl-9,21,24,29,36,39-hexaoxo-12,15,18-trioxa-4,8,22,25,28,35-hexaazanonadecanoyl)carbamoyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A131, 3.96 mg, yield 84%). MS (ESI): 1064.69 [M+2H] 2+ .

[0143] 5. Synthesis of Compound 19: A131 (4.00 mg, 1.88 μmol) and DOTA-NHS ester (1.14 mg, 2.27 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.43 mg, 18.79 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-25-((2-((S)-2,6-bis(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)carbamoyl)-1-(4 -(3-((2-carboxymethylbenzyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-6-methyl-1,11,23,31-tetraoxo-14,17,20-trioxa-2,6,10,24,30-pentazatridodecane-32-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (19, 3.21 mg, yield 68%). MS (ESI): 847.48 [M+3H] 3+ .

[0144] Example 20: Synthesis of Compound 20 The synthesis route is as follows:

[0145] 1. Synthesis of compound A133: N-fluorenylmethoxycarbonyl-L-glutamic acid 5-allyl ester (A132, 20.00 mg, 48.85 μmol) and HATU (24.14 mg, 63.50 μmol) were dissolved in 800 μL of DMF, followed by the addition of DIPEA (25.24 mg, 195.39 μmol), and the mixture was stirred at room temperature. After 0.5 h, A81 (38.84 mg, 48.85 μmol) was added, and the reaction was continued at room temperature for another 4 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 8 mL of ice water, and a large amount of solid precipitated. The mixture was filtered and dried at 50°C. The crude product was slurried at room temperature with a mixture of 4 mL isopropanol and 4 mL n-hexane for 2 h, filtered, and dried to obtain the target product tert-butyl(S)-2-(1-(4-(4-(1-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(allyloxy)-5-oxopentanoyl)piperidin-4-yl)piperazine-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A133, 43.47 mg, yield 75%). MS (ESI): 1187.64 [M+H] + .

[0146] 2. Synthesis of compound A134: A133 (40.00 mg, 33.71 μmol) was dissolved in a mixed solvent of 4 mL DCM and 1 mL morpholine, and the reaction system was shaken at room temperature for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The mixture was stirred with a mixed solvent of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product tert-butyl(S)-2-(1-(4-(4-(1-(5-(allyloxy)-2-amino-5-oxopentanoyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A134, 32.50 mg, yield 75%). MS (ESI): 965.31 [M+H] + .

[0147] 3. Synthesis of compound A136: A134 (30.00 mg, 31.11 μmol), DOTA-tert-butyl succinimide ester (A135, 22.92 mg, 34.22 μmol), and DIPEA (16.05 mg, 124.45 μmol) were dissolved in 4 mL of DCM, and the reaction system was shaken at room temperature for 4 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated and stirred with a mixed solvent of 4 mL isopropanol and 4 mL n-hexane for 2 h. The mixture was filtered, and the filter cake was dried to obtain the target product, tri-tert-butyl 2,2',2''-(10-(2-((5-(allyloxy)-1-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentane-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)(S)-triacetate (A136, 35.44 mg, yield 85%). MS (ESI): 760.01 [M+2H] 2+ .

[0148] 4. Synthesis of compound A137: A136 (30.00 mg, 19.75 μmol), tetraphenylphosphine palladium (2.28 mg, 1.975 μmol) and phenylsilane (10.69 mg, 98.75 μmol) were dissolved in 400 μL of DMF, and the reaction system was shaken at room temperature for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product (S)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)5-oxo-4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamoxy)valerate (A137, 23.37 mg, yield 80%). MS (ESI): 739.95 [M+2H] 2+ .

[0149] 5. Synthesis of compound A139: 4-((tert-Butoxycarbonylamino)methyl)benzoic acid (A138, 10.00 mg, 39.80 μmol) and HATU (19.67 mg, 51.74 μmol) were dissolved in 400 μL of DMF, followed by the addition of DIPEA (20.53 mg, 159.18 μmol), and the mixture was stirred at room temperature. After 0.5 h, A46 (33.87 mg, 39.80 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was added to 5 mL of ice water and extracted three times with 10 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the target product tert-butyl(4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-1-oxo-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinyl)pentan-2-yl)carbamoyl)benzyl)carbamate (A139). This target product was used directly in the next step without purification.

[0150] 6. Synthesis of compound A140: Dissolve the above-mentioned A139 in 5 mL of a mixed solution (V TFA V DCM The reaction system was mixed in a ratio of 1 mL to 4 mL and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 7-((4-((4-(aminomethyl)benzoyl)arginyl)piperazin-1-yl)methyl)-N-(2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A140, 17.47 mg, yield 60%). MS (ESI): 732.80 [M+H] + .

[0151] 7. Synthesis of compound A141: A137 (10.00 mg, 6.76 μmol) and HATU (3.34 mg, 8.79 μmol) were dissolved in 800 μL of DMF, followed by the addition of DIPEA (3.49 mg, 27.05 μmol), and the mixture was stirred at room temperature. After 0.5 h, A140 (4.95 mg, 6.76 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tri-tert-butyl2,2',2''-(10-(2-(((2S)-1-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-5-((4-((1- (4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-1,5-dioxopentane-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (A141, 8.89 mg, 65% yield). MS (ESI): 1096.88 [M+2H] 2+ .

[0152] 8. Synthesis of Compound 20: The A141 (8.00 mg, 3.64 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at room temperature for 4 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(2-(((2S)-1-(4-(4-(4-(3-((2-carboxymethylcarbamoyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-5-((4-((1-(4-((4-( (2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-1,5-dioxopentane-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (20, 3.66 mg, 51% yield). MS (ESI): 985.43 [M+2H] 2+ .

[0153] Example 21: Synthesis of Compound 21 The synthesis route is as follows:

[0154] 1. Synthesis of compound A145: Nota-BIS (tert-butyl ester) (A142, 20.00 mg, 48.13 μmol) and HATU (23.79 mg, 62.57 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (24.87 mg, 192.53 μmol), and the mixture was stirred at room temperature. After 0.5 h, FMOC-1-amino-3,6-dioxa-8-octylamine hydrochloride (A143, 20.74 mg, 48.13 μmol) was added, and the reaction was continued at room temperature for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was added to 8 mL of water and extracted three times with 10 mL of ethyl acetate (EA). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain intermediate A144. Intermediate A144 was dissolved in a mixed solution of 2 mL of TFA and 2 mL of DCM, and the reaction system was shaken at room temperature for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(7-(1-(9H-fluorene-9-yl)-3,14-dioxo-2,7,10-trioxa-4,13-diazapentadecan-15-yl)-1,4,7-triazacyclononane-1,4-diyl)diacetic acid (A145, 15.78 mg, yield 50%). MS (ESI): 656.68 [M+H] + .

[0155] 2. Synthesis of compound A146: A145 (10.00 mg, 15.25 μmol) and HATU (15.07 mg, 39.65 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (15.76 mg, 121.99 μmol), and the mixture was stirred at room temperature. After 0.5 h, A140 (11.16 mg, 15.25 μmol) and A128 (11.33 mg, 15.25 μmol) were added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl2-(1-(4-((3-((3-(2-(4-(1-(9H-fluoren-9-yl)-3,14-dioxo-2,7,10-trioxa-4,13-diazapentadecan-15-yl)-7-(2-((4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2- Oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-yl)acetamoxy)propyl)(methyl)amino)propyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid ester (A146, 10.22 mg, yield 32%). MS (ESI): 1047.78 [M+2H] 2+ .

[0156] 3. Synthesis of compound A147: Dissolve A146 (10.00 mg, 4.77 μmol) in 1 mL of a mixed solution (V TFA V DCMThe reaction system was mixed with 200 μL of DCM and 0.5 mL of morpholine and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. Then, it was dissolved in a mixed solvent of 2 mL DCM and 0.5 mL morpholine, and the reaction system was shaken at room temperature for 2 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography, freeze-dried, and the target product 2-(1-(4-((3-((3-(2-(4-(2-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-7-(2-((4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline -7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-yl)acetamamido)propyl)(methyl)amino)propyl)amino)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A147, 4.33 mg, 50% yield). MS (ESI): 908.64 [M+2H] 2+ .

[0157] 4. Synthesis of Compound 21: A147 (4.00 mg, 2.20 μmol) and DOTA-NHS ester (1.12 mg, 2.20 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.84 mg, 22.02 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-(14-(4-(2-((3-((3-((4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)amino)propyl)(methyl)amino)propyl)amino)-2-oxoethyl)-7-(2-((4-((1-(4-((4-(2- ((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-yl)-2,13-dioxo-6,9-dioxa-3,12-diatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (21, 2.91 mg, 60% yield). MS (ESI): 1102.23 [M+2H] 2+ .

[0158] Example 22: Synthesis of Compound 22 The synthesis route is as follows:

[0159] 1. Synthesis of compound A149: 4,4'-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(5-(tert-butoxy)-5-oxovalerate) (A148, CAS No.: 1049020-11-2, 30.00 mg, 38.81 μmol), EDCI (22.32 mg, 116.43 μmol), N-hydroxysuccinimide (NHS, 17.87 mg, 155.25 μmol) and DIPEA (20.06 mg, 155.25 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 45 °C for 6 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product 4,4'-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(5-(tert-butoxy)-5-oxovalerate 2,5-dioxopyrrolidine-1-yl ester) (A149, 37.54 mg, yield 50%). MS (ESI): 968.50 [M+H] + .

[0160] 2. Synthesis of compound A150: A149 (5.00 mg, 5.17 μmol), A81 (4.11 mg, 5.17 μmol), A140 (3.78 mg, 5.17 μmol) and DIPEA (4.01 mg, 31.02 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 40 °C for 6 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product di-tert-butyl2,2'-(4-(1-(tert-butoxy)-5-((4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-1,5-di Oxopentane-2-yl)-10-(1-(tert-butoxy)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentane-2-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A150, 5.85 mg, 40% yield). MS (ESI): 1132.45 [M+2H] 2+ .

[0161] 3. Synthesis of compound 22: A150 (5.00 mg, 2.20 μmol) was dissolved in 1 mL of LTFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(1-carboxy-4-((4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-4 -O-butyl)-10-(1-carboxy-4-(4-(4-(4-(3-(((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (22, 2.19 mg, 50% yield). MS (ESI): 992.86 [M+2H] 2+ .

[0162] Example 23: Synthesis of Compound 23 The synthesis route is as follows:

[0163] 1. Synthesis of compound A151: A149 (5.00 mg, 5.17 μmol), A90 (4.13 mg, 5.17 μmol), A140 (3.78 mg, 5.17 μmol) and DIPEA (4.01 mg, 31.02 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 40 °C for 6 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product di-tert-butyl2,2'-(4-(1-(tert-butoxy)-5-((4-((1-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-1,5-dioxopentane- 2-yl)-10-(1-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10,17,17-pentamethyl-1,11,15-trioxo-16-oxa-2,6,10-triazaoctadecane-14-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A151, 5.86 mg, 40% yield). MS (ESI): 1134.41 [M+2H] 2+ .

[0164] 2. Synthesis of compound 23: A151 (5.00 mg, 2.20 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(1-carboxy-4-((3-((3-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-4-oxobutyl)-10-(1- Carboxy-4-((4-((1-(4-(((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-7-yl)methyl)piperazin-1-yl)-5-guanidinyl-1-oxopentane-2-yl)carbamoyl)benzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (23, 2.19 mg, 50% yield). MS (ESI): 994.83 [M+2H] 2+ .

[0165] Example 24: Synthesis of Compound 24 The synthesis route is as follows:

[0166] 1. Synthesis of compound A154: 2-[2-(tert-Butoxycarbonylamino)ethoxy]ethoxyacetic acid (A152, CAS No.: 108466-89-3, 5.93 mg, 225.2 μmol) and HATU (11.13 mg, 29.28 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (11.64 mg, 90.09 μmol), and the mixture was stirred at room temperature. After 0.5 h, A12 (40.00 mg, 22.52 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed complete reaction, the reaction mixture was added to 6 mL of ice water, and the mixture was centrifuged to precipitate and dried to obtain intermediate A153. Intermediate A153 was dissolved in 2 mL of the mixed solution (V... TFA V DCM In a mixture of 400 μL and 1600 μL, the reaction system was shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 3-(2-(2-(2-aminoethoxy)ethoxy)acetamyl)-N1,N5-bis(14-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A154, 22.81 mg, yield 55%). MS (ESI): 961.56 [M+2H] 2+ .

[0167] 2. Synthesis of compound A155: A149 (5.00 mg, 5.17 μmol), A154 (9.94 mg, 5.17 μmol), A81 (4.11 mg, 5.17 μmol), and DIPEA (4.01 mg, 31.02 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 40 °C for 6 h. After the reaction was confirmed to be complete by TLC, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product di-tert-butyl 2,2'-(4-(1-(tert-butoxy)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl Piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentane-2-yl)-10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2 ,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6, 9,12,15-Tetraoxa-3-azaheptadecyl)-35,35-dimethyl-16,20,29,33-tetraoxa-3,6,9,12,22,25,34-heptaoxa-15,19,28-triazahexadecane-32-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetate (A155, 7.14 mg, 40% yield). MS (ESI): 1151.71 [M+3H] 3+ .

[0168] 3. Synthesis of compound 24: A155 (5.00 mg, 1.45 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(32-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl) (-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,29-trioxo-3,6,9,12,22,25-hexaoxa-15,19,28-triazatridodecane-32-yl)-10-(1-carboxyl-4-(4-(4-( 4-(3-((2-carboxymethylbenzan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (24, 2.30 mg, 50% yield). MS (ESI): 1099.09 [M+3H] 3+ .

[0169] Example 25: Synthesis of Compound 25 The synthesis route is as follows:

[0170] 1. Synthesis of compound A159: Compound di-tert-butyl 2,2'-(4-(1-(tert-butoxy)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentan-2-yl)-10-(1-(4-(3-(4-( 3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine- 1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-41,41-dimethyl-16,20,35,39-tetraoxo-3,6,9,12,22,2 The synthesis of 5,28,31,40-nonoxa-15,19,34-triazatetrazo-dodecane-38-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A159) is similar to that of compound A155, except that A152 is replaced with 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-acid (A156). MS (ESI): 1181.27 [M+3H] 3+ .

[0171] 2. Synthesis of compound 25: A159 (5.00 mg, 1.45 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(38-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl) Piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)- 3-Oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,35-trioxo-3,6,9,12,22,25,28,31-octaoxa-15,19,34-triazaoctadecane-38-yl)-10-(1-carboxyl-4-(4-(4) -(4-(3-((2-carboxymethylbenzan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (25, 2.30 mg, 50% yield). MS (ESI): 1088.38 [M+3H] 3+ .

[0172] Example 26: Synthesis of Compound 26 The synthesis route is as follows:

[0173] 1. Synthesis of compound A160: Compound di-tert-butyl 2,2'-(4-(1-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10,17,17-pentamethyl-1,11,15-trioxo-16-oxa-2,6,10-triazaoctadecane-14 -yl)-10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3 -(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl The synthesis of 35,35-dimethyl-16,20,29,33-tetraoxo-3,6,9,12,22,25,34-heptaoxa-15,19,28-triazahexahexadecane-32-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A160) is similar to that of compound A155, except that A81 is replaced with A90. MS (ESI): 1153.08 [M+3H] 3+ .

[0174] 2. Synthesis of compound 26: A160 (5.00 mg, 1.45 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was confirmed to be complete by TLC monitoring, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(32-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine (1-azinyl)-3-oxopropyl)-1H-1,2,3-triazolyl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazinyl)-3-oxo (propyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,29-trioxo-3,6,9,12,22,25-hexaoxa-15,19,28-triazatridodecane-32-yl)-10-(1-carboxyl-4-((3-((3-(4-(3-(2) -Carboxymethylcarbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (26, 2.07 mg, yield 45%). MS (ESI): 1060.42 [M+3H] 3+ .

[0175] Example 27: Synthesis of Compound 27 The synthesis route is as follows:

[0176] 1. Synthesis of compound A161: Compound di-tert-butyl 2,2'-(4-(1-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10,17,17-pentamethyl-1,11,15-trioxo-16-oxa-2,6,10-triazaoctadecane-14-yl) )-10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4 -(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-41 The synthesis of ,41-dimethyl-16,20,35,39-tetraoxo-3,6,9,12,22,25,28,31,40-nonazo-15,19,34-triazatetrazo-dodecane-38-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A161) is similar to that of compound A159, except that A81 is replaced with A90. MS (ESI): 1182.43 [M+3H] 3+ .

[0177] 2. Synthesis of compound 27: A161 (5.00 mg, 1.41 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(38-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine. -1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)-3-oxopropyl) -1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,35-trioxo-3,6,9,12,22,25,28,31-octaoxa-15,19,34-triazaoctadecane-38-yl)-10-(1-carboxyl-4-((3-((3-(4-(3-(( 2-Carboxymethylcarbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (27, 2.07 mg, 45% yield). MS (ESI): 1089.69 [M+3H] 3+ .

[0178] Example 28: Synthesis of Compound 28 The synthesis route is as follows:

[0179] 1. Synthesis of compound A162: A149 (5.00 mg, 5.17 μmol), A12 (9.19 mg, 5.17 μmol), A81 (4.11 mg, 5.17 μmol), and DIPEA (4.01 mg, 31.02 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 40 °C for 6 h. After the reaction was confirmed to be complete by TLC, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product di-tert-butyl 2,2'-(4-(1-(tert-butoxy)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzene. (formyl)piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentane-2-yl)-10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)- 1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl 2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-26,26-dimethyl-16,20,24-trioxo-3,6,9,12,25-pentaoxa-15,19-diazaheptadecane-23-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetate (A162, 7.18 mg, yield 42%). MS (ESI): 1103.31 [M+3H] 3+ .

[0180] 2. Synthesis of compound 28: A162 (5.00 mg, 1.41 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(23-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl) Piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazatocetane-23-yl)-10-(1-carboxy-4-(4-(4-(4-(3-((2-carboxycarboxane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (28, 2.06 mg, 45% yield). MS (ESI): 1010.94 [M+3H] 3+ .

[0181] Example 29: Synthesis of Compound 29 The synthesis route is as follows:

[0182] 1. Synthesis of compound A163: The compound is di-tert-butyl 2,2'-(4-(1-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylphenyl)-2,6,10,17,17-pentamethyl-1,11,15-trioxo-16-oxa-2,6,10-triazaoctadecane -14-yl)-10-(1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17) -(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxazine The synthesis of (-3-azaheptadecyl)-26,26-dimethyl-16,20,24-trioxo-3,6,9,12,25-pentaoxa-15,19-diazaheptadecane-23-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A163) is similar to that of compound A162, except that A81 is replaced with A90. MS (ESI): 1104.66 [M+3H] 3+ .

[0183] 2. Synthesis of compound 29: A163 (5.00 mg, 1.41 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(23-carboxy-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)piperazin-1-yl) )-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazatocetane-23-yl)-10-(1-carboxy-4-((3-((3-(4-(3-((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (29, 2.05 mg, yield 45%). MS (ESI): 1012.06 [M+3H] 3+ .

[0184] Example 30: Synthesis of Compound 30 The synthesis route is as follows:

[0185] 1. Synthesis of compound A164: Compound di-tert-butyl 2,2'-(4-(1-(tert-butoxy)-5-(4-(4-(4-(3-((2-(tert-butoxycarbonyl)adamantane-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-1,5-dioxopentan-2-yl)-10-((14S)-23-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8- The synthesis of (A164)-14-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)-2,2-dimethyl-4,8,13,20,23-pentoxo-3-oxa-9,12,19-triazatocetane-5-yl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (A164) is similar to that of compound A163, except that A12 is replaced with A122. MS (ESI): 868.03 [M+3H] 3+ .

[0186] 2. Synthesis of compound 30: A164 (5.00 mg, 1.92 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(4-((2-((S)-2,6-bis(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)amino)-1-carboxy-4-oxobutyl 10-(1-carboxy-4-(4-(4-(4-(3-(((2-carboxymethyl-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (30, 2.05 mg, yield 46%). MS (ESI): 1162.24 [M+2H] 2+ .

[0187] Example 31: Synthesis of Compound 31 The synthesis route is as follows:

[0188] 1. Synthesis of compound A165: A152 (6.62 mg, 25.15 μmol) and HATU (12.43 mg, 32.70 μmol) were dissolved in 500 μL of DMF, followed by the addition of DIPEA (13.00 mg, 100.62 μmol), and the mixture was stirred at room temperature. After 0.5 h, A81 (20.00 mg, 25.15 μmol) was added, and the reaction was continued at room temperature for another 4 h. Once the reaction was complete as monitored by TLC, the mixture was added to 6 mL of ice water, and the mixture was precipitated by centrifugation and dried. The dried solid was dissolved in 2 mL of the mixed solution (V... TFA V DCM The reaction mixture was prepared in a 400 μL:1600 μL ratio and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A165, 12.01 mg, yield 54%). MS (ESI): 885.10 [M+H + .

[0189] 2. Synthesis of compound A166: A149 (5.00 mg, 5.17 μmol), A122 (5.54 mg, 5.17 μmol), A165 (4.57 mg, 5.17 μmol) and DIPEA (4.01 mg, 31.02 μmol) were dissolved in 400 μL of DMF, and then the mixture was reacted with shaking in a metal bath at 40 °C for 6 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2-(1-(4-(4-(1-(13-(4,10-bis(2-(tert-butoxy)-2-oxoethyl)-7-((14S)-23-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-14-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino) (-yl)amino)-4-oxobutyramido)-2,2-dimethyl-4,8,13,20,23-pentoxo-3-oxa-9,12,19-triazatocetane-5-yl)-1,4,7,10-tetraazacyclododecane-1-yl)-16,16-dimethyl-10,14-dioxo-3,6,15-trioxa-9-azaheptadecanoyl)piperidin-4-yl)piperazin-1-carbonyl)-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamido)adamantane-2-carboxylic acid (A166, 5.57 mg, yield 40%). MS (ESI): 897.73 [M+3H] 3+ .

[0190] 3. Synthesis of compound 31: A166 (5.00 mg, 1.85 μmol) was dissolved in 1 mL of TFA, and the reaction system was shaken at 40 °C for 8 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2'-(4-(4-((2-((S)-2,6-bis(4-((4-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)quinoline-8-yl)amino)-4-oxobutamido)hexamido)ethyl)amino)-1-carboxy-4-oxobutyl)-10-(1-carboxy-4-( (2-(2-(2-(4-(4-(4-(3-(((2-carboxymethylbenzan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropylbenzoyl)piperazin-1-yl)piperidin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (31, 2.29 mg, 50% yield). MS (ESI): 1235.07 [M+2H] 2+ .

[0191] Example 32: Synthesis of Compound 32 The synthesis route is as follows:

[0192] 1. Synthesis of compound A169: N-(4-chloro-5-iodo-7H-pyrrolo[2,3-D]pyrimidin-2-yl)-2,2-dimethylpropionamide (A167, 500.00 mg, 1.32 mmol), 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine (A168, 269.70 mg, 1.45 mmol), and K2CO3 (547.58 mg, 3.96 mmol) were added to 10 mL of DMF and stirred at room temperature for 24 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 100 mL of ice water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was dried at 50°C. The crude product was purified by column chromatography to obtain the target product N-(4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)neopentamide (A169, 522.77 mg, yield 75%). MS (ESI): 528.80 [M+H] + .

[0193] 2. Synthesis of compound A170: A169 (500.00 mg, 0.95 mmol) and ZnCl2 (645.62 mg, 4.73 mmol) were added to a mixed solvent of 10 mL ethanol and 0.5 mL water, and stirred at 80 °C for 10 h. TLC monitoring showed that after the reaction was complete, the reaction solution was added to 100 mL of ice water, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dried at 50 °C. The crude product was purified by column chromatography to obtain the target product 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (A170, 327.84 mg, yield 78%). MS (ESI): 444.70 [M+H] + .

[0194] 3. Synthesis of compound A172: A170 (300.00 mg, 0.68 mmol), tert-butylbut-3-yn-1-ylcarbamate (A171, 125.86 mg, 0.74 mmol), CuI (12.88 mg, 0.068 mmol), triphenylphosphine (PPh3, 17.74 mg, 0.068 mmol), 5% Pd / C (71.96 mg, 0.034 mmol), and K2CO3 (102.80 mg, 0.74 mmol) were added to a mixed solvent of 5 mL DMF and 1 mL water, and stirred at 75 °C for 4 h under nitrogen protection. After TLC monitoring showed the reaction was complete, 10 mL of water was added, and the mixture was extracted three times with 15 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain the target product tert-butyl(4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)carbamate (A172, 229.55 mg, yield 70%). MS (ESI): 486.20 [M+H] + .

[0195] 4. Synthesis of compound A173: Dissolve A172 (100.00 mg, 0.21 mmol) in 2 mL of a mixed solution (V TFA V DCMThe reaction mixture was prepared in a 400 μL:1600 μL ratio and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 5-(4-aminobut-1-yn-1-yl)-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (A173, 63.50 mg, yield 80%). MS (ESI): 385.92 [M+H] + .

[0196] 5. Synthesis of compound A174: A173 (20.00 mg, 51.96 μmol), succinic anhydride (10.39 mg, 103.93 μmol), and DMAP (0.63 mg, 5.19 μmol) were dissolved in 5 mL of THF and stirred at 60 °C for 5 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated, and the residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 4-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-4-oxobutyric acid (A174, 17.64 mg, yield 72%). MS (ESI): 485.95 [M+H] + .

[0197] 6. Synthesis of compound A175: A174 (3.00 mg, 6.19 μmol) and HATU (3.06 mg, 8.04 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (3.20 mg, 24.75 μmol), and the mixture was stirred at room temperature. After 0.5 h, A15 (12.40 mg, 6.19 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product tert-butyl((S)-21-(4-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-4-oxobutamido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl) 1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-25-yl)carbamate (A174, 10.70 mg, 70% yield). MS (ESI): 1236.59 [M+2H] 2+ .

[0198] 7. Synthesis of compound A176: Dissolve A175 (8.00 mg, 3.24 μmol) in 1 mL of a mixed solution (V TFA V DCMIn a mixture of 200 μL and 800 μL, the reaction system was shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. Subsequently, the residue was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 3-((S)-6-amino-2-(4-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-4-oxobutamido)hexamido)-N1,N5-bis(14-(4-) -(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)glutaramide (A176, 6.29 mg, 82% yield). MS (ESI): 1186.60 [M+2H] 2+ .

[0199] 8. Synthesis of compound 32: A176 (4.00 mg, 1.69 μmol) and DOTA-NHS ester (1.01 mg, 2.02 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.18 mg, 16.86 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(4-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-4-oxobutamido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1, 2,3-Triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol- 1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctacosane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (32, 3.16 mg, yield 68%). MS (ESI): 920.73 [M+3H] 3+ .

[0200] Example 33: Synthesis of Compound 33 The synthesis route is as follows:

[0201] Compound 2,2',2''-(10-((S)-21-(2-(2-((4-(2-amino-4-chloro-7-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-2-oxoethoxy)acetamyl)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3- The synthesis of (4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (33) is similar to that of compound 32, except that succinic anhydride is replaced with diethylene glycol anhydride. MS (ESI): 925.97 [M+3H] 3+ .

[0202] Example 34: Synthesis of Compound 34 The synthesis route is as follows:

[0203] 1. Synthesis of compound A180: A2 (9.00 mg, 91.74 μmol) and HATU (45.33 mg, 119.28 μmol) were dissolved in 600 μL of DMF, followed by the addition of DIPEA (47.40 mg, 366.69 μmol), and the mixture was stirred at room temperature. After 0.5 h, A173 (35.31 mg, 91.74 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product N-(4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)pent-4-ynylamide (A180, 34.12 mg, yield 80%). MS (ESI): 465.95 [M+H] + .

[0204] 2. Synthesis of compound A182: Dissolve A180 (10.00 mg, 21.51 μmol) and 3-(2-(2-azidoethoxy)ethoxy)propionic acid (A181, 4.37 mg, 21.51 μmol) in 400 μL of DMSO. Add a solution of sodium ascorbate (1.70 mg, 8.60 μmol) and copper sulfate pentahydrate (1.07 mg, 4.30 μmol) dissolved in 80 μL of water. The mixture is then reacted with shaking in a metal bath at 50 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product 3-(2-(2-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)propionic acid (A182, 11.3.5 mg, yield 79%). MS (ESI): 669.08 [M+H] + .

[0205] 3. Synthesis of compound A184: Compound 3-((S)-6-amino-2-(3-(2-(2-(4-(3-((4-(2-amino-4-chloro-7-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)propamido)hexamido)-N1,N5-bis(14-(4-(3- The synthesis of (4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A184) is similar to that of compound A176, except that A174 is replaced with A182. MS (ESI): 852.07 [M+3H] 3+ .

[0206] 4. Synthesis of compound 34: A184 (4.00 mg, 1.56 μmol) and DOTA-NHS ester (0.94 mg, 1.88 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.02 mg, 15.65 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(3-(2-(2-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5- (but-3-yne-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)propamido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine (1-azinyl)-3-oxopropyl)-1H-1,2,3-triazolyl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazinyl)-3-oxopropyl)-1H -1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (34, 3.13 mg, yield 68%). MS (ESI): 981.80 [M+3H] 3+ .

[0207] Example 35: Synthesis of Compound 35 The synthesis route is as follows:

[0208] 1. Synthesis of compound A187: Compound 3-((S)-1-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-17-(4-aminobutyl)-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecane-18-amido)-N1,N5-bis( The synthesis of 14-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A187) is similar to that of compound A184, except that A181 is replaced by A6. MS (ESI): 881.44 [M+3H] 3+ .

[0209] 2. Synthesis of compound 35: A187 (4.00 mg, 1.51 μmol) and DOTA-NHS ester (0.99 mg, 1.96 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (1.95 mg, 15.13 μmol). The mixture was reacted with shaking in a metal bath at 40 °C for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-21-(1-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yne. -1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amido)-1-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl) Piperazine-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazine-1-yl)-3-oxopropyl)-1 H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (35, 3.03 mg, yield 66%). MS (ESI): 10¹⁰.⁹¹[M+3H] 3+ .

[0210] Example 36: Synthesis of Compound 36 The synthesis route is as follows:

[0211] 1. Synthesis of compound A191: Compound 3-((S)-1-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-23-(4-aminobutyl)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azatetracosane-24-amido)-N1,N5-bis(14-( The synthesis of 4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)glutaramide (A191) is similar to that of compound A184, except that A181 is replaced with azide-hexaethylene glycol-carboxylic acid (A188). MS (ESI): 910.83 [M+3H] 3+ .

[0212] 2. Synthesis of compound 36: A191 (4.00 mg, 1.46 μmol) and DOTA-NHS ester (0.95 mg, 1.90 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (1.89 mg, 14.64 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-1-(4-(3-((4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)amino)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-23-((1,35-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxopropyl) Ethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-16,20-dioxo-3,6,9,12,24,27,30,33-octaoxa-15,21-diazapentadecane-18-yl)carbamoyl)-21,29-dioxo-3,6,9,12,15,18-hexaoxa-22,28-diazatriacontane-30-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (36, 2.91 mg, yield 64%). MS (ESI): 1040.43 [M+3H] 3+ .

[0213] Example 37: Synthesis of Compound 37 The synthesis route is as follows:

[0214] 1. Synthesis of compound A193: 2,2-Dimethyl-4-oxo-3,7,10,13,16-pentaenodecane-19-acid (A192, 10.00 mg, 28.54 μmol) and HATU (14.11 mg, 37.10 μmol) were dissolved in 300 μL of DMF, followed by the addition of DIPEA (14.75 mg, 114.15 μmol), and the mixture was stirred at room temperature. After 0.5 h, A173 (10.98 mg, 28.54 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed that the reaction was complete, the product was purified by C18 reversed-phase preparative liquid chromatography, and then freeze-dried to obtain the target product tert-butyl 21-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-16-oxo-4,7,10,13-tetraoxa-17-azatetradecano-20-acetylacetate (A193, 15.97 mg, yield 78%). MS (ESI): 718.34 [M+H] + .

[0215] 2. Synthesis of compound A194: Dissolve A193 (10.00 mg, 13.94 μmol) in 1 mL of a mixed solution (V TFA V DCM The reaction system was mixed in a 500 μL:500 μL ratio and shaken at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 21-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-16-oxo-4,7,10,13-tetraoxa-17-aza-tetraco-20-acetylic acid (A194, 7.56 mg, yield 82%). MS (ESI): 662.20 [M+H] + .

[0216] 3. Synthesis of compound A196: Compound N1-((S)-25-amino-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidone-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl) The synthesis of (-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-16,20-dioxo-3,6,9,12-tetraoxa-15,19-diazapecopentane-21-yl)-N16-(4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-yn-1-yl)-4,7,10,13-tetraoxahexadecanediamide (A196) is similar to that of compound A176, except that A174 is replaced with A194. MS (ESI): 849.750 [M+3H] 3+ .

[0217] 4. Synthesis of compound 37: A196 (4.00 mg, 1.57 μmol) and DOTA-NHS ester (1.23 mg, 2.04 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.03 mg, 15.69 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-30-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-8-((1,35-bis(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1, 4-Dihydroquinolino-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-16,20-dioxo-3,6,9,12,24,27,30,33-octaoxa-15,21-diazapentadecane-18-yl)carbamoyl)-2,10,25-trioxo-13,16,19,22-tetraoxa-3,9,26-triazatriacarbon-29-ynyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (37, 2.95 mg, yield 64%). MS (ESI): 979.40 [M+3H] 3+ .

[0218] Example 38: Synthesis of Compound 38 The synthesis route is as follows:

[0219] 1. Synthesis of compound A199: 2,4-Dihydroxy-5-isopropylbenzoic acid (A197, 500.00 mg, 2.55 mmol), EDCI (635.09 mg, 3.31 mmol), and HOBT (1.38 g, 10.19 mmol) were dissolved in 6 mL of DMF and stirred at room temperature. After 0.5 h, 5-bromoisoindoline (A198, 555.21 mg, 2.80 mmol) was added, and the reaction was continued at room temperature for another 4 h. TLC monitoring showed that the reaction was complete. The reaction mixture was then added to 50 mL of ice water, resulting in the precipitation of a large amount of solid. The mixture was filtered, the filter cake was washed with 10 mL of water, and then dried at 50 °C. The crude product was purified by column chromatography to obtain the target product (5-bromoisoindoline-2-yl)(2,4-dihydroxy-5-isopropylphenyl) methyl ketone (A199, 671.19 mg, yield 70%). MS (ESI): 367.32 [M+H] +.

[0220] Synthesis of compound A200: A199 (350.00 mg, 0.94 mmol), A40 (373.54 mg, 1.22 mmol), Pd(OAc)2 (42.19 mg, 0.19 mmol), Xantphos (267.45 mg, 0.38 mmol), and Cs2CO3 (0.64 g, 2.82 mmol) were added to a mixed solvent of 10 mL THF and 2.5 mL H2O. The reaction system was reacted at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and purified by column chromatography to obtain the target product, tert-butyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindoline-5-yl)methyl)piperazine-1-carboxylic acid ester (A200, 279.79 mg, yield 60%). MS (ESI): 496.62 [M+H] + .

[0221] 3. Synthesis of compound A201: Dissolve A200 (100.00 mg, 201.77 μmol) in 5 mL of a mixed solution (V TFA V DCM The reaction mixture was prepared in a ratio of 1 mL to 4 mL and shaken at room temperature for 1 h. After TLC monitoring showed that the reaction was complete, the reaction solution was concentrated. The residue was then purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product (2,4-dihydroxy-5-isopropylphenyl)(5-(piperazin-1-ylmethyl)isoindoline-2-yl) methyl ketone (A201, 65.44 mg, yield 82%). MS (ESI): 396.59 [M+H] + .

[0222] 4. Synthesis of compound A202: Bis-PEG3-COOH (4.09 mg, 16.35 μmol) and HATU (7.17 mg, 18.86 μmol) were dissolved in 300 μL LMF, followed by the addition of DIPEA (9.75 mg, 75.55 μmol), and the mixture was stirred at room temperature. After 0.5 h, A201 (5.00 mg, 12.58 μmol) was added, and the reaction was continued at room temperature for another 4 h. After TLC monitoring showed complete reaction, the product was purified by C18 reversed-phase preparative liquid chromatography, freeze-dried, and the target product 3-(2-(2-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindoline-5-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)propionic acid (A202, 4.03 mg, yield 51%) was obtained. MS (ESI): 628.81 [M+H]+ .

[0223] 5. Synthesis of compound A204: Compound 3-((S)-2-(4-aminobutyl)-16-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindololin-5-yl)methyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoamide)-N1,N5-bis(14-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-) The synthesis of difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecyl)pentanediamide (A204) is similar to that of compound A191, except that A189 is replaced with A202. MS (ESI): 1257.94 [M+2H] 2+ .

[0224] 6. Synthesis of compound 38: A204 (4.00 mg, 1.59 μmol) and DOTA-NHS ester (0.95 mg, 1.90 μmol) were dissolved in 300 μL LDMSO, followed by DIPEA (2.06 mg, 15.91 μmol), and the mixture was reacted in a metal bath at 40 °C with shaking for 4 h. After TLC monitoring showed that the reaction was complete, the reaction solution was purified by C18 reversed-phase preparative liquid chromatography and freeze-dried to obtain the target product 2,2',2''-(10-((S)-1-(4-(3-(4-(3-((2-(((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-18-(17-(4-(3-(4-(3-((2-((S)-2-cyano-4,4-difluoropyrrolidine-1-yl)-2-oxoethyl)carbamoyl)-1-ethyl-6-fluoro-4-oxo- 1,4-Dihydroquinoline-7-yl)piperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-1-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecyl)-21-(3-(2-(2-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindoline-5-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)propamido)-16,20,27-trioxo-3,6,9,12-tetraoxa-15,19,26-triazaoctadecane-28-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (38, 2.91 mg, yield 63%). MS (ESI): 968.30 [M+3H] 3+ .

[0225] Example 39: Radioactivity 177 Preparation of Lu-labeled complexes Add 40 µL of an aqueous solution of Vc (20 mg / mL) / VcNa (80 mg / mL) and 2 µL of a DMSO solution (2 mg / mL) containing the labeled precursor compound 1-38 to a vial, then add 2 mL of Ci 177 LuCl3 (dissolved in 0.05M HCl) was used as the eluent. The vial was placed in a metal bath and heated at 100°C for 20 min, then cooled to room temperature. The reaction solution was diluted with 4 mL of physiological saline, filtered through a C18 column (pre-activated by rinsing with 5 mL of 75% ethanol and 5 mL of physiological saline), washed with 5 mL of physiological saline, rinsed with 75% ethanol, diluted with physiological saline, and filtered through a sterile filter membrane to obtain the desired results. 177 Lu-labeled coordination compounds.

[0226] Example 40: SPECT / CT Imaging of Small Animals The preparation of Example 39 177 Lu-labeled ligands were diluted with physiological saline and injected into tumor-bearing mice via the tail vein, with 3 mice per group and each mouse receiving approximately 7.4 MBq. At 12, 24, and 48 hours post-injection, the tumor-bearing nude mice were anesthetized and placed in a Micro-SPECT / CT imaging scanner in a prone position for scanning and imaging, and the images were reconstructed using SPECT / CT image processing software. Figures 8-12 for 177 Lu-1, 177 Lu-2, 177 Lu-3, 177 Lu-4, 177 Lu-5, 177 Lu-6 177 Lu-7 177 Lu-8, 177 Lu-9 177 Lu-10, 177 Lu-11, 177 Lu-12, 177 Lu-15, 177 Lu-17 and 177 Imaging images of Lu-19 in U87MG tumor-bearing mice. 15 types. 177 Lu-labeled ligands all exhibited excellent tumor targeting and long retention capabilities, with maximum tumor uptake exceeding 15% ID / g at 12 hours post-injection. 177 Lu-1, 177 Lu-2, 177 Lu-3, 177 Lu-8, 177 Lu-9 177 Lu-10, 177 Lu-15 and 177 Lu-17 exhibits both high uptake and long retention in tumors, as well as rapid clearance from non-target organs. Among these... 177 Lu-2, 177 Lu-8 and 177 The Lu-15 has the best overall performance. Figures 13 to 14 In order 177 Lu-22, 177 Lu-24 177 Lu-25, 177 Lu-26 177 Lu-28 and 177Imaging images of Lu-30 in bilateral HCT116 / U87MG tumor-bearing mice (the left side of each mouse in the small images represents the HCT116 tumor, and the right side represents the U87MG tumor). 6 types 177 Lu-labeled ligands showed excellent targeting and long retention capabilities against both HCT116 and U87MG tumors, but also exhibited significant nonspecific retention in the liver and kidneys. Figures 15 to 17 In order 177 Lu-32, 177 Lu-33, 177 Lu-34 177 Lu-35, 177 Lu-36 177 Lu-37 and 177 Imaging images of Lu-38 in U87MG tumor-bearing mice. These 7 types... 177 Lu-labeled ligands showed excellent targeting and long retention against U87MG tumors, but also exhibited significant nonspecific retention in the liver and kidneys. Further evaluation is needed. 177 Due to the targeting and specificity of Lu-15, this invention conducted imaging studies on various tumor-bearing mouse models, and the results are as follows: Figures 18 to 19 As shown. In the FAP-transfected HCT116 tumor-bearing mouse model, 177 Lu-15 exhibited excellent tumor targeting and long retention capabilities, with tumor uptake exceeding 30% ID / g 24 hours post-injection, and rapid clearance from non-target organs. In Aspc-1, A549, 4T1, and MKN-45 tumor-bearing mice... 177 Lu-15 is taken up relatively little by tumors and is mainly metabolized and cleared through non-target organs such as the liver and kidneys.

[0227] Example 41: Radioactivity 177 Distribution experiment of Lu-labeled compounds in small animals Further assessment 177 Lu-2, 177 Lu-8 and 177 Biodistribution of Lu-15 in major organs of healthy mice, using a 7.4 MBq probe. 177 Lu-2, 177 Lu-8 and 177 Lu-15 was injected into ICR mice, six mice per group. The mice were anesthetized under an isoflurane atmosphere (2-3%). At different time points after injection (6h, 12h, and 24h), the mice were anesthetized under an isoflurane atmosphere (2-3%), then euthanized by cervical dislocation. The mice were dissected, and major organs were removed. The radioactivity of each organ was measured using a gamma counter, and the percentage of radioactivity taken up per unit mass of organ was calculated (denoted as %ID / g). Figure 20 As shown, the probe 177 Lu-2,177 Lu-8 and 177 Lu-15 was primarily distributed in the liver and kidneys at 6 and 12 hours post-injection, with lower uptake in other non-target organs. At 24 hours post-injection, the liver became the primary organ with radioactive retention. 177 Lu-8 and 177 The residual dose of Lu-15 in various organs was higher than that in other organs. 177 This trend was more pronounced in the liver with Lu-2. As time progressed, radioactive uptake in all organs of the three groups of mice significantly decreased, indicating that the probe... 177 Lu-2, 177 Lu-8 and 177 Lu-15 can be rapidly cleared from non-target organs, suggesting that it has good in vivo safety.

[0228] Example 42: Radioactivity 177 In vivo antitumor experiments of Lu-labeled compounds in small animals Treatment was initiated when the average tumor volume in U87MG tumor-bearing mice reached 100 cubic millimeters. The mice were treated with saline solution and 11.1 MBq of probe. 177 Lu-2, 177 Lu-8 and 177 Lu-15 was injected into U87MG tumor-bearing mice, with four mice in each group. Tumor volume and mouse weight were measured every two days. Figure 21 As shown, in the control group (tail vein injection of saline), the tumors in U87MG tumor-bearing mice grew rapidly, reaching an average tumor volume of 1000 mm² on day 12. 3 Compared with the blank control group, 177 Lu-2, 177 Lu-8 and 177 The Lu-15 treatment group showed significant inhibition of tumor growth in all cases, among which... 177 Lu-15's antitumor effect is slightly better than 177 Lu-2 and 177 Lu-8. However, limited by the dosage and the characteristics of the tumor model itself, although all three treatment groups effectively inhibited tumor growth, tumor growth was not completely suppressed over time. Regarding changes in mouse body weight, although the weight of mice in each treatment group decreased slightly after administration, it remained within the normal range, indicating good tolerability of the treatment.

[0229] Example 43: Radioactivity 225 Preparation of Ac-labeled complexes Add 100 µL of 0.1 M carbonate buffer (pH=9) and 2 µL of DMSO solution (1 µg / µL) containing the labeled precursor compound to a vial, then add 2 µL of Ci²². 5AcCl3 (dissolved in 0.05M HCl) was used as the eluent. The vial was placed in a metal bath and heated to 90°C for 15 minutes. The reaction solution was diluted with physiological saline and filtered through a sterile membrane to obtain the final product. 5 Ac-labeled coordination compounds.

[0230] Example 44: Radioactivity 225 Distribution experiment of Ac-labeled complexes in small animals Evaluate 225 Biodistribution of Ac-8 in major organs of ICR mice, with 6 mice per group, using 11.1 KBq of probe. 225 Ac-8 was injected into ICR mice. The mice were anesthetized under an isoflurane atmosphere (2-3%). At different time points after injection (12h and 24h), the mice were anesthetized under an isoflurane atmosphere (2-3%), then euthanized by cervical dislocation. The mice were dissected, and major organs were removed. The radioactivity of each organ was measured using a gamma counter, and the percentage of radioactivity taken up per unit mass of organ was calculated (denoted as %ID / g). Figure 22 As shown, the probe 225 Ac-8 is mainly distributed in the liver and kidneys 12 and 24 hours after injection, while its uptake in other non-target organs is low.

Claims

1. A multivalent, long-acting radiopharmaceutical, characterized in that, The multivalent long-acting radiopharmaceutical is a compound of Formula I, its pharmaceutically acceptable salt, tautomer, racemate, hydrate, solvate, or isotopic label thereof: ； Wherein, AT represents the ligand-specific binding structure of fibroblast activation protein; (AT) n Indicates the target portion and two (AT) n They do not appear simultaneously, and n is 1, 2, or 3; when n is 3, BT is hydrogen; when n is 1 or 2, BT is a functional active group. CL is the chelating ligand portion, which chelates radionuclides; La and Lb are connectors that are straight chains, branches, or ternary to 7-membered rings, and each can be a bond, monovalent connector, divalent connector, or trivalent connector independently. AT is a compound represented by formula II, wherein the general formula of II is: ； R1 and R2 are independently selected from hydrogen, halogen or methyl; R3 is selected from hydrogen, methyl, isopropyl or isobutyl; Where Ar is selected from the following structure: , , or ; The end is connected to the L1 group. The end is connected to a carbonyl group; R4 is selected from hydrogen, methyl, ethyl, or cyclopropyl; R5 is selected from hydrogen, halogen, or methyl; L1 is selected from the following structures or combinations thereof: , , Or based on -(CH2) n - substitution structures, where n is an integer from 0 to 20, wherein each -CH2- is individually replaced with or without -O-, -NH-, -(CO)-, -NH-(CO)-, -(CO)-NH-, -Gly- or -Arg-, provided that no two adjacent -CH2- groups are replaced; The general formula of BT is IIIa, IIIb, IIIc or IIId, and the general formula of IIIa is: ； R6 is selected from -H, -OH, halogen, or C. 1-5 alkyl; L2 is selected from the following structures: , or Where X is -NH-, -(CO)-, or -(CO)-NH-; The general formula for IIIb is: ； Among them, R7 is selected from H and C. 1-6 Alkyl or C 3-6 cycloalkyl; R8 is selected from H, halogens, and C. 1-6 Alkyl or C 3-6 cycloalkyl; R9 is selected from the following structure: , or ; X1 is a single bond, -NH- or -(CO)-; L3 is selected from the following structures or combinations thereof: , , , or , where p is an integer from 1 to 5; The general formula of IIIc is: ； Among them, R 1 R 2 and R 3 Independently selected from -H, -OH, halogens, or C 1-5 alkyl; L4 is selected from , , , or Where X is -CH2-, -NH-, or -(CO)-; The general formula for IIId is: ； Among them, R 4 R 5 and R 6 Independently selected from -H, -OH, halogens, or C 1-5 alkyl; R 7 Selected from H or C 1-5 alkyl; L5 is selected from , , or , where X is -CH2-, -C≡C-, -NH- or -(CO)-.

2. The multivalent long-acting radiopharmaceutical according to claim 1, characterized in that, CL is selected from: , , , , , , or .

3. The multivalent long-acting radiopharmaceutical according to claim 1, characterized in that, La and Lb are each independently selected from the following structures or combinations thereof: 。 4. The multivalent long-acting radiopharmaceutical according to claim 1, characterized in that, It has the following structure: 。 5. A radioactive preparation, characterized in that, Includes the multivalent long-acting radiopharmaceutical as described in any one of claims 1 to 4.

6. The radioactive agent according to claim 5, characterized in that, It also contains radioactive nuclides.

7. The radioactive agent according to claim 6, characterized in that, The radioactive nuclide is 64 Cu、 68 Ga、 203 Pb, 111 In、 44 Sc、 177 Lu、 188 Re、 90 Y、 225 Ac、 161 Tb, 212 Pb, 47 Sc or 67 Cu.

8. The use of the multivalent long-acting radiopharmaceutical of any one of claims 1 to 4 or the radioactive agent of any one of claims 5 to 7 in the preparation of a medicament or pharmaceutical composition for the diagnosis and / or treatment of a disease characterized by overexpression of fibroblast-activating protein.

9. The application according to claim 8, characterized in that, The diseases characterized by overexpression of fibroblast activation protein include liver cancer, lung cancer, colorectal cancer, bile duct cancer, pancreatic cancer, esophageal cancer, gastric cancer, thyroid cancer, head and neck cancer, breast cancer, or cervical cancer.

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