FAP inhibitor

Abstract

Provided in the present invention is an FAP inhibitor compound represented by formula (A). Compared with the prior art, the inhibitor compound can improve the uptake and retention time in a target organ, so that the therapeutic or diagnostic effect is improved, the uptake in non-target organs is reduced, and the safety is improved.

Description

FAP inhibitors

[0001] This application claims the priority of the Chinese patent application with application number 202410075967.X and invention name “FAP inhibitor” filed by the applicant with the State Intellectual Property Office of China on January 18, 2024, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medical technology, and particularly relates to FAP inhibitors. Background Art

[0003] Fibroblast activation protein (FAP), also known as proline endopeptidase FAP or seprase, is a type II transmembrane serine protease. In healthy adults, FAP is highly expressed on the surface of activated fibroblasts in the stroma of over 90% of epithelial malignancies, including breast, colorectal, skin, prostate, and pancreatic cancers. However, it is rarely expressed in epithelial lesions in other tissues, benign, or precancerous lesions. Furthermore, studies have shown that FAP is also significantly expressed in diseases associated with inflammation and cellular fibrosis, including wound healing, rheumatoid arthritis, osteoarthritis, cirrhosis, pulmonary fibrosis, and ventricular remodeling after myocardial infarction.

[0004] Studies have shown that inhibiting FAP can affect the motility of CAFs and tumor cells, inhibiting CAF growth and effectively slowing tumor progression. Therefore, FAP has become a highly sought-after target. With the continuous optimization of FAP small molecule inhibitors in recent years, radionuclide-labeled fibroblast activation protein inhibitors (FAPIs) have gradually become a new strategy in targeted tumor diagnosis and treatment. However, the efficacy of existing FAP-targeted radionuclide treatments and diagnostics still needs to be improved. Summary of the Invention

[0005] Existing FAP-targeted nuclide-coupled compounds have the problem of being cleared too quickly from tumor tissue and having a short tumor retention time, which hinders their therapeutic application. While attempting to introduce covalent warheads into nuclide-labeled FAP-targeted compounds, the inventors of this application unexpectedly discovered that:

[0006] 1) The covalent warheads after hydrolysis, such as the sulfonic acid group as the hydrolysis product of the fluorosulfonyl group, and the vicinal diol group and enol group as the result of the hydration and rearrangement of the epoxy group, can endow the compound with excellent properties and effects, such as enhancing tumor-specific uptake and prolonging tumor retention time;

[0007] 2) The attachment position and / or linker length of the covalent warhead have a significant impact on its performance, such as enhancing tumor-specific uptake and prolonging tumor retention time.

[0008] Specific aspects of the present invention include:

[0009] The present invention first provides a compound represented by formula (A), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs,

[0010] Where Z is the payload, T is the target,

[0011] Q is selected from the structure shown in any one of the following formulas (Q-1) to (Q-21):

[0012] L1, L2, L3, L4, A a 、L a 、L b identical or different, independently selected from bonds or linking groups,

[0013] a, b, c, m, p0 are the same or different and are independently selected from integers of 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0014] R d 、R e the same or different, independently selected from hydrogen, halogen, OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0015] Het is an optionally substituted saturated heterocyclylene or heteroarylene,

[0016] R s is selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0017] Every R t are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted thiol, optionally substituted amino, optionally substituted seleno, optionally substituted C 1-20 Alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0018] Indicates the attachment site of a group.

[0019] In some embodiments, Q is selected from the following structures represented by Formula (Q-1-1), (Q-2-1), (Q-3), (Q-4) or (Q-5):

[0020] L1, L2, L3, L4, A a 、L a 、L b identical or different, independently selected from bonds or linking groups,

[0021] a, b, c, and m are the same or different and are independently selected from integers of 0 to 6 (e.g., 0, 1, 2, 3, 4, 5, 6).

[0022] R d 、R e the same or different, independently selected from hydrogen, halogen, OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0023] Indicates the attachment site of a group.

[0024] The second aspect of the present invention also provides a use of a compound represented by formula (A-0) in the preparation of a compound represented by formula (A) wherein Q is represented by formula (Q-1), formula (Q-3) or formula (Q-4).

[0025] Wherein, Q0 is selected from the structure shown in the following formula (Q-2) or (Q-5):

[0026] In formula (A-0), Z, T, L1, L2, L3, L4, L b 、A a 、L a , a, b, c, m, R d 、R e They have the same definitions as those in formula (A).

[0027] The third aspect of the present invention provides a compound represented by the following formula (B):

[0028] Among them, Z1 is the payload, T1 is the target,

[0029] U5, X5, X6, and X7 are the same or different and are independently selected from a linking group;

[0030] R f Selected from the structure represented by the following formula (Q-2-2) or formula (Q-5-1):

[0031] L c 、L d 、A b are the same or different, independently selected from linking groups,

[0032] n is an integer selected from 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0033] R g 、R h the same or different, independently selected from hydrogen, halogen, -OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0034] Indicates the attachment site of a group.

[0035] In some embodiments, R f Selected from the structure shown in the following formula (Q-2-3):

[0036] The fourth aspect of the present invention also provides a compound represented by the following formula (D):

[0037] Among them, Z2 is the payload, T2 is the target,

[0038] U6, U7, U8, and X8 are the same or different and are independently selected from a linking group;

[0039] R i Selected from the structure shown in the following formula (Q-2-4) or formula (Q-5-2):

[0040] L e 、A c 、L f are the same or different, independently selected from linking groups,

[0041] p is an integer selected from 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0042] R j 、R k Selected from hydrogen, halogen, OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0043] Indicates the attachment site of a group.

[0044] In some embodiments, R i Selected from the structure shown in the following formula (Q-2-5):

[0045] The present invention also provides a compound represented by formula (A-4), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs,

[0046] Where Z is the payload,

[0047] Q is selected from the structure shown in any one of the following formulas (Q-1) to (Q-21):

[0048] L2, A a 、L a 、L b are the same or different and are independently selected from linking groups;

[0049] a, m, and p0 are the same or different and are independently selected from integers of 0 to 6;

[0050] R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0051] Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine;

[0052] Rf3 is selected from hydrogen or cyano;

[0053] Het is an optionally substituted saturated heterocyclylene or heteroarylene,

[0054] R s is selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0055] Every R t are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted thiol, optionally substituted amino, optionally substituted seleno, optionally substituted C 1-20 Alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0056] Indicates the attachment site of a group.

[0057] The present invention also provides a nuclear probe targeting FAP, wherein the nuclear probe is a compound represented by the above-mentioned formula (A), formula (B), formula (D) or formula (A-4) labeled with a radionuclide.

[0058] According to an embodiment of the present invention, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide. According to an embodiment of the present invention, the diagnostic radionuclide is 68 Ga, 67 Ga, 64 Cu, 18 F. 86 Y. 89 Zr, 111 In, 99m Tc, 11 C. 203 Pb, 123 I. 125 I and 124 According to an embodiment of the present invention, the therapeutic radionuclide is 177 Lu, 90 Y. 125 I. 131 I. 211 At 153 Sm, 186 Re、 188 Re、 67 Cu, 225 Ac, 227 Th, 223 Ra, 213 Bi, 212 Bihe 212 At least one of Pb.

[0059] According to an embodiment of the present invention, when the radioactive isotope is a non-metallic ion, it can be chelated by forming a complex with a metal ion such as aluminum, for example, Al 18 F.

[0060] The present invention further provides a method for preparing the above-mentioned FAP-targeting radionuclide probe, comprising:

[0061] 1) providing a compound represented by the above formula (A), formula (B), formula (D) or formula (A-4);

[0062] 2) Chelating with the above radioactive nuclides in solution or on a column.

[0063] The present invention further provides a kit for preparing the above-mentioned FAP-targeting nuclide probe, comprising:

[0064] 1) a compound represented by the above formula (A), formula (B), formula (D), or formula (A-4);

[0065] 2) The aforementioned radionuclides or reagents that provide the aforementioned radionuclides.

[0066] The present invention also provides use of the compound represented by the above formula (A), formula (B), formula (D) or formula (A-4) in the preparation of FAP inhibitors.

[0067] The present invention also provides a pharmaceutical composition comprising a compound represented by the above formula (A), formula (B), formula (D), or formula (A-4) and at least one pharmaceutically acceptable excipient or carrier.

[0068] The present invention also provides use of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition in the preparation of imaging agents and / or therapeutic agents targeting FAP.

[0069] The present invention also provides use of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition in the preparation of a drug for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein FAP.

[0070] The present invention also provides a method for diagnosing and / or treating a disease, comprising administering a diagnostically and / or therapeutically effective amount of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition to a subject for diagnosis and / or treatment, wherein the disease is a disease characterized by overexpression of fibroblast activation protein FAP.

[0071] The present invention also provides a kit comprising the above-mentioned compound, a radionuclide probe, a FAP inhibitor or a pharmaceutical composition, and instructions for diagnosing and / or treating a disease.

[0072] According to an embodiment of the present invention, the disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis (such as pulmonary fibrosis), tissue remodeling, scar disease, rheumatoid arthritis, osteoarthritis, cirrhosis, liver disease.

[0073] According to an embodiment of the present invention, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, glioma, glioma, astrocytoma, cervical cancer and prostate cancer.

[0074] The present application also provides a compound represented by formula (M-1):

[0075] wherein R1 is selected from a bond or O;

[0076] R2 is selected from hydrogen, C1-10 alkyl or C1-10 alkoxy;

[0077] L0 includes the structure shown in formula (LX):

[0078] wherein h is selected from 0, 1, 2, j is 0 or 1, g is selected from 0, 1, 2, 3, 4, and k is 0, 1 or 2;

[0079] G6 or G7 are independently -CH2- or carbonyl, and are not both -CH2-;

[0080] R4 is H, -NH2 or an amino group protected by a protecting group. Beneficial effects

[0081] The present invention provides a FAP inhibitor compound represented by formula (A), formula (B), and formula (D). The inhibitor compound has excellent inhibitory activity against FAP kinase, can increase the uptake and retention time of target organs, thereby improving the therapeutic or diagnostic effect, and reduce the uptake of non-target organs, thereby improving safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1: 68 PET-CT images of Ga-FAPI-46 in U87MG tumor-bearing mice;

[0083] Figure 2: 68 Biodistribution results of Ga-FAPI-46 in U87MG tumor-bearing mice (n=3);

[0084] Figure 3: 68 PET-CT images of Ga-S18 in U87MG tumor-bearing mice;

[0085] Figure 4: 68 PET-CT images of Ga-S19 in U87MG tumor-bearing mice;

[0086] Figure 5: 68 PET-CT images of Ga-S2 in U87MG tumor-bearing mice;

[0087] Figure 6: 68 Biodistribution results of Ga-S2 in U87MG tumor-bearing mice (n=3);

[0088] Figure 7: 68 PET-CT images of Ga-S21 in U87MG tumor-bearing mice;

[0089] Figure 8: 68 Biodistribution results of Ga-S21 in U87MG tumor-bearing mice (n=3);

[0090] Figure 9: 68PET-CT images of Ga-S22 in U87MG tumor-bearing mice;

[0091] Figure 10: 68 Biodistribution results of Ga-S22 in U87MG tumor-bearing mice (n=3);

[0092] Figure 11: 68 PET-CT images of Ga-S23 in U87MG tumor-bearing mice;

[0093] Figure 12: 68 Biodistribution results of Ga-S23 in U87MG tumor-bearing mice (n=3);

[0094] Figure 13: 68 PET-CT images of Ga-FAPI-04 in U87MG tumor-bearing mice;

[0095] Figure 14: 68 Biodistribution results of Ga-FAPI-04 in U87MG tumor-bearing mice (n=3);

[0096] Figure 15: 68 PET-CT images of Ga-S12 in U87MG tumor-bearing mice;

[0097] Figure 16: 68 Biodistribution results of Ga-S12 in U87MG tumor-bearing mice (n=3);

[0098] Figure 17: 68 PET-CT images of Ga-S15 in U87MG tumor-bearing mice;

[0099] Figure 18: 68 Biodistribution results of Ga-S15 in U87MG tumor-bearing mice (n=3);

[0100] Figure 19: 68 PET-CT images of Ga-C12 in U87MG tumor-bearing mice;

[0101] Figure 20: 68 Biodistribution results of Ga-C12 in U87MG tumor-bearing mice (n=3);

[0102] Figure 21: 68 PET-CT images of Ga-C3-3 in U87MG tumor-bearing mice;

[0103] Figure 22: 68 Biodistribution results of Ga-C3-3 in U87MG tumor-bearing mice (n=3);

[0104] Figure 23: 68PET-CT images of Ga-C2-1 in U87MG tumor-bearing mice;

[0105] Figure 24: 68 Biodistribution results of Ga-C2-1 in U87MG tumor-bearing mice (n=3)

[0106] Figure 25: 177 Biodistribution results of Lu-S23 in HT1080-FAP tumor-bearing mice (n=6);

[0107] Figure 26: 177 Biodistribution results of Lu-FAPI-46 in HT1080-FAP tumor-bearing mice (n=6);

[0108] Figure 27: 177 Experimental data on the therapeutic effect of Lu-S23 in HT1080-FAP tumor-bearing mice: (A) Schematic diagram of the treatment regimen; (B) Curve of mouse body weight changes during the treatment period; (C) Averaged tumor growth curve during the treatment period;

[0109] Figure 28: 68 Ga-S2 PET / CT imaging in lung cancer patients;

[0110] Figure 29: 68 Ga-S23 in vivo PET / CT imaging in patients with postoperative recurrence of mucinous adenocarcinoma of the right lower quadrant intestine.

[0111] Definitions and Explanations of Terms

[0112] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0113] Unless otherwise indicated, the numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-40" is equivalent to reciting each integer value in the numerical range "1-10," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40," i.e., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. It should be understood that when used herein to describe one, two, or more substituents, "more" should refer to an integer ≥ 3, such as 3, 4, 5, 6, 7, 8, 9, or 10. When describing "at least one" herein, it means that it can be one, two, or more.

[0114] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0115] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Furthermore, when the group is substituted with more than one substituent, each substituent is independent of the others, i.e., the more than one substituent may be different or the same. Unless otherwise indicated, a substituent may be substituted at each substitutable position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position. The substituents may include, but are not limited to, =0, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, hydroxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, and the like.

[0116] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently selected from" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can be independently selected from the same or different specific groups. More specifically, the term "independently selected from" can mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other.

[0117] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C1-6 "Alkyl" specifically refers to independently disclosed C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0118] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0119] The linking group in the present invention can be any divalent (subunit) or trivalent organic group (subunit), and the divalent linking group can be selected from bonds, C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic group or a combination of two or more thereof; the C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic group or a combination of two or more thereof may not be interrupted by or may be optionally interrupted by carbonyl, O, S or N atoms; the C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-10 Cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic group or a combination of two or more thereof may be optionally replaced by C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen atom, halogenated C 1-6 Alkyl substituted; optionally, the C 1-6 Alkyl or halogenated C 1-6 The alkyl group can form a C 3-6 Cycloalkyl; the trivalent linking group is derived from the above-mentioned divalent linking group by deriving a new linking site. The linking group in the present invention can be connected to other structures through any functional group, such as -O-, NH, -COO-, CONH, etc.; unless otherwise specified, the linking group of the present invention can be connected to other structures in any direction. When the linking group is a bond, it indicates that the groups at both ends of the linking group are directly connected by a chemical bond, without involving other atoms.

[0120] The term "C 1-20"Alkyl" means a straight or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-6 "Alkyl" means a straight chain or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in yet other embodiments, the alkyl group contains 1-4 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, butyl, pentyl, butyl ... butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.

[0121] The term "C 3-40 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 40 carbon atoms, preferably "C 3-10 Cycloalkyl". The term "C 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.

[0122] The term "3-20 membered heterocyclyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cyclic alkane containing 1-5 heteroatoms independently selected from N, O and S, and a non-aromatic cyclic group with a total ring number of 3-20 (such as 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably a "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cyclic alkane containing 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, such as 1, 2, or 3 heteroatoms independently selected from N, O and S. The heterocyclyl group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring such as hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic. When the 3-20-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom of the 3-20-membered heterocyclic group or to a heteroatom of the 3-20-membered heterocyclic group. For example, when the 3-20-membered heterocyclic group is selected from piperazinyl, the linking may be to a nitrogen atom of the piperazinyl group and to a carbon atom at the para position of the piperidinyl ring.

[0123] The term "C 6-20 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 Aryl". The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be at the ortho, para or meta position.

[0124] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, including aromatic or partially aromatic ones, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. When the 5-20 membered heteroaryl group is linked to other groups to form the compound of the present invention, the linking may be to a carbon atom on the 5-20 membered heteroaryl ring or to a heteroatom on the 5-20 membered heteroaryl ring. When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site; for example, a hydrogen atom linked to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom linked to a heteroatom on the heteroaryl ring may be substituted.

[0125] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0126] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0127] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0128] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0129] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0130] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0131] In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0132] The term "tautomer" refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerism is possible (such as in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (proton tautomers) (also known as prototropictautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valen cetautomers) include interconversions carried out by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0133] "Nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0134] The term "isotopically labeled" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Isotope-labeled compounds of the present invention can be used to determine the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3 H and 14 C. In addition, in some cases, substitution with heavier isotopes, such as deuterium (2H or D), can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0135] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness, and the like, when administered to a human.

[0136] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water and aqueous saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0137] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzyme conversion to the parent structure in the blood or tissue. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0138] As used herein, the term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0139] Pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in a chain or ring which are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfates, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconolactic acid, benzoic acid, benzoyl ... Sugar acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0140] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of -COOH group formed with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol.

[0141] In addition, basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0142] Since the compounds of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salts include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at two, three, or all of the salt-forming sites. To this end, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or cation of the base required for salt formation in the pharmaceutically acceptable salt can vary over a wide range, for example, it can be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0143] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0144] "Esters" herein refer to in vivo hydrolyzable esters formed from compounds containing hydroxyl or carboxyl groups. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol or acid. The compounds of formula (I) herein contain a carboxyl group and can form in vivo hydrolyzable esters with suitable groups, including, but not limited to, alkyl groups, arylalkyl groups, and the like.

[0145] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0146] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen used, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0147] Unless otherwise indicated, the abbreviations of any protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations or refer to the IUPAC-IUB Commissionon Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

[0148] The pharmaceutical excipients described herein can be those widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients described herein can be inert fillers, or can provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition. The pharmaceutical excipients described herein can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0149] Examples of pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0150] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0151] The dosage form of the medicine of the present invention can be selected according to specific circumstances. Pharmaceutical dosage forms are usually composed of medicine, excipients and container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the medicine, and the method for obtaining the required drug release curve can be provided. Therefore, the excipient type added to the medicine can be determined according to various factors, such as the physical and chemical properties, route of administration and preparation steps of the medicine. In this field, there are pharmaceutical excipients and include those listed in various pharmacopoeias. (See US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); the US Food and Drug Administration (www.fda.gov), Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Hand book of Pharmaceutical Additives, Ash, 2002, Synapse Information Resources, Inc., Endicott NY; etc.).

[0152] The pharmaceutical compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.

[0153] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, and the like. For oral administration, the compound can be formulated as a liquid or solid dosage form and as an immediate release or controlled / slow release formulation. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions. The preferred dosage form of the present invention is an injection.

[0154] The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose used in animal studies can be based on the effective concentration established in cell culture assays. The dosage range suitable for humans can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as a medicament for oral administration.

[0155] The correct formulation, administration route, dosage and dosing interval can be selected according to methods known in the art, taking into account the particularities of the individual situation.

[0156] The present invention first provides a compound represented by formula (A), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs,

[0157] Where Z is the payload, T is the target,

[0158] Q is a covalent group selected from the following structures represented by any one of formula (Q-1), (Q-2), (Q-3), (Q-4), (Q-5), or (Q-6) to (Q-21):

[0159] L1, L2, L3, L4, A a 、L a 、L b identical or different, independently selected from bonds or linking groups,

[0160] a, b, c, m, p0 are the same or different and are independently selected from integers of 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0161] R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0162] Het is an optionally substituted heterocyclylene or heteroarylene,

[0163] R s is selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0164] Every R t are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted thiol, optionally substituted amino, optionally substituted seleno, optionally substituted C 1-20Alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0165] Indicates the attachment site of a group.

[0166] According to an embodiment of the present invention, Het is a 3-20 membered heterocyclylene or a 5-20 membered heteroarylene optionally substituted by one, two or more R3; preferably, Het is a 3-10 membered heterocyclylene or a 5-10 membered heteroarylene optionally substituted by one, two or more R3. According to an embodiment of the present invention, R3 are the same or different and are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, R3 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0167] According to an embodiment of the present invention, R s Selected from: hydrogen, C optionally substituted by one, two or more R4 1-20 Alkyl, optionally substituted by one, two or more R4 3-20 Cycloalkyl, 3-20 membered heterocyclic group optionally substituted by one, two or more R4, C 6-20 Aryl, or 5-20 membered heteroaryl optionally substituted by one, two or more R4; preferably, R s Selected from: hydrogen, C optionally substituted by one, two or more R4 1-10 Alkyl, optionally substituted by one, two or more R4 3-10 Cycloalkyl, 3-10 membered heterocyclic group optionally substituted by one, two or more R4, C 6-10 Aryl, or 5-10 membered heteroaryl optionally substituted by one, two or more R4. According to an embodiment of the present invention, R4 are the same or different and are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, R4 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0168] According to an embodiment of the present invention, R t Selected from: hydrogen, halogen, nitro, cyano, mercapto optionally substituted by one, two or more R5, amino optionally substituted by one, two or more R5, seleno optionally substituted by one, two or more R5, C optionally substituted by one, two or more R5 1-20 Alkyl, optionally substituted by one, two or more R5 3-20 Cycloalkyl, 3-20 membered heterocyclic group optionally substituted by one, two or more R5, C 6-20 Aryl, or 5-20 membered heteroaryl optionally substituted by one, two or more R5; preferably, R t Selected from: hydrogen, halogen, nitro, cyano, mercapto optionally substituted by one, two or more R5, C optionally substituted by one, two or more R5 1-10 Alkyl, optionally substituted by one, two or more R5 3-10 Cycloalkyl, 3-10 membered heterocyclic group optionally substituted by one, two or more R5, C 6-10 Aryl, or 5-10 membered heteroaryl optionally substituted by one, two or more R5. According to an embodiment of the present invention, R5 are the same or different and are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, R5 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 In some embodiments, a compound contains multiple R t When each R t Can be the same or different, each R t are independently selected from the above groups.

[0169] According to an embodiment of the present invention, in formula (A), L1 is selected from a trivalent linking group; preferably, L1 is selected from N, C optionally substituted by one or more R0 1-20 Alkylene or any combination thereof; wherein each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Preferably, each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0170] According to the embodiment of the present invention, L2, L3, L4, A a 、L a 、L b The same or different, independently selected from a divalent linking group; preferably, independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-20 Alkylene, 3-20 membered heterocyclic group optionally substituted by one or more R0 or any combination thereof; further preferably, independently selected from bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C optionally substituted by one or more R0 1-10 Alkylene (C 1-6 Alkylene, C 1-4 Alkylene), 3-20 membered heterocyclic group (3-10 membered heterocyclic group, 3-6 membered heterocyclic group) optionally substituted by one or more R0 or any combination thereof.

[0171] In the embodiment of the present invention, each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0172] According to an embodiment of the present invention, the heterocyclic group contains at least one N (eg, 1 N, 2 N, 3 N or 4 N); preferably, the heterocyclic group is a piperazinyl group.

[0173] According to an embodiment of the present invention, at least one of L2 and L4 contains a 3-20 membered heterocyclic group (a 3-10 membered heterocyclic group, a 3-6 membered heterocyclic group); preferably, at least one of L2 and L4 contains a heterocyclic group having one hydrogen atom or two hydrogen atoms; preferably, contains a piperazinyl group.

[0174] According to an embodiment of the present invention, R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, independently of one another, selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0175] According to an embodiment of the present invention, the compound represented by formula (A) is a multifunctional compound comprising at least three functional groups: a target T, a covalent group Q and a payload Z.

[0176] Various embodiments of the compound of the present invention are described below.

[0177]

Target T

[0178] T is selected from a target that can target fibroblast activation protein-α, and can be a small molecule compound, a polypeptide, an antibody, etc.

[0179] In some embodiments, T is selected from the structure of the target fibroblast activation protein-α as shown in the following formula (T-0):

[0180] In formula (T-0), L5 is selected from a divalent linking group, preferably S, O or a bond;

[0181] Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine;

[0182] Rf3 is selected from hydrogen or cyano.

[0183] As an example, T can be selected from the structure targeting fibroblast activation protein-α as shown in the following formula (T-1),

[0184] wherein L5 is selected from a divalent linking group, preferably S, O or a bond, preferably a bond;

[0185] Indicates the attachment site of a group.

[0186] As an example, T is selected from the structure shown in the following formula (T-1-1):

[0187] wherein L5 is selected from a divalent linking group, preferably S, O or a bond, preferably a bond;

[0188] Indicates the attachment site of a group.

[0189] Payload Z

[0190] The payload Z can be a luminescent group, a fluorescent group, a cytotoxin, a radionuclide chelating group, etc.

[0191] According to an embodiment of the present invention, Z is selected from nuclide chelating groups.

[0192] According to an embodiment of the present invention, Z is selected from a group formed by a bifunctional chelating agent; preferably, the bifunctional chelating agent is selected from DOTA, NOTA, NODA, NODAGA, DOTP, TETA, ATSM, PTSM, EDTA, EC, HBEDCC, DTPA, SBAD, BAPEN, Df, DFO, TACN, NO2A / NOTAM, CB-DO2A, Cyclen, NOTA-AA, DO3A, DO3AP, HYNIC, MAS3, MAG3, DOTAGA, NOTAGA or isonitrile.

[0193] According to an embodiment of the present invention, Z is preferably selected from

[0194]

Covalent group Q

[0195] The covalent group Q has the function of covalently binding to fibroblast activation protein α.

[0196] In some embodiments, Q is selected from the following groups:

[0197] Furthermore, in the compound represented by formula (A), Q is selected from the structure represented by the following formula (Q-1-1), (Q-2-1), (Q-3), (Q-4) or (Q-5):

[0198] The inventors have discovered that when Q is selected from the para-position structure of formula (Q-1-1) or (Q-2-1), it has a better covalent binding effect than the ortho-position and meta-position structures.

[0199] In other embodiments, Q is selected from a group as shown in any one of formula (Q-6) to formula (Q-16), wherein Het is a 3-20-membered heterocyclylene or a 5-20-membered heteroarylene group optionally substituted by one, two or more R3; preferably, Het is a 3-12-membered (e.g., 4-12-membered, 3-10-membered) heterocyclylene or a 5-12-membered (e.g., 5-10-membered) heteroarylene group optionally substituted by one, two or more R3.

[0200] According to an embodiment of the present invention, A a、 L a and L b is a divalent linking group, which can be independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-(phosphate group), -N(R0)-, -CO-, C optionally substituted with one or more R0 1-20 alkylene, a 3-20 membered heterocyclic group optionally substituted by one or more R0, or any combination thereof; further preferably, independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, a C1-10 alkylene group (C 1-6 Alkylene, C 1-4 alkylene), a 3-20 membered heterocyclyl (a 3-10 membered heterocyclyl, a 3-6 membered heterocyclyl) optionally substituted with one or more R0, or any combination thereof;

[0201] wherein each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, identical or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6Alkoxy; further preferably, the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0202] According to an embodiment of the present invention, R d 、R e Each is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, R d 、R e Each is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, R d 、R e Each is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0203] Preferably, when m is not 0, each R d independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy.

[0204] In some embodiments, A a is oxygen; in other embodiments, A a is the key.

[0205] In some embodiments, L a 、L b Independently selected from the following structures (L-2): x is selected from 0, 1, 2, s is 0 or 1, y is selected from 0, 1, 2, 3, 4, t is 0 or 1; G1 or G2 is independently -CH2- or carbonyl, and not simultaneously -CH2-; R0 is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10Alkyl, halogenated C 1-10 alkoxy; Indicates the attachment site of a group.

[0206] In some embodiments, L a 、L b Independently selected from the following groups represented by formula (L-3) or formula (L-4):

[0207] x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, R0 is H or C 1-3 alkyl.

[0208] As an example, Q is selected from the group represented by the following formula (L-5) or formula (L-6):

[0209] x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, R0 is H or C 1-3 alkyl.

[0210] In some embodiments, L a 、L b Independently selected from:

[0211] wherein x is selected from 0, 1, 2, s is 0 or 1, and y is selected from 0, 1, 2, 3, 4;

[0212] G1 is -CH2- or carbonyl;

[0213] R0 are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 alkoxy; Indicates the attachment site of a group.

[0214] As some specific embodiments, Q can be selected from any one of the structures in the following table:

[0215]

Linking group

[0216] The compound represented by formula (A) includes the following linking groups:

[0217] wherein a, b, c can be independently selected from integers of 0-6, L2, L3, L4 are the same or different and are independently selected from divalent linking groups; preferably, they are independently selected from bonds, -O-, -S-, -N(R0)-, -CO-, C optionally substituted with one or more R0,1-20 alkylene, a 3-20 membered heterocyclic group optionally substituted by one or more R0, or any combination thereof; further preferably, independently selected from a bond, -O-, -S-, -N(R0)-, -CO-, a C 1-10 Alkylene (C 1-6 Alkylene, C 1-4 alkylene), a 3-20 membered heterocyclyl (a 3-10 membered heterocyclyl, a 3-6 membered heterocyclyl) optionally substituted with one or more R0, or any combination thereof;

[0218] L1 is selected from a trivalent linking group; preferably, L1 is selected from N, C optionally substituted with one or more R0 1-20 Alkylene or any combination thereof, preferably, L1 is selected from N, C optionally substituted by one or more R0 1-10 Alkylene (C 1-6 Alkylene, C 1-4 Alkylene) or any combination thereof;

[0219] wherein each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, identical or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0220] In some embodiments, L2, L3, and L4 each include the following structure shown in (L-1):

[0221] Wherein, q is an integer in the range of 1-20, and u is an integer in the range of 0-10;

[0222] G3 is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl;

[0223] L6 is a bond or -CO-C 1-3 Alkylene-NH-.

[0224] In some embodiments, in formula (L-1), G3 is selected from at least one of the following groups:

[0225] In some embodiments, q is an integer in the range of 1-5, and u is 0.

[0226] In some embodiments, L2, L3, and L4 each include -N(R0)- or the structure shown below (L-1):

[0227] Wherein, q is an integer in the range of 1-20, and u is an integer in the range of 0-10;

[0228] G3 is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl;

[0229] L6 is a bond or -CO-C 1-3 Alkylene-NH-.

[0230] In some embodiments, L2, L3, and L4 can be independently selected from the following linking structures:

[0231] Compound A

[0232] The compound represented by formula (A), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs,

[0233] Where Z is the payload, T is the target,

[0234] Q is selected from the following structures represented by formula (Q-1), (Q-2), (Q-3), (Q-4), or (Q-5), or any one of (Q-6) to (Q-21):

[0235] L1, L2, L3, L4, A a 、L a 、L b identical or different, independently selected from bonds or linking groups,

[0236] a, b, c, m, p0 are the same or different and are independently selected from integers of 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0237] R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0238] Het is an optionally substituted saturated heterocyclylene or heteroarylene,

[0239] R s is selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0240] Every R t are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, optionally substituted thiol, optionally substituted amino, optionally substituted seleno, optionally substituted C 1-20 Alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroaryl;

[0241] Indicates the attachment site of a group.

[0242] In the compound represented by formula (A), Q is selected from the structure represented by the following formula (Q-1-1), (Q-2-1), (Q-3), (Q-4) or (Q-5):

[0243] According to an embodiment of the present invention, the compound represented by formula (A) has a structure represented by the following formula (A-1):

[0244] in,

[0245] U is selected from -U1-, -U2-U3(R a )-U4-;

[0246] X is selected from -X1-, -X2-X3(R b )-X4-;

[0247] When U is selected from -U1-, X is not -X1-;

[0248] U1, U2, U3, U4, X1, X2, X3, X4 are the same or different and are independently selected from a linking group;

[0249] Ra 、R b The same or different, independently selected from the structure represented by formula (Q-1), (Q-2), (Q-3), (Q-4) or (Q-5).

[0250] In some embodiments, in the compound represented by formula (A-1), U is selected from -U2-U3(R a )-U4-, X is selected from -X1-; or in the compound represented by formula (A-1), U is selected from -U1-, X is selected from -X2-X3 (R b )-X4-.

[0251] In some embodiments, the compound represented by formula (A) is selected from the compound represented by the following formula (A-2):

[0252] Among them, R a A structure selected from formula (Q-1), (Q-2), (Q-3), (Q-4) or (Q-5);

[0253] Z, T, U2, U3, U4, X1, A a 、L a 、L b 、R d 、R e , m has the above definition.

[0254] In some embodiments, the compound represented by formula (A) is selected from the compound represented by the following formula (A-3):

[0255] Among them, R b A structure selected from formula (Q-1), (Q-2), (Q-3), (Q-4) or (Q-5);

[0256] Z, T, U1, X2, X3, X4, A a 、L a 、L b 、R d 、R e , m has the above definition.

[0257] According to an embodiment of the present invention, U3 and X3 are the same or different and are independently selected from a trivalent linking group; preferably, they are independently selected from N, C optionally substituted with one or more R0 1-20 Alkylene (C 1-10 Alkylene, C 1-6 Alkylene, C 1-4 alkylene) or any combination thereof.

[0258] According to the embodiment of the present invention, U1, U2, U4, X1, X2, X4, L a 、L b 、A a The same or different, independently selected from a divalent linking group; preferably, independently selected from a bond, -O-, -S-, -NR0-, -CO-, C optionally substituted with one or more R0 1-20 Alkylene (C 1-10 Alkylene, C 1-6 Alkylene, C 1-4 alkylene) or any combination thereof.

[0259] According to an embodiment of the present invention, R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, independently of one another, selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0260] According to an embodiment of the present invention, R0 are the same or different and are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy; preferably, identical or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; further preferably, the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0261] According to an embodiment of the present invention, U1 is selected from a bond. According to an embodiment of the present invention, A a According to an embodiment of the present invention, X4 is selected from a bond. According to an embodiment of the present invention, X3 is selected from N. According to an embodiment of the present invention, X2 is selected from C 1-10 Alkylene (preferably C 1-6 Alkylene, C 1-4 According to an embodiment of the present invention, L a Selected from -CO-, -CO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-NH-CO-, -CO-C 1-3 Alkylene-NH-CO-C 1-3 Alkylene-, -C 1-3 Alkylene-, C 1-3 Alkylene-NH-CO-C 1-3 Alkylene, -CO-C 1-4 Alkylene-N(CH3)-CO-, -CO-C 1-6 Alkylene-CO-NH-C 1-3 Alkylene-; According to an embodiment of the present invention, L a Selected from -CO-C 1-6 Alkylene-N(R0)-CO-; preferably selected from -CO-C 1-4 Alkylene-N(R0)-CO-, such as -CO-methylene-N(R0)-CO-; preferably, R0 is selected from C 1-4 Alkyl groups, such as methyl.

[0262] According to an embodiment of the present invention, in the compound represented by formula (A), Q is selected from the structure represented by formula (Q-1), formula (Q-3) or formula (Q-4).

[0263] According to an embodiment of the present invention, the compound represented by formula (A) is selected from any one of the following compounds:

[0264] In some embodiments, the compound represented by formula (A) is a compound represented by the following formula (B):

[0265] The compound represented by formula (B), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, is characterized in that:

[0266] Among them, Z1 is the payload, T1 is the target,

[0267] U5, X5, X6, and X7 are the same or different and are independently selected from a linking group;

[0268] R f Selected from the structure represented by the following formula (Q-2-2) or formula (Q-5-1):

[0269] L c 、L d 、A b are the same or different, independently selected from linking groups,

[0270] n are the same or different and are independently selected from integers of 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0271] R g 、R h the same or different, independently selected from hydrogen, halogen, -OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0272] Indicates the attachment site of a group.

[0273] Preferably, R f Selected from the structure shown in the following formula (Q-2-3):

[0274] According to the embodiment of the present invention, Z1, T1, U5, X5, X6, X7, L c 、L d 、A b 、R g 、R h Respectively have the aforementioned Z, T, U1, X2, X3, X4, L a 、L b 、A a 、R d 、R e The definition stated.

[0275] According to an embodiment of the present invention, U5 is selected from a bond or -C 0-4 Alkyl CO-.

[0276] According to an embodiment of the present invention, A a Selected from a bond, -O-.

[0277] According to an embodiment of the present invention, X7 is selected from a bond.

[0278] According to an embodiment of the present invention, X6 is selected from N.

[0279] According to an embodiment of the present invention, X5 is selected from C 1-10 Alkylene (preferably C 1-6 Alkylene, C 1-4 alkylene, C3 alkylene).

[0280] According to an embodiment of the present invention, L c 、L d The same or different, independently selected from -CO-, -C 1-6 Alkylene-, -CO-C 1-6 Alkylene-, -C 1-6 Alkylene-CO-N(R0)-, -C 1-6 Alkylene-N(R0)-CO-, -CO-C 1-6 Alkylene-N(R0)-CO-C 1-6 Alkylene-, -CO-C 1-6 Alkylene-CO-N(R0)-C 1-6 Alkylene-, -C 1-6 Alkylene-CO-N(R0)-C 1-6 Alkylene-, -C 1-6 Alkylene-N(R0)-CO-C 1-6 Alkylene-, -C 1-6 Alkylene-N(R0)-CO-C 1-6 Alkylene-COO-C 1-6 Alkylene-, -C 1-6 Alkylene-CO-N(R0)-C 1-6 Alkylene-COO-C 1-6 Alkylene-, -CO-C 1-6 Alkylene-N(R0)-CO-C 1-6 Alkylene-COO-C 1-6 Alkylene-, -CO-C 1-6 Alkylene-CO-N(R0)-C 1-6 Alkylene-COO-C 1-6 Alkylene-, etc.; preferably, independently selected from -C 1-3 Alkylene-, -CO-C 1-3 Alkylene-, -C 1-3 Alkylene-CO-N(R0)-, -C 1-3 Alkylene-N(R0)-CO-, -CO-C 1-3 Alkylene-N(R0)-CO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-CO-N(R0)-C 1-3 Alkylene-, -C 1-3 Alkylene-CO-N(R0)-C 1-3Alkylene-, -C 1-3 Alkylene-N(R0)-CO-C 1-3 Alkylene-, -C 1-3 Alkylene-N(R0)-CO-C 1-3 Alkylene-COO-C 1-3 Alkylene-, -C 1-3 Alkylene-CO-N(R0)-C 1-3 Alkylene-COO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-N(R0)-CO-C 1-3 Alkylene-COO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-CO-N(R0)-C 1-3 Alkylene-COO-C 1-3 Alkylene- etc.

[0281] According to an embodiment of the present invention, R0 is selected from C 1-4 Alkyl groups, such as methyl.

[0282] According to an embodiment of the present invention, L c Selected from -CO-, -CO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-NH-CO-, -CO-C 1-3 Alkylene-NH-CO-C 1-3 Alkylene-, C 1-3 Alkylene-NH-CO-C 1-3 Alkylene, -CO-C 1-6 Alkylene-CO-NH-C 1-3 Alkylene-, -CO-C 1-6 Alkylene-N(R0)-CO-, -CO-C 1-4 Alkylene-N(CH 3) -CO-.

[0283] According to an embodiment of the present invention, R g Selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy.

[0284] According to an embodiment of the present invention, L d Selected from -CO-, -CO-C 1-4 Alkylene-, -CO-C 1-4 Alkylene-N(CH3)-CO-, -CO-C 1-4 Alkylene-NH-CO-.

[0285] According to an embodiment of the present invention, R h Selected from hydrogen, C1-6 Alkyl, C 1-6 Alkoxy.

[0286] According to an embodiment of the present invention, A b is selected from a bond or oxygen. According to an embodiment of the present invention, R g is selected from H or methoxy.

[0287] In some embodiments, the compound represented by formula (A) has the structure represented by formula (A-4):

[0288] Where Z is the payload,

[0289] Q is selected from the following structures represented by formula (Q-1), (Q-2), (Q-3), (Q-4) or (Q-5):

[0290] L2, A a 、L a 、L b are the same or different and are independently selected from linking groups;

[0291] a and m are the same or different and are independently selected from integers from 0 to 6;

[0292] R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0293] Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine;

[0294] Rf3 is selected from hydrogen or cyano;

[0295] Indicates the attachment site of a group.

[0296] According to an embodiment of the present invention, in formula (A-4), L2, A a 、L a 、L b has the same meaning as in the linking group and covalent group as described above.

[0297] According to an embodiment of the present invention, in formula (A-4), L2 includes the structure shown in the following (L-1):

[0298] Wherein, q is an integer in the range of 1-20, and p is an integer in the range of 0-10;

[0299] G3 is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 Aryl; preferably C 3-6 Cycloalkyl, 3-6 membered heterocycloalkane

[0300] yl, 5-10 membered heteroaryl, C 6-10 Aryl;

[0301] L6 is a bond or -CO-C 1-3 Alkylene-NH-;

[0302] and / or, L a 、L b Independently selected from:

[0303] x is selected from 0, 1, 2, s is 0 or 1, y is selected from 0, 1, 2, 3, 4, t is 0 or 1;

[0304] G1 or G2 are independently -CH2- or carbonyl, and are not both -CH2-;

[0305] R0 are independently selected from hydrogen, halogen, OH, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 alkoxy;

[0306] Indicates the attachment site of a group.

[0307] According to an embodiment of the present invention, in formula (L-1), G3 is selected from at least one of the following groups:

[0308] q is an integer in the range of 1-5, and u is 0.

[0309] In some embodiments, L a 、L b Independently selected from the following groups represented by formula (L-3) or formula (L-4):

[0310] x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, R0 is H or C 1-3 alkyl.

[0311] In some embodiments, in formula (A-4), Q is selected from the group represented by formula (L-5) or formula (L-6):

[0312] x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, R0 is H or C 1-3 alkyl.

[0313] In the present invention, the inventors unexpectedly discovered that the compound represented by formula (A-4) has better tumor targeting performance than when Q is connected closer to the Z side.

[0314] In some embodiments, Q is Formula (L-5) having better tumor targeting performance and tumor retention ability.

[0315] According to an embodiment of the present invention, the present invention provides the following compounds:

[0316] In some embodiments, the compound of formula (A) has the structure shown in formula (D):

[0317] Among them, Z2 is the payload, T2 is the target,

[0318] U6, U7, U8, and X8 are the same or different and are independently selected from a linking group;

[0319] R i Selected from the structure shown in the following formula (Q-2-4) or formula (Q-5-2):

[0320] L e 、A c 、L f are the same or different, independently selected from linking groups,

[0321] p is an integer selected from 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6),

[0322] R j 、R k Selected from hydrogen, halogen, -OH, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0323] Indicates the attachment site of a group.

[0324] Preferably, R i Selected from the structure shown in the following formula (Q-2-5):

[0325] According to the embodiment of the present invention, Z2, T2, U6, U7, U8, X8, L e 、L f 、A c 、R j 、R k Respectively have the aforementioned Z, T, U2, U3, U4, X1, L a 、L b 、A a 、R d 、R e The definition stated.

[0326] According to an embodiment of the present invention, U6 is selected from -NH-, -CONH- or -C 0-4 AlkylCONH-.

[0327] According to an embodiment of the present invention, U7 is selected from C 1-4 The alkyl group is a straight-chain or branched alkylene group, preferably a methine group.

[0328] According to an embodiment of the present invention, U8 is selected from -CO-.

[0329] According to an embodiment of the present invention, X8 is selected from #-OC 1-10 Alkylene-*, preferably #-OC 1-6 Alkylene-*, #-OC 1-4 Alkylene-*, #-OC 1-3 Alkylene-*, wherein # is the site of connection to the quinoline ring and * is the site of connection to the piperazine ring.

[0330] According to an embodiment of the present invention, L e Selected from -C 1-3 Alkylene-, -CO-, -O- or -NH- or a combination thereof, such as: -C 1-3 Alkylene-, -C 1-3 Alkylene-NH-CO-C 1-3 Alkylene-, -CO-, -CO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-NH-CO-, -CO-C 1-3 Alkylene-NH-CO-C 1-3 Alkylene-. According to an embodiment of the present invention, R g Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

[0331] According to an embodiment of the present invention, L f Selected from -C 1-4 Alkylene-, -CO-, -O- or -NH- or a combination thereof, such as: -C 1-4Alkylene-, -C 1-4 Alkylene-CO-NH-C 1-4 Alkylene-, or -C 1-4 Alkylene-CO-NH-C 1-4 Alkylene-CO-OC 1-4 Alkylene-.

[0332] According to an embodiment of the present invention, L e 1, 2 or 3 carbon atoms in length.

[0333] In some specific examples, the structure of formula (D) is selected from the following compounds:

[0334] The present invention also provides a compound represented by formula (A-5), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs,

[0335] Wherein, Z is a payload, T is a target, and Q is selected from the structures shown in the following formula (Q-1), (Q-2), (Q-3), (Q-4) or (Q-5):

[0336] L1, L2, L3, L4, A a 、L a 、L b identical or different, independently selected from bonds or linking groups,

[0337] a, b, c, and m are the same or different and are independently selected from integers of 0 to 6 (e.g., 0, 1, 2, 3, 4, 5, 6).

[0338] R d 、R e the same or different, independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 Alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkyl;

[0339] represents the attachment site of the group;

[0340] Among them, L a 、L b Independently selected from the structure shown in formula (L-2):

[0341] x is selected from 0, 1 and 2, s is 0 or 1, y is selected from 0, 1, 2, 3 and 4, and t is 0 or 1;

[0342] G1 or G2 are independently -CH2- or carbonyl, and are not both -CH2-;

[0343] R0 are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, Indicates the attachment site of a group.

[0344] It is understood that each group in formula (A-5) has the same definition as in formula (A).

[0345] According to an embodiment of the present invention, L1 is selected from a trivalent linking group; preferably, L1 is selected from N, C optionally substituted with one or more R0 1-20 Alkylene or any combination thereof; further preferably, L1 is selected from N, C optionally substituted by one or more R0 1-10 Alkylene (C 1-6 Alkylene, C 1-4 Alkylene) or any combination thereof;

[0346] and / or, A a is selected from a divalent linking group; preferably, selected from a bond, -O-, -S-, -NR0-, -CO-, a C1-20 alkylene group optionally substituted with one or more R0 (C1-10 alkylene group, C1-6 alkylene group, C1-4 alkylene group) or any combination thereof; preferably, Aa is selected from a bond;

[0347] and / or, L2, L3, L4, A a The same or different, independently selected from a divalent linking group; preferably, independently selected from a bond, -O-, -S-, -NR0-, -CO-, C optionally substituted with one or more R0 1-20 Alkylene, 3-20 membered heterocyclic group optionally substituted by one or more R0 or any combination thereof; further preferably, independently selected from bond, -O-, -S-, -NR0-, -CO-, C optionally substituted by one or more R0 1-10 Alkylene (C 1-6 Alkylene, C 1-4 alkylene), a 3-20 membered heterocyclyl (a 3-10 membered heterocyclyl, a 3-6 membered heterocyclyl) optionally substituted with one or more R0, or any combination thereof;

[0348] Preferably, the heterocyclic group contains at least one N; preferably, the heterocyclic group is piperazinyl;

[0349] Preferably, at least one of L2 and L4 comprises a 3-20 membered heterocyclic group; preferably, at least one of L2 and L4 comprises a heterocyclic group having one or two hydrogen atoms; preferably, comprises a piperazinyl group.

[0350] According to an embodiment of the present invention, the compound has a structural formula as shown in Formula (A-4).

[0351] According to an embodiment of the present invention, the compound has a structural formula as shown in formula (A-6):

[0352] Z is the payload, Q and L2 have the above definitions,

[0353] a is an integer from 0 to 6;

[0354] Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine;

[0355] Rf3 is selected from hydrogen or cyano;

[0356] L 4a is selected from a bond, -O-, -S-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-20 alkylene, a 3-20 membered heterocyclyl optionally substituted with one or more R0, or any combination thereof.

[0357] In some embodiments, L a 、L b Independently selected from:

[0358] wherein x is selected from 0, 1, 2, s is 0 or 1, and y is selected from 0, 1, 2, 3, 4;

[0359] G1 is -CH2- or a carbonyl group.

[0360] In some embodiments, L a 、L b Independently selected from -CH2- or a group as shown below:

[0361] Wherein x is selected from 0, 1, 2, and y is selected from 0, 1, 2, 3, and 4.

[0362] In some embodiments, L 4a Including the structure shown below (L-9):

[0363] Wherein, w is an integer in the range of 1-20, and v is an integer in the range of 0-10;

[0364] G4 has the definition as described in G3 above;

[0365] L7 is carbonyl or C 1-10 Alkylene.

[0366] In some embodiments, L2 comprises -N(R0)- or the structure shown below (L-1):

[0367] Wherein, q is an integer in the range of 1-20, and u is an integer in the range of 0-10;

[0368] G3 has the above definition, L6 is a bond or -CO-C 1-3 Alkylene-NH-.

[0369] The present invention also provides a radionuclide probe targeting FAP, wherein the radionuclide probe is a compound represented by the above-mentioned formula (A), formula (B), formula (D), formula (A-1), formula (A-2), formula (A-3), formula (A-4), formula (A-5) or formula (A-6) or a derivative thereof, which is labeled with a radionuclide.

[0370] According to an embodiment of the present invention, the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide. According to an embodiment of the present invention, the diagnostic radionuclide is 68 Ga, 67 Ga, 64 Cu, 18 F. 86 Y. 89 Zr, 111 In, 99m Tc, 11 C. 203 Pb, 123 I. 125 I and 124 According to an embodiment of the present invention, the therapeutic radionuclide is 177 Lu, 90 Y. 125 I. 131 I. 211 At 153 Sm, 186 Re、 188 Re、 67 Cu, 225 Ac, 227 Th, 223 Ra, 213 Bi, 212 Bihe 212 At least one of Pb.

[0371] According to an embodiment of the present invention, when the radioactive isotope is a non-metallic ion, it can be chelated by forming a complex with a metal ion such as aluminum, for example, Al 18 F.

[0372] The present invention further provides a method for preparing the above-mentioned FAP-targeting radionuclide probe, comprising:

[0373] 1) providing a compound represented by the above formula (A), formula (B) or formula (D);

[0374] 2) Chelating with the above radioactive nuclides in solution or on a column.

[0375] The present invention further provides a kit for preparing the above-mentioned FAP-targeting nuclide probe, comprising:

[0376] 1) a compound represented by the above formula (A), formula (B) or formula (D);

[0377] 2) The aforementioned radionuclides or reagents that provide the aforementioned radionuclides.

[0378] The present invention also provides use of the compound represented by the above formula (A), formula (B) or formula (D) in the preparation of FAP inhibitors.

[0379] The present invention also provides a pharmaceutical composition comprising a compound represented by the above formula (A), formula (B) or formula (D) and at least one pharmaceutically acceptable excipient or carrier.

[0380] The present invention also provides use of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition in the preparation of imaging agents and / or therapeutic agents targeting FAP.

[0381] The present invention also provides use of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition in the preparation of a drug for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein FAP.

[0382] The present invention also provides a method for diagnosing and / or treating a disease, comprising administering a diagnostically and / or therapeutically effective amount of the above-mentioned compound, radionuclide probe, FAP inhibitor or pharmaceutical composition to a subject for diagnosis and / or treatment, wherein the disease is a disease characterized by overexpression of fibroblast activation protein FAP.

[0383] The present invention also provides a kit comprising the above-mentioned compound, a radionuclide probe, a FAP inhibitor or a pharmaceutical composition, and instructions for diagnosing and / or treating a disease.

[0384] According to an embodiment of the present invention, the disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis (such as pulmonary fibrosis), tissue remodeling, scar disease, rheumatoid arthritis, osteoarthritis, cirrhosis, liver disease.

[0385] According to an embodiment of the present invention, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, bile duct cell carcinoma, clear cell renal carcinoma, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, glioma, glioma, astrocytoma, cervical cancer and prostate cancer.

[0386] The present invention also provides a use of a compound represented by formula (A-0) in preparing a compound represented by formula (A) wherein Q is represented by formula (Q-1), formula (Q-3) or formula (Q-4).

[0387] Wherein, Q0 is selected from the structure shown in the following formula (Q-2) or (Q-5):

[0388] In formula (A-0), Z, T, L1, L2, L3, L4, L b 、A a 、L a , a, b, c, m, R d 、R e They have the same definitions as those in formula (A).

[0389] The present invention further provides some new compounds, including the structure shown in formula (M-1):

[0390] wherein R1 is selected from a bond or O;

[0391] R2 is selected from hydrogen, C1-10 alkyl or C1-10 alkoxy;

[0392] Lx includes the structure shown in formula (LX):

[0393] wherein h is selected from 0, 1, 2, j is 0 or 1, g is selected from 0, 1, 2, 3, 4, and k is 0, 1 or 2;

[0394] G6 or G7 are independently -CH2- or carbonyl, and are not both -CH2-;

[0395] R4 is H, -NH2 or an amino group protected by a protecting group.

[0396] According to an embodiment of the present invention, the compound of (M-1) is selected from the compound represented by formula (M-2) or formula (M-3):

[0397] Wherein, R2 is hydrogen or methoxy,

[0398] R1 is a bond or O,

[0399] n1 is an integer from 0 to 2 (e.g., 0, 1, 2),

[0400] m1 is an integer from 1 to 3 (e.g., 1, 2, 3),

[0401] m2 is an integer of 1-3 (eg, 1, 2, 3).

[0402] According to an embodiment of the present invention, the compound represented by formula (M-1) is selected from any one of the compounds shown below:

[0403] The present invention also provides use of the compound represented by the above formula (M-1) in the preparation of radioactive drugs.

[0404] In the embodiments of the present invention, the radiopharmaceutical is a radionuclide-conjugated drug, such as a radionuclide-conjugated small molecule compound, a radionuclide-conjugated polypeptide, a radionuclide-conjugated antibody, or a radionuclide-conjugated nucleic acid aptamer. The compound represented by formula (M-1) reacts with a compound having a targeting group to generate a covalently warhead-substituted conjugated compound.

[0405] In an embodiment of the present invention, the compound represented by formula (M-1) is used to prepare the compound provided in the first aspect, the second aspect, etc. of this application.

[0406] In an embodiment of the present invention, the radiopharmaceutical comprises the compound as described above, and is a drug with diagnostic and / or therapeutic effects formed by labeling compound A with a radionuclide.

[0407] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0408] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention. DETAILED DESCRIPTION

[0409] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0410] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0411] 1. Instruments and Materials

[0412] 1. Experimental Materials

[0413] 1.1 Compound synthesis and characterization materials

[0414] 1.2 Enzyme inhibition test materials

[0415] (1) Fibroblast activation protein (FAP, source: MCE, HY-P72659)

[0416] (2) Fibroblast activation protein substrate (Z-Gly-Pro-7-AMC, source: MCE, HY-D0027)

[0417] (3) Fibroblast activation buffer (i.e., FAB, 50 mM Tris, 100 mM NaCl, 1 mM EDTA, pH = 7.4)

[0418] 1.3 Small Animal Imaging Test Materials

[0419] (1) Experimental animals

[0420] Species and strain: BALB / c Nude mice

[0421] Sex / Quantity: Female, 30

[0422] Weight / age: 4-6 weeks, 15-18g

[0423] Grade: SPF

[0424] (2) Tumor cell lines

[0425] FAP-positive cell line U87MG: human brain astroglioma cells, cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin. After expansion, the cells were inoculated into the right lower limb of nude mice near the back, with an injection dose of 1×10 6 Tumor cells can be used for imaging experiments 2-3 weeks after inoculation.

[0426] FAP-positive cell line HT1080: human fibrosarcoma cell line, cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin. After expansion, the cells were inoculated into the right lower limb of nude mice near the back, with an injection dose of 1×10 6 Tumor cells can be used for imaging experiments 2-3 weeks after inoculation.

[0427] 2. Main instruments

[0428] 2.1 Compound synthesis and characterization

[0429] 2.2 Small animal imaging test

[0430] 2.3 Compound characterization methods and chromatographic conditions

[0431] HRMS characterization method: Take an appropriate amount of sample and dissolve it in 0.1% formic acid aqueous solution to prepare a sample solution with a concentration at the ppm level, inject the sample, and analyze and process the experimental data.

[0432] NMR characterization method: Weigh 3-5 mg of sample, dissolve in 500 μL of deuterated reagent (D2O, DMSO-d6 or CD3OD), detect, and analyze the experimental results.

[0433] Chromatographic conditions:

[0434] Chromatographic conditions (HPLC)

[0435] Semi-Prep HPLC

[0436] LCMS:

[0437] 2. Preparation Example

[0438] An exemplary synthetic route is shown below:

[0439] 1. Synthesis method and synthesis route of compound S1 in Preparation Example 1

[0440] The specific synthetic route of S1 is as follows:

[0441] 1.1 Preparation of compound 6-2

[0442] Step 1: Synthesis of compound 2-2

[0443] At room temperature (25°C), compound 1-2 (10.0 g, 39.8 mmol) was dissolved in dioxane (50.0 mL), followed by the addition of pyridine (9.5 g, 120.2 mmol), NH4HCO3 (6.0 g, 71.5 mmol), and Boc2O (15.6 g, 71.5 mol). The resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (250 mL), washed with 1M HCl (100 mL × 2), and then washed with saturated brine (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 2-2 (10.0 g, yield 100%) as a white solid.

[0444] Step 2: Synthesis of compound 3-2

[0445] Compound 2-2 (10.0 g, 39.9 mmol) was dissolved in HCl / ethyl acetate (100 mL, 4.0 M) at room temperature, and the resulting reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a white solid, compound 3-2 (7.5 g, 100% yield), which was used directly in the next step without further purification.

[0446] Step 3: Synthesis of compound 4-2

[0447] At room temperature, compound 3-2 (7.5 g, 49.9 mmol) and Boc-Glycine (10.5 g, 59.9 mmol) were dissolved in anhydrous DMF (10.0 mL). DIEA (N,N-diisopropylethylamine) (19.3 g, 1496 mmol) and HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (22.8 g, 59.9 mmol) were then added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (250 mL) and washed with 1M HCl (100 mL × 2) and saturated brine (100 mL × 2), respectively, and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 4-2 (8.6 g, yield 70.4%) as a white solid.

[0448] Step 4: Synthesis of compound 5-2

[0449] At 0°C, compound 4-2 (4.8 g, 15.6 mmol) was dissolved in anhydrous DMF (20 mL), and then tricyanuric chloride TCT (2.0 g, 10.8 mmol) was added. The resulting reaction solution was stirred at 0-10°C for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (150 mL), washed with saturated NaHCO3 aqueous solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain a white solid product, compound 5-2 (4.2 g, yield 93.1%).

[0450] Step 5: Synthesis of compound 6-2

[0451] Compound 5-2 (1.0 g, 3.4 mmol) was dissolved in anhydrous dichloromethane (DCM) (5.0 mL) at room temperature, and trifluoroacetic acid (TFA) (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and concentrated under reduced pressure to obtain compound 6-2 (653.9 mg, 100% yield) as a colorless oil, which was used directly in the next step without further purification.

[0452] 1.2 Preparation of compound S1

[0453] Step 6: Synthesis of Compound 2

[0454] At room temperature, compound 1 (5.0 g, 19.8 mmol) and compound 1-1 (19.8 g, 98.8 mmol) were dissolved in anhydrous tetrahydrofuran (100 mL) and reacted at 55°C for 3 hours. After the reaction was complete, ethyl acetate (150 mL) was added for dilution, and the mixture was washed with water (50 ml x 2) and saturated brine (50 ml x 1), respectively, then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 2 (4.8 g, yield 78.5%) as a white solid. LCMS: [M+HC(CH3)3] + =254.2 / 256.2.

[0455] Step 7: Synthesis of Compound 3

[0456] At room temperature, compound 2 (3.7 g, 12.0 mmol), compound SM2 (3.14 g, 41.8 mmol), cesium carbonate (22.0 g, 67.5 mmol), and BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine)) (1.5 g, 3.1 mmol) were dissolved in anhydrous toluene (100 ml). The mixture was purged with a nitrogen balloon three times, and then Pd2(dba)3 (883.0 mg, 2.4 mmol) was added. The mixture was purged with a nitrogen balloon three times, and the reaction was continued at 90°C overnight for 12 hours. After the reaction was complete, ethyl acetate (100 ml) was added for dilution, and the mixture was washed with water (30 ml × 2) and saturated brine (50 ml × 1), respectively, then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to give a brown-red solid compound 3 (2.1 g, yield 57.8%). LCMS: [M+HC(CH3)3] + =247.1.

[0457] Step 8: Synthesis of Compound 4

[0458] At room temperature, compound 3 (1.5 g, 4.9 mmol) and DIEA (3.2 g, 24.8 mmol) were dissolved in anhydrous dichloromethane (20.0 ml), and MsCl (910.0 mg, 7.9 mmol) was added dropwise. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the solvent was dried, and then DMF (20.0 ml) and N-tert-butyloxycarbonylpiperazine (3.3 g, 17.7 mmol) were added to the reaction flask. After stirring and heating to 50°C, KI (12.0 g, 72.2 mmol) was added, and then the temperature was raised to 60°C and the reaction was allowed to react for 2 hours. After the reaction was complete, ethyl acetate (100 ml) was added to dilute the mixture, washed with brine (30 ml × 2), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain compound 4 (1.9 g, 81.5% yield) as a yellow solid. LCMS: [M+H] + =471.3.

[0459] Step 9: Synthesis of Compound 5

[0460] At room temperature, compound 4 (2.0 g, 4.0 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), and trifluoroacetic acid (8.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25.0 mL) and the solvent was dried to obtain compound 5 (1.3 g, 100% yield) as a brown oil. This was used directly in the next step without further purification. LCMS: [M+H] + =315.3.

[0461] Step 10: Synthesis of Compound 6

[0462] At room temperature, compound 5 (1.3 g, 4.1 mmol) was dissolved in dioxane / water (1:1, v / v, 20 ml), and sodium bicarbonate (1.04 g, 12.3 mmol) and Boc2O (1.8 g, 8.2 mmol) were added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, a yellow solid precipitated from the reaction solution. The solid was filtered to obtain a yellow solid. The solid was washed with water, and the aqueous phase was passed through a high-performance liquid chromatography column (0.1% aqueous acetic acid, acetonitrile). After lyophilization, a yellow solid compound 6 (1.5 g, 87.8% yield) was obtained. LCMS: [M+H] + =415.3.

[0463] Step 11: Synthesis of Compound 7

[0464] At room temperature, compound 6 (880.0 mg, 2.1 mmol), compound 6-2 (582.1 mg, 3.0 mmol), and DIEA (1.37 g, 10.6 mmol) were dissolved in anhydrous DMF (10.0 ml) solution, and then HBTU (O-benzotriazole-tetramethyluronium hexafluorophosphate) (1.0 g, 2.6 mmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 ml), washed with saturated brine (50 ml × 2 times), and the organic phase was dried. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain yellow solid compound 7 (700.0 mg, yield 56.4%). LCMS: [M+H] + =587.6.

[0465] Step 12: Synthesis of Compound 8

[0466] At room temperature, compound 7 (150.0 mg, 0.19 mmol) and compound 7-2 (59.4 mg, 0.29 mmol) were dissolved in anhydrous dichloromethane (10 mL), pyridine (767.6 mg, 9.7 mmol) and POCl3 (148.6, 0.97 mmol) were added, and the resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 ml), washed with water (15 ml × 2) and saturated brine (15 ml × 2), respectively, and the organic phase was dried. The resulting residue was purified by semi-preparative high performance liquid chromatography and lyophilized to obtain yellow solid powder compound 8 (80.0 mg, yield 40.5%). LCMS: [M+H] + =773.2.

[0467] Step 13: Synthesis of Compound 9

[0468] At room temperature, compound 8 (60.0 mg, 3.2 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 ml) and the solvent was dried to obtain compound 9 (52.2 mg, 100% yield) as a brown-red oil. The product was directly used in the next step without further purification. LCMS: [M+H] + =673.2.

[0469] Step 14: Synthesis of Compound S1

[0470] At room temperature, compound 9 (80.0 mg, 119.0 μmol) and DOTA-NHS (CAS No. 170908) (120.0 mg, 239.5 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (46.0 mg, 356.5 μmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was dried and separated and purified by semi-preparative high performance liquid chromatography (0.1% aqueous acetic acid, acetonitrile) to obtain compound S1 as a white solid (29.1 mg, purity 96.3%, yield 26.5%). LCMS: [M+H] + =1059.2.

[0471] Compound S1 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ8.92(d,J=4.3Hz,1H),8.22–8.03(m,1H),7.94(s,1H),7.87(t,J=9.5Hz,3H),7.69–7.60(m,3H),7.58–7.40(m,3H),5.28– 5.19(m,1H),4.38–4.10(m,6H),3.89–3.68(m,6H),3.62–3.46(m,6H),3.45–3.28(m,10H),3.22–2.93(m,12H),2.24–1.99(m,3H).

[0472] Meanwhile, compound S25 can be further prepared from compound S1 by referring to step 5 of the synthesis of compound S2:

[0473] 2. Synthesis method and synthesis route of compound S3 in Preparation Example 2

[0474] Specific synthetic route of compound S3:

[0475] Step 1: Synthesis of compound 7-C3

[0476] At room temperature, compound 7-2 (250 mg, 122.4 μmol) and tert-butyl 3-aminopropionate (213.4 mg, 146.9 μmol) were dissolved in anhydrous DMF (10.0 mL), followed by the addition of DIEA (474.0 mg, 367.4 μmol) and HATU (558.5 mg, 146.9 μmol). The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 ml), washed with saturated brine (50 ml × 2 times), and the organic phase was dried. The resulting residue was then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-C3 (355.2 mg, yield 87.5%) as a white solid.

[0477] Step 2: Synthesis of compound 7-3

[0478] At room temperature, compound 7-C3 (355.2 mg, 107.2 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL), the solvent was dried, and the residue was dissolved and diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL × 2), and the organic phase was dried and rotary evaporated with petroleum ether 2-3 times to obtain a white solid powder compound 7-3 (140.2 mg, yield 48.3%). It was directly put into the next step without further purification.

[0479] Step 3: Synthesis of compound S3-8

[0480] At room temperature, compound 7 (200 mg, 0.3 mmol) (see Preparation Example 1, Step 11) and compound 7-3 (59.4 mg, 0.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (1.34 g, 16.9 mmol) and POCl3 (260.8 mg, 1.6 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 ml), washed with water (15 ml × 2) and saturated brine (15 ml × 2), respectively, and the organic phase was dried by spin drying. The resulting residue was purified by semi-preparative high performance liquid chromatography and lyophilized to obtain yellow solid powder compound S3-8 (75.2 mg, yield 26.1%). LCMS: [M+H] + =844.2.

[0481] Step 4: Synthesis of compound S3-9

[0482] At room temperature, compound S3-8 (75.2 mg, 89.1 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) was added, and the reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to obtain a brown-red oily compound S3-9 (66.2 mg, 100% yield). It was directly used in the next step without further purification. LCMS: [M+H] + =744.2.

[0483] Step 5: Synthesis of Compound S3

[0484] At room temperature, compound S3-9 (66.2 mg, 89.0 μmol) and DOTA-NHS (89.1 mg, 178.0 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (57.4 mg, 445.0 μmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was dried and separated and purified by semi-preparative high-performance liquid chromatography (0.1% aqueous acetic acid, acetonitrile) to obtain compound S3 as a white solid (21.8 mg, purity 94.4%, yield 17.0%). LCMS: [M+H] + =1130.31.

[0485] Compound S3 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ9.02(d,J=4.5Hz,1H),8.23(s,1H),8.20–8.09(m,2H),7.86(t,J=8.5Hz,2H),7.8 0–7.73(m,2H),7.73–7.66(m,1H),5.12–5.07(m,1H),5.02–4.95(m,1H),4.43–4.22(m,3H) ,4.20–4.06(m,2H),3.87–3.71(m,7H),3.64(s,2H),3.61–3.46(m,7H),3.41(s,7H),3.32 –3.20(m,3H),3.19–2.97(m,12H),2.94–2.81(m,2H),2.63(s,2H),2.03(d,J=16.6Hz,2H).

[0486] Meanwhile, compound S26 can be further prepared from compound S3 by referring to step 5 of the synthesis of compound S2:

[0487] (LCMS: [M+2H] 2+ / 2:564.63).

[0488] 3. Synthesis method and synthesis route of compound S4 in Preparation Example 3

[0489] Synthesis route of compound S4:

[0490] Step 1: Synthesis of compound 7-C4

[0491] At room temperature, compound 7-2 (250.0 mg, 122.4 μmol) and tert-butyl 3-aminobutyrate (234.0 mg, 146.9 μmol) were dissolved in anhydrous DMF (10.0 mL). DIEA (474.0 mg, 367.4 μmol) and HATU (558.5 mg, 146.9 μmol) were added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated brine (50 mL × 2 times). The organic phase was spin-dried and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-C4 (390.1 mg, yield 92.2%) as a white solid.

[0492] Step 2: Synthesis of compound 7-4

[0493] At room temperature, compound 7-C4 (390.1 mg, 113.5 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 ml), the solvent was dried, and the residue was dissolved and diluted with ethyl acetate (100 ml), washed with saturated brine (50 ml × 2 times), and the organic phase was dried and petroleum ether was added and dried together. This was repeated 2 times to obtain compound 7-4 (245.2 mg, yield 75.1%) as a white solid powder. It was directly put into the next step without further purification.

[0494] Step 3: Synthesis of compound S4-8

[0495] At room temperature, compound 7 (see Preparation Example 1, Step 11) (200 mg, 0.3 mmol) and compound 7-4 (148.4 mg, 0.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (1.3 g, 16.9 mmol) and POCl3 (260.8 mg, 1.6 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 ml), washed with water (15 ml × 2) and saturated brine (15 mL × 2), respectively, and the organic phase was dried. The resulting residue was purified by semi-preparative high performance liquid chromatography and lyophilized to obtain a yellow solid powder compound S4-8 (65.2 mg, yield 22.3%). LCMS: [M+H] + =859.3.

[0496] Step 4: Synthesis of compound S4-9

[0497] At room temperature, compound S4-8 (65.2 mg, 75.9 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to obtain compound S4-9 (57.5 mg, 100% yield) as a brown-red oil. It was directly used in the next step without further purification. LCMS: [M+H] + =758.7.

[0498] Step 5: Synthesis of Compound S4

[0499] At room temperature, compound S4-9 (57.5 mg, 75.8 μmol) and DOTA-NHS (76.0 mg, 151.7 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (48.9 mg, 379.0 μmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative HPLC (0.1% aqueous acetic acid, acetonitrile) to obtain compound S4 as a white solid (26.3 mg, purity 97.0%, yield 30.2%). LCMS: [M+H] + =1145.47.

[0500] Compound S4 1 The H-NMR data are as follows: 1H NMR(400MHz,Deuterium Oxide)δ8.77(dd,J=7.8,4.5Hz,1H),8.19(s,1H),8.09–7.89(m,2H),7.82–7.74(m,1H),7. 65–7.54(m,2H),7.42(d,J=8.3Hz,1H),7.24(d,J=8.0Hz,1H),5.20–5.11(m,1H),4.45–4.25 (m,3H),4.24–4.10(m,1H),3.88–3.68(m,8H),3.54(d,J=32.5Hz,7H),3.41(s,7H),3.27(d, J=7.9Hz,5H),3.20–2.88(m,13H),2.36–2.24(m,2H),2.03–1.94(m,2H),1.94–1.82(m,2H).

[0501] Meanwhile, compound S27 can be further prepared from compound S4 by referring to step 5 of the synthesis of compound S2:

[0502] 4. Synthesis Method and Synthesis Route of Compound S5 in Preparation Example 4

[0503] Synthesis route of compound S5:

[0504] Step 1: Synthesis of compound 7-5

[0505] Compound A (200.0 mg, 122.4 μmol) was dissolved in anhydrous pyridine (5.0 mL) at room temperature, followed by the addition of succinic anhydride (98.4 mg, 122.4 μmol). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford Compound 7-5 (200.0 mg, 67.0% yield) as a colorless liquid oil.

[0506] Compound 7-5 1 H-NMR data: 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.2Hz,2H),7.51(d,J=8.0Hz,2H),3.6 2(q,J=6.8Hz,3H),3.03(t,J=7.0Hz,2H),2.81–2.67(m,2H),2.58–2.43(m,2H).

[0507] Step 2: Synthesis of compound S5-8

[0508] At room temperature, compound 7 (see Preparation Example 1, Step 11) (200 mg, 0.3 mmol) and compound 7-5 (155.1 mg, 0.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (1.34 g, 16.9 mmol) and POCl3 (260.8 mg, 1.6 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 ml), washed with water (15 ml × 2) and saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The resulting residue was purified by semi-preparative high performance liquid chromatography and lyophilized to obtain a yellow solid powder compound S5-8 (65.2 mg, yield 22.3%). LCMS: [M+H] + =872.9.

[0509] Step 3: Synthesis of compound S5-9

[0510] At room temperature, compound S5-8 (65.2 mg, 75.9 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to obtain a brown-red oily compound S5-9 (57.9 mg, 100% yield). It was directly used in the next step without further purification. LCMS: [M+H] + =772.9.

[0511] Step 4: Synthesis of compound S5

[0512] At room temperature, compound S5-9 (57.9 mg, 75.1 μmol) and DOTA-NHS (75.2 mg, 150.0 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (48.9 mg, 379.0 μmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative HPLC (0.1% aqueous acetic acid, acetonitrile) to obtain compound S5 as a white solid (25.2 mg, purity 97.9%, yield 28.9%). LCMS: [M+H] + =1158.71.

[0513] Compound S5 1 The H-NMR data are as follows: 1H NMR (400MHz, Methanol-d4) δ9.02(d,J=4.4Hz,1H),8.58(s,1H),8.22(d,J=8.9Hz,1H),7.92(d,J= 8.1Hz,2H),7.86(d,J=9.0Hz,1H),7.72(d,J=4.5Hz,1H),7.54(d,J=8.1Hz,2H),5.18(dd,J=9.3,2. 8Hz,1H),4.43–4.09(m,5H),3.71–3.51(m,5H),3.48(p,J=1.6Hz,1H),3.41(t,J=7.0Hz,4H),3.35 –3.27(m,16H),3.21–3.01(m,8H),2.91(q,J=8.5,6.9Hz,6H),2.42(s,5H),2.01(d,J=20.7Hz,3H).

[0514] Meanwhile, referring to step 5 of the synthesis of compound S2, compound S28 can be further prepared from compound S5:

[0515] 5. Synthesis Method and Synthesis Route of Compound S6 in Preparation Example 5

[0516] Synthesis route of compound S6:

[0517] Step 1: Synthesis of compound 7-6

[0518] Compound A (200.0 mg, 122.4 μmol) was dissolved in anhydrous pyridine (5.0 mL) at room temperature, followed by the addition of glutaric anhydride (112.3 mg, 122.4 μmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford Compound 7-6 (220.1 mg, 70.4% yield) as a colorless liquid oil.

[0519] Step 2: Synthesis of compound S6-8

[0520] At room temperature, compound 7 (200 mg, 0.3 mmol) and compound 7-6 (108.1 mg, 0.5 mmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (1.34 g, 16.9 mmol) and POCl3 (260.8 mg, 1.6 mmol) were added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 ml), washed with water (15 ml × 2) and saturated brine (15 ml × 2), and dried over anhydrous sodium sulfate. The organic phase was dried and the resulting residue was purified by semi-preparative high performance liquid chromatography and freeze-dried to obtain a yellow solid powder compound S6-8 (66.5 mg, yield 22.3%). LCMS: [M+H] + =886.5.

[0521] Step 3: Synthesis of compound S6-9

[0522] At room temperature, compound S6-8 (66.5 mg, 75.1 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to obtain compound S6-9 (58.9 mg, 100% yield) as a brown-red oil. It was directly used in the next step without further purification. LCMS: [M+H] + =786.6.

[0523] Step 4: Synthesis of compound S6

[0524] At room temperature, compound S6-9 (58.9 mg, 75.1 μmol) and DOTA-NHS (75.2 mg, 150.0 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (48.9 mg, 379.0 μmol) was added. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative HPLC (0.1% aqueous acetic acid, acetonitrile) to obtain compound S6 as a white solid (23.4 mg, purity 95.6%, yield 26.6%). LCMS: [M+H] + =1172.85.

[0525] Compound S6 1 The H-NMR data are as follows: 1H NMR(400MHz, Methanol-d4)δ8.98(d,J=4.4Hz,1H),8.63–8.46(m,1H),8.20(d,J=8.9 Hz,1H),7.94(d,J=8.2Hz,2H),7.82(d,J=8.4Hz,1H),7.69(d,J=4.4Hz,1H),7.46(d,J =8.0Hz,2H),5.18(dd,J=9.4,2.9Hz,1H),4.46–4.07(m,6H),3.35–3.29(m,24H),3.18 –3.00(m,9H),3.00–2.68(m,10H),2.17(s,3H),2.11–1.93(m,5H),1.91–1.77(m,2H).

[0526] Meanwhile, referring to step 5 of the synthesis of compound S2, compound S29 can be further prepared from compound S6:

[0527] Compound S7 can be prepared by referring to the synthesis method of compound S6. The structural formula of compound S7 is as follows:

[0528] Mass spectra of compound S7 and 1 The H-NMR data are as follows:

[0529] LC-MS: [M+H] + :1187.12

[0530] HR MS (ESI): [M+2H] 2+ Calculated value of / 2: 593.25409, measured value: 593.2546

[0531] 1H NMR(400MHz,Deuterium Oxide)δ9.00(d,J=4.4Hz,1H),8.27(d,J=8.9Hz,1H),8.20(d,J=2.3Hz,1H),7.85(d,J=8.3Hz,2H),7.80(dd,J=8.9,2.5Hz, 1H),7.77(d,J=4.5Hz,1H),7.42(d,J=8.1Hz,2H),5.15(dd,J=8.5,4.1Hz,1H),4.44–4.26(m,4H),4.23–4.11(m,2H),3.80( d,J=13.0Hz,3H),3.74(s,2H),3.56(s,3H),3.53–3.47(m,3H),3.47–3.34(m,8H),3.32–3.21(m,4H),3.21–3.08(m,6H),3. 07–2.90(m,5H),2.85(t,J=6.4Hz,2H),2.08(t,J=6.9Hz,2H),2.06–1.96(m,4H),1.34(d,J=7.0Hz,1H),1.30–1.17(m,4H).

[0532] 6. Synthesis Method and Synthesis Route of Compound S2 in Preparation Example 6

[0533] The synthesis steps of compound S2 are as follows:

[0534] Step 1: Synthesis of compound S2-a

[0535] Compound 7-2 (250 mg, 1.2 mmol) was dissolved in anhydrous DMF (10 mL) at room temperature, followed by the addition of tert-butyl sarcosinate (296.2 mg, 1.3 mmol), DIEA (774.0 mg, 6.0 mmol), and HATU (532.0 mg, 1.4 mmol). The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), washed with an aqueous solution (50 mL × 2) and saturated brine (50 mL × 2), and dried. The organic phase was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain compound S2-a (230 mg, yield 86.4%) as a white solid.

[0536] Step 2: Synthesis of compound S2-b

[0537] Compound S2-a (230 mg, 0.7 mmol) was dissolved in anhydrous DCM (3 mL) at room temperature, followed by the addition of trifluoroacetic acid (5.0 mL). The resulting reaction solution was stirred at room temperature for 0.5 h. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL), concentrated, diluted with ethyl acetate (50 mL), and washed with water (50 mL × 2) and saturated brine (50 mL × 2), respectively. The mixture was dried to afford compound S2-b (135 mg, 70.6% yield) as a white solid, which was used directly in the next step without further purification.

[0538] Step 3: Synthesis of compound 8-2

[0539] At room temperature, compound 7 (200.0 mg, 341.0 μmol) and compound S2-b (140.0 mg, 511.5 μmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (1.34 g, 17.0 mmol) and POCl3 (260 mg, 1705.0 μmol) were added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, it was diluted with dichloromethane (50 mL), washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively, and the organic phase was dried. The resulting residue was purified by semi-preparative liquid chromatography and lyophilized to obtain a yellow solid powder compound 8-2 (90.1 mg, yield 31.3%). LCMS: [M+H] + =844.4.

[0540] Step 4: Synthesis of compound 9-2

[0541] At room temperature, compound 8-2 (90.1 mg, 106.9 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was diluted with dichloromethane (25 mL) and dried to give a brown-red oily compound 9-2 (27.0 mg, 100% yield). The product was directly used in the next step without further purification. LCMS: [M+H] + =744.1.

[0542] Step 5: Synthesis of Compound S2

[0543] Compound 9-2 (79.4 mg, 106.8 μmol) and DOTA-NHS (107.1 mg, 213.6 μmol) were dissolved in anhydrous DMF (3.0 mL) at room temperature, followed by the addition of DIEA (41.3 mg, 320.4 μmol). The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative liquid chromatography to obtain compound S2 as a white solid (3.6 mg, 96.8% purity). LCMS: [M+H] = 1128.

[0544] Compound S2 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ9.11–8.99(m,1H),8.43–8.30(m,1H),8.19(d,J=9.0Hz,1H),7.98–7.92(m,1H),7.88(d,J=8.2Hz ,1H),7.82(d,J=4.5Hz,1H),7.78–7.73(m,2H),7.54(d,J=8.2Hz,1H),7.34–7.24(m,2H),5.17–5.09(m,1 H),4.44–4.23(m,5H),4.23–4.12(m,3H),4.12–3.91(m,5H),3.88–3.70(m,11H),3.62(s,5H),3.57–3.48 (m,5H),3.47–3.37(m,10H),3.26–3.00(m,21H),3.00–2.87(m,5H),2.16–2.01(m,1H),1.98–1.86(m,2H).

[0545] 7. Synthesis Method and Synthesis Route of Compound S17 in Preparation Example 7

[0546] S17 synthetic route

[0547] The synthesis steps of S17 are as follows:

[0548] Step 1: Synthesis of compound E2

[0549] At room temperature, compound E1 (5 g, 58.1 mmol) and EDTA-2Na (600 mg, 1.6 mmol) were dissolved in anhydrous acetone (250 mL). The resulting reaction solution was stirred at room temperature for 2 hours, then added dropwise to 250 mL of a mixed aqueous solution (prepared by dissolving potassium peroxymonosulfonate OXONE (50 g, 87.1 mmol) and NaHCO3 (22 g, 261.4 mmol) in 250 mL of water). The resulting reaction solution was stirred at room temperature for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5.0, and then washed with ethyl acetate (50 mL), water (15 mL × 2), and saturated brine (15 mL × 2), respectively. The organic phase was spin-dried, and the resulting residue was purified by semi-preparative liquid chromatography and lyophilized to obtain compound E2 (2.3 g, 38.7% yield) as a colorless oil.

[0550] Step 2: Synthesis of Compound E3

[0551] Compound E2 (350 mg, 3.4 mmol) was dissolved in anhydrous DMF (10 mL) at room temperature, followed by the addition of benzyl 5-aminovalerate (296.2 mg, 1.3 mmol), DIEA (774.0 mg, 6.0 mmol), and HATU (532.0 mg, 1.4 mmol). The resulting reaction solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to afford compound E3 (790 mg, 79% yield) as a white solid.

[0552] Step 3: Synthesis of Compound E4

[0553] Compound E3 (790 mg, 58.1 mmol) and Pd / C (79 mg, 5.8 mmol) were dissolved in anhydrous methanol (10 mL) at room temperature. The atmosphere was replaced with nitrogen three times and hydrogen three times. The resulting reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the organic phase was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford Compound E4 (375.1 mg, 68.7% yield) as a colorless oil.

[0554] Step 4: Synthesis of compound 7-Fmoc

[0555] Compound 7 (500 mg, 853.8 μmol) was dissolved in anhydrous dichloromethane (10 mL) at room temperature, followed by the addition of trifluoroacetic acid (2 mL). The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (10 mL) and the solvent was evaporated to afford a brown-red oily compound (414 mg, 852.5 μmol, 100% yield). The brown-red oily compound was dissolved in 10 mL of a mixed solution (dioxane / H2O=1:1), and sodium bicarbonate (218.4 mg, 2.5 mmol) was added. At 0°C, Fmoc-Cl (220.8 mg, 852.5 μmol) was dissolved in 5 mL of dioxane and added dropwise to the above reaction solution. The resulting reaction solution was stirred at 0-10°C for 1 hour. After the reaction was complete, it was diluted with ethyl acetate (50 mL) and washed with water (15 mL×2) and saturated brine (15 mL×2), respectively. The organic phase was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1-5 / 1) to give a yellow solid compound 7-Fmoc (230 mg, yield 38.1%).

[0556] Step 5: Synthesis of compound 8-3

[0557] At room temperature, compound 7-Fmoc (100 mg, 141.3 μmol) and compound E4 (42.6 mg, 211.9 μmol) were dissolved in anhydrous dichloromethane (10 mL), followed by the addition of pyridine (553 mg, 7.0 mmol) and POCl3 (108.0 mg, 706.5 μmol). The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (50 mL), washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was dried and the resulting residue was purified by semi-preparative liquid chromatography and lyophilized to obtain compound 8-3 (33.5 mg, 25.3% yield) as a yellow solid powder. LCMS: [M+H] + =892.2.

[0558] Step 6: Synthesis of compound 9-3

[0559] At room temperature, compound 8-3 (33.5 mg, 37.5 umol) was dissolved in 2 mL of a mixed solution (tetrahydrofuran / DBU aqueous solution = 100:1), and the resulting reaction solution was stirred at room temperature for 2 min. The resulting reaction solution was purified by semi-preparative liquid phase and lyophilized to obtain a colorless oily compound 9-3 (18 mg, yield 71.7%).

[0560] Step 7: Synthesis of Compound S17

[0561] At room temperature, compound 9-3 (18 mg, 26.9 μmol) and DOTA-NHS (26.9 mg, 53.8 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (10.4 mg, 80.7 μmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative liquid phase separation to obtain compound S17 as a white solid (7.5 mg, purity 96.7%, yield 26.4%). LCMS: [M+H] + =1056.4;HR MS(ESI):[M+H] + Calculated value: 1055.51205, measured value: 1055.51245.

[0562] Compound S17 1 The H-NMR data are as follows:

[0563] 1H NMR(400MHz,Deuterium Oxide)δ9.03(d,J=4.5Hz,1H),8.27(d,J=9.0Hz,1H),8.23(s,1H),7.83(dd,J=9.0,2.3Hz,1H),7.78(d,J=4.5Hz,1H),5.17 (dd,J=8.5,4.2Hz,1H),4.45–4.25(m,4H),4.25–4.11(m,2H),3.79(q,J=16.3Hz,7H),3.70(s,2H),3.57–3.32(m,14H),3.31 –3.22(m,4H),3.14(d,J=6.1Hz,6H),3.02(t,J=6.9Hz,4H),2.98–2.95(m,1H),2.95–2.91(m,1H),2.86(d,J=4.8Hz,1H),2. 78(d,J=4.8Hz,1H),2.23(t,J=7.5Hz,2H),2.07–1.96(m,3H),1.55–1.43(m,3H),1.42(s,3H),1.35(dt,J=13.7,6.2Hz,3H).

[0564] Compound S15 and compound S16 can be prepared by referring to the synthesis method of compound S17.

[0565] The structural formula of compound S15 is as follows:

[0566] Mass spectra of compound S15 and 1 The H-NMR data are as follows:

[0567] LC-MS: [M+H] + :1028.57

[0568] HR MS (ESI): [M+H] + Calculated value: 1027.48075, measured value: 1027.48022.

[0569] 1 H NMR(600MHz,Deuterium Oxide)δ9.07–8.96(m,1H),8.33–8.22(m,2H),7.90–7.83(m,1H),7.81–7.72(m,1H),5.20–5.08(m ,1H),4.43–4.35(m,1H),4.35–4.24(m,3H),4.20–4.09(m,1H),4.08–3.86(m,4H),3.86–3.69(m,5 H),3.66(s,3H),3.53–3.29(m,13H),3.24(s,4H),3.11(s,6H),3.08(s,4H),3.04–2.96(m,5H),2. 96–2.89(m,2H),2.88(d,J=6.5Hz,2H),2.00(s,2H),1.50(d,J=2.5Hz,2H),1.39(d,J=5.0Hz,1H).

[0570] The structural formula of compound S16 is as follows:

[0571] Mass spectra of compound S16 and 1 The H-NMR data are as follows:

[0572] LC-MS: [M+H] + :1028.30

[0573] HR MS (ESI): [M+H] + Calculated value: 1027.48075, measured value: 1027.48047.

[0574] 1H NMR(400MHz,Deuterium Oxide)δ9.03(d,J=4.5Hz,1H),8.27(d,J=9.0Hz,1H),8.22(s,1H),7.81(d,J=2.3Hz,1H) ,7.78(d,J=4.5Hz,1H),5.17(dd,J=8.4,4.2Hz,1H),4.44–4.28(m,4H),4.23–4.11(m,2H ),3.89–3.72(m,7H),3.70(s,2H),3.50–3.32(m,14H),3.14(s,8H),3.08–2.95(m,7H),2 .92(d,J=4.5Hz,2H),2.84(d,J=4.8Hz,1H),2.48–2.41(m,2H),1.95(s,2H),1.45(s,3H).

[0575] 8. Synthesis Method and Synthesis Route of Compound S12 in Preparation Example 8

[0576] S12 synthetic route

[0577] The synthesis steps of S12 are as follows:

[0578] Step 1: Synthesis of compound T2

[0579] Compound T1 (1.3 g, 3.8 mmol) and compound b (1.4 g, 4.56 mmol) were dissolved in anhydrous tetrahydrofuran at room temperature, followed by the dropwise addition of DBU (1.2 g, 8.3 mmol). The resulting reaction solution was stirred at room temperature for 10 minutes. After completion of the reaction, the solution was diluted with ethyl acetate (50 mL) and washed with dilute hydrochloric acid (50 mL x 2). The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to afford Compound T2 (1.55 g, 96% yield) as a white solid.

[0580] Step 2: Synthesis of Compound T3

[0581] At room temperature, compound T2 (1.0 g, 2.38 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), followed by the addition of trifluoroacetic acid (8 mL). The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL), and the solvent was evaporated to obtain compound T3 (627.6 mg, 100% yield) as a brown-red oil. This was used directly in the next step without further purification.

[0582] Step 3: Synthesis of Compound T4

[0583] Compound T3 (627 mg, 2.3 mmol) was dissolved in 10 mL of a mixed solution (dioxane / H₂O = 1:1) at room temperature. Sodium bicarbonate (601 mg, 6.9 mmol) and (Boc)₂O (1.0 g, 4.6 mmol) were added, respectively. The resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 5.0, then diluted with ethyl acetate (50 mL), washed with water (15 mL x 2) and saturated brine (15 mL x 2), respectively. The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain Compound T4 (630 mg, 72.7% yield) as a white solid.

[0584] Step 4: Synthesis of compound 3a

[0585] At room temperature, compound 2 (3.0 g, 9.7 mmol), (Bpin)2 (4.9 g, 19.4 mmol), KOAc (3.0 g, 9.7 mmol), and Pd(dppf)Cl2 (731.7 mg, 0.2 mmol) were dissolved in 60 mL of dioxane solution. The resulting reaction solution was purged with nitrogen three times at room temperature and stirred at 85°C for 12 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), and then washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give compound 3a (3.45 g, yield 100%) as a white solid.

[0586] Step 5: Synthesis of compound 4a

[0587] At room temperature, compound 3a (3.45 g, 9.7 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydroxide solution (1.16 g dissolved in 30 mL of water) was added, followed by dropwise addition of 30% H₂O₂ (1.98 g, 58.2 mmol). The resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was adjusted to pH 6-7 with dilute hydrochloric acid, diluted with ethyl acetate (50 mL), and washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to afford compound 4a (2.38 g, 100% yield) as a white solid.

[0588] Step 6: Synthesis of compound 5a

[0589] Compound 4a (2.38 g, 9.7 mmol), 1-bromo-3-chloropropane (2.75 g, 17.4 mmol), and potassium carbonate (4.0 g, 29.1 mmol) were dissolved in anhydrous DMF (25 mL) at room temperature, and the resulting reaction solution was stirred at 65°C for 12 hours. After the reaction was complete, the solution was diluted with ethyl acetate (50 mL), washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was spin-dried and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1:10 / 1) to afford compound 5a (2.3 g, 73.9% yield) as a white solid.

[0590] Step 7: Synthesis of compound 6a

[0591] Compound 5a (1.3 g) was dissolved in anhydrous dichloromethane (2.0 mL) at room temperature, followed by the addition of trifluoroacetic acid (8 mL). The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to afford compound 6a (1.07 g, 100% yield) as a brown-red oil. This was used directly in the next step without further purification.

[0592] Step 8: Synthesis of compound 7-ether

[0593] At room temperature, compound 6a (850 mg, 3.2 mmol) and N-Boc-piperazine (985 mg, 6.4 mmol) were dissolved in DMF (20 mL), and KI (880 mg, 6.4 mmol) was added. The reaction solution was stirred at 80°C for 12 hours, diluted with ethyl acetate (50 mL), and washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was concentrated and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1) to give white solid compound 7-ether (550 mg, yield 37.8%).

[0594] Step 9: Synthesis of Compound 8-4

[0595] At room temperature, compound 7-ether (1.15 g, 2.7 mmol) and compound d (757 mg, 3.9 mmol) were dissolved in anhydrous DMF (10 mL). DIEA (1.78 g, 13.5 mmol) and HBTU (1.3 g, 3.4 mmol) were added, and the resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated and dried, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain the white solid product compound 8-4 (780 mg, yield 48.1%).

[0596] Step 10: Synthesis of Compound 9-4

[0597] Compound 8-4 (240 mg) was dissolved in anhydrous dichloromethane (5.0 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was evaporated to obtain a brown-red oily compound 9-4 (199 mg, 100% yield), which was directly used in the next step without further purification.

[0598] Step 11: Synthesis of Compound 10

[0599] At room temperature, compound 9-4 (199 mg, 40.9 μmol) and compound T4 (178.3 mg, 49.1 μmol) were dissolved in anhydrous DMF (10 mL), followed by the addition of DIEA (158.2 mg, 122.7 μmol) and HBTU (186.1 mg, 49.1 mmol). The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated and dried. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain compound 10 (231 mg, yield 67.9%) as a white solid.

[0600] Step 12: Synthesis of Compound 11

[0601] Compound 10 (130 mg, 156.2 μmol) was dissolved in anhydrous dichloromethane (5.0 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mL). The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to afford compound 11 (114.3 mg, 100% yield) as a brown-red oil. This was used directly in the next step without further purification.

[0602] Step 13: Synthesis of Compound S12

[0603] Compound 11 (114.3 mg, 156.2 μmol) and DOTA-NHS (156.5 mg, 312.4 μmol) were dissolved in anhydrous DMF (3.0 mL) at room temperature, and DIEA (60.2 mg, 459.6 μmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative liquid phase separation to obtain compound S12 as a white solid (31.1 mg, 98.0% purity, 17.8% yield). LCMS: [M+H] + =1119.1.

[0604] Compound S12 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ8.77(d,J=4.5Hz,1H),8.01(d,J=9.3Hz,1H),7.63(d,J=4.5Hz,1H),7.61(d,J=2.9 Hz,1H),7.50(dd,J=9.3,2.7Hz,1H),7.46(s,3H),5.17(dd,J=8.7,4.2Hz,1H),5.05(t,J=8 .1Hz,1H),4.35(d,J=4.2Hz,2H),4.32–4.09(m,4H),3.87–3.62(m,6H),3.53–3.27(m,12H) ,3.27–3.16(m,3H),3.10(s,4H),3.06–2.92(m,5H),2.81–2.70(m,2H),2.31–2.17(m,2H).

[0605] Compound S8, compound S9, compound S13, and compound S14 can be prepared by referring to the synthesis method of compound S12.

[0606] The structural formula of compound S8 is as follows:

[0607] Mass spectra of compound S8 and 1The H-NMR data are as follows:

[0608] LC-MS: [M+H] + :1174.49

[0609] HR MS (ESI): [M+2H] 2+ The calculated value of / 2 is 587.23590, and the measured value is 587.2357.

[0610] 1 H NMR(400MHz,Deuterium Oxide)δ8.78(d,J=4.5Hz,1H),8.00(d,J=9.2Hz,1H),7.95(d,J=8.2Hz,2H),7.64(dd,J=4.1 ,2.4Hz,1H),7.62(d,J=2.8Hz,1H),7.57–7.48(m,3H),5.17(dd,J=8.8,4.1Hz,1H),5.03–4.9 6(m,1H),4.36(d,J=4.2Hz,2H),4.34–4.25(m,3H),4.24–4.11(m,2H),3.89–3.71(m,5H),3.5 9–3.30(m,18H),3.16–2.98(m,7H),2.98–2.87(m,4H),2.75–2.61(m,2H),2.42–2.28(m,2H).

[0611] Meanwhile, referring to step 5 of the synthesis of compound S2, compound S30 can be further prepared from compound S8:

[0612] The structural formula of compound S9 is as follows:

[0613] Mass spectra of compound S9 and 1 The H-NMR data are as follows:

[0614] LC-MS: [M+H] + :1188.42

[0615] HR MS (ESI): [M+H+K] 2+ The calculated value of / 2 is 613.22167, and the measured value is 613.2185.

[0616] 1H NMR(400MHz,Deuterium Oxide)δ8.78(d,J=4.5Hz,1H),8.01(d,J=9.3Hz,1H),7.96(d,J=8.5Hz,2H),7.63(t, J=3.6Hz,2H),7.56–7.48(m,3H),5.18(dd,J=8.6,4.3Hz,1H),4.68–4.59(m,1H),4.39 –4.25(m,5H),4.25–4.08(m,2H),3.90–3.71(m,5H),3.60–3.30(m,18H),3.18–2.99(m ,7H),2.99–2.88(m,4H),2.42–2.33(m,2H),2.29(t,J=7.5Hz,2H),1.95–1.73(m,2H).

[0617] The structural formula of compound S13 is as follows:

[0618] Mass spectra of compound S13 and 1 The H-NMR data are as follows:

[0619] LC-MS: [M+H] + :1202.62

[0620] HR MS (ESI): [M+H] + Calculated value: 1201.49583, measured value: 1201.49708.

[0621] 1 H NMR(400MHz,Deuterium Oxide)δ8.76(d,J=4.5Hz,1H),7.96(d,J=9.3Hz,1H),7.89(d,J=8.1Hz,2H),7.62(d,J=4.5Hz,1H),7.58(d,J =2.8Hz,1H),7.50(d,J=8.3Hz,2H),7.46(dd,J=9.3,2.7Hz,1H),5.17(dd,J=8.7,4.1Hz,1H),4.74–4.68(m,1 H),4.35(d,J=5.0Hz,2H),4.33–4.25(m,3H),4.25–4.11(m,2H),3.88–3.71(m,5H),3.63–3.39(m,15H),3.39 –3.29(m,4H),3.21–3.03(m,7H),3.03–2.86(m,5H),2.41–2.28(m,2H),2.24–2.12(m,2H),1.65–1.44(m,4H).

[0622] The structural formula of compound S14 is as follows:

[0623] Mass spectra of compound S14 and 1 The H-NMR data are as follows:

[0624] LC-MS: [M+H] + :1158.71

[0625] 1 H NMR(400MHz,Deuterium Oxide)δ8.97(d,J=5.2Hz,1H),8.19(d,J=9.3Hz,1H),8.00(d,J=5.2Hz,1H),7.80–7.70(m,2H),4.65(dd,J =9.4,5.6Hz,2H),4.44(s,1H),4.41–4.33(m,3H),4.27–4.19(m,2H),4.18–4.09(m,2H),4.09–4.03(m,1H), 3.88–3.65(m,8H),3.62–3.30(m,13H),3.25–2.94(m,10H),2.91–2.80(m,2H),2.75(s,3H),2.60–2.49(m, 2H),2.43–2.35(m,2H),1.77–1.67(m,3H),1.60–1.52(m,2H),1.38(s,2H),1.33(s,4H),1.31–1.23(m,2H).

[0626] 9. Synthesis Method and Synthesis Route of Compound S18 in Preparation Example 9

[0627] The synthesis steps of S18 are as follows:

[0628] Step 1: Synthesis of compound M2-1

[0629] At room temperature, compound M2 (3.0 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (30.0 mL), and compound a (11.8 g, 59.1 mmol) was then added. The resulting reaction solution was stirred at 55°C for 3 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (100 mL × 2 times), dried and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound M2-1 (3.28 g, 80% yield) as a white solid.

[0630] Step 2: Synthesis of compound M2-2

[0631] Compound M2-1 (600 mg, 2.8 mmol) and compound b (1.05 g, 3.3 mmol) were dissolved in anhydrous tetrahydrofuran at room temperature, and DBU (936.3 mg, 6.1 mmol) was added dropwise. The resulting reaction solution was stirred at room temperature for 10 min. After the reaction was complete, the reaction solution was diluted with ethyl acetate (50 mL) and washed with 1M dilute hydrochloric acid (50 mL x 2). The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound M2-2 (850.2 mg, 100% yield) as a white solid.

[0632] Step 3: Synthesis of Compound M2-3

[0633] Compound M2-2 (850.2 mg, 2.9 mmol) was dissolved in anhydrous DCM (10.0 mL) at room temperature, and trifluoroacetic acid (2.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with dichloromethane (25 mL) and concentrated under reduced pressure to afford compound M2-3 (673.5 mg, 100% yield) as a brown oil, which was used directly in the next step without further purification.

[0634] Step 4: Synthesis of compound 8

[0635] At room temperature, compound 7 (100.0 mg, 170.4 μmol) and compound M2-3 (77.9 mg, 255.9 μmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (672.9 mg, 8.5 mmol) and POCl3 (130.0 mg, 853.0 μmol) were added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, it was diluted with dichloromethane (50 mL), washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively, and the organic phase was dried. The resulting residue was purified by semi-preparative liquid chromatography and lyophilized to obtain a yellow solid powder compound 8 (35 mg, yield 25.6%). LCMS: [M+H] + =874.4.

[0636] Step 5: Synthesis of compound 9

[0637] At room temperature, compound 8 (35 mg, 59.6 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, it was diluted with dichloromethane (25 mL) and dried to give a brown-red oily compound 9 (27.0 mg, 100% yield). It was directly used in the next step without further purification. LCMS: 20-95% B 4 min, RT = 2.56 min, [M+H] + =703.2.

[0638] Step 6: Synthesis of Compound S18

[0639] Compound 9 (30.7 mg, 43.7 μmol) and DOTA-NHS (43.7 mg, 87.4 μmol) were dissolved in anhydrous DMF (3.0 mL) at room temperature, and DIEA (16.9 mg, 131.1 μmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative liquid phase separation to obtain compound S18 as a white solid (19.1 mg, purity 98.9%, yield 47.2%). LCMS: [M+H] + =1089.2.

[0640] Compound S18 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ9.04(d,J=4.5Hz,1H),8.17(d,J=9.0Hz,1H),8.09(s,1H),7.79(d,J=4.5Hz,1H),7.73– 7.68(m,1H),7.24(d,J=8.3Hz,2H),7.05(d,J=8.3Hz,2H),5.17(dd,J=8.5,4.1Hz,1H),4.41–4. 28(m,3H),4.27–4.12(m,2H),4.08–3.96(m,2H),3.87–3.72(m,7H),3.69(s,2H),3.65(s,2H),3 .57–3.48(m,4H),3.46–3.36(m,6H),3.32–3.21(m,3H),3.19–2.93(m,13H),2.10–2.00(m,2H).

[0641] Compound S19 and compound S20 can be prepared by referring to the synthesis method of compound S18.

[0642] The structural formula of compound S19 is as follows:

[0643] Mass spectra of compound S19 and 1 The H-NMR data are as follows:

[0644] LC-MS: [M+H] + :1103.63

[0645] HR MS (ESI): [M+H] + Calculated value: 1102.42741, measured value: 1102.42822.

[0646] 1 H NMR(400MHz,Deuterium Oxide)δ9.01(d,J=4.5Hz,1H),8.16(d,J=8.9Hz,1H),7.95(s,1H),7.76(d,J=4.5Hz,1H),7.40(dd,J= 8.8,2.3Hz,1H),7.33(d,J=8.5Hz,2H),7.15(d,J=8.7Hz,2H),5.15(dd,J=8.3,4.3Hz,1H),4.45–4.38( m,1H),4.35–4.26(m,2H),4.23–4.13(m,1H),4.08–3.95(m,1H),3.94–3.62(m,10H),3.58–3.33(m,11H ),3.30–3.09(m,10H),3.09–2.90(m,6H),2.87(t,J=6.9Hz,2H),2.60–2.52(m,2H),1.97–1.86(m,2H).

[0647] The structural formula of compound S20 is as follows:

[0648] Mass spectra of compound S20 and 1 The H-NMR data are as follows:

[0649] LC-MS: [M+H] + :1089.56

[0650] HR MS (ESI): [M+H] + Calculated value: 1088.41176, measured value: 1088.41237.

[0651] 1H NMR(400MHz,Deuterium Oxide)δ9.04(d,J=4.5Hz,1H),8.17(d,J=9.0Hz,1H),8.09(s,1H),7.79(d,J=4.5Hz,1H),7.70( d,J=7.6Hz,1H),7.24(d,J=8.3Hz,2H),7.05(d,J=8.3Hz,2H),5.17(dd,J=8.5,4.1Hz,1H),4.41– 4.28(m,3H),4.27–4.12(m,2H),4.08–3.96(m,2H),3.87–3.72(m,7H),3.69(s,2H),3.65(s,2H), 3.57–3.48(m,4H),3.46–3.36(m,6H),3.32–3.21(m,3H),3.19–2.93(m,13H),2.10–2.00(m,2H).

[0652] 10. Preparation Example 10

[0653] Synthesis method and synthetic route of compound S22

[0654] S22 synthesis steps:

[0655] Step 1: Synthesis of compound M2-4

[0656] Compound M2-3 (400 mg, 1.7 mmol) was dissolved in anhydrous DMF (10 mL) at room temperature, and tert-butyl 3-aminopropionate (296.2 mg, 2.0 mmol), DIEA (657.9 mg, 5.1 mmol), and HATU (760 mg, 2.0 mmol) were added sequentially. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL × 2) and saturated brine (50 mL × 2), and dried. The organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain compound M2-4 (550.2 mg, 89% yield) as a white solid.

[0657] Step 2: Synthesis of Compound M2-5

[0658] Compound M2-4 (550.2 mg, 1.5 mmol) was dissolved in anhydrous DCM (2 mL) at room temperature, and trifluoroacetic acid (8.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the mixture was diluted with dichloromethane (25 mL), concentrated under reduced pressure, and diluted with ethyl acetate (50 mL). The mixture was washed with water (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried to obtain compound M2-5 (350 mg, yield 75.3%) as a colorless oil, which was used directly in the next step without further purification.

[0659] Compound M2-5: 1 H NMR (400MHz, Chloroform-d) δ7.43(d,J=8.7Hz,2H),7.37(d,J=8.6Hz,2H),6.19(s,1H),3.63(s,2H),3.57(q,J=5.9Hz,2H),2.64(dd,J=11.4,2.9Hz,2H).

[0660] Step 6: Synthesis of compound 8-1

[0661] At room temperature, compound 7 (100.0 mg, 170.6 μmol) and compound M2-5 (77.9 mg, 255.9 μmol) were dissolved in anhydrous dichloromethane (10 mL), and then pyridine (672.9 mg, 8.5 mmol) and POCl3 (130.0 mg, 853.0 μmol) were added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, it was diluted with dichloromethane (50 mL), and then washed with water (15 mL × 2) and saturated brine (15 mL × 2), respectively. The organic phase was dried and the resulting residue was purified by semi-preparative liquid chromatography and lyophilized to obtain a yellow solid powder compound 8-1 (35 mg, yield 23.5%). LCMS: [M+H] + =874.4.

[0662] Step 7: Synthesis of compound 9-1

[0663] At room temperature, compound 8-1 (30.0 mg, 34.3 μmol) was dissolved in anhydrous dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added. The resulting reaction solution was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (25 mL) and the solvent was dried to obtain a brown-red oily compound 9-1 (27.0 mg, 100% yield). It was directly used in the next step without further purification. LCMS: 20-95% B 4 min, RT = 2.56 min, [M+H] +=774.1.

[0664] Step 8: Synthesis of Compound S22

[0665] At room temperature, compound 9-1 (27.0 mg, 30.9 μmol) and DOTA-NHS (30.9 mg, 61.8 μmol) were dissolved in anhydrous DMF (3.0 mL), and DIEA (13 mg, 92.7 μmol) was added. The resulting reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was spin-dried and purified by semi-preparative liquid phase separation to obtain white solid compound S22 (19.1 mg, purity 98.9%, yield 47.2%). LCMS: [M+H] + =1160.2.

[0666] Compound S22 1 The H-NMR data are as follows: 1 H NMR(400MHz,Deuterium Oxide)δ9.02(d,J=4.5Hz,1H),8.21–8.16(m,2H),7.77(d,J=4.5Hz,1H),7.49–7 .43(m,3H),7.42–7.37(m,2H),5.15–5.08(m,1H),4.40–4.23(m,4H),4.20–4.07 (m,2H),3.88–3.69(m,9H),3.54(s,2H),3.52–3.34(m,14H),3.24–3.09(m,10H) ,3.08–2.97(m,3H),2.96–2.88(m,2H),2.41(t,J=6.6Hz,2H),2.02–1.92(m,2H).

[0667] Compound S21, compound S23, and compound S24 can be prepared by referring to the synthesis method of compound S22.

[0668] The structural formula of compound S21 is as follows:

[0669] Mass spectra of compound S21 and 1 The H-NMR data are as follows:

[0670] LC-MS: [M+H] + :1146.71

[0671] HR MS (ESI): [M+H] + Calculated value: 1145.43323, measured value: 1145.43469.

[0672] 1 H NMR(400MHz,Deuterium Oxide)δ9.01(d,J=4.5Hz,1H),8.24(d,J=2.2Hz,1H),8.16(d,J=8.9Hz,1H),7.80–7.70(m,4H), 7.56(d,J=8.6Hz,2H),5.07(dd,J=8.6,4.0Hz,1H),4.39–4.21(m,4H),4.20–4.07(m,2H),4.06–3 .87(m,3H),3.79(q,J=16.3Hz,6H),3.69(s,2H),3.56(t,J=6.3Hz,2H),3.51–3.36(m,10H),3.2 7–3.10(m,10H),3.07–2.97(m,3H),2.95–2.85(m,2H),2.61(t,J=6.1Hz,2H),2.05–1.93(m,2H).

[0673] Compound S23 was prepared by referring to the synthetic steps of compound S22.

[0674] The structural formula of compound S23 is as follows:

[0675] Mass spectra of compound S23 and 1 The H-NMR data are as follows:

[0676] LC-MS: [M+H] + :1174.91

[0677] HR MS (ESI): [M+H] + Calculated value: 1173.46453, measured value: 1173.46594.

[0678] 1H NMR(400MHz,Deuterium Oxide)δ9.07(d,J=4.5Hz,1H),8.30(d,J=9.0Hz,1H),8.22(d,J=2.3Hz,1H),7.82(d,J=4.5Hz,1H),7.74(dd,J =9.0,2.3Hz,1H),7.16(d,J=8.7Hz,2H),7.09(d,J=8.5Hz,2H),5.14(dd,J=8.3,4.3Hz,1H),4.41–4.23(m,4H) ,4.21–4.05(m,2H),3.80(q,J=16.3Hz,7H),3.70(s,2H),3.55–3.36(m,12H),3.26–3.11(m,12H),3.08–2.98( m,3H),2.98–2.89(m,2H),2.83(t,J=7.0Hz,2H),2.43(t,J=7.0Hz,2H),2.13–2.05(m,2H),2.04–1.94(m,2H).

[0679] The structural formula of compound S24 is as follows:

[0680] Mass spectra of compound S24 and 1 The H-NMR data are as follows:

[0681] LC-MS: [M+H] + :1160.70

[0682] HR MS (ESI): [M+H] + Calculated value: 1159.44888, measured value: 1159.44874

[0683] 1H NMR(400MHz,Deuterium Oxide)δ8.99(d,J=4.5Hz,1H),8.26–8.17(m,3H),8.12(d,J=8.9Hz,1H),7.75(dd,J=9.4,3. 2Hz,2H),7.41(d,J=9.7Hz,1H),5.05(d,J=8.8Hz,1H),4.37–4.19(m,4H),4.18–4.07(m,2H), 4.00(s,3H),3.80(q,J=16.3Hz,6H),3.69(s,2H),3.61–3.53(m,3H),3.52–3.33(m,11H),3.3 1–3.09(m,11H),3.08–2.96(m,3H),2.92–2.81(m,2H),2.67–2.59(m,2H),2.04–1.95(m,2H).

[0684] 11. Preparation Example 11 Synthesis of Compound C12:

[0685] Referring to the synthesis steps of S12 in Preparation Example 8, compound C12 was prepared.

[0686] 12. Preparation Example 12 Synthesis of Compound C3-3:

[0687] The synthetic route of C3-3 is as follows:

[0688] 13. Preparation Example 13 Synthesis of Compound C2-1

[0689] Compound C2-1 was prepared by referring to the synthetic route of compound C3-3.

[0690] 3. Effect Examples

[0691] 1. Enzyme Inhibition Test

[0692] 1.1 Enzyme inhibition test method

[0693] 1) The compound was dissolved in DMSO to prepare a stock solution, and then diluted to 300 nM using fibroblast activation buffer (FAB).

[0694] 2) Take 2 μL of each compound (300 nM) and add it to 38 μL of FAB to dilute to 15 nM. Dilute each compound in a 384-well plate in two-fold serial dilutions from 15 nM to 3.662 pM, with 20 μL of compound in each well.

[0695] 3) 20 μL of FAP (2 ng) was added to the wells described in 2) and incubated at room temperature for 30 minutes.

[0696] 4) 20 μL of FAP substrate (60 μM) was added to the wells described in 3) and cultured at 37° C. for 25 hours.

[0697] 5) No inhibitor control (NIC) served as a positive control.

[0698] 6) Add the following negative controls to each group of compounds:

[0699] No protein control (NPC): 20 μL compound + 20 μL FAB + 20 μL FAP substrate;

[0700] Pure protein control (POC): 20 μL FAP + 40 μL FAB.

[0701] 7) The measurement is repeated.

[0702] 8) The emission spectrum was read for 10 ms at 465 nm (excitation wavelength 360 nm) using a Molecular Devices SpectraMax iDS microplate reader.

[0703] 1.2 Enzyme inhibition test results

[0704] Table 1 IC values ​​of compounds against kinases at 24h 50 value

[0705] Table 2 IC values ​​of compounds against kinases at 24h 50 value

[0706] The structural formula of S0 is as follows:

[0707] The structural formula of S11 is as follows:

[0708] 2. Imaging Experiment

[0709] 2.1 Radioactivity 68 Ga labeling method

[0710] 1) Preparation of precursor compound solution: Dissolve an appropriate amount of precursor compound in DMSO to a concentration of 3 nmol / 10 μL and store at -20°C until use.

[0711] 2) Preparation of 0.25 M ammonium acetate solution: Dissolve 205.08 mg of demetallated ammonium acetate (82.03 g / mol) in 10 mL of deionized water to obtain a 0.25 M ammonium acetate solution, which was stored at 4°C until use.

[0712] 3) Activation of C18 Cartridges: Activate within 30 minutes before use by slowly injecting 5 mL of anhydrous ethanol and 10 mL of deionized water in sequence, then drain the liquid and set aside.

[0713] 4) Radioactivity 68 GaCl3 elution: Automated program elution to obtain 1 mL of radioactive 68 GaCl3 hydrochloric acid (0.05M) solution, activity is 2-5mCi.

[0714] 5) Labeling and purification: Take 270 μL of ammonium acetate solution and add it to the above 68 Adjust the pH to 3.5-4.5 in a 0.05M solution of GaCl3 hydrochloric acid, add a tube of spare precursor solution, heat the mixed solution at 95℃~105℃ for 10-15 minutes, and terminate the reaction. Load the reaction solution into C18 Cartridges and rinse with 3mL of deionized water to remove free 68 Ga, then use 500 μL of anhydrous ethanol for gradient elution of the product, collect the eluate and measure its radioactivity, evaporate the anhydrous ethanol and redissolve it with normal saline, filter with 0.22 μM membrane to remove the heat source, and prepare an injection with a radioactivity concentration of 100-200 μCi / 100 μL for analysis and subsequent experiments.

[0715] 6) Radiochemical Purity Assay: 10 μCi of the radioactive injection solution was analyzed for radiochemical purity by HPLC. The threshold of the radioactivity detector was set at 200 K. Chromatographic conditions were: gradient elution from 5% to 95% phase B over 0-12 min, maintaining 95% phase B over 12-15 min (mobile phase A: aqueous solution containing 0.1% TFA, mobile phase B: acetonitrile solution containing 0.1% TFA), flow rate: 1 mL / min.

[0716] Each compound 68 The radiochemical purity after Ga labeling is shown in Table 3 below.

[0717] Table 3. 68 Radiochemical purity after Ga labeling

[0718] 2.3 Experimental animals and cell lines

[0719] Species and strain: BALB / c Nude mice

[0720] Age / weight: 4-6 weeks, 15-18g

[0721] FAP-transfected HT1080 cell line: human fibrosarcoma cell line, cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin. After expansion, the cells were inoculated into the right lower limb of nude mice near the back, with an injection dose of 1×10 6 Tumor cells can be used for imaging experiments 2-3 weeks after inoculation.

[0722] U87MG: Glioblastoma cell line, cultured in MEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin. After expansion, the cells were inoculated into the right lower limb of nude mice near the back, with an injection dose of 1×10 6 Tumor cells can be used for imaging experiments 2-3 weeks after inoculation.

[0723] 2.4 Small Animal Imaging Test Methods

[0724] 2.4.1 Instrument parameters

[0725] CT scanning and reconstruction protocol: CT_Conventional_Scan / CT_FDK_Recon

[0726] PET scan and reconstruction protocols: PET_Conventional_Scan / PET_OSEM_Recon

[0727] Image processing workstation: Inveon Research Workplace

[0728] 2.4.2 Administration: Inject 100-200 μCi of radioactive injection solution in a volume of 100-150 μL via the tail vein using a 1 mL disposable sterile syringe.

[0729] 2.4.3 Anesthesia: Anesthesia was performed using a Portable Anesthesia System for small animals using isoflurane gas (isoflurane, 100 ml, room temperature storage, manufactured by Reward Life Science Co., Ltd.). Prior to imaging, the animal was placed in an anesthesia induction box. After anesthesia, the animal was placed in the PET / CT chamber and maintained in a prone position. Anesthesia was maintained for approximately 10–20 minutes during the PET / CT scan and imaging. The isoflurane flow rate was set to 1.5 LPM (liters per minute).

[0730] 2.4.4 PET-CT Imaging Methods

[0731] Mice bearing subcutaneous transplanted tumors (U87 MG cells) were selected. The tumor size was approximately 150 mm. 3 About 7.4MBq was injected through the tail vein 68PET / CT imaging was performed 30, 60, and 120 minutes after injection of Ga-labeled compounds. Tumor imaging in each group was observed.

[0732] 2.4.5 Biodistribution

[0733] After completing the small animal PET scan, image reconstruction was performed. The images and data were processed using the device's own software. The tumor, heart (including contents), liver, kidney, and muscle were delineated as regions of interest. The percentage injected dose per gram of tissue (abbreviated as %ID / g) in the region of interest was calculated.

[0734] Figures 1 to 24 show 68 PET-CT imaging results and biodistribution of each Ga-labeled compound in U87 MG tumor-bearing mice. The results showed that the compound provided in the embodiment of the present application with a covalent warhead was 68 Ga-FAPI-46 and 68 Ga-FAPI-04 exhibits higher tumor uptake, higher target-to-substance ratio, and better tumor targeting performance.

[0735] Specifically, according to Figure 3, Figure 1 and Figure 13, 68 Ga-S18 is highly uptaken in tumors and less uptaken in kidneys and other organs. PET-CT images show 68 Tumor uptake of Ga-S18 was significantly higher than 68 Ga-FAPI-46 and 68 Ga-FAPI-04, tumor uptake at 0.5h was about 13% ID / g, indicating 68 Ga-S18 has good tumor targeting properties and can be used for tumor radiodiagnosis.

[0736] According to Figure 4, Figure 1 and Figure 13, 68 Ga-S19 is metabolized by the kidney and has a high uptake in tumors. The tumor uptake value is about 7% ID / g at 0.5h. 68 The tumor uptake values ​​of Ga-S18 were comparable, indicating that 68 Ga-S19 also has good tumor targeting and can be used for tumor radiodiagnosis.

[0737] According to Figure 5, Figure 1 and Figure 13, 68 Ga-S2 is a renal metabolic pathway, with high uptake in tumors and very low uptake in non-target organs. PET-CT images show 68 Tumor uptake of Ga-S2 was significantly higher than 68 Ga-FAPI-46 and 68Ga-FAPI-04 exhibits excellent tumor targeting performance and provides excellent imaging effects. As can be seen from the comparison between Figure 6 and Figures 2 and 14, 68 The tumor uptake of Ga-S2 was about 9% ID / g at 0.5h. 68 Ga-FAPI-46 (7% DccMean) was comparable and significantly higher than 68 The tumor uptake value of Ga-FAPI-04 (2% ID / g) and 68 The non-target organ uptake of Ga-S2 was significantly lower than 68 Ga-FAPI-46, therefore 68 Ga-S2 compared to 68 Ga-FAPI-46 and 68 Ga-FAPI-04 provides superior PET-CT image quality and is very effective as a tumor diagnostic drug.

[0738] According to Figures 7-12 and Figures 1, 2, 13, and 14, 68 Ga-S21, 68 Ga-S22 and 68 Ga-S23 showed excellent tumor targeting performance. From the PET-CT images, it can be seen that the uptake in tumors was high and the uptake in non-target organs was very low. The tumor uptake was significantly higher than 68 Ga-FAPI-46 and 68 Ga-FAPI-04, showing excellent imaging quality; according to the corresponding biodistribution data, 68 The uptake value of Ga-S21 at 0.5h is about 23%ID / g. 68 The uptake value of Ga-S22 at 0.5h is about 12%ID / g. 68 The uptake value of Ga-S23 at 0.5h was about 20% ID / g, which was significantly higher than 68 Ga-FAPI-46 and 68 Ga-FAPI-04, and the uptake of the three compounds in non-tumor organs is very low. In addition, PET-CT images and biodistribution data show that the retention time of the three compounds in the tumor site can reach more than 2 hours. 68 Ga-S22 can be significantly retained in tumors for 2 hours and maintain an uptake value of 11% ID / g. 68 Ga-S23 can be significantly retained in the tumor for 2 hours and maintain an uptake value of 20% ID / g, and its tumor retention ability is significantly improved. 68After Ga is replaced by therapeutic radionuclides, S21, S22 and S23 labeled with therapeutic radionuclides will be able to provide excellent tumor targeting and tumor retention capabilities, and have extremely low toxicity to non-target organs. The above three compounds labeled with therapeutic radionuclides have excellent therapeutic effects as tumor treatment drugs.

[0739] Furthermore, comparing Figures 11 and 12 with Figures 21 and 22, 68 The tumor targeting and tumor retention abilities of Ga-S23 are significantly better than those of 68 Ga-C3-3, and 68 The uptake of Ga-C3-3 in non-target organs (such as heart, liver, and lungs) is relatively high. 68 The target / non-target ratio of Ga-C3-3 is much higher than 68 Ga-S23; compare Figures 5 and 6 with Figures 23 and 24, 68 The tumor uptake value of Ga-S2 (about 9% ID / g at 0.5h) was higher than 68 Ga-C2-1 (uptake value at 0.5h was about 4% ID / g), while the uptake values ​​of non-target organs were lower than 68 Ga-C2-1, 68 The tumor targeting of Ga-S2 is significantly better than 68 Ga-C2-1, indicating that compared with the case where the covalent warhead is connected to the side close to the chelating group, connecting the covalent warhead to the side close to the FAPI targeting group makes the compound have better targeting, can significantly improve the target / non-target ratio of the compound, and has better tumor uptake ability.

[0740] According to Figures 15, 16, 1, 2, 13, and 14, 68 Ga-S12 is a renal metabolic pathway with high uptake in tumors and very low uptake in non-target organs. 68 The tumor uptake of Ga-S12 is about 21% ID / g at 0.5h. It can be seen from the PET-CT images and biodistribution data that 68 Tumor uptake of Ga-S12 was significantly higher than 68 Ga-FAPI46 and 68 Ga-FAPI04, indicating 68 Ga-S12 has better tumor targeting performance, and PET-CT images and biodistribution data also show that 68 The retention time of Ga-S12 in the tumor site can reach 2 hours, and its tumor retention ability is significantly better than 68 Ga-FAPI46 and 68 Ga-FAPI04 indicates that if therapeutic radionuclides are used to label S12, it can provide excellent tumor targeting and tumor retention capabilities and can be used as a tumor treatment drug.

[0741] Furthermore, by comparing Figures 15 and 16 with Figures 19 and 20, 68 Ga-S12 and 68 Ga-C12 has different covalent warhead linker chain lengths, 68 The tumor uptake value of Ga-S12 (about 21% ID / g at 0.5h) was higher than 68 Ga-C12 (uptake value at 0.5h was about 4% ID / g), and at different time points 68 The tumor / heart ratio, tumor / liver ratio, and tumor / lung ratio of Ga-C12 are all less than 1. 68 Ga-S12 tumor targeting compared to 68 Ga-C12 is better, indicating that a shorter linker chain length provides the compound with better tumor targeting performance. Preferably, the number of carbon atoms in the linker in the covalent warhead is ≤3, and the compound can obtain better tumor targeting performance and has better tumor uptake ability.

[0742] Figures 17 and 18 show 68 The PET-CT imaging and biodistribution results of Ga-S15 in U87MG tumor-bearing mice showed that 68 Ga-S15 was significantly taken up in tumors, and its uptake in non-target organs was significantly lower than that in non-target organs. 68 Ga-FAPI46, with relatively low target cost, can provide better 68 The PET-CT imaging quality of Ga-FAPI46 can be used for tumor diagnostic drugs, and also shows that epoxy-based covalent warheads can significantly improve the specific targeting performance of compounds.

[0743] 3. 177 Animal experimental evaluation of the tumor therapeutic effect of Lu-labeled S23:

[0744] 3.1 Radioactivity 177 Lu labeling method

[0745] 1) Preparation of precursor compound solution: Dissolve an appropriate amount of precursor compound in DMSO to a concentration of 3 nmol / 10 μL and store at -20°C until use.

[0746] 2) Preparation of 0.01 M ammonium acetate solution: Dissolve 8.2 mg of demetallated ammonium acetate (82.03 g / mol) in 10 mL of deionized water to obtain a 0.01 M ammonium acetate solution. Adjust the pH to 4.0 with acetic acid and refrigerate at 4°C until ready to use.

[0747] 3) Activation of C18 Cartridges: Activate within 30 minutes before use by slowly injecting 5 mL of anhydrous ethanol and 10 mL of deionized water in sequence, then drain the liquid and set aside.

[0748] 4) Labeling and purification: Take 300 μL of ammonium acetate solution (0.01 M, pH = 4.0) and add 177 Adjust the pH of LuCl3 solution to 4.0, add 3nM precursor solution, heat the mixed solution at 95℃~105℃ for 10~15 minutes, and terminate the reaction. Load the reaction solution into C18 Cartridges and rinse with 3mL deionized water to remove free 177 Lu, then 500 μL of anhydrous ethanol was used for gradient elution of the product, the eluate was collected and its radioactivity was measured, the anhydrous ethanol was heated and dried, and then it was redissolved in normal saline, and the heat source was removed by 0.22 μM filter membrane, and an injection solution with a radioactivity concentration of 1 mCi / 100 μL was prepared for analysis and subsequent experiments.

[0749] 5) Labeling efficiency and radiochemical purity detection: Take 10μCi of the radioactive injection solution after reaction and purification and load it on SG paper, use 500μL 0.01M citric acid / sodium citrate to develop, and place it in iTLC to identify the labeling efficiency and radiochemical purity. 177 The labeling yield of Lu-labeled S23 was 95.89% and the radiochemical purity was 99.00%.

[0750] 3.2 177 Biodistribution test of Lu-S23:

[0751] 1) Trial Grouping

[0752] Twelve HT1080-FAP tumor-bearing mice were randomly divided into two groups ( 177 Lu-S23 group and 177 Lu-FAPI46 group).

[0753] 2) Organ samples and data collection plan

[0754] Tail vein injection 177 Lu-S23 and 177 Lu-FAPI46 was administered to mice by cervical dislocation at 4, 12, 24, 48, and 72 hours after administration. Tissue samples, including tumors, blood, heart, lungs, liver, spleen, kidneys, stomach, intestines, bones, meat, and brain, were collected. The heart was squeezed for blood, the stomach and intestines were sampled for contents, skeletal muscle was obtained from the hind leg, and bones were obtained from the hind leg. All organs were weighed. Radioactivity in the tissues was counted using a gamma counter. Simultaneously, the injected sample was accurately diluted 100-fold, and 1% of the sample was placed in a counter tube as a 1% ID standard (i.e., 1% of the administered dose). The radioactivity counts of the 1% ID standard and the biological sample were simultaneously measured on a gamma counter.

[0755] 3) Parameter and data analysis

[0756] Biodistribution data are expressed as the percentage of radioactive counts per gram of tissue or organ to the total administered dose (radioactive counts) (%ID / g). Specific calculation formula:

[0757] The data of each sampling point were expressed as the mean ± standard deviation (mean ± SD) of tumor-bearing mice.

[0758] 3.3 177 Evaluation of the tumor therapeutic effect of Lu-S23

[0759] 1) HT1080-FAP cells were suspended in PBS at a density of 1×10 8 / mL, inoculated into the right rib cage of 35 nude mice from the same batch, and when the tumor volume was 50-200mm 3 At the same time, 35 tumor-bearing mice were randomly divided into 5 groups (n=7), namely PBS group, 177 Lu-S23(0.5mCi) group, 177 Lu-S23(1mCi) group, 177 Lu-S23(1.5mCi) group, 177 Lu-FAPI-46 (1 mCi) group, PBS group was injected with 0.1 mL of PBS, and treatment group was injected with corresponding doses of 177 Lu-S23 or 177 Lu-FAPI-46;

[0760] 2) Tumor volume was measured before and after administration on the second day (tumor volume was calculated by measuring the long diameter and short diameter of the tumor and the volume was calculated as follows: volume = 0.5 × long diameter × short diameter 2 ) and mouse body weight, and then monitor and record the mouse body weight and tumor size every two days. If the body weight decreased by 5% or the volume was greater than 1200mm 3 The treatment plan is shown in Figure 27 (A).

[0761] Experimental results: Figure 25 shows 177 Figure 26 shows the biodistribution results of Lu-S23 in HT1080-FAP tumor-bearing mice (n=6). 177 The biodistribution results of Lu-FAPI46 in HT1080-FAP tumor-bearing mice (n=6) are shown in Figures 25 and 26. 177 The uptake of Lu-S23 in the tumor site was maintained at about 18% ID / g at 4 hours and 8% ID / g at 72 hours. The uptake in non-tumor sites was also maintained at a low level, less than 5% ID / g except for the kidney, indicating that 177Lu-S23 has excellent tumor targeting and tumor retention capabilities. 177 The tumor uptake value of Lu-FAPI46 was only about 5% ID / g at 4 hours, and it was almost completely metabolized at 72 hours, with poor tumor targeting and retention capabilities. 177 The experimental data of the tumor treatment effect of Lu-S23 in HT1080-FAP tumor-bearing mice include (A) a schematic diagram of the treatment plan, (B) a curve of the change in mouse body weight during the treatment period, and (C) an averaged tumor growth curve during the treatment period. Figure 27 (C) shows that the use of various doses of Lu-S23 177 Lu-S23 could significantly inhibit tumor growth compared with PBS blank control group and 177 Compared with Lu-FAPI46, both showed significantly superior tumor inhibition effects, even at a low dose of 0.5 mCi 177 Lu-S23, also better than 1mCi 177 Lu-FAPI46 has a better tumor suppression effect, and the dose is increased to 1mCi or 1.5mCi. 177 Lu-S23 has a better tumor suppression effect. At the same time, the mice did not lose significant weight, and their eating and behavior were normal, indicating that the safety of increasing the dose is good. 177 Lu-S23 has excellent tumor therapeutic effects and can be used as a tumor therapeutic drug.

[0762] 4. Clinical trial research

[0763] 4.1 68 Ga-S2 PET / CT imaging in lung cancer patients

[0764] Intravenous injection in lung cancer patients 68 Ga-S2 (144 MBq) was injected 1 hour after injection. A static 3D PET scan was acquired at 2 minutes per bed position using Ingenuity TF PET / CT (Philips, Amsterdam, Holland), covering the entire body. The PET / CT images are shown in Figure 28 . Regions of interest were delineated, and tumor uptake was measured using PMOD software. Maximum SUV (SUVmax) was calculated, and the results are shown in Table 4.

[0765] Table 4. 68 SUVmax values ​​of Ga-S2 probe in muscle, kidney and tumor of patients with FAP positive tumor expression

[0766] As can be seen from Table 4, the patient's tumor site had obvious 68The radioactive uptake of Ga-S2 is mainly metabolized by the kidneys, and the radioactive uptake in the lesion area is significantly higher than the muscle background.

[0767] As can be seen from Figure 28, the patient had obvious 68 Ga-S2 uptake, 68 Ga-S2 is mainly metabolized by the kidneys. In addition, the uptake value in the liver, muscle blood pool and other parts is low, which shows that it has excellent targeting. 68 Ga-S2 has a high specific uptake in lung cancer tumors and a high tumor / background ratio in the human body, and has the potential to become a diagnostic probe. 68 This study provides strong evidence for the application of Ga-S2 in internal targeted radiotherapy.

[0768] 4.2 68 Ga-S23 in vivo PET / CT imaging of patients with postoperative recurrence of right lower quadrant intestinal mucinous gland adenocarcinoma

[0769] Intravenous injection for patients with postoperative recurrence of mucinous gland adenocarcinoma in the right lower quadrant 68 Ga-S23 (148 MBq) was injected 1 hour after injection. A static 3D PET scan was acquired at 2 minutes per bed position using Ingenuity TF PET / CT (Philips, Amsterdam, Holland), covering the entire body. The PET / CT images are shown in Figure 29 . Tumor uptake was determined using PMOD software after delineation of the region of interest, and the maximum SUV (SUVmax) was calculated. The results are shown in Table 5.

[0770] Table 5. 68 SUVmax values ​​of Ga-S23 probe in muscle, kidney, primary tumor and largest metastasis of patients with FAP-positive tumors

[0771] As can be seen from Table 5, the primary tumor lesions and metastatic lesions of the patients have obvious 68 The radioactive uptake of Ga-S23 was significantly higher in the pancreas and liver than in the liver.

[0772] As can be seen from Figure 29, the patient had a recurrence of mucinous gland adenocarcinoma in the right lower abdomen. The patient had a high 68 Ga-S23 uptake revealed numerous tiny lesions. The drug is primarily metabolized by the kidneys, with low uptake in the liver and other sites. This suggests that the probe can accurately detect lesions in patients with intestinal mucinous adenocarcinoma while maintaining a low background value, demonstrating its potential as a diagnostic probe.

[0773] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound represented by formula (A), its stereoisomers, tautomers, isotopically labeled compounds, pharmaceutically acceptable salts or prodrugs, Among them, Z is the payload, and T is the targeting agent. Q is a covalent group selected from the structures represented by the following formula (Q-1) to formula (Q-21): L1, L2, L3, L4, A a , L a , L b identical or different and each independently selected from a bond or a linking group a, b, c, m, and p0 are the same or different and are independently selected from the integers 0 - 6 (e.g., 0, 1, 2, 3, 4, 5, 6). R d 、R e are the same or different and are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; Het is an optionally substituted saturated heterocyclic group or heteroaryl group. R s Selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; Each R t is independently selected from: hydrogen, halogen, nitro, cyano, optionally substituted mercapto, optionally substituted amino, optionally substituted seleno, optionally substituted C 1-20 alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; Represents the attachment site of the group.

2. The compound, stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 1, characterized in that: In the compound represented by formula (A), Q is selected from the structures represented by the following formula (Q-1-1), (Q-2-1), formula (Q-3), formula (Q-4) or formula (Q-5):

3. The compound, stereoisomer, tautomer, isotope-labeled compound, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that: In formula (A), L1 is selected from trivalent linking groups; preferably, L1 is selected from N, C 1-20 subalkyl or any combination thereof; wherein each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy; preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy; more preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; Preferably, L1 is selected from N, a C alkylene group optionally substituted by one or more R0 1-10 alkylene group (C 1-6 alkylene group, C 1-4 alkylene group) or any combination thereof.

4. The compound, stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 1 or 2, characterized in that: In formula (A), L2, L3, L4, A a , L a , L b are the same or different and are each independently selected from divalent linking groups; preferably, each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-20 alkylene, 3-20 membered heterocyclic group optionally substituted with one or more R0 or any combination thereof; more preferably, each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-10 alkylene (C 1-6 alkylene, C 1-4 alkylene), 3-20 membered heterocyclic group optionally substituted with one or more R0 (3-10 membered heterocyclic group, 3-6 membered heterocyclic group) or any combination thereof; Preferably, each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy; Preferably, the heterocyclic group contains at least one N; preferably, the heterocyclic group is a piperazinyl group. Preferably, a and c are not both 0 at the same time. Preferably, at least one of L2 and L4 contains a 3 - 20 membered heterocyclic group; preferably, at least one of L2 and L4 contains a heterocyclic group having one or two nitrogen atoms; preferably, it contains a piperazinyl group. Preferably, A a is selected from keys.

5. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 1 or 2, characterized in that: R d selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy; preferably, R d is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; more preferably, R d is selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy; Preferably, when m is not 0, each R d is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy.

6. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 1, characterized in that: Z is selected from nuclide chelating groups. Preferably, Z is selected from the groups formed by bifunctional chelating agents; preferably, the bifunctional chelating agents are selected from DOTA, NOTA, NODA, NODAGA, DOTP, TETA, ATSM, PTSM, EDTA, EC, HBEDCC, DTPA, SBAD, BAPEN, Df, DFO, TACN, NO2A / NOTAM, CB - DO2A, Cyclen, NOTA - AA, DO3A, DO3AP, HYNIC, MAS3, MAG3 or isonitriles. Preferably, Z is selected from 7. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 1, characterized in that: T is selected from the structure targeting fibroblast activation protein-α shown in the following formula (T-1), Among them, L5 is selected from divalent linking groups, preferably S, O or a bond, preferably a bond; Represents the attachment site of the group. Preferably, T is selected from the structure represented by the following formula (T-1-1):

8. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 1, characterized in that: The compound represented by formula (A) has the structure represented by the following formula (A-1), Wherein, U is selected from -U1-, -U2-U3(R a )-U4-; X is selected from -X1-, -X2-X3(R b )-X4-; When U is selected from -U1 -, X is not -X1 -. U1, U2, U3, U4, X1, X2, X3, X4 are the same or different and are independently selected from linking groups. R a and R b are the same or different and are each independently selected from the structures represented by formula (Q-1), (Q-2), formula (Q-3), formula (Q-4) or formula (Q-5).

9. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 8, characterized in that: In the compound represented by formula (A-1), U is selected from -U2-U3(R a )-U4-, and X is selected from -X1-; or in the compound represented by formula (A-1), U is selected from -U1-, and X is selected from -X2-X3(R b )-X4-.

10. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to any one of claims 8 or 9, characterized in that: U3 and X3 are the same or different and are each independently selected from trivalent linking groups; preferably, each is independently selected from N, C 1-20 subalkyl (C 1-10 subalkyl, C 1-6 subalkyl, C 1-4 subalkyl) or any combination thereof; and / or U1, U2, U4, X1, X2, X4, L a , L b , A a identical or different, and each independently selected from divalent linking groups; preferably, each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C 1-20 alkylene (C 1-10 alkylene, C 1-6 alkylene, C 1-4 alkylene) or any combination thereof; preferably, A a is selected from a bond; Wherein, each R0 is the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy; preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; more preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy.

11. The compound, stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 10, characterized in that: In the compound represented by formula (A-1), U is selected from -U1-, X is selected from -X2-X3(R b )-X4-, and U1 is selected from a bond. X4 is selected from a bond. X3 is selected from N. X2 is selected from C 1-10 alkylene (preferably C 1-6 alkylene, C 1-4 alkylene, C3 alkylene); Q is selected from the structure of formula (Q-1) or (Q-2), and A a is selected from a bond, L a is selected from -CO-, -CO-C 1-3 alkylene-, -CO-C 1-3 alkylene-NH-CO-, -CO-C 1-3 alkylene-NH-CO-C 1-3 alkylene-, -C 1-3 alkylene-, C 1-3 alkylene-NH-CO-C 1-3 alkylene, -CO-C 1-6 alkylene-N(R0)-CO-, -CO-C 1-4 alkylene-N(CH3)-CO-, -CO-C 1-6 alkylene-CO-NH-C 1-3 alkylene-; preferably selected from -CO-C 1-4 alkylene-N(R0)-CO-, such as -CO-methylene-N(R0)-CO-; preferably, R0 is selected from C 1-4 alkyl.

12. The compound, its stereoisomers, tautomers, isotope - labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 1, characterized in that: Q is selected from the structure shown in formula (Q - 1); Preferably, the compound represented by formula (A) is selected from:

13. Use of the compound represented by formula (A-0) in the preparation of the compound represented by formula (A) as claimed in claim 1, wherein, In the compound represented by formula (A), Q is a structure represented by formula (Q-1), formula (Q-3), or formula (Q-4): Among them, Q0 is selected from the structures represented by the following formula (Q-2) or (Q-5): L1, L2, L3, L4, A a , L a , L b identical or different and each independently selected from a key or a linking group a, b, c, m are the same or different and are independently selected from the integers 0 - 6 (e.g., 0, 1, 2, 3, 4, 5, 6). R d and R e are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; Represents the attachment site of the group.

14. A compound represented by formula (B), its stereoisomers, tautomers, isotopically labeled compounds, pharmaceutically acceptable salts or prodrugs, characterized in that: Wherein, Z1 is the payload and T1 is the targeting agent. U5, X5, X6, X7 are the same or different and are independently selected from linking groups. R f selected from the structures represented by the following formula (Q-2-2) or formula (Q-5-1): L c 、L d 、A b are the same or different and are each independently selected from linking groups n is the same as or different from each other and is independently selected from the integers of 0 - 6 (for example, 0, 1, 2, 3, 4, 5, 6), R g 、R h are the same or different and are each independently selected from hydrogen, halogen, -OH, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; indicating the connection site of the group.

15. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 14, characterized in that: R f selected from the structures represented by the following formula (Q-2-3):

16. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 14 or 15, characterized in that: X6 is selected from a trivalent linking group; preferably independently of one another selected from N, C 1-20 subalkylene (C 1-10 subalkylene, C 1-6 subalkylene, C 1-4 subalkylene) or any combination thereof; Preferably, U5, X5, X7, L c , L d , A b are the same or different and are each independently selected from divalent linking groups; preferably, they are each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P═O)-O-, -N(R0)-, -CO-, C 1-20 alkylene (C 1-10 alkylene, C 1-6 alkylene, C 1-4 alkylene) or any combination thereof; Preferably, A a is selected from a key; Preferably, R g and R h are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo C 1-20 alkyl; Preferably, each R0 is the same or different and is independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy; preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy; more preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy.

17. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 16, characterized in that: U5 is selected from a bond, -CO- or -C 1-4 alkyl CO-; X7 is selected from a bond; X6 is selected from N; X5 is selected from C 1-10 an alkylene group, preferably C 1-6 alkylene, C 1-4 alkylene, C3 alkylene; L c 、L d are the same or different and are each independently selected from -CO-, -C 1-6 alkylene-, -CO-C 1-6 alkylene-, -C 1-6 alkylene-CO-N(R0)-, -C 1-6 alkylene-N(R0)-CO-, -CO-C 1-6 alkylene-N(R0)-CO-C 1-6 alkylene-, -CO-C 1-6 alkylene-CO-N(R0)-C 1-6 alkylene-, -C 1-6 alkylene-CO-N(R0)-C 1-6 alkylene-, -C 1-6 alkylene-N(R0)-CO-C 1-6 alkylene-, -C 1-6 alkylene-N(R0)-CO-C 1-6 alkylene-COO-C 1-6 alkylene-, -C 1-6 alkylene-CO-N(R0)-C 1-6 alkylene-COO-C 1-6 alkylene-, -CO-C 1-6 alkylene-N(R0)-CO-C 1-6 alkylene-COO-C 1-6 alkylene-, -CO-C 1-6 alkylene-CO-N(R0)-C 1-6 alkylene-COO-C 1-6 alkylene- and the like; preferably, each is independently selected from -C 1-3 alkylene-, -CO-C 1-3 alkylene-, -C 1-3 alkylene-CO-N(R0)-, -C 1-3 alkylene-N(R0)-CO-, -CO-C 1-3 alkylene-N(R0)-CO-C 1-3 alkylene-, -CO-C 1-3 alkylene-CO-N(R0)-C 1-3 alkylene-, -C 1-3 alkylene-CO-N(R0)-C 1-3 alkylene-, -C 1-3 alkylene-N(R0)-CO-C 1-3 alkylene-, -C 1-3 alkylene-N(R0)-CO-C 1-3 alkylene-COO-C 1-3 Alkylene-, -C 1-3 Alkylene-CO-N(R0)-C 1-3 Alkylene-COO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-N(R0)-CO-C 1-3 Alkylene-COO-C 1-3 Alkylene-, -CO-C 1-3 Alkylene-CO-N(R0)-C 1-3 Alkylene-COO-C 1-3 Alkylene-; R0 is selected from C 1-4 alkyl groups such as methyl; L c Selected from -CO-, -CO-C 1-3 alkylene-, -CO-C 1-3 alkylene-NH-CO-, -CO-C 1-3 alkylene-NH-CO-C 1-3 alkylene-; R g Selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkylene-NH-CO-C 1-3 alkylene-, -CO-C 1-6 alkylene-N(R0)-CO-, -CO-C 1-4 alkylene-N(CH3)-CO-, -CO-C 1-6 alkylene-CO-NH-C 1-3 alkylene-; L d Selected from -CO-, -CO-C 1-4 alkylene-, -CO-C 1-4 alkylene-N(CH3)-CO-, -CO-C 1-4 alkylene-NH-CO-; R h selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy; A b selected from a bond or oxygen; R g Selected from H or methoxy.

18. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 16, characterized in that: The compound represented by the formula (B) is selected from the following compounds: The compound according to formula (D), its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, Among them, Z2 is a payload, and T2 is a targeting agent, U6, U7, U8, X8 are the same as or different from each other and are independently selected from linking groups; R i Selected from the structures represented by the following formula (Q-2-4) or formula (Q-5-2): L e 、A c 、L f are the same or different and are each independently selected from linking groups p is selected from the integers of 0 - 6 (for example, 0, 1, 2, 3, 4, 5, 6), R j and R k are selected from hydrogen, halogen, -OH, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; indicating the connection site of the group.

20. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 19, characterized in that: R i selected from the structure represented by the following formula (Q-2-5):

21. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 19 or 20, characterized in that: U7 is selected from trivalent linking groups; preferably independently of each other selected from N, C 1-20 subalkyl (C 1-10 subalkyl, C 1-6 subalkyl, C 1-4 subalkyl) or any combination thereof; Preferably, U6, U8, X8, L f , L e , A c are the same or different and are each independently selected from divalent linking groups; preferably, they are each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C 1-20 alkylene (C 1-10 alkylene, C 1-6 alkylene, C 1-4 alkylene) or any combination thereof; Preferably, A c is selected from a key; Preferably, R j and R k are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; Preferably, each R0 is the same or different and independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy; preferably, the same or different and independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; more preferably, the same or different and independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy.

22. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 20, characterized in that: U6 is selected from -NH-, -CONH- or -C 0-4 alkyl CONH-; U7 is selected from C 1-4 alkyl, linear or branched alkylene, preferably methylene; U8 is selected from -CO-; X8 is selected from #-O-C 1-10 alkylene-*, preferably #-O-C 1-6 alkylene-*, #-O-C 1-4 alkylene-*, #-O-C 1-3 alkylene-*, where # is the connection site to T2 and * is the connection site to the piperazine ring; L e selected from -C 1-3 alkylene-, -CO-, -O- or -NH- or combinations thereof, such as: -C 1-3 alkylene-, -C 1-3 alkylene-NH-CO-C 1-3 alkylene-, -CO-, -CO-C 1-3 alkylene-, -CO-C 1-3 alkylene-NH-CO-, -CO-C 1-3 alkylene-NH-CO-C 1-3 alkylene-; R k selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; R j selected from hydrogen, methyl or methoxy; L f selected from -C 1-4 alkylene-, -CO-, -O- or -NH- or combinations thereof, such as: -C 1-4 alkylene-, -C 1-4 alkylene-CO-NH-C 1-4 alkylene-, -C 1-4 alkylene-, -C 1-4 alkylene-CO-NH-C 1-4 alkylene-CO-O-C 1-4 alkylene-; R0 is selected from hydrogen or C 1-4 alkyl, such as methyl; A c Selected from a bond or oxygen.

23. The compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to claim 20, characterized in that: The compound represented by formula (D) is selected from the following compounds:

24. Use of the compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to any one of claims 1 - 23 in the preparation of an FAP inhibitor.

25. A radionuclide probe targeting FAP, wherein the radionuclide probe is a radioisotope-labeled compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to any one of claims 1 - 23.

26. A radionuclide probe targeting FAP, wherein the radionuclide probe is a radioisotope-labeled compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to any one of claims 1 - 23, and the radioisotope is a diagnostic radioisotope or a therapeutic radioisotope; Preferably, the diagnostic radionuclide is 68 Ga, 67 Ga, 64 Cu, 18 F, 86 Y, 89 Zr, 111 In, 99m Tc, 11 C, 203 Pb, 123 I, 125 I, 124 I, Al 18 at least one of F; Preferably, the therapeutic radionuclide is 177 Lu, 90 Y, 125 I, 131 I, 211 At, 153 Sm, 186 Re, 188 Re, 67 Cu, 225 Ac, 227 Th, 223 Ra, 213 Bi, 212 Bi and 212 at least one of Pb.

27. A pharmaceutical composition, which comprises the compound, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug according to any one of claims 1 - 23, or comprises the radionuclide probe targeting FAP according to claim 25 or 26, and at least one pharmaceutically acceptable adjuvant or carrier.

28. Use of the compound according to any one of claims 1-23, its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, the inhibitor according to claim 24, or the FAP-targeted radionuclide probe according to claim 25 or 26, or the pharmaceutical composition according to claim 27 in the preparation of an FAP-targeted imaging agent and / or therapeutic agent.

29. Use of the compound according to any one of claims 1-23, its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, the inhibitor according to claim 24, or the FAP-targeted radionuclide probe according to claim 25 or 26, or the pharmaceutical composition according to claim 27 in the preparation of a drug for diagnosing and / or treating a disease, wherein the disease is a disease characterized by overexpression of fibroblast activation protein FAP.

30. A method for diagnosing and / or treating a disease, the method comprising administering to a subject to be diagnosed and / or treated a diagnostically and / or therapeutically effective amount of the compound according to any one of claims 1-23, its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, the inhibitor according to claim 24, or the FAP-targeted radionuclide probe according to claim 25 or 26, or the pharmaceutical composition according to claim 27, wherein the disease is a disease characterized by overexpression of fibroblast activation protein FAP.

31. A kit, the kit comprising the compound according to any one of claims 1-23, its stereoisomers, tautomers, isotope-labeled substances, pharmaceutically acceptable salts or prodrugs, the inhibitor according to claim 24, or the FAP-targeted radionuclide probe according to claim 25 or 26, or the pharmaceutical composition according to claim 27, and an instruction manual for diagnosing and / or treating a disease characterized by overexpression of fibroblast activation protein (FAP); Preferably, the disease characterized by overexpression of fibroblast activation protein (FAP) is selected from cancer, chronic inflammation, atherosclerosis, fibrosis (such as pulmonary fibrosis), tissue remodeling, keloid disease, rheumatoid arthritis, osteoarthritis, liver cirrhosis, liver disease; Preferably, the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, multiple myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal cell carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (primary unknown cancer), thymic cancer, glioma, glioblastoma, astrocytoma, cervical cancer and prostate cancer.

32. A method for preparing the FAP-targeted radionuclide probe according to claim 25 or 26, comprising: 1) Providing the compound according to any one of claims 1-23; 2) Reacting with the radionuclide according to claim 26 or a reagent providing the radionuclide in solution or on a column to complete the labeling.

33. A kit or reagent combination for implementing the preparation method according to claim 32, comprising: 1) The compound according to any one of claims 1-23; 2) The radionuclide as described in claim 26 or a reagent providing the radionuclide.

34. A kit or reagent combination for integrated diagnosis and treatment, comprising: 1) The compound as described in any one of claims 1-15; 2) The compound as described in any one of claims 16-23.

35. A compound represented by formula (A-4), its stereoisomers, tautomers, isotopically labeled compounds, pharmaceutically acceptable salts or prodrugs, Among them, Z is a payload, Q is selected from the structures represented by the following formula (Q-1), (Q-2), formula (Q-3), formula (Q-4) or formula (Q-5): L2, A a , L a , L b are the same or different and are each independently selected from linking groups; a and m are the same or different and are independently selected from integers of 0-6; R d 、R e are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine; Rf3 is selected from hydrogen or cyano; represents the connection site of the group.

36. The compound as described in claim 35, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: L2, A a , L a , L b are the same or different and are each independently selected from divalent linking groups; preferably, each is independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -NR0-, -CO-, C 1-20 alkylene optionally substituted with one or more R0s, a 3- to 20-membered heterocyclic group optionally substituted with one or more R0s, or any combination thereof; more preferably, each is independently selected from a bond, -O-, -S-, -P-, -O-(HO-P=O)-O-, -N(R0)-, -CO-, C 1-10 alkylene (C 1-6 alkylene, C 1-4 alkylene), a 3- to 20-membered heterocyclic group (3- to 10-membered heterocyclic group, 3- to 6-membered heterocyclic group) optionally substituted with one or more R0s, or any combination thereof; wherein each R0 is the same or different and is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy; preferably, they are the same or different and are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy; more preferably, they are the same or different and are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; Preferably, the heterocyclic group contains at least one N; preferably, the heterocyclic group is a piperazinyl group; Preferably, A a is selected from keys; Preferably, L2 contains a 3-20 membered heterocyclic group; preferably, L2 contains a heterocyclic group having one nitrogen atom or two nitrogen atoms; preferably, it contains a piperazinyl group; wherein each R0 is the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy; preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy; more preferably, the same or different and independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy.

37. The compound as described in claim 36, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: L2 includes the structure shown in (L-1) below: wherein, q is an integer in the range of 1-20, and u is an integer in the range of 0-10; G3 is C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, 5- to 10-membered heteroaryl, C 6-10 aryl; L6 is a key or -CO-C 1-3 alkylene-NH-; and / or, L a 、L b are independently selected from the structures shown in (L-2) below: x is selected from 0, 1, 2, s is 0 or 1, y is selected from 0, 1, 2, 3, 4, and t is 0 or 1; G1 or G2 is independently -CH2- or a carbonyl group, and they are not both -CH2- at the same time; R0 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy, represents the connection site of the group.

38. The compound as described in claim 37, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: In formula (L-1), G3 is selected from at least one of the following groups: q is an integer in the range of 1-5, and u is 0.

39. The compound as described in claim 37, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: L a 、L b are independently selected from the groups represented by the following formula (L-3) or formula (L-4): x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, and R0 is H or C 1-3 alkyl group.

40. The compound as described in any one of claims 35-39, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: In formula (A-4), Q is selected from the groups represented by the following formula (L-5) or formula (L-6): x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, and R0 is H or C 1-3 alkyl group.

41. A compound represented by formula (A-5), its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs, Among them, Z is a payload, and T is a targeting agent, Q is selected from the structures represented by the following formula (Q-1), (Q-2), formula (Q-3), formula (Q-4) or formula (Q-5): L1, L2, L3, L4, A a , L a , L b identical or different and each independently selected from a bond or a linking group a, b, c, m are the same or different and are independently selected from integers of 0-6 (such as 0, 1, 2, 3, 4, 5, 6), R d 、R e are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-20 alkyl, C 1-20 alkoxy, halo-C 1-20 alkyl; represents the connection site of the group; Among them, L a , L b are independently selected from the structure shown in formula (L-2): x is selected from 0, 1 and 2, s is 0 or 1, y is selected from 0, 1, 2, 3 and 4, and t is 0 or 1; G1 or G2 is independently -CH2- or a carbonyl group, and they are not both -CH2- at the same time; R0 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C 1-10 alkyl, C 1-10 alkoxy, halo-C 1-10 alkyl, halo-C 1-10 alkoxy, represents the connection site of the group.

42. The compound as described in claim 41, its stereoisomer, tautomer, isotope-labeled substance, pharmaceutically acceptable salt or prodrug, characterized in that: L1 is selected from a trivalent linking group; preferably, L1 is selected from N, C 1-20 subalkylene optionally substituted by one or more R0s, or any combination thereof; more preferably, L1 is selected from N, C 1-10 subalkylene (C 1-6 subalkylene, C 1-4 subalkylene) or any combination thereof; And / or Aa is selected from divalent linking groups; preferably selected from a bond, -O-, -S-, -P-, -O-(HO-P═O)-O-, -N(R0)-, -CO-, C alkylene optionally substituted by one or more R0 1-20 alkylene (C 1-10 alkylene, C 1-6 alkylene, C 1-4 alkylene) or any combination thereof; preferably, A a is selected from a bond; and / or L2, L3, L4, A a identical or different, and each independently selected from divalent linking groups; preferably, each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P═O)-O-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-20 alkylene, 3- to 20-membered heterocyclic group optionally substituted with one or more R0 or any combination thereof; more preferably, each independently selected from a bond, -O-, -S-, -P-, -O-(HO-P═O)-O-, -N(R0)-, -CO-, C optionally substituted with one or more R0 1-10 alkylene (C 1-6 alkylene, C 1-4 alkylene), 3- to 20-membered heterocyclic group (3- to 10-membered heterocyclic group, 3- to 6-membered heterocyclic group) optionally substituted with one or more R0 or any combination thereof; Preferably, the heterocyclic group contains at least one N; preferably, the heterocyclic group is a piperazinyl group; Preferably, at least one of L2 and L4 contains a 3-20 membered heterocyclic group; preferably, at least one of L2 and L4 contains a heterocyclic group having one nitrogen atom or two nitrogen atoms; preferably, it contains a piperazinyl group.

43. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 41 or 42, characterized in that: Having a structural formula shown in Formula (A-4): Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine; Rf3 is selected from hydrogen or cyano.

44. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 43, characterized in that: L a 、L b are independently selected from the groups represented by the following formula (L-3) or formula (L-4): x is selected from 0, 1, 2, y is selected from 0, 1, 2, 3, 4, and R0 is H or C 1-3 alkyl group.

45. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to any one of claims 41-42, characterized in that: Having a structural formula shown in Formula (A-6): Rf1 and Rf2 are independently selected from hydrogen or halogen, such as fluorine, chlorine, iodine, bromine, preferably fluorine; Rf3 is selected from hydrogen or cyano; L 4a selected from a bond, -O-, -S-, -P-, -O-(HO-P═O)-O-, -N(R0)-, -CO-, C alkylene optionally substituted by one or more R0s 1-20 a 3- to 20-membered heterocyclic group optionally substituted by one or more R0s, or any combination thereof.

46. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to claim 45, characterized in that: L a and L b are independently selected from: wherein, x is selected from 0, 1, 2, s is 0 or 1, and y is selected from 0, 1, 2, 3, 4; G1 is -CH2- or a carbonyl group.

47. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to any one of claims 46, characterized in that: L a and L b are independently selected from -CH2- or a group as shown below: wherein x is selected from 0, 1, 2, and y is selected from 0, 1, 2, 3, 4.

48. The compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to any one of claims 45-47, characterized in that, L 4a including the structure shown in the following formula (L-9): wherein, w is an integer in the range of 1-20, and v is an integer in the range of 0-10; G4 is a C3-C 10 cyclic group, and L7 is a carbonyl group or a C 1-10 alkylene group.

49. A compound, stereoisomer, tautomer, isotopically labeled compound, pharmaceutically acceptable salt or prodrug according to any one of claims 45 - 48, characterized in that: L2 includes -N(R0)- or a structure represented by the following formula (L-1): wherein, q is an integer in the range of 1-20, and u is an integer in the range of 0-10; G3 is C 3-10 cycloalkyl, 3- to 10-membered heteroalkyl, 5- to 10-membered heteroaryl, C 6-10 aryl; L6 is a key or -CO-C 1-3 alkylene-NH-.

50. The compound represented by formula (M-1): Among them, R1 is selected from a bond or O; R2 is selected from hydrogen, C1-10 alkyl or C1-10 alkoxy; L0 includes a structure shown in formula (L-X): wherein, h is selected from 0, 1, 2, j is 0 or 1, g is selected from 0, 1, 2, 3, 4, and k is 0, 1 or 2; G6 or G7 is independently -CH2- or a carbonyl group, and they are not both -CH2- at the same time; R4 is H, -NH2 or an amino group protected by a protecting group.

51. The compound according to claim 50, characterized in that, The compound of formula (M-1) is selected from the compounds represented by formula (M-2) or formula (M-3): wherein, R2 is hydrogen or methoxy, R1 is a bond or oxygen, n1 is an integer from 0 to 2, m1 is an integer from 1 to 3, m2 is an integer from 1 to 3.

52. The compound according to claim 50, characterized in that, Selected from the compounds shown below:

53. Use of the compound according to any one of claims 50-52 in the preparation of a radiopharmaceutical.

54. The use according to claim 53, wherein the radiopharmaceutical comprises the compound, its stereoisomers, tautomers, isotope-labeled compounds, pharmaceutically acceptable salts or prodrugs according to any one of claims 1-23, 35-49.

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