Ligand compound with quinoline structure, radioactive or non-radioactive marker of ligand compound and application of ligand compound

Abstract

The invention relates to a ligand compound with a quinoline structure as well as a radioactive or non-radioactive marker and application thereof, in particular to a ligand compound as shown in a formula I, a non-radioactive marker as shown in a formula II and a radioactive marker as shown in a formula III, and application of the ligand compound, the non-radioactive marker and the radioactive marker in diagnosis or treatment of diseases caused by abnormal cell proliferation.

Description

A class of quinoline structure ligand compounds and radioactive or non-radioactive markers and applications thereof

[0001] Cross-references

[0002] This disclosure is based on and claims priority to the application with Chinese application number 202311414691.5 and application date October 27, 2023, and the application with Chinese application number 202410268912.0 and application date March 8, 2024. The disclosed contents of the Chinese applications are hereby introduced into this disclosure as a whole. Technical Field

[0003] The present disclosure relates to ligand compounds with quinoline structures and radioactive or non-radioactive labels and applications thereof. Background Art

[0004] The tumor microenvironment (TME) is a dynamic and complex local environment that is closely associated with tumor growth, metastasis, immune evasion, and drug resistance. Although traditional cancer diagnostic and treatment approaches primarily focus on tumor cells, the tumor stroma, as a key component of the TME, plays a crucial role in the development and progression of cancer and has garnered extensive attention from researchers. Tumor-associated fibroblasts (CAFs) are the predominant cell type in the TME, present in nearly all solid tumors and accounting for approximately 50% of the total tumor tissue cell population. Fibroblast activation protein (FAP) is a key tool in the tumor-promoting effects of CAFs. It is a serine protease that promotes the recruitment, differentiation, and proliferation of CAFs. It is primarily present on the surface of tumor-associated fibroblasts, mesenchymal cells, and tumor cells. It is a member of the type II transmembrane serine protease family and possesses both dipeptidase and collagenase activities. FAP is selectively upregulated on the surface of stromal fibroblasts in over 90% of epithelial malignancies, including breast, colorectal, skin, prostate, and pancreatic cancers. Its expression in normal tissues is very low. Besides tumors, it is expressed only in certain inflammatory areas, such as wound healing, scar tissue, rheumatoid arthritis, osteoarthritis, myocarditis, liver fibrosis, pulmonary fibrosis, and cirrhosis. Furthermore, high FAP expression is closely associated with the invasion, metastasis, and poor prognosis of malignant tumors. Therefore, FAP is considered a potential target for tumor treatment and diagnosis and has been dubbed the "next billion-dollar nuclear therapeutic target."

[0005] In recent years, radioactive diagnostic and therapeutic drugs targeting FAP have become a hot topic among researchers, including radionuclide-labeled antibodies, cyclic peptides (such as FAP-2286) and small molecule inhibitors (such as FAPI-74, FAPI-46, FAPI-04, OncoFAP, PNT-6555, EB-FAPI, SA.FAPI, etc.). Although FAP antibodies were developed in 1988, only a few anti-FAP diagnostic and therapeutic agents have been reported (Eur J Nucl Med Mol Imaging. 2023, 10.1007 / s00259-023-06300-6.;Clin Cancer Res. 2012, 18(22):6208-6218.;J Nucl Med. 2015, 56(5):778-783.;J Clin Oncol. 1994, 12(6):1193-1203.;Clin Cancer Res. 2020, 26(18):4882-4891.;Molecules. 2020, 25(16):3672.;Clin Cancer Res. 2020, 26(18):4882-4891). Radionuclide-labeled antibodies as molecular imaging agents have been hampered by pharmacokinetic limitations such as slow clearance from blood and non-target tissues and nonspecific tissue uptake, hindering their further development. Low-molecular-weight FAP-targeted radiotherapeutics have been widely reported and demonstrated clinical value due to their strong tissue penetration, high specificity, and amenable structure modification and radiolabeling.

[0006] A team from Heidelberg University has discovered a series of quinoline-based FAP inhibitors (WO2019154886A1), of which FAPI-02, FAPI-04, FAPI-46, and FAPI-74 have been shown to be useful for high-contrast tumor imaging of various cancers in PET imaging. They exhibit rapid tumor accumulation and a good tumor-to-background ratio (J Nucl Med. 2018, 59(9):1423-1429.; J Nucl Med. 2018, 59(9):1415-22; J Nucl Med. 2019, 60(10):1421-9). Preclinical studies have shown that radiolabeled FAPI-04 inhibits tumor growth in xenograft models of glioma (131I) and pancreatic cancer (225Ac) (Mol Pharm. 2021, 18(11):4179-87; J Nucl Med. 2020, 61(4):563-9). Similarly, 177Lu-FAPI-46 and 225Ac-FAPI-46 showed tumor growth inhibition in a pancreatic cancer mouse model. However, tumor retention was only 0.3% ID / g 3 hours after injection and only 0.1% ID / g 24 hours later (Eur J Nucl Med Mol Imaging. 2022, 49(3):871-880). Although FAPI-46 has been modified with the linker to prolong tumor retention, the rapid clearance of radionuclide-labeled FAPI-46 from the blood and tumor tissues limits its therapeutic effect on tumors.

[0007] Tufts University reported the development of a class of FAP-targeting ligands with pyrrole boronic acid fragments in patent WO 2021195198A1. The clinical translation of PNT6555 is underway, and no clinical data has been released yet. POINT Biopharma presented preclinical data for PNT6555 in an abstract presented at the 2022 AACR meeting (https: / / doi.org / 10.1158 / 1538-7445.AM2022-3303). 68Ga / 177Lu-PNT6555 showed rapid and sustained uptake in FAP-expressing tumors, while limited uptake and retention were observed in normal tissues.

[0008] In 2022, the Xiamen University Molecular Imaging Center team developed a series of Evans blue (EB)-modified FAP-targeted radiotracers based on FAPI-02. 177Lu-EB-FAPI-B1, B2, B3, B4 (Theranostics. 2022, 12(1): 422-433), however, the persistent high radioactivity of Lu-EB-FAPI-B2, B3, and B4 in the liver and kidneys may be toxic to normal organs and are not suitable for further development. In addition, the team also developed fatty acid-bound FAPI radiopharmaceuticals 177 Lu-FAPI-C16, but its liver uptake was also high, suggesting that it may cause toxicity in high-dose treatment studies (Mol Pharm. 2022, 19: 3429–3438).

[0009] There are also studies involving the multivalent effects of radioligands. 177 Lu-DOTAGA.(SA.FAPi)2 has been extensively studied in radionuclide therapy for patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) (Pharmaceuticals (Basel). 2021, 14(12):1212.;Clin Nucl Med. 2022, 47(6):e444-e445.;Nucl Med Mol Imaging. 2021, 11(6):476-491.;Thyroid. 2022; 32(1):65-77.). Tumor retention can be detected for up to one week by planar scintigraphy and single-photon emission computed tomography imaging, but this also increases whole-body radiation exposure, including to the gallbladder, pancreas, kidneys, and liver (Pharmaceuticals (Basel). 2021, 14(12):1212.). The subsequently developed dimeric DOTA-2P(FAPi)2 still exhibited lower tumor-to-organ ratios at 1 and 4 hours, and higher kidney uptake compared to monomeric FAPI-46 (J Nucl Med. 2022, 63(6):862-868.). Similarly, ND-bisFAPI exhibited lower tumor-to-organ ratios in A549-FAP xenografts at all studied time points (1 to 72 hours post-dose) (Eur J Nucl Med Mol Imaging. 2022, 49:2705–15).

[0010] 3B Pharmaceuticals GmbH disclosed the development of FAP cyclic peptide ligands in patents WO 2022148851A1, WO 2022148843 A1, WO 2021005131A1, WO 2021005125 A1, and EP 3763726 A1. The first preclinical data of FAP-2286 were published by Zboralski et al. in 2020 (Eur J Nucl Med Mol Imaging. 2022, 49(11): 3651-3667), and the first human study results of FAP-2286 for radiodiagnostic therapy were reported in 2022 (J Nucl Med. 2022, 63(3): 415-423).

[0011] Long circulation is often a double-edged sword for radiopharmaceutical development. It can lead to higher tumor accumulation but also increase nonspecific uptake in normal organs, hindering clinical translation. Therefore, developing FAP-targeting ligands with enhanced tumor uptake, longer retention, lower non-target tissue uptake, and rapid clearance is crucial for advancing the development of integrated FAP-targeted diagnostic and therapeutic drugs. Summary of the Invention

[0012] The purpose of the present disclosure is to provide a novel structure, tumor-targeting, and therapeutically integrated FAP-binding radioactive or non-radioactive marker and its ligand compound with good pharmacokinetic characteristics.

[0013] In a first aspect, the present disclosure provides a radioactive or non-radioactive labeled ligand compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein the compound has a structure of formula (I):

[0014] In the above formula (I),

[0015] Ring A is selected from a 9-20 membered heterocyclic group;

[0016] Each of X1, X2 and X3 is independently selected from a single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, -C(=O)-, 4-6 membered heterocyclic group, cyclobutene-dione residue

[0017] L1, L2 and L3 are each independently selected from hydrogen, C 1-6 Alkyl, carboxyl, sulfonic acid, amino acid residue, FAP affinity ligand, albumin binding ligand or R c ;

[0018] Wherein, the FAP affinity ligand is selected from

[0019] The albumin binding ligand is selected from Evans blue residues or the following structure R2 is selected from halogen (such as iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), hydroxy, amino, nitro, cyano;

[0020] Y are each independently selected from a single bond, C 1-6 Alkylene, -C(=O)-, -S-, -NH-, -O-, -(CH2CH2OCH2CH2) n -, cyclobutene-dione residue Piperazine, triazole or amino acid residues;

[0021] R c Chelating agents selected from radionuclides or non-radionuclides, including but not limited to 99mTc(CO)3-chelator, CB-TE2A, CHX-A"-DTPA, DTPA, DATA, DFO, HBED, Crown, DOTA, DOTAGA, DOTAM, FSC, H4octapa, Macropa, HEHA, HOPO, Hynic, PCTA, PSC, NETA, NOTA, NOTA-MPAA, NODAGA, NOTP, NOPO, Pycup, RESCA, Sarcophagine, TETA, THP or TRAP;

[0022] m is each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;

[0023] n is each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0024] In some embodiments, m is independently selected from 1, 2, 3, and 4.

[0025] In some embodiments, each m is independently 1.

[0026] In some embodiments, n is each independently selected from 1, 2, 3, and 4.

[0027] In some embodiments, each n is independently 1.

[0028] In some embodiments, R2 is selected from halogen (eg, iodine, bromine, chlorine, fluorine). In some embodiments, R2 is iodine.

[0029] In some embodiments, Ring A is selected from a 9-membered or 12-membered nitrogen-containing heterocyclic group.

[0030] In some embodiments, each of X1, X2, and X3 is independently selected from a single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, -C(=O)-, or a 4- to 6-membered heterocyclic group.

[0031] In some embodiments, the compounds of the present disclosure have the structure shown in Formula I-1 or Formula I-2:

[0032] In some embodiments, the present disclosure provides compounds of formula I, I-1, or I-2, wherein Rc is selected from the following structures:

[0033] R1 is selected from halogen (such as iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g., methoxy), hydroxy, amino, nitro, cyano.

[0034] In some embodiments, the present disclosure provides compounds of formula I, I-1 or I-2, wherein R1 is selected from halogen (eg, iodine, bromine, chlorine, fluorine), C 1-4 Alkyl (such as methyl), C 1-4 Alkoxy (e.g., methoxy), hydroxy, amino, nitro, cyano.

[0035] In some embodiments, the present disclosure provides compounds of Formula I, I-1, or I-2, wherein R c Selected from

[0036] In some embodiments, the present disclosure provides compounds of Formula I, I-1, or I-2, wherein Y is selected from a single bond and C 1-6 Alkylene.

[0037] In some embodiments, the present disclosure provides compounds of Formula I, I-1, or I-2, wherein Y is selected from a single bond and C 1-4 Alkylene.

[0038] In some embodiments, the present disclosure provides compounds of Formula I, I-1, or I-2 in which Y is a single bond.

[0039] In some embodiments, the present disclosure provides compounds of formula I-1, wherein -(X1) m -L1 and -(X2) m Same as -L2.

[0040] In some embodiments, in the compound I-1 provided herein, L1 and L2 are both selected from Preferably, L1 and L2 are selected from

[0041] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m - each independently selected from Preferably, each independently selected from R' is selected from H or C 1-6 Alkyl (eg, methyl); p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5, and 6; preferably 1, 2, 3, or 4).

[0042] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -Selected Preferably R' is selected from H or C 1-6 alkyl (eg, methyl); p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5, and 6; preferably 1, 2, 3, or 4), and -(X1) m -and-(X2) m -same.

[0043] In some embodiments, the present disclosure provides compounds of I-1, wherein R' is selected from H or C 1-4 alkyl.

[0044] In some embodiments, the present disclosure provides compounds of I-1 in which R' is H.

[0045] In some embodiments, in the compound of I-1 provided herein, R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0046] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -Selected

[0047] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m - each independently selected from

[0048] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -same, and selected from

[0049] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m - Each independently selected

[0050] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -same, and selected from

[0051] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -Selected Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

[0052] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m - each independently selected from Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

[0053] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m -same, and selected from Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

[0054] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m - each independently selected from Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

[0055] In some embodiments, the present disclosure provides compounds of I-1, -(X1) m -and-(X2) m-same, and selected from Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

[0056] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, C 1-6 Alkylene, Preferably selected from single bond, C 1-6 Alkylene, p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2, 3 or 4).

[0057] In some embodiments, the disclosure provides compounds of I-2 wherein R' is as defined for compounds of I-1.

[0058] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently a single bond.

[0059] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - each independently selected from C 1-6 Alkylene.

[0060] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - each independently selected from C 1-4 Alkylene.

[0061] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from methylene, ethylene, propylene and butylene.

[0062] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1)m -、-(X2) m -or-(X3) m - are each independently methylene.

[0063] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - each independently selected from Preferably selected from More preferably, selected from p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2, 3 or 4).

[0064] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - Each independently p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2, 3 or 4).

[0065] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, a methylene group, Preferably selected from single bonds, methylene,

[0066] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - each independently selected from Preferably More preferably, selected from

[0067] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - Each independently

[0068] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, a methylene group, Preferably selected from single bonds, methylene, Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0069] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - each independently selected from Preferably selected from More preferably, selected from Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0070] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - Each independently Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0071] In some embodiments, in the I-2 compounds provided herein, L1, L2, and L3 are each independently selected from hydrogen, C 1- 6 alkyl, carboxyl, Rc,

[0072] In some embodiments, in the I-2 compounds provided herein, L1, L2, and L3 are each independently selected from hydrogen, carboxyl,

[0073] In some embodiments, the present disclosure provides I-2 compounds in which L1, L2, and L3 are each independently hydrogen.

[0074] In some embodiments, in the I-2 compounds provided herein, L1, L2, and L3 are each independently a carboxyl group.

[0075] In some embodiments, the present disclosure provides I-2 compounds, L1, L2 and L3 are each independently

[0076] In some embodiments, the present disclosure provides I-2 compounds, L1, L2 and L3 are each independently

[0077] In some embodiments, the present disclosure provides I-2 compounds, L1, L2 and L3 are each independently

[0078] In some embodiments, the present disclosure provides I-2 compounds, L1, L2 and L3 are each independently

[0079] In some embodiments, the present disclosure provides I-2 compounds, L1, L2 and L3 are each independently

[0080] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -、-(X2) m -or-(X3) m -, there are at least two of them that are the same, for example -(X1) m -with-(X2) m -same,-(X1) m -with-(X3) m -same, or -(X1) m -、-(X2) m -with-(X3) m -All the same.

[0081] In some embodiments, in the I-2 compounds provided herein, at least two of L1, L2, and L3 are identical, for example, L1 is identical to L2, L1 is identical to L3, or L1, L2, and L3 are all identical.

[0082] In some embodiments, the present disclosure provides compounds of I-2, wherein -(X1) m -L1, -(X2) m -L2 or -(X3) m -At least two of L3 are the same, for example -(X1)m -L1 and -(X2) m -L2 same, -(X1) m -L1 and -(X3) m -L3 same, or -(X1) m -L1, -(X2) m -L2 and -(X3) m -L3 are all the same.

[0083] In some embodiments, the present disclosure provides compounds of I-2, when -(X1) m -、-(X2) m -or-(X3) m -When there are two identical ones, two identical -(X1) m -、-(X2) m -or-(X3) m -Selected Preferably selected from p is each independently selected from 1-6 (eg, each independently selected from 1, 2, 3, 4, 5 and 6; preferably 1, 2, 3 or 4);

[0084] Another different one - (X1) m -、-(X2) m -or-(X3) m - is selected from a single bond, C 1-6 Alkylene, Preferably selected from single bond, C 1-6 Alkylene,

[0085] In some embodiments, the present disclosure provides compounds of I-2, when -(X1) m -、-(X2) m -or-(X3) m -When there are two identical ones, two identical -(X1) m -、-(X2) m -or-(X3) m -Selected Preferably selected from

[0086] Another different one - (X1) m -、-(X2) m -or-(X3) m - is selected from a single bond, a methylene group, Preferably selected from single bonds, methylene,

[0087] In some embodiments, the present disclosure provides compounds of I-2, when -(X1) m -、-(X2) m -or-(X3) m -When there are two identical ones, two identical -(X1) m -、-(X2) m -or-(X3) m -Selected Preferably selected from wherein position 1 is connected to L1, L2, or L3, and position 2 is connected to the A ring;

[0088] Another different one - (X1) m -、-(X2) m -or-(X3) m - is selected from a single bond, a methylene group, Preferably selected from single bonds, methylene, Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0089] In some embodiments of the present disclosure, in the I-2 compound provided by the present disclosure, when two of L1, L2 and L3 are the same, the two same L1, L2 or L3 are selected from Another different L1, L2 or L3 is selected from H, carboxyl, Rc,

[0090] In some embodiments of the present disclosure, in the I-2 compound provided by the present disclosure, when two of L1, L2 and L3 are the same, the two same L1, L2 or L3 are selected from Another different L1, L2 or L3 is selected from H, carboxyl, Rc,

[0091] In some embodiments of the present disclosure, in the I-2 compound provided by the present disclosure, when two of L1, L2 and L3 are the same, the two same L1, L2 or L3 are selected from Another different L1, L2 or L3 is selected from H, carboxyl, Rc,

[0092] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, when -(X1) m -、-(X2)m -or-(X3) m -When all are the same, -(X1) m -、-(X2) m -or-(X3) m -Selected p is each independently selected from 1-6.

[0093] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, when -(X1) m -、-(X2) m -or-(X3) m -When all are the same, -(X1) m -、-(X2) m -or-(X3) m -Selected

[0094] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, -(X1) m -、-(X2) m -or-(X3) m -When all are the same,

[0095] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, when -(X1) m -、-(X2) m -or-(X3) m -When all are the same, -(X1) m -、-(X2) m -or-(X3) m -Selected Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0096] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, -(X1) m -、-(X2) m -and-(X3) m - are the same, Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

[0097] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, when L1, L2 and L3 are the same, L1, L2 and L3 are all selected from

[0098] In some embodiments of the present disclosure, in the compound I-2 provided by the present disclosure, when L1, L2 and L3 are the same, L1, L2 and L3 are all selected from

[0099] The present disclosure covers any combination of the above embodiments.

[0100] In some embodiments, the compound of formula (I) is selected from:

[0101] A second aspect of the present disclosure also provides a non-radioactive marker or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein the compound has the structure of formula (II):

[0102] In the above formula (II),

[0103] Ring A, X1, X2, X3, L1, L2, L3, Y, Rc, m and n are as described above; Ring Z is a chelate structure of the above Rc and the non-radioactive nuclide Rn;

[0104] Rn is selected from 69 Ga and 175 Lu;

[0105] In some embodiments, the compound of formula (II) of the present disclosure is selected from:

[0106] A third aspect of the present disclosure further provides a radiolabel or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, wherein the compound has the structure of formula (III):

[0107] In the above formula (III),

[0108] Ring Z' is a chelate structure of the above-mentioned Rc and radionuclide R'n; ring A, X1, X2, X3, L1, L2, L3, Y, Rc, m and n are as described above;

[0109] R'n selected 43 Sc, 44 Sc, 47 Sc, 55 Co、 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 86 Y. 89 Zr, 90 Y. 90 Nb, 99m Tc, 111 In, 135 Sm, 140 Pr, 149 Tb, 159 Gd, 160 Tb, 161 Tb, 165 Second, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re、 188 Re、 211 At 212 Pb, 213 Bi, 225 Ac or 232 Th.

[0110] In some embodiments, the compound of formula (III) of the present disclosure is selected from:

[0111] The compounds of the first, second and third aspects of the present disclosure are optionally substituted with the following groups: halogen (eg, iodine, bromine, chlorine, fluorine), hydroxyl, amino, nitro, cyano, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (such as methoxy), C 1-6 Halogenated alkyl, C 6-10 Aryl (e.g. phenyl), C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl.

[0112] intermediates

[0113] In some embodiments, the present disclosure provides a compound as shown below, or a salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, or metabolite thereof:

[0114] wherein ring X1, X2, X3, L1, Y, m and n are as described in any of the preceding items;

[0115] L2' is L2 or L2 protected by a protecting group (e.g., a carboxyl protecting group);

[0116] L3' is L3 or L3 protected by a protecting group (e.g., a carboxyl protecting group);

[0117] Rc' is Rc or Rc protected by a protecting group (e.g., a carboxyl protecting group);

[0118] L2, L3, and Rc are as described in the previous item;

[0119] The carboxyl protecting group is preferably selected from C 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl;

[0120] PG1, PG2, PG3, PG4 are each independently H or an amino protecting group, and the amino protecting group is preferably selected from alkoxycarbonyl amino protecting groups, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; acyl amino protecting groups, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Cyclohexyl), methylamino ... alkyl (Tfa), o-(p-)nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn).

[0121] In some embodiments, the present disclosure provides a compound as shown below, or a salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, or metabolite thereof:

[0122] wherein PG1, PG2, PG3, PG4 and R2 are as defined in the preceding clause;

[0123] PG5 are each independently H or a carboxyl protecting group, the carboxyl protecting group is preferably selected from C 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl.

[0124] In some embodiments, the aforementioned intermediate compounds, or salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopic labels or metabolites thereof, can be used to prepare the ligand compounds, radiolabeled substances, non-radiolabeled substances, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopic labels, metabolites or prodrugs of the present disclosure.

[0125] Pharmaceutical compositions and diagnostic and therapeutic methods

[0126] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a diagnostically or therapeutically effective amount of a ligand compound of the present disclosure, a radiolabel, a non-radiolabel, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0127] In some embodiments, the present disclosure provides use of the ligand compound, radiolabel, non-radiolabel, or pharmaceutical salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, or the pharmaceutical composition of the present disclosure in the preparation of a medicament, particularly in the preparation of a medicament for the diagnosis or treatment of diseases involving abnormal cell proliferation (e.g., solid tumors, e.g., advanced solid tumors).

[0128] In some embodiments, the present disclosure provides a ligand compound, a radiolabel, a non-radiolabel, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, or a pharmaceutical composition of the present disclosure, for use in diagnosing or treating diseases involving abnormal cell proliferation (e.g., solid tumors, such as advanced solid tumors).

[0129] In some embodiments, the present disclosure provides a method for diagnosing or treating a disease involving abnormal cell proliferation (e.g., solid tumors, e.g., advanced solid tumors), comprising administering to a subject in need thereof an effective amount of a ligand compound, a radiolabel, a non-radiolabel, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, or a pharmaceutical composition of the present disclosure.

[0130] In some embodiments, the present disclosure provides a pharmaceutical composition for diagnosing or treating a disease involving abnormal cell proliferation (e.g., a solid tumor, e.g., an advanced solid tumor), comprising a ligand compound of the present disclosure, a radiolabel, a non-radiolabel, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof. Beneficial effects

[0131] The present invention provides novel, tumor-targeting, and well-characterized FAP-binding radioactive or non-radioactive markers and their ligand compounds for integrated diagnosis and treatment, which can achieve at least one or more of the following effects:

[0132] (1) High FAP inhibitory activity;

[0133] (2) good targeting effect, such as high uptake level in target tissue (e.g., tumor tissue) and / or low uptake level in non-target tissue;

[0134] (3) have a high tumor-to-background ratio;

[0135] (4) have a high tumor-to-organ ratio;

[0136] (5) having a high target to non-target signal ratio;

[0137] (6) having better pharmacokinetic characteristics, such as higher uptake levels and longer residence time in target tissues (e.g., tumor tissues), and / or lower uptake levels and faster clearance rates in non-target tissues;

[0138] (7) Excellent safety (e.g., lower toxicity and / or fewer side effects, wider therapeutic window, etc.);

[0139] (8) The radiochemical purity of the radiolabeled substance is 80% or higher, for example, 85% or higher or 90% or higher.

[0140] definition

[0141] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain this disclosure.

[0142] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0143] As used herein, represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific;

[0144] As used herein, the term "alkyl" is defined as a monovalent straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 Alkyl" and "C 1-4 The term "alkyl" refers to a linear or branched group of 1 to 6 carbon atoms and 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl), which is optionally substituted with one or more (e.g., one to three) suitable substituents such as halogen (in which case the group is referred to as a "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.).

[0145] As used herein, the term "alkylene" is defined as a divalent straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkylene group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 Alkylene" and "C 1-4 "Alkylene" refers to a linear or branched divalent group of 1 to 6 carbon atoms and 1 to 4 carbon atoms (e.g. methylene, ethylene, propylene, butylene, pentylene, hexylene), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as C 1-6 Alkyl substitution (e.g., -CH(CH3)-, -CH(CH3)CH2- or -CH(CH3)CH2CH2-, etc.).

[0146] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above, for example, C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Alkoxy and C 1-4 Alkoxy refers to -OC 1-6 Alkyl and -OC 1- alkyl, representative examples of which include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, wherein the alkoxy group is optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to an alkoxy group in which the hydrogen atoms are substituted with one or more (e.g., 1 to 3) identical or different halogen atoms.

[0147] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring carbon atoms, for example, C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, etc., which can be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spiroalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed cycloalkyl, C 5-6 Spiroalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups are optionally substituted with one or more (such as one to three) suitable substituents, for example methyl-substituted cyclopropyl groups.

[0148] As used herein, the term "heterocyclyl" refers to an aliphatic monocyclic or fused polycyclic group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, including but not limited to oxygen atoms, nitrogen atoms, and sulfur atoms, wherein the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with an oxo group (e.g., to form C=O, S(=O), or S(=O)2). The term "3-10 membered heterocyclyl" means a heterocyclyl group containing 3-10 ring atoms, including but not limited to a 4-10 membered heterocyclyl group, a 4-9 membered heterocyclyl group, a 4-8 membered heterocyclyl group, a 4-7 membered heterocyclyl group, a 5-6 membered heterocyclyl group, a 3-8 membered heterocyclyl group, a 3-7 membered heterocyclyl group, a 3-6 membered heterocyclyl group, a 4-6 membered heterocyclyl group, a 4-7 membered nitrogen-containing heterocyclyl group, a 4-7 membered oxygen-containing heterocyclyl group, a 4-7 membered sulfur-containing heterocyclyl group, a 5-6 membered nitrogen-containing heterocyclyl group, a 5-6 membered oxygen-containing heterocyclyl group, a 5-6 membered sulfur-containing heterocyclyl group, and the like, wherein each of the "nitrogen-containing heterocyclyl group", "oxygen-containing heterocyclyl group" and "sulfur-containing heterocyclyl group" optionally further contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of the aforementioned heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (e.g. ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl. The term "9-20 membered heterocyclyl" refers to a heterocyclyl group having 9 to 20 ring atoms, including 9-20 membered nitrogen-containing heterocyclyl groups, such as 9-membered nitrogen-containing heterocyclyl groups (e.g., 1,4,7-triazacyclononyl) or 12-membered nitrogen-containing heterocyclyl groups (e.g., 1,4,7,10-tetraazacyclododecyl, etc.).

[0149] As used herein, the term "heteroaryl" includes 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) aromatic monocyclic or polycyclic rings containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, for example, 1 to 3 heteroatoms, i.e., 1, 2, or 3 heteroatoms, with the remainder being carbon atoms. Specific examples include, but are not limited to, 5-10 membered heteroaryl, 5-6 membered heteroaryl, and the like, for example, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, and the like.

[0150] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0151] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0152] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0153] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0154] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0155] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0156] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0157] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a separate diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present disclosure can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0158] In this article, solid lines can be used Solid wedge or virtual wedge The carbon-carbon bonds of the compounds of the present disclosure are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown exists. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present disclosure are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present disclosure may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0159] The present disclosure encompasses all possible crystalline forms or polymorphs of the compounds of the present disclosure, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0160] It should also be understood that certain compounds of the present disclosure may exist in free form for diagnosis or treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present disclosure or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present disclosure," the various derivative forms of the compounds described above are also intended to be encompassed.

[0161] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable salts are reviewed in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0162] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present disclosure in the form of free acid or alcohol). The compounds of the present disclosure themselves can also be esters.

[0163] The compounds of the present disclosure may exist in the form of solvates (preferably hydrates), wherein the compounds of the present disclosure contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0164] Also included within the scope of the present disclosure are metabolites of the compounds of the present disclosure, i.e., substances formed in vivo upon administration of the compounds of the present disclosure. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present disclosure includes metabolites of the compounds of the present disclosure, including compounds produced by contacting the compounds of the present disclosure with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0165] The present disclosure further includes within its scope prodrugs of the compounds of the present disclosure. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compound in vivo. Therefore, in these cases, the term "administering" as used in the methods of treatment of the present disclosure should include treating various diseases or conditions with one or more prodrug forms of the claimed compounds, but the prodrug forms are converted into the aforementioned compounds in vivo after administration to the individual. For example, conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design of Prodrug", ed. H. Bundgaard, Elsevier, 1985.

[0166] The present disclosure also encompasses compounds of the present disclosure containing protecting groups. In any process for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a form of chemical protection for the compounds of the present disclosure. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0167] For the compounds described in this disclosure, if the name and structural formula of the same compound are inconsistent, the structural formula of the compound shall prevail.

[0168] In this disclosure, "diagnosis" refers to the detection of a disease or condition, or the determination of the stage or extent of a disease or condition. Typically, the diagnosis of a disease or condition is based on the evaluation of one or more factors and / or symptoms indicative of the disease. That is, a diagnosis can be made based on the presence, absence, or amount of factors indicative of the presence or absence of a disease or condition. Diagnostic methods can be used independently or in combination with other diagnostic and / or classification methods known in the medical field for specific diseases or conditions.

[0169] In this disclosure, "treating" generally refers to the partial or complete stabilization or cure of a disease and / or side effects resulting from a disease. As used herein, "treating" encompasses any treatment of a patient's disease that: (a) suppresses the symptoms of the disease, i.e., arrests its progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or its symptoms.

[0170] In this disclosure, a "subject" refers to a vertebrate. In some embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, a mammal refers to a human.

[0171] In the present disclosure, an "effective amount" refers to an amount that is effective to achieve the desired effect at the necessary dosage and time. The "therapeutically effective amount" may vary according to factors such as the disease state, age, sex, and weight of the individual and the ability of the active ingredient to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the active ingredient outweigh any toxic or deleterious consequences. In the treatment of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of a tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] Figure 1 is the MIP image of tumor-bearing mice in vivo. DETAILED DESCRIPTION

[0173] The present disclosure is further described below by describing specific embodiments, but this is not intended to limit the present disclosure. Those skilled in the art can make various modifications or improvements based on the teachings of the present disclosure without departing from the basic idea and scope of the present disclosure.

[0174] The abbreviations in this disclosure have the following meanings:

[0175] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance (1H NMR) or mass spectrometry (MS).

[0176] Nuclear magnetic resonance (NMR) 1 H NMR was measured using a Bruker 400 MHz nuclear magnetic resonance instrument; hexadeuterated dimethyl sulfoxide (DMSO-d6); and tetramethylsilane (TMS) as the internal standard.

[0177] The abbreviations used in the nuclear magnetic resonance (NMR) spectra in the examples are shown below.

[0178] s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, J: coupling constant, Hz: hertz, DMSO-d6: deuterated dimethyl sulfoxide. δ values ​​are expressed in ppm.

[0179] The mass spectrometry (MS) was performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0180] The following preparation examples are merely illustrative, and other ligand compounds of the present application, and their radioactive or non-radioactive labels can be prepared similarly with reference to the following preparation examples. In some embodiments, the ligand compound is also referred to as a precursor compound.

[0181] Intermediate Preparation Example 1: Preparation of (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (INT-1)

[0182] Step 1:

[0183] (S)-4,4-Difluoropyrrolidine-2-carbonitrile (6.00 g, 35.6 mmol) and (tert-butoxycarbonyl)glycine (6.24 g, 35.6 mmol) were dissolved in DMF (60.0 mL). HATU (16.2 g, 42.7 mmol) and DIPEA (13.8 g, 106 mmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was directly concentrated to obtain the crude product, which was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1 to 2:1) and concentrated again to obtain the intermediate INT-1-2(S)-tert-butyl(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate (8.70 g, 30.1 mmol).

[0184] Its structural characterization data are as follows:

[0185] 1 H NMR (400MHz, CDCl3) δ5.31 (s, 1H), 4.98 (t, J = 6.4Hz, 1H), 3.83-4.01 (m, 3H), 2.72-2.81 (m, 2H), 1.46 (s, 9H)

[0186] MS m / z(ESI):234.0[M-55] +

[0187] Step 2:

[0188] Dissolve tert-butyl (S)-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamate (6.00 g, 20.7 mmol) in acetonitrile (112 mL). Cool to 0°C, add a 2M solution of hydrogen chloride in dioxane (115 mL), and continue stirring for 6 hours after returning the reaction mixture to 25°C. The reaction mixture was directly concentrated to obtain the crude intermediate INT-1-3(S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile hydrochloride (4.82 g), which was used directly in the next step without purification.

[0189] Its structural characterization data are as follows:

[0190] 1 H NMR (400MHz, CD3OD) δ5.15 (dd, J=9.2, 3.2Hz, 1H), 3.93-4.11 (m, 4H), 2.78-2.89 (m, 2H)

[0191] Step 3:

[0192] Crude (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile hydrochloride (4.60 g, 20.4 mmol) was dissolved in DMF (80.0 mL). DIPEA (7.90 g, 61.2 mmol), 6-hydroxyquinoline-4-carboxylic acid (3.86 g, 20.4 mmol), and HATU (8.53 g, 22.4 mmol) were added sequentially, and the mixture was stirred at 25°C for 3 hours. Dichloromethane (400 mL) and water (400 mL) were added to the reaction system, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the intermediate INT-1-4(S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxyquinoline-4-carboxamide (9.65 g), which was used directly in the next step without purification.

[0193] Its structural characterization data are as follows:

[0194] MS m / z(ESI):361.0[M+H] +

[0195] Step 4:

[0196] Dissolve the crude (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-hydroxyquinoline-4-carboxamide (8.00 g, 22.2 mmol) in DMF (200 mL). Add DIPEA (5.74 g, 44.4 mmol) and tert-butyl (4-bromobutyl)carbamate (6.16 g, 24.4 mmol). Heat to 60°C and stir for 3 hours. Add dichloromethane (200 mL) and water (200 mL) to the reaction system, separate the organic phase, collect it, dry it over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. After purification on a silica gel column (dichloromethane:methanol=10:0-10:1), the reaction mixture was concentrated again to give the crude intermediate INT-1-5(S)-tert-butyl(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamate (3.54 g), which was used in the next step without purification.

[0197] Its structural characterization data are as follows:

[0198] MS m / z(ESI):532.3[M+H] +

[0199] Step 5:

[0200] Crude tert-butyl (S)-(4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamate (621 mg, 1.17 mmol) was dissolved in acetonitrile (12.0 mL). A solution of hydrogen chloride in dioxane (2M, 15.5 mL) was added, and the mixture was stirred at 25°C for 3 hours. The reaction solution was directly concentrated to obtain the intermediate INT-1(S)-6-(4-aminobutyloxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (715 mg), which was used directly in the next step without purification.

[0201] Its structural characterization data are as follows:

[0202] MS m / z(ESI):432.2[M+H] +

[0203] Intermediate Preparation Example 2: Preparation of (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid (INT-2)

[0204] Step 1:

[0205] 6-Hydroxyquinoline-4-carboxylic acid (1 g, 5.29 mmol) and glycine methyl ester (706 mg, 5.63 mmol) were dissolved in DMF (26 mL). DIPEA (1.71 g, 13.22 mmol, 2.30 mL) and HATU (1.71 g, 13.22 mmol) were added and reacted at room temperature for 16 h. The intermediate INT-2-2 (6-hydroxyquinoline-4-carbonyl) glycine methyl ester (1.24 g, 4.76 mmol) was obtained by purification by reverse-phase column chromatography and freeze-drying.

[0206] Its structural characterization data are as follows:

[0207] MS m / z(ESI):261.1[M+H] +

[0208] The purification method is as follows:

[0209] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0210] Step 2:

[0211] (6-Hydroxyquinoline-4-carbonyl)glycine methyl ester (1.24 g, 4.76 mmol) and tert-butyl 4-bromobutyrate (1.32 g, 5.72 mmol) were dissolved in DMF (24 mL), and cesium carbonate (1.86 g, 5.72 mmol) was added and reacted at room temperature for 24 h. Water (30 mL) and ethyl acetate (30 mL) were added to the system for extraction. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude intermediate INT-2-3 tert-butyl 4-((4-((2-methoxy-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoate (2.13 g, 4.76 mmol), which was used directly in the next step without purification.

[0212] Step 3:

[0213] Crude tert-butyl 4-((4-((2-methoxy-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoate (2.13 g, 4.76 mmol) was dissolved in THF (50 mL) and water (50 mL), followed by the addition of lithium hydroxide (214.84 mg, 8.97 mmol) and the reaction was allowed to react at room temperature for 1 h. After removal of THF, acetonitrile was added until complete dissolution, followed by purification by reverse-phase column chromatography and freeze-drying to afford the intermediate INT-2-4(6-(4-(tert-butoxy)-4-oxobutoxy)quinoline-4-carbonyl)glycine (1.2 g, 3.09 mmol).

[0214] Its structural characterization data are as follows:

[0215] MS m / z(ESI):389.1[M+H] +

[0216] The purification method is as follows:

[0217] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0218] Step 4:

[0219] After dissolving (6-(4-(tert-butoxy)-4-oxobutoxy)quinoline-4-carbonyl)glycine (655 mg, 1.69 mmol) and (S)-4,4-difluoropyrrolidine-2-carbonitrile (341.13 mg, 2.02 mmol) in DMF (18 mL), DIPEA (392.30 mg, 3.04 mmol, 528.70 μL) and HATU (769.44 mg, 2.02 mmol) were added and reacted at room temperature for 1 h. After the reaction was completed, LCMS detected that 80 mL of water was added to the reaction solution, and the system turned reddish brown. Then, ethyl acetate was added and extracted three times (30 mL×3). The organic phases were combined and washed twice with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100:1 to 10:1) and concentrated again to obtain the intermediate INT-2-5(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid tert-butyl ester (618 mg, 1.23 mmol).

[0220] Its structural characterization data are as follows:

[0221] MS m / z(ESI):503.2[M+H] +

[0222] Step 5:

[0223] Tert-butyl (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoate (618 mg, 1.23 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and reacted at room temperature for 1 h. After removal of DCM and TFA, the product was purified by reverse-phase column chromatography and freeze-dried to obtain the intermediate INT-2(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid trifluoroacetate (532 mg, 0.816 mmol).

[0224] Its structural characterization data are as follows:

[0225] MS m / z(ESI):447.1[M+H] +

[0226] The purification method is as follows:

[0227] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% TFA)

[0228] Intermediate Preparation Example 3: Preparation of (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (INT-3)

[0229] Step 1:

[0230] Dissolve 8-aminoquinoline-4-carboxylic acid (500 mg, 2.66 mmol) in DMF (10.0 mL), add DIPEA (1.03 g, 7.98 mmol, 1.39 mL) and HATU (1.01 g, 2.66 mmol), and stir at 25°C for 1 hour. Then, add crude (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile hydrochloride (780 mg, 3.46 mmol) to the reaction system and continue stirring for 1 hour. Add water (250 mL) to the reaction solution, and extract with ethyl acetate three times (250 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the intermediate INT-3-1(S)-8-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (1.10 g), which was used directly in the next step without purification.

[0231] Its structural characterization data are as follows:

[0232] MS m / z(ESI):359.9[M+H] +

[0233] Step 2:

[0234] The crude (S)-8-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (700 mg, 1.95 mmol) was dissolved in dichloromethane (20.0 mL). Succinic anhydride (0.390 g × 3, 11.6 mmol) was added in batches, followed by triethylamine (394 mg, 3.90 mmol, 542 μL) and DMAP (120 mg × 3, 2.92 mmol). The mixture was reacted at 25 ° C for 11 hours. The reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column (dichloromethane:methanol=100:1-90:10) and concentrated again to obtain the intermediate INT-3(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (810 mg, 1.50 mmol).

[0235] Its structural characterization data are as follows:

[0236] MS m / z(ESI):460.1[M+H] +

[0237] Intermediate Preparation Example 4: Preparation of (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (INT-4)

[0238] Step 1:

[0239] To DMF (2.13 mL) was added crude (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile hydrochloride (1.5 g, 4.95 mmol), HATU (2.26 g, 5.94 mmol), 6-aminoquinoline-4-carboxylic acid hydrochloride (1.33 g, 5.94 mmol), and DIPEA (1.73 g, 13.36 mmol, 2.33 mL). The mixture was stirred at room temperature for 6 hours. After partial removal of DMF, the product was purified by reverse phase column chromatography (acetonitrile-0.05% formic acid aqueous solution = 0-50%) and lyophilized to afford the intermediate INT-4-1(S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (1.65 g, 4.59 mmol).

[0240] Its structural characterization data are as follows:

[0241] MS m / z(ESI):360.2[M+H] +

[0242] Step 2:

[0243] To tetrahydrofuran (10 mL) was added (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (1.65 g, 4.59 mmol) and dihydrofuran-2,5-dione (668.40 mg, 6.68 mmol), followed by DMAP (136.00 mg, 1.11 mmol). After addition, the mixture was heated to 60°C and stirred for 5 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, the residue was extracted with water and dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase column chromatography (acetonitrile: 0.05% formic acid aqueous solution = 0-30%) and lyophilized to obtain the intermediate INT-4(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (748 mg, 1.63 mmol).

[0244] Its structural characterization data are as follows:

[0245] MS m / z(ESI):460.2[M+H] +

[0246] Example 1: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (A-5)

[0247] Step 1:

[0248] The intermediate INT-2(S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid trifluoroacetate (462.92 mg, 536.91 μmol) was dissolved in DMF (10 mL), and DIPEA (138.78 mg, 1.07 mmol) was added to alkalize the system. Di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (100 mg, 268.46 μmol) was added, followed by HATU (224.56 mg, 590.60 μmol), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, 30 mL of water was added to the reaction solution, and then extracted three times with ethyl acetate (15 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude intermediate A-5-1 4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid tert-butyl ester (500 mg, 203.37 μmol), which was used directly in the next reaction without further purification.

[0249] Its structural characterization data are as follows:

[0250] MS m / z(ESI):1229.4[M+H] +

[0251] Step 2:

[0252] To the crude product of tert-butyl 4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (500 mg, 406.74 μmol) was added dichloromethane (2.5 mL) and then trifluoroacetic acid (2.5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the crude product is purified by preparative high performance liquid chromatography and freeze-dried to obtain 6,6'-(((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) formate, which is then further purified by reverse phase column chromatography (0.05% aqueous ammonium bicarbonate solution-acetonitrile = 0-60%) and freeze-dried to obtain intermediate A-5-2. 6,6'-(((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (60 mg, 58.31 μmol). Its structural characterization data are as follows:

[0253] MS m / z(ESI):1029.5[M+H] +

[0254] The purification method is as follows:

[0255] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0256] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0257] Step 3:

[0258] 6,6'-(((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (30 mg, 29.15 μmol) and 5-(tert-butoxy)-5-oxo-4-(4,7 ,10-Tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (20.43 mg, 29.15 μmol) was dissolved in DMF (1 mL), and HATU (13.30 mg, 34.98 μmol) and DIPEA (15.07 mg, 116.61 μmol) were added. After the addition was complete, the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly purified by preparative high performance liquid chromatography and then freeze-dried to obtain the intermediate A-5-3 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate trifluoroacetate (50 mg, 27.38 μmol).

[0259] Its structural characterization data are as follows:

[0260] MS m / z(ESI):856.7[M / 2+H] +

[0261] The purification method is as follows:

[0262] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0263] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0264] Step 4:

[0265] tert-Butyl 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate trifluoroacetate (35 mg, 19.17 μmol) was dissolved in DMF (2 mL). DIPEA (32 mg, 247.60 μmol) and tert-butyl 2-bromoacetate (18.69 mg, 95.84 μmol) were added, and the temperature was raised to 50°C and stirred for 48 hours. Then, tert-butyl 2-bromoacetate (18.69 mg, 95.84 μmol) was added, and the reaction was continued at 50°C with stirring for 24 hours. tert-butyl 2-bromoacetate (18.69 mg, 95.84 μmol) was added again, and the reaction was continued at 50°C with stirring for 24 hours. After the reaction was completed, the reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate A-5-4 tert-Butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetic acid salt (10 mg, 5.15 μmol).

[0266] Its structural characterization data are as follows:

[0267] MS m / z(ESI):1827.8[M+H] + ;913.5[M / 2+H] +

[0268] The purification method is as follows:

[0269] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0270] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0271] Step 5:

[0272] To the trifluoroacetic acid salt (10 mg, 5.15 μmol) of tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate was added trifluoroacetic acid (2 mL). After the addition was complete, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure at room temperature, and then purified by preparative high performance liquid chromatography and freeze-dried to obtain compound A-5. 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetic acid salt (1.30 mg).

[0273] Its structural characterization data are as follows:

[0274] MS m / z(ESI):1545.7[M+H] + ; 773.5[M / 2+H] + ;516.1[M / 2+H] +

[0275] The purification method is as follows:

[0276] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0277] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0278] Example 2: 5-(7-(4-carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanoyl)-4,10-bis(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)-6-quinolinyl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-oxo-2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoic acid (A-9)

[0279] Step 1:

[0280] 6,6'-(((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (30 mg, 29.15 μmol) and 5-(tert-butoxy)-5-oxo-4-(4,7, 10-Tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (20.43 mg, 29.15 μmol) was dissolved in DMF (1 mL), and HATU (13.30 mg, 34.98 μmol) and DIPEA (15.07 mg, 116.61 μmol) were added. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate A-9-1. Tert-butyl 5-(7-(5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoyl)-4,10-bis(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)-6-quinolinyl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-oxo-2-(4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoate, trifluoroacetate (14 mg, 5.58 μmol).

[0281] Its structural characterization data are as follows:

[0282] MS m / z(ESI):1198.7(M / 2+H) + ; 599.6 (M / 4+H) +

[0283] The purification method is as follows:

[0284] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0285] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0286] Step 2:

[0287] 5-(7-(5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-4,10-bis(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)-6-quinolinyl) Trifluoroacetic acid (1 mL) was added to the trifluoroacetic acid salt of tert-butyl (1,4,7,10-tetraazacyclododecan-1-yl)-5-oxo-2-(4,7,10-tris(2-tert-butoxy-2-oxo-ethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoate (14.00 mg, 5.85 μmol), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, and the residual trifluoroacetic acid was removed under reduced pressure using a lyophilizer. The crude product was directly purified by preparative HPLC and freeze-dried to give compound A-9 5-(7-(4-carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanoyl)-4,10-bis(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)-6-quinolinyl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecan-1-yl)-5-oxo-2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanoic acid trifluoroacetate (3.11 mg, 1.37 μmol).

[0288] Its structural characterization data are as follows:

[0289] MS m / z(ESI):974.1(M / 2+H) + ,649.6(M / 3+H) + ,487.5(M / 4+H) +

[0290] The purification method is as follows:

[0291] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0292] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0293] Example 3: 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (A-12)

[0294] Step 1:

[0295] To 1,4,7,10-tetraazacyclododecane (5 g, 29.02 mmol) was added ethanol (100 mL) and then diethyl oxalate (4.24 g, 29.02 mmol). After stirring at room temperature for 16 hours, the reaction solution containing the intermediate A-12-2 1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-11,12-dione was obtained, which was used directly in the next reaction without any treatment.

[0296] Its structural characterization data are as follows:

[0297] MS m / z(ESI):227.3[M+H] +

[0298] Step 2:

[0299] To the reaction solution containing 1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-11,12-dione (6.57 g, 29.04 mmol) obtained in Step 1, BOC anhydride (25.35 g, 116.14 mmol) was added dropwise. A large amount of gas was generated. After the addition, the reaction mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure to yield a crude white solid. The crude product was purified twice by slurrying with ethyl acetate:methyl tert-butyl ether (1:4). The collected solid was dried under reduced pressure to yield intermediate A-12-3, tert-butyl 11,12-dioxo-1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-4,7-dicarboxylate (8.2 g, 19.23 mmol).

[0300] Its structural characterization data are as follows:

[0301] MS m / z(ESI):315.2[M-56-56+H] + ;875.5[2M+Na] +

[0302] Step 3:

[0303] Dissolve tert-butyl 11,12-dioxo-1,4,7,10-tetraazabicyclo[8.2.2]tetradecane-4,7-dicarboxylate (8.2 g, 19.23 mmol) in ethanol (80 mL) and add a 10M aqueous sodium hydroxide solution (63.45 mL) dropwise. The mixture was heated to 100°C and refluxed for 24 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble matter. Ethanol was removed by concentration under reduced pressure, and the residue was extracted with water and dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to yield the crude intermediate A-12-4, tert-butyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (7 g, 18.79 mmol), which was used directly in the next step without further purification.

[0304] Its structural characterization data are as follows:

[0305] MS m / z(ESI):373.4[M+H] + ;767.6[2M+H] +

[0306] Step 4:

[0307] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid (48 mg, 107.53 μmol) and tert-butyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (20 mg, 53.69 μmol) were dissolved in DMF (2 mL). DIPEA (48 mg, 371.40 μmol) was added, followed by HATU (51.04 mg, 134.23 μmol). The mixture was stirred at room temperature for 20 hours. After completion of the reaction, 8 mL of water was added to the reaction solution. Solid precipitated, which was ultrasonically dispersed and filtered. The filter cake was washed with water and dried under reduced pressure to give the intermediate A-12-5 di-tert-butyl 7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (35 mg, 28.47 μmol).

[0308] MS m / z(ESI):1230.6[M+H] + ; 615.5[M / 2+H] +

[0309] Step 5:

[0310] Di-tert-butyl 7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (35 mg, 28.47 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure at room temperature to give the crude trifluoroacetate of intermediate A-12-6 6,6'-(((1,4,7,10-tetraazacyclododecane-1,4-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (32.55 mg, 28.48 μmol).

[0311] Its structural characterization data are as follows:

[0312] MS m / z(ESI):1030.7[M+H] + ; 515.3[M / 2+H] +

[0313] Step 6:

[0314] The crude trifluoroacetic acid salt of 6,6'-(((1,4,7,10-tetraazacyclododecane-1,4-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (32 mg, 27.99 μmol) was dissolved in DMF (1 mL) and DIPEA ( To the mixture was added 45 mg, 348.18 μmol) to make it alkaline, and then 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (19.62 mg, 27.99 μmol) and HATU (12.77 mg, 33.59 μmol) were added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was extracted with water (15 mL) and ethyl acetate (15 mL). The organic phase was washed with brine and concentrated under reduced pressure to give the crude product of tert-butyl intermediate A-12-7 2,2',2"-(10-(5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (44 mg, 25.70 μmol).

[0315] Its structural characterization data are as follows:

[0316] MS m / z(ESI):1713.8[M+H] + ;856.7[M / 2+H] + ; 571.5[M / 3+H] +

[0317] Step 7:

[0318] 2,2',2"-(10-(5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3- ...2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl) The crude product of tert-butyl triacetate (30 mg, 17.52 μmol) was dissolved in DMF (2 mL), and then tert-butyl bromoacetate (20 mg, 102.54 μmol) was added and stirred at 50°C for 8 hours. Tert-butyl bromoacetate (20 mg, 102.54 μmol) was added and the reaction was continued at 50°C with stirring for 40 hours. After the reaction was completed, the reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate A-12-8. tert-Butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetic acid salt (6 mg, 3.09 μmol).

[0319] Its structural characterization data are as follows:

[0320] MS m / z(ESI):1828.0[M+H] + ;913.8[M / 2+H] + ';647.7[M / 3+H] +

[0321] The purification method is as follows:

[0322] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0323] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0324] Step 8:

[0325] To the trifluoroacetic acid salt (6 mg, 3.09 μmol) of tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate was added TFA (1 mL) and the reaction was stirred at room temperature for 5 hours. After the reaction was completed, The reaction solution was directly concentrated under reduced pressure at room temperature to remove the solvent. The crude product was dissolved in acetonitrile, purified twice by preparative high performance liquid chromatography, and then freeze-dried to obtain compound A-122,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid trifluoroacetate (0.99 mg, 0.60 μmol).

[0326] Its structural characterization data are as follows:

[0327] MS m / z(ESI):1547.7[M+H] +

[0328] The first purification method is as follows:

[0329] Chromatographic column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0330] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0331] The second purification method is as follows:

[0332] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0333] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0334] Example 4: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S))-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (C-3)

[0335] Step 1:

[0336] Di-tert-butyl 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (0.50 g, 1.25 mmol) was added to a mixed solvent of dioxane (5 mL) and concentrated hydrochloric acid (5 mL), heated to 60 ° C and reacted for 16 hours. The reaction was concentrated to obtain the intermediate C-3-2 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid hydrochloride crude product (432 mg, 1.20 mmol), which was used directly in the next step without purification.

[0337] Its structural characterization data are as follows:

[0338] MS m / z(ESI):289.1[M+H] +

[0339] Step 2:

[0340] Crude 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid hydrochloride (200 mg, 0.69 mmol), DIPEA (717.2 mg, 5.55 mmol), and di-tert-butyl dicarbonate (604.8 mg, 2.77 mmol) were added to a mixed solvent of ethanol (8 mL) and water (1 ml), heated to 60°C for 2 hours, and concentrated to obtain intermediate C-3-3 crude 2,2'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (450 mg, 644.73 μmol).

[0341] Its structural characterization data are as follows:

[0342] MS m / z(ESI):489.3[M+H] +

[0343] Step 3:

[0344] The crude product of 2,2'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (400.0 mg, 409.36 μmol), (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (446.6 mg, 818.71 μmol) and DIPEA (264.5 mg, 2.05 mmol) were added to DMF (6 mL) and stirred for 5 minutes. HATU (466.9 mg, 1.23 mmol) was added and reacted at 25°C for 2 hours. The reaction solution was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 10-80%) and freeze-dried to obtain intermediate C-3-4 tert-Butyl 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl))quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (460.0 mg, 349.70 μmol).

[0345] Its structural characterization data are as follows:

[0346] MS m / z(ESI):1315.7[M+H] +

[0347] Step 4:

[0348] 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid tert-butyl ester (460.0 mg, 349.70 μmol) was added to a mixed solvent of TFA (2 mL) and dichloromethane (4 mL), reacted at 25° C. for 2 hours, concentrated to give a crude product, purified by C18 reverse column (ACN:H 2 O (containing 0.1% trifluoroacetic acid) = 10-60%), and freeze-dried to give intermediate C-3-5. 6,6'-((((2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (235.0 mg, 191.18 μmol).

[0349] Its structural characterization data are as follows:

[0350] MS m / z(ESI):1115.6[M+H] +

[0351] Step 5:

[0352] 6,6'-((((2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (50.0 mg, 40.68 μmol) was dissolved in DMF (2 mL), and 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanoic acid (31.4 mg, 44.74 μmol), DIPEA (31.5 mg, 244.06 μmol), H ATU (30.9 mg, 81.35 μmol) was added and reacted at 25°C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography and then freeze-dried to obtain intermediate C-3-6A2,2',2"-(10-(5-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butyloxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate (7.0 mg, 3.89 μmol) and intermediate C-3-6B Tert-butyl 5-(7-(5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-tert-butoxy-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-4,10-bis(2-oxo-2-(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6-yl)oxy)butylamino)ethyl)-1,4,7,10-tetraazacyclododec-1-yl)-5-oxo-2-(4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoate (39.0 mg, 15.72 μmol).

[0353] Its structural characterization data are as follows:

[0354] C-3-6A:MS m / z(ESI):899.8[M / 2+H]+ ,600.3[M / 3+H] +

[0355] C-3-6B:MS m / z(ESI):1241.4[M / 2+H] + ,621.3[M / 4+H] +

[0356] The purification method is as follows:

[0357] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0358] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0359] Step 6:

[0360] tert-Butyl 2,2',2"-(10-(5-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (7.0 mg, 3.66 μmol) was dissolved in DMF (1 mL), and DIPEA (4.7 mg, 36.61 μmol) and tert-butyl 2-bromoacetate (3.6 mg, 18.30 μmol) were added. The reaction mixture was heated to 50°C for 4 hours and cooled to room temperature. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to give the intermediate C-3-72,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triacetic acid tert-butyl ester (4.0 mg, 1.91 μmol).

[0361] Its structural characterization data are as follows:

[0362] MS m / z(ESI):1912.0[M+H] + , 956.8[M / 2+H] +,638.3[M / 3+H] +

[0363] The purification method is as follows:

[0364] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0365] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0366] Step 7:

[0367] 2,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate tert-butyl ester (4.0 mg, 1.91 μmol) was dissolved in trifluoroacetic acid (0.5 mL), heated to 50 °C for 4 hours, and concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound C-3. 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S))-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (1.80 mg, 0.98 μmol).

[0368] Its structural characterization data are as follows:

[0369] MS m / z(ESI):816.6[M / 2+H] + , 408.8[M / 4+H] + ,

[0370] The purification method is as follows:

[0371] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0372] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0373] Example 5: 5-(7-(4-carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane)butanoyl)-4,10-bis(2-oxo-2-(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6-yl)oxy)butylamino)ethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-5-oxo-2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanoic acid (C-5)

[0374] 5-(7-(5-tert-butoxy-5-oxo-4-(4,7,10-tris(2-tert-butoxy-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-4,10-bis(2-oxo-2-(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6-yl)oxy)butylamino)ethyl Tert-butyl 1,4,7,10-tetraazacyclododec-1-yl)-5-oxo-2-(4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoate (39.0 mg, 15.72 μmol) was dissolved in trifluoroacetic acid (1 mL), heated to 50°C for 6 hours, and concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound C-5. 5-(7-(4-Carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane)butanoyl)-4,10-bis(2-oxo-2-(4-((4-((2-oxo-2-((2S)-2-cyano-4,4-difluoropyrrolidin-1-yl)ethyl)carbamoyl)quinolin-6-yl)oxy)butylamino)ethyl)-1,4,7,10-tetraazacyclododec-1-yl)-5-oxo-2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (5.22 mg, 2.31 μmol).

[0375] Its structural characterization data are as follows:

[0376] MS m / z(ESI):1017.1[M / 2+H] + , 508.9[M / 4+H] + .

[0377] The purification method is as follows:

[0378] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0379] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0380] Example 6: 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)succinyl)-1,4,7-triazacyclononane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (H-2)

[0381] Step 1:

[0382] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid (37.42 mg, 83.83 μmol) and 1,4,7-triazacyclononane (10 mg, 41.91 μmol) were dissolved in DMF (1 mL), and DIPEA (54.17 mg, 419.14 μmol, 73 μL) and HATU (31.87 mg, 83.83 μmol) were added, and the reaction was carried out at room temperature for 16 hours. The solvent was removed, the mixture was purified by high performance preparative chromatography, and freeze-dried to give the intermediate H-2-1 6,6'-(((1,4,7-triazacyclononane-1,4-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide)formate (11 mg, 10.66 μmol).

[0383] Its structural characterization data are as follows:

[0384] MS m / z(ESI):493.8[M / 2+H] +

[0385] The purification method is as follows:

[0386] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0387] Step 2:

[0388] 6,6'-(((1,4,7-triazacyclononane-1,4-diyl)bis(4-oxobutane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide)formate (11 mg, 10.66 μmol) and 5-(tert-butoxy)-5-oxo-4-(4,7, 10-Tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (8.96 mg, 12.79 μmol) was dissolved in DMF (1 mL), and DIPEA (13.78 mg, 106.59 μmol, 18.5 μL) and HATU (5.31 mg, 13.95 μmol) were added and reacted at room temperature for 2 h. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to give the intermediate H-2-2 2,2',2"-(10-(5-(4,7-bis(4-((4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7-triazacyclononan-1-yl)-1-tert-butoxy-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tert-butyl triacetate (8 mg, 4.79 μmol).

[0389] Its structural characterization data are as follows: MS m / z (ESI): 835.1 [M / 2+H] +

[0390] The purification method is as follows:

[0391] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0392] Step 3:

[0393] 2,2',2"-(10-(5-(4,7-bis(4-((4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyryl)-1,4,7-triazacyclononane-1-yl)-1-tert-butoxy-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tert-butyl triacetate (8 mg, 4.79 μmol) was dissolved in TFA (1 mL) and reacted at room temperature for 5 h. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound H-2 2,2′,2″-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)succinyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (1.79 mg, 1.18 μmol).

[0394] Its structural characterization data are as follows: MS m / z (ESI): 1445.6 [M+H] +

[0395] The purification method is as follows: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% TFA)

[0396] Example 7: 2,2',2"-(10-(2-(4,7-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7-triazacyclononane-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (H-3)

[0397] Step 1:

[0398] (S)-6-(4-Aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (774.90 mg, 1.42 mmol), DIPEA (367.21 mg, 2.84 mmol), and N,N'-carbonyldiimidazole (204.50 mg, 1.42 mmol) were dissolved in DMF (20 mL) and stirred for 1 hour. (9H-fluoren-9-yl)-1,4,7-triazacyclononane-1-carboxylate hydrochloride (200 mg, 473.54 μmol) was added and the mixture was allowed to react at 20°C for 2 hours. The reaction system was diluted with water (150 mL) and extracted three times with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The reaction mixture was purified by silica gel column chromatography (dichloromethane:methanol=100:0-100:10) and concentrated again to give the intermediate H-3-1(9H-fluoren-9-yl)methyl 4,7-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7-triazacyclononane-1-carboxylate (130 mg, 92.40 μmol).

[0399] Its structural characterization data are as follows:

[0400] MS m / z(ESI):1267.5[M+H] +

[0401] Step 2:

[0402] (9H-fluoren-9-yl)methyl 4,7-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7-triazacyclononane-1-carboxylate (130 mg, 92.40 μmol) was dissolved in DMF (2 mL), and diethylamine (15.02 mg, 205.32 μmol) was added, and the mixture was reacted at 20°C for 1 hour. The reaction solution was vacuum-evacuated, purified by preparative high performance liquid chromatography, and freeze-dried to obtain the intermediate H-3-2N 1 ,N 4 -bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7-triazacyclononane-1,4-dicarboxamide (100 mg, 86.20 μmol).

[0403] Its structural characterization data are as follows:

[0404] MS m / z(ESI):1045.6[M+H] +

[0405] The purification method is as follows:

[0406] Column: SunFire Prep C18 OBD (5μm*19mm*150mm)

[0407] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0408] Step 3:

[0409] N 1 ,N 4 -bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7-triazacyclononane-1,4-dicarboxamide (10 mg, 9.58 μmol) and 2,2',2"-(10-(2-((2,5-dioxocyclopentyl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (9.61 mg, 19.16 μmol) were dissolved in DMF (1 mL), and DIPEA (7.43 mg, 57.47 μmol) was added, followed by stirring at 20°C for 2 hours. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound H-3. 2,2′,2″-(10-(2-(4,7-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7-triazacyclononan-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (1.57 mg, 1.02 μmol).

[0410] Its structural characterization data are as follows:

[0411] MS m / z(ESI):1431.6[M+H] +

[0412] The purification method is as follows:

[0413] Column: SunFire Prep C18 OBD (5μm*19mm*150mm)

[0414] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0415] Example 8: 2,2',2"-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (H-5)

[0416] Step 1:

[0417] 1,4,7-Triazacyclononane trihydrochloride (5.0 g, 20.96 mmol) was dissolved in DCM (50 mL) at 25 ° C, DBU (42.23 g, 167.65 mmol) was added, and the mixture was stirred for 5 minutes. (Boc)2O (9.14 g, 41.88 mmol) was dissolved in DCM (100 mL) and slowly added dropwise into the system. The reaction was continued at 25 ° C for 6 hours; water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane 3 times (10 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain the intermediate H-5-2 1,4,7-triazacyclononane-1,4-dicarboxylic acid di-tert-butyl ester (15.0 g) crude product, which was used directly in the next step without purification.

[0418] Its structural characterization data are as follows:

[0419] MS m / z(ESI):330.3[M+H] +

[0420] Step 2:

[0421] Crude di-tert-butyl 1,4,7-triazacyclononane-1,4-dicarboxylate (15.0 g) was dissolved in a mixed solvent of THF (50 mL), MeOH (15 mL), and water (15 mL). NaHCO₃ (2.55 g, 30.36 mmol) and Fmoc-Osu (4.61 g, 13.66 mmol) were added sequentially, and the mixture was stirred at 25°C for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 100:1 to 3:1) and concentrated again to give the intermediate H-5-3 1-((9H-fluoren-9-yl)methyl)4,7-di-tert-butyl 1,4,7-triazacyclononane-1,4,7-tricarboxylate (4.0 g, 7.26 mmol).

[0422] Its structural characterization data are as follows:

[0423] MS m / z(ESI):552.3[M+H] +

[0424] Step 3:

[0425] 1-((9H-fluoren-9-yl)methyl)4,7-di-tert-butyl 1,4,7-triazacyclononane-1,4,7-tricarboxylate (2.0 g, 3.63 mmol) was dissolved in 1,4-dioxane (5 mL), stirred to dissolve, and a dioxane solution of hydrogen chloride (4 M, 7.19 mL) was added. The temperature was raised to 50°C and the reaction was allowed to react for 2 hours. The reaction solution was concentrated and MTBE was added. The mixture was ultrasonically mixed and filtered to obtain the crude intermediate H-5-4(9H-fluoren-9-yl)1,4,7-triazacyclononane-1-carboxylate hydrochloride (1.3 g, 3.06 mmol), which was used directly in the next step without purification.

[0426] Its structural characterization data are as follows:

[0427] MS m / z(ESI):352.2[M+H] +

[0428] Step 4:

[0429] The crude product of (9H-fluoren-9-yl)1,4,7-triazacyclononane-1-carboxylate hydrochloride (1.5 g, 3.46 mmol, 2CL), tert-butyl bromoacetate (3.38 g, 17.32 mmol) and DIPEA (3.13 g, 24.25 mmol) were dissolved in DMF (5 mL) and reacted at 25°C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by beating with petroleum ether and concentrated again to obtain the intermediate H-5-5 2,2'-(7-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,4,7-triazacyclononane-1,4-diyl)diacetate (1.8 g, 3.10 mmol).

[0430] Its structural characterization data are as follows:

[0431] MS m / z(ESI):580.4[M+H] +

[0432] Step 5:

[0433] Di-tert-butyl 2,2'-(7-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,4,7-triazacyclononane-1,4-diyl)diacetate (1.8 g, 3.04 mmol) was dissolved in a 4 M solution of hydrogen chloride in dioxane (20.0 mL) and reacted at 25°C for 8 hours. The reaction solution was concentrated and MTBE was added. The mixture was ultrasonically mixed and filtered to obtain the crude intermediate H-5-6 2,2'-(7-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,4,7-triazacyclononane-1,4-diyl)diacetate (600 mg, 1.28 mmol), which was used in the next step without purification.

[0434] Its structural characterization data are as follows:

[0435] MS m / z(ESI):468.2[M+H] +

[0436] Step 6:

[0437] Crude 2,2'-(7-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,4,7-triazacyclononane-1,4-diyl)diacetic acid (125.0 mg, 0.23 mmol) and (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (240.0 mg, 0.44 mmol) were dissolved in DMF (5 mL), and HATU (440.0 mg, 1.16 mmol) and DIPE were added. A (179.4 mg, 1.39 mmol) was added and reacted at 25°C for 1 hour; the reaction solution was directly purified by preparative high performance liquid chromatography and then freeze-dried to obtain the intermediate H-5-7(9H-fluoren-9-yl)methyl 4,7-bis(2-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-carboxylate (160 mg, 0.12 mmol).

[0438] Its structural characterization data are as follows:

[0439] MS m / z(ESI):1295.6[M+H] +

[0440] The purification method is as follows:

[0441] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[0442] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0443] Step 7:

[0444] (9H-fluoren-9-yl)methyl 4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-carboxylate (150.0 mg, 0.12 mmol) and diethylamine (84.7 mg, 1.16 mmol) were dissolved in DMF (5 mL) and reacted at 25°C for 1 hour; the reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate H-5-8 6,6'-((((2,2'-(1,4,7-triazacyclononane-1,4-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (109 mg, 0.10 mmol).

[0445] Its structural characterization data are as follows:

[0446] MS m / z(ESI):1073.6[M+H] +

[0447] The purification method is as follows:

[0448] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[0449] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0450] Step 8:

[0451] 6,6'-((((2,2'-(1,4,7-triazacyclononane-1,4-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (10.0 mg, 8.94 μmol) and DIPEA (11.56 mg, 8 9.43 μmol) was dissolved in DMF (1 mL), 2,2',2"-(10-(2-((2,5-dioxocyclopentyl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (8.97 mg, 17.89 μmol) was added, and the temperature was raised to 55 ° C for 16 hours. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound H-5. 2,2′,2″-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (1.62 mg, 1.0 μmol).

[0452] Its structural characterization data are as follows:

[0453] MS m / z(ESI):730.5[M / 2+H] +

[0454] The purification method is as follows:

[0455] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[0456] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0457] Example 9: 2,2',2"-(10-(4-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (H-6)

[0458] Step 1:

[0459] 6,6'-((((2,2'-(1,4,7-triazacyclononane-1,4-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (10.0 mg, 8.94 μmol) and DIPEA (11.56 mg, 89.43 μmol) were dissolved in DMF (1 mL), and 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (6.9 mg, 9.84 μmol) and H ATU (6.8 mg, 17.89 μmol) was added and reacted at 25°C for 1 hour; the reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain the intermediate H-6-1, which was a white solid compound 2,2',2"-(10-(5-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-1-(tert-butyloxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tert-butyl triacetate (5.0 mg, 2.85 μmol).

[0460] Its structural characterization data are as follows:

[0461] MS m / z(ESI):1756.2[M+H] +

[0462] The purification method is as follows:

[0463] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[0464] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium formate)

[0465] Step 2:

[0466] 2,2',2"-(10-(5-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-1-(tert-butyloxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tert-butyl triacetate (10.0 mg, 5.7 μmol) was dissolved in TFA (1 mL) and reacted at 25°C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound H-6. 2,2′,2″-(10-(4-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (5.21 mg, 3.07 μmol).

[0467] Its structural characterization data are as follows:

[0468] MS m / z(ESI):766.0[M / 2+H] +

[0469] The purification method is as follows:

[0470] Column: Waters XBridge Prep C18 OBD (5μm*19mm*150mm)

[0471] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0472] Example 10: 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (H-8)

[0473] Step 1:

[0474] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (93 mg, 202.44 μmol) was dissolved in DMF (3 mL), and DIPEA (59.46 mg, 460.08 μmol), DMTMM (50.93 mg, 184.04 μmol) and (9H-fluoren-9-yl)methyl 1,4,7-triazacyclononane-1-carboxylate hydrochloride (39.05 mg, 92.01 μmol) were added sequentially, and the mixture was reacted at room temperature for 8 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give the intermediate H-8-1(9H-fluoren-9-yl)methyl 4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononane-1-carboxylate (31.5 mg, 25.52 μmol).

[0475] Its structural characterization data are as follows:

[0476] MS m / z(ESI):1235.2[M+H] +

[0477] The purification method is as follows:

[0478] Chromatographic column: Waters XBridge Prep C18OBD (5μm*19mm*150mm)

[0479] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0480] Step 2:

[0481] (9H-fluoren-9-yl)methyl 4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononane-1-carboxylate (31.5 mg, 25.52 μmol) was dissolved in DMF (2 mL), diethylamine (5.60 mg, 76.56 μmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain the intermediate H-8-2 8,8'-((4,4'-(1,4,7-triazacyclononane-1,4-diyl)bis(4-oxobutanoyl))bis(azadiyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (20.02 mg, 19.76 μmol).

[0482] Its structural characterization data are as follows:

[0483] MS m / z(ESI):1013.2[M+H] +

[0484] The purification method is as follows:

[0485] Chromatographic column: Waters XBridge Prep C18OBD (5μm*19mm*150mm)

[0486] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0487] Step 3:

[0488] 8,8'-((4,4'-(1,4,7-triazacyclononane-1,4-diyl)bis(4-oxobutanoyl))bis(azadiyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (20.02 mg, 19.76 μmol) was dissolved in DMF (2 mL), 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (16.62 mg, 23.72 μmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give the intermediate H-8-3-tert-butoxy 4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-5-oxo-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoate (11.01 mg, 6.49 μmol).

[0489] Its structural characterization data are as follows:

[0490] MS m / z(ESI):1695.8[M+H] +

[0491] The purification method is as follows:

[0492] Chromatographic column: Waters XBridge Prep C18OBD (5μm*19mm*150mm)

[0493] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0494] Step 4:

[0495] 5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-5-oxo-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (11.01 mg, 6.49 μmol) was dissolved in DCM (0.5 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was reacted at room temperature for 6 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give compound H-8 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (4.33 mg, 2.77 μmol).

[0496] Its structural characterization data are as follows:

[0497] MS m / z(ESI):1471.4[M+H] +

[0498] The purification method is as follows:

[0499] Chromatographic column: Waters XBridge Prep C18OBD (5μm*19mm*150mm)

[0500] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0501] Example 11: 2,2',2"-(10-(4-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyryl)-7-(4-(4-iodophenyl)butyryl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (J-1)

[0502] Step 1:

[0503] 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate Butyl ester trifluoroacetate (8 mg, 4.38 μmol) and 4-(4-iodophenyl)butyric acid (3.81 mg, 13.14 μmol) were dissolved in DMF (0.5 mL), HATU (5.00 mg, 13.14 μmol) and DIPEA (2.83 mg, 21.91 μmol) were added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate J-1-1. tert-Butyl 2,2′,2″-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetic acid salt (5 mg, 2.38 μmol).

[0504] Its structural characterization data are as follows:

[0505] MS m / z(ESI):1985.0[M+H] + ,993.0[M / 2+H] + ,662.1[M / 3+H] +

[0506] The purification method is as follows:

[0507] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0508] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0509] Step 2:

[0510] 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2- Trifluoroacetic acid (0.5 mL) was added dropwise to the trifluoroacetic acid salt of tert-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (5 mg, 2.38 μmol). After the addition was complete, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at room temperature, and then the residual trifluoroacetic acid was removed using a freeze dryer. The resulting crude product was directly purified by preparative high-performance liquid chromatography and freeze-dried to obtain compound J-1. 2,2′,2″-(10-(4-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetate (2.23 mg, 1.14 μmol).

[0511] Its structural characterization data are as follows:

[0512] MS m / z(ESI):1760.6[M+H] + ,880.5[M / 2+H] + ,587.4[M / 3+H] + ,440.9[M / 4+H] +

[0513] The purification method is as follows:

[0514] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0515] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0516] Example 12: 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyryl)-10-(4-(4-iodophenyl)butyryl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (J-3)

[0517] Step 1:

[0518] Tert-butyl 2,2′,2″-(10-(5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (14 mg, 8.18 μmol) and 4-(4-iodophenyl)butanoic acid (4.74 mg) were added. , 16.36μmol) was dissolved in DMF (1mL), DIPEA (8mg, 61.90μmol) and HATU (6.84mg, 17.99μmol) were added, and the mixture was stirred at room temperature for 8 hours. 4-(4-iodophenyl)butyric acid (4.74mg, 16.36μmol) and HATU (6.84mg, 17.99μmol) and DIPEA (8mg, 61.90μmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate J-3-1. tert-Butyl 2,2′,2″-(10-(5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetate (5 mg, 2.38 μmol).

[0519] Its structural characterization data are as follows:

[0520] MS m / z(ESI):992.8[M / 2+H] + ; 662.1[M / 3+H] +

[0521] The purification method is as follows:

[0522] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0523] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0524] Step 2:

[0525] 2,2',2"-(10-(5-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyryl)-10-(4-(4-iodophenyl)butyryl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate trifluoroacetate (5 mg, 2.38 μmol) was added to trifluoroacetic acid (1 mL) and stirred at room temperature for 6 hours. The reaction solution was directly concentrated under reduced pressure at room temperature, then dissolved in acetonitrile, purified by preparative high performance liquid chromatography, and freeze-dried to obtain compound J-3. 2,2′,2″-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetic acid salt (2.5 mg, 1.20 μmol).

[0526] Its structural characterization data are as follows:

[0527] MS m / z(ESI):880.6[M / 2+H] + ; 587.5[M / 3+H] + ; 440.9[M / 3+H] +

[0528] The purification method is as follows:

[0529] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0530] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0531] Example 13: 2,2',2"-(10-(4-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine)-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (J-5)

[0532] Step 1:

[0533] Di-tert-butyl 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (414.2 mg, 1.03 mmol) was dissolved in DMF (8 mL), and DIPEA (267.3 mg, 2.07 mmol) and HATU (589.8 mg, 1.55 mmol) were added. 4-(4-iodophenyl)butyric acid (300 mg, 1.03 mmol) was added in batches. The mixture was reacted at 25°C for 1 hour. The DMF was partially removed by concentration. The residue was purified by C18 reverse column (ACN:H2O (containing 0.05% formic acid) = 10-70%) and freeze-dried to obtain intermediate J-5-2. Di-tert-butyl 2,2'-(4-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (190.0 mg, 282.47 μmol).

[0534] Its structural characterization data are as follows:

[0535] MS m / z(ESI):673.3[M+H] +

[0536] Step 2:

[0537] Di-tert-butyl 2,2'-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (190.0 mg, 282.47 μmol) was dissolved in DMF (5 mL), and DIPEA (54.8 mg, 423.71 μmol) and Fmoc-Osu (142.9 mg, 423.71 μmol) were added. The mixture was reacted at 25°C for 2 hours, and water (15 ml) was added. The product was extracted with ethyl acetate (30 mL) and concentrated to obtain a crude product. The crude product was purified by column chromatography (MeOH:DCM=0-15%) and concentrated again to obtain intermediate J-5-3. Tert-butyl 2,2'-(4-(((9H-fluoren-9-yl)methoxy)carbonyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (260.0 mg, 261.49 μmol).

[0538] Its structural characterization data are as follows:

[0539] MS m / z(ESI):895.4[M+H] +

[0540] Step 3:

[0541] Tert-butyl 2,2'-(4-(((9H-fluoren-9-yl)methoxy)carbonyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (260.0 mg, 290.54 μmol) was added to a solution of hydrogen chloride in dioxane (4 M, 5 mL), the temperature was raised to 70°C, the reaction was allowed to proceed for 2 hours, and the mixture was concentrated to obtain a crude product. The crude product was purified by C18 reverse column (ACN:H2O (containing 0.5% trifluoroacetic acid) = 20-60%) and freeze-dried to give intermediate J-5-4 2,2'-(4-(((9H-fluoren-9-yl)methoxy)carbonyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (58.0 mg, 70.81 μmol).

[0542] Its structural characterization data are as follows:

[0543] MS m / z(ESI):783.3[M+H] +

[0544] Step 4:

[0545] 2,2'-(4-(((9H-fluoren-9-yl)methoxy)carbonyl)-10-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (48.0 mg, 58.60 μmol), (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (63.9 mg, 117.20 μmol) and DIPEA (60.6 mg, 468.79 μmol) were added to DMF (6 mL), stirred for 5 minutes, and HATU (89.1 mg, 234.40 μmol) was added. The reaction was carried out at 25°C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to give the intermediate J-5-5(9H-fluoren-9-yl)methyl 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1-carboxylate (28.0 mg, 17.40 μmol).

[0546] Its structural characterization data are as follows:

[0547] MS m / z(ESI):805.5[M / 2+H] +

[0548] The purification method is as follows:

[0549] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0550] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0551] Step 5:

[0552] (9H-fluoren-9-yl)methyl 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1-carboxylate (28.0 mg, 17.40 μmol) was dissolved in DMF (1 mL), and diethylamine (6.36 mg, 86.98 μmol) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate J-5-6. 6,6'-((((2,2'-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (14.0 mg, 9.59 μmol).

[0553] Its structural characterization data are as follows:

[0554] MS m / z(ESI):1387.4[M+H] +

[0555] The purification method is as follows:

[0556] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0557] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0558] Step 6:

[0559] 6,6'-((((2,2'-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(acetyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (14.0 mg, 10.09 μmol) was dissolved in DMF (1 mL) and added 5-(tert-Butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-Butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (10.61 mg, 15.14 μmol), DIPEA (5.2 mg, 40.37 μmol), HATU (7.7 mg, 20.18 μmol) were reacted at 25 ° C for 1 hour. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate J-5-7 tert-Butyl 2,2′,2″-(10-(5-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (16.0 mg, 7.73 μmol).

[0560] Its structural characterization data are as follows:

[0561] MS m / z(ESI):1036.6[M / 2+H] +

[0562] The purification method is as follows:

[0563] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0564] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0565] Step 7:

[0566] 2,2',2"-(10-(5-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)- 1-(tert-Butyloxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tert-butyl triacetate (16.0 mg, 7.73 μmol) was dissolved in DCM (2 mL), trifluoroacetic acid (1 mL) was added, the temperature was raised to 40°C and the reaction was carried out for 4 hours, and the mixture was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound J-5. 2,2′,2″-(10-(4-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)-7-(4-(4-iodophenyl)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (5.9 mg, 2.86 μmol).

[0567] Its structural characterization data are as follows:

[0568] MS m / z(ESI):616.1[M / 3+H] +

[0569] The purification method is as follows:

[0570] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0571] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0572] Example 14: Preparation of 2,2',2"-(10-(4-(4,10-bis((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (B-1)

[0573] Step 1:

[0574] To DMF (3 mL) were added (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (417 mg, 766.24 μmol), DIPEA (540.16 mg, 4.18 mmol), and CDI (110.30 mg, 766.24 μmol). After addition, the mixture was stirred at 22°C for 15 min. 1,4,7,10-tetraazacyclododecane (60 mg, 348.29 μmol) was then added. After addition, the mixture was stirred at 22°C for 4 h. The reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate B-1-1N. 1 ,N 7 -bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxamide (143 mg, 121.02 μmol).

[0575] Its structural characterization data are as follows:

[0576] MS m / z(ESI):1087.5[M+H] +

[0577] The purification method is as follows:

[0578] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0579] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% ammonium bicarbonate)

[0580] Step 2:

[0581] To DCM (8 mL) was added N 1 ,N 7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxamide (140 mg, 128.78 μmol), 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (135.39 mg, 193.17 μmol), DIPEA (116.50 mg, 901.46 μmol), and HATU (97.92 mg, 257.56 μmol) were added and the reaction was stirred at 22 ° C for 4 h. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give intermediate B-1-2 2,2',2"-(10-(5-(4,10-bis((4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butyloxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate tri-tert-butyl formate (51 mg, 25.84 μmol).

[0582] Its structural characterization data are as follows:

[0583] MS m / z(ESI):1769.9[M+H] +

[0584] Step 3:

[0585] To a mixed solvent of DCM (1 mL) and trifluoroacetic acid (4 mL) was added tri-tert-butyl 2,2',2"-(10-(5-(4,10-bis((4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) triacetate formate (45 mg, 24.78 μmol), and the mixture was stirred at 35 ° C for 3 h. After completion of the reaction, the solvent was evaporated on a rotary evaporator, and the residue was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound B-1. 2,2′,2″-(10-(4-(4,10-bis((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetate (20.26 mg, 11.60 μmol).

[0586] Its structural characterization data are as follows:

[0587] MS m / z(ESI):1545.63[M+H] +

[0588] The purification method is as follows:

[0589] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0590] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0591] Example 15: Preparation of 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-9)

[0592] Step 1:

[0593] To DMF (6 mL) were added tert-butyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (600 mg, 1.61 mmol), DIPEA (1.04 g, 8.05 mmol), and benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.69 g, 6.44 mmol). The mixture was stirred at 50°C for 20 h. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 0:1) and freeze-dried to obtain the formate salt of intermediate B-9-1 (1,4,7-di-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylate, 1,4-dibenzyl ester) (740 mg, 1.00 mmol).

[0594] Its structural characterization data are as follows:

[0595] MS m / z(ESI):641.3[M+H] +

[0596] Step 2:

[0597] 1,4,7-Di-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid-1,4-dibenzyl ester (740 mg, 1.00 mmol) was added to a mixed solvent of DCM (3 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 20°C for 3 h. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography (C18, water (containing 0.05% trifluoroacetic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to obtain intermediate B-9-2 (1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid dibenzyl ester trifluoroacetate salt) (555 mg, 920.73 μmol).

[0598] Its structural characterization data are as follows:

[0599] MS m / z(ESI):441.3[M+H] +

[0600] Step 3:

[0601] To DMF (2 mL) were added dibenzyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (520 mg, 937.68 μmol) and DIPEA (969.49 mg, 7.50 mmol), and the mixture was stirred at 22°C for 15 min. 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (537.04 mg, 937.68 μmol) and HATU (713.02 mg, 1.88 mmol) were then added, and the mixture was stirred at 22°C for 3 h. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give the intermediate B-9-3 7-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid dibenzyl ester formate (859 mg, 824.95 μmol).

[0602] Its structural characterization data are as follows:

[0603] MS m / z(ESI):995.6[M+H] +

[0604] Step 4:

[0605] To DMF (3 mL) were added dibenzyl 7-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate formate (300 mg, 288.11 μmol), DIPEA (446.82 mg, 3.46 mmol), and tert-butyl bromoacetate (168.59 mg, 864.32 μmol). After the addition was complete, the mixture was heated to 50°C and stirred for 20 h. The reaction solution was directly purified by preparative HPLC and freeze-dried to give the intermediate B-9-4 7-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid dibenzyl formate (170 mg, 147.14 μmol).

[0606] Its structural characterization data are as follows:

[0607] MS m / z(ESI):1110.7[M+H] +

[0608] The purification method is as follows:

[0609] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0610] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0611] Step 5:

[0612] To methanol (15 mL) were added dibenzyl 7-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate formate (170 mg, 147.14 μmol), 10% palladium hydroxide (170 mg), and 10% Pd / C (170 mg). After the addition was complete, the atmosphere was replaced with hydrogen and the reaction was stirred at 22°C for 4 h. After the reaction was completed, the reaction was filtered and the filtrate was evaporated to dryness using a rotary evaporator to obtain the intermediate B-9-5 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) triacetate (137 mg), which was used directly in the next step without purification.

[0613] Its structural characterization data are as follows:

[0614] MS m / z(ESI):842.7[M+H] +

[0615] Step 6:

[0616] To DMF (3 mL) were added trifluoroacetate of (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (51.88 mg, 95.11 μmol), DIPEA (30.73 mg, 237.78 μmol) and CDI (15.42 mg, 95.11 μmol). After the addition was complete, the reaction was stirred at 22°C for 15 min. Then add crude tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (20 mg). After the addition is complete, the temperature is raised to 80 ° C and stirred for 24 hours. The reaction solution is directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate B-9-6. Tri-tert-butyl 2,2′,2″-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (12 mg, 6.66 μmol).

[0617] Its structural characterization data are as follows:

[0618] MS m / z(ESI):1756.2[M+H] +

[0619] The purification method is as follows:

[0620] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0621] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0622] Step 7:

[0623] To a mixed solvent of trifluoroacetic acid (4 mL) and DCM (1 mL) was added tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (12 mg, 6.66 μmol). After the addition was complete, the mixture was heated to 40 ° C and stirred for 4 h. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound B-9. 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4),4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetic acid salt (4.09 mg, 2.36 μmol).

[0624] Its structural characterization data are as follows:

[0625] MS m / z(ESI):1531.6[M+H] +

[0626] The purification method is as follows:

[0627] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0628] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0629] Example 16: Preparation of 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-10)

[0630] Step 1:

[0631] To DMF (3 mL) were added dibenzyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate trifluoroacetate (0.7 g, 523.50 μmol) and DIPEA (1.1 g, 8.51 mmol) to make the mixture alkaline. Then, 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (403.61 mg, 575.85 μmol) and HATU (238.86 mg, 628.80 μmol) were added. After the addition was complete, the reaction was stirred at 22 °C for 16 h. After the reaction is completed, the reaction solution is added to water (100 mL) and stirred for crystallization. The mixture is filtered and the solid is dried to obtain the intermediate B-10-1 dibenzyl 7-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (770 mg, 514.06 μmol).

[0632] Its structural characterization data are as follows:

[0633] MS m / z(ESI):1123.8[M+H] +

[0634] Step 2:

[0635] To DMF (7 mL) were added dibenzyl 7-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (770 mg, 514.06 μmol), DIPEA (265.75 mg, 2.06 mmol), and tert-butyl bromoacetate (267.38 mg, 1.37 mmol). After the addition was complete, the mixture was heated to 50°C and stirred for 16 h. After the reaction, the reaction solution was added dropwise to water (100 mL) and stirred for crystallization. The mixture was filtered and the filter cake was dried to obtain the intermediate B-10-2 dibenzyl 7-(2-(tert-butoxy)-2-oxoethyl)-10-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (763 mg, 616.53 μmol).

[0636] Its structural characterization data are as follows:

[0637] MS m / z(ESI):1238.9[M+H] +

[0638] Step 3:

[0639] To THF (20 mL) were added dibenzyl 7-(2-(tert-butoxy)-2-oxoethyl)-10-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (760 mg, 614.11 μmol) and 10% Pd / C (300 mg). After the addition was completed, the atmosphere was replaced with hydrogen and the mixture was stirred and hydrogenated at 22°C for 20 h. After the reaction is completed, the mixture is filtered through a pad of celite, and the filtrate is evaporated to dryness on a rotary evaporator to obtain the crude intermediate B-10-3 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (500 mg), which is used in the next step without purification.

[0640] Its structural characterization data are as follows:

[0641] MS m / z(ESI):970.8[M+H] +

[0642] Step 4:

[0643] To DMF (3 mL) were added (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (178 mg, 326.33 μmol) and DIPEA (84.27 mg, 652.02 μmol). The mixture was stirred at 22°C for 10 min. CDI (52.86 mg, 326.01 μmol) was then added. The mixture was stirred for 15 min. Finally, add crude tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (158 mg). After the addition is complete, the temperature is raised to 80 ° C and stirred for 16 hours. The reaction solution is directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate B-10-4 Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (113 mg, 55.62 μmol).

[0644] Its structural characterization data are as follows:

[0645] MS m / z(ESI):1885.9[M+H] +

[0646] The purification method is as follows:

[0647] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0648] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0649] Step 5:

[0650] To a mixed solvent of DCM (2 mL) and trifluoroacetic acid (5 mL) was added 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl After the addition of tri-tert-butyl triacetate (100 mg, 51.81 μmol), the mixture was heated to 45°C and stirred for 3 hours. The mixture was directly purified by preparative HPLC and freeze-dried to obtain compound B-10. 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-)cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetate (67.02 mg, 37.07 μmol).

[0651] Its structural characterization data are as follows:

[0652] MS m / z(ESI):802.4[1 / 2M+H] +

[0653] The purification method is as follows:

[0654] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0655] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0656] Example 17: Preparation of 2,2',2"-(10-(1-carboxy-4-oxo-4-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)butyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-11)

[0657] Step 1:

[0658] To DMF (3 mL) were added (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (42 mg, 77.00 μmol) and DIPEA (45.01 mg, 348.29 μmol) and stirred at 22°C for 15 min. CDI (11.07 mg, 76.91 μmol) was then added and stirred at 22°C for 15 min. Finally, 1,4,7,10-tetraazacyclododecane (5 mg, 29.02 μmol) was added. After addition, the mixture was heated to 90°C and stirred for 5 h. The reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate B-11-1N. 1 ,N 4 ,N 7 -Tris(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxamide formate (10 mg, 6.47 μmol).

[0659] Its structural characterization data are as follows:

[0660] MS m / z(ESI):1545.8[M+H] +

[0661] The purification method is as follows:

[0662] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0663] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0664] Step 2:

[0665] To DMF (2 mL) was added N 1 ,N 4 ,N 7-Tris(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxamide formate (10 mg, 6.47 μmol), 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (8.89 mg, 12.95 μmol), DIPEA (4.18 mg, 32.37 μmol), and HATU (4.92 mg, 12.95 μmol) were added and the reaction was stirred at 22 ° C for 3 h. After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (10 mL×2). The organic phase was collected and washed once with water (6 mL) and saturated brine (6 mL). After drying, the solvent was removed by rotary evaporation to obtain the intermediate B-11-2 2,2',2"-(10-(1-(tert-butoxy)-1,5-dioxo-5-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentan-2-yl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl)triacetate (14 mg).

[0666] Its structural characterization data are as follows:

[0667] MS m / z(ESI):1114.2[M / 2+H] +

[0668] Step 3:

[0669] To trifluoroacetic acid (2 mL) was added crude tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-1,5-dioxo-5-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)pentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (14 mg), and the mixture was stirred at 22 ° C for 4 h. After the reaction, the trifluoroacetic acid was removed by rotary evaporation, and the residue was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound B-11. The trifluoroacetic acid salt of 2,2′,2″-(10-(1-carboxy-4-oxo-4-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)butyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (3.40 mg, 1.46 μmol).

[0670] Its structural characterization data are as follows:

[0671] MS m / z(ESI):1002.3[M / 2+H] +

[0672] The purification method is as follows:

[0673] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0674] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0675] Example 18: Preparation of 2,2',2"-(10-(2-oxo-2-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)ethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-12)

[0676] To DMF (2 mL) was added N 1 ,N 4 ,N 7-Tris(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxamide (10 mg, 6.47 μmol), 2,2',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (5.24 mg, 12.95 μmol), DIPEA (5.02 mg, 38.85 μmol), and Carter condensation agent (5.73 mg, 12.95 μmol). After the addition, the temperature was raised to 65°C and stirred for 16 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give compound B-12 2,2',2"-(10-(2-oxo-2-(4,7,10-tris((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)ethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid formate (2.15 mg, 1.03 μmol).

[0677] Its structural characterization data are as follows:

[0678] MS m / z(ESI):966.6[M / 2+H] +

[0679] The purification method is as follows:

[0680] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0681] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0682] Example 19: Preparation of 2,2',2"-(10-(4-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (D-1)

[0683] Step 1:

[0684] To DCM (4 mL) were added di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (317 mg, 851.00 μmol) and succinic anhydride (425.81 mg, 4.26 mmol). The mixture was stirred at 22°C for 2 h. After completion of the reaction, the reaction solution was evaporated to dryness using a rotary evaporator. The residue was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to afford the intermediate D-1-2, 4,4'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoic acid) formate (248 mg, 398.43 μmol).

[0685] Its structural characterization data are as follows:

[0686] MS m / z(ESI):573.3[M+H] +

[0687] Step 2:

[0688] To DMF (1 mL) were added 4,4'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoic acid) formate (185 mg, 323.06 μmol), 8-aminoquinoline-4-carboxylic acid (182.38 mg, 969.18 μmol), DIPEA (334.02 mg, 2.58 mmol) and HATU (368.48 mg, 969.18 μmol). After the addition was complete, the reaction was stirred at 22°C for 2 h. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give the intermediate D-1-3 8,8'-((4,4'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoyl))bis(azadiyl)))bis(quinoline-4-carboxylic acid) formate (162 mg, 163.25 μmol).

[0689] Its structural characterization data are as follows:

[0690] MS m / z(ESI):913.5[M+H] +

[0691] Step 3:

[0692] To DMF (2 mL) were added 8,8'-((4,4'-(4,10-bis(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoyl))bis(azadiyl)))bis(quinoline-4-carboxylic acid) formate (142 mg, 155.53 μmol), (S)-4,4-difluoro-1-glycylpyrrolidine-2-carbonitrile formate (146.32 mg, 622.14 mg), DIPEA (160.81 mg, 1.24 mmol), and HATU (236.54 mg, 622.14 μmol). After the addition was complete, the reaction was stirred at 22°C for 3 h. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (10 mL×3). The organic phase was washed once with water (10 mL), and dried to obtain the intermediate D-1-44,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid di-tert-butyl ester (195 mg), which was used in the next step without purification.

[0693] Its structural characterization data are as follows:

[0694] MS m / z(ESI):1257.6[M+H] +

[0695] Step 4:

[0696] To a mixed solvent of DCM (2 mL) and trifluoroacetic acid (1 mL) was added crude di-tert-butyl 4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (195 mg). After the addition was complete, the reaction was stirred at 22°C for 2 h. After the reaction, the solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give the intermediate D-1-5 8,8'-((4,4'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoyl))bis(azadiyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) formate (143 mg, 110.39 μmol).

[0697] Its structural characterization data are as follows:

[0698] MS m / z(ESI):1055.5[M+H] +

[0699] Step 5:

[0700] To DMF (2 mL) were added 8,8'-((4,4'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoyl))bis(azadiyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) formate (18.05 mg, 17.11 μmol) and DIPEA (26.53 mg, 205.29 μmol). After the addition was complete, the reaction was stirred at 22°C for 10 min. 5-(tert-Butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-Butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (11.99 mg, 17.11 μmol) and HATU (9.76 mg, 25.66 μmol) were added, and the reaction was stirred at 22°C for 3 h. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give the intermediate D-1-6 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate tri-tert-butyl formate (13 mg, 7.29 μmol).

[0701] Its structural characterization data are as follows:

[0702] MS m / z(ESI):1738.9[M+H] +

[0703] Step 6:

[0704] To a mixed solvent of DCM (1 mL) and trifluoroacetic acid (1 mL) was added tri-tert-butyl 2,2',2"-(10-(5-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butoxy)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (13 mg, 7.29 μmol). After the addition was complete, the mixture was stirred at 22 ° C for 20 h. After the reaction was completed, the solvent was removed by rotary evaporator, and the residue was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound D-1. 2,2′,2″-(10-(4-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, formate salt (8 mg, 4.72 μmol).

[0705] Its structural characterization data are as follows:

[0706] MS m / z(ESI):757.4[M / 2+H] +

[0707] The purification method is as follows:

[0708] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0709] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0710] Example 20: Preparation of 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (D-3)

[0711] Step 1:

[0712] To DMF (6 mL) were added di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (600 mg, 1.61 mmol), DIPEA (1.04 g, 8.05 mmol), and benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.69 g, 6.44 mmol). The mixture was stirred at 50°C for 20 hours. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 0:1) and freeze-dried to afford the intermediate D-3-2, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid 1,7-dibenzyl 10,4-di-tert-butyl ester formate (740 mg, 1.00 mmol).

[0713] Its structural characterization data are as follows:

[0714] MS m / z(ESI):641.3[M+H] +

[0715] Step 2:

[0716] To a mixed solvent of DCM (3 mL) and trifluoroacetic acid (2 mL) was added 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylic acid 1,7-dibenzyl ester, 10,4-di-tert-butyl formate (740 mg, 1.00 mmol). The mixture was stirred at 20°C for 3 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by flash column chromatography (C18, water (containing 0.05% trifluoroacetic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to obtain intermediate D-3-3 (1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester, trifluoroacetic acid salt) (555 mg, 920.73 μmol).

[0717] Its structural characterization data are as follows:

[0718] MS m / z(ESI):441.3[M+H] +

[0719] Step 3:

[0720] To DMF (3 mL) were added dibenzyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate trifluoroacetate (0.35 g, 261.25 μmol) and DIPEA (0.6 g, 4.26 mmol) to make the mixture alkaline. Then, 5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoic acid (201.31 mg, 287.93 μmol) and HATU (119.43 mg, 314.40 μmol) were added. After the addition was complete, the mixture was stirred at 22°C for 16 hours. After the reaction was completed, the reaction solution was added to water (100 mL) and stirred for crystallization. The mixture was filtered and the solid was dried to obtain the intermediate D-3-4 4-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester (385 mg, 257.03 μmol).

[0721] Its structural characterization data are as follows:

[0722] MS m / z(ESI):1124.8[M+H] +

[0723] Step 4:

[0724] To DMF (3 mL) were added dibenzyl 4-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (300 mg, 288.11 μmol), DIPEA (446.82 mg, 3.46 mmol), and tert-butyl bromoacetate (168.59 mg, 864.32 μmol). After the addition was complete, the mixture was heated to 50°C and stirred for 20 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give the intermediate D-3-5 4-(2-(tert-butoxy)-2-oxoethyl)-10-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester formate (120 mg, 125.14 μmol).

[0725] Its structural characterization data are as follows:

[0726] MS m / z(ESI):1238.6[M+H] +

[0727] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0728] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0729] Step 5:

[0730] To methanol (15 mL) were added dibenzyl 4-(2-(tert-butoxy)-2-oxoethyl)-10-(5-(tert-butoxy)-5-oxo-4-(4,7,10-tris(2-(tert-butoxy))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)pentanoyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate formate (120 mg, 125.14 μmol), 10% palladium hydroxide (170 mg), and 10% Pd / C (170 mg). After the addition was complete, the atmosphere was replaced with hydrogen and the reaction was stirred at 22°C for 4 hours. After the reaction is completed, the reaction mixture is filtered and the filtrate is evaporated to dryness using a rotary evaporator to obtain the intermediate D-3-6 2,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tri-tert-butyl triacetate (90 mg), which is used directly in the next step without purification.

[0731] Its structural characterization data are as follows:

[0732] MS m / z(ESI):970.31[M+H] +

[0733] Step 6:

[0734] To DMF (3 mL) were added crude tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (35 mg) and (S)-4-((4-((2-(2-cyano-4, To the mixture of 4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (33.18 mg, 72.22 μmol), DIPEA (14.00 mg, 108.33 μmol) was added, followed by HATU (34.32 mg, 90.27 μmol) and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to obtain intermediate D-3-7. Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (12 mg, 6.48 μmol).

[0735] Its structural characterization data are as follows:

[0736] MS m / z(ESI):1853.11[M+H] +

[0737] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0738] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0739] Step 7:

[0740] To a mixed solvent of trifluoroacetic acid (4 mL) and DCM (1 mL) was added 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4- After the addition of tri-tert-butyl triacetate (12 mg, 6.48 μmol) (1,4,7,10-tetraazacyclododecane-1-yl, 1,5-dioxolane-2-yl, 1,4,7,10-tetraazacyclododecane-1,4,7-triyl) (1,5-dioxolane-2-yl, 1,4,7,10-tetraazacyclododecane-1,4,7-triyl) and tri-tert-butyl triacetate, the mixture was heated to 40°C and stirred for 4 hours. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound D-3. 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (1.13 mg, 0.65 μmol).

[0741] Its structural characterization data are as follows:

[0742] MS m / z(ESI):1572.6[M+H] +

[0743] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0744] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0745] Example 21: Preparation of 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (D-4)

[0746] Step 1:

[0747] To DMF (2 mL) were added dibenzyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (520 mg, 937.68 μmol) and DIPEA (969.49 mg, 7.50 mmol), and the mixture was stirred at 22°C for 15 min. 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (537.04 mg, 937.68 μmol) and HATU (713.02 mg, 1.88 mmol) were then added, and the mixture was stirred at 22°C for 3 hours. The reaction solution was purified by flash column chromatography (C18, water (containing 0.05% formic acid): acetonitrile = 9:1 to 3:7) and freeze-dried to give the intermediate D-4-1 4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester formate (859 mg, 824.95 μmol).

[0748] Its structural characterization data are as follows:

[0749] MS m / z(ESI):995.6[M+H] +

[0750] Step 2:

[0751] To DMF (3 mL) were added dibenzyl 4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate formate (300 mg, 288.11 μmol), DIPEA (446.82 mg, 3.46 mmol), and tert-butyl bromoacetate (168.59 mg, 864.32 μmol). After the addition was complete, the mixture was heated to 50°C and stirred for 20 hours. The reaction solution was directly purified by preparative HPLC and freeze-dried to give the intermediate D-4-2 4-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester formate (170 mg, 147.14 μmol).

[0752] Its structural characterization data are as follows:

[0753] MS m / z(ESI):1110.7[M+H] +

[0754] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0755] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0756] Step 3:

[0757] To methanol (15 mL) were added dibenzyl 4-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate formate (170 mg, 147.14 μmol), 10% palladium hydroxide (170 mg), and 10% Pd / C (170 mg). After the addition was complete, the atmosphere was replaced with hydrogen and the reaction was stirred at 22°C for 4 hours. After the reaction, the mixture was filtered and the filtrate was evaporated to dryness using a rotary evaporator to obtain the intermediate D-4-3 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) triacetate (137 mg), which was used in the next step without purification.

[0758] Its structural characterization data are as follows:

[0759] MS m / z(ESI):842.1[M+H] +

[0760] Step 4:

[0761] To DMF (3 mL) were added crude tri-tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (80.0 mg, 95.11 μmol) and (S)-4-((4-((2-(2-cyano-4,4-diyl)-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate. To the mixture of 1-fluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (87.39 mg, 190.22 μmol), DIPEA (36.88 mg, 285.33 μmol) was added, followed by HATU (108.48 mg, 285.33 μmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate D-4-4. Tri-tert-butyl 2,2′,2″-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (36 mg, 20.88 μmol).

[0762] Its structural characterization data are as follows:

[0763] MS m / z(ESI):1724.9[M+H] +

[0764] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0765] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0766] Step 5:

[0767] To a mixed solvent of trifluoroacetic acid (4 mL) and DCM (1 mL) was added tri-tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (18 mg, 10.44 μmol). After the addition was complete, the mixture was heated to 40°C and stirred for 4 hours. The reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain compound D-4. 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (6.92 mg, 4.07 μmol).

[0768] Its structural characterization data are as follows:

[0769] MS m / z(ESI):1500.6[M+H] +

[0770] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0771] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0772] Example 22: Preparation of 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (D-7)

[0773] Step 1:

[0774] To DMF (5 mL) were added tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (52.75 mg, 54.42 μmol), (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidine-1 -yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoic acid (50.00 mg, 108.84 μmol), DIPEA (21.0 mg, 163.26 mmol), and then HATU (51.73 mg, 136.05 mmol) were added, and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was extracted with water (30 mL) and ethyl acetate (60 mL), and the organic phase was washed with brine, dried, and concentrated under reduced pressure to obtain intermediate D-7-1. Crude tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (80 mg, 43.19 μmol).

[0775] Its structural characterization data are as follows:

[0776] MS m / z(ESI):1854.2[M+H]+

[0777] Step 2:

[0778] 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl) TFA (3 mL) was added to the crude product of tri-tert-butyl triacetate (60 mg, 32.4 μmol) (1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was extracted with water (30 mL) and ethyl acetate (60 mL). The organic phase was washed with brine, dried, and concentrated under reduced pressure to obtain compound D-7. 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (13.0 mg, 8.02 μmol).

[0779] Its structural characterization data are as follows:

[0780] MS m / z(ESI):1572.5[M+H] +

[0781] The purification method is as follows:

[0782] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0783] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0784] Example 23: Preparation of 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (D-8)

[0785] Step 1:

[0786] To DMF (5 mL) were added crude tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (80.0 mg, 95.11 μmol), (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, and the mixture was stirred for 2 h. To the mixture of 4-nitro-1,4-dimethylamino-2-nitropropane-1-yl) ... Crude tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (90 mg, 52.2 μmol).

[0787] Its structural characterization data are as follows:

[0788] MS m / z(ESI):1724.9[M+H] +

[0789] Step 2:

[0790] To the crude product of tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (90 mg, 52.2 μmol) was added TFA (3 mL) and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was extracted with water (30 mL) and ethyl acetate (60 mL). The organic phase was washed with brine, dried, and concentrated under reduced pressure to obtain compound D-8. 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (1.72 mg, 1.03 μmol).

[0791] Its structural characterization data are as follows:

[0792] MS m / z(ESI):1500.5[M+H] +

[0793] The purification method is as follows:

[0794] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0795] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0796] Example 24: Preparation of 2,2',2"-(10-(2-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (D-11)

[0797] Under nitrogen purge, 8,8'-((4,4'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(4-oxobutanoyl))bis(azadiyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) formate (40 mg, 37.92 μmol) was dissolved in DMF (2 mL), DIPEA (21.6 mg, 56.86 μmol) was added, followed by HATU (29.4 mg, 227.4 μmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure at room temperature to remove the solvent. The crude product was dissolved in acetonitrile, purified by two preparative high performance liquid chromatography cycles, and freeze-dried to obtain compound D-112,2',2"-(10-(2-(4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (1.98 mg, 1.56 μmol).

[0798] Its structural characterization data are as follows:

[0799] MS m / z(ESI):1441.6[M+H] +

[0800] The purification method is as follows:

[0801] Chromatographic column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[0802] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0803] Example 25: Preparation of 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (K-1)

[0804] Step 1:

[0805] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (37.92 mg, 82.53 μmol) and 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2 -yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tri-tert-butyl triacetate (40 mg, 41.27 μmol) was dissolved in DMF (2 mL), and DIPEA (48.00 mg, 371.40 μmol) and HATU (34.52 mg, 90.79 μmol) were added and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate K-1-1 Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (15 mg, 8.10 μmol).

[0806] Its structural characterization data are as follows:

[0807] MS m / z(ESI):1852.3[M+H] + ;926.5[M / 2+H] + ; 618.3[M / 3+H] +

[0808] The purification method is as follows:

[0809] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0810] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0811] Step 2:

[0812] Trifluoroacetic acid (2 mL) was added directly to tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (15 mg, 8.10 μmol), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at room temperature to remove trifluoroacetic acid. The crude product was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound K-1. 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (8.24 mg, 4.64 μmol).

[0813] Its structural characterization data are as follows:

[0814] MS m / z(ESI):786.6[M / 2+H] + ; 524.8[M / 3+H] +

[0815] The purification method is as follows:

[0816] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0817] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0818] Example 26: Preparation of 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (K-3)

[0819] Step 1:

[0820] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (50 mg, 108.84 μmol) and 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10- Tri-tert-butyl tetraazacyclododecane-1,4,7-triyl triacetate (52.75 mg, 54.42 μmol) was dissolved in DMF (2 mL), and DIPEA (80.00 mg, 618.99 μmol) and HATU (45.52 mg, 119.72 μmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: water (containing 0.05% trifluoroacetic acid) = 0-60%) and freeze-dried to obtain intermediate K-3-1. Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (85 mg, 43.23 μmol).

[0821] Its structural characterization data are as follows:

[0822] MS m / z(ESI):927.0[M / 2+H] + ; 618.3[M / 3+H] +

[0823] Step 2:

[0824] Trifluoroacetic acid (3 mL) was added directly to tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododecane-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (85 mg, 45.89 μmol), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at room temperature to remove trifluoroacetic acid. The crude product was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound K-3. 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (27.46 mg, 15.48 μmol).

[0825] Its structural characterization data are as follows:

[0826] MS m / z(ESI):1572.8[M+H] + ;786.4[M / 2+H] + ; 524.7[M / 3+H] +

[0827] The purification method is as follows:

[0828] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0829] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0830] Example 27: Preparation of 2,2',2"-(10-(2-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidino)-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L-1)

[0831] Step 1:

[0832] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (114.4 mg, 0.80 mmol) was dissolved in methanol (3 mL), and di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (50.0 mg, 0.13 mmol) and DIPEA (34.7 mg, 0.27 mmol) were added. The mixture was reacted at 25°C overnight (16 hours), and the crude product was obtained by concentration. The crude product was purified by C18 reverse phase column. The purified solution was added with ethyl acetate-petroleum ether (ethyl acetate:petroleum ether=2:1, 40 ml) to extract the product, and the product was concentrated to obtain the intermediate L-1-14,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid di-tert-butyl ester (49.0 mg, 0.083 mmol).

[0833] Its structural characterization data are as follows:

[0834] MS m / z(ESI):593.4[M+H] +

[0835] Step 2:

[0836] 4,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid tert-butyl ester (49.0 mg, 0.083 mmol) was dissolved in methanol (4 mL), and (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (110 mg, 0.20 mmol) and DIPEA (64.1 mg, 0.50 mmol) were added. The temperature was raised to 40°C for 6 hours, and the reaction was concentrated to obtain a crude product. The crude product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 20-80%), and the purified solution was lyophilized to obtain intermediate L-1-2 Di-tert-butyl 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl))quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (109.0 mg, 0.070 mmol).

[0837] Its structural characterization data are as follows:

[0838] MS m / z(ESI):1391.6[M+H] +

[0839] Step 3:

[0840] 4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid tert-butyl ester (109.0 mg, 0.070 mmol) was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (1 mL), heated to 35° C. for 2 hours, and concentrated to obtain intermediate L-1-3. The crude trifluoroacetate of 6,6'-(((((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(3,4-dioxetane-1-ene-2,1-diyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (215.0 mg, 0.070 mmol) was used directly in the next step.

[0841] Its structural characterization data are as follows:

[0842] MS m / z(ESI):1191.6[M+H] +

[0843] Step 4:

[0844] The crude trifluoroacetic acid salt of 6,6'-(((((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(3,4-dioxetane-1-ene-2,1-diyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) (215.0 mg, 0.070 mmol) was dissolved in DMF (4 mL) and DIPEA was added. The mixture was stirred for 5 minutes, and then 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (65.1 mg, 0.11 mmol) and HATU (57.6 mg, 0.15 mmol) were added. The mixture was reacted at 25°C for 2 hours. The reaction solution was directly purified by C18 reverse column (ACN:H2O (containing 0.1% formic acid) = 20-80%) and lyophilized to obtain intermediate L-1-4. Tri-tert-butyl 2,2′,2″-(10-(2-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (80.0 mg, 0.04 mmol).

[0845] Its structural characterization data are as follows:

[0846] MS m / z(ESI):1745.8[M+H] + , 873.9[M / 2+H] +

[0847] Step 5:

[0848] 2,2',2"-(10-(2-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)tert-butyl triacetate (30.0 mg, 0.017 mmol) was dissolved in trifluoroacetic acid (2 mL), reacted at 25 °C for 8 hours, and concentrated. The crude product was purified by preparative high performance liquid chromatography and lyophilized to give compound L-12,2',2"-(10-(2-(4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine)-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (3.54 mg, 0.002 mmol).

[0849] Its structural characterization data are as follows:

[0850] MS m / z(ESI):1577.7[M+H] +

[0851] The purification method is as follows:

[0852] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0853] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0854] Example 28: Preparation of 2,2',2"-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidine)-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L-3)

[0855] Step 1:

[0856] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (114.4 mg, 0.80 mmol) was dissolved in methanol (3 mL), and di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (50.0 mg, 0.13 mmol) and DIPEA (34.7 mg, 0.27 mmol) were added. The mixture was reacted at 25°C overnight (16 hours), and concentrated to obtain a crude product, which was purified by C18 reverse column chromatography ( The reaction mixture was stirred for 2 hours. The mixture was stirred for 3 hours. ACN:H2O (containing 0.1% formic acid) = 10-70%), and the purified solution was added with ethyl acetate-petroleum ether (ethyl acetate:petroleum ether = 2:1, 40 ml) to extract the product. The product was concentrated to obtain the intermediate L-3-17,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid di-tert-butyl ester (42.0 mg, 0.071 mmol).

[0857] Its structural characterization data are as follows:

[0858] MS m / z(ESI):593.4[M+H] +

[0859] Step 2:

[0860] 7,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid di-tert-butyl ester (42.0 mg, 0.071 mmol) was dissolved in methanol (4 mL), and (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (77.3 mg, 0.14 mmol) and DIPEA (55.0 mg, 0.42 mmol) were added. The temperature was raised to 40°C for 3 hours, and the reaction was concentrated to obtain a crude product. The crude product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 20-80%) and lyophilized to obtain intermediate L-3-2. Di-tert-butyl 7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (79.0 mg, 0.054 mmol).

[0861] Its structural characterization data are as follows:

[0862] MS m / z(ESI):1391.6[M+H]+

[0863] Step 3:

[0864] Di-tert-butyl 7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (79.0 mg, 0.054 mmol) was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (1 mL), and the mixture was heated to 35°C and reacted for 2 hours. , and concentrated to give the crude intermediate L-3-3 6,6'-(((((1,4,7,10-tetraazacyclododecane-1,4-diyl)bis(3,4-dioxocyclobut-1-ene-2,1-diyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxyl))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) trifluoroacetate (82.0 mg, 0.052 mmol), which was directly used in the next step.

[0865] Its structural characterization data are as follows:

[0866] MS m / z(ESI):1191.6[M+H]+

[0867] Step 4:

[0868] 6,6'-(((((1,4,7,10-tetraazacyclododecane-1,4-diyl)bis(3,4-dioxocyclobut-1-ene-2,1-diyl))bis(azadiyl))bis(butane-4,1-diyl))bis(oxy))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide) trifluoroacetate (82.0 mg, 0.052 mmol) was dissolved in DMF (2 mL) and DIPEA ( The mixture was stirred for 5 minutes, and then 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (49.7 mg, 0.087 mmol) and HATU (44.0 mg, 0.11 mmol) were added. The mixture was reacted at 25°C for 2 hours. The reaction solution was directly purified by C18 reverse column (ACN:H2O (containing 0.1% formic acid) = 20-80%) and lyophilized to obtain intermediate L-3-4. Tri-tert-butyl 2,2′,2″-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (91.0 mg, 0.052 mmol).

[0869] Its structural characterization data are as follows:

[0870] MS m / z(ESI):1745.8[M+H] + , 873.9[M / 2+H] +

[0871] Step 5:

[0872] 2,2',2"-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)tri-tert-butyl triacetate (30.0 mg, 0.017 mmol) was dissolved in trifluoroacetic acid (2 mL), the temperature was raised to 50 ° C. and the reaction was carried out for 2 hours. The crude product was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and lyophilized to obtain compound L-3. 2,2′,2″-(10-(2-(4,7-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (11.5 mg, 0.006 mmol).

[0873] Its structural characterization data are as follows:

[0874] MS m / z(ESI):1577.7[M+H] +

[0875] The purification method is as follows:

[0876] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0877] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0878] Example 29: Preparation of 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-)cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-3)

[0879] Step 1:

[0880] To DMF (2 mL) was added 2,2',2"-(10-(5-(4,10-bis((4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1-(tert-butyloxy)-1,5-dioxolan-2-yl)-1-yl)-2-nitropropane )-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) tri-tert-butyl triacetate formate (60 mg, 33.89 μmol), DIPEA (32 mg, 248.06 μmol), tert-butyl bromoacetate (99.24 mg, 50.73 μmol), after addition, stirred at 22 ° C for 20 hours. The reaction solution was purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate B-3-1 Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (34 mg, 18.05 μmol).

[0881] Its structural characterization data are as follows:

[0882] MS m / z(ESI):1884.07[M+H] + ;

[0883] The purification method is as follows:

[0884] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0885] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0886] Step 2:

[0887] To a mixed solvent of DCM (2 mL) and trifluoroacetic acid (4 mL) was added 2,2′,2″-(10-(1-(tert-butoxy)-5-(7-(2-(tert-butoxy)-2-oxoethyl))-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)- Tri-tert-butyl triacetate (34 mg, 18.05 μmol) was added and stirred at 22°C for 3 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the residue was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound B-3. 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-)cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetate (22.13 mg, 12.37 μmol).

[0888] Its structural characterization data are as follows:

[0889] MS m / z(ESI):802.5[M / 2+H] + ;

[0890] The purification method is as follows:

[0891] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0892] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0893] Example 30: Preparation of 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (B-4)

[0894] Step 1:

[0895] To DMF (3 mL) were added trifluoroacetate of (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (233.45 mg, 428.00 μmol), DIPEA (165.94 mg, 1.28 mmol) and CDI (69.40 mg, 428.00 μmol). After the addition was complete, the reaction was stirred at 22 °C for 15 min. Then add crude tri-tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (117 mg). After the addition is complete, the temperature is raised to 85 ° C and stirred for 5 hours. The reaction solution is purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate B-4-7 Tri-tert-butyl 2,2′,2″-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate as formate (65 mg, 36.07 μmol).

[0896] Its structural characterization data are as follows:

[0897] MS m / z(ESI):1755.91[M / 2+H] + ;

[0898] The purification method is as follows:

[0899] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0900] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0901] Step 2:

[0902] To a mixed solvent of DCM (2 mL) and trifluoroacetic acid (6 mL) was added tri-tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate formate (65 mg, 36.07 μmol). After the addition was complete, the mixture was heated to 45°C and stirred. The reaction was stirred for 4 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the residue was purified by preparative high performance liquid chromatography and freeze-dried to obtain compound B-42,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid trifluoroacetate (15.90 mg, 9.18 μmol).

[0903] Its structural characterization data are as follows:

[0904] MS m / z(ESI):766.5[M / 2+H] + ;

[0905] The purification method is as follows:

[0906] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0907] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0908] Example 31: Preparation of 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(2-((4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (L-7)

[0909] Step 1:

[0910] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (81.1 mg, 0.57 mmol) was dissolved in methanol (5 mL), and crude tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl))-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (80.0 mg, 0.095 mmol) and DIPEA (61.5 mg, 0.48 mmol) were added. The mixture was heated to 35 °C for 6 hours, and concentrated to obtain a crude product. The crude product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 10-80%) and lyophilized to obtain intermediate L-7-1. Tri-tert-butyl 2,2′,2″-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(2-methoxy-3,4)-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (61.0 mg, 0.057 mmol).

[0911] Its structural characterization data are as follows:

[0912] MS m / z(ESI):1061.7[M+H] +

[0913] Step 2:

[0914] Tri-tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(2-methoxy-3,4)-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (50.0 mg, 0.047 mmol) was dissolved in methanol. To the alcohol (5 mL), (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (55.5 mg, 0.10 mmol) and triethylamine (28.6 mg, 0.28 mmol) were added, the temperature was raised to 50 ° C and the reaction was carried out for 6 hours. The crude product was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and lyophilized to obtain intermediate L-7-2. Tri-tert-butyl 2,2′,2″-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (43.0 mg, 0.022 mmol).

[0915] Its structural characterization data are as follows:

[0916] MS m / z(ESI):930.7[M / 2+H] +

[0917] The purification method is as follows:

[0918] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0919] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0920] Step 3:

[0921] 2,2',2"-(10-(2-(4-(2-(tert-butyloxy)-2-oxoethyl)-7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10 Tri-tert-butyl triacetate (43.0 mg, 0.022 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and the mixture was heated to 35 ° C for 4 hours. The crude product was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and lyophilized to obtain compound L-7. 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis(2-((4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (9.0 mg, 0.0053 mmol).

[0922] Its structural characterization data are as follows:

[0923] MS m / z(ESI):1635.8[M+H] + ;818.5[M / 2+H] +

[0924] The purification method is as follows:

[0925] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0926] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0927] Example 32: Preparation of 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(2-((4-((4-((2-((S))-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (L-8)

[0928] Step 1:

[0929] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (118.7 mg, 0.84 mmol) was dissolved in methanol (6 mL), and crude tri-tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxolane-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (140 mg, 0.14 mmol) and DIPEA (90.0 mg, 0.69 mmol) were added. The mixture was heated to 30°C for 10 hours, and concentrated to obtain a crude product. The product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 10-70%) and lyophilized to obtain intermediate L-8-1. Tri-tert-butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (78.0 mg, 0.052 mmol).

[0930] Its structural characterization data are as follows:

[0931] MS m / z(ESI):1189.7[M+H] +

[0932] Step 2:

[0933] 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)tri-tert-butyl triacetate (60.0 mg, 0.11 mmol) was dissolved in 0.2 M phosphate buffer ( To a mixed solution of 4 mL (pH = 9), methanol (3 mL) and acetonitrile (3 mL) was added (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (57.8 mg, 0.10 mmol), the temperature was raised to 40 ° C for 4 hours, and the reaction solution was directly purified by C18 reverse column (ACN:H2O (containing 0.1% formic acid) = 10-80%) and lyophilized to obtain intermediate L-8-2 tert-Butyl 2,2′,2″-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (32.0 mg, 0.016 mmol).

[0934] Its structural characterization data are as follows:

[0935] MS m / z(ESI):1988.0[M+H] + , 995.1[M / 2+H] +

[0936] Step 3:

[0937] Tert-butyl 2,2',2"-(10-(1-(tert-butoxy)-5-(4-(2-(tert-butoxy)-2-oxoethyl))-7,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (32.0 mg, 0.016 mmol) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL). The reaction mixture was stirred for 4 hours at 37 ℃ for 1 h at 4 ℃, and the temperature was raised to 35 ℃ for reaction. The crude product was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and lyophilized to obtain compound L-82,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(2-((4-((4-((2-((S))-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (10.0 mg, 0.0056 mmol).

[0938] Its structural characterization data are as follows:

[0939] MS m / z(ESI):1707.8[M+H] + ;855.0[M / 2+H] +

[0940] The purification method is as follows:

[0941] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[0942] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[0943] Example 33: Preparation of 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (A-6)

[0944] Step 1:

[0945] To dibenzyl 1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (1.55 g, 3.52 mmol) was added DIPEA (545 mg, 4.22 mmol) and DMF (30 mL). Allyl (2,5-dioxopyrrolidin-1-yl) carbonate (700.74 mg, 3.52 mmol) was then added portionwise. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was extracted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude intermediate A-6-2 (4-allyl-1,7-dibenzyl-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate) (2.0 g, 3.43 mmol), which was used directly in the next reaction without purification.

[0946] Its structural characterization data are as follows:

[0947] MS m / z(ESI):525.3[M+H] +

[0948] Step 2:

[0949] To crude 4-allyl-1,7-dibenzyl-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (2 g, 3.43 mmol) was added DMF (30 mL), followed by tert-butyl 2-bromoacetate (1.00 g, 5.15 mmol) and DIPEA (886.90 mg, 6.86 mmol). The mixture was heated to 50°C for 24 hours. After completion, the reaction solution was diluted with ethyl acetate and washed four times with brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude intermediate A-6-3 (4-allyl-1,7-dibenzyl-10-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate) (2.9 g, 3.18 mmol), which was used directly in the next step without purification.

[0950] Its structural characterization data are as follows:

[0951] MS m / z(ESI):639.2[M+H] +

[0952] Step 3:

[0953] The crude product of 4-allyl 1,7-dibenzyl 10-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (2.9 g, 3.18 mmol) was dissolved in DMF (15 mL), and tetrahydropyrrole (678.08 mg, 9.53 mmol) was added, followed by tetrakistriphenylphosphine palladium (183.62 mg, 158.90 μmol). After nitrogen replacement, the reaction was stirred at room temperature for 4 hours. After the reaction is completed, the reaction solution is diluted with ethyl acetate, then directly washed with brine four times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane:methanol=0-30%) and concentrated under reduced pressure again to obtain intermediate A-6-4 4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester (1.25 g, 2.25 mmol).

[0954] Its structural characterization data are as follows:

[0955] MS m / z(ESI):555.4[M+H] +

[0956] Step 4:

[0957] 2-(4,7,10-Tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (618.41 mg, 1.08 mmol) and dibenzyl 4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,7-dicarboxylate (600 mg, 1.08 mmol) were dissolved in DMF (6 mL), and DIPEA (279.09 mg, 2.16 mmol) and HATU (451.34 mg, 1.19 mmol) were added, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude intermediate A-6-5 4-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylic acid dibenzyl ester (1.3 g, 1.17 mmol), which was used directly in the next reaction without purification.

[0958] Its structural characterization data are as follows:

[0959] MS m / z(ESI):1237.8[M+H] + ; 619.5[M / 2+H] +

[0960] Step 5:

[0961] A crude product of dibenzyl 4-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,7-dicarboxylate (1.3 g, 1.17 mmol) was dissolved in ethanol (40 mL). Acetic acid (1.43 g, 5.86 mmol) was added, followed by wet palladium on carbon (0.13 g, 10% purity). The atmosphere was purged with hydrogen and stirred at room temperature for 24 hours. The reaction mixture was filtered, the filter cake was washed with ethanol, and the mixture was concentrated under reduced pressure. The resulting crude product was again added to ethanol (40 mL), followed by wet palladium on carbon (0.13 g, 10% purity). The atmosphere was purged with hydrogen and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated under reduced pressure. The concentrated product was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate to remove residual acetic acid, then washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude intermediate A-6-6 tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (0.82 g, 682.42 μmol), which was used directly in the next reaction without purification.

[0962] Its structural characterization data are as follows:

[0963] MS m / z(ESI):841.7[M+H] +

[0964] Step 6:

[0965] ((S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid (200 mg, 448.03 μmol) and 2,2′,2″-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) The crude product of tert-butyl triacetate (269.18 mg, 224.01 μmol) was dissolved in DMF (4 mL), and DIPEA (144.76 mg, 1.12 mmol) and HATU (187.27 mg, 492.83 μmol) were added. The mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography and freeze-dried to obtain intermediate A-6-7. tert-Butyl 2,2′,2″-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetate (171 mg, 94.37 μmol).

[0966] Its structural characterization data are as follows:

[0967] MS m / z(ESI):1698.9[M+H] +

[0968] The purification method is as follows:

[0969] Chromatographic column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0970] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0971] Step 7:

[0972] To the trifluoroacetic acid salt of tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (50 mg, 27.59 μmol) was added dichloromethane (1 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at room temperature to remove the solvent, purified by preparative high performance liquid chromatography, and freeze-dried to obtain compound A-6. 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetic acid salt (28 mg, 17.28 μmol).

[0973] Its structural characterization data are as follows:

[0974] MS m / z(ESI):1474.7[M+H] + ; 737.5[M / 2+H] + ; 492.1[M / 3+H] +

[0975] The purification method is as follows:

[0976] Chromatographic column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[0977] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[0978] Example 34: Preparation of 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (A-17)

[0979] Step 1:

[0980] Benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (8.03 g, 32.21 mmol) and di-tert-butyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (3.16 g, 8.05 mmol) were dissolved in DMF (25.58 mL). DIPEA (3.12 g, 24.16 mmol) was added dropwise, and the mixture was heated to 50°C and stirred for 48 hours. After completion of the reaction, the reaction solution was extracted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0-80%) and concentrated again under reduced pressure to obtain intermediate A-17-1: 1,4-dibenzyl-10,7-di-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylate (5.27 g, 7.40 mmol).

[0981] Its structural characterization data are as follows:

[0982] MS m / z(ESI):541.5[M+H-Boc] +

[0983] Step 2:

[0984] Dissolve 1,4-dibenzyl-10,7-di-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracarboxylate (5.27 g, 7.40 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (15 mL), and stir at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution under reduced pressure, add an appropriate amount of dichloromethane, and continue concentrating. Repeat this process three times. The residue is dissolved in dichloromethane, and the system is made alkaline by adding saturated aqueous sodium bicarbonate. After vigorous stirring for 0.5 hour, extract with dichloromethane, and the organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate A-17-2: dibenzyl-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (3.65 g, 7.04 mmol).

[0985] Its structural characterization data are as follows:

[0986] MS m / z(ESI):441.1[M+H] +

[0987] Step 3:

[0988] To dibenzyl 1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (1.6 g, 3.63 mmol) was added DIPEA (469.39 mg, 3.63 mmol) and DMF (30 mL). Allyl (2,5-dioxopyrrolidin-1-yl) carbonate (723.34 mg, 3.63 mmol) was then added portionwise. The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was extracted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0-90%) and concentrated again under reduced pressure to afford Intermediate A-17-3 1-allyl 4,7-dibenzyl 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (1.39 g, 2.65 mmol).

[0989] Its structural characterization data are as follows:

[0990] MS m / z(ESI):525.2[M+H] +

[0991] Step 4:

[0992] 1-Allyl 4,7-dibenzyl 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (2.6 g, 4.96 mmol) was dissolved in DMF (30 mL), and tert-butyl 2-bromoacetate (1.35 g, 6.94 mmol) was added, followed by DIPEA (1.28 g, 9.91 mmol). The mixture was heated to 50°C and reacted for 24 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and washed four times with brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude intermediate A-17-4, 1-allyl 4,7-dibenzyl 10-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (3.17 g, 4.96 mmol), which was used directly in the next reaction without purification.

[0993] Its structural characterization data are as follows:

[0994] MS m / z(ESI):639.2[M+H] +

[0995] Step 5:

[0996] The crude product of 1-allyl 4,7-dibenzyl 10-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylate (3.3 g, 5.17 mmol) was dissolved in DMF (20 mL), and tetrahydropyrrole (1.10 g, 15.50 mmol) was added, followed by tetrakistriphenylphosphine palladium (336 mg, 290.77 μmol). After nitrogen replacement, the reaction was stirred at room temperature for 4 hours. After the reaction is completed, the reaction solution is diluted with ethyl acetate, then directly washed with brine four times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (dichloromethane: methanol = 0-30%) and concentrated under reduced pressure again to obtain intermediate A-17-5 7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid dibenzyl ester (2.65 g, 4.78 mmol).

[0997] Its structural characterization data are as follows:

[0998] MS m / z(ESI):555.4[M+H] +

[0999] Step 6:

[1000] 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (929.30 mg, 1.62 mmol) and dibenzyl 7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4-dicarboxylate (900 mg, 1.62 mmol) were dissolved in DMF (5 mL), and DIPEA (419.41 mg, 3.25 mmol) and HATU (739.89 mg, 1.95 mmol) were added, and the reaction was stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude intermediate A-17-6 7-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylic acid dibenzyl ester (1.75 g, 1.58 mmol), which was used directly in the next reaction without purification.

[1001] Its structural characterization data are as follows:

[1002] MS m / z(ESI):1109.8[M+H] + ;555.5[M / 2+H] +

[1003] Step 7:

[1004] Crude dibenzyl 7-(2-(tert-butoxy)-2-oxoethyl)-10-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetyl)-1,4,7,10-tetraazacyclododecane-1,4-dicarboxylate (1.77 g, 1.60 mmol) was dissolved in ethanol (50 mL). Wet palladium on carbon (170 mg, 10% purity) was added, and the atmosphere was purged with hydrogen. The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the filter cake was washed with ethanol, and the crude product was concentrated under reduced pressure. Ethanol (50 mL) was added again, followed by acetic acid (1.95 g, 7.99 mmol) and wet palladium on carbon (170 mg, 10% purity). The atmosphere was purged with hydrogen, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, the filter cake was washed with ethanol, and the crude product was concentrated under reduced pressure. Ethanol (50 mL) was added to dissolve the crude product. Acetic acid (1.95 g, 7.99 mmol) and wet palladium on carbon (170 mg, 10% purity) were then added. After hydrogen substitution, the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated under reduced pressure. The crude product was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution to remove residual acetic acid, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude intermediate A-17-7 tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (1.27 g, 1.51 mmol), which was used directly in the next reaction without purification.

[1005] Its structural characterization data are as follows:

[1006] MS m / z(ESI):841.7[M+H] + ;863.7[M+Na] +

[1007] Step 8:

[1008] ((S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoic acid (200 mg, 448.03 μmol) and 2,2′,2″-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) Tert-butyl triacetate (269.18 mg, 224.01 μmol) was dissolved in DMF (4 mL), and DIPEA (144.76 mg, 1.12 mmol) and HATU (187.27 mg, 492.83 μmol) were added. The mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography and freeze-dried to obtain intermediate A-17-8. tert-Butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate, trifluoroacetic acid salt (190 mg, 104.86 μmol).

[1009] Its structural characterization data are as follows:

[1010] MS m / z(ESI):1699.0[M+H] + ; 849.7[M / 2+H] +

[1011] The purification method is as follows:

[1012] Chromatographic column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[1013] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[1014] Step 9:

[1015] To the trifluoroacetic acid salt (100 mg, 58.90 μmol) of tert-butyl 2,2',2"-(10-(2-(4-(2-(tert-butoxy)-2-oxoethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate was added dichloromethane (2 mL), and trifluoroacetic acid (6 mL) was added dropwise. The mixture was stirred at room temperature for 4 hours. After completion, the reaction solution was concentrated under reduced pressure at room temperature to remove the solvent, purified by preparative high performance liquid chromatography, and freeze-dried to obtain compound A-17. 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid, trifluoroacetic acid salt (25 mg, 15.42 μmol).

[1016] Its structural characterization data are as follows:

[1017] MS m / z(ESI):1474.7[M+H] + ; 735.7[M / 2+H] + ; 492.1[M / 3+H] +

[1018] The purification method is as follows:

[1019] Chromatographic column: Waters Sunfire Prep C18 OBD (5μm*19mm*150mm)

[1020] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[1021] Example 35: Preparation of 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (L-5)

[1022] Step 1:

[1023] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (142.6 mg, 1.00 mmol) was dissolved in methanol (5 mL), and tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (201 mg, 0.17 mmol) and DIPEA (172.9 mg, 1.34 mmol) were added. The mixture was heated to 35 °C for 6 hours and concentrated to obtain a crude product. The crude product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 10-80%) and lyophilized to obtain intermediate L-5-1. Tert-butyl 2,2',2"-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (49 mg, 43.86 μmol).

[1024] Its structural characterization data are as follows:

[1025] MS m / z(ESI):1061.7[M+H] +

[1026] Step 2:

[1027] 2,2',2"-(10-(2-(7-(2-(tert-butyloxy)-2-oxoethyl)-4,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate (49 mg, 43.86 μmol) was dissolved in methanol (5 mL) ), (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (55.4 mg, 101.6 μmol) and triethylamine (37.4 mg, 369.37 μmol) were added, the temperature was raised to 55°C for reaction for 24 hours, and the crude product was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography and lyophilized to obtain intermediate L-5-2 Tert-butyl 2,2′,2″-(10-(2-(7-(2-(tert-butoxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (22 mg, 11.83 μmol).

[1028] Its structural characterization data are as follows:

[1029] MS m / z(ESI):931.1[M / 2+H] +

[1030] The purification method is as follows:

[1031] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[1032] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1033] Step 3:

[1034] 2,2',2"-(10-(2-(7-(2-(tert-butyloxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10 tert-Butyl triacetate (22 mg, 11.83 μmol) was dissolved in a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), heated to 35 ° C for 4 hours, and concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography and lyophilized to obtain compound L-5. 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (11.9 mg, 6.91 μmol).

[1035] Its structural characterization data are as follows:

[1036] MS m / z(ESI):1635.8[M+H]+

[1037] The purification method is as follows:

[1038] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[1039] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1040] Example 36: Preparation of 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (L-6)

[1041] Step 1:

[1042] 3,4-Dimethoxycyclobut-3-ene-1,2-dione (77.6 mg, 545.96 μmol) was dissolved in methanol (5 mL), and 2,2',2"-(10-(1-tert-butoxy)-5-(7-(2-tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate (126 mg, 90.99 μmol) and DIPEA (58.8 mg, 454.97 μmol) were added. The mixture was heated to 35 °C for 6 hours and concentrated to obtain a crude product. The crude product was purified by C18 reverse phase column (ACN:H2O (containing 0.1% formic acid) = 10-70%) and lyophilized to obtain intermediate L-6-4. Tert-butyl 2,2',2"-(10-(1-tert-butoxy)-5-(7-(2-tert-butoxy)-2-oxoethyl)-4,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (76 mg, 57.51 μmol).

[1043] Its structural characterization data are as follows:

[1044] MS m / z(ESI):1189.7[M+H] +

[1045] Step 2:

[1046] 2,2',2"-(10-(1-tert-butoxy)-5-(7-(2-tert-butoxy)-2-oxoethyl)-4,10-bis(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) tert-butyl triacetate (76 mg, 57.51 μmol) was dissolved in methanol (5 mL) and added Add (S)-6-(4-aminobutoxy)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate (76.7 mg, 140.57 μmol) and triethylamine (64.7 mg, 638.96 μmol), heat to 55°C and react for 6 hours, concentrate to obtain a crude product, and purify by C18 reverse column (ACN:H2O (containing 0.05% formic acid) = 10-90%), and lyophilize to obtain intermediate L-6-5. Tert-butyl 2,2′,2″-(10-(1-tert-butoxy)-5-(7-(2-tert-butoxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (82 mg, 37.12 μmol).

[1047] Its structural characterization data are as follows:

[1048] MS m / z(ESI):994.5[M / 2+H] +

[1049] Step 3:

[1050] tert-Butyl 2,2',2"-(10-(1-tert-butoxy)-5-(7-(2-tert-butoxy)-2-oxoethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-1,5-dioxopentan-2-yl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetate (82 mg, 37.12 μmol) was dissolved in a mixture of dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred for 2 hours at room temperature in a mixed solvent, the temperature was raised to 35°C, and the reaction was carried out for 2 hours. The crude product was purified by preparative high performance liquid chromatography and lyophilized to give compound L-62,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)triacetic acid (7.47 mg, 3.90 μmol).

[1051] Its structural characterization data are as follows:

[1052] MS m / z(ESI):1707.8[M+H] +

[1053] The purification method is as follows:

[1054] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[1055] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% trifluoroacetic acid)

[1056] Preparation Example 1: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (A-5- 69 Preparation of Ga

[1057] 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl ) triacetic acid trifluoroacetate (10.00 mg, 6.47 μmol) was dissolved in sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 7 mL), and then gallium chloride aqueous solution (1 mM, 22.65 mL) was added. After nitrogen replacement, the mixture was heated to 50 ° C and stirred for 2 hours. After the reaction was completed, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-5- 69 Ga 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (5.40 mg, 3.18 μmol).

[1058] Its structural characterization data are as follows:

[1059] MS m / z(ESI):1613.8[M+H] + ;806.6[M / 2+H] +

[1060] Preparation Example 2: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (A-5- 175 Preparation of Lu

[1061] 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl ) triacetic acid trifluoroacetate (10.00 mg, 6.47 μmol) was dissolved in sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 7 mL), and then lutetium chloride aqueous solution (1 mM, 22.65 mL) was added. After nitrogen displacement, the mixture was heated to 50 ° C and stirred for 2 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-5- 175 Lu 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (8.07 mg, 4.46 μmol).

[1062] Its structural characterization data are as follows:

[1063] MS m / z(ESI):1719.8[M+H] + ;859.6[M / 2+H] +

[1064] Preparation Example 3: 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (A-12- 69 Preparation of Ga

[1065] 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3- ...,4,7-triazolo[3-(4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3-(4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7, The trifluoroacetic acid salt of (15.00 mg, 9.71 μmol) triacetic acid was dissolved in a sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 10 mL), and then an aqueous gallium chloride solution (1 mM, 30 mL) was added. After nitrogen displacement, the mixture was heated to 50°C and stirred for 2 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-12- 69 Ga 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (6.10 mg, 3.59 μmol).

[1066] Its structural characterization data are as follows:

[1067] MS m / z(ESI):1613.8[M+H] + ;807.2[M / 2+H] + ;837.7[M / 3+H] +

[1068] Preparation Example 4: 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (A-12- 175 Preparation of Lu

[1069] 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3- ...,4,7-triazolo[3-(4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3-(4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7, The trifluoroacetic acid salt of (15.00 mg, 9.71 μmol) triacetic acid was dissolved in a sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 10 mL), and then an aqueous solution of lutetium chloride (1 mM, 30 mL) was added. After nitrogen displacement, the mixture was heated to 50°C and stirred for 2 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-12- 175 Lu 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano)-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (10.05 mg, 5.56 μmol).

[1070] Its structural characterization data are as follows:

[1071] MS m / z(ESI):1718.0[M+H] + ;859.6[M / 2+H] + ; 573.5[M / 3+H] +

[1072] Preparation Example 5: 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)gallium triacetate (H-8- 69 Preparation of Ga

[1073] To a sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 8 mL) were added GaCl3 (21.01 μmol, 20 mL), 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl))-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1, 4,7-triazacyclononane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (10 mg, 6.80 μmol) was added and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at room temperature to remove the solvent. The crude product was dissolved in acetonitrile, purified by two preparative high performance liquid chromatography, and freeze-dried to obtain compound H-8- 69 Ga 2,2′,2″-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)gallium triacetate (4.88 mg, 3.08 μmol).

[1074] Its structural characterization data are as follows:

[1075] MS m / z(ESI):1538.14[M+H] +

[1076] The purification method is as follows:

[1077] Chromatographic column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[1078] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1079] Preparation Example 6: 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)lutetium triacetate (H-8- 175 Preparation of Lu

[1080] To a sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 8 mL) were added LuCl3 (21.01 μmol, 20 mL) and 2,2',2"-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononane-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (10 mg, 6.80 μmol). After the addition was complete, the reaction was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure at room temperature to remove the solvent. The crude product was dissolved in acetonitrile, purified by two preparative high performance liquid chromatography steps, and freeze-dried to obtain compound H-8- 175 Lu 2,2′,2″-(10-(4-(4,7-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7-triazacyclononan-1-yl)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)lutetium triacetate (4.88 mg, 3.08 μmol).

[1081] Its structural characterization data are as follows:

[1082] MS m / z(ESI):1643.38[M+H] +

[1083] The purification method is as follows:

[1084] Chromatographic column: Waters Xbridge Prep C18 OBD (5μm*19mm*150mm)

[1085] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1086] Preparation Example 7: 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (A-6- 69 Preparation of Ga

[1087] 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) ) triacetic acid trifluoroacetate (10 mg, 6.30 μmol) was dissolved in sodium acetate-acetic acid buffer (0.4 M, pH = 5, 5 mL), and gallium chloride aqueous solution (1 mM, 18.90 mL) was added. After nitrogen replacement, the mixture was heated to 50 ° C and stirred for 3 hours. After completion of the reaction, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-6- 69 Ga 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (8.40 mg, 5.32 μmol).

[1088] Its structural characterization data are as follows:

[1089] MS m / z(ESI):1542.5[M+H] + ;770.5[M / 2+H] +

[1090] Preparation Example 8: 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (A-6- 175 Preparation of Lu

[1091] 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) ) triacetic acid trifluoroacetate (8 mg, 5.04 μmol) was dissolved in sodium acetate-acetic acid buffer (0.4 M, pH = 5, 5 mL), and lutetium chloride aqueous solution (1 mM, 15.12 mL) was added. Then, nitrogen was replaced and the mixture was heated to 50 ° C and stirred for 3 hours. After the reaction was completed, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-6- 175 Lu 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (6.44 mg, 3.85 μmol).

[1092] Its structural characterization data are as follows:

[1093] MS m / z(ESI):1646.6[M+H] + ;823.5[M / 2+H] +

[1094] Preparation Example 9: 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (A-17- 69 Preparation of Ga

[1095] 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl) ) triacetic acid trifluoroacetate (9 mg, 5.67 μmol) was dissolved in sodium acetate-acetic acid buffer (0.4 M, pH = 5, 6 mL), and gallium chloride aqueous solution (1 mM, 17.01 mL) was added. Then, nitrogen was replaced and the mixture was heated to 50°C and stirred for 3 hours. After the reaction was completed, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound A-17- 69 Ga 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (8 mg, 4.93 μmol).

[1096] Its structural characterization data are as follows:

[1097] MS m / z(ESI):1542.6[M+H] + ;770.5[M / 2+H] +

[1098] Preparation Example 10: 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (A-17- 175 Preparation of Lu

[1099] 2,2',2"-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triazolo[3-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl ... The trifluoroacetic acid salt of (9 mg, 5.67 μmol) triacetic acid was dissolved in sodium acetate-acetic acid buffer (0.4 M, pH = 5, 6 mL). Lutetium chloride aqueous solution (1 mM, 17.01 mL) was added, and then nitrogen was replaced. The mixture was heated to 50°C and stirred for 3 hours. After the reaction was completed, the reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain A-17- 175 Lu 2,2′,2″-(10-(2-(4-(carboxymethyl)-7,10-bis(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (9 mg, 5.20 μmol).

[1100] Its structural characterization data are as follows:

[1101] MS m / z(ESI):1646.6[M+H] + ;823.5[M / 2+H] +

[1102] Preparation Example 11: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (B-3- 69 Preparation of Ga

[1103] To a sodium acetate-acetic acid aqueous solution (0.4 M, pH = 5, 2.7 mL) was added 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10 -tetraazacyclododecan-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecan-1,4,7-triyl) triacetic acid (9 mg, 5.24 μmol) and GaCl3 (1 mM, 16 mL) were added and stirred at 35 ° C for 2 h. The reaction solution was purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound B-3- 69 Ga 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (5.22 mg, 3.08 μmol).

[1104] Its structural characterization data are as follows:

[1105] MS m / z(ESI):835.3[M / 2+H] +

[1106] Preparation Example 12: 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (B-3- 175 Preparation of Lu

[1107] To a sodium acetate-acetic acid aqueous solution (0.4 M, pH = 5, 9 mL) was added 2,2',2"-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclo (1-Dodecyl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (7 mg, 4.08 μmol) and LuCl3·6H20 solution (1 mM, 16 mL) were added and stirred at 35°C for 2 h. The reaction solution was purified by reverse phase column chromatography (acetonitrile:H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound B-3- 175 Lu 2,2′,2″-(10-(1-carboxy-4-(7-(carboxymethyl)-4,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (4.90 mg, 2.61 μmol).

[1108] Its structural characterization data are as follows:

[1109] MS m / z(ESI):888.8[M / 2+H] +

[1110] Preparation Example 13: 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (B-10- 69 Preparation of Ga

[1111] To a sodium acetate-acetic acid aqueous solution (0.4 M, pH = 5, 14 mL) was added 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclo (1-dodecyl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (21.47 mg, 13.39 μmol) and GaCl3 solution (1 mM, 40 mL) were added and stirred at 35°C for 2 h. The reaction solution was purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound B-10- 69 Ga 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (16.43 mg, 9.96 μmol).

[1112] Its structural characterization data are as follows:

[1113] MS m / z(ESI):835.3[M / 2+H] +

[1114] Preparation Example 14: 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (B-10- 175 Preparation of Lu

[1115] To a sodium acetate-acetic acid aqueous solution (0.4 M, pH = 5, 30 mL) was added 2,2',2"-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclopent ... Heterocyclododecane-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (38 mg, 22.12 μmol) and LuCl3 solution (1 mM, 40 mL) were added and stirred at 35°C for 2 h. The reaction solution was purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound B-10- 175 Lu 2,2′,2″-(10-(1-carboxy-4-(4-(carboxymethyl)-7,10-bis((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)carbamoyl)-1,4,7,10-tetraazacyclododec-1-yl)-4-oxobutyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (22.47 mg, 13.04 μmol).

[1116] Its structural characterization data are as follows:

[1117] MS m / z(ESI):888.5[M / 2+H] +

[1118] Preparation Example 15: 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (D-4- 69 Preparation of Ga

[1119] 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1, 4,7-Trimethyl) triacetic acid (12.00 mg, 8.00 μmol) was dissolved in sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 9 mL), and after adding gallium chloride aqueous solution (1 mM, 24.00 mL), the atmosphere was replaced with nitrogen and the temperature was raised to 50 ° C and stirred for 3 hours. The reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound D-4- 69 Ga 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)gallium triacetate (8.3 mg, 4.98 μmol).

[1120] Its structural characterization data are as follows:

[1121] MS m / z(ESI):1567.2[M+H] +

[1122] The purification method is as follows:

[1123] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[1124] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1125] Preparation Example 16: 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (D-4- 175 Preparation of Lu

[1126] 2,2',2"-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1, 4,7-Trimethyl)triacetic acid (28.00 mg, 18.67 μmol) was dissolved in sodium acetate-acetic acid buffer system (0.4 M, pH = 5, 18 mL). Lutetium chloride aqueous solution (1 mM, 44.00 mL) was added, nitrogen was replaced, and the temperature was raised to 50 ° C. and stirred for 3 hours. The reaction solution was directly purified by reverse phase column chromatography (acetonitrile: H2O (containing 0.05% formic acid) = 0-90%) and freeze-dried to obtain compound D-4- 175 Lu 2,2′,2″-(10-(2-(7-(carboxymethyl)-4,10-bis(4-((4-((2-((S)-2-cyano-4,4)-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-8-yl)amino)-4-oxobutanoyl)-1,4,7,10-tetraazacyclododec-1-yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1,4,7-triyl)lutetium triacetate (25.0 mg, 14.21 μmol).

[1127] Its structural characterization data are as follows:

[1128] MS m / z(ESI):1671.4[M+H] +

[1129] The purification method is as follows:

[1130] Column: Waters SunFire Prep C18 OBD (5μm*19mm*150mm)

[1131] Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.05% formic acid)

[1132] Example of hot medicine preparation

[1133] 1. 68 Preparation method of Ga marker

[1134] 1) Solution preparation

[1135] Buffer solution: Weigh 10 mg of gentisic acid and 0.41 g of sodium acetate and prepare 10 ml of aqueous solution with water.

[1136] 2) Marking process

[1137] Precursor solution: Weigh the precursor and dissolve it in buffer to make a 0.1 mg / ml solution.

[1138] Nuclide: Elute 0.5 ml of nuclide with 0.1 M HCl 68 GaCl3, determine the activity.

[1139] Marking: To 200 μl of precursor solution, add 0.5 ml of 68 GaCl3, mix well and determine the activity.

[1140] Reaction: 95°C, heating for 10 min.

[1141] 3) The results of activity, radiochemical purity (abbreviated as radiochemical purity), and specific activity after labeling are shown in Table A. The radiochemical purity test method is as follows: After labeling, the reaction solution is injected into an HPLC equipped with a radioactivity detector. After separation on a C18 column, the solution flows through the radioactivity detector. The signals of the free nuclide and the labeled substance are collected according to their retention times. The percentage of the labeled substance peak area is the radiochemical purity.

[1142] Table A

[1143] 2. 177 Preparation method of Lu marker

[1144] 1) Solution preparation

[1145] Buffer solution: Weigh 0.20 g gentisic acid, 0.60 g acetic acid, and 0.84 g sodium acetate and dissolve them in 20 ml water. Mix well and set aside.

[1146] 2) Marking process

[1147] The precursor compound (3 mg) was dissolved in 6 ml of buffer, and then 40 μl of the above solution was taken into a sterile tube (1.5 ml), and then about 20 uCi of 177 0.04M hydrochloric acid solution of LuCl3; heat the above reaction solution to 95℃ for 15 minutes, then cool to 25℃ for later use.

[1148] 3) Radiochemical purity test

[1149] Thin layer chromatography: Take about 0.5 μl of the above reaction solution and spot it on a gel254 thin layer plate (200 mm x 200 mm) and use saturated EDTA aqueous solution as the developing solvent. 177 Radiochemical purity test of Lu markers.

[1150] Biological evaluation

[1151] Test Example 1: FAP protein activity inhibition test

[1152] Test system:

[1153] Fluorogenic FAP Assay Kit,BPS Bioscience,Catalog:80210

[1154] Test parameters:

[1155] FAP human recombinant protein concentration: 1ng / μl

[1156] DPP substrate 1 concentration: 2.5 μM

[1157] Incubation time of compound and enzyme: 15 minutes at room temperature

[1158] Enzyme and substrate reaction time: 60 minutes at room temperature

[1159] Microplate reader parameters: BMG PHERAstar Fluorescence, excitation wavelength 340nm, emission wavelength 450nm

[1160] Test steps:

[1161] After serial dilutions of the compound with DMSO, a working solution was prepared using assay buffer (50 mM Tris, 1 M NaCl, 1 mg / mL BSA, pH 7.5). 10 μL / well of the compound working solution was added to a 384-well plate. FAP human recombinant protease was prepared using assay buffer to prepare an enzyme working solution. 5 μL / well of the enzyme working solution was added to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 15 minutes. DPP substrate 1 working solution was prepared using assay buffer. 5 μL of the substrate working solution was added to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Fluorescence signal detection was performed using a BMG microplate reader.

[1162] Data processing:

[1163] The group without compound was used as the vehicle control, and the group without enzyme and compound was used as the blank control. The relative inhibitory activity of each concentration group was calculated. Inhibition rate = 100% - (test group - blank group) / (vehicle group - blank group) * 100%. The half-maximal inhibitory concentration (IC) of the compound was calculated according to the four-parameter model fitting curve. 50 ).

[1164] Test results:

[1165] The inhibition of the compounds on FAP protease activity was determined according to the above method. The results are shown in Tables 1, 2 and 3.

[1166] Table 1. Results of FAP protease activity inhibition test

[1167] Table 2. Results of FAP protease activity inhibition test

[1168] Table 3. FAP protease activity inhibition test results

[1169] Experimental conclusion: In the FAP protease activity inhibition test, the compounds disclosed in the present invention exhibited strong inhibitory activity.

[1170] Experimental Example 2: Uptake of Compounds in H_FAP HEK-293 CDX Model

[1171] 1. Cell culture:

[1172] H_FAP HEK-293 cells (from Yoshiman Biotechnology) were cultured in DMEM medium supplemented with 10% fetal bovine serum and 0.75 μg / mL puromycin at 37°C in an incubator containing 5% CO₂ in air. When the cells reached the exponential growth phase, they were harvested, counted, and the original culture medium was tested for mycoplasma.

[1173] 2. Vaccination, grouping and medication:

[1174] About 5×10 6 When the tumor grows to about 200-400 mm 3 The patients were randomly divided into groups. 68 Ga-FAP-2286 and 68 Ga-A-5 was injected into tumor-bearing mice via the tail vein.

[1175] 3. In vivo imaging in animals:

[1176] At 0.5, 1, and 3 hours after drug administration, the animals were placed in the prone position on the PET / CT scanner bed and anesthetized with mixed gas (isoflurane induction concentration adjusted to 3-4% and maintenance concentration adjusted to 1-1.5%) before imaging. Following the scan, the PET sequence was reconstructed.

[1177] PMOD was used to quantitatively analyze tumors, heart, lungs, liver, kidneys, muscles, blood and other parts. The results were expressed as %ID / g. The data were entered into Office software and then tabulated and analyzed.

[1178] 4. Imaging results:

[1179] The data analysis results are shown in Table 4, and the in vivo MIP imaging is shown in Figure 1. The results show that at different time points, 68 The uptake of Ga-A-5 is higher in tumors and lower in other organs such as the heart, lungs, and kidneys. 68 The uptake of Ga-A-5 in tumors was significantly higher than that in 68 Ga-FAP-2286.

[1180] Table 4. 68 Ga-A-5 tumor and organ imaging uptake rate (%ID / g)

[1181] The above embodiments do not limit the scope of the present invention in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: In the above formula (I), Ring A is selected from a 9-20 membered heterocyclic group; Each of X1, X2 and X3 is independently selected from a single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, -C(=O)-, 4-6 membered heterocyclic group, cyclobutene-dione residue For example, it is selected from a single bond, -O-, -S-, -NH-, -N(C 1-6 Alkyl)-, C 1-6 Alkylene, -C(=O)-, 4-6 membered heterocyclic group; L1, L2 and L3 are each independently selected from hydrogen, C 1-6 Alkyl, carboxyl, sulfonic acid, amino acid residue, FAP affinity ligand, albumin binding ligand or R c ; in, The FAP affinity ligand is selected from The albumin binding ligand is selected from Evans blue residues or the following structure R2 is selected from halogen (e.g. iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (such as methyl), C 1- 6 alkoxy (e.g. methoxy), hydroxy, amino, nitro, cyano; Y is independently selected from a single bond, C 1-6 Alkylene, -C(=O)-, -S-, -NH-, -O-, -(CH2CH2OCH2CH2) n -, cyclobutene-dione residue Piperazine, triazole or amino acid residues; R c Chelating agents selected from radionuclides or non-radionuclides, including but not limited to 99mTc(CO)3-chelating agents, CB-TE2A, CHX-A"-DTPA, DTPA, DATA, DFO, HBED, Crown, DOTA, DOTAGA, DOTAM, FSC, H4octapa, Macropa, HEHA, HOPO, Hynic, PCTA, PSC, NETA, NOTA, NOTA-MPAA, NODAGA, NOTP, NOPO, Pycup, RESCA, Sarcophagine, TETA, THP or TRAP; m is each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; n is each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein ring A is selected from a 9-membered or 12-membered nitrogen-containing heterocyclic group.

3. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has a structure shown in Formula I-1 or Formula I-2:

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein: Y is selected from a single bond and C 1-6 Alkylene, preferably a single bond; and / or Rc is selected from the following structures: R1 is selected from halogen (e.g. iodine, bromine, chlorine, fluorine), C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (e.g. methoxy), hydroxy, amino, nitro, cyano; Preferably, R c Selected from 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has a structure as shown in Formula I-1, wherein L1 and L2 are both selected from -(X1) m -and-(X2) m -Selected from R' is selected from H or C 1-6 Alkyl (eg methyl), p is independently selected from 1-6, and -(X1) m -and-(X2) m -same; Preferably, -(X1) m -and-(X2) m -Selected from More preferably, -(X1) m -and-(X2) m -Selected from Position 1 is connected to L1 or L2, and position 2 is connected to the A ring.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has a structure as shown in Formula I-2, wherein -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, C 1-6 Alkylene, R' is selected from H or C 1-6 Alkyl (eg methyl), p is independently selected from 1-6; Preferably, -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, C 1-6 Alkylene, R' is selected from H or C 1-6 Alkyl (eg methyl), p is independently selected from 1-6; Preferably, -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, a methylene group, More preferably, -(X1) m -、-(X2) m -or-(X3) m - are each independently selected from a single bond, a methylene group, Position 1 is connected to L1, L2 or L3, and position 2 is connected to the A ring.

7. The compound according to any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound has a structure as shown in Formula I-2, wherein L1, L2 and L3 are each independently selected from hydrogen, C 1-6 Alkyl, carboxyl, Rc, Preferably, L1, L2 and L3 are each independently selected from hydrogen, carboxyl, 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound is selected from:

9. A compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: In the above formula (II), Ring Z is a chelate structure of Rc and non-radioactive nuclide Rn as described in any one of claims 1 to 8; Ring A, X1, X2, X3, L1, L2, L3, Y, Rc, m and n are as described in any one of claims 1 to 8; Rn is selected from 69 Ga and 175 Lu.

10. The compound of claim 9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound is selected from:

11. A compound having the structure of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof: In the above formula (III), Ring Z' is a chelate structure of Rc and a radionuclide R'n as described in any one of claims 1 to 8; Ring A, X1, X2, X3, L1, L2, L3, Y, Rc, m and n are as described in any one of claims 1 to 8; R’n is selected from 43 Sc、 44 Sc、 47 Sc、 55 Co、 62 Cu、 64 Cu、 67 Cu、 66 Ga、 67 Ga、 68 Ga、 86 Y、 89 Zr、 90 Y、 90 Nb、 99m Tc、 111 In、 135 Sm、 140 Pr、 149 Tb、 159 Gd、 160 Tb、 161 Tb、 165 Er、 166 Dy、 166 Ho、 175 Yb、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb、 213 Bi、 225 Ac or 232 Th。 12. The compound of claim 11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising a diagnostically or therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers.

14. Use of the compound according to any one of claims 1 to 12 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for diagnosing or treating a disease in terms of abnormal cell proliferation (e.g., solid tumors, e.g., advanced solid tumors).

15. The compound as shown below, or its salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance or metabolite: in, Ring X1, X2, X3, L1, Y, m and n are as defined in any one of claims 1 to 8; L2' is L2 or L2 protected by a protecting group (e.g., a carboxyl protecting group); L3' is L3 or L3 protected by a protecting group (e.g., a carboxyl protecting group); Rc' is Rc or Rc protected by a protecting group (eg, a carboxyl protecting group); L2, L3, Rc are as defined in any of claims 1-8; The carboxyl protecting group is preferably selected from C 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl; PG1, PG2, PG3, and PG4 are each independently H or an amino protecting group, and the amino protecting group is preferably selected from an alkoxycarbonyl amino protecting group, such as benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methyl (or ethyl)oxycarbonyl; an acyl amino protecting group, such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (TFA), thiazolyl ... alkyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn).

16. The compound as shown below, or its salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance or metabolite: in, PG1, PG2, PG3, PG4 are as defined in claim 15; R2 is as defined in any one of claims 1 to 8; PG5 are each independently H or a carboxyl protecting group, the carboxyl protecting group is preferably selected from C 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl.

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